As I look back to this wonderful though tiresome journey, I can't finish it without expressing my immense gratitude for all the people who have shared it with me and were there in all my ups and downs I have witnessed. It is my pleasure to cross my appreciation to all those who have contributed in a way or another to the success of this research study and made it an unforgettable experience for me.

First and foremost, I would like to say thank you, Dr. Philippe DELAIR, for guiding me through my entire journey. I hope that the work I did in 3 years was within your expectation. You've put in so much time, effort, and trust into my education and I hope you're proud of the chemist that I have become. Thank you for your precious and priceless knowledge, your wise advice and your generous help with everything.

I would like to express my sincere acknowledgements to the Ministère de la Recherche et de l'Enseignement Supérieur and Initiatives d'Excellence (IDEX) for the financial support received for this research work, and to the director of Département de Pharmacochimie Moléculaire (DPM), Prof.

Ahcène BOUMENDJEL, for the support and interest he showed in this project.

A very special gratitude goes out to all the members of my thesis committee of whom I was honored and privileged to be evaluated by: Prof. Olivier RENAUDET who chaired the jury, Pr. Mercedes AMAT and Pr. David AITKEN (the reviewers), and Pr. Peter GEOKJIAN and Dr. Sandrine PY (the examiners) for taking the time to appraise my work and to give valuable comments and remarks required for the adjustments of my thesis.

I also deeply appreciate the assistance of the members of the Comité de Suivi Individuel (CSI): Prof.

Peter GEOKJIAN and Dr. Olivier HAMELIN. I am very thankful for their follow-up and their valuable comments and suggestions given on my work during the three years of my PhD.

Many thanks go to all the permanent and non-permanent staff and colleagues in the medchem team (past and present): Emile, Mathieu, Brayan, Kim, Farda, Martine, Yung-Sing, Benjamin, Vinicius, David, Mohamad etc... I would like to express my gratitude also to the NMR staff: Marie-Carmen MOLINA v This thesis details the synthetic journey toward alkaloid (-)-205B which was isolated from the skin of Dendrobatidae neotropical frog (Figure 1). In addition to the challenging 8b-azaacenaphthylene ring system rarely encountered in the structure of natural products and the presence of 5 stereogenic carbons, our effort was stimulated by its promising biological activity. This target compound is expected to display a selective activity for the inhibition of specific type of neuronal receptors which are recognized to be involved in the starting point of Alzheimer's disease (AD). Thus, selective inhibitors of these receptors can be considered as potential therapeutic agents for this neurodegenerative disease. On this basis, this manuscript is divided into four principal parts:

List of Figures and Tables

-The first chapters are devoted to highlight the importance of the targeted alkaloid; both from a synthetic and biological aspect.

-The following chapter will cover a brief description of the previously reported syntheses.

-A main chapter will detail our successful multi-step synthesis of this alkaloid based on the difficulties faced in a previous approach, whereupon a new strategy was explored.

-Finally, all the experimental procedures and characterization data of the synthesized molecules will be provided in the experimental part. Cette thèse décrit le détail du travail effectué conduisant à la synthèse de l'alcaloïde (-)-205B (Figure 1). Celui-ci a été isolé en très faible quantité d'extraits de peau de grenouilles de la famille des Dendrobatidae. En plus de son système tricyclique de type 8b-azaacenaphthylene peu fréquemment rencontré dans la structure des produits naturels et de la présence de 5 centres asymétriques, l'intérêt de ce travail est également dû à l'activité biologique prometteuse de ce composé. En effet, cet alcaloïde est suspecté d'être un inhibiteur sélectif d'un certain type de récepteur neuronal qui a récemment été identifié comme un point de départ de la maladie d'Alzheimer. Ainsi, tout inhibiteur sélectif de ces récepteurs peut être considéré comme un agent thérapeutique potentiel de cette maladie neurodégénérative. Ce manuscrit est ainsi divisé en quatre parties principales:

-Les premiers chapitres ont pour but de montrer l'importance de cet alcaloïde cible, aussi bien d'un point de vu synthétique que biologique.

-Le chapitre suivant permettra de décrire brièvement les précédentes approches publiées dans la littérature.

-Le chapitre principal présentera en détail les différentes étapes de notre approche synthétique et particulièrement montrera les solutions développées afin de résoudre les difficultés rencontrées lors de notre première stratégie.

-Enfin, la partie expérimentale donnera les modes opératoires et décrira les caractéristiques spectrales de chaque molécule synthétisée. By natural products, we mean molecules of nature. Nature is extremely generous in offering mankind a pool of unique and diverse products inspiring novel discoveries in the field of medicine and live-saving therapies. With the recent technological advances, a New Golden Era of natural product-based drugs is dawning. Natural products possess enormous structural and chemical diversity of molecules having tremendous impact in the drug discovery field for the treatment of the most challenging diseases. The curiosity of chemists and biologists impulses them to discover the reason behind the nature for all the medicines offered to human.

The record of these bioactive natural products has been incredible for their medicinal impact.

Plant-based drug discovery is as old as the mankind itself. The essential need of human for healthcare prompted him to explore the surrounding nature. All the story begins with the traditions of yesterday being transformed by scientists to the drugs of tomorrow. Herewith, nature's cures are passing from one generation to another with the addition of the solid scientific foundations.

Traditional Chinese and Indian Medicine are the most ancient of all the medicinal traditions and undoubtedly, they spread all over the world. Examples for the Indian and Chinese medicinal herbs are; Rheum palmatum, Panax ginseng, Cenetella asiatica, Santalum album, Ephedra sinica, etc.. .1

Besides, the ancient Egyptian medicine epitomized in the known 'Ebers Papyrus' 2 is dated about 1550 BC. It includes about 700 medicinal compounds mainly of vegetal sources.

Many plants were recorded in the early years for their biological properties that open promising avenues to treat many diseases. Within the 18 th -19 th century, a method to extract, purify and isolate these biological active compounds from the plants was developed in order to elucidate their structure.

We owe the first breakthrough in this realm to Friedrich Serturnen who was able to isolate the first well-known drug, Morphine, from Papaver somniferum in 1806 that is used as narcotic and analgesic. 3 Moreover, this plant was found to be a valuable source for other medicinally used alkaloids including antitussive codeine, spasmolytic papaverine, and several derived semi-synthetic drugs such as oxycodone, buprenorphine and naltrexone. 4 After this date, more and more herbal medicines were discovered such as, Quinine, atropine, Caffeine, Coiine, Emetine, strychnine, Tubocurarine and Acetylsalicylic acid (Aspirin).

About the quarter of all the European Medical Agency (EMA) approved drugs are plant based with well-known drugs. 5 Also, according to the World Health Organization; 80% of the world's population rely on derivatives extracted from plants in their medicine. 6 The discovery of bioactive natural products is not only to maintain human health, but also to fight plant viral diseases that affect the yield and the quality of the crops. This was studied by Q. Wang, A. Lu & Z. Wang who discover the alkaloid Gramine (Figure 2) and its analogues as a novel agent against plant virus. 7

Figure 2: Gramine On the other hand, an array of natural products bearing interesting pharmacological properties are known in the literature to be of diverse non-vegetal sources. Fungi have a clear track record for the diverse bioactive natural products they possess. 75% of the studied polypore fungi possess antimicrobial activity and many others have shown other biological activities such as antiviral, cytotoxic, cardiovascular, anti-inflammatory, anti-cancer activities. In 1953, a glycopeptide antibiotic, Vancomycin, was isolated from Amycolatopsis orientalis by Edmund Kornfeld which was approved by FDA in 1958 and reported to be effective against severe infections. 8 Also, ganoderic acid b, isolated from Ganoderma lucidum, was proved to have anti-HIV protease activity. 9 (Figure 3) 4 Wijekoon, C. P.; Facchini, P. J. Plant J 2012Plant J , 69, 1052Plant J -1063. 5 . 5 Patridge, E.; Gareiss, P.; Kinch, M. S.; Hoyer, D. Drug Discovery Today 2016, 21, 204-207. Furthermore, exploration the marine source for more medicinal products was highlighted in the past 40 years where thousands of bioactive natural products were isolated. In October 2007, the European Union approved the first marine anticancer drug the Trabectedin which was isolated from the ascidian Ecteinascidia turbinate (Figure 3). 10,11 Bacteria also contributes highly to medicine through providing a wide range of antibiotics, antitumor agents, immunomodulators and enzyme inhibitors. 12

II. Introduction to Alkaloids

Between 1983 and 1994, 39% of the approved drugs were originated from natural products, and according to Cragg et al., 60-80% of the anticancer and antibacterial medicines were natural products-based. 13 The interest in nature as a source of more challenging therapeutic agents continues to highlight the importance of plant secondary metabolite either as drug or drug precursors. The biodiversity of nature is progressing from time to time to provide a wide array of these secondary metabolites.

Plants usually produce a wide variety of molecules divided between primary and secondary metabolites. Primary metabolites are those of intrinsic function integrating directly in the essential roles for survival as growth, development and reproduction. They are composed of the core building block

NP -Marine Source NP -Fungi Source

Me molecules such as sugars, nucleic acids, fatty acids and amino acids that are the raw materials for the synthesis of the major macromolecules within the body (protein, carbohydrates, DNA, RNA and lipids). Whereas secondary metabolites are believed to act as additives that have no relation with survival, but with protection and species interaction.

As mentioned before, a wide array of secondary metabolites is produced by plants where about 100,000 metabolites have been detected to date according to Afendi Study. 14 They are categorized based on their carbon skeletal structure and functional groups into alkaloids, terpenes, steroids, polyketides, peptides and porphyrins. Many of these metabolites were proved to be of highly significant pharmaceutical properties (Table 1). The biogenesis of these secondary metabolites is highlighted in Figure 4.

Alkaloids are basic nitrogenous secondary metabolites, where their name come out from their alkaline chemical structure. They were known in ancient time by the easiness of their extraction from plants and the powerful and deadly effect they possess. They were found to be diverse in their structures where more than 3000 alkaloids were detected in about 4000 plant species. All are of amino acids' precursors. 15 The role of these alkaloids in plants is believed to be related to their protection and defense against predators; including herbivores and pathogens. These low molecular mass secondary metabolites are released and activated under diverse stressors to exhibit their defense activity. For example, it was shown that aporphine alkaloid save the tulip tree from parasitic mushrooms. 16 14 Afendi, F. M.; Okada, T.; Yamazaki, A.; Hirai-Morita, A.; Nakamura, Y.; Nakamura, K.; Ikeda, S.; Takahashi, H.; Altaf-Ul-Amin, M.; Darusman, L. K.; Saito, K.; Kanaya, S. Plant Cell Physiology 2012, 53, 1-12. 15 Kumar, V.; Wani, S. H.; Suprasanna, P.; Tran, L. P. Salinity Responses & Tolerance in Plants 2018, 2. 16 Nissar, A. R.; Sudarshana, M. S.; Smitha, N.; Guru, C. World Journal of Pharmaceutical Research 2014, 3, 731-741. Many of these naturally occurring alkaloids possess potent pharmacological activity and some show interesting use in modern medicine. To illustrate, Atropine which is an alkaloid existing in various plants of the family Solanaceae such as belladonna, Datura, henbane and mandrake, is widely used as antidote to nerve gas poisoning. Moreover, Caffeine is known in modern medicine as central nerve system stimulant and Quinine for its antipyretic, analgesic and most importantly for its antimalarial property. More interestingly, some natural products show an inhibiting activity against more challenging diseases. Vinblastine and Vincristine, isolated from Catharanthus roseus plants, are used for cancer therapy by inhibiting the hydrolysis of guanosine-5'-triphosphate (GTP) and thus inhibiting cell division at metaphase level and promoting cell death. 17

The first synthesized alkaloid is the piperidine alkaloid coniine by Ladenburg in 1886, 18 which was first extracted from poison hemlock (Conium Maculatum) in 1826 by Giseke. 19 This alkaloid was proven to be extremely toxic where it was the reason behind the death of Socrates. It causes paralysis of motor nerve endings by blocking the nicotinic receptors on the post-synaptic membrane of the neuromuscular junction, followed by death due to cessation of breath. 20 As for the more challenging diseases; Galantamine which is a naturally occurring plant tertiary alkaloid The vogue of natural products discovery is increasing as they are not only proven to be an invaluable resource of novel drugs but also, they can be used as inspiration and blueprints for the fashioning of non-natural molecules of pharmaceutical value. Between 1981 and 2002, natural product analogues-based drugs proved to be 65% in the field of antihypertension and 70% as antimigraine out of the synthetic new chemical entities. 21 The history of medicine is full of remarkable examples of how the natural products have impacted the field of biology and drug discovery. An example of drug agent inspired from natural products is Cabergoline, analogue of the natural ergot alkaloids, which was approved for the treatment of Parkinson's disease (Figure 5). 22 These natural ergot alkaloids were the raw materials for a lot of key synthetic intermediates that led to drug discovery. 23 Moreover, cocaine was the inspiration for the synthesis of a wide range of anesthetic drugs such as procaine, bupivacaine, eucaine, etc. which were proved to be less toxic than cocaine. 24 Figure 5: Cabergoline as Drug Agent III. Amphibians as a Source of Bioactive Alkaloids Although poisons are most widely known to be found in plants as a defense against herbivores, but later some studies have investigated the chemistry of poisons in animals' skin and microorganisms leading to the development of new therapeutic agents. Several studies had discussed the potential pharmaceutical significance of products derived from amphibian skin secretions ranging from amines, peptides, proteins, steroids and alkaloids. 25 These secretions were used as a poison defensive weapon against predators, and some of these compounds were found to exhibit considerable 21 Newman, D. J.; Gragg, G. M.; Snader, K. M. J. Nat. Prod. 2003, 66, 1022-1037. 22 Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329-8351. 23 Liu, H.; Jia, Y. Nat. Prod. Rep. 2017, 34, 411-432. 24 Ruetsch, Y. A.; Boni, T.; Borgeat, A. Current Topics in Medicinal Chemistry 2001, 1, 175-182. 25 , cardiotonic, antimicrobial, antifungal, antimalarial, antiasthma, anticancer, or antibacterial activity, etc.. 26 Tempone had studied the activity of the amphibian secretions for the treatment of not well studied infectious diseases. It was found that Chaunus ictericus secretions possess high fungistatic activity, and the Phyllomedusa distincta secretions present anti-Toxoplasma activity. Also, it was reported for the first time an antileishmanial activity for the secretions of Siphonops annulatus. 27 Alkaloids are not only limited to plants but also generated or accumulated by other living organisms: frogs, ants, bacteria, fungi, beetles, mammals and spiders. 50% of the known antibiotics nowadays are isolated from Streptomyces, the most productive genus of Actinomycete (class of marine bacteria). 28 In the past three decades, the John Daly group reported the detection and characterization of about 800 alkaloids from amphibian sources. Their structures were either determined by NMR analysis or required additional confirmation based on the mass spectra analysis. These biologically active lipidsoluble alkaloids are distributed among different classes; samandarines, batrachotoxins, histrionicotoxins, epibatidine, pumiliotoxins, diverse array of izidines (pyrrolizidines, lehmizidines, indolizidines, quinolizidines), epiquinamide, piperidines, gephyrotxins, quinolines and coccinellinelike tricyclics. Whereas, some of the extracted alkaloids remained unclassified as their structures have remained unknown due to their limited abundance. 29 These noxious alkaloids were found to be stored in the granular skin glands of the amphibians, and they can be either of endogenic or exogenic origin.

Even though, some studies showed that amphibians serve as an indirect source of some natural alkaloids through their diet on alkaloid-containing plants. 30 Dendrobatidae, a subgroup of the poison dart frogs allocated in South and Central America, are characterized by their designs and hues that 2013, 68, 301-333. 29 Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556-1575. are deliberately ostentatious to ward off potential predators, a tactic called aposematic coloration. 31 The skin of these frogs is a stock of toxic plant alkaloids originating from their feeding on arthropods which in turn fed on plants. The enthusiasm to study profoundly the secretions from the subgroup skin came out initially because Indians on the Pacific coast of Colombia used the alkaloids extracted from the skin of Phyllobates to poison their blow-darts and directly killing or paralyzing their preys. 32 This points out that these extracts can be of remarkable biological activity targeting the central nervous system.

Batrachotoxins (BTX), the most effective neurotoxic and cardiotoxic steroidal alkaloid, is secreted by the most toxic genus of the dart frogs, Phyllobates, and also detected in the feathers and skin of birds. This neurotoxin alkaloid (BTX) drastically alters the properties of the voltage-gated sodium channel once bind. Accordingly, this binding causes the irreversible and permanent opening of these channels due to conformational change, leading to change in membrane potential. Death can result due to muscular and respiratory paralysis. 33 Also several classes of frog skin alkaloids; pseudophrynaminol, pyrrolidines, spiropyrrolizidines and piperidines, were proved to be potent blockers of nicotinic channels. 34 Whereas epibatidine, discovered by John Daly, was demonstrated to act as an agonist on the nicotinic receptors and then proved to be analgesic 200 times more powerful than morphine. 35 But it is no longer been considered for a potential therapeutic uses due to its toxicity.

Nevertheless, these frogs accumulate also bioactive amino acids that were proved to affect the GTPase activity of G proteins that are involved in signal transduction. 36 31 Caldwell, J. P. J. Zool. 1996, 240, 75-101. 32 Daly, J. W. Journal of Medicinal Chemistry 2003, 46, 445-452. 33 Wang, S. Y.; Mitchell, J.; Tikhonov, D. B.; Zhorov, B. S.; Wang, G. K. Mol. Pharmacol. 2006, 69, 788-795. 34 (a) Badio, B.; Garraffo, H. M.; Padgett, W. L.; Greig, N. H.; Daly, J. W. Biochem. Pharmacol. 1997, 53, 671-676. (b) Daly, J. W.; Nishizawa, Y.; Edwards, M. W.; Waters, J. A.; Aronstam, R. S.; Neurochem. Res. 1991, 16, 489-500. (c) Badio, B.;Shi, D.; Shin, Y.; Hutchinson, K. D.; Padgett, W. L.; Daly, J. W. Biochem. Pharmacol. 1996, 52, 933-939. 35 Badio, B.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Med. Chem. Res. 1994, 4, 440-448. 36 Moni, R. W.; Romero, F. S.; Daly, J. W. Cell. Mol. Neurobiol. 1995, 15, 465-493. Figure 6: Alkaloids isolated from amphibians Reliance only on nature to broaden the scope of these valuable bioactive natural products is hazardous. Sometimes, their isolation lead to change of the biological activity. In addition, the stock of products in the skin of these animals can change over time especially with the alteration of the ecosystem that impact directly the biodiversity. On the other hand, some of the natural products found in the skin of the poison dart frogs or other amphibians remain with unknown structure and biological activity due to the limited distribution of these compounds. Subsequently, the chemical synthesis of these natural products can stand in for their supply and thus for their biological evaluation as a way to avoid their isolation. Synthetic chemistry has never been and never will be solely concerned with the challenges it offers while targeting complex structures. Thanks to synthetic organic chemistry, the library of compounds available today has helped in nurturing drug discovery research field, in addition to developing everyday materials due to the other interesting properties they possess. Every year brings its bounty.

The work presented in this thesis is another collaborative record that can be added to the vast number of syntheses seeking to better understand other fields through the construction of natural products.

IV. Alkaloid (-)-205B

The structure of the alkaloid (-)-205B, that belong to coccinelline-like tricylics, was first reported in 1987 as diastereoisomers 37 but extensive FTIR, NMR and HRMS analysis were required to confirm the relative stereochemical configuration. 38 This alkaloid, isolated from Dendrobates pumilio, 37,38 has a unique tricyclic structure of 8b-azaacenaphthylene with five stereocenters. No other alkaloids from amphibian skin is known to belong to this group. Notably, skins of 3620 frogs were required to deliver only 13 mg of (-)-205B. The synthetic efforts covered in this thesis were embarked upon not just for their opportunity as challenging and intriguing targets but also for their relevance to other fields. Promising selective activity against central nervous system motivated the pursuit of these neurotoxic frog's alkaloids extract.

More interestingly, their potential to impact neurodegenerative disease has inspired our work specifically toward the alkaloid (-)-205B. This is fully discussed in the following chapter.

37 Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.; Daly, J. W. Tetrahedron 1987, 43, 643-652. 38 Tokuyama, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Anal. Asoc. Quim. Argentina 1998, 86, 291-298. For providing wide array of synthetic pharmacological active analogues of the interesting bioactive natural alkaloids, understanding the detailed mechanism of their mode of action is essential. The ability of alkaloids to defend plants or animals indicates that they interfere with important molecular and cellular targets in the predators such as ion channels, receptors, signal transduction, biomembrane, DNA, Endoplasmic Reticulum and Golgi. 39 During their evolution, the structure of alkaloids is shaped in a way that they mimic endogenous substances such as neurotransmitter in their structure and thus they are able to bind to neuroreceptors.

This stands for addressing alkaloids as "neurotransmitter analogs" 40 especially that both alkaloids and neurotransmitters are derived from amino acids.

Neurotransmitters are endogenous substances that act as chemical messenger to transmit signal between neurons or between neuron and muscle. The electric signal that travel throughout the neuron is converted into a chemical one in the axon by allowing the vesicles-containing neurotransmitters to fuse with presynaptic membrane thus releasing the neurotransmitters into the synapse. The communication occurs across the synapse where the neurotransmitters bind to receptors on the postsynaptic neuron, thus stimulating the latter by mediating either inhibitory, excitatory or modulatory effect.

39 Fattorusso, E. Therefore, the biological activity associated with these alkaloids have stimulated research in several synthetic groups to provide alkaloids with unknown biological activity. A significant attention was given to the alkaloid of interest, (-)-205B, that might have selective activity on the a 7 nAChR as either agonist or antagonist.

iii. nAChRs -Neurodegenerative Diseases Affinity

For more than 20 years, the neuronal nAChRs have been the target for drug discovery for several neurodegenerative diseases, with a special focus on the (a 4 ) 2 (b 2 ) 3 and (a 7 ) 5 receptors as they are the most expressed in the central nervous system. Freedman et al had studied potential new candidates as therapeutic agents for Schizophrenia. 46 It was noted that schizophrenic people have reduced level of a 4 b 2 and a 7 subunits receptors. This might explain the relation of high level of smoking in people with schizophrenia where tobacco is considered as an external source for nicotine that will regulate the number of biding sites on the cell surface. More rewarding, a lot of efforts had been done by SIBIA (Salk Institute Biomedical Industry Association), in particular by R.J. Reynolds and Abbott, for the discovery of nAChR agonists as a potential treatment of pain, Schizophrenia and Alzheimer's disease (AD) (Figure 12). 44 Figure 12: early discovered nAChRs agonists as potential therapeutic agent

Recently several studies have linked specifically the a 7 nAChR to neurodegenerative diseases, thus targeting this receptor may be a potential approach for developing a new medication. 47 AD has been considered as a challenging disease to treat. It is one of the common dementias suffered by aged people and its therapy is still very limited. On-going developments in biological research had opened the way for proposing agonists and antagonists as therapeutic agents for such disease. In the 90s, several inhibitors for acetylcholinesterase were approved for the treatment of mild to moderate AD.

Later on, more attention was given for the development of a 7 nACHRs agonists as anti-AD agents,

where some represent a promising potential candidate for the treatment of AD. 48 (Figure 13) Even though most studies focus on the neurotoxic effects of these Ab peptides causing the neurodegeneration in AD, it was proved that they are of important physiological role. At low concentration, these peptides are found in their monomer soluble form that are proved to exhibit neuroprotective properties. Several studies supported the participation of Ab in the synaptic activity, memory formation and neuronal cell growth and survival. 52 Moreover, there is evidences indicating that they are of properties conferring species survival such as the anti-microbial and anti-cancer properties. 53 However, the Ab peptides become pathological only when its production and degradation are imbalanced, thus the effect of these peptides is concentration-dependent. Once the amyloid beta protein is no longer regulated, this led to the overproduction of these sticky peptides that will aggregate over time leading to the formation of the indissoluble fibrils and then creating the senile plaques. Consequently, these Ab peptides become of neurotoxic properties leading to synaptic dysfunction, loss of connection between nerve cells, memory impair and structural damage of the brain. This consolidates the idea of targeting Ab deposition rather than Ab production for treating AD.

The amyloid plaques are observed initially in the cortex, secondly in the hippocampus and then it reaches the whole brain. These amyloid plaques will lead later to the formation of neurofibrillary tangles causing eventually cell death.

The brain of AD patients shows a decrease in the a 7 nAChRs. 54 The high affinity of this receptor to Ab proteins lead to the formation of a 7 nAChRs-Ab complex thus increasing the concentration of Ab in the synapse resulting in the formation of plaques and thus leading to the impairment of the signal transmission and neuronal dysfunction. Sequentially, the a 7 nAChRs play a key role in AD pathology.

As a way for treating AD, at what point ideally should neuroscientists intervene to treat this disease?

A lot of studies had addressed either the b secretase to modify its production or the enzyme responsible for its degradation. Others focus on keeping amyloid plaques from reaching the tipping point and triggering the cascade.

Drug discovery is largely focused on the development of active agents toward the reduction of Ab peptide accumulation. The a 7 nAChRs should be the target to prevent the complexation with the peptides. Thus, the use of a 7 nAChR agonist or antagonist can be a possible therapeutic approach for AD as it will compete with a 7 nAChR-Ab interaction. It is also believed that Ab peptides also interact with other subtypes of nAChRs contributing in AD pathology that could be targeted for the AD therapy. 55 There are many examples in the literature of a 7 nAChR agonists that exhibit neuroprotective effect. 44,56 Nicotine has induction effect on these receptors with clearance of these plaques and this justifies the fact that tobacco smokers are found with less possibility to have AD. But the toxic side effects of nicotine and its addiction property can't be discarded. However, Cotinine was found to be an interesting molecule to be studied for the AD treatment. It is a nicotine metabolite that was found to improve memory and attention with none of the toxic and addictive effects of nicotine. 57 It was proved to decrease the concentration of the Ab peptides once treated to mouse model of AD. 58 Also, it was reported that 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium, S 24795, is a partial agonist selectively acting on the a 7 nAChR and proved to decrease the a 7 nAChR-Ab complexes (Figure 15). 59 Recently, another point of view has been reported in the literature. Most recent studies have suggested that the internalization of the Ab peptide inside the neurons is the earliest marker in AD patients as it is detected before the extracellular senile plaque deposition. 47a Nonetheless, it was proposed that it might be also the inducing signal for the extracellular Ab peptide accumulation. These intracellular Ab proteins were found to affect the synaptic plasticity leading to the axon degradation and eventually cell death. Seeking other neurodegenerative diseases, people with Down's Syndrome are also faced to AD-like neuropathology (their brain develop same changes as AD people) in their third decade. The presence of an extra copy of the gene for the amyloid precursor protein (APP) on the chromosome 21 results in the acceleration of the amyloid plaque deposition in their brain. 60 Consequently, any a 7 nAChR agonists might intervene in the binding between Ab and a 7 nAChR and thus preventing or slowing the cascade that lead to the deposition of amyloid plaques. In such case, this can prevent progressive dementia and improve memory and cognition in people with Down's Syndrome.

On the whole, our interest toward the alkaloid (-)-205B is driven first by the fact that the natural form belongs to the blow-dart poison used by Colombian Indians to paralyze their preys. Furthermore, the possibility that it might act selectively on a 7 nAChR arises the expectation to interfere with neurodegenerative diseases involving aggregation of amyloid beta peptide such as Alzheimer's disease.

Due to the scarcity of this natural product, we decided to embark in the chemical total synthesis of this alkaloid. As an extension of this work, biological evaluation will then be performed in collaboration with biological teams allowing to assess its selective activity toward a 7 nAChR and its ability to modulate the toxicity of Ab peptides.

60 Wisniewski, K. E.; Wisniewski, H. M.; Wen, G. Y. Ann. Neurol. 1985, 17, 278-282. CHAPTER III: REPORTED SYNTHESES OF (-)-

205B

The challenged structure of alkaloid 1 coupled with its biological interest prompted several research groups to find out a synthetic approach for this natural product. But till now, its pharmacological properties are not reported yet probably because of its limited abundance.

I. Toyooka Synthesis

The first enantioselective total synthesis of this structurally unique 205B alkaloid was realized by Toyooka and Nemoto that led to the unnatural antipode 15a. 61 However, this work had allowed to establish the absolute configuration of the natural product. The synthesis commenced with the enaminoester 5 that was synthesized from the commercially available lactam 2 in 3 steps. Upon the steric and stereoelectronic effects, treating the enaminoester 5 with Gilman reagent allowed the axial attack of the methyl group forming the methylated product as a single stereoisomer. The N-methoxy carbonyl group is believed to direct this addition by freezing the ring conformation with the methyl silyloxy substituent in an axial orientation owing to 1,3-allylic strain. After the reduction of the ester group, the oxazolidinone ring 6 was constructed in basic medium. The corresponding ketone 11 formed from the ester group is then protected as acetal, followed by hydrolysis of the oxazolidinone ring and amine-Boc protection (12). Simple Swern oxidation and Horner-Wadsworth-Emmons olefination yielded piperidine 13. The tricyclic core of the target product was constructed via intramolecular Mannich-type cyclization affording the ketone intermediate 14.

Finally, the alkaloid (+)-205B 15a was obtained after Wittig olefination forming the exo-alkene followed : by the regioselective acid-catalyzed isomerization revealing that the desired isomer 15a is lower in energy than the other isomer 15b (6:1 ratio respectively).

This synthesis is characterized by the elegant control of the stereochemistry and the efficient formation of the tricyclic framework. However, due to several transformation of functional groups, the main drawback of this sequence is the length of the synthesis (30 steps). favors the equatorial approach of the proton, where the repulsion between the protonated amine and the upcoming axial hydronium ion disfavors this delivery. (Scheme 3) Scheme 4:Synthesis of intermediate 23a

II. Smith Synthesis

The desired methyl group 25 was formed by successive reductions followed by applying the Stork protocol to remove the dithiane producing the ketone 26. The last step to furnish the alkaloid 1 was same as Toyooka's comprising of methylenation and isomerization. (Scheme 5)

This synthetic pathway is distinguished by the efficient linchpin coupling strategy developed by Smith.

However, this approach is accomplished in 27 steps to reach the final product starting from commercially available starting materials. In addition, it presents the difficulty of introducing the axial oriented methyl substituent.

III. Comins Synthesis

In 2011, another concise and highly stereocontrolled total synthesis of this alkaloid was reported by Comins and Tsukanov (Scheme 6). 64 The synthesis started with the enantiopure dihydropyridone 28 that was prepared according to the author developed asymmetric addition of Grignard reagent on the in situ formed chiral N-acylpyridinium salt of 4-methoxy-3-(triisopropylsilyl)pyridine 27. 65 This dihydropyridone 28 undergoes deprotection followed by cross metathesis with (Z)-but-2-ene-1,4-diyl acetate using the Grubbs-Hoveyda 2 nd generation catalyst forming the pyridone 29. Then the indolizidnone ring 30 was constructed utilizing the intramolecular Tsuji-Trost allylic amination in a highly optimized conditions for high diastereoselective outcome (minor isomer not shown).

The stereoselective introduction of the equatorial methyl group at C 8 was achieved by a direct alkylation that leads to the expected methylated product in a fairly low diastereomeric ratio. Fortunately, only the desired isomer could be obtained by careful kinetic protonation of the enolate of the methylated mixture. After extensive experimentation, the axial 5a-methallyl group was introduced by 64 (a) Tsukanov, S. V.; Comins, D. L. Angew. Chem. Int. Ed. 2011, 50, 8626-8628. (b) Introducing the axial C 6 -methyl group as a single stereoisomer was achieved with the rigid tricyclic ring system 32 in hand, otherwise a mixture of inseparable diastereoisomers was obtained if methylation was done on the indolizidinone 31. Thereby, the ring closing metathesis of 31 was conducted using Grubbs second-generation catalyst followed by stereoselective enolate alkylation to introduce the axial methyl group at C 6 to afford the tricyclic intermediate 33. Reductive cleavage of the ketone was accomplished through a three-step protocol. Birch reduction of the ketone generated only the equatorial alcohol 34 which was reduced through a modified Barton-McCombie strategy using PhSeH as the hydrogen donor to give the targeted natural product 1. Oxidation of the primary amine followed by the highly stereoselective intramolecular [3+2] cycloaddition upon heating with butylglyoxylate afforded the piperidine intermediate 39 (Scheme 7).

66 Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. This synthetic pathway was realized in 15 steps with 0.7% overall yield and it is mainly characterized with the high control over the stereogenic centers.

V. Cha Synthesis

Lastly in 2015, Cha and Rao 68 provided another synthetic approach for this alkaloid. It is based on an anti-S N 2' alkylation, an electrophilic allene cyclization and a ring closing metathesis for the endocyclic double bond formation in 1 (Scheme 10). 1997, 119, 8572-8573. 68 Rao, N. N.; Cha, J. K. J. Am. Chem. Soc. 2015,137,[2243][2244][2245][2246].

OPMB Me Me OH 1-LDA (2 equiv), LiCl 91% 2-4N NaOH, CH 2 N 2 95% 3-EtMgBr, Ti(Oi-Pr) 4 92% 1-TBSOTf 2-DDQ (76% -2 steps) 3-(PhO) 2 P(O)N 3 , DIAD, Ph 3 P 4-CSA, MeOH (73% -2 steps) 47 Me CH 2 N 3 Me Me OH OTs H 2 C
principle importance of this solvent that could favor the appropriate conformation for unidentified reasons.

Scheme 10: Completion of Cha Synthesis Stereoselective cyclization of the amino allene 52 involving chiral transfer from the enantiopure allene to form 3,5-cis indolizidinone 53 was promoted by silver. Finally, the desired alkaloid 1 was achieved through RCM allowing the formation of the endocyclic olefin.

Up to date, it seems that this synthesis (Scheme 10) is the shortest where it was accomplished in 12 steps. However, the preparation of reagents 46 and 49 requires an additional 7 and 9 steps respectively, rendering this sequence of 28 steps at least.

H R = (CH 2 ) 3 CH=CH 2 R H 2 C H 2 C C R 53 N Me Me Me H 2 C C R Me C R Me N 3 H 2 C Me O CHAPTER IV: START OF THE JOURNEY TOWARD (-)-205B
With this overview of the reported syntheses of the chiral alkaloid 205B in the literature, our research study has been directed for the development of another synthetic approach targeting this natural products (-)-205B (1). Accordingly, the intended biological studies of 1 will allow revealing its pharmacological properties.

I. Retrosynthetic Strategy of Alkaloid (-)-205B

The synthesis, started some years ago, is based on the powerful strategy developed by Greene et al. 73 leading to the chiral pyrrolidinone through a highly stereoselective [2+2] cycloaddition of dichloroketene and a chiral enol ether. This strategy highlights the remarkable ability of the easily available chiral alcohol 55 (Stericol) as an external chiral inductor. 74 In addition, several ready accessible commercial building blocks were the starting point of the highly stereoselective formation of an advanced intermediate, indolizidinone 54. (Scheme 11) Despite of the elegant synthetic strategy developed so far to reach 54, the alkaloid of interest 1 remained difficult to access due to faced constraints in the subsequent steps. Driven by these chemical difficulties and by the final goal regarding the biological evaluations, a new chemistry was then explored as an entry to the target compound 1.

Scheme 11: Retrosynthetic Strategy of (-)-205B

The strategy detailed in this chapter for the synthesis of intermediate 54 was reproduced during this work on large scale and being applied in its chiral version.

73 Deprés, J.; Delair, P.; Poisson, J.; Kanazawa, A.; Greene, A. E. Acc. Chem. Res. 2016, 49, 252-261. 74 Delair, P.; Kanazawa, A. M.; de Azevedo, M. B. M.; Greene, A. E. Tetrahedron Asymmetry, 1996, 7, 2707-2710.

II. Synthesis of Indolizidinone Intermediate

Application of this strategy to the synthesis of the non-chiral pool 205B alkaloid led to the publication of the "first trial" approach which will be described briefly in this section. 75 The correct absolute stereochemistry responsible for the formation of (-)-205B is displayed in the schemes of this chapter, however the results of this first approach were obtained as racemic.

i. Synthesis of Enol Ether

On the basis of precedent work for the formation of the chiral pyrrolidinone intermediate, 76 the synthesis commenced by the successive deprotonation of the inductor, (±)-Stericol 55, with potassium hydride. Thereafter, the alcoholate ion attack the dichloroethyne, formed in situ by the deprotonation-elimination of trichloro ethylene. Addition of 1-2 drops of MeOH speeds up the reaction as it increases the concentration of the base in the reaction mixture. The corresponding dichloroenol ether 56 was isolated in 79% yield after purification.

Scheme 12: Synthesis of Enol Ether 58

The enol ether 56 was transformed to ynol ether 57 by treating it with 2 equiv of n-BuLi and allyl iodide. The mechanism of this step consists of syn elimination of HCl forming the corresponding chloro-alkyne followed by lithium-halogen exchange to form the acetylide ion that is responsible for the S N 2 substitution with the methyl allyl iodide. 77 The formed ynol ether 57 was observed to be thermally unstable generating variable amount of styrene derivative 60 along with the ketene 61 which was not identified nor any other subsequent byproducts according to the following proposed mechanism (Scheme 13). 78 Isolation of this ynol ether 57 could be possible only by keeping the temperature as close to 0°C as possible during the work-up procedure and was used for the next step without any further purification.

Scheme 13: Decomposition of Ynol Ether 57

Hydrogenation of the alkyne 57 to cis alkene 58 was achieved with Rosenmund catalyst in presence of ethylene diamine and 1-hexene that prevent the over reduction of the alkenes especially the terminal one. Nevertheless with all these precautions, 8% of the dihydroenol ether 59 was formed (identified from 1 H NMR of crude material). (Scheme 12)

ii. Formation of Lactam Intermediate

The enol ether 58 was then transformed to lactam 64 by a highly stereoselective [2+2] cycloaddition with ketene forming first the cyclobutanone 62, followed by Beckman rearrangement for ring expansion to the corresponding dichlorolactam 63. In both reactions, regioselectivity and stereoselectivity are of great importance and fully controlled. Zn-mediated reductive dehalogenation then gave the chiral lactam 64 that was isolated in 72% yield from enol ether 58. 75 (Scheme 14) chloride upon treating it with activated zinc. 79 The reaction proceeds smoothly forming a single regioisomer of the expected cyclobutanone 62 with high diastereomeric excess (95:5).

In the conventional knowledge; thermal [2+2] cycloaddition forming cyclobutanes are thermally symmetric forbidden but photochemically allowed based on the HOMO alkene and LUMO ketene interaction. 80 In contradiction, ketene-alkene thermal cycloadditions are orbital-symmetry allowed which it is analyzed by the concerted [p2 s + p2a] reaction mechanism. 81 The ketene approaches antarafacially that is geometrically favored as they are linear and sterically less encumbered than alkene. (Figure 16) 1985, 50, 3149-3155. 83 Valenti, E.; Pericas, M. A.; Moyano, A. J. Org. Chem. 1990, 55, 3582-3593.

C C O Antarafacial Approach -Allowed Suprafacial Approach -Forbidden LUMO of ketene HOMO of alkene C C O C CH C C C C O O O d- d+
as a consequence of electronic effects in the transition state. Due to the non-synchronous mechanism of this reaction, the partial positive charge should be located on the carbon with richer electron environment. Figure 18 shows the 2 possible transition states through which this reaction could pass taking into account its concerted non-synchronous type. Transition state II is of lower energy as the electron deficiency on the carbon is much more compensated by the alkoxy group due to its electron donating property. Regarding the diastereospecificity, the stereochemistry of the alkene is retained in the final cyclobutanone product. On the other hand, appending the (R)-Stericol alcohol to the alkene had induced facial selectivity, where the diastereoselectivity of this reaction is believed to be induced by this external chiral auxiliary group. According to a previously reported synthesis, theoretical calculations showed that one conformer of enol ether is greatly favored over the other. 84 This lowest energy conformation had a face of the olefin blocked by one of the isopropyl groups thus orienting the approach of the ketene mainly from the other face.

Cyclobutanones are useful intermediates that possess synthetic interest as it undergoes facile ring expansions in order to relieve ring strain. 85 Later on, Baeyer-Villiger oxidation, Beckman rearrangement and pinacol-type rearrangement conditions were more developed that give rise to lactones, lactams and cyclopentanones derivatives respectively.

Lactam 1975,14,[473][474][475][476][477][478][479][480][481][482][483][484][485].

O O R 2 O R 1 more stable transition state TS I TS II R 2 O R 1 Cl Cl O R 1 OR 2 Cl Cl Cl Cl O R 1 OR 2 Cl Cl d- d+ d+ d-
and stereospecificity. 86 The electronic effect is responsible for this region-control where the presence of the 2 chlorine atoms at α-position decrease electron density on the adjacent bond. 87 Thus, directing the regioselectivity through reducing the migration aptitude of the adjacent C-C bond results in only one isomer of the lactam 63. The anionotropic nature of this rearrangement ensures the stereo-integrity of the migrating chiral center. Both cyclobutanone 62 and dichlorolactam 63 are susceptible to degradation over silica gel thus no purifications were attempted.

iii. Formation of Indolizidinone Construction of the indolizidinone ring 54 was planned to be formed through intramolecular cyclization of the amine with a butenolide group, which in turn is synthesized from pyrrolidinone 64 via vinylogous Mannich reaction.

This synthesis started with the protection of the lactam 64 with Boc group that was performed in 81% yield. The formed Boc-lactam 65 was subjected to partial reduction followed by conversion of hydroxyl into methoxy group forming the hemiaminal derivative 66. The second key step of this strategy was the vinylogous Mannich reaction that control the stereochemistry of 2 chiral centers. (Scheme 15) It was observed that treating the hemiaminal 66 with silyloxyfuran and Lewis acid resulted in the formation of only 2 diastereoisomers out of the possible 4. This selectivity is sterically controlled where the 2 substituents on the in situ generated cyclic iminium intermediate block the front face and direct the approach of the silyloxyfuran only from the least sterically hindered face.

The butenolide is formed by the addition of the silyloxyfuran on the formed iminium ion under the effect of Lewis acid. According to Martin's ab-initio calculations, the lowest energy transition state adopts a preferential endo Diels-Alder like approach which is favored either by cumulative steric interactions or by stabilizing stereoelectronic factors. 88 Such approach led to the formation of the threo adduct 67a majorly. (Scheme 16) Scheme 16: 2 Approaches of Vinylogous Mannich Reaction With great satisfaction, it was noticed that these transformations are highly efficient allowing the isolation of 72% of the major threo isomer 67a from the corresponding lactam-Boc 65 for this 3 steps-sequence. Minor isomer 67b was also isolated in 26% yield.

For the formation of the target indolizidinone 54, the conjugated double bond was reduced chemoselectively in the presence of the terminal olefinic group. This was achieved by using NaBH 4 in MeOH in the presence of CuCl 2 .2H 2 O which furnish pure lactone 68 in 87%. 89 The next challenging step was the selective deprotection of Boc group in the presence of the acid-sensitive 88 Bur, S. K.; Martin, S. Org. Lett. 2000,2, 3445-3447. 89 (a) Dankwardt, S. M.; Dankwardt, J. W.; Schlessinger, R. H. Tetrahedron Lett. 1998, 39, 4971-4974. (b) Gemal, A. L.; Luche, J-M. J. Am. Chem. Soc. In this approach, the C 6 -methyl group was introduced in a classical way by alkylation of the enolate with methyl iodide. It was expected that the equilibrium between the 2 conformations of the generated enolate is shifted to favor conformer (I). Thus, the axial position of the methyl group could be directed by the stereoelectronic effect. Also, by analogy of the previous vinylogous Mannich reaction, this attack direction could be also supported by the steric hindrance requirements where the substituents of the 5-membered ring would favor the introduction of the electrophile as desired. (Scheme 18)

N OLi LiO H R 1 O R 2 R 1 = CH(CH 3 )Ar R 2 = CH 2 CH(CH 2 )CH 3 stereoelectronically favored attack N OLi R 1 O R 2 H LiO
However, treatment of lactam 54 with an excess of t-BuLi in THF at -78°C followed by the addition of MeI afforded methylated products in favor of the unexpected isomer 70b in 7:1 ratio. This stereochemical outcome is better explained through either the convex/concave nature of this bicyclic framework or the conformer (II) where the steric and the stereoelectronic arguments would disfavor an endo-bicyclic approach of methyl iodide.

So, in order to attain the desired diastereoisomer 70a, the methylated lactam 70b had to be epimerized. Thus, after extensive experimentation, the isolated major isomer 70b was subjected to deprotonation-protonation that yielded only a 1:1 epimeric mixture of the 2 diastereoisomers. It was necessary to perform 2 recycling of such process to obtain the pure desired methylated indolizidinone 70a in 61% yield. 75 (Scheme 19)

Scheme 19: First Difficulty encountered in the previous approach

ii. Construction of the Tricyclic Core of the Target Product

After protection of the hydroxyl group of 70a as benzyl ether 71, the tricyclic product 72 was constructed through an aza-Prins cyclization. 75,90 After extended experimentation, the lactam 71 was reduced partially using LAH at low temperature followed by aza-Prins cyclization upon iminium formation by formic acid. Despite the mild conditions (-10°C), partial reduction was accompanied with the unavoidable formation of the over-reduced product 74

:

Scheme 20: Formation of the tricyclic intermediate 73

However, upon structural determination through X-ray analysis, it was surprisingly discovered that the C 6 chiral center was totally epimerized. It was surprising to note that the imine-enamine equilibrium proceeded rapidly resulting in the formation of the more stable configuration of the product where the axial methyl group shifts totally to the equatorial position (as shown in 72).

This unexpected easy epimerization compromised strongly this synthetic approach which was complicated also by the difficult control of the partial reduction and the unfavorable stereochemical outcome of the alkylation reaction. Therefore, a new approach should be explored allowing to reach the target alkaloid, (-)-205B. Silicon protecting groups are widely used in modern organic synthesis as they are adaptable to a variety of reaction conditions and their high affinity for fluorine permits their deprotection smoothly. 91 Thereafter, the simplest way to introduce the desired cycle is by temporary silicon tether (TST) where it can be easily and smoothly introduced to the secondary hydroxyl group and allow the formation of the 6-membered silyl ring by nucleophilic displacement. In addition, upon the aza-Prins cyclization, the presence of this transient cycle will prevent the formation of a double bond at the bridgehead of a bridged ring system, according to Bredt's rule. 92 Consequently, upon subjecting the lactam to a reducing agent leading to the imine, enamine will not be formed avoiding the possible C 6 epimerization. This silyl cycle can finally release the hydroxyl and methyl group by the known proto-

II. Temporary Silicon-Tethered Chemistry

Silicon tethers are widely used due to their ease of preparation, their stability and adaptability toward wide array of reaction conditions and their selective and ease of de-functionalization to afford the desired product. The most common employed TSTs are illustrated by medium-sized silicon cycles either as disiloxane, siloxane or silane linker (Figure 19). Tethering two partners through a silyl link renders the reaction to run in an intramolecular version implicating several advantages over their intermolecular counterparts. These links are proved to influence the rate of the reaction which run also with higher regio-and stereoselectivity as these tethers constrain the transition states thus having fewer degrees of freedom. They, in turn, work as an important synthon due to their considerable potential for further transformations into various intermediates in synthesis through reactions like protodesilylation, Fleming-Tamao oxidation, silane-group transfer or transmetallation. This strategy is valuable as it is employed in the synthesis of wide range of natural products. 93 93 Čusak, A. Chemistry 2012, 18, 5800-5824. This chemistry was initially introduced in the 80s by Nishiyama and Stork, where silyl tethers were applied for the synthesis of 1,3-diols from allylic alcohol based on radical cyclization. 94 Later, these tethers were used for wider applications that are beneficial in organic chemistry and have been reviewed periodically. 95 Due to the importance of this subject and in order to give a brief overview of some of the TST applications, selected interesting transformations are highlighted in the following paragraph.

i. Diels-Alder Reaction

The synthetic utility of TST methodology was exhibited by Stork in Diels-Alder chemistry allowing the access of endo product 77 displaying high regio-and stereoselectivity. 96 Targeting the alkaloid (-)-Calyciphylline 80, Smith 97 had also integrated these tethers upon intramolecular Diels-Alder reaction for high diastereoselective outcome. This synthetic strategy was responsible for the introduction of 4 stereogenic centers of the final natural alkaloid. It was achieved using a Lewis acid that promote the endo approach allowing the formation of the desired isomer in high diastereoselectivity through the proposed transition state 81. (Scheme 23) 94 (a) H. Nishiyama, T. Kitajima, M. Matsumoto, K. Itoh J. Org. Chem. 1984Chem. , 49, 2298Chem. -2300. (b) . (b) G. Stork, M. Kahn, J. Am. Chem. Soc. ii. Alkene Metathesis Applications of this TST strategy were further extended for RCM which showed an improved difference in their efficiency and selectivity compared to untethered cross metathesis. The selectivity has been manifested by the formation of the Z-alkene as an alternative to the usual E-alkene geometry for conventional cross metathesis as a consequence of the cycle constraint. In this strategy, one of the tethered components of 82 should be derived from a prochiral alcohol.

Si O R R' disiloxane siloxane silane X X' O Si R R' X X' Si R R' X X' Me CO 2 Me
Thereby, a considerable diastereoselectivity was observed in the 1,4-silaketal products (83 and 84) upon the RCM where chirality transfer occurs within the chiral allylic ether 82. A newly stereogenic center has been introduced as a consequence of the steric interactions in the transition state. is notable that having bulky substituents on silicon is necessary to afford diastereoselectivity as high as 99:1 (Scheme 24).

Interestingly, this TST-RCM strategy was proved to be valuable in the total synthesis of natural products. In 2002, an elegant synthesis of (+)-brasilenyne 88 was reported by Denmark et al.

highlighting the importance of integrating this strategy to reach the target product. 99 A tandem TST-RCM/Hiyama cross-coupling was developed to access the 9-membered ring 87. The TST-RCM product 86 was showed to be the ideal substrate for the further functionalization through an intramolecular Hiyama cross-coupling. (Scheme 25) As an extension of hydrosilylation, TST carbosilylation seems to be more complex as it will result in the formation of at least one C-C bond. Recently, Leighton and co-workers had elevated this chemistry to the "one pot" stereoselective carbosilylation-allylation tandem reaction. It could be either applied to alkenyl or alkynyl substrates, and thus resulting in syn or anti 1,5-diols respectively (Scheme 31). 105 The observed diastereoselectivity of 110 arises as a result of the preferential attack of the allyl group that lies in closer proximity to the activated aldehyde. However, engaging silyl tethers will lead to the enhancement of the stereoselectivity and orient such addition regardless of the other impactful factors. Nakada et al. had applied this protocol in a study toward the total synthesis of Taxol where chirality transfer was realized from silyl ether 122 to the bicyclic tertiary alcohol 123. 107 On the other hand, it was noticed that upon using LDA as the base resulted in a stereoselective intramolecular alkylation upon reversing the polarity leading to the chiral diol 127 after tamao oxidation. To the best of our knowledge, this is the only reported result of such kind of stereoselective alkylation through a silyl linkage.

Scheme 33: Chiral Transfer upon TST -Nucleophilic Addition

III. Retrosynthetic Analysis of New Strategy

Inspired by the chemistry introduced by Nakada, 107 we think whether this methodology would be applicable on our substrate for an introduction of the C 6 -axial methyl group. This stereoselective reaction could be directed by the C 8 -hydroxyl group occupying an axial position.

Retrosynthetically speaking, the C 6 -axial methyl group (75) would be installed by the known protodesilylation of the silyl moiety after the construction of the polycyclic scaffold 128. This polycyclic structure 128 would be achieved via the aza-Prins cyclization of the lactam 129. Finally, the first key intermediate 129 Detailed synthesis will be discussed in the following section according to this general scheme.

SYNTHESIS OF (-)-205B

As discussed in the previous chapter, the aim of our work is the development of a new approach for the synthesis of the natural alkaloid, (-)-205B.

I. Synthesis of the First Advanced Intermediate

Following the previously published procedure, 75 the first advanced intermediate 54 was synthesized in an optically active form. The first consideration in this synthetic approach of the natural alkaloid (-)-205B was the choice of the enantiomer of the external inductor in order to obtain the desired absolute configuration of the final alkaloid. Based on previous syntheses, 108 it was defined that the R enantiomer 55 is the effective chiral controller for the introduction of such stereochemistry. A. E. J. Chem. Soc., Perkin Trans. I 1997, 1911-1912. (c)

II. Formation of Silyl Tether

Looking up for the development of a novel methodology for controlling the stereoselective installation of the C 6 -axial methyl group with enough stability to avoid epimerization upon the ensuing steps, we have great hope with the methodology investigated by Nakada based on silicon tethered chemistry. 107 Therefore, the first step to explore will be the silyl ether linkage of the secondary hydroxyl group with the appropriate silyl reagent followed by intramolecular alkylation of the lactam's enolate.

Our initial attempts for the formation of this TST relied on the commercial chloro(bromomethyl)dimethylsilane. It was observed that the rate of the silylation step is quite slow probably because the substrate 54 is sterically hindered. Thus, unusual heating was necessary to take the reaction to completion affording the protected alcohol 130 in 95% yield. 109 After several experiments, it was discovered that subjecting the lactam to LHMDS allowed the formation of the corresponding enolate which in turn undergoes nucleophilic substitution with the expected transfer of chirality. Upon this basic condition, the desired cyclic silyl ether 131 was obtained at best in 65%.

Unfortunately, basic hydrolysis of Si-O bond had occurred in variable and unavoidable amount forming back the intermediate 54.

Scheme 36: Formation of dimethyl-TST Knowing that the silicon's substituents can alter the steric and electronic characteristics of the alcohol protecting group contributing to their relative stability, 110 we embarked this sequence with bulkier silyl reagents expecting that it will ensure the required basic stability of the corresponding silyl ether. In order to reach a more stable silyl ether derivative, chloro(chloromethyl)diphenylsilane 133 was first considered due to its readily accessibility in spite of the fact that diphenyl substituted silyl reagents are not particularly known to form silyl ether with very high stability toward basic hydrolysis. Silane 133 was prepared through a Grignard addition of phenyl magnesium bromide solution on the trichloro(chloromethyl)silane in 93% yield. 111 Silylation ran smoothly yielding 66% of the protected alcohol 132 whereas it was noticed that this silyl ether is so sensitive to basic treatment. Protection of alcohols by TIPS group is known for their stability against basic treatment. 110,112 Thus, substituting the 2 groups on silicon with isopropyl can stand for improving the hydrolytic stability of the silylated alcohol. This corresponding silyl reagent, chloro(chloromethyl)diisopropylsilane 134, is not commercial and partially described in the literature. The preparation of this silyl reagent was done according to Gevorgyan procedure who described the iodo derivative. 113 The commercially available chlorodiisopropylsilane undergo nucleophilic substitution with chloromethyl lithium generated in situ which is followed by an oxidative chlorination. The volatile silyl reagent 134 was prepared with enough purity to be used without any further purification in a yield range from 85 to 94%.

Silylation of the secondary hydroxyl 54 using the prepared silyl reagent 134 afforded the corresponding silylated indolizidinone 135 in 85% yield. As a side product, the disiloxane 137 was Cl also isolated in a range of 5-15% depending on the quality of the used silyl reagent. The plausible explanation for the formation of this product 137 is due to the slow hydrolysis of the commercial diisopropylchlorosilane upon standing forming the corresponding dihydrodisiloxane. Upon the preparation of the silyl reagent, this dihydrodisiloxane is then oxidized to the dichlorodisiloxane 138 by TCCA.

Scheme 38: Synthesis of diisopropyl-TST With great satisfaction, exposing the lactam 135 to basic conditions (LHMDS) allowed the intramolecular cyclization 136 to run in 91% yield with no trace of Si-O hydrolysis. In order to get experimental evidence of the stereochemistry of the newly formed stereogenic center at C 6 of 136, coupling constants relative to H 6 were extracted. Due to the bicyclic nature of the silyloxy bridge, it was expected that this proton occupies an equatorial position. The four J values of H 6 were found to be all below 10 Hz indicating the occupancy of an equatorial position. 114 As predicted, exploiting the silicon tethered chemistry in our synthesis allowed the smooth successful installation of the C 6 -"methyl group equivalent" axially.

It is worthy to note that this result is, to the best of our knowledge, the second example of a stereoselective intramolecular alkylation reaction induced through a silyl link. Due to the high stability 114 (a) Karplus, M. J. Chem. Phys. Following the previous approach, 75 the lactam 136 was partially reduced using LiAlH 4 (commercial standardized ethereal solution) at low temperature to avoid the formation of tertiary amine as much as possible followed by the addition of formic acid. Surprisingly, this condition led to the isolation of 2 Me cyclized products as it was observed that acidic medium provokes the partial hydrolysis of Si-O bond.

Accordingly, both hydrolyzed 139 and unhydrolyzed 140 silyl tether were isolated in 68% and 13.6%

respectively. Regarding the problem of the complete reduction of lactam, we were pleased to find out that the tertiary amine 141 was obtained only in 9%. (Scheme 40)

Foreseeing that the presence of TST would avoid the reversible imine-enamine equilibrium and thereby preventing the epimerization of the C 6 stereogenic center, the unexpected hydrolysis of the silyl ether linker weakens this anticipation. Therefore, the stereochemical integrity of the C 6 chiral center of the tricyclic intermediate 139 was again evaluated. It should be proved that the hydrolysis of the silyl tether ring had occurred after the tricyclic ring system construction.

Once again, H 6 is expected to occupy an equatorial position in the chair conformation confirmed by the observed NOE signals between the axial protons; H 7 , H 8a and H 5 . Then, the J values extracted for the axial H 7 are all below 10 Hz (except for the 2 J) which is consistent to the fact that both H 6 and H 8 occupy an equatorial position. Fortunately, this 3-steps sequence is an efficient and effective track for the optimization of the previous approach and introduction of the desired stereochemistry. In addition, this NOE experiment (CDCl 3 , 500 MHz) performed for the formate 139 had verified the other stereochemistries so far introduced and allowed the determination of the inconsequential stereochemistry of C 4 . For the identification of the over-reduction ratio upon this step, isolation of the bicyclic tertiary amines was planned. Lactam 136 was subjected to 3 equiv of LiAlH 4 at RT resulting in the formation of the expected tertiary amine 144. Acid treatment led to the complete hydrolysis of the silyl ether linker forming the untethered tertiary amine 141 (Scheme 42). Again, the H 6 stereochemistry of 141 was confirmed by the coupling constant correlating it with axial H 5a (J H5a = 3.5, 11.3 Hz).

Scheme 42: Over-reduction of Lactam 136

At this stage, an intriguing observation has to be mentioned. By comparing the over-reduced amine 145 obtained by the proto-desilylation of the silylated amine 141 (see next part for the conditions)

with the previously isolated one As a consequence, the epimerization of the C 6 chiral center (compound 74) observed in the previous approach occurred even before the over-reduction step. In these conditions, epimerization of the iminium through the enamine is very unlikely in an aprotic solvent with even excess of hydride source

(2 equiv. of LAH were used). If epimerization occurs after the addition of formic acid, this implies that quenching the excess of LAH with formic acid led to the formation of an enough reducing agent toward iminium ion allowing the formation of the over-reduced product (Scheme 44). This assumption is further supported by the fact that formic acid can be used as a reducing agent for enamines at elevated temperature (100°C). 115 However, enamine reduction forming amine 74 had occurred at ambient temperature, so does aluminum catalyze this reduction step in the presence of formic acid?

No further experiments were performed in order to get more evidences on this puzzling observation.

At this stage, we can say that the order of the elementary steps of this cascade is not well defined yet.

Scheme 44: Suggested mechanism for the formation of amine 74 115 (a) Leonard, N. J.; Sauers, R. R. J Am Chem Soc On the other hand, it was further noticed that cyclization based on LAH reducing agent was irreproducible once the scale is increased as the corresponding over-reduced product 141 was isolated in at least 30%. Subsequently, our attention was turned from a too highly reactive reducing reagents to avoid as much as possible the over-reduction to uncyclized tertiary amine 141.

The titanium tetraisopropoxide/diphenylsilane reducing agent system, introduced by Buchwald, 116 was described in the literature to effectively allow the transformation of amide to aldehyde under mild conditions passing through the enamine intermediate. Treating our lactam 136 with this hydride source followed by the addition of formic acid resulted in the formation of a mixture of tricyclic systems; the olefinic product 146 as the major and the hydrolyzed formate 139 (Scheme 45).

Scheme 45: Buchwald's Conditions -Formic acid

It is proposed that the active reducing agent in this system being the titanium hydride-like complex that is formed as a result of the titanium tetraisopropoxide catalyst and the silane. Lactam is then inserted into this complex, and the titanium alkoxide intermediate is formed after the hydride transfer.

Acidic elimination of titanium oxide allows the formation of the iminium intermediate that is attacked with the double bond, as described before. According to our results, it was hypothesized that the olefinic product 146 would be the result of the early generation of the iminium intermediate through the departure of triisopropyltitanate as an enough leaving group, followed by the aza-Prins cyclization leading to the generation of the tertiary carbocation. Due to the absence of any efficient nucleophile in the reaction mixture at that stage (solvent is hexane), the carbocation is quenched by proton elimination.

To verify this expectation, the lactam 136 was subjected to the same reduction conditions but with no acid quenching. A 1:1 mixture of tertiary alcohol 142 and terminal double bond 147 was obtained with 7% of the tertiary amine 144 (Scheme 46). Therefore, probably the acidity of titanium provokes the earlier iminium formation. Despite that these conditions seems to strongly favor the formation of cyclized products with acceptable low percentage of over-reduced product, the presence of the double bond at early stage of the synthetic pathway is however undesirable as the subsequent planned steps included hydrogenation of a terminal double bond to install the remaining methyl group.

Depending on this result, a potentially less Lewis acidic reducing agent system should be applied as a way to avoid this earlier cyclization. as well as other amide reductive functionalization 118 that could be the answer for the required reactivity for our substrate. This system is based on the iridium(I) -tetramethyldisiloxane (TMDS) couple ensuring the partial reduction of lactam. In this case, the species resulting from the hydride addition is believed to exist in the reaction mixture as the corresponding silyloxy intermediate 148, stable enough not to spontaneously generate the iminium intermediate until the addition of formic acid driving the followed cyclization. In our case, a mixture of cyclized products 139 and 140 were isolated in 55% and 15% 117 Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. J. Chem. Eur. J. 2015, 21, 111-114. 118 + respectively differing only by the partial hydrolysis of the silyl ether linkage. The noteworthy result of these conditions is that the over-reduction of lactam can be controlled where the ratio of the tertiary amine 141 was drastically diminished to 1-2% (Scheme 47).

Further in the synthesis, this mixture of formates 139 and 140 was used unpurified without any consequences, even if it made the NMR analysis of the crude more complicated. However, analytical samples of 139 and 140 were obtained by silica gel chromatography allowing full characterization for each compound.

Scheme 47: Dixon's partial reduction and aza-Prins Cyclization This Aza-Prins reaction is expected to proceed through a plausible mechanism shown in Scheme 47.

Vaska's complex IrCl(CO)(PPh 3 ) 2 catalyzes efficiently the hydride transfer from the silane through an iridium hydride-like complex to reduce partially the lactam 136 forming the silyloxy intermediate. This silyloxy intermediate is believed to be enough stable in the reaction medium preventing the formation of the corresponding iminium and thus the possibility of over-reduction. The addition of the acid triggers the elimination of silanol forming the iminium intermediate, followed by the aza-Prins cyclization that lead to the construction of the tricyclic core of the natural product. The generated carbocation is then trapped by the formate ion.

IV. Unmasking of C 6 -axial methyl group

To release the C 6 -axial methyl group embedded in the structure of 139, the unactivated C(sp 3 )-SiR(i-Pr) 2 was subjected to the known proto-desilylation. 119 In order to define the best optimized conditions for a mild and efficient proto-desilylation reaction, a range of conditions were studied.

Si RO R i-Pr i-Pr X Si RO R i-Pr i-Pr X Y Si RO R i-Pr i-Pr - 2- X - Y - Penta Hexa Tetra H + H + R H R H
According to Woerpel, proto-desilylation of a bulky substituents-silyl moiety is effective with KO(t-Bu) and n-Bu 4 NF in a mixture of DMSO:THF (4:1) at 120°C. 122 Treating our silylated substrate 139 with the described conditions for 9 hours yielded the desired product 75 in 50% (Scheme 50A). The presence of the tert-butoxide seems to increase the electron density where silicon carbon bond is indeed highly more activated toward cleavage. The major unsolvable restriction of these conditions was the cleavage of the chiral auxiliary group in variable and unavoidable amount leaving behind the (R)-Stericol 55.

Extra addition of 5% of water to the reaction mixture led to the failure of the reaction. It seems that the proton source is internally from the TBAF solution that contains certain percentage of water. In an attempt to know the most susceptible bonds to be cleaved first, early quenching of the reaction was done (after 4h). It was noticed that this reaction passes through the intermediate 149 where desilylation of an isopropyl group occurs first while restoring the silyl-ether link and promoting saponification in basic medium (Scheme 50B).

Throughout the several optimization trials, it was observed that the reaction does not work with moderately aged bottle of TBAF/THF solution, and even sometimes with freshly new bottle. This behavior was related to the effect of the water percentage in TBAF solution on the desilylation reaction. Vaghefi et al. noted that too wet TBAF is the reason behind the failure of desilylation reactions where they recommend not using a TBAF solution exceeding 5% water content. 123 For the control of the water content in every reaction, we have subrogated the fluoride source with cesium fluoride accompanied with the addition of 3% water (v/v) in DMSO. These conditions appeared to us as the most practicable and reproducible reaction conditions so far studied.

For synthetic purpose, it was reasonable to think that running proto-desilylation of both formates 139 and 140 separately is not necessary and that the crude product of the aza-Prins reaction (see Scheme 47) could be used unpurified for this proto-desilylation step. Thus, the corresponding 2 steps-4 transformations cascade yielded the advanced alcohol intermediate 75 in 52% yield (Scheme 51).

Scheme 51: Aza-Prins cyclisation -protodesilylation sequence

V. Toward Alkaloid (-)-205B Retrosynthetically

Once the C 6 -axial methyl group is successfully installed, our attention was focused toward the final part of the synthetic pathway. The target alkaloid 1 was planned to be synthesized via the tricyclic intermediate 150 by sequential deoxygenation and regioselective dehydration forming the internal double bond. This advanced intermediate 150 can be obtained by the stereoselective hydrogenation affording the equatorial methyl group followed by chiral auxiliary group cleavage. The exomethylene group (151) in turn can be prepared from the secondary hydroxyl group (75) So, our focus was then directed toward the formation of the mesylated product 155. Using triethylamine as the base yielded a 0.2:1 mixture of the mesylated product 155 and the terminal olefin 156 respectively, from which olefin 156 was isolated in 48% (Scheme 55). This result was not surprising as these conditions were described in the literature to be an efficient method for the conversion of tertiary alcohol into olefin. 124 The strong base is responsible for the formation of the sulfene which is more reactive than MsCl thus reacting with tertiary alcohol allowing the formation of the kinetic olefin 156. As an attempt to slow down the formation of sulfene, reaction was carried out at 0°C for 1h. However, the ratio was only improved at best 0.36:1 of the desired mesylated product 155 and byproduct 156 respectively.

Even not expected, the adduct 156 is probably produced due to the reaction of the alcohol function with (methylsulfonyl)-methanesulfonate which is formed in situ based on sulfene intermediate. This kind of adducts has been scarcely reported in the literature. 125 Scheme 55: Mesylation using triethylamine as base 124 Yadav, J. S.; Mysorekar, S. V. Synthetic Communications Considering weaker base such as pyridine had solved the elimination problem, but the conversion of this reaction was low (30%) (Scheme 56). Prolonging the reaction time led to the deviation of the desired pathway allowing the formation of byproducts that are expected to correspond for the elimination of the mesylated group at RT.

Scheme 56: Mesylation using pyridine as base

To our knowledge, elimination reaction could be faster than the desired substitution with cyclohexyl carbocation. This was also mentioned by Smith for the substitution of the tosylate derivative 157 with a wide variety of nucleophiles that led majorly for the elimination product (Scheme 57A). 62 Furthermore, displacing the derived mesylate in a model compound 158 with the organocuprate nucleophile furnished the starting material (Scheme 57B), emphasizing more on the difficulty of the formation of the desired equatorial methyl group through this approach. Due to all the encountred difficulties within this pathway and having to undergo substitution on a six membered ring let us look further for other more promising approach for such transformation. ketone that was difficult to handle and store even with the precautions to keep it always at low temperature. During manipulation, TLC analysis indicated the consumption of the starting material 75, however NMR spectra of isolated products were most often complex. Even under less electrophilic oxidation conditions such as Dess-Martin periodinane, the ketone was not stable enough to be isolated.

Despite of this fact, ketone 153 was obtained only once allowing basic analytical characterization ( 1 H NMR and mass spectroscopy). Upon treating a well isolated ketone 153 with Wittig reagent at -30°C without any delay, the epimerized ketone 159 was isolated in 50% yield according to the first spectral analysis (Scheme 58A). In a sharp contrast, this epimerized ketone 159 seems to be more stable than our desired ketone 153 as it was purifiable over silica gel, easier to be handled and stored for several weeks without any noticed decomposition.

Because this encountered difficulty might be due to possible intrinsic instability of ketone 153, we attempted to test its reactivity. The isolated crude "expected ketone" was subjected to nucleophilic addition (Grignard and Shapiro reagents) immediately. Unfortunately, no expected products were detected (Scheme 58B). This allowed us to infer that the formed amino ketone 153 might face total decomposition upon the oxidation work-up.

Scheme 58: Swern Oxidation -Nucleophilic Addition sequence After these extensive trials for running oxidation that led most of the case to the isolation of unidentified materials, we came across an approach developed by Ireland who tackle with the same behavior with a series of ketones. 126 In this study, it was highlighted the difficulty of isolating ketones bearing electronegative substituents as they would be prone to hydration and/or decomposition. This problem of the high reactivity of the carbonyl compounds was overpassed by the direct addition of the subsequent reagent to the crude of Swern oxidation mixture with no isolation of ketone (Scheme 59).

This one pot strategy seems to be promising for the isolation of our desired olefin intermediate 151.

Scheme 59: One pot of Swern Oxidation -Nucleophilic Addition (Ireland Research)

Considering that Swern oxidation was effective and that previous difficulties came out from the isolation of the ketone 153, we wondered if a one pot-two steps procedure could be more rewarding.

In addition, to avoid the possible epimerization of the expected ketone 153 by strong basic nucleophile, we considered a methylenation agent mild enough to be used with epimerizable ketone.

We have considered Julia-Kocienski olefination as an efficient tool for the generation of alkene via the reaction of metallated heteroaryl sulfone with carbonyl compound. Recently, a new Julia reagent was described by Aissa that could fill our requirements; the TBT sulfone. 127 Moreover, the derived metallated TBT sulfone was proved to be the more resistant to self-condensation under basic conditions. 128 In this case, the direct addition of the premetallated TBT sulfone to the Swern oxidation mixture, once consumed all the starting alcohol, could overcome the previous difficulty. The first trial was carried out with THF being the solvent of both Swern oxidation and Wittig olefination (Scheme 60A). To our 126 Ireland, R. E.; Norbeck, D. W. J. Org. Chem. great satisfaction, the alkene 151 was isolated for the first time in 40% yield. However, we faced to the incompletion of the Swern oxidation in THF in spite of the several attempts. The remained alcohol 75 in basic medium reacts with the excess of TBTSO 2 Me forming the intermediate 164 in 0.26:1 ratio with respect to the alkene 151 and was isolated in 12% yield.

As the usual solvent of Swern oxidation is DCM, this one pot procedure was then tried using this solvent. Unfortunately, this solvent-change had affected the olefination step resulting in the formation of unidentified byproducts with alkene 151 as minor product. Therefore, after the complete formation of the ketone 153 in DCM (as noticed by TLC analysis), it was decided to perform solvent exchange (DCM to THF) followed by the addition of an excess of the freshly prepared solution of the premetallated sulfone in THF (Scheme 60B). 129 To our great satisfaction, this one pot reaction led only to the formation of the expected alkene 151 in 50% yield. As an attempt to improve the yield, Barbier-type procedure was applied where also 50% yield of the alkene 151 was obtained. However, it is important to note the irreproducibility of these conditions once the scale was increased.

A) B)

This olefination termed as "modified Julia reaction" was first described by Sylvestre Julia and coworkers 130 and then modified by Kociensky. 131 The mechanism is known to involve nucleophilic addition of the metallated sulfone on the carbonyl compound, followed by the irreversible Smiles rearrangement within the alkoxide intermediate. 132 In our case, we had faced to the reversibility of the initial addition of the metallated sulfone to our ketone. Thus, the efficiency of the formation of the olefin will depend on the position of the first equilibrium (Scheme 61).

Scheme 61: Julia-Kociensky Olefination Mechanism

Knowing that Smiles rearrangement requires RT to occur, quenching the reaction at -60°C allowed the isolation of the hydroxy sulfone derived from the intermediate 165 in 48% yield. Much to our surprise, subjecting this hydroxy sulfone to basic medium resulted in the formation of 1:0.25 mixture of the ketone 153 and the alkene 151 indicating that the equilibrium is in favor of the starting materials.

It was observed that the counter ion (Li + or Na + ) has no influence on the position of the equilibrium.

Thus, to favor the formation of the alkene 151, a high concentration of metallated TBT sulfone is required in order to shift the equilibrium forward and allowing the rearrangement to occur.

Due to the demand of the high equivalence of this expensive sulfone, olefination was attempted with 1-phenyl-1H-tetrazol-5-yl (PT) sulfone. 133 This sulfone was considered as it was reported that simple alkyl PT sulfone metallates added irreversibly to aldehyde. 128 In order to bypass this unfavorable reversible step, we re-considered the Wittig reagent due to its expected higher nucleophilicity. Treating the unisolated ketone with the corresponding phosphonium salt with NaHMDS as a base at -78°C (avoiding ketone epimerization) allowed the production of 40% of the olefin 151 (Scheme 62). The same irreproducibility problem was encountered with these conditions.

Note: Due to the partial stability of the alkene, it was subjected to pseudo-purification over silica gel.

Thus, the yield provided is estimated from the NMR of the alkene that is contaminated with Wittig reagent.

Scheme 62: One pot of Swern Oxidation -Wittig Olefination At this stage, several observations seemed to say that amino-ketone 153 could be more stable than expected so far and that the in situ formation of this ketone did not solve the problem completely. For example, running the same one pot reaction starting with a 1:0.09 mixture of alcohol 75 and over reduced alcohol 145, led to the isolation of a mixture of the corresponding alkenes 151 and 166 in a ratio of 1:0.66 respectively (Scheme 63). This can be a hint for the difference in stability of the 2 corresponding ketones indicating that the tricyclic ketone 153 is still subjected to decomposition even without isolation. In addition, the previous successful isolation of ketone 153 (with well analyzed NMR)

+

On the other hand, the isolation of the byproduct 170 after this one pot-2 steps transformation allowed us to hypothesize that earlier observed decomposition of the tertiary amino ketone might be due to Grob-type fragmentation triggered by an electrophilic activation during the Swern oxidation (Scheme 64). This kind of fragmentation is observed at this stage probably because the ketone might weaken the C-N bond increasing its susceptibility for cleavage. This fragmentation is known to mainly proceed through a concerted mechanism for which the orbitals should obey conformational requirements where anti-periplanarity alignment is required for maximum orbital overlap, but some stepwise Grob like fragmentation are also reported in the literature. 134 In our case, as the lone pair of the oxygen, the s-bond C 4 -C 5 and the s-bond C 5a -N are not parallel to each other, we expect that fragmentation occur in stepwise manner triggered by an electrophile species (E) during the Swern oxidation (Scheme 64).

Scheme 64: Grob-type Fragmentation Also, an indirect support to this expectation is the fact that Smith had characterized amino ketone-like substrate 22 in his synthetic approach without any mention to particular degradation. 62 Noteworthy, no tertiary hydroxyl group is present in his structure that could be engaged in a fragmentation process.

To confirm this assumption, Swern oxidation was ran on the acylated compound 173 which was prepared by a conventional protection-acylation-deprotection sequence from 75 (Scheme 65). Thanks to our expectation, ketone's stability improvement was observed where it was isolated in 74% yield (estimated from the NMR). This acylated amino ketone 174 was easier to handle and can be stored for several days but purification remains impossible. We expect that the stability might be further improved with other protecting groups. But for our synthetic purpose, this solution does not seem to be the best compromised due to the additional steps. This challenging oxidation of amino alcohol into amino carbonyl compounds was reported in the literature to be very difficult without the protection of the amine group. 135 This can emphasize that ketone's behavior is a reflection of the basicity and the conformation of the fixed nitrogen lone pair that interacts with the oxidant. To answer to this limitation, Iwabuchi 136 had developed a new mild direct route for this transformation that is based on nitroxyl radical/copper catalytic system with oxygen being the oxidant. A simplified mechanism of this reaction is given in Scheme 66. 137 Scheme 66: AZADO oxidation mechanism 135 (a) Geoghegan, K.; Evans, P. J. Org. Chem.

R 1 R 2 R N R OH 1/2 O 2 R N R O R 1 R 2 O OH H 2 O L n Cu I R 1 R 2 O Cu II L n R N R OH R N R O
Applying these conditions to our amino alcohol 75 led to the clean isolation of the ketone 153 and then used later for the Wittig olefination step without any further purification. Again, due to the partial stability of the alkene over silica, the crude was subjected to pseudo-purification allowing the isolation of alkene being contaminated with some Wittig reagent (45% yield estimated from NMR). Therefore, after the wide optimization conditions trials, it was found that AZADO oxidation followed by Wittig olefination are the best fit conditions for the reproducible production of the desired alkene 151 (Scheme 67).

Scheme 67: AZADO oxidation -Wittig Olefination

The NOE experiment (CDCl 3 , 500 MHz) was performed on the alkene intermediate 151 to confirm that no epimerization occurs upon methylenation. The space correlations between the axials; H 5 -H 8a and H 3 -H 8a emphasize the integrity of C 8a stereochemistry.

b. Hydrogenation

Affording the equatorial methyl group at C 8 was first planned by subjecting the exocyclic alkene 151 to hydrogenation under standard pressure. As described by Smith on a related structure, 62 hydrogenation was expected to occur through the most accessible face leading to isomer 152. However, hydrogenation at normal pressure and temperature was not efficient enough to reduce the double bond. Thus, the hydrogenation was attempted at higher pressure-6 bars (Scheme 68). The NMR analysis showed that hydrogenation proceeded with poor selectivity producing an inseparable equimolar mixture of both epimers (152 and 175). Differentiation between both isomers is based on the coupling constant Taking the advantage of avoiding hydrogen gas manipulation, affording the alkane was sought by NaBH 4 -NiCl 2 .6H 2 O mixture system according to a recently described procedure. 138 Reduction of alkenes 151 are catalyzed by the in situ generated Ni(0) nanoparticles, where PEG-300 ensures their stabilization. In these conditions, a 4:1 mixture of isomers was obtained (Scheme 69). However, spectral analysis showed that the major isomer would be of axial methyl group (175). The high diastereofacial selectivity is believed to be controlled by the steric hindrance where C 6 axial methyl group could direct the approach of the catalyst which seems not to favor the desired equatorial methyl position 152.

Scheme 69: Ni(0) NPs catalyzed Reduction of Methylene Thus, hydrogenation of the exomethylene using common standard methods yielded at best 1:1 mixture of both isomers. This behavior is in a sharp contrast to the case described by Smith and could be the result of the presence of the axial methyl group at C 6 which was absent in Smith's case. This methyl group could bring enough steric hindrance to reduce the rate of the axial hydrogen delivery due to the 1,3-diaxial interaction. Thus, having control over the stereochemistry is challenging as to deliver the hydrogen axially without any intrinsic steric bias of the substrate in order to get the expected methyl group equatorially. Therefore, it is prerequisite to afford a hydrogenation transfer favoring the thermodynamic orientation of this methyl group.

Quite recently, Shenvi and co-workers had reported a procedure to afford the thermodynamically favored configuration selectively under mild reaction conditions and with lower substrate-reagent steric interaction directivity (Scheme 70). 139 This stereoselective hydrogenation proceeds through the generation of a tertiary carbon radical via the hydrogen atom transfer (HAT) from an in situ formed metal hydride to an alkene. The resulting tertiary radical is then trapped by a second HAT. As the stereochemical integrity of the tertiary radical is not defined, this second HAT will favor the formation of the more stable isomer. The active species of this transformation "HMn(dpm) 2 " is formed as an effect of the reducing agent PhSiH 3 on the Mn 3+ catalyst provided. In addition, the tert-butyl hydroperoxide (TBHP) is added as a re-oxidant to turn over the manganese catalyst from Mn 2+ to Mn 3+ . This scenario seems to be well suited to our desired stereoselective delivery of hydrogens favoring the thermodynamically isomer 151. With great satisfaction, subjecting our alkene 151 to HAT hydrogenation allowed the isolation of the desired isomer 152 in 85% yield as one diastereoisomer, where the other isomer was not detected on the NMR of the crude material (Scheme 71).

Scheme 71: HAT Reduction of Alkene 151

VII. Completion of Total Synthesis of (-)-205B

With the tricyclic product 152 in hand with full stereochemistry being introduced, the next step was the cleavage of the chiral auxiliary group. As expected, treatment of a DCM solution of 152 with TFA at 0°C afforded the diol 150 in 75% yield (Scheme 72).

The following considered task was the deoxygenation of the secondary hydroxyl group. The standard Barton-McCombie procedure consists of converting the hydroxyl to xanthate followed by radical tinbased mechanism for the reduction step. 140 However, organotin compounds are known for their bad smell, difficulty to be chromatographically separated and their toxicity which is not applicable for expected biological active compounds. For these reasons, organotin reducing agents should be avoided. A lot of research efforts had been done to find suitable organosilanes as alternatives for the hydrogen donor. The used organosilane should be of Si-H bond weak enough to expedite the hydrogen atom abstraction rate. It was found that tris(trimethylsilyl)silane have a high hydrogen donation ability, 141 also it is not toxic and very unpolar thus can be separated easily by purification. Curr. Org. Synth. 2014,11,. (c) Baguley, P. A.; Walton, J. C. Angew. Chem. Int. Ed. 1998, 37, 3072-3082. 141 AIBN as the radical initiator to give the deoxygenated product 177 in almost quantitative yield following a published procedure. 142 (Scheme 72)

Targeting the final alkaloid (-)-205B, the tertiary alcohol 177 should be dehydrated chemoselectively.

According to Toyooka's work, 61 dehydration was done using PTSA in refluxing benzene allowing the formation of a 6:1 mixture of both isomers 1 and 178, from which the desired internal olefin 1 was isolated in 63% yield (Scheme 72).

Scheme 72: Toward Alkaloid (-)-205B

In comparison with the analytical data provided in the literature for the alkaloid (-)-205B 1, our data perfectly match for the 1 H, 13 C NMR, IR and mass spectroscopy (HRMS). (Table 2)

Regarding the optical rotation, the reported value [α] 20 D is -8.3 (c 0.12, CHCl 3 ). However, the measured optical rotation for our synthesized alkaloid is +2.6 (c 0.31, CHCl 3 ). We attribute this difference to impurities that might present in our substrate affecting the measurement. Further purification is under progress. In tandem with the total synthesis, a novel synthetic methodology was developed focusing on the stereo-directed alkylation via temporary silyl tether that comes up for a difficulty encountered within the synthesis of the alkaloid 205B. Investigation of this new methodology and expansion is currently under progress in order to define its scope and limitation. Thereafter, the synthesis of the targeted alkaloid 1 was accomplished through efficient transformations for the construction of the tricyclic core and the introduction of the remaining stereocenters. This sequence proceeded efficiently through 23 steps from the chiral auxiliary 55 with an overall yield of 1.3% thus placing this approach among the most effective pathways described so far.

Perspectives

The synthetic efforts covered in this thesis were embarked upon not just for their opportunity as challenging targets but also for their relevance to other fields. Neurotoxic activity had inspired our work toward alkaloid (-)-205B.

As discussed in the first chapters, this rare alkaloid 1 belongs to a family of natural products that likely possess potent and diverse neurological functions. Therefore, we look forward to exploring the pharmacological profile of the synthetic (-)-205B. In particular, its selective activity toward the a 7 nAChR will be studied in collaboration with Dr. Christophe Moreau at the Institut de Biologie Structurale in Grenoble. Also, its ability to modulate the toxicity of Ab peptide will be evaluated in collaboration with Dr. Mireille Albrieux at Grenoble Institute of Neurosciences.

On the other hand, the valuable efficient strategy applied for the synthesis of the advanced intermediate 54 can be applicable for the total synthesis of natural products bearing indolizidine core.

(Figure 20) Furthermore, this new synthetic pathway explores new chemistry that allows the access not only to the target alkaloid but also to a wide scope of isomers. To illustrate, the 8-epi 179 can be readily synthesized by applying the standard hydrogenation conditions allowing the installation of the axial C 8 -methyl group. Also, following the previous approach to introduce the C 6 -methyl group axially In addition, this strategy also allows the stereoselective synthesis of several analogs of this alkaloid.

For instance, introduction of new functional groups can be done via the secondary hydroxyl group of 150.

Perspectives

Le travail développé dans cette thèse n'a pas été motivé uniquement par le défit synthétique représenté par la structure particulière de la molécule cible mais aussi pour l'intérêt de celle-ci dans un autre domaine. En particulier, l'activité neurotoxique de sa source naturelle a également contribué à notre intérêt vis à vis de l'alcaloïde (-)-205B.

Comme mentionné dans les premiers chapitres, cet alcaloïde rare fait partie de la famille des produits naturels pressenties comme possédant des fonctions neurologiques fortes et variées. Ainsi, nous envisageons d'explorer une partie du profil neurologique de notre alcaloïde synthétisé. En particulier, son activité sélective vis à vis des récepteurs nicotiniques de type a 7 sera étudié en collaboration avec le Dr. Christophe Moreau de l'Institut de Biologie Structurale de Grenoble, et son effet de modulation de la toxicité du peptide Ab sera évaluée en collaboration avec le Dr. Mireille Albrieux l'Institut des Neurosciences de Grenoble. D'autre part, la stratégie efficace mise en oeuvre pour la synthèse de l'intermédiaire avancé 54 peut s'appliquer à la synthèse totale de produits naturels portant le noyau indolizidine (Figure 20). Chromatography. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.20 mm E. Merck silica gel plates (60F-254), using UV light as the visualizing agent and by KMnO 4 and heat as developing agents. Purifications were performed by column chromatography using silica gel 60 M (0.04-0.063 mm).

Infrared spectra (IR) were performed using Fourier Transform Infrared Spectrometer (FT/IR-4100) and were recorded as neat samples placed between NaCl pellets.

Optical rotations (𝜶 𝑫 𝟐𝟎 ) were recorded on a Perkin Elmer 341 polarimeter.

Melting points (M p ) were measured on Büchi 510 melting point apparatus and are uncorrected.

Mass spectra (MS). Electrospray ionization (ESI) mass spectra were obtained on an Esquire 3000

Plus Bruker Daltonis instrument with a nanospray inlet. High-resolution mass spectra (HRMS) were carried out on an ESI/QTOF with the Waters Xevo G2-S QTof device. Analyses were performed by the analytical service of Institut de Chimie Molećulaire de Grenoble (ICMG).

500 spectrometers where chemical shifts are reported as δ values in parts per million (ppm) relative to internal chloroform (δ 7.26 for 1 H and δ 77.0 for 13 C) or benzene (δ 7.16 for 1 H and δ 128.39 for 13 C). As to avoid the quaternization of tertiary amine with chloroform causing broadening of NMR spectra, a drop of 10% NaOD was added. All coupling constants are given in hertz (Hz) and are calculated using the methods described by Hoye et al. 143 . The following abbreviations were used to explain NMR peak multiplicities: s= singlet, d= doublet, dd= doublet of doublet, t= triplet, q= quartet, sept= septet, m= multiplet, br= broad, app= apparent.

NB: Analytical data of some compounds are under progress.

143 (a) Hoye, T. R.; Hanson, P. R.; Vyvyan, J. R. J. Org. Chem. (R, E)-2-(1-(1,2-Dichlorovinyl)oxy)ethyl)-1,3,5-triisopropylbenzene (56). In an argon flushed flask, a 30% suspension of potassium hydride in mineral oil (21.4 g, 160 mmol, 2.3 equiv) was washed three times with pentane. A solution of (R)-1-(2,4,6-triisopropylphenyl)ethanol 55 (16.7 g, 67.2 mmol, 1.0 equiv) in 200 ml THF was then added slowly to the KH suspension in 100 ml of dry THF. Also, 2 drops of MeOH was added to catalyze the reaction. The reaction mixture was stirred for 30 min at 0°C then 2h at room temperature. After cooling to -50°C, trichloroethylene (8.2 ml, 91.3 mmol, 1.3 equiv) was added dropwise. The reaction was then allowed to warm to room temperature over 4h and carefully quenched by methanol at 0°C (H 2 evolution). Extraction was then done after diluting the solution with pentane and washing with an aqueous solution of NH 4 Cl. The obtained organic phase was dried over MgSO 4 and concentrated in vacuo to leave 24.5 g of crude material. Purification of the crude product over deactivated silica (100% cyclohexane) produced 17.5 g of pure product 56 (76%). Analytical data are in agreement with those reported in the literature. 76 IR (film): ν 3087, 1624, 1612, 1081, 1045 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.05 (s, 2H), 6.00 (q, J= 6.8 Hz, 1H), 5.60 (s, 1H), 3.15-3.75 (m, 2H), 2.90 (sept, J= 6.9 Hz,1H), 1.70 (d, J= 6.9 Hz, 3H), 1.20-1.35 (m, 18H).

MS (ESI): m/z 343 and 341 (M + ), 248, 231 (100%).

3-Iodo-2-methylprop-1-ene (S1). The commercially available methyl allyl chloride (15 ml, 153 mmol, 1.0 equiv) was mixed with sodium iodide (29.0 g, 193.5 mmol, 1.3 equiv) in acetone (30 ml). The mixture was refluxed for 3h followed by the addition of water and extraction with pentane. The organic layer was then washed with Na 2 S 2 O 5 (1M) then with water and dried over MgSO 4 . Pentane was then removed by gentle distillation over copper through a vigreux column to yield quantitatively 31.2 g of crude pale yellow product S1 which is stored over the copper turnings. (R)-1,3,5-Triisopropyl-2-(1-((4-methylpent-4-en-1-ynl)oxy)ethyl)benzene (57). A solution of n-butyl lithium in hexane (49.7 ml, 2.5 M, 124.25 mmol, 2.5 equiv) was added dropwise to a solution of dichloro enol ether 56 (17.1 g, 49.8 mmol, 1.0 equiv) in 360 ml dry THF at -90°C. Once the reaction was warmed to -40 °C, allyl iodide S1 (15.4 ml, 143.3 mmol, 2.9 equiv) was added dropwise followed by addition of HMPA (39 ml, 224.16 mmol, 4.5 equiv). The reaction mixture was then allowed to warm to 0°C over 3h and the mixture was poured to cold NH 4 Cl and cold pentane. The aqueous layer was extracted 3 times with cold pentane and the combined organic phase was washed with cold water. The organic layer was dried over MgSO 4 . The mixture was concentrated in vacuo at 0/+5°C to give of 17.2 g of crude product 57 which was used further without any purification.

IR (film): ν 2998, 2926, 2807, 2268, 1631, 1460, 1299, 1195 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.02 (s, 2H), 5.68 (q, J= 6.9 Hz, 1H), 4.72 (br s, 1H), 4.64 (br s, 1H), 3.25-3.45 (m, 2H), 2.82-2.91 (m, 1H), 2.74-2.75 (m, 2H), 1.72 (d, J= 6.9 Hz, 3H), 1.59-1.60 (m, 3H), 1.23-1.28 (m, 18H).

(R, Z)-1,3,5-Triisopropyl-2-(1-((4-methylpenta-1,4-dienyl)oxy)ethyl)benzene (58). To a solution of crude ynol ether 57 (17.2 g, 52.7 mmol, 1.0 equiv) in 79 ml dry DMF at 0°C, Pd/BaSO 4 (10%, 6.6 g) and ethylene diamine (1.8 ml, 26.9 mmol, 0.5 equiv) were added. The flask was flushed with vacuum before stirring under hydrogen atmosphere for 10 min at room temperature. Then, 1-hexene (17.3 ml, 139.4 mmol, 2.6 equiv) was added dropwise and the reaction was stirred at room temperature until the complete disappearance of the IR absorbance at ~2270 cm -1 . The mixture was then diluted with pentane and filtered over celite. Then the filtrate was washed with water and brine Zn-Cu Couple Preparation. Zinc powder (20.1 g) was agitated with 100 ml of 10% hydrochloric acid for 15 min. The obtained suspension was filtered, and the zinc was washed 2 times with 100 ml acetone and 2 times with 100 ml Et 2 O to produce 13.792 g of activated zinc. A suspension of the activated zinc (13.792 g, 210.95 mmol) in 50 ml of water is degassed with argon for 15 minutes and then treated with hydrated copper sulfate CuSO 4 .5H 2 O (3.86 g, 15.2 mmol) and lead chloride PbCl 2 (0.31 g, 1.11 mmol). Degassing is continued for 45 minutes. Filtration was then done under argon and the obtained solid was washed with 200 ml of water and 200 ml of acetone already degassed with argon. The Zn-Cu couple obtained (13.6 g) is dried under vacuum for 5 hours and stored under an inert atmosphere. 62). Freshly distilled trichloroacetyl chloride (5.5 ml, 49.3 mmol, 1.1 equiv) was added dropwise to a solution of crude enol ether 58 (14.6 g, 44.4 mmol, 1.0 equiv) and prepared Zn-Cu (22 g) in 265 ml of dry Et 2 O at room temperature. During this addition, sonication was done 3-4 times. The reaction

(3R,4S)-2,2-Dichloro-4-(2-methylallyl)-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)cyclobutan-1-one (
O Me CH 2 Me O Cl Cl i-Pr i-Pr i-Pr
was followed by TLC until disappearance of the starting material and then diluted with pentane and stirred for 10 min. The mixture was then filtered over celite and concentrated under reduced pressure.

Dilution with pentane and concentration were repeated until turbidity is disappeared (all zinc chloride was removed). 20.1 g of crude product 62 was obtained and used for the next step without any further purification. Analytical data are in agreement with those reported in the literature. 75 IR (film): ν 2961, 2922, 2870, 1808, 1608, 1460 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.09 (d, J= 2 Hz, 1H), 7.02 (d, J= 2 Hz, 1H), 5.47 (q, J= 6.8 Hz, 1H), 4.82 (br s, 1H), 4.79 (br s, 1H), 4.36 (d, J= 9.3 Hz, 1H), 3.86 (sept, J= 6.9 Hz, 1H), 3.64-3.73 (m, 1H), 3.31 (sept, J= 6.9 Hz, 1H), 2.89 (sept, J= 6.9 Hz, 1H), 2.43-2.62 (m, 2H), 1.74 (s, 3H), 1.69 (d, J= 6.8 Hz, 3H), 1.15-1.37 (m, 18H).

13 C NMR (CDCl 3 , 100 MHz): δ 195.9 (C), 149.2 (C), 148.4 (C), 147.2 (C), 141.8 (C), 130.8 (C), 123.5 (CH 3 ), 120.9 (CH 3 ), 112.8 (CH 2 ), 77.5 (CH 3 ), 73.7 (CH 3 ), 57.5 (CH 3 ), 34.2 (CH 2 ), 33.2 (CH 2 ), 28.6 (CH 3 ), 28.5 (CH 3 ), 25.4 (CH 3 ), 24.1 (CH 3 ), 23.9 (CH 3 ), 22.5 (CH 3 ).

Ethyl N-((mesitylsulfonyl)oxy)acetimidate (S2). To a solution of ethyl N-hydroxy acetimide (8.37 g, 81.1 mmol, 1.0 equiv) in 53 ml of DMF was added dropwise 22.7 ml of triethyl amine (163.17 mmol, 2.0 equiv) under argon. The reaction mixture was cooled to 0°C followed by portionwise addition of O-mesitylene sulfonyl chloride (17.75 g, 81.16 mmol, 1.0 equiv). The mixture was stirred vigorously for 1h. It was then diluted with EtOAc (200 ml) and washed with water (3*150 ml) and brine (150 ml).

The aqueous layer was extracted three times with EtOAc followed by drying the combined organic layers over MgSO 4 . Concentration under reduced pressure afforded 23.1 g of ethyl N-((mesitylsulfonyl)oxy)acetimidate S2 which was used further without purification. Analytical data are in agreement with those reported in the literature. 86c IR (film): ν 2988, 2947, 1682, 1649, 1608 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 6.96 (s, 2H), 3.90 (q, J= 7.1 Hz, 2H), 2.64 (s, 6H), 2.31 (s, 3H), 2.03 (s, 3H), 1.18 (t, J= 7.1 Hz, 3H). O-(mesitylsulfonyl)hydroxylamine (MSH) (S3). 144 70% perchloric acid (18 mL, 208.7 mmol, 2.6 equiv) was added dropwise to a solution of crude ethyl N-((mesitylsulfonyl)oxy)acetimidate S2 (23.1 g, 81.1 mmol, 1.0 equiv) in 34 ml dioxane at 0°C. The resulting mixture was strongly stirred at 0°C for 1h30 min and then 50g of ice, 250 ml of water and 250 ml of Et 2 O were added. The organic layer was washed again with water and then neutralized with K 2 CO 3 for 2 min. After filtration, the filtrate was concentrated under reduced pressure to a total volume of ~70-75 ml. Then ~150 ml of cold pentane was added, and crystallization started immediately. The flask was then kept at -40°C overnight to ensure complete crystallization. Filtration furnished 16.7 g of MSH S3 as white crystals (95.6 % over 2 steps). Analytical data are in agreement with those reported in the literature. 86c IR (film): ν 3339, 2979, 2940, 1610 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.00 (s, 2H), 4.86 (br. s, 2H), 2.64 (s, 6H), 2.32 (s, 3H). 63). To a solution of crude cyclobutanone 62 (20.1 g, 45.7 mmol, 1.0 equiv) in 370 ml of dry dichloromethane was added O-mesitylenesulfonylhydroxylamine S3 (34.1 g, 158.4 mmol, 3.5 equiv) portionwise at room temperature, accompanied with a small amount of sodium sulfate. The reaction was followed by IR until the disappearance of the absorption peak at ~1806 cm -1 . After filtration of the mixture over celite, the filtrate was concentrated under reduced pressure. The remained MSH was removed by dissolving the residue in 180 ml of toluene and passing the solution over basic alumina (590 ml) and eluted with methanol. After concentrating the combined fractions under reduced pressure, the residue was triturated with DCM followed by filtration through celite and evaporation in 144 It is reported that MSH decomposes violently once dried thoroughly under vacuum at RT: Mendiola, J.; Rincon, J. A. R.; Mateos, C.; Soriano, J. F.; de Frutos, O. S.; Niemeier, J. K.; Davis, E. M. Org. Process Res. Dev. 1 H NMR (CDCl 3 , 400 MHz): δ 7.07 (d, J= 1.9 Hz, 1H), 6.98 (d, J= 1.9 Hz, 1H), 5.67 (q, J= 6.9 Hz, 1H), 4.88 (br s, 1H), 4.71 (br s, 1H), 4.50 (d, J= 7.3 Hz, 1H), 3.89 (sept, J= 6.8 Hz, 1H), 3.72-3.80 (m, 1H), 3.36 (sept, J= 6.8 Hz, 1H), 2.86 (sept, J= 6.8 Hz, 1H), 2.59-2.63 (m, 1H), 2.27-2.31 (m, 1H), 1.71 (d, J= 6.9 Hz, 3H), 1.68 (s, 3H), 1.14-1.31 (m, 18H). (CH 3 ), 24.8 (CH 3 ), 22.8 (CH 3 ), 21.8 (CH 3 ), 21.1 (CH 3 ), 20.9 (CH 3 ), 20.8 (CH 3 ).

(4R,5S)-3,3-Dichloro-5-(2-methylallyl)-4-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)pyrrolidin-2-one (
(4S,5S)-5-(2-Methylallyl)-4-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)pyrrolidin-2-one (64). A mixture of crude dichlorolactam 63 (20.6 g, 21.21 mmol) and Zn-Cu couple (20.9 g) in 365 ml of MeOH saturated with NH 4 Cl was stirred at room temperature for 2h and then refluxed for 5h. After filtration over celite and evaporation under reduced pressure, the obtained residue was dissolved in DCM and washed with water and brine. The organic phase was dried over MgSO 4 and concentrated in vacuo to give 17.4 g of crude material. Purification over silica gel with 0% ® 5% MeOH NH3 /DCM as eluting system to produce 9.31 g of pure lactam 64 (48.5% over 5 steps/86.5% per step). Analytical data are in agreement with those reported in the literature. 75 M p = 118-119 °C.

[α] 20 D +76.1 (c 0.585, CHCl 3 ). 1 H NMR (CDCl 3 , 400 MHz): δ 7.07 (s, 1H), 6.97 (s, 1H), 5.09 (q, J= 6.8 Hz, 1H), 4.82 (s, 1H), 4.75 (s, 1H), 4.18 (ddd, J= 6.8 Hz, 1H), 3.90 (sept, J= 6.5 Hz, 1H), 3.78 (ddd, J=10.6, 7.0, 2.8 Hz, 1H), 3.18 (sept, J= 6.9 Hz, 1H), 2.87 (sept, J= 6.9 Hz, 1H), 2.17-2.60 (m, 4H), 1.71 (s, 3H), 1.56 (d, J= 6.8 Hz, 3H), 1.19-1.32 (m, 18H). tert-Butyl

(2S,3S)-2-(2-methylallyl)-5-oxo-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)pyrrolidine-1- carboxylate (65).
To a solution of lactam 64 (9.2 g, 23.8 mmol, 1.0 equiv) in 60 ml dry dichloromethane at 0°C were added Et 3 N (4 ml, 28.7 mmol, 1.2 equiv), (Boc) 2 O (10.6 g, 48.6 mmol, 2 equiv) in 20 ml of dry dichloromethane and DMAP (3.6 g, 29.5 mmol, 1.3 equiv). The reaction was stirred first 5 min at 0°C then 2h at RT. After checking the disappearance of starting material by TLC, the reaction mixture was diluted with dichloromethane and quenched with saturated NH 4 Cl. The organic layer was washed 3 times with HCl (1M) and 1 time with saturated NaHCO 3 , followed by drying it over MgSO 4 and evaporating under reducing pressure. The excess of Boc anhydride was removed at 0.2 mbar, 50°C for 1h to yield 10.43 g of pure Boc-lactam 65 (90% yield). Analytical data are in agreement with those reported in the literature. 75 M p = 160-161 °C.

[α] 20 D +101.0 (c 0.49, CHCl 3 ). (CH 2 ), 34.1 (CH 3 ), 28.0 (CH 3 ), 27.9 (CH 3 ), 25.1 (CH 3 ), 24.0 (CH 3 ), 23.2 (CH 3 ), 22.8 (CH 3 ).

MS (ESI): m/z 508 (MNa + , 100%), 231.

tert-Butyl (2S,3S)-5-hydroxy-2-(2-methylallyl)-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)pyrrolidine-1- carboxylate (S4).
A solution of 1 M LiBHEt 3 in THF (super-hydride) (30.5 ml, 30.5 mmol, 1.4 equiv)

was added to a solution of Boc-lactam 65 (10.4 g, 21.4 mmol, 1.0 equiv) in 70 ml of THF at -94°C.

The reaction mixture was stirred for 1h15min while maintaining temperature below -70°C. A solution of sodium bicarbonate (85 ml) was added slowly followed by 2h stirring till the temperature reached 0°C. Then, H 2 O 2 (30% solution, 15 ml) was added at 0°C and the reaction was stirred at RT for 30 min. After dilution with Et 2 O, the aqueous layer was washed 3 times with Et 2 O, dried over MgSO 4 and evaporated under reduced pressure to give 12.6 g of crude hemiaminal product S4. Analytical data are in agreement with those reported in the literature. 75 IR (film): ν 3448, 2962, 2931, 2869, 1786, 1753, 1681, 1608, 1458, 1392, 1367, 1304, 1255 (CH 2 ), 36.4 (CH 2 ), 34.1 (CH 3 ), 28.2 (CH 3 ), 27.9 (CH 3 ), 24.9 (CH 3 ), 23.3 (CH 3 ), 22.8 (CH 3 ). To a solution of crude hemiaminal S4 (12.6 g, 25.83 mmol, 1.0 equiv) in 70 ml of 2,2-dimethoxypropane at 0°C was added camphorsulfonic acid (2.5 g, 10.8 mmol, 0.4 equiv) and the reaction was stirred at this temperature for 1h30min. The reaction was followed by TLC then diluted with Et 2 O and quenched with NaHCO 3 . The aqueous layer was washed again with Et 2 O and the combined organic layers were dried over MgSO 4 and evaporated under reduced pressure. The excess of dimethoxy propane was removed at 0.2 mbar at RT for 1h30min to yield 12.2 g of crude hemiaminal derivative 66. Analytical data are in agreement with those reported in the literature. 75 IR (film): ν 2962, 2869, 1702, 1607, 1456, 1390, 1367, 1167, 1098 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.04 (s, 1H), 6.95 (s, 1H), 5.05-5.20 (m, 1H), 5.03 (q, J= 6.8 Hz, 1H), 4.75 (br s, 1H), 4.72 (br s, 1H), 3.79-3.92 (br m, 3H), 3.35-3.39 (m, 3H), 3.10-3.30 (br m, 1H), 2.86 (sept, J= 6.9 Hz, 1H), 2.56-2.70 (m, 2H), 2.28-2.31 (m, 2H), 1.73 (br s, 3H), 1.48-1.53 (m, 3H), 1.39-1.43 (m, 9H), 1.18-1.32 (m, 18H). (CH 2 ), 37.3 (CH 2 ), 34.1 (CH), 29.3 (CH 3 ), 28.5(CH 3 ), 28.2 (CH 3 ), 24.9 (CH 3 ), 24.0 (CH 3 ).

MS (DCI, NH 3 + isobutane): m/z 502 (MH + ), 472, 431, 372, 231.

NBoc OMe O Me CH 2 Me i-Pr i-Pr i-Pr tert-Butyl (2S,3S,5R)-2-(2-methylallyl)-5-((R)-5-oxo-2,5-dihydrofuran-2-yl)-3-((R)-1-(2,4,6-triisopropyl phenyl)ethoxy)pyrrolidine-1-carboxylate (67a).
To a solution of crude hemiaminal derivative 66 (12.2 g, 24.32 mmol, 1.0 equiv) in 330 ml dichloromethane were added dropwise 2-(trimethylsiloxy) furan (8.5 ml, 50.54 mmol, 2.0 equiv) and BF 3 .Et 2 O (5.4 ml, 43.75 mmol, 1.8 equiv) at -95°C. The reaction mixture was stirred 2h and the temperature was kept below -90°C. The reaction mixture was followed by TLC then diluted with dichloromethane and quenched with saturated NaHCO 3 . The aqueous layer was washed with DCM (3 times) and the combined organic layers were dried over MgSO 4 and evaporated under reduced pressure. The excess of furanone was removed at 0.2 torr at 30 °C for 2-3h to yield 15.1 g of crude butenolide. Elution over silica gel (700 ml) with 10% EtOAc/cyclohexane yielded 7.55 g of pure threo butenolide intermediate 67a over 3 steps (64%).

Analytical data are in agreement with those reported in the literature. 75 IR (film): ν 2961, 2926, 2868, 2869, 1762, 1692, 1611, 1457, 1387, 1367 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.09-7.23 (m, 1H), 7.03 (s, 1H), 6.94 (s, 1H), 5.50-5.90 (m, 2H), 4.98 (q, J= 6.8 Hz, 1H), 4.75 (s, 2H), 4.32-4.41 (m, 1H), 3.97 (q, J= 6.7 Hz, 1H), 3.74-3.90 (m, 2H), 3.00-3.15 (br m, 1H), 2.85 (sept, J= 6.9 Hz, 1H), 2.39-2.56 (m, 1H), 2.07-2.22 (m, 1H), 1.91-1.98 (m, 1H), 1.74-1.85 (m, 4H), 1.49 (d, J= 6.7 Hz, 3H), 1.41-1.45 (m, 9H), 1.10-1.31 (m, 18H). (CH), 54.9 (CH), 36.9 (CH), 34.0 (CH), 28.7 (CH 2 ), 28.6 (CH 2 ), 28.1 (CH), 28.1 (CH 3 ), 27.9 (CH 3 ), 26.5 (CH 3 ), 25.2 (CH 3 ), 24.8 (CH 3 ), 23.1 (CH 3 ).

MS (ESI): m/z 576.4 (MNa + , 100%).

NBoc O Me CH 2 Me O O H i-Pr i-Pr i-Pr tert-Butyl (2S,3S,5R)-2-(2-methylallyl)-5-((R)-5-oxotetrahydrofuran-2-yl)-3-((R)-1-(2,4,6-triisopropyl phenyl)ethoxy)pyrrolidine-1-carboxylate (68).
To a solution of butenolide 67a (7.31 g, 13.20 mmol, 1.0 equiv) in 175 ml MeOH at 0°C was added 2.5 g of CuCl 2 .2H 2 O (14.66 mmol, 1.1 equiv) and the mixture was stirred at 0°C for 5 min. Then, 6.4 g of sodium borohydride (169.18 mmol, 12.8 equiv)

was added portionwise over 2h. The reaction was followed by TLC and quenched with saturated NH 4 Cl. The aqueous layer was extracted 3 times with DCM and the combined organic layers were dried over MgSO 4 and evaporated under reduced pressure. Filtration over 10 ml silica gel provided 7.15 g of pure lactone 68 (97%) eluted with 100% DCM. Analytical data are in agreement with those reported in the literature. 75 M p = 148 °C.

[α] 20 D +81.7 (c 0.77, CHCl 3 ).

IR (film): ν 3063, 2962, 2922, 2868, 1783, 1694, 1607, 1458, 1392, 1369 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.05 (s, 1H), 6.94 (s, 1H), 5.20-5.30 (m, 1H), 5.07 (q, J= 6.8 Hz, 1H), 4.76 (s, 2H), 3.80-4.40 (m, 4H), 3.10-3.25 (br m, 1H), 2.85 (sept, J= 6.8 Hz, 1H), 1.88-2.60 (m, 8H), 1.77 (br s, 3H), 1.53 (d, J= 6.4 Hz, 3H), 1.40-1.45 (m, 9H), 1.15-1.30 (m, 18H). (CH), 34.1 (CH), 37.0 (CH 2 ), 28.6 (CH 2 ), 24.2 (CH 2 ), 28.5 (CH 3 ), 24.2 (CH 3 ), 23.9 (CH 3 ).

MS (ESI): m/z 578.4 (MNa + , 100%). To a solution of lactone 68 (7.15 g, 12.86 mmol, 1.0 equiv) in 100 ml DCM at 0°C were added 2,6-lutidine (6.7 ml, 57.53 mmol, 4.4 equiv) and TMSOTf (7.71 ml, 42.6 mmol, 3.3 equiv). The reaction mixture was stirred for 1h at 0°C and it was followed by TLC. Then quenching was done with saturated NH 4 Cl at 0°C and allowed to warm to RT. The reaction was then diluted with DCM and the aqueous layer was washed 3 times with DCM. The combined organic layers were washed further with saturated NaHCO 3 2 times. Drying over MgSO 4 followed by evaporation under reduced pressure afforded 6.54 g of amine 69 (contaminated with 2,6-lutidine), which is used for the next step without any further purification. Analytical data are in agreement with those reported in the literature. 75 IR (film): ν 2961, 2930, 2868, 1777, 1608, 1459, 1382, 1176 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.04 (s, 1H), 6.94 (s, 1H), 5.07 (q, J= 6.8 Hz, 1H), 4.74 (s, 1H), 4.66 (s, 1H), 4.41 (td, J= 5.6, 7.1 Hz, 1H), 3.70-3.98 (m, 3H), 3.51 (td, J= 5.6, 7.7 Hz, 1H), 3.15-3.30 (m, 1H) M p = 170-190 °C (decomposition).

[α] 20 D +66.5 (c 0.88, CHCl 3 ).

IR (film): ν 3348, 3074, 2961, 2922, 2869, 1614, 1461, 1410, 1370, 1326, 1210 cm -1 .

Cl

Si Cl Ph Ph mixture was then heated to reflux for 4 hours. The reaction mixture was filtered over celite and solvent was removed under reduced pressure to give a colorless oil. Addition of dry Et 2 O (4 ml), filtration over celite and evaporation were repeated until no more formation of white precipitate and left 1.56 g (93%) of colorless oil 133. Analytical data are in agreement with those reported in the literature. 132). To a solution of alcohol 54 (5.4 mg, 0.012 mmol, 1.0 equiv) in 300 µl of dry DCM were added Et 3 N (0.050 ml, 0.36 mmol, 30 equiv) and (chloromethyl)chlorodiphenylsilane (30.5 mg, 0.114 mmol, 9.5 equiv). The reaction mixture was stirred at 50°C in a sealed tube for 4.5h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with pentane to give 28.1 mg of crude material. Purification over silica gel (0-20% of EtOAc in pentane) gave 5.7 mg (66%) of 132 as colorless oil.

1 H NMR (CDCl 3 , 500 MHz): δ 7. 65-7.58 (m, 4H), 7.52-7.46 (m, 2H), 7.44-7.37 (m, 4H), 7.02 (s, 1H), 6.89 (s, 1H), 4.97 (q, J= 6.7 Hz, 1H), 4.65 (ddd, J= 6.6, 6.6, 7.8 Hz, 1H), 4.64 (s, 1H), 4.52 (s, 1H), 4.32 (ddd, J= 1.9, 1.9, 4.2 Hz, 1H), 4.05 (ddd, J= 6.2, 6.2, 7.4 Hz, 1H), 3.80 (ddd, J= 2.8, 7.5, 8.3 Hz, 1H), 3.84-3.72 (m, 1H), 3.30 (d, J= 2.1 Hz, 2H), 3.15-3.03 (m, 1H), 2.46 (ddd, J= 7.2, 11.7, 17.8 Hz, 1H), 2.34-2.23 (m, 2H), 2.22-2.15 (m, 2H), 1.90 (ddd, J= 6.0, 8.3, 12.5 Hz, 1H), 1.85 (dddd, J= 1.7, 4.2, 7.2, 13.6 Hz, 1H), 1.74 (dddd, J= 2.0, 7.3, 12.1, 13.9 Hz, 1H), 1.67 (s, 3H), 1.47 (d, J= 6.7 Hz, 3H), 1.31-1.12 (m, 18H). (Chloromethyl)diisopropylsilane (S5). To a solution of chlorodiisopropylsilane (3.8 ml, 22.3 mmol, 1.0 equiv) and chloroiodomethane (2.7 ml, 37 mmol, 1.6 equiv) in 30 ml of dry THF at -78°C, a solution of MeLi was added dropwise (1.6 M in Et 2 O, 22 ml, 35.2 mmol, 1.5 equiv). The reaction mixture was stirred for 3h as temperature increases from -78 °C to -20 °C and then allowed to stir at room temperature for 2h before quenching it with saturated NH 4 Cl solution. The aqueous layer was extracted 3 times with pentane. The combined organic layer was dried over anhydrous MgSO 4 and concentrated under reduced pressure to give 3.6 g of silane S5. Analytical data are in agreement with those reported in the literature. 113 1 H NMR (CDCl 3 , 400 MHz): δ 3.63 (quint, J= 2.5 Hz, 1H), 2.95 (d, J= 2.5 Hz, 2H), 1.13-1.21 (m, 2H), 1.07-1.12 (m, 12H).

Chloro(chloromethyl)diisopropylsilane (134). A solution of crude (chloromethyl)diisopropylsilane S5 (3.6 g, 21.9 mmol, 1.0 equiv) in 15 ml of dry DCM was added dropwise to a solution of TCCA (2.8 g, 12.0 mmol, 0.55 equiv) in 25 ml DCM at 0 °C under argon. The mixture was stirred for 1h at 0°C then allowed to warm to RT. After dilution with pentane, it was filtered through celite and then concentrated. This was repeated several times till no turbidity is observed (no TCCA remained) to yield 4.2 g of 134 (95% over 2 steps) as a colorless oil. The crude product (>95% purity) was used for the next step without further purification.

1 H NMR (CDCl 3 , 400 MHz): δ 3.03 (s, 2H), 1.38 (sept, J= 7.5 Hz, 2H), 1.14 (d, J= 7.5 Hz, 12H). 13 C NMR (CDCl 3 , 500 MHz): δ 26.2 (CH 2 ), 17.0 (2CH 3 ), 16.7 (2CH 3 ), 12.8 (2CH). 135). To a solution of indolizidinone 54 (925.0 mg, 2.03 mmol, 1.0 equiv) in 5 ml of dry DCM was added 680 mg of a chloro(chloromethyl)diisopropylsilane 134 (3.41 mmol, 1.7 equiv). Also, imidazole (300 mg, 4.40 mmol, 2.1 equiv) and DMAP (45 mg, 0.37 mmol, 0.18 equiv) were added and the solution was stirred at 60°C in a sealed tube for 2h. Additional 1.1 g of the silyl reagent 134 were added in 4-time portions with 2-hour intervals (5.52 mmol, 2.7 equiv). The reaction was followed with TLC until the disappearance of the starting material. Then it was quenched with water and brine, and the aqueous layer was extracted 3 times with pentane. The combined organic phases were dried over MgSO 4 and concentrated under reduced pressure to give 1.7 g of crude material which was purified over silica gel (0-20% EtOAc/cyclohexane) leaving 1.06 g of pure silyl ether 135 (85%), along with 100.0 mg of the siloxane byproduct 137 (7%).

Data for compound 135: IR (film): ν3582, 3274, 2959, 2868, 1645, 1458, 1070 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.03 (s, 1H), 6.92 (s, 1H), 5.01 (q, J= 6.6 Hz, 1H), 4.65 (s, 1H), 4.59 (ddd, J= 6.0, 6.0, 8.5 Hz, 1H), 4.53 (s, 1H), 4.32 (ddd, J= 1.7, 2.4, 4.2 Hz, 1H), 4.02 (ddd, J= 5.7, 6.0, 7.3 Hz, 1H), 3.83 (ddd, J= 2.4, 8.0, 8.0 Hz, 1H), 3.78-3.87 (m, 1H), 2.92 (s, 2H), 3.13 (sept, J= 6.9 Hz, 1H), 2.84 (sept, J= 6.9 Hz, 1H), 2.44 (ddd, J= 6.9, 12.1, 18.0 Hz, 1H), 2.32 (ddd, J= 1.6, 7.2, 18.0 Hz, 1H), 2.16-2.30 (m, 3H), 2.04 (dddd, J= 1.6, 4.2, 6.9, 13.9 Hz, 1H), 1.99 (dddd, J= 5.7, 8.0, 12.6 Hz, 1H), 1.86 (dddd, J= 1.7, 7.2, 12.1, 13.9 Hz, 1H), 1.67 (s, 3H), 1.50 (d, J= 6.6 Hz, 3H), 1.14-1.32 (m, 19H), 1.04-1.10 (m, 12H), 0.79 (m, 1H). (CH 3 ), 25.0 (CH 3 ), 24.8 (CH 3 ), 24.1 (CH 3 ), 24.0 (CH 3 ), 23.9 (CH 3 ), 22.7 (CH 3 ), 22.5 (CH 3 ), 17.5 (CH 3 ), 17.5 (CH 3 ), 12.1 (CH 3 ), 11.9 (CH 3 ). Data for compound 137: IR (film): ν 3305, 2958, 2866, 1621, 1464 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.03 (s, 1H), 6.92 (s, 1H), 5.00 (q, J= 6.7 Hz, 1H), 4.64 (s, 1H), 4.59 (ddd, J= 6.1, 6.1, 8.9 Hz, 1H), 4.52 (s, 1H), 4.33 (ddd, J= 1.9, 2.6, 4.2 Hz, 1H), 4.04 (ddd, J= 5.9, 5.9, 7.3 Hz, 1H), 3.82 (ddd, J= 2.5, 7.6, 7.6 Hz, 1H), 3.78-3.86 (m, 1H), 3.14 (sept, J= 6.9 Hz, 1H), 2.84 (sept, J= 6.9 Hz, 1H), 2.50 (ddd, J= 7.2, 12.0, 18.6 Hz, 1H), 2.15-2.37 (m, 4H), 2.10 (dddd, J= 1.5, 4.3, 7.2, 13.5 Hz, 1H), 1.97 (ddd, J= 5.6, 8.1, 13.1 Hz, 1H), 1.82 (dddd, J= 1.3, 7.1, 11.9, 13.5 Hz, 1H), 1.66 (s, 3H), 1.50 (d, J= 6.7 Hz, 3H), 1.14-1.31 (m, 18H), 0.90-1.10 (m, 28H). (CH 2 ), 34.0 (CH), 33.8 (CH 2 ), 29.3 (CH), 28.9 (CH), 28.2 (CH 2 ), 26.4 (CH 2 ), 25.2 (CH 3 ), 25.0 (CH 3 ), 24.8 (CH 3 ), 24.1 (CH 3 ), 24.0 (CH 3 ), 23.9 (CH 3 ), 22.52 (CH 3 ), 22.49 (CH 3 ), 17.6 (CH 3 ), 17.5 (CH 3 ), 17.42 (CH 3 ), 17.40 (2CH 3 ), 17.36 (3CH 3 ), 13.62 (2CH), 13.59 (CH), 13.5 (CH). 136). To a solution of silyl ether 135 (1.0 g, 1.62 mmol, 1.0 equiv) in 15 ml THF at -78°C was added a freshly prepared solution of 0.4M LiHMDS in THF (16 ml, 6.4 mmol, 3.9 equiv). The reaction was allowed to warm to -20°C over 1h30min, followed by TLC and quenched with brine at -25 °C. The aqueous layer was extracted 3 times with DCM. After drying over MgSO 4 , the organic phase was concentrated under vacuum to leave 932.2 mg of crude material which was purified over silica gel (0-10% EtOAc/cyclohexane) to give 860.0 mg of pure cyclic silyl ether 136 (91%). Preparation of LiHMDS solution in THF; At -20°C,4.8 ml of n-Buli solution (2.5M, 12 mmol, 1.0 equiv) was added to a solution of HMDS (3 ml, 14.28 mmol, 1.2 equiv) in 22.2 ml THF. The mixture was allowed to stir at -20°C<T<-10°C for 30 min before being ready to be used. IR (film): ν 3357, 2959, 2866, 1644, 1462, 1610 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 6.90 (s, 1H), 6.8 (s, 1H), 4.96 (q, J= 6.9 Hz, 1H), 4.6 (s, 1H), 4.46-4.5 (m, 2H), 4.2 (ddd, J= 1.9, 1.9, 4.2 Hz, 1H), 3.95 (ddd, J= 5.0, 7.3, 7.3 Hz, 1H), 3.89 (sept, J= 6.9 Hz, 1H), 3.8 (ddd, J= 2.5, 8.1, 8.1 Hz, 1H), 3.1 (sept, J= 7.05 Hz, 1H), 2.8 ( sept, J= 6.9 Hz, 1H), 2.7 (dddd, J= 1.3, 2.3, 5.8, 7.7 Hz ,1H), 2.3-2.4 (ddd, J= 8.0, 8.0, 12.7 Hz, 1H), 2.16-2.27 (m, 2H), 1.81-1.95 (m, 3H), 1.64 (s, 3H), 1.46 (d, J= 6.7 Hz, 3H), 1.12-1.2 (m, 19 H), 0.9-0.95 (m, 8H), 0.73 (d, J= 7.2 Hz, 3H), 0.69 (d, J= 7.4 Hz, 3H), 0.54(sept, J= 7.5 Hz, 1H). (CH 2 ), 34.0 (CH), 32.9 (2CH 2 ), 32.7 (CH), 29.1 (CH), 28.4 (CH), 25.1 (2CH 3 ), 24.9 (CH 3 ), 24.0 67.3, 64.5, 64.0, 53.9, 34.0, 33.1, 32.5, 32.1, 31.2, 29.6, 29.1, 28.2, 25.1, 24.9, 24.7, 24.5, 24.0, 23.9, 23.2, 20.5, 17.8, 17.5, 17.5, 17.4, 13.4, 13.3. MS (ESI): m/z 584.6 (MH + , 100%).

HRMS calcd for C 36 H 62 NO 3 Si: 584.44935. Found: 584.44765 (MH + ).

(1S,5R,5aR,7S,7aS,10aR)-3,3-Diisopropyl-9-methylene-7-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) dodecahydro-1,5-methano[1,6,2]oxazasilocino [7,6,5-cd]indolizine (147). To a solution of lactam 136 (6.0 mg, 0.010 mmol, 1.0 equiv) and Ph 2 SiH 2 (22 µl, 0.12 mmol, 12 equiv) in 120 µl hexane was added dropwise Ti(Oi-Pr) 4 (15 µl, 0.05 mmol, 5.0 equiv) at 0°C. After stirring 5h at RT, the reaction mixture was quenched with water and stirred for 15 min. The aqueous layer was extracted with Et 2 O (3 times) then the combined organic layers were dried over MgSO 4 and concentrated in vacuo to afford 35 mg of crude product. Purification over 1 ml of silica gel allowed the isolation of 2.7 mg of the tertiary alcohol 142 (40% yield), and 3.0 mg mixture of the olefinated compound 147 and over-reduced amine 144 in 1:0.15 ratio respectively (47% yield) using 0-10% EtOAc/pentane as eluting system. (vide infra for data characterization of 142 and 144) Data for compound 147 IR (film): ν2958, 2926, 28634, 1645, 1608, 1461, 1381, 1262, 1122, 1080 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7. 04 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 4.67 (s, 2H), 3.97 (app s, 1H), 3.92 (sept, J= 6.8 Hz, 1H), 3.90 (ddd, J= 3.2 Hz, 6.5 Hz, 9.1 Hz, 1H), 3.24 (app t, J= 9.1 Hz, 1H), 3.17 (sept, J= 6.8 Hz, 1H), 3.09 (ddd, J= 4.2 Hz, 6.7 Hz, 11.9 Hz, 1H), 2.86 (sept, J= 6.9 Hz, 1H), 2.79 (app dd, J= 2.9 Hz, 12.4 Hz, 1H), 2.41 (t, J= 12.4 Hz, 1H), 28 (t, J= 11.9 Hz, 1H), 2.20 (ddd, J= 9.1, 9.1, 12.6 Hz, 1H), 1.96 (ddd, J= 1.3, 4.2, 13.9 Hz, 1H), 1.94-1.20 (m, 1H), 1.65-1.79 (m, 4H), 1.49 (d, J= 6.8 Hz, 3H), 1.12-1.31 (m, 18 H), 0.79-1.05 (m, 15H), 0.53 (ddd, J= 1.9, 1.9, 14.7 Hz, 1H). 13 C NMR (CDCl 3 ,125 MHz): δ 148. 8, 148.4, 147.1, 145.9, 133.4, 123.1, 120.2, 107.2, 74.5, 70.7, 68.1, 64.3, 62.9, 54.7, 34.0, 32.9, 32.3, 31.6, 31.4, 29.6, 29.2, 28.1, 25.2, 24.8, 24.8, 24.3, 24.0, 23.8, 23.3, 17.9, 17.7, 17.2, 16.8, 15.0, 14.5, 13 IrCl(CO)[P(C 6 H 5 ) 3 ] 2 (32 mg, 0.041 mmol, 2.4 %mol) was added to a solution of lactam 136 (990.0 mg, 1.7 mmol, 1.0 equiv) in 41 ml toluene at RT. The obtained yellow suspension was stirred at RT for 5 min before the addition of TMDS (750 µl, 4.24 mmol, 2.5 equiv). The reaction mixture was stirred for more 5 min before noticing the total disappearance of starting material by TLC. Formic acid (18 ml) was then added and the solution was stirred for 1h30min at RT. The resultant solution was diluted with Et 2 O and then basified with saturated K 2 CO 3 solution. It was then washed with brine and the aqueous phase was extracted 3 times with Et 2 O. The combined organic layers were dried over MgSO 4 and evaporated under reduced pressure to yield 1 g of crude mixture that is used for the next step without any further purification. Pure unhydrolysed 140 and hydrolysed formate product 139 were obtained after purification over silica gel and eluted with 2% and 10% EtOAc/cyclohexane respectively. 1 H NMR (CDCl 3 , 500 MHz): δ 8. 03 (s, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 3.99 (ddd, J=4.3 Hz, 6.7 Hz, 9.3 Hz, 1H), 3.89 (sept, J= 6.8 Hz, 1H), 3.78 (app s, 1H), 3.31 (ddd, J= 1.3 Hz, 8.4 Hz, 9.3 Hz, 1H), 3.25 (ddd, J= 3.9 Hz, 6.7 Hz, 12.8 Hz, 1H), 3.15 (sept, J= 6.8 Hz, 1H), 2.79-2.9 (m, 2H), 2.23 (dd, J= 12.8 Hz, 12.8 Hz, 1H), 2.14 (ddd, J= 9.3 Hz, 9.3 Hz, 13.1 Hz, 1H), 2.08 (ddd, J= 1.9 Hz, 3.4 Hz, 14.8 Hz, 1H), 2.0 (dd, J= 12.8 Hz, 12.8 Hz, 1H), 1.66-1.80 (m, 4H), 1.62 (ddd, J= 2.44 Hz, 6.04 Hz, 14.8 Hz, 1H), 1.57 (s, 3H), 1.49 (d, J= 6.8Hz, 3H), 1.17-1.32 (m, 18 H), 1.1 (dd, J= 10.4 Hz, 15.3 Hz, 1H), 0.93-1.05 (m, 12H), 0.8-0.9 (m, 3H). .2 (CH), 53.9 (CH), 33.9 (CH), 33.7 (CH 2 ), 32.6 (CH 2 ), 31.9 (CH), 31.0 (CH 2 ), 30.4 (CH 2 ), 29.1 (CH), 28.0 (CH), 24.9 (CH 3 ), 24.9 (CH 3 ), 24.8 (CH 3 ), 24.6 (CH 3 ), 24.5 (CH 3 ), 23.9 (2CH 3 ), 23.3 (CH 3 ), 22.9 (CH 3 ), 20.7 (CH 2 ), 17.7 (CH 3 ), 17.5 (CH 3 ), 17.4 (CH 3 ), 13.3 (CH), 13.2 (CH). (1S,2aR,3R,5S,5aR,7R,8aS)-5-((Hydroxydiisopropylsilyl)methyl)-7-methyl-1-((R)-1-(2,4,6triisopropylphenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizine-3,7-diol (143). K 2 CO 3 (280 mg, 2.03 mmol, 13.5 equiv) was added to a solution of formate 139 (94.0 mg, 0.15 mmol, 1.0 equiv) in 2.7 ml MeOH and stirred for 1h at RT. Then the reaction was diluted with DCM and quenched with brine, and the aqueous layer was extracted 3 times with DCM. The combined organic layers were dried with MgSO 4 and concentrated under reduced pressure. 1 H NMR (CDCl 3 , 500 MHz): δ 7.03 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 5.00 (q, J= 6.9 Hz, 1H), 3.99 (ddd, J= 4.2, 6.6, 9.4 Hz, 1H), 3.91 (sept, J= 6.9 Hz, 1H), 3.76 (app s, 1H), 3.28 (ddd, J= 1.5, 8.3, 8.3 Hz, 1H), 3.11-3.22 (m, 2H), 2.85 (sept, J= 6.9 Hz, 1H), 2.75 (app dd, J= 3.0, 13.1 Hz, 1H), 2.04-2.17 (m, 2H), 1.86 (dd, J= 13.1, 13.1 Hz, 1H), 1.59-1.80 (m, 4H), 1.48 (d, J= 6.9Hz, 3H), 1.43 (ddd, J= 2.1, 3.8, 13.5 Hz, 1H), 1.16-1.31 (m, 22H), 1.1 (dd, J= 10.5, 15.3 1 H NMR (CDCl 3 , 500 MHz): δ 7.04 (d, J= 2.0 Hz, 1H), 6.92 (d, J= 2.0 Hz, 1H), 4.98 (q, J= 6.9 Hz, 1H), 3.96 (app s, 1H), 3.87-3.93 (m, 2H), 3.08-3.19 (m, 3H), 2.86 (sept, J= 6.9 Hz, 1H), 2.77 (ddd, J= 0.8, 3.0, 12.8 Hz, 1H), 2.16 (ddd, J= 9.2, 9.2, 12.6 Hz, 1H), 1.95 (br s, 1H), 1.82 (dd, J= 12.8, 12.8 Hz, 1H), 1. 58-1.75 (m, 4H), 1.47 (d, J= 6.9Hz, 3H), 1.40 (ddd, J= 2.0, 3.7, 13.4 Hz, 1H), 1.15-1.28 (m, 22H), 0.82-1.07 (m, 15H), 0.53 (ddd, J= 1.9, 1.9, 15.0, 1H). 24.8 (CH 3 ), 24.7 (CH 3 ), 24.3 (CH 3 ), 24.0 (CH 3 ), 23.8 (CH 3 ), 23.3 (CH 3 ), 17.9 (CH 3 ), 17.7 (CH 3 ), 17.2 (CH 3 ), 16.8 (CH 3 ), 15.0 (CH), 14.8 (CH 2 ), 13.1 (CH). (135 µl, 0.135 mmol, 6.0 equiv) was added dropwise to a solution of lactam 136 (13.0 mg, 0.022 mmol, 1.0 equiv) in 300 µl of dry Et 2 O and stirred for 5h30min at RT. The reaction was followed by TLC then quenched with water, and the aqueous layer was extracted 3 times with Et 2 O. The organic layers were dried over MgSO 4 and evaporated under reduced pressure. Purification over silica gel gave 8.2 mg of pure unhydrolyzed amine 144 as colorless oil (65%) which was eluted with 100% cyclohexane.

N H H H O Me Si O i-Pr i-Pr CH 2 i-Pr i-Pr i-Pr 2.

Data for compound 139

IR (film): ν 2959, 2864, 1608, 1461, 1268 cm -1 .

1 H NMR (CDCl 3 , 500 MHz): δ 7.02 (d, J= 1.7 Hz, 1H), 6.92 (d, J= 1.7 Hz, 1H), 5.07 (q, J= 6.8 Hz, 1H), 4.77 (br s, 1H), 4.75 (br s, 1H), 3.96 (sept, J= 6.8 Hz, 1H), 3.89 (app s, 1H), 3.87 (ddd, J= 6.4, 6.4, 9.2 Hz, 1H), 3.35 (ddd, J= 4.0, 6.4, 6.4 , 2960, 2928, 2869, 1607, 1459, 1372, 1263, 1112, 1082 cm -1 .

1 H NMR (C 6 D 6 , 500 MHz): δ 7.26 (d, J= 1.8 Hz, 1H), 7.10 (d, J= 1.8 Hz, 1H), 5.06 (q, J= 6.8 Hz, 1H), 4.19 (sept, J= 6.9 Hz, 1H), 3.91 (ddd, J= 4.9, 6.4, 9.2 Hz, 1H), 3.56 (app s, 1H), 3.19 (sept, J= 6.9 Hz, 1H), 2.95 (t, J= 7.9 Hz, 1H), 2.89(ddd, J= 3.9, 6.4, 12.2 Hz, 1H), 2.80 (sept, J= 6.9 Hz, 1H), 2.48 (ddd, J= 1.7, 3.0, 13.1 Hz, 1H), 2.27 (ddd, J= 7.9, 9.2, 12.8 Hz, 1H), 2.00 (br s, 1H), 1.51-1.65 (m, 4H), 1.61 (d, J= 6.8 Hz, 3H), 1.31-1.48 (m, 12H), 1.22-1.24 (m, 6H), 1.20 (d, J= 6.9 Hz, 3H), 1.14 (d, J= 7.4 Hz, 3H), 1.05 (s, 3H), 0.97 (app d, J= 12.8 Hz, 1H). 13 C NMR (C 6 D 6 , 125 MHz): δ 149. 4, 148.0, 146.5, 134.2, 123.7, 120.8, 75.6, 71.4, 70.6, 67.2, 61.4, 58.2, 54.0, 38.5, 35.1, 34.6, 31.8, 31.2, 29.5, 28.6, 26.0, 25.4, 25.3, 24.8, 24.8, 24.3, 24.3, 24.1, 23.5. MS (ESI): m/z 472.4 (MH + , 100%).

HRMS calcd for C 30 H 50 NO 3 : 472.3791. Found: 472.3789 (MH + ).

(2S,3S,6S,8R,8aR)-6-Methyl-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)octahydro indolizin-8-ol (145). KOt-Bu (1.2 g, 10.7 mmol, ~12 equiv) and TBAF (1M in THF, 6.3 ml, 6.3 mmol, ~7 equiv) were added to a solution of 560.0 mg crude silylated compounds (139, 140 and 144) in 21 ml DMSO. The reaction mixture was stirred for 9h at 120°C. The mixture was then diluted with Et 2 O and quenched with water. The aqueous layer was extracted with Et 2 O 3 times. The combined organic layers were dried over MgSO 4 , filtered and concentrated. The crude product was purified over 26 ml silica gel to afford 130.0 mg of the alcohol 75 (38% over 2 steps) and 7.1 mg of the bicyclic amino alcohol 145 (2% over 2 steps). (vide supra for data characterization of 75) Data for compound 145 IR (film): ν 3433, 2960, 2928, 2870, 1645, 1608, 1459, 1381, 1261, 1123, 1080, 1045 cm -1 . , 145.8, 145.5, 133.4, 123.1, 120.4, 111.0, 75.9, 71.1, 68.2, 64.5, 61.2, 55.1, 36.8, 33.9, 31.9, 30.8, 29.1, 28.1, 27.8, 25.3, 24.9, 24.8, 24.4, 23.9, 23.9, 23.2, 22.9, 21.3 2.86 (sept, J= 6.9 Hz, 1H), 2.73 (app dd, J= 2.9, 13.0 Hz, 1H), 2.13 (ddd, J= 8.5, 8.5, 12.7 Hz, 1H), 1.97 (br s, 1H), 1.83 (dd, J= 13.0, 13.0 Hz, 1H), 1. 78-1.84 (m, 1H), 1.61-1.71 (m, 3H), 1.48 (d, J= 6.8Hz, 3H), 1.43 (ddd, J= 2.1, 3.8,13.7 Hz, 1H), 1.15-1.28 (m, 22H), 0.74-0.94 (m, 9H). 13 C NMR (CDCl 3 , 125 MHz): δ 148.8 (C), 147.2 (C), 145.9 (C), 133.2 (C), 123.1 (CH), 120.2 (CH), 74.2 (CH), 71.5 (C), 70.7 (CH), 69.6 (CH), 60.9 (CH), 58.9 (CH), 54.1 (CH), 36.5 (CH 2 ), 34.0 (CH), 33.6 (CH 2 ), 32.1 (CH), 32.0 (CH 2 ), 31.6 (CH 2 ), 29.2 (CH), 28.0 (CH), 25.9 (CH 3 ), 25.1 (CH 3 ), 24.8 (CH 3 ), 24.7 (CH 3 ), 24.3 (CH 3 ), 24.0 (CH 3 ), 23.8 (CH 3 ), 23. (1S,2aR,3R,5S,5aR,7R,8aS)-7-Hydroxy-5,7-dimethyl-1-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) decahydro-1H-pyrrolo[2,1,5-de]quinolizin-3-yl methanesulfonate (155). To a solution of alcohol 75 (5.0 mg, 0.011 mmol, 1.0 equiv) in 200 µl DCM were added 15 µl of pyridine (0.185 mmol, 17 equiv), 12 µl of MsCl (0.155 mmol, 14.6 equiv) and ~3 mg of DMAP (0.024 mmol, 2.3 equiv) at RT. The reaction mixture was stirred for 6h at RT before being quenched with saturated NaHCO 3 solution and diluted with DCM. The aqueous layer was separated, and the organic layer was washed with saturated NaHCO 3 (2 times) and brine. The organic layer was dried over MgSO 4 and concentrated in vacuo. Purification over silica gel using MeOH NH3 /DCM (0.5% ® 2%) as eluent afforded 1.0 mg of the mesylated product 155 (17.2%) and 1.0 mg of the starting alcohol 75 (20%). (vide supra for data characterization 75) Data for compound 155 IR (film): ν 3407, 2959, 2925, 2854, 1608, 1461, 1377, 1261, 1173, 1122, 1099 cm -1 . 1 H NMR (CDCl 3 , 400 MHz): δ 7.01 (s, 1H), 6.92 (s, 1H), 5.08 (q, J= 6.8 Hz, 1H), 4.89 (br. s, 1H), 4.01 (ddd, J= 3.9, 6.2, 8.5 Hz, 1H), 3.89 (sept, J= 6.7 Hz, 1H), 3.41 (ddd, J= 1.9, 8.1, 8.1 Hz, 1H), 3.08-3.20 (m, 2H), 2.98 (s, 3H), 2.84 (sept, J= 6.8 Hz, 1H), 2.71 (ddd, J= 3.3, 3.3, 12.6 Hz, 1H), 2.02-2.14 (m, 1H), 1.96 (ddd, J= 4.4, 5.9, 15.4 Hz, 1H), 1.87 (ddd, J= 4.3, 4.3, 14.8 Hz , 1H), 1.81-1.90 (m, 1H), 1.55-1.75 (m, 3H), 1.50 (d, J= 6.8 Hz, 3H), 1.45 (ddd, J= 2.0, 3.9, 16.2 Hz, 1H), 1.12-1.35 (m, 22H), 1.05 (d, J= 7.1 Hz, 3H).

HRMS calcd for C 31 H 52 NO 5 S: 550.35607 Found: 550.35461 (MH + ).

(1S,2aR,3R,5S,5aR,8aS)-5-Methyl-7-methylene-1-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) deca hydro-1H-pyrrolo[2,1,5-de]quinolizin-3-yl (methylsulfonyl)methanesulfonate (156). To a stirred solution of 75 (5.5 mg, 0.012 mmol, 1 equiv) in 180 µl DCM were added Et 3 N (30 µl, 0.21 mmol, 17.5 equiv) and MsCl (10 µl, 0.14 mmol, 11.7 equiv) at ambient temperature. The mixture was stirred for 4h at room temperature and followed by TLC till the consumption of all the starting materials. After which it was diluted with DCM and extracted with saturated NaHCO 3 (2 times) and brine. The organic extract was then dried over MgSO 4 and the solvent was evaporated to afford 1:0.2 mixture of 156 and 155 respectively. Chromatography of the residue over silica gel using 0.25% MeOH NH3 /DCM as eluent furnished 156 (3.1 mg, 48%). (vide supra for data characterization 155) Data for compound 156 IR (film): ν 2957, 2925, 2854, 1641, 1608, 1459, 1363, 1345, 1290, 1260, 1176, 1112 8, 147.6, 145.8, 143.3 132.7, 123.1, 120.7, 112.7, 74.7, 74.1, 71.3, 65.9, 63.9, 53.8, 49.8, 38.5, 38.2, 34.0, 33.6, 32.6, 29.7, 29.1, 28.0, 25.2, 25.1, 24.1, 24.0, 24.0, 23.3, 22.7, 22.7, 22.5. and DMAP (4 mg, 0.032 mmol, 1.8 equiv) at room temperature. Tertbutyldimethylsilyl chloride (40 mg, 0.266 mmol, 15.6 equiv) was also added in 2 portions with 3h30min interval. The reaction mixture was stirred for 7h at 60°C, quenched with water and diluted with pentane. The aqueous layer was washed with pentane (3 times) and the combined organic layers were dried over MgSO 4 .

Evaporation of the solvent provided the crude product, which was purified by 1 ml silica gel chromatography and eluted with 20% EtOAc in cyclohexane to provide protected-alcohol 171 (6.6 mg, 67 %).

1 H NMR (CDCl 3 , 400 MHz): δ 7.02 (d, J= 2.0 Hz, 1H), 6.91 (d, J= 2.0 Hz, 1H), 5.08 (q, J= 6.9 Hz, 1H), 3.83-4.0 (m, 3H), 3.28 (ddd, J= 2.2, 8.0, 8.0 Hz, 1H), 3.20 (sept., J= 6.9 Hz, 1H), 2.95 (ddd, J= 3.2, 5.5, 12.1 Hz, 1H), 2.84 (sept, J= 6.9 Hz, 1H), 2.65 (ddd, J= 3.1, 6.3, 11.8 (2S,2aR,4R,5aR,6S,8R,8aR)-8-((tert-Butyldimethylsilyl)oxy)-4,6-dimethyl-2-((R)-1-(2,4,6-triisopropyl phenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-yl acetate (172). To a solution of the tertiary alcohol 171 (9.5 mg, 0.016 mmol) in 500 µl of DCM at RT were added Et 3 N (190 µl, 1.36 mmol), Ac 2 O (125 µl, 1.32 mmol) and 8 mg of DMAP (0.06 mmol) sequentially over the whole course of the reaction. The reaction mixture was stirred for 15h at 60°C, after which it was quenched with water and diluted in pentane. The resultant aqueous phase was washed with pentane (3 times) and the combined organic layers dried over MgSO 4 . The solvent was evaporated in vacuo to obtain the crude product. Upon purification over silica gel (5-10% EtOAc in cyclohexane), furnished 6.0 mg of the acylated compound 172 (60% yield). IR (film): ν 2956, 2926, 2852, 1733, 1462, 1249, 1108, 1078 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.02 (d, J= 1.8 Hz, 1H), 6.91 (d, J= 1.8 Hz, 1H), 5.06 (q, J= 6.9 Hz, 1H), 3.94 (sept, J= 6.8 Hz, 1H), 3.89 (ddd, J= 2.3, 5.5, 7.6 Hz, 1H), 3.85 (quint, J= 2.3, 1H), 3.31 (ddd, J= 2.2, 8.1, 8.1 Hz, 1H), 3.19 (sept, J= 6.9 Hz, 1H), 3.0 (ddd, J= 3.5, 5.6, 11.9 Hz, 1H), 2.84 (sept, J= 6.9 Hz, 1H), 2.70 (ddd, J= 2.9, 5.7, 12.1 Hz, 1H), 1.97 (s, 3H), 1.73-2.06 (m, 7H), 1.52 (d, J= 6.9 Hz, 3H), 1.39-1.46 (m, 1H), 1.17-1.32 (m, 22H), 1.06 (d, J= 7.0 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H). Purification over silica gel allows the isolation of 4.5 mg (eluted with 1-2% MeOH NH3 /DCM) of the deprotected compound 173 (95% yield).

1 H NMR (CDCl 3 , 400 MHz): δ 7.03 (d, J= 1.9 Hz, 1H), 6.93 (d, J= 1.9 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 3.94(ddd, J= 4.7, 6.5, 9.2 Hz, 1H), 3.90 (sept, J= 6.9 Hz, 1H), 3.70 (q, J= 3.0 Hz, 1H), 3.33 (ddd, J= 1.7, 8.1, 8.1 Hz, 1H), 3.12-3.21 (m, 2H), 2.84 (sept, J= 6.9 Hz, 1H), 2.73 (ddd, J= 1.5, 3.1, 12.9 Hz, 1H), 2.19 (ddd, J= 7.9, 9.2, 12.9 Hz, 1H), 2.13 (t, J= 12.9 Hz, 1H), 2.00 (s, 3H), 1.91 (ddd, J= 0.7, 12.5, 13.2 Hz, 1H), 1.66-1.79 (m, 5H), 1.50 (d, J= 6.8 Hz, 3H), 1.14-1.30 (m, 25H). mmol, 29.0 equiv). After stirring for 40 min at -80°C<T<-65°C, the mixture was re-cooled to -78 °C and acylated alcohol 173 (5.0 mg, 9.7*10 -3 mmol, 1.0 equiv) was added slowly as a solution in dry DCM (200 µl). Once the reaction mixture was stirred for 1h at -80°C <T<-65°C, Et 3 N (40 µl, 0.28 mmol, 29.0 equiv) was injected slowly and then the mixture was allowed to stir for 1 h so the temperature reached 0°C. The reaction mixture was diluted in DCM and quenched with H 2 O. The aqueous layer was washed with DCM (3 times) then the combined organic layers were dried over MgSO 4 and concentrated under reduced pressure to give 18.0 mg of the crude ketone 174 contaminated with DMSO and Et 3 N (with ratio 1:17:6 respectively). Due to the instability of ketone 174 over silica gel, no further purification was done and an estimated yield from the NMR was provided (3.7 mg, 74%). IR (film): ν 2958, 2925, 2854, 1732, 1658, 1246 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.00 (d, J= 1.8 Hz, 1H), 6.89 (d, J= 1.8 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 3.90 (ddd, J= 4.2, 6.0, 7.9 Hz, 1H), 3.89 (sept, , J= 6.8 Hz, 1H), 3.74 (dd, J= 7.2, 9.2 Hz, 1H), 3.13 (sept, J= 6.8 Hz, 1H), 3.05 (ddd, , J= 3.8, 6.0, 11.7 Hz, 1H), 2.81 (sept, J= 6.9 Hz, 1H), 2.46-2.52 (m, 1H), 2. 19-2.36 (m, 2H), 2.14 (ddd, J= 1.8, 3.1, 12.5 Hz, 1H), 1.97 (s, 3H), 1.75-1.97 (m, 3H), 1.52-1.66 (m, 3H), 1.48 (d, J= 6.8 Hz, 3H), 1.13-1.28 (m, 21H), 0.99 (d, J= 6.7 Hz, 3H). MS (ESI): m/z 512.45 (MH + , 100%).

HRMS calcd for C 32 H 50 NO 4 : 512.3734. Found: 512.3720 (MH + ).

1-(tert-Butyl)-1H-tetrazole-5-thiol (S6). To a refluxing solution of sodium azide (2.80 g, 43.1 mmol, 1.0 equiv) in 15.0 ml of water was added a solution of t-butylisothiocyanate (5.0 g, 43.4 mmol, 1.0 equiv) dropwise in 10 ml of i-PrOH. The mixture is refluxed for 16h, cooled to 0°C and 7 ml of 37% HCl solution was added. The solvents were removed under reduced pressure and the crude oil was triturated at 0°C with 30 ml of water and filtrated. The resulting solid was washed with water, dry over P 2 O 5 under reduced pressure for 48h to furnish 5.24 g (76%) of S6 as light yellow solid. Analytical data are in agreement with those reported in the literature. 1-(tert-Butyl)-5-(methylthio)-1H-tetrazole (S7). To a suspension of sodium hydride (1.42 g, 60% in mineral oil, 33.3 mmol, 1.0 equiv) in 20.0 ml of dry THF at 0°C was added drop wise a solution of 5.17 g of the thiol S6 (32.7 mmol, 1.0 equiv) in 60 ml of dry THF. After stirring for 20 min at 0°C, methyl iodide was added (2.6 ml, 6.67g, 47.0 mmol, 1.4 equiv) and the reaction mixture was stirred over night at room temperature then quenched with saturated NH 4 Cl solution (30 ml) and extracted with DCM to give 5.70 g (100%) of S7 as light yellow solid. Analytical data are in agreement with those reported in the literature. 127 1 H NMR (CDCl3, 400 MHz): δ 2.81 (s, 3H), 1.72 (s, 9H).

1-(tert-Butyl)-5-(methylsulfonyl)-1H-tetrazole (S8). To a solution of the thioether S7 (5.90 g, 34.2 mmol, 1.0 equiv) in 150.0 ml of EtOH at 0°C was added dropwise a solution of ammonium molybdate tetrahydrate (3.41 g, 2.76 mmol, 0.08 equiv) in 34 mL of 30% H 2 O 2 . After stirring for 5h at room temperature, EtOH was removed under reduced pressure. The residue was dissolved in DCM, washed with water and brine, dried and evaporated to give 6.78 g (97%) of S8 as yellow solid.

Analytical data are in agreement with those reported in the literature. 127 1 H NMR (CDCl3, 400 MHz): δ 3.66 (s, 3H), 1.85 (s, 9H).

5-(Methylthio)-1-phenyl-1H-tetrazole (S9). To a solution of 60% NaH (1.3 g, 32.5 mmol, 1.16 equiv) in 30 ml THF, 1-phenyl-1H-tetrazole-5-thiol (5.0 g, 28.1 mmol, 1.0 equiv) was added as a solution in 78 ml dropwise over 20 min. After stirring 30 min at 0°C, MeI (2.2 ml, 35.3 mmol, 1.26 equiv) was added dropwise at 0 °C and the reaction mixture was stirred for 14h at room temperature. Then the the organic layer was washed with brine and then dried over MgSO 4. After filtration, the solvent was removed in vacuo to afford S9 as pale yellow solid (6.0 g) that was used in the next step without any further purification. Analytical data are in agreement with those reported in the literature. 133 1 H NMR (400 MHz, CDCl 3 ): δ 7. 54-7.60 (m, 5H), 2.84 (s, 3H).

5-(Methylsulfonyl)-1-phenyl-1H-tetrazole (S10). To a solution of sulfide S9 (6.0 g, 31.2 mmol, 1.0 equiv) in 195 ml EtOH were added ammonium molybdate tetrahydrate (15.7 g, 12.70 mmol, 0.4 equiv) and 30% H 2 O 2 (16 ml, 156.66 mmol, 5.0 equiv) at 0 °C. Then, the mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated under high vacuum and then diluted with DCM. The organic layer was washed with water followed with brine, dried over MgSO 4 and then concentrated in vacuo. Crystallization from cyclohexane afforded the sulfone product S10 (5.88 g, 93% yield) as a white solid. Analytical data are in agreement with those reported in the literature. equiv) was injected slowly and the reaction was allowed to warm slowly to -20°C over 1h. Meanwhile, a mixture of 170 mg of TBTSO 2 CH 3 S8 (0.83 mmol) and 830 µl of freshly prepared LiHMDS solution (0.95 M in THF, 0.79 mmol) in 450 µl THF was stirred for 30 min at -80°C<T<-60°C. The reaction bath was cooled back to -80°C and the reaction was treated with a freshly prepared solution of TBTSO 2 CH 2 Li (800 µl in THF, 0.61 M, 0.49 mmol, 23 equiv). The reaction mixture was stirred for 2h30min allowing the temperature to reach 0°C, then stirred 1h at RT. After dilution with Et 2 O followed by quenching with H 2 O, the aqueous layer was extracted with Et 2 O (3 times) and the combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure.

Purification over silica gel afforded 4.0 mg of the alkene 151 (40%) and 1.5 mg of the byproduct 164 (12%) using 0.5-1% MeOH NH3 /DCM as eluant system. (vide infra for data characterization of 151) Data for compound 164 IR (film): ν 3399, 2959, 2927, 2856, 1607, 1551, 1461, 1438, 1374, 1261, 1155, 1120 cm -1 .

1 H NMR (CDCl 3 , 500 MHz): δ 7.03 (d, J= 1.7 Hz, 1H), 6.90 (d, J= 1.8 Hz 1H), 5.23 (ddd, J= 2.5, 2.5, 5.0 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 3. 88-3.96 (m, 2H), 3.53 (ddd, J= 2.5, 8.2, 8.2 Hz, 1H), 3.14 (ddd, J= 3.6, 6.3, 12.4 Hz, 1H), 3.08 (sept., J= 6.8 Hz, 1H), 2.84 (sept, J= 6.8 Hz, 1H), 2.70 (ddd, J= 2.9, 2.9, 12.6 Hz, 1H), 1.95-2.07 (m, 2H), 1.87-1.91 (m, 2H), 1.62-1.75 (m, 3H), 1.59 (s,9H), 1.48 (d, J= 6.8 Hz, 3H), 1.46-1.52 (m, 1H), 1.35 (ddd, J= 2.9, 2.9, 10.9 Hz, 1H), 1.15-1.30 (m, 21H), 1.07 (d, J= 7.1 Hz, 3H). 13 C NMR (CDCl 3 , 125 MHz): δ 21. 3, 23.2, 23.9, 23.9, 24.4, 24.6, 25.0, 25.1, 25.8, 27.9, 28.5, 29.1, 29.7, 31.2, 31.6, 31.7, 34.0, 34.9, 39.0, 57.5, 59.5, 61.4, 70.7, 71.3, 74.6, 80.4, 120.2, 123.2, 133.0, 145.9, 147.3, 149.0, 161. Oxalyl chloride (10 µl, 0.12 mmol, 3.7 equiv) in dry DCM (200 µl) was treated dropwise with DMSO (25 µl, 0.35 mmol, 11.0 equiv) at -78 °C. The mixture was stirred for 40 min at -80°C<T<-65°C and the alcohol 75 (15.0 mg, 0.032 mmol, 1.0 equiv) was added in 450 µl DCM at -78°C. The reaction mixture was then stirred for 1h at -80°C<T<-65°C and Et 3 N (80 µl, 0.57 mmol, 18 equiv) was then injected slowly followed by increasing the temperature slowly to -40°C over 45 min. When the TLC showed a complete consumption of starting material, the Swern solution was concentrated in vacuo at -5°C and 500 µl of dry THF was added. The bath was cooled back to -80°C and treated with a solution of freshly prepared TBTSO 2 CH 2 Li in THF (1 ml, 0.67 M, 0.67 mmol, 21 equiv). The reaction mixture was stirred for 3h where temperature was maintained below -40°C. At this temperature, the reaction was quenched with brine and diluted with Et 2 O. The aqueous layer was washed with Et 2 O (3 times) and the combined organic layers dried over MgSO 4 and concentrated under reduced pressure. Purification over silica gel afforded 10.2 mg of the hydroxy sulfone intermediate (48%, hydrolyzed form of 165) using 0.5% MeOH NH3 /DCM as eluant.

IR (film): ν 3461, 2961, 2928, 2870, 1607, 1573, 1462, 1407, 1345, 1307, 1163, 1116 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.02 (d, J= 1.8 Hz, 1H), 6.93 (d, J= 1.8 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 4.15 (d, AB system, J= 14.7 Hz, 1H), 3.94 (ddd, J= 4.9, 6.4, 9.2 Hz, 1H), 3.88 (sept, J= 6.8 Hz, 1H), 3.77 (d, AB system, J= 14.7 Hz, 1H), 3.29 (t, J= 7.8 Hz, 1H), 3.11-3.21 (m, 2H), 2.84 (sept, J= 6.9 Hz, 1H), 2.68 (ddd, J= 2.6, 2.6, 12.9 Hz, 1H), 2.19 (ddd, J= 7.8, 9.2, 13.0 Hz, 1H), 2.13 (dd, J= 3.2, 14.2 Hz, 1H), 1.85 (s, 9H), 1. 48-1.94 (m, 6H), 1.48 (d, J= 6.8 Hz, 3H), 1.15-1.32 (m, 22H), 1.12 (d, J= 7.4 Hz, 3H). IR (film): ν 3408, 2959, 2926, 2867, 1727, 1649, 1561, 1457, 1380, 1228, 1103 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.01 (s, 1H), 6.92 (s, 1H), 5.03 (q, J= 6.9 Hz, 1H), 3.94 (ddd, J= 4.3, 6.0, 7.9 Hz, 1H), 3.89 (sept, , J= 6.7 Hz, 1H), 3.74 (dd, J= 7.0, 9.1 Hz, 1H), 3.16 (sept, J= 6.9

Hz, 1H), 3.06 (ddd, J= 4.2, 6.0, 11.3 Hz, 1H), 2.83 (sept, J= 6.9 Hz, 1H), 2.56 (ddd, J= 3.5, 7.4, 11.1 Hz, 1H), 2.22-2.36 (m, 3H) (50% over 2 steps) using 20% EtOAc/pentane as the eluant.

1 H NMR (CDCl 3 , 400 MHz): δ 7.00 (s, 1H), 6.91 (s, 1H), 5.04 (q, J= 6.8 Hz, 1H), 3.99 (ddd, J= 6.5, 6.5, 8.8 Hz, 1H), 3.89 (sept, , J= 6.7 Hz, 1H), 3.78 (dd, J= 5.8, 9.3 Hz, 1H), 3.12-3.20 (m, 2H), 2.83 (sept, J= 6.9 Hz, 1H), 2.71 (ddd, J= 5.8, 8.8, 13.9 Hz, 1H), 2.64 (ddd, J= 3.6, 6.0, 11.8 Hz, 1H), 2.28 (dd, J= 4.5, 14.3 Hz, 1H), 1.79-1.90 (m, 2H), 1.70 (dd, J= 9.7, 14.3 Hz, 1H), 1.40-1.62 (m, 4H), 1.50 (d, J= 6.8 Hz, 3H), 1.16-1.35 (m, 21H), 1.03 (d, J= 6.8 Hz, 3H). 2.28 mmol, ~9.8 equiv) was added to a solution of methyltriphenylphosphonium bromide (913 mg, 2.55 mmol, ~10.9 equiv) in 6.4 ml THF at -78°C. The yellow suspension was stirred for 45 min as the temperature was allowed to warm to 0°C then stirred 15 min at this temperature. The mixture was cooled back to -90°C and crude ketone 153 (203.0 mg, ~0.233 mmol, 1.0 equiv) was added as a solution in 9 ml THF. The reaction mixture was stirred for 1h at -90°C<T<-80°C and temperature was increased to 0°C over 2h followed by stirring at RT for 1h. Quenching was done with water and the aqueous layer was extracted with pentane (3 times). The combined organic layers were dried with MgSO 4 and the solvent was evaporated under vacuo. Partial purification over 11 ml of silica gel allowed the isolation of 600.0 mg of alkene 151 in mixture with excess of Wittig reagent in a ratio of ~1.0:17.7 respectively (45% estimated yield over 2 steps) using 10% EtOAc/cyclohexane as eluant system. No further purification was done for the alkene as it was noticed its instability over silica gel was noticed and used for the next step in its impure form. IR (film): ν 3387, 2958, 2925, 2854, 1658, 1607, 1462, 1379, 1260, 1104 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.01 (d, J= 2.0 Hz, 1H), 6.91 (d, J= 2.0 Hz 1H), 5.06 (q, J= 6.8 Hz, 1H), 4.71 (q, J= 1.6 Hz, 1H), 4.69 (q, J= 1.6 Hz, 1H), 4.02 (ddd, J= 2.8, 6.9, 8.6 Hz, 1H), 3.92 (sept., J= 6.8 Hz, 1H), 3.65 (t, J= 8.0 Hz, 1H), 3.19 (sept, J= 6.8 Hz, 1H), 3.16 (ddd, J= 3.6, 6.9, 12.3 Hz, 1H), 2.83 (sept, J= 6.9 Hz, 1H), 2.67 (ddd, J= 3.0, 3.0, 12.7 Hz, 1H), 2.39 (dd, J= 5.6, 14.4 Hz, 1H), 1.69-2.01 (m, 6H), 1.50 (d, J= 6.8 Hz, 3H), 1.41 (ddd, J= 2.3, 3.6, 13.4 Hz, 1H), 1.16-1.3 (m, 22H), 0.98 (d, J= 7.0 Hz, 3H). µl DCM was added dropwise DMSO (90 µl, 1.27 mmol, ~19.9 equiv) at -78 °C. The mixture was stirred for 40 min at -80°C<T<-65°C and 30.0 mg of a mixture of alcohol 75 and tertiary amine 145 of ratio 1:0.09 respectively was added in 900 µl THF at -78°C. The reaction mixture was then stirred for 1h at -80°C<T<-65°C and Et 3 N (300 µl, 2.15 mmol, ~33 equiv) was then injected slowly and temperature allowed to warm slowly to -35°C over 1h. When the TLC showed a complete consumption of the starting alcohols, the Swern solution was concentrated in vacuo at -5°C and 1.1 ml of dry THF was added. The bath was cooled back to -80°C and treated with a solution of freshly prepared TBTSO 2 CH 2 Li in THF (1.7 ml, 0.65 M, 1.11 mmol, ~17 equiv). The reaction mixture was stirred for 2h allowing the temperature to reach -20°C then stirred 1h at RT. After dilution with Et 2 O followed by quenching with brine, the aqueous layer was extracted with Et 2 O (3 times) and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure.

Purification over silica gel afforded 8.8 mg of a mixture of the tricyclic alkene 151 and the bicyclic alkene 166 in a ratio of 1:0.66 respectively using 1% MeOH NH3 /DCM as eluant (30% yield). Further purification gave analytical pure material of alkene 166. (vide supra for data characterization of 151)

Data for compound 166 IR (film): ν 2959, 2925, 2854, 1650, 1607, 1462, 1378, 1260, 1123, 1081, 1025 cm -1 .

1 H NMR (CDCl 3 , 400 MHz): δ 7.04 (d, J= 1.9 Hz, 1H), 6.93 (d, J= 1.9 Hz 1H), 5.04 (q, J= 6.8 Hz, 1H), 4. 75 (s, 1H), 4.83 (s, 1H), 4.72 (s, 1H), 4.70 (s, 1H), 4.10 (ddd, J= 3.0, 7.3, 7.3 Hz, 1H), 3.93 (sept., J= 6.8 Hz, 1H), 3.72 (dd, J= 7.2, 9.6 Hz, 1H), 3.13-3.23 (m, 2H) (2S,2aS,4R,5aR,6S,8S,8aR)-4,6,8-Trimethyl-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-ol (152). To a solution of alkene 151 (4.7 mg, 0.010 mmol, 1.0 equiv) in 250 µl i-PrOH were added phenyl silane (60 µl, 0.486 mmol, 48.0 equiv), tert-butyl hydroperoxide solution (5.0-6.0M in decane, 12 µl, 0.06-0.072 mmol, 6.0-7.0 equiv) and Mn(dpm) 3 (2 mg, 3.3*10 -3 mmol, 33% by mole) at RT. The reaction mixture was stirred for 4h then the solvent was evaporated. The crude mixture was directly loaded on silica gel eluted with 1% MeOH NH3 /DCM to afford 4.0 mg of the alkane 152 (85% yield).

1 H NMR (CDCl 3 , 500 MHz): δ 7.00 (d, J= 1.9 Hz, 1H), 6.90 (d, J= 1.9 Hz, 1H), 5.00 (q, J= 6.8 Hz, 1H), 4.01 (ddd, J= 2.7, 7.1, 9.6 Hz, 1H), 3.92 (sept, J= 6.9 Hz, 1H), 3.16 (sept, J= 6.8 Hz, 1H), 3.14 (ddd, J= 3.8, 7.1, 12.4 Hz, 1H), 2.83 (sept, J= 6.9 Hz, 1H), 2.72 (ddd, J= 7.0, 9.4, 9.4 Hz, 1H), 2.68 (ddd, J= 1.4, 3.1, 13.0 Hz, 1H), 1.81-1.91 (m, 2H), 1.54-1.76 (m, 3H), 1.48 (d, J= 6.8 Hz, 3H), 1.39-1.47 (m, 1H), 1.36 (ddd, J= 2.3, 3.8,13.4 Hz, 1H), 1.15-1.34 (m, 23H), 1.13 (ddd, J= 2.3, 3.0, 12.5 Hz, 1H ), 1.09 (d, J= 7.1 Hz, 3H), 0.83 (d, J= 6.4 Hz, 3H). MS (ESI): m/z 470.39 (MH + , 100%).

HRMS calcd for C 31 H 52 NO 2 : 470.39926. Found: 470.39795 (MH + ). (1S,2aR,3S,5S,5aR,7R,8aS)-3,5,7-Trimethyldecahydro-1H-pyrrolo[2,1,5-de]quinolizine-1,7-diol (150). To a solution of the tertiary alcohol 152 (5.3 mg, 0.011 mmol) in 250 µl of DCM at 0 °C was added dropwise 25 µl TFA with vigorous stirring. The reaction mixture was stirred for another 1 h at 0°C, after which it was quenched with 10% NaOH solution and diluted with DCM. The aqueous phase was washed with DCM (3 times) then the resultant organic phases were dried over MgSO 4 . The solvent was evaporated in vacuo to obtain the crude product which furnished 2.0 mg of pure diol 150 (75% yield) upon purification over silica gel with 6.0% MeOH NH3 /DCM as eluant system. 145 145 Starting from 110 mg of alcohol 75 afforded 600 mg of alkene 151 contaminated with Wittig reagent (as described in the previous pages); then subjecting this crude alkene 151 to Shenvi hydrogenation followed by acidic treatment for chiral auxiliary cleavage allowed the isolation of 20 mg of pure alcohol 150 (36% over 4 steps). 9, 5.1, 7.1 Hz, 1H), 2.96 (ddd, J= 3.3, 5.1, 12.1 Hz, 1H), 2.84 (ddd, J= 6.9, 9.1, 10.4 Hz, 1H), 2.50 (ddd, J= 2.8, 5.5, 12.0 Hz, 1H), 1.85 (ddd, J= 2.0, 6.9, 13.4 Hz, 1H), 1.72 (ddd, J= 7.3, 9.0, 13.4 Hz, 1H), 1.32-1.71 (m, 8H), 1.26 (s, 3H), 1.02 (d, J= 7.0 Hz, 3H), 0.79 (d, J= 6.5 Hz, 3H).

O-((1S,2aR,3S,5S,5aR,7R,8aS)-7-Hydroxy-3,5,7-trimethyldecahydro-1H-pyrrolo[2,1,5-de]

quinolizin-1-yl) O-phenyl carbonothioate (176). To a solution of the diol 150 (5.0 mg, 0.021 mmol, 1.0 equiv) in 250 µl DCM were added DMAP (10.0 mg, 0.082 mmol, 3.9 equiv) and O-phenyl chlorothionoformate (7.0 µl, 0.051 mmol, 2.4 equiv). The reaction mixture was stirred for 5h at RT and then quenched with 10% NaOH and diluted with DCM. The aqueous layer was then extracted with DCM (3 times) and the combined organic phases were dried over MgSO 4 and concentrated under reduced pressure. The residue was purified over silica gel to afford 6.5 mg of 176 (83% yield) eluted with 0-0.5% MeOH NH3 /DCM.

1 H NMR (CDCl 3 , 500 MHz): δ 7.39-7.45 (m, 2H), 7.27-7.31 (m, 1H), 7.07-7.12 (m, 2H), 5.70 (ddd, J= 2.6, 6.6, 9.2 Hz, 1H), 3.58 (ddd, J= 3.6, 6.6, 12.4 Hz, 1H), 2.78 (ddd, J= 6.8, 9.5, 9.5 Hz, 1H), 2.72 (ddd, J= 2.2, 2.9, 12.7 Hz, 1H), 1. 94-2.11 (m, 3H), 1.83 (t, J= 12.6 Hz, 1H), 1.46-1.74 (m, 4H), 1.21-1.39 (m, 2H), 1.28 (s, 3H), 1.13 (d, J= 7.2 Hz, 3H), 0.84 (d, J= 6.6 Hz, 3H).

(2aR,4S,5aR,6S,8S,8aR)-4,6,8-Trimethyldecahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-ol (177). To a refluxing solution of the O-phenyl carbonothioate 176 (17.5 mg, 0.047 mmol, 1.0 equiv) in 2.8 ml of benzene was added dropwise a mixture of AIBN (3.6 mg, 0.022 mmol, 0.5 equiv) and TMS 3 SiH (34.5 µl, 0.11 mmol, 2.3 equiv) in 510 µl benzene over 45 min. The mixture was refluxed for (2aR,3S,5S,5aR,8aR)- 3,5,7-Trimethyl-2,2a,3,4,5,5a,6,8a-octahydro-1H-pyrrolo[2,1,5-de] quinolizine (1). To a solution of the tertiary alcohol 174 (10.4 mg, 0.05 mmol, 1.0 equiv) in 6 ml of benzene was added p-TsOH.H 2 O (70 mg, 0.37 mmol, 7.4 equiv) followed by refluxing the reaction mixture for 8 h. The reaction was then cooled down and diluted with DCM and quenched with 10%

NaOH. The aqueous layer was extracted 4 times with DCM and the combined organic layers were dried over magnesium sulphate and evaporated in vacuo to obtain the crude product containing both isomers 1 and 175 in a ratio of 6:1 respectively. Purification over silica gel using pentane/EtOAc (10% ® 50%) as eluant afforded 1 (6.0 mg, 63% yield) as a colorless oil. R f 0.20 (100% EtOAc).

IR (film): ν 2955, 2925, 2852, 1658, 1459, 1376 cm -1 .

1 H NMR (C 6 D 6 , 500 MHz): δ 5.17 (br s, 1H), 3.89 (br s, 1H), 2.97 (ddd, J= 1.2, 4.7, 11.6 Hz, 1H), 2.15 (ddd, J= 5.2, 9.9, 9.9 Hz, 1H), 1.96-2.09 (m, 2H), 1.80 (dddd, J= 1.6, 5.1, 8.7, 10.7 Hz, 1H), 1.59 (s, 3H), 1.53-1.60 (m, 1H), 1.20-1.40 (m, 6H), 1.30 (d, J= 7.1 Hz, 3H), 0.81 (d, J= 6.5 Hz, 3H).

13 C NMR (C 6 D 6 , 125 MHz): δ 129. 91, 126.79, 60.97, 58.95, 57.02, 36.35, 33.34, 33.11, 30.13, 29.17, 28.72, 24.15, 20.76, 19.41. HRMS calcd for C 14 H 23 N: 206.19033 Found: 206.19045 (MH) + .

FIGURE 1 :

 1 FIGURE 1: ALKALOID (-)-205B ................................................................................................... --FIGURE 2: GRAMINE ................................................................................................................ --FIGURE 3: BIOACTIVE NATURAL PRODUCTS FROM DIVERSE SOURCES .................................................. --FIGURE 4: BIOGENESIS OF SECONDARY METABOLITES ..................................................................... --FIGURE 5: CABERGOLINE AS DRUG AGENT .................................................................................. --FIGURE 6: ALKALOIDS ISOLATED FROM AMPHIBIANS ...................................................................... --FIGURE 7: ALKALOID (-)-205B -DENDROBATES PUMILIO ............................................................. --FIGURE 8: NEUROTRANSMITTERS ACROSS SYNAPSE ....................................................................... --FIGURE 9: DIAGRAMMATIC REPRESENTATION OF THE NACHR ION-CHANNEL PENTAMERS ...................... --FIGURE 10: NEURONAL NACHRS AGONISTS AND ANTAGONISTS ..................................................... --FIGURE 11: SELECTIVE ACTIVITY OF DENDROBATID FROG'S ALKALOIDS AND ANALOGUES ON NACHR ...... --FIGURE 12: EARLY DISCOVERED NACHRS AGONISTS AS POTENTIAL THERAPEUTIC AGENT ...................... --FIGURE 13: THERAPEUTIC AGENTS FOR AD ................................................................................. --FIGURE 14: FORMATION OF AMYLOID PLAQUE -AD BRAIN ........................................................... --FIGURE 15: PARTIAL AGONIST FOR a 7 NACHR ............................................................................. --FIGURE 16: POSSIBLE MECHANISMS OF [2+2] CYCLOADDITION ...................................................... --FIGURE 17: ORBITAL INTERACTIONp ELECTRON MOVEMENTS ASSOCIATED WITH [p2 S + (p2 S + p2S)] MECHANISM ................................................................................................................. --FIGURE 18: 2 POSSIBLE TRANSITION STATES OF [2+2] CYCLOADDITION ............................................. --FIGURE 19: COMMON SILICON TETHERS .................................................................................... --FIGURE 20: NATURAL PRODUCTS BEARING INDOLIZIDINE CORE ....................................................... --FIGURE 21: 1 H NMR OF ALKALOID (-)-205B ............................................................................. --FIGURE 22: 13 C NMR OF ALKALOID (-)-205B ........................................................................... --

Figure 1 :

 1 Figure 1: Alkaloid (-)-205B

Figure 1 :

 1 Figure 1: Alcaloïde (-)-205B

6

  (a) Nirmal, S. A.; Pal, S. C.; Otimenyin, S.; Aye, T.; Elachouri, M.; Kundu, S. K.; Thandavarayan, R. A.; Mandal, S. C. "Contribution of Herbal Products in Global Market" The Pharma Review 2013. (b) Ekor M. Front. Pharmacol.

Figure 3 :

 3 Figure 3: Bioactive Natural Products from Diverse Sources

Figure 4 :

 4 Figure 4: Biogenesis of secondary metabolites

  photosynthesis in plants

  (a) Lazarus, L. H.; Bryant, S. D.; Attila, M.; Salvadori, S. Environ. Health Perspect. 1994, 102, 648-654. (b) Sullivan, J. P.; Decker, M. W.; Brioni, J. D.; Donnelly-Roberts, D.; Anderson, D. J.; Bannon, A. W.; Kang, C. H.; Adams, P.; Piattoni-Kaplan, M.; Buckley, M. J. J.Pharmacol. Exp. Ther. 1994, 271, 624-631.

Figure 7 :

 7 Figure 7: Alkaloid (-)-205B -Dendrobates Pumilio

  of Biological Activity of AlkaloidsAlkaloids are widely distributed in plants, bacteria, marine animals, fungi, arthropods, amphibians, algae, also in birds and mammals. It seems that their presence is fundamental for the protection of the living organism, opposing the previous beliefs considering them as waste products. Although alkaloids accumulated in the skin of animals were proved to serve as neurotoxin such as the Dendrobatid frog's alkaloids, they can also act as therapeutic agent if they are supplied in lower doses. In such case, their poisonous effects are avoided and converted into interesting pharmacological activities such reducing blood pressure, killing tumor cells and relieving pain.39

Figure 8 :

 8 Figure 8: Neurotransmitters across synapse

Figure 9 :FigureFigure 11 :

 911 Figure 9: Diagrammatic representation of the nAChR ion-channel pentamers

  to the d-secretase found at the plasma membrane releasing the APP intracellular Cterminal domain (AICD) in the cell and the soluble peptide p3 out of the cell. Whereas in the amyloidogenic pathway, the APP is first cleaved by the b-secretase releasing the soluble APP fragment b (sAPPb) followed by the d-secretase to give the AICD intracellularly leaving behind the Ab peptides monomers out the neurons that are normally degraded by specific enzymes and metabolized by microglia (Figure14). These peptides have the capacity to interact with similar molecules to self-assemble into insoluble fibrils, which in turn bond with other fibrils to form amyloid sheets. Their molecular conformation makes them strongly resistant to degradation by proteolytic enzymes. The deposition of these Ab peptides extracellularly is a characteristic of several neurodegenerative diseases; Alzheimer's disease and Down's syndrome.

Figure 14 :

 14 Figure 14: Formation of Amyloid Plaque -AD Brain

Figure 15 :

 15 Figure 15: partial agonist for a7 nAChR

  Scheme 8: Completion of Micalizio Synthesis

  67 (a) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-484. (b) Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc.

  Scheme 9: Synthesis of Intermediate 50

Figure 16 :

 16 Figure 16: Possible mechanisms of [2+2] cycloadditionMore precisely, the reaction is now described, according to Burke's suggestion 82 , to proceed through a concerted non-synchronous process which follows [p2 s + (p2 s + p2s)] mechanism 83 which is illustrated in Figure17. This mechanism counts for the non-synchronous formation of the bonds giving rise to partial separation of charges.

Figure 17 :

 17 Figure 17: orbital interactionp electron movements associated with [p2s + (p2s + p2s)] mechanism The [2+2] cycloaddition reactions are known to proceed with high degree of regioselectivity and stereoselectivity. The high degree of regiocontrol observed when non-symmetrical alkenes are used

Figure 18 :

 18 Figure 18: 2 possible transition states of [2+2] cycloaddition

  Figure 19: Common Silicon Tethers

O

  Scheme 23: TST-based Diels Alder Reaction

  Scheme 24: TST application in Metathesis(1,4-stereocontrol) Asymmetric RCM being induced by TST was studied by Evans et al.98 on wide variety of substrates.

(

  Scheme 34: Retrosynthetic Analysis of New Approach

  Scheme 35: Synthesis of Indolizidinone Intermediate 45

  Scheme 39: Mechanistic representation for the reduction-cyclization sequence

  Scheme 46: Buchwald's Conditions -No Formic acid

  (a) Arriba, À. L. F.; Lenci, E.; Sonawane, M.; Formery, O.; Dixon, D. J. Angew. Chem. Int. Ed. 2017, 56, 3655-3659. (b) Xie, L.-G.; Dixon, D. J. Chem. Sci. 2017, 8, 7492-7497. (c) Gabriel, P.; Gregory, A. W.; Dixon, D. J. Org. Lett. 2019, 21, 6658-6662. (d) Xie, L.-G.; Dixon, D. J. Nat. Comm. 2018, 9, 2841.

Fluoride-induced desilylation

  Scheme 48: Unsuccessful fluoride-induced protodesilylation

  Scheme 50: KO(t-Bu) and TBAF-based proto-desilylation

  122 (a) Clark, T.B.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9522-9523. (b) Nevarez, Z.; Woerpel, K. A. Org. Lett. 2007, 9, 3773-3776. (c) Anderson, L. L.; Woerpel, K. A. Org. Lett. 2009, 11, 425-428.

  Scheme 70: HAT Reduction of Alkene

  The Barton-McCombie sequence was achieved by first acylating the secondary alcohol 150 with phenyl thionochloroformate catalyzed by DMAP. The O-phenyl thionocarbonate 176 was isolated in 83% yield. Much to our delight, this thionocarbonate was reduced by TMS 3 SiH in the presence of 140 (a) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Organic Reactions 2012, 77, 161-591. (b) Majid, M.; Bakhtiari, A.; Faghihi, Z.

  project, an efficient and highly stereoselective synthetic strategy was developed for the synthesis of the alkaloid, (-)-205B. This multi-step synthesis features three remarkable reactions for the construction of the 8b-azaacenaphthylene ring and the set-up of the major stereocenters; an asymmetric [2+2] cycloaddition, a stereoselective vinylogous Mannich reaction, and a stereo-directed aza-Prins cyclization. These developed chemical transformations can be of potential use for other natural products syntheses.

Figure 20 :

 20 Figure 20: Natural Products bearing Indolizidine core

  can provide the access to both epimers 180 and 181. Moreover, by looking further on the initial steps of the synthesis, this array of isomers can be extended by applying the conditions of the trans hydrogenation (LiAlH 4 or Na/NH 3liq. ) of the alkyne 57 affecting the stereoselectivity of the[2+2] cycloaddition and the subsequent steps. (Scheme 74)

Figure 20 :

 20 Figure 20: Produits naturels portant le noyau Indolizidine

Schéma 70 :

 70 Isomères de Alcaloïde (-)-205B

  (CDCl 3 , 400 MHz): δ 5.19 (m, 1H), 4.89 (m, 1H), 3.91 (d, J= 0.8 Hz, 2H), 1.90 (dd, J= 1.4, 0.8 Hz, 3H).

  13 C NMR (CDCl 3 , 100 MHz): δ 167.5 (C), 148.8 (C), 148.1 (C), 146.5 (C), 130.9 (CH), 123.7 (CH), 120.9 (CH), 114.34 (CH), 82.1 (CH), 53.1 (CH), 53.1 (CH 2 ), 38.8 (CH 2 ), 34.4 (CH), 28.4 (CH), 25.4

  IR (film): ν 3225, 2960, 2869, 1698, 1608, 1461 cm -1 .

  13 C NMR (CDCl 3 , 100 MHz): δ 174.8 (C), 148.9 (C), 147.9 (C), 146.2 (C), 142.2 (C), 132.2 (C), 123.4 (CH), 120.8 (CH), 113.3 (CH 2 ), 72.5 (CH), 71.2 (CH), 55.4 (CH), 38.2 (CH 2 ), 36.7 (CH 2 ), 34.1 (CH 3 ), 29.3 (CH 3 ), 28.1 (CH 3 ), 25.1 (CH 3 ), 23.2 (CH 3 ), 22.4 (CH 3 ). MS (ESI): m/z 408 (MNa + , 100%), 386 (MH + ).

  13 C NMR (CDCl 3 , 100 MHz): δ 155.0 (C), 148.9 (C), 147.6 (C), 145.5 (C), 142.5 (C), 133.3 (C), 123.4 (CH), 120.6 (CH), 113.6 (CH 2 ), 80.3 (C), 80.2 (CH), 74.3 (CH), 71.9 (CH), 56.9 (CH), 38.4

  , NH 3 + isobutane): m/z 472 (M-16), 372, 358, 231. tert-Butyl (2S,3S)-5-methoxy-2-(2-methylallyl)-3-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)pyrrolidine-1carboxylate (66).

  13 C NMR (CDCl 3 , 100 MHz): δ 148.9 (C), 147.5 (C), 145.5 (C), 142.9 (C), 133.4 (C), 123.5 (CH), 120.6 (CH), 113.3 (CH 2 ), 87.3 (CH), 80.1 (C), 75.2 (CH 2 ), 72.2 (CH), 57.6 (CH), 56.7 (CH), 37.6

  13 C NMR (CDCl 3 , 100 MHz): δ 153.3(C), 152.6 (C), 148.7 (C), 145.6 (C), 142.8 (C), 132.5 (C), 125.1 (CH), 123.1(CH), 121.9 (CH), 113.7 (CH 2 ), 82.2 (CH 2 ), 81.7 (CH 2 ), 74.8 (CH), 71.2 (CH), 59.1

  13 C NMR (CDCl 3 , 100 MHz): δ 176.7 (C), 149.1 (C), 147.8 (C), 145.8 (C), 142.8 (C), 131.9 (C), 123.5 (CH), 120.6 (CH), 113.7 (CH 2 ), 80.5 (C), 78.6 (CH), 74.4 (CH), 71.2 (CH), 58.8 (CH), 55.3

  triisopropylphenyl)ethoxy)pyrrolidin-2-yl) dihydro furan-2(3H)-one (69).

  111

  1 H NMR (CDCl 3 , 400 MHz): δ 7.80-7.25 (m, 10H), 3.40 (s, 2H).(2S,3S,8R,8aR)-8-(((Chloromethyl)diphenylsilyl)oxy)-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropyl phenyl)ethoxy)hexahydroindolizin-5(1H)-one (

  3S,8R,8aR)-8-(((Chloromethyl)diisopropylsilyl)oxy)-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropyl phenyl)ethoxy)hexahydroindolizin-5(1H)-one (

  13 C NMR (CDCl 3 , 125 MHz): δ 168.1 (C), 148.3 (C), 147.3 (C), 144.6 (C), 143.8 (C), 134.0 (C), 123.1 (CH), 120.3 (CH), 111.4 (CH 2 ), 75.1 (CH), 73.2 (CH), 66.2 (CH), 59.5 (CH), 56.7 (CH), 35.3 (CH 2 ), 34.0 (CH), 33.6 (CH 2 ), 29.3 (CH), 28.8 (CH), 28.3 (CH 2 ), 26.4 (CH 2 ), 26.2 (CH 2 ), 25.1

(

  2S,3S,8R,8aR)-8-((3-Hydroxy-1,1,3,3-tetraisopropyldisiloxanyl)oxy)-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)hexahydroindolizin-5(1H)-one (137).

  13 C NMR (CDCl 3 , 125 MHz): δ 168.7 (C), 148.3 (C), 147.2 (C), 144.5 (C), 143.8 (C), 134.2 (C), 123.1 (CH), 120.3 (CH), 111.4 (CH 2 ), 75.2 (CH), 73.3 (CH), 65.8 (CH), 59.6 (CH), 56.7 (CH), 35.2

  MS (ESI): m/z 716.52 (MH + , 100%). HRMS calcd for C 41 H 74 NO 5 Si 2 : 716.5100. Found: 716.5075 (MH +). 5S,8S,9S,10aR)-3,3-Diisopropyl-8-(2-methylallyl)-9-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) hexahydro-1H-1,5-methanopyrrolo[1,2-f][1,6,2]oxazasilocin-6(3H)-one (

  13 C NMR (CDCl 3 ,125 MHz): δ 170.9 (C), 148.4 (C), 147.2 (C), 145.1 (C), 143.7 (C), 133.3 (C), 123.1 (CH), 120.3 (CH), 111.4 (CH 2 ), 74.3 (CH), 72.4 (CH), 66.0 (CH), 60.8 (CH), 56.8 (CH), 35.3

(

  2S,2aS,4R,5aR,6S,8R,8aR)-8-Hydroxy-6-((hydroxydiisopropylsilyl)methyl)-4-methyl-2-((R)-1-(2,4,6triisopropylphenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-yl formate (139).

  ): ν 3398, 2959, 2866, 1722, 1607, 1462 cm -1 .

  13 C NMR (CDCl 3 ,125 MHz): δ 160.3 (CH), 148.8 (C), 147.3 (C), 145.9 (C), 133.1 (C), 123.2 (CH), 120.4 (CH), 84.7 (C), 74.5 (CH), 71.1 (CH), 67.1 (CH), 60.4 (CH), 59

  MS (ESI): m/z 630.6 (MH + , 100%).HRMS calcd for C 37 H 64 NO 5 Si: 630.4554. Found: 630.4565 (MH + ).

(

  1S,5R,5aR,7S,7aS,9R,10aR)-3,3-Diisopropyl-9-methyl-7-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) dodecahydro-1,5-methano[1,6,2]oxazasilocino[7,6,5-cd]indolizin-9-yl formate (140).

(

  1S,5R,5aR,7S,7aS,9R,10aR)-3,3-Diisopropyl-9-methyl-7-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) dodecahydro-1,5-methano[1,6,2]oxazasilocino[7,6,5-cd]indolizin-9-ol (142). Data for compound 142 IR (film): ν 3365, 2959, 2864, 1608, 1461 cm -1 .

  13 C NMR (CDCl 3 , 125 MHz): δ 148.8 (C), 147.1 (C), 146.0 (C), 133.4 (C), 123.1 (CH), 120.2 (CH), 74.3 (CH), 71.6 (C), 70.6 (CH), 68.0 (CH), 60.9 (CH), 59.2 (CH), 54.5 (CH), 36.8 (CH 2 ), 34.0 (CH), 33.4 (CH 2 ), 32.3 (CH 2 ), 31.6 (CH 2 ), 31.4 (CH), 29.2 (CH), 28.0 (CH), 25.7 (CH 3 ), 25.2 (CH 3 ),

(

  1R,5S,8S,9S,10aR)-3,3-Diisopropyl-8-(2-methylallyl)-9-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) octahydro-1H-1,5-methanopyrrolo[1,2-f][1,6,2]oxazasilocine (144). A solution of 1M LAH in Et 2 O

(

  2S,2aR,4R,5aR,6S,8R,8aR)-8-((tert-Butyldimethylsilyl)oxy)-4,6-dimethyl-2-((R)-1-(2,4,6-triisopropyl phenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-ol (171). To a solution of alcohol 75 (8.0 mg, 0.017 mmol, 1.0 equiv) in dry DCM (300 µl) were added Et 3 N (30 µl, 0.215 mmol, 12.6 equiv)

  MS (ESI): m/z 628.58 (MH + , 100%).

  2aR,4R,5aR,6S,8R,8aR)-8-Hydroxy-4,6-dimethyl-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-yl acetate (173). To a THF solution (500 µl) of the silylated alcohol172 (5.8 mg, 9.2*10 -3 mmol, 1.0 equiv) was added 40 mg of TBAF.H 2 O (0.14 mmol, 15 equiv) at RT. The reaction mixture was stirred for 24h before diluting with Et 2 O and quenching with water. The aqueous layer was extracted with Et 2 O (3 times) and the combined organic layers were dried over MgSO 4 , then concentrated under vacuum to afford 23.7 mg of the crude product.

(

  2S,2aR,4R,5aR,6S,8aR)-4,6-Dimethyl-8-oxo-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-yl acetate (174). A solution of oxalyl chloride (5 µl, 0.06 mmol, 6.0 equiv) in dry DCM (150 µl) was cooled at -78 °C and treated dropwise with DMSO (20 µl, 0.28

  127

  (CDCl3, 400 MHz): δ 1.86 (s, 9H).

  with saturated NH 4 Cl and diluted with EtOAc. Both layers were separated, and

  133

  1 H NMR (400 MHz, CDCl 3 ): δ 7.58-7.73 (m, 5H), 3.64 (s, 3H).

(

  2S,2aS,4R,5aR,6S,8R,8aR)-8-((1-(tert-Butyl)-1H-tetrazol-5-yl)oxy)-4,6-dimethyl-2-((R)-1-(2,4,6triisopropylphenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizin-4-ol (164). Oxalyl chloride (12 µl, 0.142 mmol, 6.6 equiv) in dry THF (150 µl) was treated dropwise with DMSO (70 µl, 0.98 mmol, 46.0 equiv) at -78 °C. After stirring for 40 min at -80°C<T<-65°C, the mixture was re-cooled to -78 °C and alcohol 75 (10.0 mg, 0.021 mmol, 1.0 equiv) was added slowly as a solution in 200 µl of THF. Once the reaction mixture was stirred for 1h at -80°C<T<-65°C, Et 3 N (70 µl, 0.50 mmol, 23.6

  0. MS (ESI): m/z 596.29 (MH + , 100%). HRMS calcd for C 35 H 58 N 5 O 3 : 596.4534. Found: 596.4526 (MH + ).(1S,2aR,5S,5aR,7R,8aS)-3-(((1-(tert-Butyl)-1H-tetrazol-5-yl)sulfonyl)methyl)-5,7-dimethyl-1-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)decahydro-1H-pyrrolo[2,1,5-de]quinolizine-3,7-diol (165-H).

  ): m/z 674.50 (MH + , 100%).HRMS calcd for C 36 H 60 N 5 O 5 S: 674.43097. Found: 674.42996 (MH + ).(1S,2aR,5S,5aR,7R,8aS)-7-Hydroxy-5,7-dimethyl-1-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) deca hydro-3H-pyrrolo[2,1,5-de]quinolizin-3-one (153). To a solution of alcohol 75 (110.0 mg, 0.233 mmol, 1.0 equiv) in 2.4 ml MeCN were added DMAP (22.7 mg, 0.186 mmol, 0.8 equiv), 2,2'bipyridyl (22.7 mg, 0.145 mmol, 0.6 equiv) and 2-azaadamantane N-oxyl (12.9 mg, 0.085 mmol, 0.4 equiv) and CuCl (37.7 mg, 0.381 mmol, 1.6 equiv) at room temperature. The mixture was stirred at the room temperature under open air atmosphere for 30 min. The reaction was monitored by TLC, noting the color change of the mixture from brown to green indicating the completion of the reaction.The reaction was quenched with saturated NaHCO 3 and Na 2 S 2 O 3 and the mixture was stirred vigorously at room temperature for 5 min. The mixture was then diluted with pentane and the aqueous layer extracted with pentane (3 times). The combined organic layers were dried over MgSO 4 and evaporated yielding 203.0 mg of product 153 in mixture with 2,2'-bipyridyl. It was used for the next step without any further purification.

  2aS,5S,5aR,7R,8aS)-7-Hydroxy-5,7-dimethyl-1-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) deca hydro-3H-pyrrolo[2,1,5-de]quinolizin-3-one (159). A solution of n-BuLi in hexane (2.5 M, 75 µl, 0.1875 mmol, 8.8 equiv) was added to a solution of methyltriphenylphosphonium bromide (77 mg, 0.215 mmol, 10.1 equiv) in 0.3 ml THF at 0°C. The resulting yellow suspension was stirred for 30 min at 0°C then the mixture was cooled down to -35°C. The ketone 153 (10.0 mg, 0.021 mmol, 1.0 equiv) was added to this suspension as a solution in 0.3 ml THF and stirred for 30 min at -35°C< T<-20°C then it was warmed up to 0°C and stirred for 40 min at 0°C with subsequent 40 min at ambient temperature. The reaction was quenched with H 2 O and the aqueous layer was extracted with Et 2 O (3 times). The combined organic layers were dried over MgSO 4 and the solvent was evaporated under reduced pressure. Purification over silica gel afforded 5.3 mg of the epimerized ketone159

  MS (ESI): m/z 452.36 (MH + -H 2 O, 100%). (2S,2aS,4R,5aR,6S,8aR)-4,6-Dimethyl-8-methylene-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) deca hydro-1H-pyrrolo[2,1,5-de]quinolizin-4-ol (151). A solution of 0.6 M NaHMDS in toluene (3.8 ml,

  MS (ESI): m/z 468.22 (MH + , 100%). HRMS calcd for C 31 H 50 NO 2 : 468.3836. Found: 468.3827 (MH + ).(2S,3S,6S,8aR)-6-Methyl-3-(2-methylallyl)-8-methylene-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) octahydroindolizine (166). To a solution of oxalyl chloride (30 µl, 0.35 mmol, ~5.5 equiv) in 450

  (CDCl 3 , 500 MHz): δ 4.33 (ddd, J= 1.

  Figure 21: 1 H NMR of alkaloid (-)-205B

  1981, 103, 5454-5459. chiral inductor, which was overcome by using bulky electrophile such as TMSOTf in the presence of 2,6-lutidine generating the amino lactone 69. The basic intramolecular cyclization of the butenolide 69 afforded the indolizidinone 54 in 84% over 2 steps.(Scheme 17)

				Endo-Approach					H
				Me		O		Me	H	O	O
		OMe		Ar	O	NBoc	O SiMe 3	Ar	O	NBoc	Threo Isomer (67a)
			O	OSiMe 3		Me				Me
		NBoc
	Me		Me			CH 2				CH 2
	O		BF 3 .Et 2 O
	Ar	66	CH 2	Exo-Approach		O			H	O	O
							SiMe 3		H
				Me		O	Me
				Ar	O	NBoc		Ar	O	NBoc	Erythro Isomer (67b)
						Me				Me
						CH 2				CH 2

Scheme 17: Synthesis of Indolizidinone Intermediate III. Toward (-)-205B: "Unsuccessful Approach" i. Installation of the C 6 -axial methyl group

  Basics of the New ApproachBased on the difficult installation of the C 6 -axial methyl group by standard methylation method, 75 a new strategy was suggested ensuring a stereo-directed alkylation. This methodology is based on linking C 6 to the C 8 -hydroxyl group of the indolizidinone intermediate 54 by a transient cycle. In such way, a methyl-equivalent group is forced to be introduced at C 6 with same stereochemistry as the C 8 -hydroxyl group which was identified by X-ray analysis to be of axial position 75 (Scheme 21). This transient additional cycle should implicate certain conditions. First, it should be introduced easily and should be stable enough towards the subsequent steps for the construction the 8bazaacenaphthylene ring system. Finally, it should be easily cleaved and be able to release the expected methyl group.

	I.	H HO	Me		H BnO	6	Me		H BnO	6	H Me		H BnO		Me
	Me	N	Me O	NaH, BnBr 83%	Me	N	Me O	LiAlH 4 , -10°C formic acid	Me	N	OR	+	Me	N	Me
		O			O				O	H	Me		O
	Ar	70a	CH 2		Ar	71	CH 2		Ar	72: R = C(O)H		Ar	74	CH 2
														> 30%
										73: R = H 62% -2 steps
		CHAPTER V: ALTERNATIVE STRATEGY
					DEVELOPMENT

Scheme 21: Retrosynthetic Strategy of New Approach

  Tetrahedron 1998, 54, 2289-2338. (d) Bracegirdle, S.; Anderson, E. A. Chem Soc Rev 2010, 39, 4114-4129.

	1985,107, 500-501.

95

(a) Bols, M.; Skrydstrup, T. Chem Rev 1995, 95, 1253-1277. (b) Fensterbank, L.; Malacria, M.; Sieburth, S. M. N. Synthesis 1997, 1997, 813-854. (c) Gauthier, D. R.; Zandi, K. S.; Shea, K. J. 96 Stork, G.; Chan, T. Y.; Breault, G. A. J. Am. Chem. Soc. 1992, 114, 7578-7579. 97 Shvartsbart, A.; Smith, A. B. J. Am. Chem. Soc. 2015, 137, 3510-3519.

  In this category, the silyl tethers is used to link a directing group that can be either nitrogen-or oxygen-based in order to control the regioselectivity mainly through proximity. The scope of this methodology had been applied for C-H alkenylation, alkylation, arylation, acylation and halogenation of phenols and anilines which are difficult to be achieved in intermolecular conditions. Some examples are highlighted in Scheme 27.

	Hiyama Group complementary selectivity of vinyl silane products which seems to be dependent on the used catalyst As an application of the intramolecular alkene-hydrosilylation strategy, a new chiral center was
	Scheme 26: Silicon Tethers in C-H activation NMe Pd(OAc) 2 , PCy 3 Et 2 NH, DMA 56% Si O Me Me H 2 PtCl 6 i-Pr OTf Si 91 H Si i-Pr i-Pr efficiently introduced en route to the synthesis of (+)-obtusenyne 108, a medium ring oxacycle. 104 i-Pr Si N Me 92 i-Pr i-Pr O Si H Me Me O O Si (RuCl 2 (C 6 H 6 )) 2 Me i-Pr i-Pr and the silicon substituents (Scheme 28). Me (Scheme 30B)
						Me					90%			Me		Me		Me	71%	H
	On the other hand, recent studies have provided the access for a wide range of functionalized organic Marshall, Denmark: syn, exo Denmark: anti, exo 98 99 100 101
	molecules through the efficient construction C-C, C-X, C-O and C-B bonds by C-H activation. 101 HO Me Scheme 30: TST-based Hydrosilylation of Alkenes
									Me									1-(HMe 2 Si) 2 NH	Me	O Si Me
	H 2 C	CH 2		I					102		5	Me	I	Trost: anti, endo 2-(Cp*Ru(MeCN) 3 )PF 6 97%	103	H	5	Me
	Me	Si PMBO O Me		O	Me	Schrock catalyst 92%	Me	Si PMBO O Me		O		Me	(allylPdCl) 2 TBAF 61%	HO PMBO	O	Me	6 steps	HO	O	Me
					85									86				87	88
																		(+)-brasilenyne
																		CH
		i-Pr		Si i-Pr	N N			Pd(PAc) 2 , NXS Halogenation		i-Pr		Si i-Pr		N N	+	n-Bu-B(OH) 2	Alkylation Pd(PAc) 2 , Boc-L-Leu	i-Pr	Si i-Pr	N N
					I				PhI(OAc) 2 , DCE 88%					H	Ag 2 O, Li 2 CO 3 1,4-benzpquinone	n-Bu
	Ph		Ph	95 OTBS	OH 104	Me	Me	R 2-karstedt's catalyst 1-(HMe 2 Si)NH oxidation CH 2 CH 2 Pt	93a: R=OMe Me 93b: R=Ph 94: R=F Pd(PAc) 2 , PhI(OPiv) 2 , Me AgOAc, DCE 82% OTBS Si O Ph 105	Me	Me	H 2 O 2 KF	85%	Ph	MeO OTBS OH 85% dr 93:7 syn OH 106	97 Me Me
										Me Me	Si	O	Si	Me Me		i-Pr		N	reductive elimination
														i-Pr		Si
																		N	Me	Me
				R	H	i-Pr Br Gevorgyan Group H H R Me O Si i-Pr Me L Pt	i-Pr	1-Pd(OAc) 2 , P(C 6 F 5 ) 3 K 3 PO 4 , Ag 2 CO 3 Scheme 27: TST directed C-H activation M=PtL n Me OPiv F 96 Ph Ph Me R = Si OTBS M O	OTBS	R	AcO
	O iv. Hydrosilylation and Carbosilylation Si 2-TBAF O 3-Ac 2 O, Py 89 51-96% -3 steps	OAc 90
	TSTs have also seen well developed applications in unsaturated systems. Alkyne-hydrosilylations are
	challenging as they require the control over both the regioselectivity and the stereoselectivity. Several

Scheme 25: TST-RCM applied in natural products synthesis iii. C-H functionalization Employment of silyl tethers for intramolecular C-H bond activation had given significant attention due to its beneficial use in organic synthesis. The silicon tethered chemistry had been investigated in this arena by both the Hiyama and Gevorgyan groups for the formation of silicon-bridged biaryls (Scheme 26).

100

It is notable that the silyl group can be further functionalized either by oxidation or protodesilylation.

99 Denmark, S. E.; Yang, S. M. J. Am. Chem. Soc.,

2002, 124, 15196-15197. 100

(a) Shimizu, M.; Mochida, K.; Hiyama, T. Angew. Chem., Int. Ed. 2008, 47, 9760-9764. (b) Huang, C.; Gevorgyan, V. Org. Lett. 2010, 12, 2442-2445. groups have developed hydrosilylation's catalysts that provide access to a wide range of 101 (a) Parasram M.; Gevorgyan V. Acc. Chem. Res. 2017, 50, 2038-2053. (b) Usman, M.; Zhang, X.W.; Liu, W.B. Synthesis 2019, 51, 1529-1544. 102 Scheme 28: TST-based Hydrosilylation of Alkynes Applying this strategy to alkenes is more interesting as it will lead to the installation of new stereocenters. The chair-like transition state with the olefin being in a pseudo-equatorial position is expected to be responsible for the stereocontrol allowing the formation of a product 105 with high level of stereoinduction (Scheme 30A). 103 Scheme 29: TST-based Hydrosilylation of Alkenes 102 (a) Tamao, K.; Maeda, K.; Tanaka, T.; Ito, Y. Tetrahedron Lett. 1988, 29, 6955-6956. (b) Marshall, J. A.; Yanik, M. M. Org. Lett., 2000, 2, 2173-2175. (c) Denmark, S. E.; Pan, W. T. Org. Lett., 2001, 3, 61-64. (d) Denmark, S. E.; Pan, W. T. Org. Lett., 2003, 5, 1119-1122. (e) Denmark, S. E.; Pan, W. T. Org. Lett., 2002, 4, 4163-4166. (f) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc., 2003, 125, 30-31. 103 Li, F. Z.; Roush, W. R. Org. Lett. 2009, 11, 2932-2935.

  Scheme 31:Tandem Carbosilylation -Allylation Worthwhile, tether-controlled asymmetric stereoinduction can be achieved by utilizing chiral TST where it can control the diastereoselectivity of the silylformylation/allylation reaction.106 This is demonstrated in the total synthesis of the polyketide dolabelide D 120, where syn 1,5-stereocontrol was achieved as a result of the chiral TST 117 (Scheme 32).

	H 2 C	O	Si	H	CH 2			Rh(acac)(CO) 2			O	Si		CH 2 O	CH 2		H 2 O 2	OH	O	OH	CH 2
	i-Pr										CO		i-Pr								NaHCO 3	i-Pr
			112												113					114
																							83% -2 steps
																							dr 8:1
												O
								Me	O Si H i-Pr Me (a) more accessible than (b) OTBDPS H O Si H b O a CH 2 Me	then H 2 O 2 , KOH (Ph 3 P) 3 RhCl + O 2 reflux 58% dr 21:1		HO	HO	O	Me	OTBDPS
												107											108
																		Me
	Me	H	Si	H t-Bu	+	HC		OH	n-Pr	CuCl, NaOt-Bu 95%, d.r. 4:1 PPh 2 PPh 2		HC	H	Si	O t-Bu	n-Pr	1-(Rh(acetone) 2 -(P(OPh) 3 ) 2 )BF 4 CO	H Me	O	Si	t-Bu	O	n-Pr	2-MeLi
		115								116								117
																							OH	OH
						H 2 C																Me
																							Me
	Me CH 2 H 2 C OH Me			O TBS Si H OH	CH 2 n-Pr	Rh(acac)(CO) 2 CO 1-TESCl, Et 3 N 2-BuLi, CuBr, SMe 2 , THF/DMPU, MeI	Me CH 2 Me	O OTES	Si Me	O CH 2 OTES n-Pr	CH 2	NaHCO 3 H 2 O 2 HO	OAc Me	Me	O Me	OH O Me	OH Me	OH OAc n-Pr CH 2
			Me	118	Me							Me	Me 119							Me	Me
			109 56%, dr 4:1								68%	110					Me	111
																							dolabelide D 120	59% -2 steps 5% of other diastereoisomers
												Scheme 32: TST-based Synthesis of Dolabelide D
								H 2 C
																		O
	O H 2 C v. Silicon-Tethered Nucleophilic Addition Reactions O Si O Si H
	Me TST have been applied for the formation of a chiral tertiary alcohol via the nucleophilic addition to a Me Me H Me Me Me
	ketone based on chirality transfer within the molecule. In the intermolecular fashion, the
	stereochemical outcome of this kind of addition is directed by steric hindrance and/or

Whereas the 1,5-stereoinduction observed in 113 from alkynyl substrates is sterically directed with the transfer of the back-allyl group from the least hindered face. 104 .(a) Mak, S. Y. F.; Curtis, N. R.; Payne, A. N.; Congreve, M. S.; Wildsmith, A. J.; Francis, C. L.; Davies, J. E.; Pascu, S. I.; Burton, J. W. Holmes, A. B. Chem. Eur. J. 2008, 14, 2867-2885. (b) Burton, J. W.; Anderson, E. A.; O'Sullivan, P. T.; Collins, I.; Davies, J. E.; Bond, A. D.; Feeder, N.; Holmes, A. B. Org. Biomol. Chem. 2008, 6, 693-702. 105 (a) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587-8588. (b) O'Malley, S. J.; Leighton, J. L. Angew. Chem., Int. Ed. 2001, 40, 2915-2917.

stereoelectronic effects. In consequence, a low to moderate diastereoselectivity will be obtained. 106 (a) Schmidt, D. R.; O'Malle, S. J.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 1190-1191. (b) Park, P. K.; O'Malley, S. J.; Schmidt, D.

R.; Leighton, J. L. J. Am. Chem. Soc.

2006, 128, 2796-2797.

  would be synthesized by tethering the indolizidinone intermediate 54 by the appropriate silyl reagent followed by intramolecular alkylation.

																NHBz			AcO	O	OH
							Me	Me						Me	Ph	O	Me	Me
	A)	OH	O Me Me	Si 2-NaI 98% 96% Cl Me Me 1-	Cl		O	O Me Me Si	I	t-BuLi 86%		O Me	Si	Me Me OH	HO	O		HO	OBz H Me Me	OAc	O
		121					122						123	124 Taxol TM
				B)	O Me	Me Si Me	I					Me	Me			OH	Me Me
						Me		LDA 80%	Me	Si	O			O	H 2 O 2 , KF 71%			O
						O					Me								OH
						125						126						127

107 Iwamoto, M.; Miyano, M.; Utsugi, M.; Kawada, H.; Nakada, M. Tetrahedron Letters 2004, 45, 8647-8651.

  Stericol alcohol 55, indicating the high efficiency of this pathway (17.3% yield over 13 steps Þ 87%/step). (Scheme 35)

	starting from 16.7 g of the (R)-
												O
		i-Pr	Me
			OH	1-KH, trichloroethylene 76%	Me			Me	1-(2+2) cycloaddtion	Me		NH	Me
	i-Pr	55	i-Pr	2-n-BuLi, allyl iodide 3-Hydrogenation	Ar	O	58	CH 2	2-Tamura's Reagent 3-Zn-Cu	Ar	O	64	CH 2
	(R)-Stericol chiral auxilliary								48.5% -5 steps
												1-(Boc) 2 O 90% 2-LiBHEt 3 3-dimethoxy propane
												4-Vinylogous-Mannich reaction
													64% -3 steps
												O
					HO						O
					H		N	O	1-NaBH 4 , CuCl 2 .2H 2 O 97%		H	NBoc
				Me			Me	2-TMSOTf	Me			Me
					O				3-NaOMe 84% -2 steps		O
				Ar				CH 2		Ar			CH 2
							54					67a

Nebois, P.; Greene, A. E. J. Org.

Chem. 1996, 61, 5210-5211. (d)

Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J. Org. Chem. 1998, 63, 4660-4663. (e) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. J. Org. Chem. 1999, 64, 1383.

  The output of the cyclization condition is the Si-O bond cleavage exclusively with 0% of the desired silyl tethered intermediate. (Scheme 37)

Scheme 37: Trial with Chloro(choloromethyl)diphenylsilane

  this linker toward basic hydrolysis, this strategy argues well for the development of a more general new chiral transfer methodology through silyl tethers. Work is currently in progress in the laboratory in order to define the scope and limitation of this chiral transfer methodology.

				i-Pr H	Si	i-Pr Cl	I -78°C	Cl	MeLi -20°C	i-Pr H	Si	i-Pr	Cl	TCCA, DCM RT	Cl i-Pr	Si 134	i-Pr	Cl
																85 -94 % over 2 steps
																Cl
																i-Pr	i-Pr	i-Pr
														i-Pr	Si	O	Si
																O
																6
																H	H
								i-Pr Cl	Si 134	i-Pr	Cl	Me		N	Me O	LHMDS, THF	Me	N	O Me
									85%							O	-78°C	-20°C	O
												Ar			135	CH 2	91%	Ar	136	CH 2
		HO
	Me Ar	O H	N 54	Me CH 2 O	DMAP, imidazole DCM, 50°C	i-Pr Si Cl Si O i-Pr 5-15% i-Pr i-Pr Cl 138	Me	i-Pr	i-Pr Si i-Pr O H O	i-Pr Si O N	OH	Me O	H O	J H6 = 1.3 Hz, 2.3 Hz, 5.8 Hz, 7.7 Hz CH 2 H O H 6 Me N O Me Si H Ar H
												Ar				137	CH 2	i-Pr	i-Pr	136

1959, 30,[11][12][13][14][15]

. (b) Karplus, M. J. Am. Chem. Soc.

1963, 85, 2870-2871.

of

  Saponification of the untethered tricyclic formate 139 led to the corresponding tertiary alcohol. As noticed that Si-O bond is favored in basic medium, saponification furnished 2 products; cyclized 142 and uncyclized 143 in approximately 5:4 ratio (Scheme 41). This result can stand for another evidence that no epimerization occurred at the C 6 chiral center upon the previous step.

			i-Pr O	Si	i-Pr		HO	HO i-Pr	Si	i-Pr							i-Pr O	Si	i-Pr				HO	i-Pr HO	Si	i-Pr
		H					H					H						H		H				H
	Ar Me	O	136 N	CH 2 O Me	-5°C < T < 0°C then HCOOH 1h LiAlH 4	Ar Me	O	N H 68% 139	Me	O	O	H	+	Ar Me	O	N H 13.6% Me 140	O	O	H	+	Ar Me	O	9% 141 N	CH 2 Me
													O
						J (H 7 axial -H 6 ) = 6.0 Hz				H
						J (H 7 axial -H 8 ) = 2.5 Hz
									NOE			O
								H 7	H 5					Me
							NOE		H 8a	H 6
														H
							H 8				N				H		NOE
													O
							OH										Me
							HO		Si	i-Pr		Ar
							i-Pr			139

Scheme 40: LAH-based reduction and Aza-Prins Cyclization Scheme 41: Saponification of formate 139

  74, it was noticed that H 5a (azaacenapthylene numbering conserved for clarity) has different coupling constants with the surrounding protons (Scheme 43). Contrary to what was published previously, 75 the coupling constant of H 5a in74 (10.6 Hz) infers that H 6 more probably occupies an axial position.

				Scheme 43: 2 epimers of the over-reduced product (145 and 74)
	i-Pr	i-Pr					i-Pr	i-Pr			i-Pr	i-Pr
			Si						Si				Si
		HO						O			HO
	HO											HO
	H			H				H		H		H	H
	Me		N	O	H	K 2 CO 3 , MeOH RT	Me		N	OH	+	Me	N	OH
	O		H	Me	O			O	H	Me		O	H	Me
	Ar						Ar					Ar
			139						142				143
									52 %				42 %
	i-Pr	i-Pr				i-Pr	i-Pr				i-Pr	i-Pr
		O	Si				O	Si				HO	HO	Si
													6
	H		N	O	LiAlH 4 then H 2 O	H	N	HCOOH		H	N	5a
	Me			Me	65%	Me			Me	61%		Me	Me
	O						O					O
	Ar	136	CH 2		Ar	144	CH 2			Ar	141	CH 2

  the variable formation of the styrene derivative 60 probably because of the medium acidity or the high electrophilicity of the reagent triggering this benzyl ether cleavage. (Scheme 54)

	Me		Me		Me						H 2 C					HO
	H	N	H		H	N		Me H			H	N		Me H		H	N	Me H
		H	Me		HO	H	Me	OH		Me Ar	O	H	Me	OH	Me Ar	O	H	Me	OH
		1				150						151					75
		Alkaloid (-)-205B
	N H With the requisite 8b-azaacenaphthylene ring system 75 in hand, the next step is the conversion of H H HO Me O Ar Me OH Me N H Si O i-Pr i-Pr O O Me Ar Me CH 2 1-IrCl(CO)(PPh 3 ) 2 , (Me 2 SiH) 2 O then HCOOH 2-CsF, KOt-Bu, 3% H 2 O (v/v) DMSO, 120°C VI. Formation of C 8 -equatorial methyl group the secondary axial hydroxyl group at C 8 to equatorial methyl group 152. There is 2 plausible pathways for such transformation (Scheme 53); either by the 2 steps-conversion to a good leaving group followed by substitution with Gilman reagent (pathway A) or the 3 steps-oxidation, olefination and hydrogenation -with the equatorial methyl group being the major epimer according to Smith work 62 (pathway B). H H XO Me H H Me Me Me 2 CuLi 136 Scheme 52 : Retrosynthetic Strategy of alkaloid (-)-205B Scheme 54: Triflation of alcohol 75
			pathway A			Me		N	OH				52% -2 steps Me	N		OH
								O	H	Me				O	H	Me
			HO		Me		Ar							Ar	152
			H		H
				N
		Me			OH										hydrogenation
			O	H	Me
		Ar	75
								O		Me				H 2 C		Me
			pathway B					H		H				H		H
					oxidation				N	OH	olefination		N		OH
						Me							Me
								O	H	Me				O	H	Me
							Ar		153					Ar	151
					Scheme 53: 2 pathways for the formation of C8-equatorial methyl group	by the standard
	oxidation-methylenation sequence. (Scheme 52)
	i. The 2-Steps Approach

123 Hogrefe, R. I.; McCaffrey, A. P.; Borozdina, L. U.; McCampbell, E. S.; Vaghefi, M. M. Nucleic Acids Research 1993, 21, 4739-4741.

Having to convert the hydroxy group into good leaving group, we have started by the attempt to produce the triflated alcohol 154. Unfortunately, we faced to the low conversion of the starting alcohol 75 yielding at best 1:2 mixture of the triflate derivative 154 and alcohol 75 respectively. Along with

  1989, 19, 1057-1060.

	HO		Me				TfO		Me		i-Pr
	H		H				H		H
	Me	N	OH	Tf 2 O, pyridine DCM, DMAP	Me		N	OH	+	i-Pr	i-Pr
	O	H	Me	conversion: 33.3%		O	H	Me
	Ar	75				Ar		154			60
									Ms		O
	HO		Me		MsO		Me			S	O	Me
	H		H	MsCl, Et 3 N	H			H			O	H	H
	Me	N	OH	DCM 4h, RT	Me		N	OH	+	Me	N
	O	H	Me		O	H	Me			O	H	CH 2
	Ar				Ar					Ar
		75					155				156
							0.2		:		1
					O						48%
				H 2 C	S
					O

125 (a) Ciabattoni, J.; Cabell, M. Tetrahedron Letters 1968, 2693-2696. (b) Shealy, Y. F.; Krauth, C. A.; Laster, W. R. Journal of Medicinal Chemistry 1984, 27, 664-670.

  2016, 138, 4962-4971.

			Mn 3+ (dpm) 3
	H		PhSiH 3
	t-Bu	Me
	high d.e.
			HMn 3+ (dpm) 2	TBHP
		t-Bu	CH 2
	HAT
			HAT
			Mn 2+ (dpm) 2
			Me
	t-Bu	Me	t-Bu

  and Reagents. All experiments were carried out under argon atmosphere with dry solvents under anhydrous conditions unless otherwise stated. Solvents and some reagents were freshly distilled and dried by standard techniques just before use. THF and Et 2 O were distilled over Nabenzophenone. DCM, DMSO, HMDS, diisopropyl amine, HMPA, Et 3 N, acetonitrile, 2,6-lutidine, pyridine, toluene, MeCN and i-PrOH were distilled over CaH 2 . Camphorsulphonic acid was crystallized from EtOAc and dried under vacuum. Trichloroacetyl chloride and oxalyl chloride were distilled over CaCl 2 . Ethylene diamine was distilled over Na. MeOH was distilled over magnesium turnings (Mg) and iodine. DMF was distilled over CaSO 4 . K(Ot-Bu) was purified by sublimation at 0.3 mmHg, 200°C. CsF and MePPh 3 Br were strictly dried at high vacuum for several hours immediately prior to use. Tf 2 O and MsCl were purified by distilling from P 2 O 5 . All other products were directly used as received from commercial sources without any purification.

					Materials and Methods
	H 2 C		Me				Me	8	Me	Me	8	Me
	H		H				H		H	H	H
			N	OH	NiCl 2 .6H 2 O, NaBH 4			N	OH		N
	Me	O	H	Me	EtOH-PEG300 (3/2) 30°C, 4h	Me	O	H	Me		H	Me
	Ar		151				Ar		175			179
	N CHAPTER VIII: EXPERIMENTAL PROCEDURE H H Me Me 6
		HO					HO		Me
		H					H					H	Me
			N	O	t-BuLi			N	O			180
	Me			Me	MeI	Me			Me
		O					O
	Ar			CH 2		Ar			CH 2		Me	8	6	Me
			54					70b			H	H
												N
												Me
												H
												181
												O
									Me
				Me								NH
	Me				Na/NH 3 liq	Me			CH 2	Me		Me
				CH 2	/ LiAlH 4		O				O
	Ar	O	57			Ar		182	Ar		183	CH 2

Solvents

  the organic layer was dried over MgSO 4 and concentrated in vacuo to afford 14.6 g of crude product58. No purification was done prior to the next step. Analytical data are in agreement with

	those reported in the literature. 75	Me
	Me IR (film): ν 2960, 2929, 2869, 1661, 1608, 1460, 1384, 1255 cm -1 . CH 2 i-Pr
		O
	i-Pr 1 H NMR (CDCl 3 , 400 MHz): δ 7.01 (s, 2H), 6.03 (d, J= 6.9 Hz, 1H), 5.34 (q, J= 6.8 Hz, 1H), 4.72 i-Pr
	(br s, 1H), 4.68 (br s, 1H), 4.33 (q, J= 6.9 Hz, 1H), 3.20-3.64 (m, 2H), 2.71-2.96 (m, 3H), 1.74 (s,
	3H), 1.61 (d, J= 6.8 Hz, 3H), 1.20-1.27 (m, 18H).
	13 C NMR (CDCl 3 , 100 MHz): δ 147.7 (C), 145.6 (C), 144.8 (C), 133.2 (CH), 120.6 (CH 3 ), 109.6
	(CH 2 ), 103.8 (CH), 75.5 (CH), 34.1 (CH), 32.7(CH 2 ), 29.2 (CH 3 ), 24.8 (CH 3 ), 24.2 (CH 3 ), 22.7
	(CH 3 ).
	Me	Me
	i-Pr	O
		CH 2
		i-Pr
	i-Pr

and

  2009, 13, 263-267.

	Me vacuo to produce 20.6 g of crude dichlorolactam 63. Analytical data are in agreement with those S O O
	reported in the literature. 75	O	NH 2
	Me	Me
	IR (film): ν 2961, 2869, 1731, 1606, 1562, 1454 cm -1 .
		O
	Cl
	Cl	NH
	Me		Me
	i-Pr	O
			CH 2
	i-Pr
	i-Pr

  The reaction was stirred 1h at RT and then diluted with DCM and quenched with brine. The aqueous layer was washed 3 times with DCM and the combined organic layers were dried over MgSO 4 and evaporated under reduced pressure. Precipitation in Et 2 O gave 4.9 g of pure hydroxyindolizidinone 54 as white solid (84% over 2 steps). Analytical data are in agreement with those reported in the literature.75

		O
		O
		H
		NH
	Me	Me
	i-Pr	O
		CH 2
		i-Pr
	i-Pr (2S,3S,8R,8aR)-8-Hydroxy-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)hexahydro
	indolizine-5(1H)-one (54). To a solution of amine 69 (6.54 g, 14.35 mmol, 1.0 equiv) in 46 ml dry
	MeOH was added 40.5 ml of freshly prepared solution of sodium methoxide in MeOH (1 M, 40.5
	mmol, 2.8 equiv).
	, 2.85 (sept, J= 6.9 Hz, 1H), 2.42-2.70 (m, 2H), 1.76-2.32 (m, 6H), 1.64 (s, 3H),
	1.52 (d, J= 6.8 Hz, 3H), 1.16-1.30 (m, 18H).
	13 C NMR (CDCl 3 , 100 MHz): δ 176.7 (C), 156.8 (C), 146.5 (C), 144.4 (C), 142.8 (C), 132.8 (C),
	122.3 (C), 111.1 (CH 2 ), 82.7 (CH), 77.6 (CH), 70.5 (CH), 58.4 (CH), 57.9 (CH), 36.7 (CH 2 ), 33.1
	(CH 3 ), 32.4 (CH 2 ), 28.3 (CH 3 ), 27.8 (CH 2 ), 27.5 (CH 3 ), 24.5(CH 3 ), 24.2 (CH 3 ), 24.1 (CH 3 ), 22.4
	(CH 3 ), 21.2 (CH 3 ).
	MS (DCI, NH 3 + isobutane): m/z 456 (MH + ), 400, 231.

  EtOAc) showed a complete consumption of starting material. The reaction mixture was quenched with water and extracted with DCM. The organic solution was dried on MgSO 4 and the solvent was removed under reduced pressure to give 5.9 mg of crude material.

		Me	Si O H HO Me Me	Si Br	Me
			O	N	O
		Me	H		Me
	i-Pr		O H	N	O
	i-Pr i-Pr i-Pr	Me Me	i-Pr O O	N	CH 2 Me O Me CH 2 CH 2
			i-Pr i-Pr
	i-Pr i-Pr
	(2S,3S,8R,8aR)-8-(((Bromomethyl)dimethylsilyl)oxy)-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropyl (1R,5S,8S,9S,10aR)-3,3-Dimethyl-8-(2-methylallyl)-9-((R)-1-(2,4,6-triisopropylphenyl)ethoxy) hexa
	phenyl)ethoxy)hexahydroindolizin-5(1H)-one (130). To a solution of alcohol 54 (6.4 mg, 0.014 hydro-1H-1,5-methanopyrrolo[1,2-f][1,6,2]oxazasilocin-6(3H)-one (131). To a solution of silyl ether
	mmol, 1.0 equiv) in 250 µl of dry DCM, Et 3 N (0.030 ml, 0.22 mmol, 15.7 equiv) and 130 (5.0 mg, 0.008 mmol, 1.0 equiv) in 300 µl of dry THF at -78°C was added 60 µl of LiHMDS
	(bromomethyl)chlorodimethylsilane (20 µl, 27.5 mg, 0.147 mmol, 10.5 equiv) were added. The solution in THF (1.0 M, 0.06 mmol, 7.5 equiv). The reaction temperature was gradually increased to
	reaction mixture was stirred at 50°C in a sealed tube for 2.5h. After cooling to room temperature, the reaction mixture was extracted with DCM to give 30.1 mg of crude material which, after silica gel purification (0-20% EtOAc in pentane), gave 8.1 mg (95% yield) of 130 as colorless oil. 1 H NMR (CDCl 3 , 500 MHz): δ 7.02 (s, 1H), 6.92 (s, 1H), 5.01 (q, J= 6.7 Hz, 1H), 4.60 (s, 1H), -15°C over 1 hour. TLC analysis (Purification over silica gel (10 ® 100% EtOAc in pentane) produced 2.8 mg (65%) of 131 as colorless
	4.58 (ddd, J= 6.2, 6.2, 8.7 Hz, 1H), 4.45 (s, 1H), 4.14 (ddd, J= 2.0, 2.0, 4.1 Hz, 1H), 3.95 (ddd, oil and 0.8 mg (22%) of the alcohol 54. (vide supra for data characterization of 54)
	J= 6.3, 6.3, 7.4 Hz, 1H), 3.80-3.70 (m, 2H), 3.15 (sept, J= 6,8 Hz, 1H), 2.84 (sept, J= 6.8 Hz, 1H), Data for compound 131
	1 H NMR (CDCl 3 , 400 MHz): δ 7.04 (s, 1H), 6.92 (s, 1H), 5.02 (q, J= 6.7 Hz, 1H), 4.66 (s, 1H), 2.43 (s, 2H), 2.41 (ddd, J= 7.0, 11.9, 18.5 Hz, 1H), 2.29 (ddd, J= 1.7, 7.2, 18.5 Hz, 1H), 2.27-2.16 1 H NMR (CDCl 3 , 500 MHz): δ 7.03 (s, 1H), 6.92 (s, 1H), 5.02 (q, J= 6.8 Hz, 1H), 4.64 (s, 1H),
	4.54-4.61 (m, 2H), 4.06 (ddd, J= 2.0 Hz , 1H), 3.95 (q, J= 7.0 Hz, 1H), 3.78-3.90 (m, 2H), (m, 3H), 1.99-1.91 (m, 2H), 1.84 (dddd, J= 1.9, 7.3, 12.1, 14.1 Hz, 1H), 1.69 (s, 3H), 1.53 (d, J= 6,6 4.57 (s, 1H), 4.56 (ddd, J= 5.8, 6.2, 9.4 Hz, 1H), 4.26 (ddd, J= 2.2, 2.2, 4.6 Hz, 1H), 3.80-3.90
	3.10-3.22 (m, 1H), 2.84 (sept, J= 6.9 Hz, 1H), 2.14-2.44 (m, 5H), 1.84-2.04 (m, 3H), 1.71 (s, 3H), Hz, 3H), 1.33-1.15 (m, 18H), 0.26 (s, 6H). (m, 3H), 3.16 (sept, J= 6.8 Hz, 1H), 2.84 (sept, J= 6.8 Hz, 1H), 2.80 (dddd, J= 2.0, 3.1, 5.3, 7.1 Hz,
	1.52 (d, J= 6.7 Hz, 3H), 1.15-1.29 (m, 18H). 13 C NMR (CDCl 3 , 100 MHz): δ 168.1 (C), 147.3 (C), 144.8 (C), 143.8 (C), 133.7 (C), 123,2 (CH), 1H), 2.41 (ddd, J= 7.8, 7.8, 13.6 Hz, 1H), 2.33 (A of ABX, J= 5.8, 14.2 Hz, 1H), 2.27 (B of ABX, J=
	120.4 (CH), 111.5 (CH 2 ), 74.6 (CH), 72.9 (CH), 66.1 (CH), 59.1 (CH), 56.7 (CH), 35.4 (CH 2 ), 34.0 9.4, 14.2 Hz, 1H), 1.98-1.90 (m, 3H), 1.72 (s, 3H), 1.54 (d, J= 6,8 Hz, 3H), 1.31-1.14 (m, 19H), 13 C NMR (CDCl 3 , 100 MHz): δ 168.5 (C), 148.5 (C), 147.4 (C), 145.2 (C), 143.8 (C), 133.8 (C), 123.3 (2CH), 120.5, 111.7 (CH 2 ), 74.8 (CH), 72.9 (CH), 64.5 (CH), 58.9 (CH), 56.9 (CH), 35.4 (CH), 33.4 (CH 2 ), 29.2 (CH), 28.7 (CH), 28.2 (CH 2 ), 26.2 (CH 2 ), 25.1, 24.9, 24.3, 24.0, 23.9, 0.94 (dd, J= 7.1, 14.8 Hz, 1H), 0.14 (s, 3H), 0,17 (s, 3H).
	(CH 2 ), 34.1 (CH), 33.2 (CH 2 ), 29.3 (CH), 28.8 (CH), 27.9 (CH 2 ), 26.2 (CH 2 ), 25.4 (CH 3 ), 25.2 22.8, 22.4, 15.7 (CH 2 ), -2.5 (CH 3 ). MS (ESI): m/z 532.45 (MLi + , 100%).
	(CH 3 ), 25.1 (CH 3 ), 24.4 (CH 3 ), 24.3 (CH 3 ), 24.2 (CH 3 ), 23.1 (CH 3 ), 22.7 (CH 3 ).
	MS (DCI, NH 3 + isobutane): m/z 456 (MH + ), 400, 371, 231. Chloro(chloromethyl)diphenylsilane (133). To a solution of chloromethyltrichlorosilane (1.0 g, 5.44
	mmol, 1.0 equiv) in 8.0 ml of dry Et 2 O was added a solution of phenylmagnesium bromide (1.7 M in
	THF, 6.40 mL, 10.8 mmol, 2.0 equiv) leading to the formation of strong white solid. The reaction

  MS (ESI): m/z 640.42 (MNa + , 100%), 618.42 (MH + ). HRMS calcd for C 36 H 61 NO 3 SiCl: 618.4109. Found: 618.4123 (MH + ).

  .1. calcd for C 36 H 60 NO 2 Si: 566.4393. Found: 566.44 (MH + ).

	MS (ESI): m/z 566.6 (MH + , 100%).

HRMS

  calcd for C 37 H 62 NO 4 Si: 612.4448. Found: 612.4451 (MH + ).

	2.11-2.23 (m, 2H), 2.01 (dd, J= 13.1, 13.1 Hz, 1H), 1.96 (br peak, 1H), 1.58-1.76 (m, 5H), 1.58 (s,
	3H), 1.48 (d, J= 6.8 Hz, 3H), 1.14-1.34 (m, 18H), 1.05 (dd, J= 7.8, 15.0 Hz, 1H), 1.0 (d, J= 6.4 Hz,
	3H), 0.84-0.98 (m, 5H), 0.83 (d, J= 7.3 Hz, 3H), 0.82 (d, J= 7.2 Hz, 3H), 0.53 (ddd, J= 2.0, 2.0,
	15.0 Hz, 1H).
	13 C NMR (CDCl 3 , 125 MHz): δ 160.3 (CH), 148.8 (C), 147.2 (C), 146.0 (C), 133.2 (C), 123.1 (CH),
	120.2 (CH), 85.2 (C), 74.3 (CH), 70.7 (CH), 67.9 (CH), 60.1 (CH), 58.3 (CH), 54.7 (CH), 34.0
	(CH), 33.4 (CH 2 ), 32.2 (CH 2 ), 31.5 (CH 2 ), 31.2 (CH), 30.2(CH 2 ), 29.2 (CH), 28.0 (CH), 25.1 (CH 3 ),
	24.8 (CH 3 ), 24.7 (CH 3 ), 24.3 (CH 3 ), 24.0 (CH 3 ), 23.8 (CH 3 ), 23.4 (CH 3 ), 22.9 (CH 3 ), 17.9 (CH 3 ),
	17.6 (CH 3 ), 17.2 (CH 3 ), 16.8 (CH 3 ), 15.1 (CH), 14.8 (CH 2 ), 13.1 (CH).
	MS (ESI): m/z 612.6 (MH + , 100%).
		i-Pr	i-Pr
			Si
		O
		H		H
			N	O	H
	Me
	i-Pr	O	H	Me	O
		i-Pr
	i-Pr
	Data for compound 140
	IR (film): ν 2959, 2864, 1722, 1607, 1461 cm -1 .
	1 H NMR (CDCl 3 , 500 MHz): δ 8.05 (s, 1H), 7.04 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 4.99
	(q, J= 6.8 Hz, 1H), 3.97 (app s, 1H), 3.84-3.93 (m, 2H), 3.08-3.23 (m, 3H), 2.78-2.92 (m, 2H),

HRMS

  calcd for C 36 H 64 NO 4 Si: 602.4605. Found: 602.4611 (MH + ).

	Hz, 1H),
	0.93-1.05 (m, 13 H), 0.81-0.91 (m, 2H).
	13 C NMR (CDCl 3 ,125 MHz): δ 148.8 (C), 147.2 (C), 145.9 (C), 133.3 (C), 123.2 (CH), 120.3 (CH),
	74.5 (CH), 71.3 (C), 71.0 (CH), 67.2 (CH), 61.2 (CH), 60.1 (CH), 53.7 (CH), 37.2 (CH 2 ), 33.6 (CH),
	32.8 (CH 2 ), 32.0 (CH 2 ), 31.0 (CH), 29.1(CH 2 ), 28.0 (CH), 25.8 (CH 3 ), 25.0 (CH 3 ), 24.9 (CH 3 ), 24.6
	(CH 3 ), 24.5 (CH 3 ), 23.9 (2CH 3 ), 23.2 (CH 3 ), 20.8 (CH 2 ), 17.7 (CH 3 ), 17.5 (2CH 3 ), 17.4 (CH 3 ), 13.4
	(CH), 13.2 (CH).
	MS (ESI): m/z 602.46 (MH + , 100%).

HRMS

  calcd for C 36 H 62 NO 3 Si: 584.4499. Found: 584.4500 (MH + ).

	MS (ESI): m/z 584.6 (MH + , 100%), 606.6 (MNa + ).

HRMS

  Hz, 1H), 3.19 (sept, J= 6.8 Hz, 1H), 2.84 (sept, J= 6.9 calcd for C 36 H 62 NO 2 Si: 568.4550. Found: 568.4542 (MH + ). calcd for C 36 H 64 NO 3 Si: 586.4655. Found: 586.4652 (MH + ).

	Hz, 1H), 2.81 ( dd, J= 2.9, 11.0 Hz, 1H), 2.70 (app t, J= 8.6 Hz, 1H), 2.65 (ddd, J= 1.9, 1.9, 10.9 1 H NMR (CDCl 3 , 500 MHz): δ 7.04 (d, J= 1.8 Hz, 1H), 6.95 (d, J= 1.8 Hz,1H), 5.04 (q, J= 6.8 Hz, IR (film): ν 3408
	Hz, 1H), 2.33 (dd, J= 4.0, 14.7 Hz, 1H), 2.09-2.19 (m, 3H), 1.77 (s, 3H), 1.76 (dddd, J= 2.2, 2.2, 1H), 4.74 (br s, 2H), 4.00 (ddd, J= 6.3, 6.3, 8.7 Hz, 1H), 3.91 (sept, J= 6.8 Hz, 1H), 3.77 (app s,
	3.6, 13.6 Hz, 1H), 1.64 (ddd, J= 6.4, 8.6, 12.3 Hz, 1H), 1.50 (d, J= 6.8 Hz, 3H), 1.43 (dddd, J= 2.2, 1H), 3.38 (ddd, J= 3.3, 6.3, 9.3 Hz, 1H), 3.19 (sept, J= 6.8 Hz, 1H), 2.96 (ddd, J= 2.3, 6.8, 9.2 Hz,
	2.2, 4.4, 13.6 Hz, 1H), 1.13-1.32 (m, 18H), 0.74-0.99 (m, 3H), 0.97 (d, J= 7.2 Hz, 3H), 0.90 (d, 1H), 2.86 (sept, J= 6.9 Hz, 1H), 2.78 (dd, J= 3.5, 11.3 Hz, 1H), 2.48 (app d, J= 11.3 Hz, 1H), 2.31
	J= 7.1 Hz, 3H), 0.75 (d, J= 7.4 Hz, 3H), 0.54 (d, J= 7.3 Hz, 3H), 0.42 (ddd, J= 1.9, 1.9, 14.8 Hz, (app d, J= 15.4 Hz, 1H), 2.12-2.22 (m, 2H), 1.90-1.97 (m, 2H), 1.75 (ddd, J= 6.3, 9.2, 12.9 Hz,
	1H). 1H), 1.72 (s, 3H), 1.54 (ddd, J= 2.5, 6.2, 14.5 Hz, 1H), 1.50 (d, J= 6.8 Hz, 3H), 1.16-1.32 (m, 18H),
	13 C NMR (CDCl 3 , 125 MHz): δ 148.7 (C), 147.1 (C), 146.0 (C), 145.8 (C), 133.1 (C), 122.9 (CH), 0.80-1.03 (m, 15H), 0.69 (dd, J= 6.7, 15.0 Hz, 1H).
	120.6 (CH), 110.9 (CH 2 ), 74.3 (CH), 70.6 (CH), 68.7 (CH), 63.5 (CH), 62.3 (CH), 55.4 (CH 2 ), 35.3 13 C NMR (CDCl 3 , 125 MHz): δ 148.8 (C), 147.2 (C), 145.7 (C), 145.3 (C), 133.5 (C), 123.1(CH),
	(CH 2 ), 34.1 (CH), 31.6 (CH 2 ), 29.6 (CH 2 ), 29.0 (CH), 27.6 (CH), 27.6 (CH), 25.2 (2CH 3 ), 25.1 120.4 (CH), 111.3 (CH 2 ), 75.8 (CH), 71.2 (CH), 68.2 (CH), 63.8 (CH), 61.6 (CH), 56.7 (CH 2 ), 36.3
	(CH 3 ), 24.1 (CH 3 ), 24.0 (CH 3 ), 24.0 (CH 3 ), 23.4 (CH 3 ), 23.0 (CH 3 ), 18.1 (CH 3 ), 17.9 (CH 3 ), 16.9 (CH 2 ), 33.9 (CH), 31.2 (CH 2 ), 31.1 (CH 2 ), 29.1 (CH), 28.4 (CH), 28.2 (CH), 25.3 (CH 3 ), 24.9 (CH 3 ),
	Si 24.8 (CH 3 ), 24.5 (CH 3 ), 23.9 (CH 3 ), 23.9 (CH 3 ), 23.2 (CH 3 ), 22.9 (CH 3 ), 17.9 (CH 2 ), 17.6 (CH 3 ), i-Pr i-Pr (CH 3 ), 16.2 (CH 3 ), 15.2 (CH), 13.1 (CH), 12.7 (CH 2 ).
				O
	17.5 (2CH 3 ), 17.3 (CH 3 ), 13.4 (CH), 13.3 (CH).
			H
					N
		Me			Me
		i-Pr	O
			i-Pr	i-Pr	CH 2
			i-Pr	Si
		HO HO	HO	Me
		i-Pr	H H		H
					N N	OH
		Me Me			Me
		i-Pr i-Pr	O O		H	Me
					CH 2
			i-Pr
			i-Pr
		i-Pr
		i-Pr
	(2S,3S,6S,8R,8aR)-6-((Hydroxydiisopropylsilyl)methyl)-3-(2-methylallyl)-2-((R)-1-(2,4,6-triisopropyl (1S,2aR,3R,5S,5aR,7R,8aR)-5,7-Dimethyl-1-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)decahydro-1H-
	phenyl)ethoxy)octahydroindolizin-8-ol (141). Formic acid (200 µl) was added to 150 µl ethereal pyrrolo[2,1,5-de]quinolizine-3,7-diol (75). To a solution of the crude tricyclic silylated compounds
	solution of 7.5 mg amine 144 (0.013 mmol). The reaction mixture was stirred for 2h30min at RT, then 139 and 140 (116.0 mg) in 4.7 ml DMSO were added KOt-Bu (340 mg, 3.03 mmol, ~15 equiv), CsF
	diluted with Et 2 O and quenched with saturated K 2 CO 3 solution until the pH become alkaline. Then it (250 mg, 1.65 mmol, ~8 equiv) and 140 µl of H 2 O (3%) at RT. After stirring 9h at 120°C, the reaction
	was washed with brine and the aqueous phase was extracted 3 times with Et 2 O. The combined organic was diluted with Et 2 O, quenched with water and the aqueous layer was extracted 3 times with Et 2 O.
	layers were dried over MgSO 4 and evaporated under reduced pressure. Elution with 20% After drying the combined organic layers over MgSO 4 , evaporation was done under reduced
	pressure. Purification over 15 ml silica gel yielded 41.0 mg of the corresponding protodesilylated
	alcohol 75 (52% yield over 2 steps) eluted with 3% MeOH NH3 /DCM.
	[α] 20	D +14.6 (c 0.48, CHCl 3 ).

MS (ESI): m/z 568.46 (MH + , 100%).

HRMS

EtOAc/cyclohexane over silica gel gave 5.0 mg of the hydrolyzed amine 141 as white solid (65%). IR (film): ν 3366,

2958, 2865, 1608, 1462, 1382, 1261, 881 cm -1

. MS (ESI): m/z 586.47 (MH + , 100%), 608.46 (MNa + ). HRMS

  . HRMS calcd for C 30 H 50 NO 2 : 456.38361. Found: 456.38254 (MH + ).

		i-Pr	OH
			Si
		O
		H		H
			N	OH
	Me
	i-Pr	O	H	Me
		i-Pr
	i-Pr
	(1S,5R,5aR,7S,7aR,9R,10aR)-3-Isopropyl-9-methyl-7-((R)-1-(2,4,6-triisopropylphenyl)ethoxy)
	dodecahydro-1,5-methano[1,6,2]oxazasilocino[7,6,5-cd]indolizine-3,9-diol (149). To a solution of
	silylated formate 139 (95.0 mg, 0.151 mmol, 1 equiv) in 2.3 ml DMSO were added 450 mg of KOt-
	Bu (4.01 mmol, 26.5 equiv) and 1.2 ml of 1M TBAF solution in THF (1.2 mmol, 7.9 equiv). The reaction
	mixture was stirred 4h at 120°C then it was diluted with Et 2 O and quenched with water. The aqueous
	layer was extracted 3 times with Et 2 O, and the combined organic layers were dried over MgSO 4 and
	evaporated under reduced pressure. Purification over 9 ml silica gel yielded 37.0 mg of the
	intermediate 149 (44% yield) using 30% ® 70% of EtOAc/cyclohexane as eluant system.
	IR (film): ν 3365, 2959, 2866, 1608, 1462, 1362, 1114 cm -1 .

1 H NMR (CDCl 3 , 500 MHz): δ 7.04 (d, J= 1.9 Hz, 1H), 6.93 (d, J= 1.9 Hz, 1H), 4.99 (q, J= 6.8 Hz, 1H), 4.04 (app s, 1H), 3.

85-3.94 (m, 2H), 3.16 (app dd, J= 8.5, 8.5 Hz, 1H), 3.07-3.15 (m, 2H),

  calcd for C 33 H 56 NO 4 Si: 558.3979. Found: 558.3987 (MH + ).

	3 (CH 3 ), 19.6 (CH 2 ), 17.0 (CH 3 ),
	15.8 (CH 3 ), 14.6 (CH).
	MS (ESI): m/z 558.51 (MH + , 100%).

HRMS

  calcd for C 32 H 52 NO 4 : 514.3891. Found: 514.3877 (MH + ).

	MS (ESI): m/z 514.38 (MH + , 100%).

HRMS

  calcd for C 30 H 48 NO 3 : 470.3629. Found: 470.3616 (MH + ).

	, 1.87-2.06 (m, 2H), 1.51-1.70 (m, 4H), 1.13-1.31 (m, 21H), 1.02
	(d, J= 6.7 Hz, 3H).

MS (ESI): m/z 470.43 (MH + , 100%). HRMS

  , 2.85 (sept, J= 6.9 Hz, 1H), 2.66(app d, J= 10.3 Hz, 1H), 2.34 (dd, J= 3.8, 15.0 Hz, 1H), 2.02-2.24 (m, 3H), 1.76-1.89 (m, 3H), 1.71 (s,3H), 1.51 (d, J= 6.8 Hz, 3H), 1.17-1.43 (m, 19H), 0.83 (d, J= 6.4 Hz, 3H).HRMS calcd for C 31 H 50 NO: 452.38869. Found: 452.38764 (MH + ).

		Me		Me
		H		H
			N
				OH
	Me
	i-Pr	O	H	Me
		i-Pr
	i-Pr

  then cooled and evaporated. The residue was loaded directly on silica gel for purification to give 10.2 mg of tertiary alcohol 177 (98%) eluted with 3% MeOH NH3 /DCM.1 H NMR (CDCl 3 , 500 MHz): δ 3.11 (dddd, J= 2.2, 4.0, 7.5, 11.8 Hz, 1H), 2.78 (ddd, J= 2.2, 3.0, 12.8 Hz, 1H), 2.43 (ddd, J= 6.5, 9.6, 9.6 Hz, 1H), 1.88-2.09 (m, 2H), 1.64-1.77 (m, 3H), 1.26-1.54 (m, 7H), 1.26 (s, 3H), 1.14 (d, J= 7.2 Hz, 3H), 0.82 (d, J= 6.5 Hz, 3H). MS (ESI): m/z 224.15 (MH + , 100%). HRMS calcd for C 14 H 26 NO: 224.2009. Found: 224.2008 (MH + ).

	additional 4h30min,
	Me		Me
	H		H
		N
			OH
	S
	O	H	Me
	PhO
	Me	Me
	H	H
	N
			OH
	H	Me

Gurib-Fakim, A. Molecular Aspects of Medicine

2006, 27, 1-93. 2 Aboelsoud, N. H. J. Med. Plant. Res.2010, 4, 82-86. 3 Kong, J. M.; Goh, N. K.; Chia, L. S.; Chia T. F. Acta Pharmacologica Sinica2003, 24, 7-21.

Plant Toxins (Part of the Toxinology book series)2015,1-15.

Bishop, G. M.; Robinson, S. R. Drugs Aging2004, 21, 621-630.

(a) Pearson, H. A.; Peers, C. J. Physiol. 2006, 5-10. (b) Brothers, H. M.; Gosztyla, M. L.; Robinson, S. R. Frontiers in Aging Neuroscience, 2018, 10.

/ LiAlH 4

Nuclear magnetic resonance (NMR) spectra were recorded on Bruker Avance 400 or Varian U +

C NMR (CDCl 3 ,125 MHz): δ

148.8, 147.4, 147.2, 145.8, 133.4, 123.2, 120.4, 107.9, 74.8, 71.1,

Acknowledgements