Renato Dalpozzo

Alessandra Lattanzi

Hélène Pellissier
email: h.pellissier@univ-amu.fr

Applications of Chiral Three-Membered Rings for Total Synthesis: A Review

Keywords: Asymmetric synthesis, biological activity, chirality, natural products, strained molecules, total synthesis

This review updates recent applications of asymmetric aziridination, azirination, thiirination, epoxidation, and cyclopropanation in the total synthesis of biologically active compounds, including natural products, using chiral substrates or chiral catalysts, covering the literature since 2000. The interest towards these synthetic methodologies of chiral three-membered rings has increased in the last decade, dictated either by the biological activities that display many naturally occurring products bearing a three-membered unit or by the ring strain of three-membered rings making them useful precursors of many more complex interesting molecules. Classic as well as modern protocols in asymmetric aziridinations, azirinations, epoxidations, thiirinations, and cyclopropanations have been widely applied as key steps of a number of syntheses of important products. Although the use of chiral substrates and auxiliaries is still highly employed particularly in asymmetric aziridination and cyclopropanation, the development of enantioselective catalytic methodologies has witnessed exponential growth during the last decade. The present review is subdivided into three parts, dealing successively with the use of chiral nitrogen-containing three-membered rings, chiral epoxides and thiiranes, and chiral cyclopropanes in total synthesis.

INTRODUCTION

Chiral three-membered rings are useful building blocks in synthesis, as well as important synthetic targets. The interest towards synthetic methodologies for their preparation has increased in the last decade, dictated either by the biological activities displayed by many naturally occurring products bearing a three-membered unit or by being useful precursors for accessing more complex interesting molecules [START_REF] Salaun | Cyclopropane derivatives and their diverse biological activities[END_REF]. The goal of the present review is to highlight the major developments and applications in the use of asymmetric three-membered ring formations in total synthesis reported in the last fifteen years. It must be noted that a range of reviews, which will be cited in the respective sections of the present review, have been separatively devoted to asymmetric aziridinations, epoxidations, or cyclopropanations [2]. On the other hand, to the best of our knowledge, no previous review compiling all types of chiral threemembered rings and their synthetic applications exists. In 2000, a book dedicated to cyclopropanes in synthesis was published by de Meijere [3], while a special issue published in Chemical Reviews in 2014 was consecrated to small heterocycles in synthesis but did not especially focus on the asymmetric total synthesis of bioactive and natural products [START_REF] Andrei | Introduction: Small heterocycles in synthesis[END_REF]. The present review is subdivided into three parts, dealing successively with the use of chiral nitrogencontaining three-membered rings, chiral epoxides and thiiranes, and chiral cyclopropanes in total synthesis. The first part is subdivided into two sections successively devoted to chiral aziridines and chiral azirines. The second part of the review is also subdivided into two sections, dealing successively with chiral epoxides and thiiranes. The third part of the review is subdivided into four sections, treating successively asymmetric Simmons Smith cyclopropanations as key steps, asymmetric transition-metal decomposition of diazoalkanes as key steps, asymmetric Michael-initiated ring closures as key steps, and miscellaneous asymmetric cyclopropanations as key steps.

CHIRAL NITROGEN-CONTAINING THREE-MEMBERED RINGS IN TOTAL SYNTHESIS

Chiral Aziridines

Aziridines are among the most fascinating heterocyclic intermediates in organic synthesis [START_REF] Murphree | Three-Membered Heterocycles. Structure and Reactivity[END_REF], acting as precursors of many complex molecules including natural and biologically active products due to the high strain incorporated in their skeletons [START_REF] Aggarwal | For reviews concentrating on not especially asymmetric aziridination (and epoxidation)[END_REF]. The last decade has witnessed tremendous activity in the area of discovering new methodologies for their synthesis and transformations [7]. This growing interest is related to their striking chemical properties. The high strain energy associated with the aziridine ring enables easy cleavage of the C N bond, leading to a series of important nitrogen-containing products [START_REF] Padwa | Intermolecular 1,3-Dipolar Cycloadditions[END_REF]. Obtaining aziridines, especially optically active aziridines, has become of great importance in organic chemistry for many reasons. These reasons may include the antitumor, antibacterial and other biological properties associated with a great number of aziridine-containing compounds, such as mitomycins, azinomycins, and epothilones [START_REF] Zalialov | Aziridines and aziridinium ions in the practical synthesis of pharmaceutical intermediates-a perspective[END_REF]. Indeed, as powerful alkylating agents, aziridines have an inherent in vivo potency through their ability to act as DNA cross-linking agents via nucleo-philic ring opening of the aziridine moiety. Structure activity relationships have identified the aziridine ring is very essential for the antitumor activity, and a vast amount of work has concentrated on synthesizing derivatives of these natural products with increased potency. Various antitumor agents related to mitosanes and mitomycins, for example, have been synthesized and demonstrated to possess activity against a variety of cancers. A number of other synthetic chiral aziridines have also been shown to exhibit other useful biological properties such as enzyme-inhibitory activities. In addition to these important biological activities related to the aziridine unit, these molecules constitute key chiral building blocks for the easy construction of other types of biologically relevant as well as naturally occuring chiral nitrogen-containing compounds. Chiral aziridines can be prepared by either asymmetric catalytic methods or from chiral substrates. The main approaches to the synthesis of chiral aziridines can be classified as asymmetric nitrene transfer to alkenes, asymmetric carbene transfer to imines such as ylide-mediated aziridinations, asymmetric cyclization reactions through addition/elimination processes such as Gabriel Cromwell reactions, and miscellaneous asymmetric reactions such as intramolecular substitutions [7].

Asymmetric Aziridinations of Chiral Substrates as Key Steps Nitrene Transfer to Alkenes

Nitrogen-atom transfer to alkenes is a particularly appealing strategy for the generation of aziridines because of the ready avail-ability of olefinic starting materials and the direct nature of such a process.

The nitrene (or nitrenoid) source for this reaction can be generated from various methodologies, such as the metal-catalyzed reaction of [N-(p-toluenesulfonyl)imino]aryliodinanes [START_REF] Dauban | Iminoiodanes and C-N bond formation in organic synthesis[END_REF]. In 2006, Trost and Dong reported a total synthesis of (+)-agelastatin A, possessing nanomolar activity against several cancer cell lines, which was based on the aziridination of chiral piperazinone 1 (Scheme 1) [START_REF] Trost | New class of nucleophiles for palladium-catalyzed asymmetric allylic alkylation. total synthesis of agelastatin A[END_REF]. This process was performed in the presence of PhI=NTs as the nitrene source and a catalytic amount of copper N-heterocyclic carbene complex 2, providing the corresponding aziridine 3 as the only detected stereoisomer in 52% yield. This chiral aziridine was further converted into the expected (+)-agelastatin A in four supplementary steps. This natural product is also known to inhibit glycogen synthase kinase-3b, a behaviour that might provide an approach for the treatment of Alzheimer's disease.

In 2003, Dauban and Dodd applied the Ses iminoiodane (PhI=NSes) to the copper-catalyzed aziridination of 11-pregnane derivatives to prepare chiral 11,12-aziridino analogues of neuroactive steroids [START_REF] Di Chenna | PhI=NSes mediated aziridination of 11-pregnane derivatives: Synthesis of an 11,12-aziridino analogue of neuroactive steroids[END_REF]. As shown in Scheme 2, the reaction of chiral 11pregnene-3,20-dione 4a or 3--acetoxy-11-pregnen-20-one 4b with PhI=NSes in the presence of CuOTf led to the corresponding , -11,12-aziridino steroids 5a-b in moderate yields (45-53%). The 3acetoxy-11-pregnen-20-one derivative 5b was further converted via TASF-mediated removal of the N-Ses blocking group into N-methyl-11,12-aziridino-3 -hydroxy-5 -pregnan-20-one, which is a conformationally constrained analogue of the endogenous neuros- teroid, pregnanolone, and a structural analogue of the synthetic general anesthetic, minaxolone.

In 2005, Wood and Keaney explored the use of rhodium perfluorobutyramide (Rh 2 (pfm) 4 ) for the aziridination of olefins [START_REF] Keaney | Rhodium perfluorobutyramide (Rh2(pfm)4): A synthetically useful catalyst for olefin aziridinations[END_REF]. The authors found that the treatment of chiral olefin 6 by trichloroethylsulfamate ester in the presence of a combination of Rh 2 (pfm) [START_REF] Andrei | Introduction: Small heterocycles in synthesis[END_REF] with PhI(OAc) 2 provided the expected trichloroethoxysulfonylaziridine 7 in good yield and moderate diastereoselectivity (66% de), as shown in Scheme 3. Notably, this product constituted a potent intermediate for the formal synthesis of (+)-kalihinol A.

With the aim of developing a synthesis for the orally active neuraminidase inhibitor, ( )-oseltamivir, Trost and Zhang investigated the asymmetric aziridination of chiral diene 8 (Scheme 4) [14]. In this case, the best result for the aziridination was obtained when the reaction was performed in the presence of SesNH 2 as the nitrene source, PhI(OPiv) 2 as the oxidant, bis-[rhodium( , , ', 'tetramethyl-1,3-benzenedipropionate] [Rh 2 (esp) 2 ] as the catalyst, and chlorobenzene as the solvent, as shown in Scheme 4. Under these reaction conditions, the corresponding , -aziridine 9 was obtained as the only detected stereoisomer in 86% yield. This chiral product was further converted into required (-)-oseltamivir through four supplementary steps with an overall yield of 30%.

Another methodology to generate nitrenes consists of the in situ oxidation of hydrazine derivatives in the presence of Pb(OAc) [START_REF] Andrei | Introduction: Small heterocycles in synthesis[END_REF] ethyl-3,4-dihydroquinazolin-4-one combined with Pb(OAc) 4 and hexamethyldisilazide (HMDS) [START_REF] Diaper | The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase[END_REF]. An asymmetric version of this method was developed by these authors by using chiral 3acetoxyaminoquinazolinones for the aziridination of unsaturatedaminopimelic ester in order to prepare aziridine analogues of diaminopimelic acid which is an inhibitor of diaminopimelic acid epimerase [START_REF] Diaper | The stereoselective synthesis of aziridine analogues of diaminopimelic acid (DAP) and their interaction with dap epimerase[END_REF]. As shown in Scheme 5, the reaction of chiral alkene 10, performed in the presence of chiral aminoquinazolinone 11 and Pb(OAc) 4 , led to the expected corresponding aziridine 12 in 49% yield along with moderate diastereoselectivity of 72% de.

Another methodology to prepare aziridines is based on the thermolytic or photolytic decomposition or organic azides [START_REF] Katsuki | Azide compounds: Nitrogen sources for atom-efficient and ecologically benign nitrogen-atom-transfer reactions[END_REF]. In 2008, Tanaka et al. employed this methodology as key step of a total synthesis of ( )-agelastatin A, a potent antineoplastic agent [START_REF] Yoshimisu | Total synthesis of (-)-agelastatin A[END_REF]. Indeed, the nitrogen functionality of the agelastatin core was installed through thermolytic intramolecular aziridination of chiral azidoformate 13. The formed tricyclic aziridine 14 obtained as the only detected stereoisomer was further submitted to a regioselective azidation, leading to trans-diamination of the double bond. The obtained chiral azide was subsequently converted into the expected ( )-agelastatin A (structure in Scheme 1), as shown in Scheme 6.

Earlier in 2006, Lowary et al. reported the synthesis of Ldaunosamine and L-ristosamine glycosides based on photoinduced intramolecular aziridinations of acylnitrenes derived from Lrhamnose [START_REF] Mendlik | Synthesis of L-Daunosamine and L-ristosamine glycosides via photoinduced aziridination. Conversion to thioglycosides for use in glycosylation reactions[END_REF]. As shown in Scheme 7, upon exposure to UV light (254 nm), chiral acyl azide 15 was converted to the corresponding aziridine 16 in 79% yield and as the only detected stereoisomer through the generation of a presumed acylnitrene intermediate. This aziridine was further converted into expected glycoside L-daunosamine derivative. Similarly, the irradiation of a 2:1 : anomeric mixture of acyl azide 17 of an L-erythro-hex-2-enopyranoside derivative led to a mixture of the corresponding aziridines 18 in 91% yield (Scheme 7). These products were further separated by chromatography and then converted into important glycoside L-ristosamine derivatives.

Gabriel Cromwell Reactions

The Gabriel Cromwell aziridine synthesis involves a nucleophilic addition of a formal nitrene equivalent to a 2-haloacrylate or similar reagent. It involves an initial

13

none 19 derived from ( )-quinic acid [START_REF] Barros | Aziridines as a protecting and directing group. Stereoselective synthesis of (+)-Bromoxone[END_REF]. The aziridination, performed in the presence of 4-methoxybenzylamine and Cs 2 CO 3 as a base, afforded the corresponding aziridine 20 in good yield (84%) as an 80:20 mixture of diastereomers, as shown in Scheme 8. This reaction constituted the key step of a short synthesis of (+)bromoxone, the acetate of which showed potent antitumor activity.

In the same context, Dodd et al. have developed a total synthesis of the non-natural enantiomer of polyoxamic acid on the basis of the domino aza-Michael-type addition/elimination reaction of chiral triflate 21 derived from D-ribonolactone [START_REF] Tarrade | Enantiospecific total synthesis of (-)-Polyoxamic acid using 2,3-aziridino--lactone methodology[END_REF]. This triflate reacted with 3,4-dimethoxybenzylamine to provide the corresponding aziridine 22 as the only detected stereoisomer in good yield (Scheme 9). The complete diasteroselectivity of the reaction was explained as a result of a aza-Michael-type addition of 3,4-dimethoxybenzylamine to the face opposite to that of the bulky silyl group at C-5. This aziridine was further converted through six supplementary steps into the expected ( )-polyoxamic acid with an overall yield of 10%.

Ylide-Mediated Aziridinations

In 2006, Aggarwal et al. developed a total synthesis of the protein kinase C inhibitor ( )-balanol [START_REF] Unthank | The use of vinyl sulfonium salts in the stereocontrolled asymmetric synthesis of epoxide-and aziridinefused heterocycles: Application to the synthesis of (-)-balanol[END_REF]. The key step of this synthesis was the reaction of diphenyl vinyl sulfonium triflate salt with chiral aminal 23 in the presence of NaH as the base, which led to the corresponding aziridine 24 in moderate yield (68%) and diastereoselectivity (50% de), as shown in Scheme 10. The mecha-nism of the key step of the synthesis, evolving through ylidemediated aziridination, is depicted in Scheme 10.

Intramolecular Substitutions

The asymmetric aziridination based on the use of 1,2-amino alcohols has been applied by several groups for developing total syntheses of various biologically active products. As an example, the A total synthesis of 7-Epi (+)-FR900482, exhibiting equal potency as antitumor agent than natural product (+)-FR900482, was later reported by Trost and O'Boyle, involving the asymmetric aziridination of chiral amino diol 27 (Scheme 12), which was selectively silylated and mesylated [START_REF] Trost | Synthesis of 7-Epi (+)-FR900482: An epimer of comparable anti-cancer activity[END_REF]. The mesylate was then exposed to cesium carbonate, affording the expected aziridine 28 as the only detected stereoisomer in 77% yield, which was further transformed into expected 7-Epi (+)-FR900482. In 2003, Terashima et al. developed the synthesis of the C1-C17 fragment of the antitumor antibiotic, carzinophilin, that involved as a key step the asymmetric aziridination of chiral pyrrolidin-2-ylidenemalonate 29 derived from -D-arabinofuranose [START_REF] Hashimoto | Synthetic studies of carzinophilin[END_REF]. As shown in Scheme 13, the treatment of this pyrrolidin-2ylidenemalonate with KHMDS as base provided the corresponding aziridine 30 as the only detected stereoisomer in 63% yield. The latter was further converted into the expected C1-C17 fragment of carzinophilin. Later, Vedejs et al. reported the synthesis of enantiopure aziridinomitosene, the key step of which was the asymmetric aziridination of chiral oxazole 1,2-amino alcohol 31 derived from L-serine (Scheme 14) [25]. The reaction yielded the corresponding aziridine 32 as the only detected stereoisomer in 65% yield which was further converted into aziridinomitosenes among which the first C6,C7-unsubstituted one, a DNA alkylating agent depicted in Scheme 14. In 2015, Kongkathip et al. reported a novel total synthesis of oseltamivir phosphate (structure of oseltamivir in Scheme 4) which was based on the asymmetric aziridination of chiral 1,2-amino mesylate 33 derived from D-glucose into aziridine 34 as the only detected stereoisomer, as shown in Scheme 15 [START_REF] Kongkathip | A new and efficient asymmetric synthesis of oseltamivir phosphate (Tamiflu) from D-glucose[END_REF]. The complete strategy gave rise to oseltamivir phosphate in 7.2% overall yield.

t-BuPh

KHMDS

The last step of an enantioselective synthesis of an aziridinomitosane, reported by Miller et al., was based on the cyclization of chiral tricyclic 1,2-azido alcohol 35 into aziridine 36 as the only detected stereoisomer (Scheme 16) [START_REF] Papaioannou | Enantioselective synthesis of an aziridinomitosane and selective functionalizations of a key intermediate[END_REF]. This process was achieved in two steps with resin-bound PPh 3 , affording the expected enantiopure aziridinomitosane with the trans configuration in moderate yield (Scheme 16).

In the same area, Metzger and Fürmeier reported the first preparation of chiral fat-derived aziridines, with the aim of gaining insight into their biological properties [START_REF] Fürmeier | Fat-Derived aziridines and their -substituted derivatives: Biologically active compounds based on renewable raw materials[END_REF]. The same methodology as described in Scheme 16, based on the use of resin-bound PPh 3 , was applied to the enantiopure azido alcohol 37 derived from chiral methyl vernolate (Scheme 17). Under these reaction conditions, the corresponding unsaturated cis-aziridine 38 was isolated in 75% yield as the only detected stereoisomer, according to the mechanism summarized in Scheme 17. This represented the first enantiomerically pure aziridine based on fats and oils.

In 2010, the cyclization of other chiral 2-azido alcohols was investigated by Coates et al. in the course of synthesizing aziridine analogues of presqualene diphosphates as inhibitors of squalene synthase [START_REF] Koohang | Enantioselective inhibition of squalene synthase by aziridine analogues of presqualene diphosphate[END_REF]. As shown in Scheme latter was subsequently converted into a diphosphate exhibiting squalene synthase inhibitory activity.

Miscellaneous Aziridinations

In 2012, Ishikawa et al. reported the synthesis of (-)-benzolactam-V8, an artificially-designed cyclic dipeptide exhibiting strong tumor-promoter activity [START_REF] Khantikaew | Synthesis of (-)-benzolactam-V8 by application of asymmetric aziridination[END_REF]. The key step of the synthesis consisted in the reaction of chiral guanidinium bromide 41 with benzyl (S)-N-(2-formylphenyl)-N-methylvalinate 42 to give the corresponding syn-aziridine 43 in 59% yield and a moderate diastereoselectivity of 36% de (Scheme 19). The latter was further converted into the expected (-)-benzolactam-V8 in five supplementary steps.

The total synthesis of ( )-oseltamivir, elaborated by Fukuyama et al. in 2007, included the formation of a bicyclic aziridine 44 by rearrangement of chiral allyl carbamate 45 [31]. Therefore, treat-ment of this carbamate with NaOEt resulted in ethanolysis of N-Boc lactam, dehydrobromination, and aziridine formation, which provided the desired aziridine 44 as the only detected stereoisomer in high yield (87%), as shown in Scheme 20. This aziridine was further converted into the final ( )-oseltamivir (structure in Scheme 4) in four steps.

In 2005, a photocyclization reaction providing chiral aziridines was developed by Mariano et al., starting from chiral pyridinium perchlorate 46 derived from D-glucose [START_REF] Feng | Pyridinium Salt photochemistry in a concise route for synthesis of the trehazolin aminocyclitol, trehazolamine[END_REF]. Irradiation of this substrate in aqueous NaHCO 3 produced a mixture of isomeric Nglycosyl-bicyclic-aziridines, which could be partially separated by chromatography to yield the major aziridine 47 (Scheme 21) as the only detected stereoisomer in 15% yield. This aziridine was subsequently converted into trehazolamine which is the aminocyclitol core of the potent trehalase inhibitor, trehazolin.

Enantioselective Aziridinations as Key Steps

Copper-Catalyzed Nitrene Transfer to Alkenes

In addition to chiral dirhodium catalysts [START_REF] Fruit | Diastereoselective rhodium-catalyzed nitrene transfer starting from chiral sulfonimidamide-derived iminoiodanes[END_REF], the most commonly employed chiral catalyst systems in enantioselective aziridination via nitrene transfer to alkenes are based on copper complexes of chiral bisoxazolines early reported by Evans et al., in 1991 [34]. In 2007, Cranfill and Lipton reported the use of Evans' bisoxazoline ligand 48 for the asymmetric aziridination of ,unsaturated ester 49 in the presence of Cu(OTf) 2 and PhINNs (N-(p-nitrophenylsulfonyl)iminophenyliodinane) as the nitrene source [START_REF] Cranfill | Enantio-and diastereoselective synthesis of (R,R)--Methoxytyrosine[END_REF]. This process allowed the corresponding chiral trans-aziridine 50 to be obtained in 89% yield, and with 90% de and 94% ee, (Scheme 22). This nice reaction constituted the key step of a total synthesis of (R,R)--methoxytyrosine, which is a constituent of several cyclic depsipeptide natural products.

Organocatalyzed Nitrene Transfer to Alkenes

In 2014, Hamada et al. developed a total synthesis of (R)sumanirole that exhibits selective dopamine D2 receptor agonist activity [START_REF] Nemoto | Enantioselective synthesis of (R)-Sumanirole using organocatalytic asymmetric aziridination of an , -unsaturated aldehyde[END_REF]. The key step of the synthesis was the aziridination of , -unsaturated aldehyde 51 organocatalyzed by chiral diphenyl-prolinol triethylsilyl ether 52 in the presence of three equivalents of a base, such as NaOAc, allowing the key intermediate aziridine 53 to be obtained in 94% yield and 97% ee (Scheme 23) [START_REF] Arai | Enantioselective aziridination reaction of , -unsaturated aldehydes using an organocatalyst and tert-butyl N-arenesulfonyloxycarbamates[END_REF]. The latter was subsequently converted into the desired (R)-sumanirole.

Carbene Transfer to Imines Through Carbene Methodology

Although most of the catalytic methods for synthesizing chiral aziridines proceeded through the transfer of a nitrogen group to an alkene, methods based on the less-studied enantioselective transfer of a carbenoid to an imine have been successfully developed in recent years [38]. For example, the formation of aziridines based on transition metal-or Lewis acid-catalyzed decomposition of diazo compounds in the presence of imines is well established. The synthetic utility of this approach was illustrated by Wulff et al. in the total synthesis of a leukointegrin LFA-1 antagonist, BIRT-377, an agent for the treatment of inflammatory and immune disorders [START_REF] Patwardhan | Highly diastereoselective alkylation of aziridine-2-carboxylate esters: Enantioselective synthesis of LFA-1 antagonist BIRT-377[END_REF]. As shown in Scheme 24, the key step of this synthesis provided chiral cis-aziridine 54, arisen from the reaction of ethyl diazoacetate with N-benzhydryl imine 55 in the presence of a combination of B(OPh) 3 as Lewis acid and (S)-VAPOL as chiral ligand.

In 2011, the highly efficient asymmetric Wulff s aziridination methodology was applied by Chen et al. to develop a total synthesis of antibacterial florfenicol shown in Scheme 25 [START_REF] Wang | An efficient enantioselective synthesis of florfenicol via asymmetric aziridination[END_REF]. In this case, the authors employed (R)-VANOL-boroxinate to aziridinate benzhydryl aldimine 56 with ethyl diazoacetate, providing the key chiral aziridine intermediate 57 in 93% yield as a single cisdiastereomer in 85% ee. The latter was further converted into expected florfenicol in 45% overall yield from commercially available p-(methylsulfonyl)benzaldehyde. hexadecanal with MEDAM amine and ethyl diazoacetate led to almost enantiopure aziridine-2-carboxylates 60 or ent-60, respecti-vely. Access to all four stereoisomers of sphinganine was achieved upon ring-opening of the enantiopure aziridine-2-carboxylate at the C-3 position through a direct S N 2 attack of an oxygen nucleophile, which occurred with inversion of configuration and by ring expansion of an N-acyl aziridine to an oxazolidinone followed by hydrolysis.

Carbene Transfer to Imines Through Sulfur Ylide-Mediated Aziridinations

Aggarwal has developed an asymmetric aziridination methodology based on the generation of a carbene from diazo decomposition with [Rh 2 (OAc) 4 ], its association to a chiral sulfide, and subsequent transfer to an imine [START_REF] Aggarwal | Catalytic, asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds: Scope, selectivity, and applications in synthesis[END_REF]. This approach was applied in 2003 to build the taxol side chain with a high degree of enantioselectivity via a trans-aziridine [START_REF] Aggarwal | Asymmetric sulfur ylide mediated aziridination: Application in the synthesis of the side chain of taxol[END_REF]. As shown in Scheme 27, the reaction of N-Ses imine 61 with tosylhydrazone salt 62 derived from benzaldehyde in the presence of a phase-transfer catalyst (PTC), Rh 2 (OAc) 4 , and 20 mol% of chiral sulfide 63 provided the corresponding aziridine 64 in 52% yield as a 89:11 trans/cis diastereoisomeric ratio. The expected trans-aziridine was obtained with an enantiomeric excess of 98% ee and was further converted into the desired final taxol side chain. A catalytic cycle was proposed, involving the decomposition of the diazo compound in the presence of the rhodium complex, to yield the metallocarbene. The latter was then transferred to the chiral sulfide, forming a sulfur ylide, which underwent a reaction with the imine to give the expected aziridine, returning the sulfide to the cycle to make it available for further catalysis (Scheme 27).

Chiral Azirines

2H-Azirines constitute the smallest nitrogen unsaturated heterocyclic system, bearing two carbon atoms and one double bond in a three-membered ring. Their stability can be attributed not only to the combined effects of bond shortening and angle compression, but also to the presence of the electron-rich nitrogen atom [44]. The biological applications and the chemistry of these molecules have been widely investigated [8h, 45]. The chemistry of 2H-azirines is related to their ring strain, reactive -bond, and ability to undergo regioselective ring cleavage. For example, they can act as nucleophiles as well as electrophiles in organic reactions, but they can also interact as dienophiles and dipolarophiles in cycloaddition reactions. Therefore, they constitute useful precursors for the synthesis of a variety of nitrogen-containing heterocyclic systems. In particular, 2H-azirines containing a carboxylic ester group are constituents of naturally occurring antibiotics. Several synthetic approaches are available to reach 2H-azirines, such as Neber rearrangement of oxime sulfonates, and elimination reaction of N-substituted aziridines, such as N-sulfinylaziridines or N-chloroaziridines. Several asymmetric versions of these methodologies have been recently applied in total synthesis.

N R 2 R 3 N R 2 R 1 R 3 R 2 S-CHR 1 R 2 S Rh 2 (OAc) 4 Rh=CHR 1 N 2 CHR 1 PTC N 2 + NaTs

Asymmetric Azirination Through Neber Approaches

In 2000, an asymmetric Neber reaction was developed by Palacios et al. for the preparation of constituants of naturally occurring antibiotics, such as alkyl-and aryl-substituted 2H-azirines bearing a phosphonate group in the 2-position of the ring [START_REF] Palacios | Simple asymmetric synthesis of 2H-Azirines derived from phosphine oxides[END_REF]. As shown in Scheme 28, the Neber reaction of -phosphorylated tosyloximes 65 provided the corresponding 2H-azirines 66 in excellent yields along with low to good enantioselectivities of up to 82% ee when employing quinidine as organocatalyst. The scope of this methodology was extended to the synthesis of enantioenriched 2H-azirines derived from phosphonates albeit with lower enantioselectivities ranging from 20 to 52% ee along with high yields (85-95%) [START_REF] Palacios | Easy and efficient synthesis of enantiomerically enriched 2H-azirines derived from phosphonates[END_REF]. Later, better enantioselectivities of up to 72% ee were reported by the same authors in the synthesis of chiral 2H-azirine phosphonates 67 performed with the same catalyst in the presence of K 2 CO 3 (Scheme 28) [START_REF] Palacios | Asymmetric synthesis of 2H-aziridine phosphonates, and -or -aminophosphonates from enantiomerically enriched 2Hazirines[END_REF]. These three-membered heterocycles constitute important building blocks in the preparation of biologically active compounds of interest in medicinal chemistry including naturally occurring antibiotics.

Later, Molinski et al. reported a total synthesis of marine natural and antifungal product (-)-Z-dysidazirine the key step of which was an enantioselective Neber reaction catalyzed by the same organocatalyst quinidine (Scheme 29) [START_REF] Skepper | Synthesis and antifungal activity of (-)-(Z)-Dysidazirine[END_REF]. The Neber reaction of tosyloxime 69 derived from pentadecyne led to the corresponding key chiral azirine 70 in good yield and moderate enantioselectivity (59% ee). This product was further converted into expected (-)-Zdysidazirine through partial hydrogenation using Lindlar's catalyst.

69

In 2010, the same conditions were applied by these authors to the synthesis of shorter chain analogues 71 and 72 of (-)-Zdysidazirine to be evaluated as antifungal agents [START_REF] Skepper | Synthesis and chain-dependent antifungal activity of long-chain 2H-azirine-carboxylate esters related to dysidazirine[END_REF]. As depicted in Scheme 30, these products were obtained in 61 and 86% ee, respectively. Their antifungal activity was found comparable to that of (-)-Z-dysidazirine.

The first enantioselective Neber reaction of -ketoxime sulfonates 73 catalyzed by bifunctional thiourea 74 was reported by Takemoto et al., in 2011 [51]. The reaction was performed in the presence of only 5 mol% of catalyst loading and 10 equivalents of Na 2 CO 3 to provide the corresponding 2H-azirine carboxylic esters 75 in good yields and moderate to high enantioselectivities of up to 93% ee (Scheme 31). The utility of this novel methodology was demonstrated by an asymmetric synthesis of (-)-Z-dysidazirine.

CHIRAL EPOXIDES AND THIIRANES IN TOTAL SYN-THESIS

Chiral Epoxides

Epoxides are strained three-membered rings of wide importance as versatile synthetic intermediates in total synthesis of a number of important products. Their strain energy allows an easy ring-opening by reacting with nucleophiles to provide a range of sulfides, hydrazino alcohols, 1,2-halohydrins, 1,2-cyanohydrins, alcohols and pharmaceuticals [START_REF] Nemoto | Catalytic asymmetric epoxidation of , -unsaturated amides: Efficient synthesis of -aryl -hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process[END_REF][START_REF]Aziridines and Epoxides in Organic Synthesis[END_REF]. Given the considerable number of asymmetric methodologies accessible to synthesize chiral epoxides, chemists have judiciously applied the combination of asymmetric epoxidation/ring-opening reactions to achieve various total syntheses of natural and biologically active compounds [START_REF] Heravi | Applications of sharpless asymmetric epoxidation in total synthesis[END_REF].

)-Z-dysidazirine. N R 1 X O O SO 2 R 2 N R 1 COX NMe 2 N H S N H Ar = 3,5-(CF 3 ) 2 C 6 H 3
For example, -adrenergic blocking agents used for the treatment of hypertension and angina pectoris, can be easily obtained from ringopening of chiral terminal epoxides including (S)-propranolol [START_REF] Sonawane | Concise synthesis of twoadrenergic blocking agents in high stereoselectivity using the readily available chiral building block (2S,2'S,2"S)-tris-(2,3-epoxypropyl)-isocyanurate[END_REF], and (R)-dichloroisoproterenol [START_REF] Wei | Asymmetric synthesis of -adrenergic blockers through multistep one-pot transformations involving in situ chiral organocatalyst formation[END_REF]. Carboxypeptidase A, a zinccontaining proteolytic enzyme of physiological importance, has been found to be irreversibly inactivated, with the highest activity among all the possible stereoisomers, by terminal epoxide (2R,3S)-2-benzyl-3,4-epoxybutanoic acid via S N 2 type ring-cleavage [56].

Moreover, [3+2] asymmetric cycloaddition reactions of epoxides have also recently emerged as valuable tools to obtain chiral dihydro-or tetrahydrofuran derivatives, important core structures present in natural products [START_REF] Chen | An asymmetric [3+2] cycloaddition of alkynes with oxiranes by selective C-C bond cleavage of epoxides: Highly efficient synthesis of chiral furan derivatives[END_REF]. Besides the relevance of chiral epoxides in synthesis, a great number of natural products and bioactive compounds exhibit the epoxide subunit in their structure as exemplified by sex pheromone for gypsy moth (+)-disparlure [58], antibiotic agent monocillin I [START_REF] Ayer | The isolation, identification, and bioassay of the antifungal metabolites produced by Monocillium nordinii[END_REF], potent oral hypoglycemic and antiketogenic agent in mammals (R)-methyl palmoxirate [START_REF] Ruano | A new general method to obtain chiral 2-alkylglycidic acid derivatives: Synthesis of methyl (R)-(+)palmoxirate[END_REF], and anticancer agents ovalicin, fumagillin and ephothilones A and B [61]. The epoxidation of alkenes is undoubtedly the most investigated and convenient approach to obtain epoxides [START_REF]Modern Oxidation Methods[END_REF]. In the last decade, total syntheses of many important natural and biologically relevant products have been based on asymmetric metal-or organocatalyzed epoxidations of alkenes, kinetic resolution of racemic epoxides, asymmetric sulfur ylide-mediated epoxidations of carbonyl compounds, and asymmetric Darzens reactions as key steps.

Asymmetric Metal-Catalyzed Epoxidations as Key Steps

In the last decade, many studies have focused on the development of asymmetric metal-catalyzed procedures for the epoxidation of alkenes [START_REF] For Reviews ; Jacobsen | Comprehensive Asymmetric Catalysis I-III[END_REF]. As a recent example, Echavarren et al. have developed a short total synthesis of three natural aromadendrane sesquiterpenes, such as (-)-epiglobulol, (-)-4 ,7 -aromadendranediol, and (-)-4 ,7 -aromadendranediol, the first step of which was the Katsuki-Sharpless asymmetric epoxidation of (E,E)-farnesol 76 (Scheme 32) [START_REF] Carreras | Gold(I) as an artificial cyclase: Short stereodivergent syntheses of (-)-epiglobulol and (-)-4 ,7 -and (-)-4 ,7 -aromadendranediols[END_REF]. These products, widespread in plant species, are endowed with a variety of antiviral, antibacterial, antifungal activities [65]. The epoxidation of 76 was performed in the presence of 5 mol% of Ti(OiPr) 4 /L-DIPT as catalyst system, leading to the corresponding chiral epoxide 77 in 88% yield and 82% ee. The latter was further converted into expected (-)-epiglobulol, (-)-4 ,7aromaden-dranediol, and (-)-4 ,7 -aromadendranediol.

Very recently, this methodology was also employed by Muthukrishnan et al. as key step in a simple synthesis of (R)-2-benzylmorpholine, an appetite suppressant agent [START_REF] Viswanadh | An alternate synthesis of appetite suppressant (R)-2-benzylmorpholine employing Sharpless asymmetric epoxidation strategy[END_REF]. As shown in Scheme 33, the Katsuki-Sharpless asymmetric epoxidation of (E)cinnamyl alcohol 78 led to the corresponding chiral epoxy alcohol 79 in high yield (86%) and excellent enantioselectivity under standard conditions. The latter was further converted into expected (R)-2-benzylmorpholine in 24% overall yield (Scheme 33). The Katsuki-Sharpless asymmetric epoxidation was also applied by Voight et al. to the total synthesis of potent antibiotic GSK966587 (Scheme 34) [START_REF] Voight | Target-directed synthesis of antibacterial drug candidate GSK966587[END_REF]. The epoxidation of allylic alcohol 80 smoothly proceeded with 10 mol% of the same metal complex, in the presence of cumyl hydroperoxide (CHP) to give the key chiral epoxy alcohol 81 in 81% yield and 90% ee. The synthesis afforded the target compound in eight steps and 25% overall yield.

Zirconium catalysts have been of limited use in the area of asymmetric epoxidation, with a particular focus on homoallylic alcohols. As a rare example, an asymmetric Zr(Ot-Bu) 4 /bishydroxamic acid-catalyzed asymmetric epoxidation of an homoallylic alcohol was very recently applied as key step in the synthesis of the tricyclic polar segment of fusarisetin A [START_REF] Kohyama | An enantiocontrolled entry to the tricyclic polar segment of (+)-fusarisetin A[END_REF], which is a fungal metabolite with anticancer activity, due to potent inhibition against acinar morphogenesis, cell migration, and cell invasion in MDAMB-231 cells [START_REF] Jang | an acinar morphogenesis inhibitor from a soil fungus, Fusarium sp. FN080326[END_REF]. The synthesis began with the epoxidation of (Z)-pent-3-en-1-ol 82, which yielded the corresponding key chiral epoxyalcohol 83 in 88% yield with 84% ee (Scheme 35). Chiral vanadium complexes have also been applied to catalyze asymmetric epoxidation. An example of the synthetic utility of this methodology was demonstrated in the synthesis of the fragrance abisabolol reported by Yamamoto et al., in 2003 [START_REF] Makita | Asymmetric epoxidation of homoallylic alcohols and application in a concise total synthesis of (-)--bisabolol and (-)-8-epi--bisabolol[END_REF]. The key step to install the second stereocenter of the molecule was based on asymmetric epoxidation of the (S)-limonene-derived homoallylic alcohol 84 using the vanadium/ligand 85/CHP catalytic system. The required epoxide intermediate 86 was isolated in good yield and 90% de (Scheme 36). More recently, an enantioselective synthesis of florfenicol, a fluorinated derivative of thiamphenicol albeit exhibiting superior antibacterial spectrum, was developed by Chen et al. [START_REF] Li | An efficient enantioselective synthesis of florfenicol via a vanadium-catalyzed asymmetric epoxidation[END_REF]. The product was obtained in 37% overall yield from commercially available 4-methylthiobenzaldehyde. The key epoxidation step was performed on the trans-cinnamyl alcohol derivative 87 in the presence of 5 mol% of the Yamamoto vanadium complex 88 and TBHP to give the key epoxide 89 in 75% yield and > 90% ee (Scheme 36). This chiral epoxide was further converted into the antibacterial agent florfenicol (structure in Scheme 25).

In 1990, a pivotal discovery was illustrated by the groups of Jacobsen [START_REF] Zhang | Enantioselective epoxidation of unfunctionalized olefins catalyzed by (Salen)manganese complexes[END_REF] and Katsuki [START_REF] Irie | Catalytic asymmetric epoxidation of unfunctionalized olefins[END_REF], who independently reported the asymmetric epoxidation of a variety of unfunctionalized alkenes with optically pure Mn(III)/salen complexes using readily available PhIO, bleach, H 2 O 2 , oxone as the terminal oxidants, providing good levels of enantioselectivity [START_REF] Krishnan | Recent advances and perspectives in the manganese-catalysed epoxidation reactions[END_REF]. Soon after their discovery, enantioselective epoxidations catalyzed by Jacobsen-Katsuki complexes were employed as key steps in the synthesis of biologically active products, such as anti-HIV compound indinavir (crixivan ® ) [START_REF] Federsel | In: Stereoselective Synthesis of Drugs -An Industrial Perspective[END_REF], and Iks-channel blockers (Scheme 37) [START_REF] Gerlach | Synthesis and activity of novel and selective IKs-channel blockers[END_REF]. In more than a decade, Fuchs et al. applied and optimized this methodology for the asymmetric epoxidation of cyclic dienyl sulfones and triflates to the corresponding chiral monoepoxides [START_REF] Chen | Synthesis of termini-differentiated 6-carbon stereotetrads: An alkylative oxidation strategy for preparation of the C21-C26 segment of apoptolidin[END_REF]. These compounds proved to be very useful intermediates to access a variety of natural products such as (+)-pretazettine alkaloid core led to the key intermediate epoxide 92 in 70% yield and high enantioselectivity of > 90% ee by using catalyst 93 and H 2 O 2 as oxidant. Epoxide 92 was further converted into (+)-pretazettine.

In 2013, Gao et al. reported the total synthesis of potassium channel activator levcromakalim the key step of which was the enantioselective Mn-catalyzed epoxidation of alkene 94 into functionalized epoxide 95 performed in the presence of porphyrininspired ligand 96 bearing chiral oxazoline groups as ligand with 92% yield and 94% ee (Scheme 39) [78].

Up to date, a few examples have been reported on stereoselective epoxidations mediated by chiral zinc complexes. In 2014, Martin et al. reported the epoxidation of trans-, -unsaturated ketone 97 mediated by overstoichiometric amounts of a complex generated from Et 2 Zn and (1R,2R)-N-methylpseudoephedrine 98 in the presence of molecular oxygen as a benign oxidant. This reaction constituted the final step in the total synthesis of citrinadrin A, an alkaloid isolated from marine-derived fungus Penicillium citrinum (Scheme 40) [START_REF] Bian | Enantioselective total syntheses of citrinadins A and B. Stereochemical revision of their assigned structures[END_REF]. Indeed, the asymmetric epoxidation of enone 97 under these conditions led to citrinadrin A in 81% yield and moderate diastereoselectivity (66% de).

In 2005, Shibasaki et al. developed a catalytic system generated in the presence of molecular sieves from Y(Oi-Pr) 3 , (Ph) 3 As=O as additive, and ligand 99 in 1:1:1 ratio, suitable for the asymmetric epoxidation of -aromatic and aliphatic , -unsaturated esters 100 into epoxides 101 with up to 99% ee (Scheme 41) [START_REF] Kakei | Catalytic asymmetric epoxidation of , -unsaturated esters using an yttrium-biphenyldiol complex[END_REF] , -unsaturated amines [START_REF] Nemoto | Catalytic asymmetric epoxidation of , -unsaturated amides: Efficient synthesis of -aryl -hydroxy amides using a one-pot tandem catalytic asymmetric epoxidation-Pd-catalyzed epoxide opening process[END_REF] and imidazolides [START_REF] Nemoto | Catalytic asymmetric synthesis of , -epoxy esters, aldehydes, amides, and , -epoxy -keto esters: Unique reactivity of , -unsaturated carboxylic acid imidazolides[END_REF] have been successfully employed in key epoxidation steps of total syntheses of various biologically active products, such as anticancer agent (+)decursin [START_REF] Nemoto | Enantioselective total syntheses of novel PKC activator (+)-decursin and its derivatives using catalytic asymmetric epoxidation of an enone[END_REF], antifeedant (-)-marmesin [START_REF] Hara | Catalytic asymmetric epoxidation of , -unsaturated phosphane oxides with a Y(O-Pr)3/biphenyldiol complex[END_REF], antifungal agent (+)strictifolione [START_REF] Tosaki | Catalytic asymmetric synthesis of both syn-and anti-3,5-dihydroxy esters: Application to 1,3polyol/ -pyrone natural product synthesis[END_REF], and antidepressant drug fluoxetin [START_REF] Kakei | Efficient synthesis of chiral -and -hydroxy amides: Application to the synthesis of ( )fluoxetine[END_REF] (Scheme 41).

Asymmetric Organocatalyzed Epoxidations as Key Steps

Asymmetric organocatalysis has increasingly become one of the most useful and practical tool to perform a synthetic transformation [START_REF]Asymmetric organocatalysis in continuous flow: Opportunities for impacting industrial catalysis[END_REF]. In particular, the organocatalyzed asymmetric epoxidation of olefins is an important part of this field, and a number of these processes have been successfully applied to the total synthesis of various important molecules in the last 15 years. Actually, this topic was reviewed in 2014 by Shi et al. [START_REF] Zhu | Organocatalytic asymmetric epoxidation and aziridination of olefins and their synthetic applications[END_REF], consequently only some representative examples will be detailed in this Section. The readers are invited to consult this comprehensive coverage for a complete coverage of the field. Asymmetric phase transfer catalysis (PTC) includes valuable methodologies for building carbon-carbon and carbon-heteroatom bonds [START_REF] Jew | Cinchona-based phase-transfer catalysts for asymmetric synthesis[END_REF]. The mildness and often environmentally friendly reaction conditions of asymmetric PTC reactions cope well for large-scale and industrial applications [START_REF] Albanese | Sustainable oxidations under phasetransfer catalysis conditions[END_REF]. In 2006, an interesting application of the cinchona alkaloid-derived PTCcatalyzed diastereo-and enantioselective epoxidation to access potent naturally-occurring cysteine protease inhibitor, the epoxysuccinyl peptide E-64c, was reported by Lygo et al. [START_REF] Lygo | Stereoselective synthesis of the epoxysuccinyl peptide E-64c[END_REF]. The key epoxidation of , -unsaturated amide 102 into the corresponding functionalized epoxide 103 occurred with 70% yield and moderate diastereoselectivity of 66% de when catalyzed with cinchona alkaloid salt 104, as shown in Scheme 42.

The most efficient class of oxidants to perform the epoxidation of alkenes are dioxiranes [START_REF] Curci | A novel approach to the efficient oxygenation of hydrocarbons under mild conditions. Superior oxo transfer selectivity using dioxiranes[END_REF]. In contrast to similar oxidizing agents, such as percarboxylic acids, the development of chiral dioxiranes for asymmetric epoxidations has met great success over the last decades [START_REF] Padwa | Intermolecular 1,3-Dipolar Cycloadditions[END_REF][START_REF] Wong | Oxidation: Organocatalyzed Asymmetric Epoxidation of Alkenes[END_REF]. In late 1990s, Shi and co-workers introduced a variety of pseudo C 2 -symmetric six-membered carbocyclic ketones derived from quinic acid as stoichiometric precursors of in situ generated chiral dioxiranes to be used in asymmetric epoxidation of trans-disubstituted, trisubstitued, terminal alkenes, and electronpoor alkenes. Oxone was used in DME under basic buffered conditions at 0 °C in the presence of only 5-10 mol% of the chiral ketone [94]. More recently, a comparable methodology was applied by Chandrasekhar and Kumar to the total synthesis of pladienolide B, a natural anticancer macrolide [START_REF] Kumar | Enantioselective synthesis of pladienolide B and truncated analogues as new anticancer agents[END_REF]. The key step of the synthesis was the epoxidation of homoallylic alcohol 105 performed in the presence of superstoichiometric amounts of ketone 106 and oxone to give epoxide 107 in 64% yield and 95% de (Scheme 43). In 2012, a simple total synthesis of (+)-ambrisentan, a drug clinically used for the treatment of pulmonary arterial hypertension, was reported by Shi et al. [START_REF] Peng | Synthesis of (+)-Ambrisentan via chiral ketonecatalyzed asymmetric epoxidation[END_REF]. It began with the asymmetric epoxidation of ethyl 3,3-diphenylacrylate 108 (Scheme 44). This electron-poor alkene was epoxidized with the most effective ketone 109 to provide the corresponding chiral epoxide 110 in 90% yield and 85% ee. The reaction crude was then directly subjected to other steps to finally afford (+)-ambrisentan in 53% overall yield and >99% ee.

Biomimetic synthesis based on intramolecular cascade ringopening reaction of chiral epoxides has been also reported by McDonald et al. (Scheme 45) [START_REF] Tong | Total syntheses of durgamone, nakorone, and abudinol B via biomimetic oxa-and carbacyclizations[END_REF]. With the aim of developing a synthetic route to abudinols A and B, oxygenated triterpenoid marine natural products, triene 111 was selectively epoxidized at two of its three carbon-carbon double bonds to give diepoxide 112 in good yield (76%) and high diastereoselectivity of > 90% de when using ketone 106 as the organocatalyst. The allylic electronwithdrawing group proximal to the other carbon-carbon double bond prevented its epoxidation. ent-Nakorone, an oxidative degradation product of abudinols, was then obtained via TMSOTfpromoted cyclization with the propargylsilane nucleophile, followed by ozonolysis.

Conceptually similar chiral iminium salts/oxaziridinium salts systems have been introduced as epoxidizing systems since the late 1980s [START_REF] Page | Oxaziridinium Salt-Mediated Catalytic Asymmetric Epoxidation[END_REF]. A tetraphenylphosphonium monoperoxybisulfate (TPPP) [START_REF] Page | Organocatalysis of asymmetric epoxidation mediated by iminium salts under nonaqueous conditions[END_REF] was employed as oxidant in combination with organocatalyst 113 in the asymmetric epoxidation of some Z-alkenes to the corresponding epoxides, which were isolated in good yields and good to high enantioselectivities of up to 97% ee (Scheme 46) [START_REF] Page | Asymmetric epoxidation of cis-alkenes mediated by iminium salts: Highly enantioselective synthesis of Levcromakalim[END_REF]. In particular, the epoxidation of a benzopyran substrate into tricyclic epoxide 114 occurred with the highest efficiency, and was applied to synthesize the antihypertensive agent (-)-cromakalim with high stereoselectivity via ring-opening of the epoxide unit with pyrrolidone, as shown in Scheme 46. In addition, organocatalyst 113 was used in the key epoxidation step for a concise asymmetric synthesis of natural coumarin derivatives (-)-lomatin, and (+)-transkhellactone [START_REF] Page | Highly enantioselective total synthesis of (-)-(3 S)lomatin and (+)-(3 S,4 R)-trans-khellactone[END_REF].

Page and co-authors reported the application of another chiral iminium salt-catalyzed epoxidation as key step in the first highly enantioselective synthesis of (+)-scuteflorin A, one of the numerous and pharmacological active compounds recently isolated from Scutellaria species (Scheme 47) [START_REF] Bartlett | Enantioselective total synthesis of (+)-scuteflorin a using organocatalytic asymmetric epoxidation[END_REF]. A previously reported chiral iminium salt 115 [START_REF] Page | New organocatalysts for the asymmetric catalytic epoxidation of alkenes mediated by chiral iminium salts[END_REF] served as organocatalyst under non aqueous conditions, to epoxidize the starting Z-alkene 116 into the corresponding key enantiopure epoxide 117 in 97% yield. Epoxide hydrolysis/oxidation and esterification completed the synthesis.

The combination of diaryl prolinol 118 as organocatalyst with an alkyl hydroperoxide, such as TBHP, as oxidant in asymmetric epoxidation system was investigated by Zhao et al., developing the first asymmetric epoxidation reactions of a variety of transdisubstituted electron-poor alkenes, such as 119, into the corresponding chiral epoxides, such as 120, in good yields, complete diastereocontrol, and good enantioselectivities [START_REF] Zheng | Highly efficient asymmetric epoxidation of electron-deficient , -enones and related applications to organic synthesis[END_REF]. As an application, the authors developed a short synthesis of natural products (-)-(5R,6S)-norbalasubramide and (-)-(5R,6S)-balasubramide which is depicted in Scheme 48. In 2010, Hayashi et al. reported a short synthesis of (R)-methyl palmoxirate, a potent oral hypoglycemic agent, based on the first successful asymmetric epoxidation of aliphatic -substituted acroleins, that was catalyzed by diphenylprolinol silyl ether 121 and H 2 O 2 as oxidant [START_REF] Bondzic | Asymmetric epoxidation of -substituted acroleins catalyzed by diphenylprolinol silyl ether[END_REF]. Terminal epoxide 122, bearing a quaternary stereocenter, was obtained as key intermediate in good yield (78%) and high enantioselectivity (up to 92% ee) starting from alkene 123, as shown in Scheme 49.

Ph

Kinetic Resolutions of Racemic Epoxides as Key Steps

Besides reactions mediated by metal complexes or organocatalysts, another important tool in asymmetric synthesis to obtain optically active products is the kinetic resolution of racemic molecules [START_REF] Pellissier | Catalytic non-enzymatic kinetic resolution[END_REF]. In 1990s, Jacobsen et al. demonstrated the exceptional catalytic performance of Cr(III)-salen complexes in the kinetic resolu-tion of racemic terminal monosubstituted and 2,2-disubstituted epoxides by TMSN 3 , which occurred with complete regioselectivity for the terminal position and very high stereoselectivity factors of up to 280 [107]. Later, these authors reported enhanced reactivity by using dimeric catalyst 124 in hydrolytic kinetic resolution of terminal epoxides (Scheme 50) [START_REF] White | New oligomeric catalyst for the hydrolytic kinetic resolution of terminal epoxides under solvent-free conditions[END_REF]. A recent synthetic application of kinetic resolution using primary alcohols was illustrated by the same authors in the total synthesis of (+)-reserpine via intermediate enone 125 [START_REF] Rajapaksa | Enantioselective total synthesis of (+)-Reserpine[END_REF]. The kinetic resolution of a racemic epoxide performed in acetonitrile with 4.5 mol% of catalyst 128 and benzyl alcohol as the nucleophile, afforded the secondary alcohol 126 in 41% yield and 96% ee, which was further converted into enone 125. Then, this product was coupled with dihydro--carboline 127 to access antipsychotic and antihypertensive drug (+)-reserpine. Rare examples of hydrolytic kinetic resolution of functionalized racemic epoxides bearing two stereocenters have been reported. The groups of Tae and Sudalai independently investigated the hydrolytic kinetic resolution of racemic syn-and anti-2-hydroxy-1oxiranes in order to obtain both enantiomers of syn-and antiepoxides (Scheme 51) [110]. Racemic syn-O-protected terminal epoxide 128 underwent hydrolytic kinetic resolution with chiral cobalt catalyst 129 to give enantioenriched syn-epoxide 128 along with 1,2-diol 130 in excellent conversions and enantioselectivities of up to 98% ee. Epoxide 128 was employed as the starting reagent for the total synthesis of the opposite enantiomer of natural product (5S,7R)-kurzilactone. Optically active trans-epoxide 131 was produced under comparable reaction conditions albeit using catalyst ent-129 and further employed in a concise total synthesis of the cytokine modulator (+)-epi-cytoxazone (Scheme 51).

R 3 R 1 R 2 R 3 R 1 R 2 O O O NC 59%,
The hydrolytic kinetic resolution methodology performed in the presence of cobalt catalyst ent-129 also constituted the key step of a total synthesis of natural product (+)-eldanolide, a long range sex attractant, which was reported by Sudalai et al., in 2013 [START_REF] Devalankar | Optically pure -butyrolactones and epoxy esters two stereocentered HKR of 3-substituted epoxy esters: A formal synthesis of (-)-paroxetine, Ro 67-8867 and (+)-eldanolide[END_REF]. As shown in Scheme 52, racemic anti-3-methyl epoxy ester 132 led to the corresponding trans-3,4-disubstituted-g-butyrolactone 133 along with unreacted chiral epoxide 132 both isolated in excellent enantioselectivities of 96-97% ee. Epoxide 132 was subsequently converted into expected natural product (+)-eldanolide. Another advantage of this methodology was the production of chiral 3,4disubstituted -butyrolactones, which constitute important scaffolds endowed with several biological activities.

The hydrolytic kinetic resolution of terminal epoxides was recently applied in the total synthesis of the anti-Parkinson agent safinamide, starting from commercially available benzyl glycidyl ether (Scheme 53) [START_REF] Reddy | A new enantioselective synthesis of the anti-Parkinson agent safinamide[END_REF]. Enantiopure epoxide 134 was obtained in good conversion (46%) via hydrolytic kinetic resolution of the corresponding racemic epoxide in the presence of ent-129 as catalyst, which secured a highly enantioselective approach to safinamide via simple elaboration steps. In addition, the hydrolytic kinetic resolution of racemic epoxides has also been used in the synthesis of other natural and bioactive compounds, such as (S)-timolol [START_REF] Narina | Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines[END_REF], decarestrictine D [START_REF] Gupta | An efficient total synthesis of decarestrictine D[END_REF], (+)-isolaurepan [START_REF] Tripathi | A general approach to medium-sized ring ethers via hydrolytic and oxidative kinetic resolutions: Stereoselective syntheses of (-)-cis-lauthisan and (+)-isolaurepan[END_REF], (R)-tuberculostearic acid [START_REF] Dyer | Synthesis and structure of phosphatidylinositol dimannoside[END_REF], (R)-mexiletine [START_REF] Sasikumar | A convenient synthesis of enantiomerically pure (R)-mexiletine using hydrolytic kinetic resolution method[END_REF], neocarazostatin B [START_REF] Czerwonka | First enantioselective total synthesis of neocarazostatin B, determination of its absolute configuration and transformation into carquinostatin A[END_REF], and amprenavir [START_REF] Gadakh | Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2phenylethyl)oxirane[END_REF].

In 2004, Bartoli, Melchiorre et al. showed that the same cobalt catalyst ent-129 could also catalyze the highly regioselective kinetic resolution of epoxides with carbamates as nucleophiles in the presence of p-nitrobenzoic acid as an additive to provide the corresponding enantiopure chiral -amino alcohols 135 (Scheme 54) [START_REF] Bartoli | Asymmetric catalytic synthesis of enantiopure N-protected 1,2-amino alcohols[END_REF]. The utility of this novel methodology was demonstrated in a total synthesis of the anti-hypertensive drug ( -blocker) (S)propanolol.

Asymmetric Sulfur Ylide-Mediated Epoxidations as Key Steps

An alternative non-oxidative preparation of chiral epoxides relies on the use of chiral sulfur ylides and aldehydes as reactive partners [START_REF] Gnas | Chiral auxiliaries -principles and recent applications[END_REF]. This methodology has been the focus of significant interest to efficiently produce chiral epoxides in the last decade [87a, 122]. For The same group also developed asymmetric sulfur ylide epoxidations of readily available hemiaminals [START_REF] Kokotos | Hemiaminals as substrates for sulfur ylides: Direct asymmetric syntheses of functionalized pyrrolidines and piperidines[END_REF]. As shown in Scheme 56, the reaction of cyclic hemiaminal 139 with chiral sulfonium salt 140 at room temperature in dichloromethane in the presence of a base, such as phosphazene P2 (N,N,N',N'tetramethyl-N'-(tris(dimethylamino)phosphoranylidene) phosphoric triamide ethylimine), led to the corresponding chiral epoxide 141 in 54% yield. The latter was further successively submitted to TMSOTf and Sc(OTf) 3 to afford the corresponding chiral piperidine 142 as the only detected diastereomer in 93% ee and with 90% yield. The synthetic utility of this novel methodology was demonstrated by its application in the synthesis of the potent neurokinin-1 (NK-1) receptor antagonist CP-122,721, as depicted in Scheme 56.

Most of the recent efforts in the asymmetric ylide-mediated epoxidation were focused on the synthesis of readily accessible optically pure sulfides able to improve and extend the scope of epoxidation in order to apply this methodology in total synthesis [START_REF] Aggarwal | Catalytic, asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds: Scope, selectivity, and applications in synthesis[END_REF][START_REF] Aggarwal | The complexity of catalysis : Origins of enantio-and diastereocontrol in sulfur ylide mediated epoxidation reactions[END_REF]. An innovative scaffold for the starting sulfide has been reported by Sarabia et al., based on the use of easily available amino acids Land D-methionines (Scheme 57) [START_REF] Sarabia | A highly efficient methodology of asymmetric epoxidation based on a novel chiral sulfur ylide[END_REF]. For example, sulfonium salt 143 was readily prepared in four steps and 70% overall yield from L-methionine. The reactions of 143 with various aldehydes were performed under basic conditions to give exclusively the corresponding chiral trans-epoxides 144 in almost diastereoisomerically pure form. Employment of enantiopure aldehydes as reagents enabled the preparation of complex epoxy amides, such as 145, with an excellent control of the diastereoselectivity. This compound constituted a useful intermediate for the synthesis of macrolide-type natural products. The same group recently reported an in-depth study on the bicyclic core ring-size of sulfonium salts of type 143, demonstrating that it was possible to increase the scope of simple and chiral aldehydes employable in the epoxidation, for instance heteroaromatic, vinyl, and hemiacetal [START_REF] Sarabia | A highly stereoselective synthesis of glycidic amides based on a new class of chiral sulfonium salts: Applications in asymmetric synthesis[END_REF]. The versatility of this methodology was demonstrated in the total syntheses of bengamides analogues [START_REF] Sarabia | Epi-, epoxy-, and C2-modified Bengamides: Synthesis and biological evaluation[END_REF], a family of marine natural products isolated from sponges, exhibiting prominent antitumor, antihelmintic, and antibiotic activities as well as natural product (-)-depudecin [START_REF] García-Ruiz | Stereoselective total synthesis of (-)-Depudecin[END_REF], an antiangiogenic microbial polyketide (Scheme 57). Further applications include the synthesis of cyclodepsipeptides globomycin and SF-1902 A5 [START_REF] Sarabia | Solid phase synthesis of globomycin and SF-1902 A5[END_REF], and sphingoid-type bases [START_REF] Sarabia | Exploring the reactivity of chiral glycidic amides for their applications in synthesis of bioactive compounds[END_REF].

Catalytic Asymmetric Darzens Reactions as Key Steps

An important transformation to obtain epoxides bearing an electron-withdrawing groups is the Darzens reaction [132] North et al. in 2007 [START_REF] Achard | Enantio-and diastereoselective Darzens condensations[END_REF], successful examples of this type of methodology have been developed and applied in total synthesis. Therefore, Gong et al. have described an enantioselective titaniumcatalyzed Darzens reaction as key step in the total synthesis of protease inhibitor (-)-bestatin [START_REF] Liu | An asymmetric catalytic Darzens reaction between diazoacetamides and aldehydes generates -glycidic amides with high enantiomeric purity[END_REF]. The reaction was catalyzed by an in situ generated complex from Ti(OiPr) 4 and (R)-BINOL. It occurred between diazoacetamide 146 and aldehyde 147 in the presence of molecular sieves (Scheme 58). A complete control of the diastereoselectivity was observed, providing the corresponding cisglycidic amide 148 in good yield (88%) and high enantioselectivity of 92% ee. This epoxide constituted a useful intermediate in the synthesis of (-)-bestatin.

Chiral Thiiranes

Sulfur-containing compounds are widespread among natural products and biologically active substances [135]. Consequently, great efforts have been devoted to develop stereocontrolled C S bond-forming procedures [136]. In particular, thiiranes are suitable precursors of numerous products, including biologically active compounds. Several methods for thiirane preparation [137] been reported, among which the most convenient one consists in the conversion of oxiranes into the corresponding thiiranes by an oxygen sulfur exchange reaction. With this aim, various sulfur reagents have been investigated such as thiourea 149 [START_REF] Ketcham | Cis-and trans-Stilbene Sulfides[END_REF]. In 2005, an asymmetric version of this methodology was applied by Mobashery et al. to the synthesis of chiral 1,2-(4-phenoxyphenylsulfonylmethyl)thiirane 150, which is a selective gelatinase inhibitor active for cancer metastasis [START_REF] Lee | Mobashery, S. 1,4-Di(1,2,3-triazol-1-yl)butane as building block for the preparation of the iron(II) Spin-Crossover 2D coordination polymer[END_REF]. The key step of the synthesis consisted in the reaction of the corresponding (S)-epoxide 151 with thiourea 149 to give the expected (R)-thiirane 151 in good yield (84%) and high enantioselectivity (> 90% ee), as shown in Scheme 59.

CHIRAL CYCLOPROPANES IN TOTAL SYNTHESIS

The strained cyclopropane subunit [2a, 140] is present in a range of biologically relevant products, such as terpenes, pheromones, fatty acid metabolites, and unusual amino acids [141], among others. These compounds exhibit a large spectrum of biological properties, including enzyme inhibition and insecticidal, antifungal, herbicidal, antimicrobial, antibiotic, antibacterial, antitumor, and antiviral activities [3,142]. This fact has inspired chemists to find novel approaches for their synthesis [143], and thousands of cyclopropane compounds have already been prepared [144]. In particular, the asymmetric synthesis of cyclopropanes has remained a challenge [2f, 145], since it was demonstrated that members of the pyrethroid class of compounds to be effective insecticides [START_REF] Arlt | Syntheses of pyrethroid acids[END_REF]. In the last decade, many important chiral cyclopropane derivatives have been synthesized according to three principal methodologies, including the Simmons-Smith reaction [START_REF] Charette | Simmons-Smith Cyclopropanation Reaction in Organic Reactions[END_REF], the transition-metal-catalyzed decomposition of diazo compounds [2f, 148], and the Michael-initiated ring-closure (MIRC) [149]. In each case, the reactions can start from chiral substrates (or auxiliaries) or can be promoted by chiral catalysts.

Asymmetric Simmons Smith Cyclopropanations as Key Steps

In 1950s, Simmons and Smith reported the reaction of alkenes with diiodomethane performed in the presence of activated zinc which afforded cyclopropanes in high yields [START_REF] Simmons | A new synthesis of cyclopropanes from olefins[END_REF]. The reactive intermediate is an organozinc species and the preparation of such species, including RZnCH 2 I or IZnCH 2 I compounds and samarium derivatives, was developed in the following years [START_REF] Chan | Relative rates and stereochemistry of the iodomethylzinc iodide methylenation of some hydroxy-and methoxysubstituted cyclic olefins[END_REF]. Ever since, asymmetric versions of the Simmons-Smith reaction [152] have been developed and applied to the synthesis of various biologically active products using either chiral substrates or chiral catalysts.

Using Chiral Substrates

Various asymmetric cyclopropanations of acyclic allylic alcohols have been reported, using the heteroatom as the directing group, through chelation with the zinc reagent. This Simmons-Smith reaction has distinct advantages over the reaction with a simple olefin in relation to the reaction rate and stereocontrol [START_REF] Hoveyda | Substrate-directable chemical reactions[END_REF]. Many asymmetric cyclopropanations of chiral allylic alcohols have been used as key steps in total synthesis of natural products of biological interest. For instance, Takemoto et al. reported in 2000s an asymmetric total synthesis of natural product halicholactone, in which a regio-and stereoselective cyclopropanation of chiral diene 152 into epoxide 153 obtained as the only detected stereoisomer constituted the key step (Scheme 60) [START_REF] Takemoto | Asymmetric total synthesis of halicholactone[END_REF].

In 2006, Smith and Simov developed the total synthesis of the marine diolide (-)-clavosolide A on the basis of the direct Simmons-Smith cyclopropanation of chiral N-methoxyamide 154, providing the corresponding key cyclopropane intermediate 155 in 74% yield and diastereoselectivity of 84% de, as shown in Scheme 61 [START_REF] Smith | Total synthesis of the marine natural product (-)-Clavosolide A. A show case for the Petasis-Ferrier Union/Rearrangement tactic[END_REF].

In 2007, a total synthesis of the two biologically active oxylipins solandelactones E and F was described by White et al. [START_REF] White | Total synthesis of solandelactones E and F, homoeicosanoids from the hydroid Solanderia secunda[END_REF]. The key step was a comparable Simmons-Smith cyclopropanation of chiral N-methoxyamide 156 which provided the corresponding functionalized cyclopropane 157 as the only detected stereoisomer diastereomer in almost quantitative yield, as shown in Scheme 62. The authors confirmed that the structures of the two solandelactones were epimeric at C11.

Brevipolides are extracted from the invasive tropical plant of Hyptis brevipes, and exhibit interesting drug properties. Recently, Mohapatra et al. developed a highly diastereoselective synthesis of the C1-C12 fragment of brevipolide H (Scheme 63) [START_REF] Mohapatra | Toward the synthesis of brevipolide H[END_REF]. The key step was the cyclopropanation of chiral alkene 158 into 159 in excellent yield (up to 97%) and diastereoselectivity (up to 98% de). A similar reaction was previously reported by Kumaraswamy et al., but with inferior results in the synthesis of another representative member of the brevipolide family [START_REF] Kumaraswamy | Towards the diastereoselective synthesis of derivative of 11 -epibrevipolide H[END_REF]. In addition to chiral allylic alcohols, chiral acetals bearing an alkene function, such as 160 and 161, have been used in diastereoselective acetal-directed cyclopropanations as key steps of total syntheses of solandelactone E (Scheme 64a, structure in Scheme 62) [START_REF] Davoren | Enantioselective synthesis and structure revision of solandelactone E[END_REF], and a marine fatty acid metabolite exhibiting lipoxygenase-inhibiting activity (Scheme 64b) [START_REF] Mohapatra | Asymmetric total synthesis of eicosanoid[END_REF], both providing the corresponding cyclopropane derivatives 162 and 163, respectively, in good to excellent yields (72-95%) and as the only detected stereoisomers.

In 2006, standard Simmons-Smith conditions were also applied by Abad et al. to the cyclopropanation of diterpene 164 [START_REF] Abad | A unified synthetic approach to trachylobane-, beyerane-, atisane-and kaurane-type diterpenes[END_REF]. The reaction occurred stereoselectively from the less hindered b-side of the double bond, affording the expected cyclopropane 165 in 94% yield and as the only detected stereoisomer (Scheme 65). This tricyclo[3.2.1.0]octane moiety constituted the key intermediate in the synthesis of biologically interesting trachylobane-, beyerane-, atisane-, and kaurane-type diterpenes.

In 2015, Tori et al. applied similar Simmons-Smith conditions to the last step of a total synthesis of natural product (+)crispatanolide starting from chiral alkene 166, as shown in Scheme 66 [START_REF] Nakashima | What is the absolute configuration of (+)-crispatanolide isolated from Makinoa crispate (liverwort)?[END_REF]. Surprisingly, the major product was not the expected (+)- crispatanolide, but a diastereomer, very likely because of the directing effect of the lactone carbonyl group. However, this synthesis allowed likewise assigning the absolute configuration of the natural (+)-crispatanolide.

In addition, various types of recoverable chiral auxiliaries have been successfully employed in asymmetric Simmons-Smith cyclo-propanations as key steps of total syntheses of various natural products. For example, the asymmetric Simmons-Smith cyclopropanation of chiral allylic alcohol 167 led to the corresponding cyclopropanes 168 in high to quantitative yields and as almost single diastereomers (> 95% de) [START_REF] Cheeseman | A novel strategy for the asymmetric synthesis of chiral cyclopropane carboxaldehydes[END_REF] to be used as key intermediates in several natural products, such as cascarillic acid [START_REF] Cheeseman | A temporary stereocentre approach for the asymmetric synthesis of chiral cyclopropanecarboxaldehydes[END_REF] (-)-clavosolide A (structure in Scheme 61) [START_REF] Son | Enantioselective total synthesis of (-)-Clavosolide B[END_REF], and grenadamide [START_REF] Green | An efficient asymmetric synthesis of grenadamide[END_REF] (Scheme 67).

Using Chiral Catalysts

In 2001, Liu and Ghosh reported the cyclopropanation of cisand trans-disubstituted allylic alcohols, such as 170 and 171, per-formed in the presence of chiral dioxaborolane ligand 169, which led to the corresponding chiral cyclopropylmethanols 172 and 173, respectively, in diastereoselectivities of up to > 95% de. These reactions constituted the key steps for biologically active product synthesis, such as an epothilone analogue [START_REF] Nicolaou | Chemical synthesis and biological evaluation of cis-and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues[END_REF], and (-)-doliculide [START_REF] Ghosh | Total synthesis of antitumor depsipeptide (-)-doliculide[END_REF], as shown in Scheme 68. It must be noted that in fact these results arose from a double induction since the starting materials were also chiral.

In 2006, (S)-phenylalanine-derived disulfonamide 174 was applied as chiral ligand to promote the cyclopropanation of a range of 3,3-diaryl-2-propen-1-ols in the presence of Et 2 Zn and CH 2 I 2 , providing the corresponding cyclopropylmethanols with moderate to good enantioselectivities (59-84% ee), as shown in Scheme 69 [START_REF] Miura | Syntheses of (R)-(+)-cibenzoline and analogues via catalytic enantioselective cyclopropanation using (S)phenylalanine-derived disulfonamide[END_REF]. Chiral cyclopropanes 175, 176 and 177, derived from the corresponding allylic alcohols 178, 179, and 180, were further converted into (+)-cibenzoline, an antiarrhythmic agent [START_REF] Koyata | Convenient preparation of optically active cibenzoline and analogues from 3,3-diaryl-2-propen-1-ols[END_REF], (+)tranylcypromine, a strong monoamineoxidase inhibitor, and (-)milnacipran, a serotonin-noradrenaline reuptake inhibitor, respectively [START_REF] Ishizuka | Asymmetric syntheses of pharmaceuticals containing a cyclopropane moiety using catalytic asymmetric Simmons-Smith reactions of allylalcohols: Syntheses of optically active tranylcypromine and milnacipran[END_REF].

Asymmetric Transition-Metal Decomposition of Diazoalkanes as Key Steps

Intermolecular Cyclopropanations Chiral Substrates

Since the pioneering work of Nozaki and Noyori reported in 1966 [START_REF] Nozaki | Asymmetric induction in carbenoid reaction by means of a dissymmetric copper chelate[END_REF], the transition-metal-catalyzed cyclopropanation of alkenes with diazo compounds has emerged as one of the most highly efficient routes to functionalized cyclopropanes. These reactions have been applied in total synthesis, starting from chiral substrates, but also in the presence of chiral catalysts. As a rare example of reaction involving a chiral substrate, Snapper et al. developed the asymmetric cyclopropanation of chiral tricyclic alkene 181 as key step in total syntheses of natural products pleocarpenene and pleocarpenone [START_REF] Williams | Intramolecular cyclobutadiene cycloaddition/cyclopropanation/thermal rearrangement: An effective strategy for the asymmetric syntheses of pleocarpenene and pleocarpenone[END_REF]. The authors observed a high stereochemical control (> 90% de) in the cyclopropanation with ethyl diazoacetate (EDA) into compound 182 followed by deacetylation reaction using Cu(acac) 2 as the catalyst (Scheme 70).

Moreover, Oppolzer's chiral sultam 183 was applied for the synthesis of novel melatoninergic agents, as in Scheme 71 [START_REF] Sun | R)-2-(4-Phenylbutyl)Dihydrobenzofuran derivatives as melatoninergic agents[END_REF].

Chiral Catalysts

Chiral copper catalysts are among the most effective catalysts for the preparation of the trans-isomer of cyclopropanes with the widest reaction scope. Among them, non-racemic C 2 -symmetric bidentate bisoxazoline ligands [START_REF] Evans | oxazolines) as chiral ligands in metal-catalyzed asymmetric reactions. Catalytic, asymmetric cyclopropanation of olefins[END_REF] have been used in cyclopropanation reactions with copper for more than thirty years (see also subsection entitled "Copper-catalyzed nitrene transfer to alkenes") [175]. Some of these copper-catalyzed reactions have been included into multistep syntheses of natural products [START_REF] Honma | Development of catalytic asymmetric intramolecular cyclopropanation of -diazo--keto sulfones and applications to natural product synthesis[END_REF]. For example, carbohydrate-based bis(oxazoline) ligand 184 and copper(I) triflate were used in the reaction of non-1-ene 185 and EDA for the total synthesis of unnatural (+)-grenadamide [START_REF] Minuth | Carbohydrate-Derived bis(oxazoline) ligand in the total synthesis of grenadamide[END_REF] (Scheme 72).

In 2012, the cyclopropanation of N-Boc-3-methylindole 186, performed in the presence of bisoxazoline ligand 187 in combination with CuOTf, yielded a key building block 188 for the synthesis of the indole alkaloid (-)-desoxyeseroline that was isolated in 59% overall yield and 96% ee (Scheme 73) [START_REF] Ozoduru | Enantioselective cyclopropanation of indoles: Construction of all-carbon quaternary stereocenters[END_REF]. Moreover, the use of ligand 48 allowed the stereoselective preparation of the tetracyclic core and key intermediate 189 in a total synthesis of cryptotrione to be achieved (Scheme 73). The key cyclopropane intermediate 189 was obtained in 93% yield and 82% de starting from alkene 190 [START_REF] Chen | Stereoselective construction of the tetracyclic core of cryptotrione[END_REF].

Copper-salen catalysts were found particularly efficient in the synthesis of chrysantemate esters, and (1R,3R)-chrysanthemic ester 191 was prepared in the presence of Cu(I)-salen complex 192 in 90% yield with 78:22 dr and enantioselectivities of 91% and 62% ee for the trans-and cis-diastereomers, respectively [START_REF] Suenobu | Reaction pathway and stereoselectivity of asymmetric synthesis of chrysanthemate with the aratani c1symmetric salicylaldimine-copper catalyst[END_REF] (Scheme 74).

Chiral dirhodium carboxamide catalysts were originally developed by Doyle for enantioselective cyclopropanations [181]. In the presence of these catalysts, allylic substrates and in particular dihydronaphthalene have a potentially competing pathway to cyclopropanation, such as allylic C-H insertion. An example was developed Moreover, chiral ruthenium catalysts have also been applied to the field of catalytic enantioselective cyclopropanation. This approach was employed by Marcin al. as key step in a total synthesis of BMS-505130, a selective serotonin reuptake inhibitor [START_REF] Marcin | Catalytic asymmetric diazoacetate cyclopropanation of 1-tosyl-3-vinylindoles. A route to conformationally restricted homotryptamines[END_REF]. As shown in Scheme 76, 1-tosyl-3-vinylindole 193 was cyclopropanated by Nishiyama's catalyst 194 with ethyl diazoacetate to give the corresponding key cyclopropane 195 in 82% yield and 86% de. The latter was further converted into expected BMS-505130.

Intramolecular Cyclopropanations Chiral Substrates

Initially, intramolecular cyclopropanation reactions were performed with appropriate chiral substrates, and generally occurred with stereocontrol, leading to the exclusive formation of one stereoisomeric product. Copper and rhodium complexes are the most popular catalysts for these reactions. For example, Rh 2 (OAc) 4 was shown to promote the last step in the synthesis of terpenes, such as dihydromayurone, as the only detected stereoisomer [184]. As shown in Scheme 77, this step evolved through the intramolecular cyclopropanation of chiral diazoketone 196 with complete diastereoselectivity and moderate yield (57%). On the other hand, a copper-catalyzed intramolecular cyclopropanation, occurring with low diastereoselectivity of 26% de, constituted the key step in the synthesis of sesquiterpenes (-)-microbiotol and (+)--microbiotene starting from chiral diazoketone 197 derived from cyclogeraniol (Scheme 77) [START_REF] Srikrishna | The first enantioselective synthesis of (-)-microbiotol and (+)--microbiotene[END_REF]. The key cyclopropane intermediate 198 was obtained in good yield (75%). In addition, the key step to construct the bicyclic system of another sesquiterpene (+)-pinguisenol was based on the diastereoselective copper-catalyzed intramolecular cyclopropanation of diazoketone 199 into cyclopropane 200 obtained as the only detected stereoisomer with moderate yield (52%), followed by regioselective cyclopropane cleavage (Scheme 77) [START_REF] Srikrishna | An enantiospecific approach to pinguisanes from (R)-carvone. Total synthesis of (+)-pinguisenol[END_REF].

Chiral Catalysts

A number of chiral catalysts have been successfully applied to the enantioselective intramolecular cyclopropanation of unsaturated diazoketones as key steps in total synthesis. For example, Nakada et al. investigated the enantioselective copper-catalyzed intramolecular cyclopropanation of -diazo--keto sulfones (Scheme 78) [187]. The success of this methodology was illustrated by its application to the total syntheses of several biologically active products, such as (-)-allocyathin B 2 [START_REF] Takano | Synthetic studies on cyathins: Enantioselective total synthesis of (+)-allocyathin B2[END_REF], (-)-malyngolide [START_REF] Miyamoto | A new asymmetric total synthesis of enantiopure (-)-malyngolide[END_REF], and, (-)-methyl jasmonate, as illustrated in Scheme 78 [START_REF] Takeda | Asymmetric total synthesis of enantiopure (-)-methyl jasmonate via catalytic asymmetric intramolecular cyclopropanation of -diazo--keto sulfone[END_REF]. Key intermediates 202a-c of these syntheses were produced with up to 97% ee and 93% yield through intramolecular cyclopropanation of the corresponding unsaturated diazoketones 201a-c catalyzed with a combination of CuOTf with a chiral bisoxazoline ligand among 203-205.

The same group also developed the enantioselective preparation of tricyclo[4.4.0.0]dec-2-ene derivatives [START_REF] Ida | Highly enantioselective preparation of tricyclo[4.4.0.0 5,7 ]decene derivatives via catalytic asymmetric intramolecular cyclopropanation reactions of -diazo--keto esters[END_REF] and tricyclo[4.3.0.0]nonenones 206 by using CuOTf combined with chiral ligand 205 [192]. The resulting chiral cyclopropanes 207 were employed as key intermediates in the (formal) total syntheses of natural and biologically active products, such as (+)-busidarasin C and acetoxytubipofuran [START_REF] Ida | Highly enantioselective preparation of tricyclo[4.4.0.0 5,7 ]decene derivatives via catalytic asymmetric intramolecular cyclopropanation reactions of -diazo--keto esters[END_REF], (+)-digitoxigenin [START_REF] Honma | Enantioselective total synthesis of (+)digitoxigenin[END_REF], (-)-platensimycin and (-)-platencin [192], as well as nemorosone, garsubellin A, clusianone, and hyperforin [START_REF] Uetake | Enantioselective approach to polycyclic polyprenylated acylphloroglucinols via catalytic asymmetric intramolecular cyclopropanation[END_REF] (Scheme 79).

A related methodology was also applied to the intramolecular cyclopropanation of various -diazo--oxo-5-hexenyl phosphonates 208 [START_REF] Sawada | Enantioselective total synthesis of (+)-Colletoic acid via catalytic asymmetric intramolecular cyclopropanation of a -Diazo-keto diphenylphosphine oxide[END_REF]. In the presence of a combination of CuBF 4 and bisoxazoline ligand 203 (structure in Scheme 78), (1R,5S)bicyclo[3.1.0]hexane 209 was obtained in good yield (79%) and high enantioselectivity of 91% ee and was futher converted into natural and bioactive product (+)-colletoic acid (Scheme 80).

Moreover, asymmetric Rh 2 (S-MEPY) 4 -catalyzed cyclization of allylic diazoacetates led to chiral [START_REF] Berberich | Total synthesis of (+)-ambruticin S[END_REF]. Furthermore, the reaction of secondary divinyldiazoacetate 212 led to the corresponding cyclopropane derivative 213 as a 50:50 mixture of two diastereomers each obtained in 94% ee and quantitative yield (Scheme 81) [START_REF] Martin | Enantio-and diastereoselectivity in the intramolecular cyclopropanation of secondary allylic diazoacetates[END_REF]. This mixture was further employed as key intermediate in the total synthesis of natural products, tremulenediol A and tremulenolide A [START_REF] Ashfeld | Enantioselective syntheses of tremulenediol A and tremulenolide A[END_REF], and to that of various cyclopropanederived peptidomimetics [START_REF] Reichelt | Synthesis and properties of cyclopropane-derived peptidomimetics[END_REF].

In 2015, Chanthamath and Iwasa reported the enantioselective intramolecular cyclopropanation of electron-deficient allylic diazoacetate 214, performed in the presence of ruthenium catalyst 215 that provided the corresponding diastereo-and enantiopure cyclopropane-fused g-lactone 216 in high yield (90%) [START_REF] Nakagawa | II)-Pheox-Catalyzed asymmetric intramolecular cyclopropanation of electron-deficient olefins[END_REF]. The latter was employed as building block in the total syntheses of drug DCG-IV and natural product dysibetaine CPa (Scheme 82).

Asymmetric Michael-Initiated Ring Closures as Key Steps

Michael-initiated ring-closing (MIRC) reactions also constitute highly efficient routes to cyclopropanes. These reactions involve a conjugate addition to an electrophilic alkene generally to produce an enolate, which then undergoes an intramolecular ring closure. A range of asymmetric Michael-initiated ring-closing reactions based on the use of chiral substrates have been applied to the synthesis of important products. As a recent example, Marek et al. have developed the MIRC reaction of chiral alkylidene bis(p-tolylsulfoxides) 217 with trimethylsulfoxonium ylide 218, leading to the corresponding chiral bis(p-tolylsulfinyl) cyclopropane 219 with a moderate diastereoselectivity of 72% de, which was further used to prepare enantiomerically enriched polyalkylated cyclopropane derivatives [START_REF] Abramovitch | Convergent preparation of enantiomerically pure polyalkylated cyclopropane derivatives[END_REF]. As illustrated in Scheme 83, this methodology was applied to the synthesis of (9R,10S)-dihydrosterculic acid, a natural fatty acid [START_REF] Palko | A flexible and modular stereoselective synthesis of (9R,10S)-dihydrosterculic acid[END_REF].

Miscellaneous Asymmetric Cyclopropanations as Key Steps

Enantioenriched cyclopropane derivatives, such as 220, can also be efficiently prepared from the addition of the dianion of (-)dimenthylsuccinate 221 to bromochloromethane 222 (Scheme 84) [START_REF] Misumi | Simple asymmetric construction of a carbocyclic framework. Direct coupling of dimenthyl succinate and 1,.Omega.-dihalides[END_REF]. This method, providing up to 98% de and 87% yield, was used in the total synthesis of natural bioactive callipeltoside [START_REF] Trost | Callipeltoside A: Assignment of absolute and relative configuration by total synthesis[END_REF], and to that of the first peptide nucleic acid (PNA) bearing a cyclopropane, (S,S)-tcprPNA [START_REF] Pokorski | Cyclopropane PNA: Cbservable triplex melting in a PNA constrained with a 3-membered ring[END_REF].

LTMP-induced intramolecular cyclopropanation of unsaturated terminal epoxides provided an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2ols. This methodology was applied to a total synthesis of natural product (+)-cuparenone, starting from chiral chlorohydrin 223 that was converted into the corresponding bicyclohexanol 224 as almost single stereoisomer (> 99% de, 97% ee) in 59% yield (Scheme 85) [START_REF] Hodgson | Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins[END_REF]. In 2015, Cramer et al. reported an efficient access to the sevenmembered ring of the cyclopropylindolobenzazepine core of antiviral agent beclabuvir [START_REF] Pedroni | Enantioselective palladium(0)-catalyzed intramolecular cyclopropane functionalization: Access to dihydroquinolones, dihydroisoquinolones and the BMS-791325 ring system[END_REF]. As shown in Scheme 86, a TADDOLbased phosphoramidite palladium(0) complex 225 enabled the enantioselective Friedel Crafts reaction by C-H insertion on cyclopropane 226 to give pentacyclic chiral product 227 with 80% yield and 89% ee. This method provided efficient access to the construction of the seven-membered ring of the cyclopropylindolobenzazepine core of beclabuvir.

In 1989, the group of Kulinkovich showed that the reaction of esters with a mixture of Ti(O-i-Pr) 4 and an excess of a Grignard reagent led to the corresponding substituted cyclopropanols [209]. Later, asymmetric versions of this methodology have been devel-oped by using either chiral substrates or chiral titanium catalysts. For example, Singh et al. demonstrated that, under Kulinkovich reaction conditions, chiral b-alkoxy ester 228 afforded the corresponding cyclopropanol 229 as the only detected stereoisomer in high yield (87%), that constituted the key intermediate for the synthesis of all the stereoisomers of tarchonanthuslactone, a naturally occurring biologically active product (Scheme 87) [START_REF] Baktharaman | Asymmetric synthesis of all the stereoisomers of tarchonanthuslactone[END_REF].

In 2006, a total synthesis of antitumor agent ( )-irofulven was developed on the basis of the reaction between strained ketene hemithioacetal 230 and methyl pyruvate 231 performed in the presence of chiral bisoxazoline copper catalyst 232 [START_REF] Movassaghi | Enantioselective total synthesis of (-)-acylfulvene and (-)-irofulven[END_REF]. The reaction afforded the corresponding functionalized chiral cyclopropane 233 in both high yield (95%) and enantioselectivity (92% ee) that was further converted into expected ( )-irofulven, as shown in Scheme 88.

CONCLUSION

This review highlighted major total syntheses of biologically active compounds, including natural products, using chiral threemembered rings as key intermediates. The interest towards synthetic methodologies for their preparation has increased in the last decades, dictated either by the biological activities that display many naturally occurring products bearing a three-membered unit or by their ring strain making them useful precursors of more complex interesting molecules. Classic as well as modern protocols, such as organocatalyzed reactions, have been applied to make asymmetric aziridination, azirination, epoxidation, thiirination, and cyclopropanation key steps of a wide number of syntheses of important products. The use of classical methods which employ chiral substrates and auxiliaries is still highly frequent particularly for asymmetric aziridination and cyclopropanation. On the other hand, the development of enantioselective catalytic methodologies has witnessed exponential growth during the last decade, in particular, in the area of asymmetric organocatalytic epoxidations. The development of new catalytic systems including organocatalysts or chiral ligands for metal catalysts for the synthesis of the other threemembered rings is still in its infancy, However, their expansion is awaited in the coming few years, opening the way to the synthesis of other biologically important products. Undoubtedly, the chemistry of three-membered rings will continue to play a dominant role in the history of total synthesis for many years.

Scheme 1 .Scheme 2 .

 12 Scheme 1. Synthesis of (+)-agelastatin A.

Scheme 5 .

 5 Scheme 5. Synthesis of an analogue of diaminopimelic acid.

20 Scheme 8 .

 208 Scheme 7. Syntheses of L-daunosamine and L-ristosamine derivatives.

Scheme 10 . 26 Scheme 11 .

 102611 Scheme 9. Synthesis of ( )-polyoxamic acid.

Scheme 12 .

 12 Scheme 12. Synthesis of 7-Epi (+)-FR900482.

  Scheme 14. Synthesis of an aziridinomitosene.

Scheme 19 .Scheme 21 .

 1921 Scheme 18. Synthesis of a squalene synthase inhibitor.

Scheme 22 .Scheme 23 .

 2223 Scheme 22. Synthesis of (R,R)--methoxytyrosine.

In 2014 ,

 2014 Scheme 24. Synthesis of BIRT-377.

Scheme 26 .

 26 Scheme 26. Synthesis of four stereoisomers of sphinganine.

Scheme 27 .

 27 Scheme 27. Synthesis of taxol side chain.

Scheme 28 .

 28 Scheme 28. Synthesis of constituants of naturally occurring antibiotics.

74 ( 5 75 Ar

 575 Scheme 31. Synthesis of (-)-Z-dysidazirine.

Scheme 33 .

 33 Scheme 33. Synthesis of (R)-2-benzylmorpholine based on Katsuki-Sharpless asymmetric epoxidation.

TiScheme 34 .PhScheme 35 .

 3435 Scheme 34. Synthsesis of GSK966587 based on Katsuki-Sharpless asymmetric epoxidation.

Scheme 37 .

 37 Scheme 37. Biologically active products synthesized through Jacobsen/Katsuki epoxidations.

90 .Scheme 36 .

 9036 Scheme 36. Syntheses of -bisabolol and florfenicol through V-catalyzed epoxidations.

Scheme 41 .

 41 Scheme 41. Syntheses of biologically active products through Shibasaki's epoxidation.

Scheme 47 .

 47 Scheme 47. Synthesis of (+)-scuteflorin A through chiral iminium salt-catalyzed epoxidation.

126 Scheme 50 .

 12650 Scheme 50. Synthesis of (+)-reserpine.

Scheme 53 .

 53 Scheme 53. Synthesis of safinamide and structures of other products.

Scheme 57 .

 57 Scheme 57. Syntheses of bengamide E and (-)-depudecin.

Scheme 59 .

 59 Scheme 58. Synthesis of (-)-bestatin.

Scheme 63 .

 63 Scheme 63. Synthesis of the C1-C12 fragment of brevipolide H.

Scheme 62 .

 62 Scheme 60. Synthesis of halicholactone.

Scheme 67 .Scheme 68 .

 6768 Scheme 67. Syntheses of cascarillic acid, (-)-clavosolide and grenadamide.

Scheme 69 . 183 Scheme 71 .

 6918371 Scheme 69. Syntheses of (+)-cibenzoline, (+)-tranylcypromine and (-)milnacipran.

203 :Scheme 79 .

 20379 Scheme 79. (Formal) syntheses of (+)-busidarasin C, acetoxytubipofuran, (+)-digitoxigenin, (-)-platencin, (-)-platensimycin, nemorosone, garsubellin A, clusianone, and hyperforin though copper-catalyzed cyclopropanations.

Scheme 80 . 81 .Scheme 82 . 83 . 84 . 85 .

 808182838485 Scheme 80. Synthesis of (+)-colletoic acid through copper-catalyzed cyclopropanation.

86 .Scheme 87 .

 8687 Scheme 86. Synthesis of the cyclopropylindolobenzazepine core of beclabuvir.

  . In 2005, Vederas et al. applied this methodology to the asymmetric aziridination of a camphor derivative in the presence of 3-amino-2-

		H
							O	O	Rh 2 (pfm) 4
							S
	O	H			+	Cl 3 C	O	NH 2	PhI(OAc) 2
			O					MgO
		6
		H	N S O	O				H	NC
				O	CCl 3
							HO	H	O
	O	H						NC
			O					Cl
		7
	73%, 66% de						(+)-kalihinol A
	Scheme 3. Formal synthesis of (+)-kalihinol A.
								(2 mol%)
	PhthN	CO 2 Et			SesNH 2 (1.1 equiv)		PhI(OPiv) 2 (1.3 equiv)
								MgO (2.3 equiv)
								C 6 H 5 Cl, 0 °C to r.t.
	Ses
		N
	PhthN		CO 2 Et
	86%, > 99% de

130 131 Scheme 51. Syntheses

				N	N
		t-Bu		Co		t-Bu
			O	OAc	O	OH	OTBS
			t-Bu		t-Bu	HO
	O	OTBS	129 (0.3-0.5 mol%)
						+	48%, 94% ee
		rac-128	H 2 O, r.t.		O	OTBS
						128
				O	48%, 98% ee
		O	OH	O
		Ph
		(5S,7R)-kurzilactone	N 3	OH
						OH
		N 3				MeO
			ent-129 (0.5 mol%)	47%, 98% ee
	MeO	O		H 2 O, r.t.		+	N 3
		rac-131				O
			O
			HN	O		48%, 98% ee
				OH
		MeO
		(+)-epi-cytoxazone

of (5S,7R)-kurzilactone and (+)-epi-cytoxazone.

  example, Aggarwal et al. developed a total synthesis of SK&F 104353, a leukotriene D 4 inhibitor, that was based on the reaction of diastereoisomerically pure O-protected sulfonium salt 136 with aromatic hindered aldehyde 137, performed in the presence of KOH at low temperature, to afford the corresponding chiral key trans-epoxide 138 in 77% yield and high enantioselectivity (90% ee) [123]. The latter was subsequently converted into expected SK&F 104353 (Scheme 55).

	O
				ent-129 (0.5 mol%)
	MeO
	rac-132	O		H 2 O, r.t.
		O
	MeO			+		OH
		132	O		O	O 133
	48%, 96% ee		46%, 97% ee
	MgBr
			THF, -30°C to 0°C
	CuBr 2 (SMe 2 ) .
	O	O
		(+)-eldanolide
	Scheme 52. Synthesis of (+)-eldanolide.
			O	OBn	ent-129 (0.5 mol%)	O	OBn
			rac-134		H 2 O, 0°C to r.t.	134 46%, > 99% ee

  . Since the first asymmetric metal-catalyzed Darzens reaction reported by

	O rac	R	+	NH 2 Boc	ent-129 (1.5 mol%) t-BuOMe, r.t. p-nitrobenzoic acid	R	OH 135	NHBoc	O > 90% ee + R
	R = alkyl, aryl				25-49%, > 99% ee
									1) CF 3 CO 2 H
					R = CH 2 O(1-Naph)		2) PtO 2 /H 2
									acetone, MeOH
									OH
								O	H N
							(S)-propanolol
								96%
	Scheme 54. Synthesis of (S)-propanolol.
		(CH 2 ) 8 Ph H		Br	O			KOH, MeOH
				O	+	S	NEt 2		-30°C
					OMe
			137		136
									S	CO 2 H
				O					CO 2 H
	Ph(H 2 C) 8	O	N(Et) 2				OH (CH 2 ) 8 Ph
			138				SK&F 104353
			77%, 90% ee
	Scheme 55. Synthesis of SK&F 104353.

Scheme 6. Synthesis of ( )-agelastatin A.

Scheme 29. Synthesis of (-)-Z-dysidazirine.

201Scheme 78. Syntheses of (-)-malyngolide, (-)-methyl jasmonate and (-)-allocyathin B2 through copper-catalyzed cyclopropanations.

ACKNOWLEDGEMENTS

Declared none.

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