Z Katbay
email: z_katbay@hotmail.com

S Sadek

Dr Pierre-François Dupré
email: pierre-francois.dupre@chu-brest.fr

M Le Roy

R Lababidi
email: raafat.lababidi@ensta-bretagne.fr

A Perennec
email: andre.perennec@univ-brest.fr

Microstrip Back-Cavity Hilbert Fractal Antenna for Experimental Detection of Breast Tumors

Keywords: back-cavity, Hilbert Fractal Antenna, breast tumor, in vivo, ex vivo

This paper presents a miniaturized microstrip back-cavity Hilbert Fractal Antenna specifically designed for breast cancer detection. This antenna is used to investigate on the possibility of detecting the presence of breast tumors by directly measuring the shift of the antenna resonance frequency. First, simulations are performed on a multi-layer breast model; then the proposed approach was applied for in vivo measurements on two different patients diagnosed with breast cancer, followed by ex vivo characterization of the electrical properties of excised tumors.

I. INTRODUCTION

Breast cancer is one of the leading causes of women mortality [START_REF] Sajjadieh | Breast Cancer Detection using Time Reversal Signal Processing[END_REF] and, premature diagnosis and treatment is considered the best hope for surviving from this disease [START_REF] Hossain | Breast Cancer Detection in Highly Dense Numerical Breast Phantoms Using Time Reversal[END_REF][START_REF] Elsdon | Early Stage Breast Cancer Detection using Indirect Microwave Holography[END_REF][START_REF] Hossain | Breast Cancer Localization in Three Dimensions using Time Reversal DORT Method[END_REF]. Different techniques are available to detect breast cancer, e.g., X-ray mammography, ultrasonography, Magnetic Resonance Imaging (MRI), microwave imaging etc. The most important ones are ultrasonography and magnetic resonance imaging (MRI), but no one of these methods is used in routine cancer screening. These methods cannot detect the early signs of cancers; they therefore have importance in later diagnostics to verify the malignity of the breast tissues [START_REF] Chaudhary | Dielectric properties of normal and malignant human breast tissues at radiowave and microwave frequencies[END_REF][START_REF] Surowiec | Dielectric properties of breast carcinoma and the surrounding tissues[END_REF][START_REF] Joines | The measured electrical properties of normal and malignant human tissues from 50 to 900 MHz[END_REF]. Moreover, inhomogeneities in breast tissues are sometimes erroneously considered malignant in mammograms. Microwave Imaging (MI) and microwave detection methods promise a highly effective complementary technique as the associated systems can be fabricated cost-effectively enabling widespread availability. In particular, microwave detection for frequent breast monitoring would provide a safe, comfortable technique that could help increasing early-stage tumor detection rates. The measurement protocol proposed in this paper consists in detecting a shift of the antenna resonance frequency [START_REF] Allam | Diagnosis of Breast Tumors using a PIFA antenna[END_REF] due to the high permittivity of the tumor. Thus, the antenna is considered as the key element in the RF front-end for the proposed microwave detection system. In this paper, the antenna design focuses first on its compactness which is required to facilitate its placement and manipulation around the breast and to restrict the targeted area and also on increasing the wave penetration in the body to emphasize the influence of the malignant area on the response. This paper is organized as follows: the breast tissues model used in the study is presented in section II, the antenna design and simulations results are described in section III. Section IV presents in vivo measurements on different patients with breast cancer diagnosis and ex vivo characterization of the electrical properties of excised tumors. Finally, the paper ends with the conclusion and future work.

II. BREAST PHANTOM MODEL

As a preliminary, female breast phantom model in this investigation is designed as a simple four layers stacked model as shown in Fig. 1. Table1 shows the properties, i.e. electrical permittivity and conductivity at 2.45 GHz [START_REF] Karli | Evaluation of a microstrip patch antenna for Breast Tumor Detection[END_REF][START_REF] Alshehri | UWB imaging for breast cancer detection using neural network[END_REF][START_REF] Sanpanich | A Basic Investigation of Cancerous Breast Microwave Ablation Using Opened-tip Applicator and Ex Vivo Experiment[END_REF][START_REF] Stang | A 3D active microwave imaging system for breast cancer screening[END_REF] and thicknesses experienced in average for each tissue layer. Due to its compactness, a Hilbert Fractal Antenna (HFA) is chosen for the initial antenna design [START_REF] Yu | A Miniature Antenna for 2.45 GHz RFID Tag[END_REF]. The antenna dimensions and shape are optimized using CST microwave studio software. The final antenna geometry together with dimensions and characteristics are shown in figure 2(a). The back side of the antenna consists of a partial ground plane of 2.5mm width (Fig. 2(b)). The antenna was designed to operate at 2.45 GHz in the air since this frequency is in ISM (Industrial, Scientific and Medical) band where the signal attenuation in human body is quite small. However, when the designed antenna is positioned in direct contact on the breast skin, the resonance frequency is down-shifted and the antenna's radiation pattern is deformed. The simulations were performed using open boundary conditions.

Indeed, the gain and the directivity, as expected, decreased due to the interaction antenna-body. The breast is a lossy medium with a high permittivity compared to the air (the first layer, i.e. for the skin, ε r =38), which implies that an important part of the incident wave is back-reflected. In order to minimize the radiation outside the human body, the antenna is placed inside a rectangular cavity with optimized dimensions (6cmx6cmx3cm) to increase the antenna directivity and to focalize the energy in the phantom. The simulation results which are depicted in Fig. 3 show that placing the antenna inside the cavity has a small influence on the resonance frequency. However, the directivity of the antenna is globally enhanced about 3 dB in the breast direction, (e.g. from 3.9 dBi to 6.9 dBi with and without the cavity respectively at 2.21 and 2.26 GHz).

Then, an inhomogeneity of a 5 mm length cubic shape is introduced in the breast phantom representing a malignant tumor [START_REF] Karli | Evaluation of a microstrip patch antenna for Breast Tumor Detection[END_REF][START_REF] Alshehri | UWB imaging for breast cancer detection using neural network[END_REF]. This tumor was located at approximately 2 centimetres below breast skin in the glandular tissues layer which corresponds to the most commonly encountered cases. The electric properties of the tumor are set to ε r =50 and σ=4 S/m. Figure 4(a) illustrates the back-cavity antenna applied on the malignant breast model and figure 4(b) shows the simulated return loss of the antenna when implanted on the healthy model and on the malignant breast phantom. When the tumor is introduced in the model, the resonant frequencies are downshifted respectively of about 30 MHz and 50 MHz for the lowest and highest resonant frequencies corresponding to 3.5% and 2.2 % relative down-shifts. It should be pointed out that many simulation and optimization runs have been made to improve the sharpness of the resonance in order to increase the detection sensitivity while keeping a satisfying forward directivity and pattern radiation. The antenna presented here corresponds to a satisfying compromise over the entire range of variation in model parameters (thicknesses and permittivities of the tissue layers). This variation range in the model is intended to take into account the variability of electrical characteristics of real patients [START_REF] Zastrow | Development of anatomically realistic numerical breast phantoms with accurate dielectric properties for modeling microwave interactions with the human breast[END_REF].

IV. MEASUREMENT RESULTS

A. Measurement protocol

The designed antenna was manufactured (Fig. 5) and the measurement protocol was applied on two different patients aged over 65 years suffering from breast cancer at the CHRU of Brest (Centre Hospitalier Régional et Universitaire de Brest). The protocol used in our measurement is identical to that of ultrasonography usually used in medical care centers for breast cancer detection. The breast is divided into several zones or areas that look like the decomposition of a wall-clock. The measurements of S 11 and resonant frequencies at each zone were performed using an Anritsu portable Vector Network Analyzer. Ultrasonography measurements have also been performed for both patients on the same zones of the breast to locate the lesion before our measurements. Hence, a comparison between measurements will be possible in order to validate or invalidate the feasibility of heterogeneity detection using a direct frequency shift measurement.  The same analysis (Fig. 7) has been performed for patient 2. The tumor was between position 1h and 1h30 at 14.8 mm below the skin with smaller dimensions: about 10x4mm. The wideband responses (Fig. 7(b)) clearly show a global down-shift in frequency of the measurement over the tumor which is confirmed by analysis of the narrow-band curves, particularly for the upper resonant frequency (Fig. 7(d)). Once again, these results are however relative, because the measurements on healthy areas present also frequency-shift variations. Furthermore, while measuring, a significant change in return loss-response has been observed at position 2h30. Thus, a thorough investigation was performed by the radiologist using ultrasonography imaging at this area, and a 4x4mm cyst was then detected. The presence of this latter explains the significant change of the returnloss response at the higher resonance frequency of the antenna. Ex-vivo measurements were performed in order to characterize the tumors' permittivity immediately after their resections in surgery. We used a microwave coaxial probe with a tiny sensing area (depth of 3 mm) which was directly placed on the excised specimens after a calibration procedure. These measurements allow us to validate the tumor permittivity used in the proposed model. Electrical properties of ex vivo tissues differ from their in vivo counterparts; therefore, it is important to get ex vivo properties of excised tissues as soon as possible after the surgery. These results were performed in two different configurations: the tumor 1 was characterized by placing the probe directly in contact with the surface of the resected portion, while the tumor 2 was cut in half to allow a direct measurement on the tumor itself.

As depicted in figure 8, the relative permittivity of tumor 2 ranges between 55 and 60 in the considered frequency band, whereas tumor 1 is closer to 50 due to the presence of fat and blood. These results confirm values used in literature and also in our simulation [START_REF] Karli | Evaluation of a microstrip patch antenna for Breast Tumor Detection[END_REF][START_REF] Alshehri | UWB imaging for breast cancer detection using neural network[END_REF][START_REF] Sanpanich | A Basic Investigation of Cancerous Breast Microwave Ablation Using Opened-tip Applicator and Ex Vivo Experiment[END_REF].

V. CONCLUSIONS AND FUTURE WORK

In this paper, the design of a Back-cavity HFA for microwave detection of breast tumors was presented. The simulation results show that the antenna response is affected in terms of frequency and return loss when it's implanted on the malignant model compared to the healthy one. The Measurement protocol was applied on 2 different patients diagnosed with breast cancer. Measurement results show significant differences compared to simulated ones, this feature is explained by the fact that the theoretical model do not represent precisely enough the real constitution of the breast, particularly the inhomogeneous structure of the glandular area. The first conclusion to be drawn is that the most often commonly used breast model, i.e. planar multi-layers, should be restricted to first steps of the antenna design. Moreover, the great disparity in the distribution and permittivity values of the glandular system [START_REF] Zastrow | Development of anatomically realistic numerical breast phantoms with accurate dielectric properties for modeling microwave interactions with the human breast[END_REF] from a woman to another greatly limits the relevance of such a direct frequency technique for breast tumor detection. Consequently, in order to design a microwave low cost and simple tumor detector that could be handled like a "simple stethoscope", our further work focuses on the design of a compact UWB directive antenna to detect and especially to localize the tumor using ultra-short pulses using time-domain techniques.

Fig. 1 .

 1 Fig. 1. Brest phantom model.

Fig. 2 .

 2 Fig. 2. Antenna geometry: (a) top view, (b) bottom view, with h=11.5mm, Ws=13.5mm, w=1.4mm, Ls=32.4mm, L=28mm on a FR4 substrate with r= 4.3, hs=1.6mm and t=35 µm.

Fig. 3 .Fig. 4 .

 34 Fig. 3. Comparison of radiation patterns without (a and c) and with the backcavity (b and d), respectively at the lowest (a and b ) and highest (c and d) resonant frequencies.

Fig. 5 .

 5 Fig. 5. Photograph of the back-cavity Hilbert-Fractal Antenna. B. Measurement Analysis  For patient 1, Fig. 6(a) illustrates the position of the measurements displayed as a clock hour around the nipple and also the tumor position localized by ultrasonography. The tumor has a width of 17.8x15.7mm and was located at 18mm below the skin at a 9h30 clock-position. Return loss for different positions of the antenna on the breast are depicted in Fig. 6(b). First of all, the overall shape of the curve is different compared to simulations results which can be explained by a rather random distribution of mammary glandular tissues not taken into account in our model. A raw and wideband analysis indicates that the measurement made over the tumor does not stand out significantly from the set of curves. A finest analysis (Fig. 6(d)) shows that the stronger shift towards the low frequencies of the high resonance frequency is observed above the tumor. The possibility of detection must however be undervalued by the relatively low frequency-shift that is obtained and by the degradation of the high-frequency resonance at 6h-and 7hpositions.

Fig. 6 .

 6 Fig. 6. Patient 1: (a) Tumor and measurement positions, (b) corresponding measured return-loss and (c) and (d) zooms on resonant frequencies.

Fig. 7 .

 7 Fig. 7. Patient 2: (a) Tumor and measurement positions, (b) measured return-loss and (c)-(d) zooms on resonant frequencies.

Fig. 8 .

 8 Fig. 8. Characterization of tumors' permittivity.

TABLE I

 I

	. Tissue Skin Fat Glandular Tissues Muscle 1.91 III. ANTENNA DESIGN AND SIMULATION RESULTS ELECTRICAL PROPERTIES OF BREAST LAYERS ε r σ(S/m) Thicknes s (mm) 38 1.46 1.5 5.2 0.1 10 20.1 0.5 20 52.4

ACKNOWLEDGMENTS

The authors would like to thank the patients for their consent for doing the measurements, also Mr. Alexis Chevalier from the lab-STICC UBO for his help in the tissue permittivity measurements. The mobility part of this work was funded by UBO (University of Brest).


Haiying Du

Yohan Dudognon

Maria Del Mar

Sanchez Duque

Sébastien Goudedranche

Damien Bonne

Jean Rodriguez

Xavier Bugaut
email: equally.xavier.bugaut@univ-amu.fr

Thierry Constantieux
email: thierry.constantieux@univ-amu.fr

Organocatalytic Multicomponent Reactions of 1,3--Dicarbonyls for the Synthesis of Enantioenriched Heterocycles

Keywords: Products: 1, 4, 5, 6-Tetrahydropyridines 3 Type II Products: 1, 2, 3, 4-Tetrahydropyridines 4 Type III Products: Bridged Perhydropyridines Dicarbonyls -Enantioselectivity -Heterocycles -Michael Addition -Multicomponent Reactions -Organocatalysis

In this feature article, we present a general perspective of our research program aimed towards the preparation of polycyclic heterocycles by the means of enantioselective organocatalytic multicomponent reactions. Guidelines for reaction design, including the selection of substrates and organocatalysts are discussed. For all transformations, scope and limitations will be presented, along with post-functionalization to afford diversified heterocyclic scaffolds.

Introduction

Heterocycles are key synthetic targets in view of their ubiquitous presence in bioactive molecules. 1 When these molecules bear stereogenic elements, it is of utter importance to control their configuration as the stereochemical information may have a deep influence on their interaction with the biological target. In that prospect, organocatalysis 2 has emerged as a very powerful tool since it allows the stereoselective synthesis of a large variety of heterocyclic compounds with high enantiomeric excesses. 3 Among these heterocycles, polyhydropyridines are both interesting synthetic targets and an inspiration for the development of new patterns of reactivity. Thus, many new strategies were designed following the seminal contributions of Renaud's and Gong's research groups using Brønsted acid catalysis 4 and Hayashi's and Jørgensen's teams by applying iminium activation. 5 When we became interested in this area of research, we hypothesized that multicomponent reactions, 6 that is to say the initial simultaneous introduction of at least three reaction partners that will be integrated in the target product, would be an interesting tool to efficiently prepare new enantioenriched polyhydropyridine motifs. β-Dicarbonyl compounds are generally used as pronucleophiles in the synthesis of these heterocycles and their polyfunctional nature makes them ideal substrates for multiple bond-forming transformations (MBFT's) including domino processes and multicomponent reactions. 7 Our starting point was the combination of an α,β-unsaturated aldehyde A, a β-dicarbonyl B and a functionalized amine C in the presence of a chiral non-racemic organocatalyst (Scheme 1). After the initial catalyst-controlled enantioselective Michael addition that forges the first stereogenic center, [START_REF] Zhang | [END_REF] the amine functionality combines with the aldehyde and the ketone of the Michael adduct D affording 1,4-dihydropyridine E with loss of two molecules of water. In 1,4-dihydropyridine E, each side of the dienamine motif can tautomerize to the corresponding iminium ion to deliver reactive intermediates F and F', whose trapping by the pendant nucleophile delivers fused 1,4,5,6tetrahydropyridines G (Type I) 9 and 1,2,3,4-tetrahydropyridines G' (Type II), bearing two or three stereogenic centers, respectively. 10 When a secondary amide group is present on the substrate, a zwitterionic intermediate H can then be envisaged, whose cyclization leads to the formation of bridged perhydropyridines I (Type III) incorporating up to four stereogenic carbon atoms. 11 Of course, for this last family of products, the order of the cyclization events can also be interchanged. In principle, all the elemental steps of the different reaction pathways (acido-basic exchanges, Michael additions, dehydrations, tautomerizations and iminium ion trappings) can be reversible. In addition to their inherent step-economic nature and high synthetic efficiency for the fast elaboration of highly complex architectures, multicomponent reactions also offer interesting opportunities in terms of efficiency and stereoselectivity. Indeed, if one or several of the bond-forming events are kinetically and/or thermodynamically favored, this could help driving the whole sequence towards the efficient Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 2 of 23 Scheme 1. General reactivity pattern for the organocatalytic multicomponent synthesis of enantioenriched heterocycles.

formation of the desired product. Moreover, for enantioselective transformations, the steps that follow the enantiodiscriminating one can prevent its reversibility, thereby avoiding the racemization of the product, which was for example already noticed in a related stepwise synthesis of 1,4-dihydropyridines. 5b However, two important conditions have to be respected for the design of multicomponent enantioselective transformations: (i) the third reaction partner should not interact in a deleterious way with the organocatalyst; (ii) all the steps of the sequence should occur fast enough in similar reaction conditions, which might become problematic, especially when low temperature is required to ensure good enantioselection during the Michael addition.

Complementary to scarce reports by other groups for the inclusion of β-dicarbonyls in organocatalytic enantioselective multicomponent transformations, 7h,12 we have recently disclosed independent synthetic routes towards three families of enantioenriched heterocycles (Figure 1): pyrrolopiperazine derivatives with a 1,4,5,6-tetrahydropyridine motif (Type I), 9 1,2,3,4-tetrahydropyridines (Type II) 10 and 2,6diazabicyclo[2.2.2]octan-3-ones (2,6-DABCOs, Type III). 11,[START_REF] Du | We have also recently described early results of organocatalytic multicomponent reactions with α-substituted enals, however with low enantioselectivities[END_REF]14 In this Feature Article, we wish to provide the readers, with a general overview of our reaction design to help trigger new development in this area. The structure of the different reaction partners, especially the β-dicarbonyl and the pendant nucleophile on the amine, the mode of action of the organocatalyst and the reaction conditions are among the key factors that control the chemo-and enantioselective formation of one defined product. Scope, limitations and bridging between the different patterns of reactivity will be discussed. Moreover, postfunctionalizations of the products to afford structurally diverse heterocyclic scaffolds will also be presented.

Type I Products: 1,4,5,6-Tetrahydropyridines (Pyrrolopiperazines)

With the general reactivity pattern presented in Scheme 1 in mind, Type I products first appeared as the easiest synthetic targets. Indeed, tautomerization of the common intermediate E should favor the formation of iminium ion F, which exhibits higher conjugation and whose electrophilic reactive center is less hindered than in its congener F'. A number of similar organocatalytic sequences involving a secondary aminecatalyzed Michael addition followed by the cyclization of a pendant nucleophile, either an electron-rich aromatic ring [START_REF] Franzén | For the original report[END_REF] or an heteroatom, [START_REF] Jin | For the original report[END_REF] had already been described before but in a stepwise fashion, with the requirement of a strong and/or stoichiometric acid. As the presence of this additive was likely to damage the activity of the secondary amine catalyst, we set out to find a nucleophilic moiety that could react even in the absence of an acid. Since the pyrrole ring is known to exhibit strong nucleophilicity, which is further increased when it is alkylated, 17 it was selected as the third reaction partner, with the aim to trap the iminium intermediate through a Pictet-Spengler-type cyclization. Pleasingly, mixing equimolar ratios of an αmethylene β-ketoester 1 and N-(2-aminoethyl)pyrrole (3) with a 1.5-fold excess of an enal 2 in the presence of Hayashi-Jørgensen catalyst 4 delivered the expected polycyclic structure 5 (Scheme 2). 9a It should be noted that other classical secondary amine organocatalysts performed very poorly in this transformation and that trifluorotoluene as the solvent had an appreciable positive impact on the enantioselectivity of the reaction. The overall transformation allowed the formation of four new bonds, a tricyclic pyrrolopiperazine core and two stereogenic carbon atoms. Twenty different products with possibilities of variation Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 3 of 23 on all three reaction partners were prepared in moderate yields because of the fragility of the pyrrole unit.

Scheme 2. Pyrrolopiperazines incorporating a 1,4,5,6tetrahydropyridine core: previous results. 9a If enantioselectivities were generally good to excellent (74-99% ee), there was no diastereoselectivity during the Pictet-Spengler cyclization, but this drawback was counterbalanced by the fact that the two diastereomers could generally be separated by flash chromatography. To widen the application range of this transformation, we then wished to pursue the four following directions (Scheme 3):

(i) Why is there no diastereoselectivity and is there a way to solve this issue? (ii) Is it possible to replace the alkyl or aryl group at R 3 by a more functionalized one? (iii)

Could the β-ketoester be replaced by other pronucleophiles? (iv)

Could other bis-nucleophilic units than N-(2aminoethyl)pyrroles participate in the reaction? Scheme 3. 1,4,5,6-Tetrahydropyridines: open questions.

Diastereoselectivity of the reaction

Before studying the diastereoselectivity of the process, it was necessary to determine whether the second stereogenic carbon atom was forged under kinetic or thermodynamic control. When diastereomerically pure cis-5a was placed back in the reaction conditions in the presence of a substituted N-(2aminoethyl)pyrrole 3b (Scheme 4a), it was recovered unchanged (neither epimerization, nor cross-over product 5b), pointing towards an irreversibility of the cyclization process. In related enantioselective Michael addition-Pictet-Spengler domino processes, an improvement of the diastereoselectivity was observed by the addition of a strong acid at the end of the reaction. 15a,18 In the present case, treatment of 5a as a 1.4:1 mixture of diastereomers with an acid resulted either in no evolution or in its complete degradation (Scheme 4b). Thus, diastereoselectivity in this system seems difficult to control since both faces of iminium ion intermediate are not enough differentiated by the relatively distant stereogenic carbon atom.

Scheme 4. Reversibility and diastereoselectivity in the synthesis of pyrrolopiperazines.

Reaction with ethyl 4-oxobut-2-enoate

In our initial studies, we had used aldehydes bearing alkyl, vinyl and (hetero)aryl substituents at their β position. To broaden the synthetic usefulness of the present transformation, we became interested in the use of ethyl 4-oxobut-2-enoate 2c (Scheme 5). Directly applying the standard multicomponent conditions or trying to alter them (use of various solvents: CH2Cl2, CH3CN; reaction at room temperature; addition of benzoic acid as cocatalyst) failed to provide the expected product. We surmised that the high electrophilicity of this enal might result in side reactions with the other reaction partners. To solve this issue, we came back to a one-pot two-step process: pleasingly, if N-(2aminoethyl)pyrrole (3a) was added after two days and the reaction mixture kept at 0 °C for an additional day, pyrrolopiperazine 5c was isolated in 45% yield as a ~1.2:1 diastereomeric mixture with high enantioselectivities (94% and 93% ee for each diastereomer, respectively).

Template for SYNTHESIS © Thieme

More diversified Michael pronucleophiles

Our initial studies were limited to the use of β-ketoesters as pronucleophiles. However, a large variety of Michael donors have demonstrated the ability to add enantioselectively to enals activated as the corresponding iminium ions by a secondary amine catalyst. 19 A certain number of these compounds of type 6a-h were evaluated and many of them proved to be able to deliver the corresponding pyrrolopiperazine products 7aa-ha, 7ad and 7fe at the cost of slight modifications of the standard reaction conditions (Table 1). With acetylacetone (6a) as the pronucleophile, a low yield of product 7aa and only moderate enantioselectivity were obtained in the standard reaction Table 1. Scope of various Michael donors for the enantioselective multicomponent synthesis of pyrrolopiperazines. [a] Entry Michael donor Enal Changes from the standard reaction conditions Product Yield (cis+trans) [b] ee [c] 1 6a 2a none 7aa <30% 72% and n.d. [d] 2 6a 2a PhCO2H (10 mol%) 7aa 60% 82% and n.d. [d] 3 6a ~50% [e] 64% and n.d. [d] 6 6b 2a PhCO2H (20 mol%) 7ba

~40% [e] 36% and n.d. [d] 7 6c CH2Cl2 as solvent 7ha 68% (1.5:1 dr) [f] 88% and 87%

a All reactions were run using 6a-h (0.200 mmol, 1 equiv), 2a,d,e (0.300 mmol, 1.5 equiv), 3a (0.200 mmol, 1 equiv) and catalyst 4 (0.020 mmol, 0.1 equiv) in CF3C6H5 (2.5 mL) for 48 h at 0 °C. Changes from these standard reaction conditions are notified in the table. b Yields of analytically pure isolated products (yields between brackets are those of the cis and trans diastereomers, respectively, when they could be separated). c Enantiomeric excesses (ee) were determined by HPLC analysis on a chiral stationary phase. d During optimization studies, only the ee of the cis diastereomer was determined, as both of them usually have similar values. e Product purities ~90%. f The diastereomers could not be separated and the diastereomeric ratios (dr) were determined by 1 H NMR spectroscopy analysis after purification. conditions (Entry 1). However, the addition of benzoic acid as a co-catalyst proved beneficial for the product formation (Entry 2). Ultimately, replacing CF3C6H5 by CH2Cl2 as the solvent and decreasing the reaction temperature to 10 °C delivered 7aa with yields and enantioselectivities similar to those obtained with the β-ketoesters (Entry 3). Those optimized reaction conditions transposed efficiently to prepare 7ad from 4-chlorocinnamaldehyde (2d) (Entry 4). On the contrary, cyclic diketones such as dimedone (6b) proved to be more challenging substrates: only moderate yields and enantioselectivities were obtained for 7ba, and the addition of an acidic co-catalyst was deleterious (Entries 5 and 6). We have recently reported that tertiary β-ketoamides can be potent Michael donors that can add to nitroolefins under hydrogen-bonding organocatalysis with high enantio-and diastereoselectivities. 20 We were intrigued whether they could also participate in the multicomponent organocatalytic synthesis of pyrrolopiperazines. Both N,Ndimethyl and Weinreb β-ketoamides 6c and 6d reacted in the standard reaction conditions (Entries 7 and 8): even though both diastereomers are present in the crude reaction mixture, only the trans diastereomers of products 7ca and 7da could be obtained pure, and their enantiomeric excesses were satisfying. β-Ketothioester 6e was also a potent pronucleophile in this transformation, but product 7ea was formed only with a moderate enantioselectivity. The next step was to substitute the ester moiety by a sulfone or a phosphonate. Both substrates 6f and 6g failed to react when cinnamaldehyde (2a) was used as the electrophile (Entries 10 and 14). However, based on literature precedents showing that 6f reacts preferentially with enals bearing an aliphatic group at the β position, 21 crotonaldehyde (2e) was combined with 6f and 3a in the standard reaction conditions (Entry 11): this time, product 7fe was obtained, but in mixture with inseparable impurities. Once again, an acidic cocatalyst was inefficient (Entry 12), but extending the reaction time somewhat improved the results (Entry 13). To finish with, 1-acetylindolin-3-ones are also known to add to enals under secondary amine catalysis. 22 Our standard reaction conditions applied to substrate 6h delivered the expected fused pentacyclic product 7ha as an inseparable mixture of diastereomers in good yield and enantioselectivities, which could even be improved by using CH2Cl2 as solvent (Entries 15 and 16).

Alternative bis-nucleophilic units

The last direction we wanted to explore for the Type I products was the possibility to replace the pyrrole ring by other nucleophilic units. Disappointingly, our initial attempts with indole derivatives failed to provide the expected products. 9a We wanted to re-investigate their use and turned our attention towards more electron-rich N-(2-aminoethyl)indole derivative 8 (Scheme 6). When it was added to the reaction mixture after an initial organocatalytic Michael addition between 1a and 2a, the expected indolopiperazine 9 was obtained as its pure trans diastereomer in 32% yield and 85% ee after purification by flash chromatography on silica gel. Alternatively, a purification of the crude reaction mixture on neutral alumina delivered the corresponding 1,4-dihydropyridine 10 in 30% yield and 91% ee. This last result demonstrates that the Pictet-Spengler cyclization with the indole derivative is not spontaneous in the reaction conditions and requires an acidic environment, thus highlighting the unique behavior of the pyrrole ring in its ability to cyclize in acid-free conditions.

In a complementary fashion, we were interested in using heteroatom-based pendant nucleophiles instead of an electronrich heteroaromatic ring. 23 tert-Butyl acetoacetate (1a) and cinnamaldehyde (2a) were combined with five different bisnucleophiles 11a-c,12ain the presence of Hayashi-Jørgensen catalyst 4 (Table 2). No product formation was observed with 2-aminoethanol (11a) and anthranilamide (11b) (Entries 1 and 2). 24 Conversely, the use of 2-aminobenzyl alcohol (11c) delivered the moderately pure expected product 13c in modest amount but with a fair enantioselectivity (Entry 3). At last, using 2-aminophenol (12a) resulted in a mixture of a small amount of expected 14 together with its regioisomer 15 (Entry 5). [START_REF] Wan | For a non-enantioselective reaction related reaction[END_REF] This result was all the more interesting since, contrary to products 13c and 14, the new 1,2,3,4-tetrahydropyridine 15 Type II product bearing three contiguous stereogenic centers was formed virtually as a single diastereomer and also with excellent enantioselectivity. This discovery paved the way for further developments towards the enantioselective synthesis of this uncommon heterocyclic motif, which will be discussed in details in the following section.

Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 6 of 23

Table 2. Screening of heteroatomic bis-nucleophiles for the enantioselective multicomponent synthesis of tetrahydropyridines. [a] Entry Bisnucleophile Product 13a-c,14

Product 15

Yield (dr) [b] ee [c] Yield (dr) [b] ee [c] 1 11a 13a: no product ---2 11b 13b: no product ---3 11c 13c: ~25% (1.3:1 dr) 88% and 90% --4 12a 14: <10% (1.5:1 dr) [d] n.d. 15: 25% (>20:1 dr) 94%

a All reactions were run using 1a (0.200 mmol, 1 equiv), 2a (0.300 mmol, 1.5 equiv), 11a-c,12a (0.200 mmol, 1 equiv) and catalyst 4 (0.020 mmol, 0.1 equiv) in CF3C6H5 (2.5 mL) for 48 h at 0 °C. b Yields of analytically pure isolated products and diastereomeric ratios (dr) determined by 1 H NMR spectroscopy analysis after purification. c Enantiomeric excesses were determined by HPLC analysis on a chiral stationary phase. d The product could not be obtained pure.

3 Type II Products: 1,2,3,4-Tetrahydropyridines

Having observed the formation of Type II product 15 (Table 2), we became interested in trying to fully counterbalance the regioselectivity of the multicomponent reaction to obtain this previously unknown family of 1,2,3,4-tetrahydropyridines, exclusively. We hypothesized that the equilibrium between iminium ions F and F' and the relative stabilities of products G and G' (Scheme 1) would be key factors to reach this goal. The usual higher stability of F and G over F' and G', respectively, can be explained by the higher delocalization of π electrons through the enaminoester. We hypothesized that replacing the ester group by a bulkier tertiary amide would create strong 1,3-allylic strain, which could outcompete the stabilization energy brought about by the conjugation, thereby forcing the amide group to turn outside of the plane.

Use of more diverse β-ketoamides

At first, we screened γ-alkyl-and γ-aryl-β-ketoamides 17a-d, which we had used in our organocatalytic Michael addition to nitroolefins, 20a in the standard reaction conditions to prepare the corresponding 1,2,3,4-tetrahydropyridines (Figure 2). Unfortunately, all of them proved to be not reactive enough and the expected products where obtained with less than 15% yields. To try to overcome this issue, γ-bromo-ketoamide 17d was prepared 27 with the hope that the inductive withdrawing effect of the bromine atom would render the activation of the βketoamide easier. Moreover, it could also serve as a handle for post-functionalization. However, once again, only low conversion into the 1,2,3,4-tetrahydropyridine was observed. The only other option left was to modify the amide moiety, by replacing the N-methoxy-N-methyl unit by a group with stronger electron-withdrawing ability and/or that could provide a better interaction with the catalyst. Following the work of Jørgensen and co-workers on the Michael addition of 1,3-dicarbonyls bearing an oxazolidinone to nitroolefins, 28 we turned our attention towards the use of the pyrrolidinone derivative 20. It was easily prepared by the thermal decomposition of 2,2,6trimethyl-4H-1,3-dioxin-4-one 18, followed by the trapping of the intermediate α-oxoketene by pyrrolidinone 19. [START_REF] Sato | This reation was already known with conventional heating[END_REF] This new substrate was then exposed to the standard conditions for the multicomponent synthesis of 1,2,3,4-tetrahydropyridines, resulting in a complex mixture including regioisomeric products 21 and 22. From this result, we can see that it seems to be a balance between reactivity and regioselectivity as β-dicarbonyl compounds with a more acidic α position are more easily activated in the catalytic conditions but also tend to provide the 1,4,5,6-tetrahydropyridine regioisomer. Scheme 10. Pyrrolidinone-derived β-ketoamide 20: synthesis and use in the multicomponent reaction.

Post-functionalization on the products

The major structural originality of 1,2,3,4-tetrahydropyridines compared to the products obtained in other methodologies targeting enantioenriched polyhydropyridines, is the presence of the enamine function. In our previous studies, we showed that both its reduction with dihydrogen in the presence of a catalytic amount of Pd/C and its isomerization into the corresponding iminium ion under Sc(OTf)3-catalysis and the subsequent trapping with a potassium alcynyltrifluoroborate proceeded with good yields and good preservation of the enantiomeric excesses. 10 . To study the reactivity on other positions of the product, the reduction was repeated on enamine 16a to furnish 23(Scheme 11). In the presence of scandium (III) triflate as a Scheme 11. Sequential post-functionalization of 1,2,3,4tetrahydropyridines 16a

Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 8 of 23 catalytic Lewis acid, potassium phenylethynyltrifluoroborate (24) could then add to the transient iminium ion obtained by the opening of aminal 23 to furnish compound 25 in moderate yield but as a single diastereomer. 30 Unfortunately, all attempts to have the Weinreb amide functionalities of 16a, 23 or 25 being reduced by treatment with metal hydrides did not meet with success, since either no conversion or extensive degradation was observed.

Another possibility to valorize the 1,2,3,4-tetrahydropyridines is to combine two multicomponent reactions sequentially to attain extremely high molecular complexity in a very short synthetic sequence. [START_REF] Paravidino | For other examples of combination of multicomponent reactions[END_REF] The three-component reaction of enamines with insitu generated 2-azadienes has been known as the Povarov reaction. 32 Combining enamine 16a with ethyl glyoxylate (26) and p-toluidine (27) in the presence of a catalytic amount of Sc(OTf)3 triggered the cycloaddition process to afford the expected product 28 in good yield (Scheme 12). Pleasingly, the two new stereogenic centers at the ring junction were installed in a cis relationship with complete diastereoselectivity. On the opposite, there was no control of the stereogenic center α to the ester functionality, presumably because the intermediate imine was formed as a mixture of (E) and (Z) diastereomers. All in all, the enantioenriched fused pentacyclic scaffold 28 has been elaborated in only two steps from five very simple starting materials.

Attempts of four-component reaction

Having post-functionalized the enamine moiety of 1,2,3,4tetrahydropyridines with potassium organotrifluoroborate 24, we also became intrigued by the possibility to integrate it directly in the multicomponent reaction (Table 3).

Scheme 12.

Post-functionalization of 1,2,3,4-tetrahydropyridine 16a by a Povarov reaction.

4-Fluorocinnamaldehyde 2f was selected as Michael acceptor to allow an easy identification of three-and four-component products 29 and 30 by 19 F NMR in the potentially complex crude reaction mixture. [START_REF]For means of comparison in 19 F NMR, an authentic sample of product 30 was prepared by[END_REF] At first, we could show that potassium phenylethynyltrifluoroborate 24 does not interfere with the initial organocatalytic process since three-component product 29 was formed in 82% NMR yield but four-component product 30 could not be observed in the crude reaction mixture (Entry 1). 34 Lewis acids were then evaluated as co-catalysts to help in the tautomerization process required to generate and trap the iminium ion. The development of such a transformation would represent a unique dually-catalyzed four-component reaction. [START_REF]For recent reviews on organo-and metal-dual catalysis[END_REF] Sc(OTf)3 had only a limited influence since it decreased the yield of 29 but did not trigger the formation of 30 (Entry 2). On the contrary, with ZrCl4 and NbCl5, small amounts (~20% yields) of four-component product 30 could be observed, unfortunately as racemic mixtures (Entries 3 and 4). The replacement of the Lewis acid with a Rh complex was also inefficient (Entry 5).

Table 3. Attempts of synthesis of tetrasubstituted piperidines by a dually-catalyzed four-component reaction. [a] Entry Metal catalyst Product 29 Product 30

NMR Yield [b] NMR Yield [b] ee [c] 1 none 82% no product - [d] 47% no product a All reactions were run using 6d (0.200 mmol, 1 equiv), 2f (0.300 mmol, 1.5 equiv), 12a (0.200 mmol, 1 equiv), 23 (0.300 mmol, 1.5 equiv), catalyst 4 (0.020 mmol, 0.1 equiv) PhCO2H (0.040 mmol, 0.2 equiv) and the metal catalyst (0.010 mmol, 10 mol%) in CH2Cl2 (2.5 mL) for 40 h at 25 °C. A careful study of the structure of 1,2,3,4-tetrahydropyridines presented in the previous section highlights the presence of the enamine moiety that could interconvert with the corresponding iminium ion and of an inert tertiary amide. Replacing the latter one by a secondary amide would add another nucleophilic position and a cyclization onto the electrophilic iminium ion could be envisioned, delivering bridged perhydropyridines as Type III products (Scheme 1). Relying on our studies on the addition of cyclic secondary β-ketoamides to α,β-unsaturated ketones and aldehydes under bifunctional hydrogen-bonding organocatalysis, 36,[START_REF] Jakubec | For related studies by other research groups[END_REF] we studied the possibility to add a bisnucleophilic species to these reaction conditions. Pleasingly, mixing cyclic secondary β-ketoamides 31 with acrolein ( 32) and aminophenols 12 in the presence of bifunctional thiourea catalyst 33 38 delivered chemoselectively bridged perhydropyridines 34 (Scheme 13). 11a Because of their resemblance with DABCO, but with the nitrogen atoms not located on the bridgehead positions, we decided to call these compounds 2,6-DABCOs. During the development of this transformation, we also uncovered the following important parameters for its success: (i)

2 Sc(OTf)3 54% no product - 3 ZrCl4 4% 21% 0% 4 NbCl5 no product 20% 0% 5 [Rh(cod)Cl]2
A strongly electron-withdrawing group is required on the β-ketoamide's nitrogen atom, such as a sulfonyl group, to ensure both productivity and enantioselectivity. In addition to this, the reaction with acyclic pronucleophiles is poorly enantioselective.

(ii)

The structure of the aminophenols has a strong influence on the enantioselectivity of the reaction. Moreover, they are the only suitable bis-nucleophiles as free or monoprotected phenylene diamine resulted in complete degradation, whereas 2-aminobenzyl alcohol (11c) or salicylic acid yielded to trace amounts of the desired products. (iii)

Other enals than acrolein (32) perform very poorly in the multicomponent reaction: low yield of product was obtained with methacrolein, while crotonaldehyde delivered virtually racemic product. (iv)

4Å molecular sieves are required to attain high levels of enantioselectivity, presumably by trapping the water produced during the course of the reaction.

In view of the intriguing structure of these products, but also the limitations is terms of substrate diversity revealed by the scope study, we deemed it interesting to proceed to more detailed studies in the following directions (Scheme 14):

(i) Could β-substituted enals participate in this transformations, possibility by modifying the other substrates and the mode of activation of the organocatalyst? (ii)

Can we envisage to get rid of the phenol moiety on the aniline, to replace the final iminium ion trapping by a tautomerization into the corresponding enamine? (iii)

Could the synthetic potential of the reaction be increased by taking advantage of the reactivities of the aminal functionalities? (iv) Is it possible to cleave the sulfonyl group on the product, whose presence on the β-ketoamide substrate is essential for the success of the transformation?

Introduction of β-substituted enals

Given the results obtained for the preparation of Type II products from α-methylene tertiary β-ketoamides and cinnamaldehyde derivatives with a secondary amine as catalyst (Scheme 8), we hypothesized that applying the very same reaction conditions to the corresponding secondary amides might be an interesting entry to expand the substrate scope of 2,6-DABCO synthesis (Scheme 15

Tautomerization into the enamine

Initially, the aromatic hydroxyl functionality appeared as an essential structural feature to observe the formation of the 2,6-DABCO products. In subsequent studies, we wanted to investigate what is happening in its absence, especially whether the iminium ion J could tautomerize into a stable tetrasubstituted enamine K, when no nucleophile is present to trap it (Scheme 16).

The presence of an additional substituent (R) on the enamine might be useful to increase its stability.

Scheme 16.

Working hypothesis for the tautomerization of the iminium ion J into the enamine K.

To test this hypothesis, we needed at first to be able to prepare the corresponding γ-substituted β-ketoamides, which had never been described in the literature before and represent a real synthetic challenge because of their sensibility to a variety of acidic or basic reaction conditions. The γ-alkylation of substrate 31a would require the intermediate preparation of a tris-anion before adding an alkylating agent, 4-fluorobenzyl bromide (37), which would react with the least stabilized anion (Scheme 17).

Unfortunately, all our attempts to obtain product 38 failed because of competing α-alkylation and degradation processes. An alternative pathway would go through a γ-aldolizationcrotonization sequence followed by the reduction of the carboncarbon double bond. 40 Alkenylation of 31a with 4chlorobenzaldehyde (39) proceeded efficiently and stereoselectively but attempts to reduce enone 40 into 41 either by catalytic hydrogenation or conjugate hydride addition resulted into complex reaction mixtures. Fortunately, γfunctionalization could eventually be attained by the bromination of 31a in classical conditions, with compound 42 being obtained as a 1:1 mixture of diastereomers.

Scheme 17. Preparation of γ-substituted β-ketoamides.

Substrate 42 was then evaluated in the multicomponent enantioselective synthesis of 2,6-DABCOs (Scheme 18). At first, aniline (43) was tested as the third reaction partner in the reaction with 42 to try to obtain enamine product 44.

Unfortunately the bromine atom did not seem to bring enough stability to the enamine and a complete degradation of the reaction mixture was observed. On the opposite, γ-bromo-βketoamide revealed itself as a potent pronucleophile in the traditional 2,6-DABCO synthesis with 2-aminophenol (12a). In this case, product 45 was obtained in 50% yield as a single diastereomer and with 39% ee. [START_REF] Werner | nOeSY analysis shows correlations for the hydrogen atom linked on the carbon atom bearing the bromine atom only with its direct neighbors. The absence of longer distance correlations is however not conclusive for the relative configuration of the additional stereocenter. (42) For reviews on multicomponent reactions with isonitriles[END_REF] Even though, this level of enantioselectivity is not high enough in a synthetic context, it indicates that kinetic resolution can occur to some extent during the multicomponent organocatalytic process. In addition to this, when γ,δ-unsaturated β-ketoamide 40 was placed in the reaction conditions, no 2,6-DABCO product could be observed (not depicted).

Template for SYNTHESIS © Thieme

Post-functionalization of the products

In our seminal publication, 11a we had shown that the N,O-aminal functionality of the 2,6-DABCO could be re-opened in the presence of a Lewis acid such as boron trifluoride etherate and the resulting iminium ion could be trapped with a potassium alkynyltrifluoroborate. We repeated those reaction conditions by combining 34a and 24 to verify that the enantiopurity of the product is maintained during this post-functionalization (Scheme 19). Pleasingly, the addition product 46 was isolated in 59% yield with only a minor erosion of the enantiomeric excess from 94% to 86%.

Scheme 19. Post-functionalization of 2,6-DABCO 34a.

Other nucleophiles were also evaluated to intercept the transient iminium ion. Neither allyltrimethylsilane nor hydride sources such as triethylsilane, sodium borohydride or Hantzsch ester showed reactivity. On the contrary, complete degradation of the starting material was observed with trimethylsilyl cyanide. We also hypothesized that it would be possible to perform an insertion reaction in the C-O bond of the N,O-aminal. Indeed, the reaction of 34a with (2,6-dimethylphenyl)isocyanide ( 47) afforded imidate 48 with good yield and complete retention of the stereochemical information. Because isocyanides are among the most popular partners in multicomponent reactions, 42 an attempt was made to introduce 47 directly in the reaction conditions used to produce the 2,6-DABCOs. Unfortunately, it behaved only as a spectator since no four-component coupling could be found but instead the reaction proceeded as usual to furnish the three-component product.

Cleavage of the sulfonyl group

To finish our study, we wanted to explore the possibility to cleave the sulfonyl group on the 2,6-DABCO products. Indeed, this group is absolutely required to obtain high yields and stereoselectivities and being able to remove it would significantly expand the synthetic potential of the method. Unfortunately, applying classical deprotection conditions for a tosyl group on the nitrogen atom of an amide (either sodium naphthalenide or TBAF) to 34a resulted in the complete degradation of the starting material. Surmising that the labile N,O-aminal was responsible for this failure, the first deprotection conditions were attempted again on compound 46 (Scheme 20). This time, the cleavage occurred smoothly and deprotected 2,6-DABCO 49 could be isolated in 48% yield without any change in the enantiomeric excess. A solution to circumvent the problems encountered during the deprotection could be to replace the tosyl group by a 4-nosyl unit, which could be cleaved in milder reaction conditions.

Scheme 20. Deprotection of the tosyl group.

Moreover, the corresponding N-nosyl-β-ketoamides such as 50 had already been used in an independent study to access enantioenriched glutarimides by coupling them with α,βunsaturated acyl cyanides. 36e Notably, the stronger electronwithdrawing effect of the 4-nosyl group also had a positive influence on the stereoselectivity of the reaction. When 50 was placed in the standard reaction conditions, the expected 2,6-DABCO 51 was formed in good yield and very high diastereoselectivity but with only 59% ee (Scheme 23). This low enantioselectivity combined with issues of solubility and stability of the product led us to abandon this direction.

Conclusion and Perspective

As a conclusion, in this Feature Article, we have thoroughly discussed all our recent work on the enantioselective preparation of nitrogen-containing six-membered heterocycles from very simple starting materials by the introduction of organocatalysts in multicomponent reactions. The general reaction scheme proceeds from a Michael donor, a Michael acceptor and a third component containing a primary amine, which will be able to cross-link the diverse carbonyl functionalities present on the two other partners after the initial Table 4. General summary of reactions parameters for the three families of organocatalytic enantioselective multicomponent reactions ( = suitable and efficient; = moderately efficient and/or selective; = not suitable). enantioselective Michael addition. Three main families of product were obtained: 1,4,5,6-tetrahydropyridines, 1,2,3,4tetrahydropyridines and bridged perhydropyridines. The main required features of the substrates for each family of products, along with the subsequent choice of the suitable organocatalyst, are summarized in Table 4.

Beyond the potential interest of the present methods to prepare previously unknown polyheterocyclic scaffolds, we believe that the main input of our work is to provide pieces of evidence that organocatalysis, because of its high functional compatibility, can develop as a general and efficient tool to effect organic transformations in complex reaction media with excellent chemo-and stereoselectivities.

The experimental section has no title; please leave this line here.

Starting Materials



Unless specified, commercial reagents and solvents were used as received.



Except the new substrates, which are described below, all βketoamides were prepared according to known literature procedures. CH2Cl2, THF and toluene were dried using a M-Braun SPS-800 system. Other solvents (α,α,α-trifluorotoluene, CH3CN, CHCl3, MeOH and AcOH) were purchased in anhydrous quality and used without further drying.

Instrumentation and Analyses



Analytical thin layer chromatography (TLC) was performed on silica gel 60 F254 aluminum plates (Macherey-Nagel) containing a 254 nm fluorescent indicator. TLC plates were visualized by exposure to short wave ultraviolet light (254 nm) and to anisaldehyde (2.5 mL of p-anisaldehyde, 3 mL of concentrated H2SO4 and 1.5 mL of AcOH in 100 mL of EtOH) or vanillin (2 g of vanillin and 4 mL of concentrated H2SO4 in 100 mL of EtOH) followed by heating.  Flash column chromatography was performed using silica gel (35-70

Procedures

General procedure A for the three-component synthesis of pyrrolopiperazines 5 and 7aa-ha,7ad,7fe, and tetrahydropyridines 13c and 15: A reaction tube was charged with (S)-(-)-α,α-diphenyl-2pyrrolidinemethanol trimethylsilyl ether (4) (6.6 mg, 0.020 mmol, 0.1 equiv), dry α,α,α-trifluorotoluene (2.5 mL), flushed with argon and placed at 0 °C. β-ketoester 1 (0.200 mmol, 1 equiv) was then added followed by freshly distilled (E)-α,β-unsaturated aldehyde 2 (0.300 mmol, 1.5 equiv) and N-(2-aminoethyl)pyrrole 3 or substituted aniline 11c,12 (0.200 mmol, 1 equiv). After 2 days, the solution was directly purified by flash column chromatography on silica gel to provide the pyrrolopiperazines 5, generally as two separable diastereomers or the tetrahydropyridines 13c or 15. For the description of products 5 (Scheme 2), see reference 9a. General procedure C for the three-component synthesis of 2,6-DABCOs 34, 45 and 51: Crushed 4Å molecular sieves (200 mg) was placed in a 25-mL reaction tube equipped with a septum. Air was evacuated under high vacuum and the reaction flask heated by means of a heat gun. After coming back to room temperature, the reaction flask was filled with argon. This operation was repeated a second time. (R,R)-Takemoto catalyst 33 (8.3 mg, 0.020 mmol, 0.1 equiv), β-ketoamide 31 (0.200 mmol, 1 equiv) and functionalized aminophenol 12 (0.300 mmol, 1.5 equiv) were introduced in the reaction flask, which was once again flushed with argon. Dry toluene (6 mL) was added and the reaction flask was cooled to -10 °C. After 10 minutes, acrolein (32) (0.400 mmol, 2 equiv) was added via syringe and the reaction mixture was stirred at -10 °C for 24 h. It was then filtered over a short pad of silica gel (2 cm) that was washed with EtOAc (50 mL). Concentration under reduced pressure afforded a solid that was purified by flash column chromatography on silica gel (CH2Cl2/EtOAc) to provide the pure 2,6-DABCO 34. For the description of products 34 (Scheme 13), see reference 11a.

General

(10R)-9-tert-butyl 10-ethyl 8-methyl-6,10,11,11a-tetrahydro-5Hpyrido[1,2-a]pyrrolo [2,1-c]pyrazine-9,10-dicarboxylate (5c). A reaction tube was charged with (S)-(-)-α,α-diphenyl-2pyrrolidinemethanol trimethylsilyl ether (4) (6.6 mg, 0.020 mmol, 0.1 equiv), benzoic acid (4.9 mg, 0.040 mmol, 0.2 equiv), dry α,α,αtrifluorotoluene (2.5 mL), flushed with argon and placed at 0 o C. tert-Butyl acetoacetate (1a) (31.6 mg, 32.9 L, 0.200 mmol, 1 equiv) and (E)-ethyl 4oxobut-2-enoate (2c) (30.8 mg, 28.9 L, 0.240 mmol, 1.2 equiv) were then added. After full conversion of tert-butyl acetoacetate (1a) as monitored by TLC, followed by the addition of N-(2-aminoethyl)pyrrole (3a) (22.0 Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 14 of 23

HPLC cis-(10R,11aR)-diastereomer (minor):

Chiralcel OD-3, Heptane/ethanol 90:10, 25°C, 1 ml/min, λ = 254 nm, τmajor = 17.66 min, τminor = 10.93 min; trans-(10R,11aS)-diastereomer (major): Chiralpak AD-H, Heptane/ethanol 90/10, 25°C, 1 ml/min, λ = 254 nm, τmajor = 6.90 min, τminor = 10.82 min.

1--(8--methyl--10--phenyl--6,10,11,11a--tetrahydro--5H--pyrido[1,2--a] pyrrolo[2,1--c]pyrazin--9--yl)ethanone (7aa). Prepared according to the

general procedure A using acetylacetone (6a) (20.0 mg, 20.5 μL, 0.200 mmol, 1 equiv), (E)--cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv) and N--(2--aminoethyl)pyrrole (3a) (22.0 mg, 21.6 μL, 0.200 mmol, 1 equiv.), with the following modifications: dry CH2Cl2 (2.5 mL) instead of α,α,α--trifluorotoluene as solvent, benzoic acid (4.9 mg, 0.040 mmol, 0.2 equiv) as co--catalyst and reaction run at -10 °C instead of 0 °C. Purification by flash chromatography (PE/Et2O 33:67) afforded cis--(10S,11aR)--7aa as a pale solid (27.5 mg, 0.090 mmol, 45% yield, 94% ee) and trans--(10S,11aS)--7aa as a pale yellow oil (14.0 mg, 0.046 mmol, 23% yield, 90% ee).

cis-(10S,11aR) diastereomer:

TLC (PE/Et2O 1:2) Rf 0.36(UV, vanillin).

1 H NMR (400 MHz, CDCl3) δ (ppm) 7.24 -7.08 (m, 5H), 6.51 (d, J = 1.8 Hz, 1H), 6.05 (dd, J = 3.4, 2.8 Hz, 1H), 5.73 (dt, J = 3.4, 1.4 Hz, 1H), 4.54 (dd, J = 9.7, 3.0 Hz, 1H), 4.12 -3.99 (m, 4H), 3.37 (ddd, J = 10.3, 7.8, 4.3 Hz, 1H), 2.62 (ddd, J = 13.6, 6.4, 3.3 Hz, 1H), 2.45 (d, J = 1.0 Hz, 3H), 2.10 -2.05 (m, 1H), 1.80 (s, 3H). [α]D 20 = -4.7 (c 0.5, CHCl3).

trans-(10S,11aS) diastereomer:

TLC (PE/Et2O 1:2) Rf 0.33(UV, vanillin).

1 H NMR (400 MHz, CDCl3) δ (ppm) 7. 35 -7.27 (m, 2H), 7.24 -7.17 (m, 3H), 6.55 (d, J = 1.8 Hz, 1H), 6.11 (t, J = 3.0 Hz, 1H), 5.80 (dt, J = 3.5, 1.2 Hz, 1H), 4.19 -4.07 (m, 3H), 4.08 -3.95 (m, 2H), 3.42 (ddd, J = 13.7, 9.5, 4.4 Hz, 1H), 2.61 (s, 3H), 2.43 (ddd, J = 13.0, 3.5, 2.8 Hz, 1H), 2.18 (dd, J = 12.1, 5.0 Hz, 1H), 2.00 (s, 3H). [α]D 20 = -9.9 (c 0.3, CHCl3). -c]pyrazin--9--yl)ethanone (7ad). Prepared according to the general procedure A using acetylacetone (6a) (20.0 mg, 20.5 μL, 0.200 mmol, 1 equiv), (E)--4--chlorocinnamaldehyde (2d) (50.0 mg, 0.300 mmol, 1.5 equiv) and N--(2--aminoethyl)pyrrole (3a) (22.0 mg, 21.6 μL, 0.200 mmol, 1 equiv.), with the following modifications: dry CH2Cl2 (2.5 mL) instead of α,α,α--trifluorotoluene as solvent, benzoic acid (4.9 mg, 0.040 mmol, 0.2 equiv) as co--catalyst and reaction run at -10 °C instead of 0 °C. Purification by flash chromatography (PE/Et2O 33:67) afforded cis--(10S,11aR)--7ad as a pale solid (25.8 mg, 0.076 mmol, 38% yield, 91% ee) and trans--(10S,11aS)--7ad as a pale yellow oil (19.8 mg, 0.058 mmol, 29% yield, 91% ee).

cis-(10S,11aR) diastereomer:

TLC (PE/EtOAc 1:2) Rf 0.36(UV, vanillin).

1 H NMR (400 MHz, CDCl3) δ (ppm) 7.16 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.53 -6.46 (m, 1H), 6.03 (dd, J = 3.4, 2.8 Hz, 1H), 5.65 (dt, J = 3.4, 1.3 Hz, 1H), 4.55 (dd, J = 9.0, 3.3 Hz, 1H), 4.13 -4.06 (m, 2H), 4.03 -3.95 (m, 2H), 3. 43 -3.31 (m, 1H), 2.58 (ddd, J = 13.6, 6.4, 3.6 Hz, 1H), 2.46 (d, J = 0.9 Hz, 3H), 2.13 -2.03 (m, 1H), 1.82 (s, 3H). [α]D 20 = -3.3 (c 0.9, CHCl3).

trans-(10S,11aS) diastereomer:

TLC (PE/EtOAc 1:2) Rf 0.33(UV, vanillin).

1 H NMR (400 MHz, CDCl3) δ (ppm) 7.36 -7.24 (m, 2H), 7.17 -7.13 (m, 2H), 6.61 -6.55 (m, 1H), 6.14 (dd, J = 3.4, 2.8 Hz, 1H), 5.85 -5.79 (dt, J = 3.4, 1.4 Hz,, 1H), 4.18 (dt, J = 13.5, 3.8 Hz, 1H), 4.14 -3.98 (m, 4H), 3.44 (ddd, J = 13.7, 9.1, 4.7 Hz, 1H), 2.61 (s, 3H), 2.44 -2.38 (m, 1H), 2.18 (ddd, J = 13.1, 12.0, 5.0 Hz, 1H), 2.01 (s, 3H). 4.16 (d, J = 7.3 Hz, 1H), 3.92 (dtt, J = 11.4, 8.2, 3.5 Hz, 2H), 3.83 -3.68 (m, 2H), 3.26 -3.14 (m, 1H), 2.78 (s, 6H), 2.27 -2.12 (m, 2H), 1.87 (s, 3H). [α]D 20 = -11.6 (c 0.2, CHCl3).

trans-(10S,11aS) diastereomer:

TLC (PE/EtOAc 4:1) Rf 0.2 (UV, vanillin). [α]D 20 = -28.9 (c 0.2, CHCl3). + : 382.1914, found: 382.1913. 1':3,4] pyrazino [1,2-a]indole-3carboxylate (9). A reaction tube was charged with (S)-α,α-bis[3,5bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (4) (12.0 mg, 0.020 mmol, 0.1 equiv), dry α,α,α-trifluorotoluene (2.5 mL), flushed with argon and placed at 0 o C. tert-butyl acetoacetate (1a) (31.6 mg, 32.9 L, 0.200 mmol, 1 equiv) and (E)-cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv) were then added. After full conversion of tert-butyl acetoacetate (1a) as monitored by TLC (48 h), followed by the addition of 2-(5-methoxy-1H-indol-1-yl)ethanamine (8) (38.0 mg, 0.200 mmol, 1 equiv), the mixture was stirred at 0 o C for another 24 h. After reaction, the solution was filtered through a short pad of silica gel, which was thoroughly washed with EtOAc. The solvent was evaporated by reduced pressure to obtain the crude compound, which was analyzed by 1 (S)-tert-butyl 1-(2-(5-methoxy-1H-indol-1-yl)ethyl)-2-methyl-4phenyl-1,4-dihydropyridine-3-carboxylate (10). A reaction tube was charged with (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2pyrrolidinemethanol trimethylsilyl ether (4) (12.0 mg, 0.020 mmol, 0.1 equiv), dry α,α,α-trifluorotoluene (2.5 mL), flushed with argon and placed at 0 o C. tert-butyl acetoacetate (1a) (31.6 mg, 32.9 L, 0.200 mmol, 1 equiv) and (E)-cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv) were then added. After full conversion of tert-butyl acetoacetate (1a) as monitored by TLC (48 h), followed by the addition of 2-(5methoxy-1H-indol-1-yl)ethanamine 8 (38.0 mg, 0.200 mmol, 1 equiv), the mixture was stirred at 0 o C for another 24 h. After reaction, the solution was filtered through a short pad of silica gel, which was thoroughly washed with EtOAc. The solvent was evaporated by reduced pressure to obtain the crude compound, which was analyzed by1 H NMR, which was identified as the dihydropyridine 10. Purification by flash column chromatography over aluminium oxide 90 neutral (PE/EtOAc 85:15) provided the pure (S)-dihydropyridine 10 as pale yellow solid (26.3 mg, 0.060 mmol, 30% yield, 91% ee). TLC (PE/EtOAc 6:1) Rf 0.42 (UV, vanillin).

1-((5S

HRMS (ESI) calc´d for [C25H23N3O+H]

HPLC cis-(10S,11aR)-diastereomer (major):

1 H NMR (400 MHz, CDCl3) δ (ppm) 7. 31 -7.26 (m, 1H), 7.23 -7.19 (m, 3H), 7.18 -7.18 -7.12 (m, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.89 (dd, J = 8.8, 2.3 Hz, 1H), 6.43 (d, J = 2.6 Hz, 1H), 5.61 (d, J = 7.8 Hz, 1H), 4.83 (dd, J = 7.8, 5.0 Hz, 1H), 4.55 (d, J = 5.0 Hz, 1H), 4. 35 -4.14 (m, 2H), 3.85 (s, 3H), 3.84 -3.73 (m, 2H), 3.60 (dt, J = 15.0, 6.2 Hz, 1H), 2.19 (s, 3H), 1.21 (s, 9H).

(3S)-tert-butyl 1-methyl-3-phenyl-3,4,4a,6tetrahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (13c).

Prepared according to the general procedure A using tert-butyl acetoacetate (1a) (31.6 mg, 32.9 L, 0.200 mmol, 1 equiv), (E)cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv), 2aminobenzyl alcohol (11c) (24.6 mg, 0.200 mmol, 1 equiv). Purification by flash chromatography over silica gel (PE/Et2O 80:20) afforded 12c as a pale yellow solid (~20 mg, ~0.050 mmol, ~2% yield, 1.3:1 dr, 88% ee). TLC (PE/Et2O 80:10) Rf 0.36 and 0.40 (UV, vanillin).

1 H NMR (400 MHz, CDCl3) δ (ppm) major diastereomer: 7.35 -7.17 (m, 5H), 7.00 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 4.79 (d, J = 14.3 Hz, 1H), 4.68 (d, J = 14.3 Hz, 1H), 4.19 -4.09 (m, 1H), 3.80 -3.75 (m, 1H), 2.33 (s, 3H), 2.15 -1.78 (m, 2H), 1.10 (s, 9H); minor diastereomer: 7.35 -7.17 (m, 5H), 7.07 (t, J = 6.9 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.80 -6.72 (m, 2H), 4.74 (app s, 2H), 4.27 -4.19 (m, 1H), 3.80 -3.73 (m, 1H), 2.31 (s, 3H), 2.10 -1.82 (m, 2H), 1.10 (s, 9H).

HPLC Chiralpak AD-H, Hexane/ethanol 90:10, 25 °C, 1.0 mL/min, λ = 254 nm, major diastereromer: τminor = 15.72 min, τmajor = 22.33 min; minor diastereromer: τminor = 17.95 min, τmajor = 19.12 min (3R,4S,4aR)-tert-butyl 4a-methyl-3-phenyl-4,4a-dihydro-3Hbenzo[4,5]oxazolo[3,2-a]pyridine-4-carboxylate (15). Prepared according to the general procedure A using tert-butyl acetoacetate (1a) (31.6 mg, 32.9 L, 0.200 mmol, 1 equiv), (E)-cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv), 2-aminophenol (12a) (21.8 mg, 0.200 mmol, 1 equiv). Purification by flash chromatography over silica gel (PE/Et2O 90:10) afforded 15 as a pale yellow oil (18.2 mg, 0.050 mmol, 25% yield, >20:1 dr, 92% ee). More polar regioisomer 14 could not be obtained pure.

TLC (PE/Et2O 80:20) Rf 0.45 (UV, vanillin). + : 364.1907, found: 364.1909.

HRMS (ESI) calc´d for [C23H25NO3+H]

1 H NMR (400 MHz, CDCl3) δ (ppm) 7. 26 -7.16 (m, 5H), 6.82 -6.77 (m, 1H), 6.73 -6.66 (m, 2H), 6.63 -6.59 (m, 1H), 6.54 (dd, J = 7.6, 2.1 Hz, 1H), 4.82 (dd, J = 7.6, 2.0 Hz, 1H), 3.81 (dt, J = 11.9, 2.0 Hz, 1H), 2.92 (d, J = 11.9 Hz, 1H), 1.70 (s, 3H), 1.21 (s, 9H). HPLC Chiralpak IA, Hexane/isopropanol 95:5, 25°C, 1.0 mL/min, λ = 254 nm, τmajor = 4.99 min, τminor = 5.99 min.

[α]D 20 = -11.3 (c 0.3, CHCl3).

4-bromo-N-methoxy-N-methyl-3-oxobutanamide (17d).

To a solution of N-methoxy-N-methyl-3-oxobutanamide (6d) (1.02 g, 7 mmol, 1 equiv) in dry chloroform (10 mL) at 0 °C was added bromine (360 µL, 7 mmol, 1 equiv) dropwise over 45 min with vigorous stirring. After the mixture was stirred at room temperature for 24 h, cold water was added (20 mL), and the organic layer washed with a sodium thiosulfate aqueous solution (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. Purification by flash column chromatography over silica gel (PE/EtOAc 70:30 to 50:50) yielded product 17d as an orange oil (710 mg, 3.17 mmol, 45% yield, ~1.3:1 ketone vs enol forms). 1 H NMR (400 MHz, CDCl3): δ (ppm) ketone form: 4.04 (s, 2H), 3.79 (s, 2H), 3.68 (s, 3H), 3.19 (s, 3H); enol form: 13.68 (s, 1H), 5.67 (s, 1H), 3.85 (s, 2H), 3.68 (s, 3H), 3.19 (s, 3H).

TLC (PE/

1-(2-oxopyrrolidin-1-yl)butane-1,3-dione (20). 2-Pyrrolidinone (19)

(1.70 g, 20 mmol, 1 equiv) was dissolved in dry toluene (10 mL) under argon atmosphere. Then, 2,2,6-trimethyl-4H-1,3-dioxin-4-one (18) (2.63 mL, 20 mmol, 1 equiv) was added and the reactor was irradiated under microwave at 150 °C during 30 min. Solvent was removed under reduced pressure. Purification by flash column chromatography over silica gel (PE/EtOAc 70:30 to 50:50) yielded product 20 as an orange oil (2.65 g, 15.7 mmol, 78% yield, ~9:1 ketone vs enol forms). 6, 173.4, 171.5, 170.1 (carbonyl C); 148.4, 143.9, 141.5, 140.7, 140.1, 140.0, 139.7, 138.5, 137.4, 131.8, 131.3, 120.1, (aromatic C); 133.1, 129.9, 129.9, 129.5, 129.4, 129.4, 128.6, 127.9, 127.8, 127.2, 127.0, 121.7, 121.6, 118.7, 118.6, 115.4, 115.3, 115.2, 108.4, 105.1 (aromatic CH); 102.3, 102.1 (aminal C); 61.5, 61.0 (aliphatic CH2); 77,4, 61.3, 57.7, 55.6, 55.3, 50.3, 48.5, 42.3, 40.2, 38.6, 32.1, 30.5, 23.7, 20.8, 20.7, 14.4, 14.3, 14.2, 13.8 (aliphatic CH and CH3). (4aR)-7-chloro-4a-methyl-3-phenyl-12-tosyl-2,3,4,4a-tetrahydro-(36b). Prepared according to the general procedure B using 3-oxo-Ntosylbutanamide (35) (48.3 mg, 0.200 mmol, 1 equiv), (E)cinnamaldehyde (2a) (38 µL, 0.300 mmol, 1.5 equiv) and 2-amino-5chlorophenol (16b) (21.8 mg, 0.200 mmol, 1 equiv). Purification by flash chromatography over silica gel (PE/EtOAc 70:30) afforded product 36b as a yellowish solid (58 mg, 0.117 mmol, 59% yield, >20:1 dr, 59% ee). TLC (PE/EtOAc 70:30) Rf 0.45 (UV, p-anisaldehyde).

TLC (PE/

HPLC

HRMS (ESI

HRMS (ESI) calc´d for [C26H23ClN2O4S+H] +

: 495.1140, found: 495.1136. 1 H NMR (400 MHz, CDCl3) δ (ppm) 7. 41 -7.25 (m, 6H), 7.22 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2, 1H), 6.95 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 5.85 (d, J = 2.6 Hz, 1H), 3.51 (ddd, J = 10.4, 5.1, 2.1 Hz, 1H), 3.10 (d, J = 2.2 Hz, 1H), 2.82 (ddd, J = 13.5, 10.6, 2.3 Hz, 1H), 2.41 (s, 3H), 2.36 (ddd, J = 13.5 Hz, 5.2, 3.2 Hz, 1H), 1.62 (s, 3H). (4aR)-4a-methyl-3-phenyl-14-tosyl-2,3,4,4a-tetrahydro-1H-1,4-(epiminomethano)naphtha[2',3':4,5]oxazolo[3,2-a]pyridin-13-one (36c). Prepared according to the general procedure B using 3-oxo-Ntosylbutanamide (35) (48.3 mg, 0.200 mmol, 1 equiv), (E)cinnamaldehyde (2a) (38 µL, 0.300 mmol, 1.5 equiv) and 3aminonaphthalen-2-ol (16c) (31.8 mg, 0.2 mmol, 1 equiv). Purification by flash chromatography over silica gel (CH2Cl2/EtOAc 99.5:0.5) afforded product 36c as a yellowish solid (54 mg, 0.109 mmol, 54% yield, >20:1 dr, 65% ee). TLC (CH2Cl2/EtOAc 99.5:0.5) Rf 0.59 (UV, p-anisaldehyde).

HRMS (ESI) calc´d for [C30H26N2O4S+H] +

: 511.1686, found: 511.1686. 1 H NMR (400 MHz, CDCl3): δ (ppm) 7. 84 -7.75 (m, 1H), 7.57 -7.51 (m, 1H), 7.48 (s, 1H), 7.45 -7.33 (m, 4H), 7.33 -7.27 (m, 3H), 7. (d, J = 8.2 Hz, 2H), 6.62 (s, 1H), 6.43 (d, J = 8.2 Hz, 2H), 6.06 (t, J = 2.4 Hz, 1H), 3.58 (ddd, J = 10.3, 4.6, 2.0 Hz, 1H), 3.19 (d, J = 2.0 Hz, 1H), 2.90 (ddd, J = 13.0, 10.5 Hz, 1.9 Hz, 1H), 2.46 (ddd, J = 13.5, 4.4 Hz, 2.4 Hz, 1H), 2.15 (s, 3H), 1.68 (s, 3H). (E)-3-(4-chlorobenzylidene)-2-oxo-N-tosylcyclopentane carboxamide (40). In a 50-mL flask under argon atmosphere, βketoamide 31a (563 mg, 2.00 mmol, 1 equiv), 4-chlorobenzaldehyde (39) (281 mg, 2.00 mmol, 1 equiv) and K2CO3 (553 mg, 4.00 mmol, 2 equiv) were stirred in dry MeOH (8 mL) at room temperature for 14 h. A 1M aqueous solution of HCl (30 mL) was added and the reaction mixture extracted with EtOAc (3 x 30 mL). Combined organic layers were washed with 1M HCl (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum. The pale yellow solid was suspended in Et2O (10 mL), filtered, washed with Et2O (10 mL) and dried under vacuum to afford product 40 as a white solid (570 mg, 1.41 mmol, 71% yield, ~2:1 mixture of ketone and enol tautomers, with still some inseparable ptosylamide inside). TLC (Tol/EtOAC/AcOH 70:30:1) Rf 0.41 (UV, p-anisaldehyde).

HRMS (ESI) calc´d for [C20H18ClNO4S+H] +

: 404.0718, found: 404.0717.

3-bromo-2-oxo-N-tosylcyclopentanecarboxamide (42).

In a 100-mL flask equipped with a dropping funnel under argon atmosphere, βketoamide 31a (1.41 g, 5.00 mmol, 1 equiv), was dissolved in glacial AcOH (15 mL) at room temperature. A solution of Br2 (283 µL, 5.50 mmol, 1.1 equiv) in glacial AcOH (10 mL) was placed in the dropping funnel and added dropwise. After 2 h of stirring at room temperature, acetone (1 mL) was added to quench the excess of Br2. After an additional hour at room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). Combined organic layers were washed with saturated Na2S2O3 aqueous solution (50 mL), water (50 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum. The pale yellow solid was suspended in Et2O (10 mL), filtered, washed with Et2O (10 mL) and dried under vacuum to afford product 42 as a white solid (1.35 g, 3.75 mmol, 75% yield). TLC (Tol/EtOAC/AcOH 80:20:1) Rf 0.36 (UV, vanillin). A mixture of product 34a (205 mg, 0.500 mmol, 1 equiv) and potassium phenylethynyltrifluoroborate (24) (312 mg, 1.50 mmol, 3 equiv) were suspended in dry CH2Cl2 (5 mL) and cooled at 0 °C. Boron trifluoride etherate (126 µL, 1.00 mmol, 2 equiv) was added dropwise and the reaction mixture allowed to reach room temperature, where it was stirred for 2 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (3 x 10 mL). Combined organic layers were washed with water (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography over silica gel (CH2Cl2/EtOAc 99.5:0.5 to 99:1) afforded product 46 as a brown foamy solid (151 mg, 0.295 mmol, 59% yield, >20:1 dr, 86% ee).

HRMS (ESI

TLC (CH2Cl2/EtOAc 98:2) Rf 0.84 (UV, p-anisaldehyde). (41.1 mg, 0.100 mmol, 1 equiv) and 2,6-dimethylphenylisocyanide (47) (26.4 mg, 0.200 mmol, 2 equiv) were dissolved in dry CH2Cl2 (1 mL) and cooled at 0 °C. Boron trifluoride etherate (25 µL, 0.200 mmol, 2 equiv) was added dropwise and the reaction mixture allowed to reach room temperature, where it was stirred for 2 h. The reaction was quenched with water (10 mL) and extracted with CH2Cl2 (3 x 10 mL). Combined organic layers were washed with water (10 mL), dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography over silica gel (pure CH2Cl2) afforded product 48 as a brown foamy solid (42.7 mg, 0.079 mmol, 79% yield, >20:1 dr, 94% ee). and cooled at -78 °C. A solution of sodium naphthalenide (0.5 M, 1.4 mL, 0.700 mmol, 10 equiv) was added dropwise and the reaction mixture stirred at -78 °C for 1 h. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3 x 5 mL). Combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated under vacuum. Purification by flash chromatography over silica gel (CH2Cl2/EtOAc 80:20 to 70:30) afforded product 49 as a yellowish solid (12.0 mg, 0.034 mmol, 48% yield, >20:1 dr, 86% ee). HPLC Chiralpak IE, Heptane/Ethanol 80:20, 1 mL/min, λ = 254 nm, τminor = 6.04 min, τmajor = 6.87 min.

HRMS (ESI

TLC (CH2Cl2

[α]D 20 = +18.9 (c 0.5, CHCl3). pyridin-14-one (51). Prepared according to the general procedure C using N-(4-nitrobenzenesulfonyl)-3-oxobutanamide (50) (62.5 mg, 0.200 mmol, 1 equiv), acrolein (32) (27 µL, 0.400 mmol, 2 equiv) and 2aminophenol (12a) (32.7 mg, 0.3 mmol, 1.5 equiv). Purification by flash chromatography over silica gel (CH2Cl2/EtOAc 99:1) afforded product 51 as a white solid (66.3 mg, 0.150 mmol, 75% yield, >20:1 dr, 59% ee).

Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 20 of 23

Figure 1 .

 1 Figure 1. Families of polyheterocycles discussed in this article.

Figure 2 .

 2 Figure 2. Unsuitable β-ketoamide substrates 17a-d.

Scheme 13 .

 13 Scheme 13. Bridged perhydropyridines (2,6-DABCOs): previous results. 11a

Scheme 14 .

 14 Scheme 14. Bridged perhydropyridines (2,6-DABCOs): open questions.

Feature

  Scheme 21. Synthesis of N-(4-nosyl)-2,6-DABCO 51.

  β-ketoamides (reduced yields) α-methylene β-ketothioesters (reduced ee) 1-acetylindolin-3-ones open-chain α-methylene β-ketoesters (mixture) open-chain α-methylene Weinreb β-ketoamides open-chain α-methylene β-Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 13 of 23

  In a reaction tube, βketoamide 6c-d,35 (0.2 mmol, 1 equiv), (E)-cinnamaldehyde derivative 2 (0.3 mmol, 1.5 equiv), functionalized 2-aminophenol 16 (0.2 mmol, 1equiv) and benzoic acid (0.08 mmol, 0.4 equiv) were dissolved in dry CH2Cl2 (2 mL) under argon and placed at 10 °C. Then, (S)-(-)-α,αdiphenyl-2-pyrrolidinemethanol trimethylsilyl ether (4) (0.04 mmol, 0.2 equiv) was added to the mixture. After 60 h, around ten drops of NH4Cl were added to the reaction mixture to deactivate the catalyst. The organic layer was then separated and concentrated under vacuum. The diastereomeric ratio of the crude product was determined by 1 H NMR. Purification by flash chromatography over silica gel yielded the corresponding three-component product. For the description of products 16 (Schemes 7 and 8), see reference 10.

13 C

 13 NMR (101 MHz, CDCl3) δ (ppm) 200.2 (C), 151.0 (C), 146.2 (C), 129.1 (C), 128.7 (2 CH), 127.2 (2 CH), 126.2 (CH), 118.6 (CH), 112.9 (C), 108.7 (CH), 103.4 (CH), 53.6 (CH), 45.2 (CH2), 44.0 (CH2), 41.8 (CH), 40.7 (CH2), 30.6 (CH3), 17.1 (CH3). HRMS (ESI) calc´d for [C20H22N2O +H] + : 307.1805, found: 307.1802. HPLC Lux-Amylose-2, Hexane/ethanol 80:20, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 11.43 min, τminor = 9.02 min.

13 C

 13 NMR (101 MHz, CDCl3) δ (ppm) 198.1 (C), 154.3 (C), 146.0 (C), 129.5 (C), 128.7 (2 CH), 128.1 (2 CH), 126.6 (CH), 118.9 (CH), 108.6 (CH), 107.8 (C), 103.0 (CH), 49.5 (CH), 45.0 (CH2), 44.5 (CH2), 39.8 (CH), 36.3 (CH2), 29.6 (CH3), 18.0 (CH3). HRMS (ESI) calc´d for [C20H22N2O+H] + : 307.1805, found: 307.1801. HPLC Lux-Amylose-2, Hexane/ethanol 90:10, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 22,68 min, τminor = 18,58 min.

13 C

 13 NMR (101 MHz, CDCl3) δ (ppm) 199.6 (C), 151.6 (C), 144.7 (C), 131.8 (C), 128.76 (2 CH), 128.72 (2 C), 128.5 (2 CH), 118.6 (CH), 112.1 (C), 108.7 (CH), 103.4 (CH), 53.4 (CH), 45.1 (CH2), 44.2 (CH2), 41.0 (CH), 39.9 (CH2), 30.5 (CH3), 17.2 (CH3). HRMS (ESI) calc´d for [C20H21N2OCl+H] + : 341.1415, found: 341.1414. HPLC Chiralpak AD-H, Hexane/ethanol 80:20, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 8.34 min, τminor = 9.90 min.

13 C

 13 NMR (101 MHz, CDCl3) δ (ppm) 197.7 (C), 154.5 (C), 144.5 (C), 132.4 (C), 129.5 (2 CH), 129.2 (C), 128.9 (2 CH), 119.0 (CH), 108.6 (CH), 107.5 (C), 103.1 (CH), 49.4 (CH), 44.9 (CH2), 44.5 (CH2), 39.3 (CH), 36.2 (CH2), 29.6 (CH3), 18.0 (CH3). HRMS (ESI) calc´d for [C20H21N2OCl+H] + : 341.1415, found: 341.1411.HPLC Lux-Amylose-2, Hexane/ethanol 80:20, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 13.32 min, τminor = 10.93 min. general procedure A using N, N-dimethyl-3oxobutanamide (6c) (25.8 mg, 0.200 mmol, 1 equiv), (E)-cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv), N-(2-aminoethyl)pyrrole (3a)(22.0 mg, 21.6 L, 0.200 mmol, 1 equiv). Purification by flash chromatography (CH2Cl2/MeOH 98:2 then CH2Cl2/MeOH/AcOH 98:2:0.5) afforded trans-(10S,11aS)-7ca as a yellow oil (16.8 mg, 0.050 mmol, 25% yield, 92% ee). TLC (CH2Cl2/MeOH 50:1) Rf 0.5 (UV, vanillin).

1 H

 1 NMR (400 MHz, CDCl3) δ (ppm) 7.29 -7.16 (m, 4H), 7.12 -7.08 (m, 1H), 6.49 -6.44 (m, 1H), 6.05 (t, J = 3.0 Hz, 1H), 5.74 (d, J = 2.7 Hz, 1H), Template for SYNTHESIS © Thieme Stuttgart • New York 2016-05-24 page 15 of 23

  calc´d for [C21H24N2OS+H] + : 353.1682, found: 353.1681. HPLC Lux-Amylose-2, Hexane/ethanol 80:20, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 7.15 min, τminor = 6.20 min.

  Chiralpak AZ-H, Hexane/ethanol 50:50, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 14.25 min, τminor = 10.45 min; trans-(10S,11aS)-diastereomer (minor): Chiralpak AZ-H, Hexane/ethanol 50:50, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 11.58 min, τminor = 7.09 min.

13 C

 13 NMR (101 MHz, CDCl3) δ (ppm) 168.5 (C), 154.3 (C), 149.1 (C), 146.4 (C), 131.1 (C), 129.4 (C), 128.7 (CH), 128.3 (2 CH), 127.8 (CH), 127.6 (2 CH), 126.1 (CH), 112.4 (CH), 109.6 (CH), 108.5 (CH), 103.0 (CH), 102.7 (C), 101.8 (CH), 79.2 (C), 56.0 (CH3), 49.7 (CH2), 46.6 (CH2), 41.1 (CH), 28.2 (3 CH3), 15.5 (CH3). HRMS (ESI) calc´d for [C28H32N2O3+H] + : 445.2486, found: 445.2487. HPLC Chiralpak AZ-H, Heptane/ethanol 90:10, 25°C, 1.0 mL/min, λ = 254 nm, τmajor = 12.11 min, τminor = 14.10 min.

  13 C NMR (101 MHz, CDCl3) δ (ppm) 170.3 (C), 149.8 (C), 141.7 (C), 134.6 (C), 128.5 (2 CH), 128.3 (2 CH), 127.3 (CH), 124.0 (CH), 121.4 (CH), 120.2 (CH), 108.9 (CH), 107.0 (CH), 106.9 (CH), 100.0 (C), 81.2 (C), 54.9 (CH), 43.4 (CH), 28.0 (3 CH3), 20.8 (CH3).

  EtOAc 50:50) Rf 0.23 (UV, p-anisaldehyde). HRMS (ESI) calc´d for [C6H10BrNO3+H] + : 223.9917, found: 223.9915.

13 C

 13 NMR (101 MHz, CDCl3): δ (ppm) ketone form: 195.7 (C), 170.5 (C), 61.6 (CH3), 44.6 (CH2), 32.2 (CH3), 34.4 (CH2); enol form: 171.6 (C), 167.4 (C), 88.6 (CH), 61.7 (CH3), 31.8 (br, CH3), 29.9 (CH2).

23 (

 23 EtOAc 50:50) Rf 0.20 (UV, p-anisaldehyde). HRMS (ESI) calc´d for [C8H11NO3+H] + :170.0812, found: 170.0814.Template for SYNTHESIS © Thieme Stuttgart • New York2016-05-24 page 17 of The three-component product 16a (144 mg, 0.411 mmol, 1 equiv) was dissolved in methanol (15 mL) under argon atmosphere. Then, Pd/C (18 mg, 0.164 mmol, 12 wt.%) was added to the solution before flushing the reaction mixture with hydrogen. The reaction was stirred at room temperature during 13 h. After filtration on celite and washing with CH2Cl2, solvents were removed under vacuum. Purification by flash column chromatography over silica gel (PE/EtOAc 80:20 to 50:50) yielded the hydrogenated product 23 as a yellowish oil (117 mg, 0.332 mmol, 81 % yield, >20:1 dr).TLC (PE/EtOAc 70:30) Rf 0.65 (UV, p-anisaldehyde). HRMS (ESI) calc´d for [C21H22N2O3+H] + : 353.1860, found: 353.1862.

  Chiralpak IE, Heptane/Ethanol 80:20, 1 mL/min, λ = 254 nm, major diastereomer: τminor = 7.35 min, τmajor = 9.19 min, minor diastereomer: τminor = 12.43 min, τmajor = 13.98 min. Prepared according to the general procedure B using Weinreb βketoamide (6d) (29.0 mg, 0.200 mmol, 1 equiv), (E)-4fluorocinnamaldehyde (2f) (45.0 mg, 39.3 L, 0.300 mmol, 1.5 equiv) and 2-aminophenol (12a) (21.8 mg, 0.200 mmol, 1 equiv), at 25 °C instead of 10 °C Purification by flash chromatography over silica gel (PE/EtOAc 80:20) afforded 29 as a yellow solid (33.8 mg, 0.092 mmol, 46% yield, >20:1 dr, 91% ee). TLC (PE/EtOAc 80:20) Rf 0.50 (UV, vanillin).

13 C

 13 NMR (101 MHz, CDCl3) δ (ppm) 171.2 (C), 162.0 (C, d, JC-F = 245 Hz), 149.5 (C), 137.7 (C, d, JC-F = 3.0 Hz), 134.5 (C), 129.7 (2 CH, d, JC-F = 7.8 Hz), 124.0 (CH), 121.5 (CH), 120.1 (CH), 115.4 (CH), 115.2 (CH), 108.6 (CH), 106.8 (2 CH, d, JC-F = 12.3 Hz), 100.6 (C), 61.2 (CH3), 48.9 (CH), 42.5 (CH3), 32.1 (CH), 21.0 (CH3).19 F NMR (376 MHz, CDCl3) δ (ppm) 115.75. HPLC Chiralpak IF, Heptane/Isopropanol 95:5, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 7.65 min, τminor = 6.79 min.

  13 C NMR (101 MHz, CDCl3) δ (ppm) 166.1 (C), 151.6 (C), 144.6 (C), 141.1 (C), 136.2 (C), 135.1 (C), 129.3 (2 CH), 129.2 (2 CH), 128.6 (2 CH), 127.7 (CH), 127.6 (2 CH), 125.8 (CH), 121.9 (CH), 117.5 (CH), 110.2 (CH), 102.1 (C), 74.2 (CH), 56.2 (CH), 36.5 (CH and CH2), 23.3 (CH3), 21.8 (CH3). HPLC Chiralpak IA, Heptane/Ethanol 50:50, 1 mL/min, λ = 254 nm, major diastereomer: τminor = 12.65 min, τmajor = 23.70 min, minor diastereomer: τminor = 21.32 min, τmajor = 10.69 min.

13 C

 13 NMR (101 MHz, CDCl3 δ (ppm) 165.8 (C), 152.4 (C), 145.0 (C), 140.9 (C), 135.1 (C), 134.8 (C), 131.2 (C), 129.4 (2 CH), 129.3 (2 CH), 128.4 (2 CH), 127.8 (CH), 127.6 (2 CH), 121.7 (CH), 117.9 (CH), 110.9 (CH), 103.7 (C), 74.3 (CH), 56.1 (CH), 36.5 (CH2), 36.4 (CH), 23.2 (CH3), 21.8 (CH3). HPLC Chiralpak IE, Heptane/Ethanol 50:50, 1 mL/min, λ = 254 nm, τminor = 8.19 min, τmajor = 11.71 min.

13 C

 13 NMR (101 MHz, CDCl3): δ (ppm) 165.9 (C), 150.5 (C), 144.3 (C), 141.1 (C), 137.7 (C), 134.5 (C), 133.2 (C), 130.3 (C), 129.4 (2 CH), 128.8 (2 CH), 128.0 (2 CH), 127.8 (CH), 127.6 (3 CH), 126.9 (CH), 125.6 (CH), 124.4 (CH), 114.3 (CH), 104.8 (CH), 102.5 (C), 75.1 (CH), 56.6 (CH), 36.5 (CH2), 36.4 (CH), 23.8 (CH3), 21.6 (CH3). HPLC Chiralpak IC, Heptane/Ethanol 80:20, 1 mL/min, λ = 254 nm, τminor = 13.50 min, τmajor = 15.73 min. [α]D 20 = +145 (c 1.0, CHCl3). m.p. = 88-90 °C.

HPLC

  Chiralpak ID, Heptane/Ethanol 80:20, 1 mL/min, λ = 205 nm, τminor = 12.83 min, τmajor = 14.54 min.

)

  calc´d for [C30H28N2O4S+H] + : 513.1843, found: 513.1840. 1 H NMR (300 MHz, CDCl3): δ (ppm) 7.97 (d, J = 8.3 Hz, 2H), 7.44 -7.29(m, 8H), 7.16 (td, J = 8.0, 1.4 Hz, 1H), 6.97 (dd, J = 8.0, 1.4 Hz, 1H), 6.81 (td, J = 8.0, 1.5 Hz, 1H), 6.64 (s, 1H), 5.57 (dd, J = 3.9, 1.4 Hz, 1H), 2.74 -2.33 (m, 3H), 2.47 (s; 3H), 2.26 -2.09 (m, 1H),1.94 -1.49 (m, 6H).

HPLC

  Chiralpak IA, Heptane/Ethanol 80:20, 1 mL/min, λ = 254 nm, τmajor = 6.78 min, τminor = 8.24 min.

13 C

 13 NMR (101 MHz, CDCl3): δ (ppm) 172.3 (C), 146.0 (C), 145.3 (C), 143.9 (C), 142.5 (C), 135.7 (C), 129.7 (2 CH), 128.6 (C), 128.5 (2 CH), 128.0 (2 CH), ~127.0 (br, 2 C), 124.3 (CH), 123.4 (CH), 121.9 (CH), 118.0 (CH), 116.8 (CH), 71.7 (CH), 63.33 (C), 57.1 (C), 37.1 (CH2), 28.1 (CH2), 25.7 (CH2), 21.8 (CH3), 20.6 (CH2), 20.4 (CH2), 18.7 (br, 2 CH3).HPLC Chiralpak IF, Heptane/Ethanol 80:20, 1 mL/min, λ = 254 nm, τminor = 10.09 min, τmajor = 11.65 min. Product 34a (35.9 mg, 0.070 mmol, 1 equiv) was dissolved in dry THF (0.6 mL)

13 C

 13 NMR (101 MHz, CDCl3): δ (ppm) 169.5 (C), 151.0 (C), 143.7 (C), 137.5 (C), 129.8 (2 CH), 126.2 (CH), 123.8 (2 CH), 121.9 (CH), 117.5 (CH), 112.6 (C), 109.9 (CH), 77.5 (CH), 68.7 (C), 54.1 (C), 33.4 (CH2), 28.8 (CH2), 25.2 (CH2), 23.9 (CH2), 19.3 (CH2). Partial degradation of the product occured during the recording of the 13 C NMR spectra. HPLC Chiralpak IB, Hexane/Ethanol 50:50, 10 °C, 1 mL/min, λ = 254 nm, τmajor = 6.15 min, τminor = 7.93 min.

TLC (PE/EtOAc 4:1) Rf

	13 C NMR (75 MHz, CDCl3) δ (ppm) 172.7 (C), 145.1 (C), 139.3 (C), 130.3
	(C), 128.5 (2 CH), 128.2 (2 CH), 126.4 (CH), 118.9 (CH), 108.4 (CH), 107.2
	(C), 102.4 (CH), 50.5 (CH), 45.2 (CH2), 44.5 (CH2), 39.5 (CH), 39.5 (2 CH3),
	35.3 (CH2), 17.2 (CH3).
	HRMS (ESI) calc´d for [C21H25N3O +H] + : 336.2070, found: 336.2071.
	HPLC Lux-Cellulose-4, Hexane/ethanol 90:10, 25 °C, 1.0 mL/min, λ = 254
	nm, τmajor = 26.36 min, τminor = 24.29 min.
	[α]D 20 = -24.6 (c 0.3, CHCl3).
	(10S,11aS)-N-methoxy-N,8-dimethyl-10-phenyl-6,10,11,11a-tetra
	hydro-5H-pyrido[1,2-a]pyrrolo[2,1-c]pyrazine-9-carboxamide
	(7da). Prepared according to the general procedure A using N-methoxy-
	N-methyl-3-oxobutanamide (6d) (29.0 mg, 0.200 mmol, 1 equiv), (E)-
	cinnamaldehyde (2a) (39.7 mg, 37.8 L, 0.300 mmol, 1.5 equiv), N-(2-
	aminoethyl)pyrrole (3a) (22.0 mg, 21.6 L, 0.200 mmol, 1 equiv).
	Purification by flash chromatography (CH2Cl2/MeOH 98:2 then
	CH2Cl2/MeOH/AcOH 98:2:0.5) afforded trans-(10S,11aS)-7da as a yellow
	oil (19.7 mg, 0.056 mmol, 28% yield, 88% ee).
	TLC (CH2Cl2/MeOH 50:1) Rf 0.36 (UV, vanillin).
	1 H NMR (400 MHz, CDCl3) δ (ppm) 7.24 -7.09 (m, 5H), 6.46 -6.42 (m,
	1H), 6.02 (t, J = 3.0 Hz, 1H), 5.72 (d, J = 2.9 Hz, 1H), 4.12 (dd, J = 9.0, 3.6 Hz,
	1H), 3.93 -3.79 (m, 4H), 3.29 (s, 3H), 3.25 -3.14 (m, 1H), 2.95 (s, 3H), 2.17
	(dtt, J = 18.7, 9.1, 5.0 Hz, 2H), 1.95 (s, 3H).
	Ethyl 8-methyl-10-phenyl-6,10,11,11a-tetrahydro-5H-pyrido[1,2-a]
	pyrrolo [2,1-c] pyrazine-9-carbothioate (7ea). Prepared according to
	the general procedure A using S-ethyl acetothioacetate (6e) (29.2 mg,
	26.8L 0.200 mmol, 1 equiv), (E)-cinnamaldehyde (2a) (39.7 mg, 37.8 L,
	0.300 mmol, 1.5 equiv), N-(2-aminoethyl)pyrrole (3a) (22.0 mg, 21.6 L,
	0.200 mmol, 1 equiv). Purification by flash chromatography (PE/Et2O
	80:20 then PE/Et2O/AcOH 80:20: 0.5) afforded cis-(10S,11aR)-7ea as a
	yellow oil (15.0 mg, 0.042 mmol, 21% yield, 49% ee) and trans-
	(10S,11aS)-7ea as a yellow oil (23.2 mg, 0.058 mmol, 29% yield, 54% ee).
	cis-(10S,11aR) diastereomer:
	04 (m,
	3H), 6.51 -6.42 (m, 1H), 5.99 (dd, J = 3.5, 2.8 Hz, 1H), 5.63 (dt, J = 3.5, 1.4
	Hz, 1H), 4.55 (dd, J = 8.6, 3.6 Hz, 1H), 4.26 -4.18 (m, 1H), 4.07 (dt, J = 13.0,
	3.4 Hz, 1H), 4.03 -3.97 (m, 2H), 3.39 (ddd, J = 13.5, 8.9, 5.2 Hz, 1H), 2.74 -
	2.57 (m, 3H), 2.42 (d, J = 1.1 Hz, 3H), 2.19 (dt, J = 13.6, 8.8 Hz, 1H), 0.95 (t,
	J = 7.4 Hz, 3H).

13 C NMR (75 MHz, CDCl3) δ (ppm) 171.3 (C), 145.1 (C), 141.7 (C), 130.3 (C), 128.5 (2 CH), 128.3 (2 CH), 126.4 (CH), 118.9 (CH), 108.4 (CH), 106.4 (C), 102.4 (CH), 60.8 (CH3), 50.7 (CH), 44.9 (CH2), 44.7 (CH2), 38.6 (CH), 35.2 (CH2), 34.0 (CH3), 17.3 (CH3). HRMS (ESI) calc´d for [C21H25N3O2+H] + : 352.2020, found: 352.2021. HPLC Chiralpak AD-H, Hexane/EtOH 80:20, 25 °C, 1.0 mL/min, λ = 254 nm, τmajor = 10.21 min, τminor = 7.59 min.

[α]D 20 = -31.2 (c 0.2, CHCl3). 0.29 (UV, vanillin).

1 H NMR (400 MHz, CDCl3) δ (ppm) 7.

19 -7.13 (m, 2H), 7.13 -7.

  H NMR, which was identified as the dihydropyridine 10. Purification by

	flash column chromatography (PE/EtOAc 80:20 and then
	PE/EtOAc/AcOH 80:20:0.5) on silica gel provided the pure trans-
	(2S,13bS)-indolopiperazine 9 as pale yellow solid (28.4 mg, 0.064 mmol,
	32% yield, 85% ee).
	TLC (PE/EtOAc 4:1) Rf 0.53 (UV, vanillin).
	1 H NMR (400 MHz, CDCl3) δ (ppm) 7.34 -7.27 (m, 2H), 7.27 -7.17 (m,
	3H), 7.15 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.82 (dd, J = 8.8, 2.3
	Hz, 1H), 6.09 (s, 1H), 4.38 -4.23 (m, 2H), 4.21 -4.08 (m, 2H), 4.02 (td, J =
	11.3, 4.2 Hz, 1H), 3.83 (s, 3H), 3.41 (ddd, J = 13.9, 11.5, 3.7 Hz, 1H), 2.55 (s,
	3H), 2.40 (dt, J = 13.3, 3.3 Hz, 1H), 2.25 (ddd, J = 13.2, 11.3, 5.7 Hz, 1H),
	1.18 (s, 9H).
	13 C NMR (101 MHz, CDCl3) δ (ppm) 168.5 (C), 154.6 (C), 152.5 (C), 147.5
	(C), 137.9 (C), 131.3 (C), 128.7 (C), 128.3 (C), 128.3 (2 CH), 128.1 (2 CH),
	126.0 (CH), 111.2 (CH), 109.3 (CH), 102.5 (CH), 96.1 (CH), 78.8 (C), 56.1
	(CH3), 50.2 (CH), 44.3 (CH2), 42.6 (CH2), 38.9 (CH), 36.1 (CH2), 28.2 (3
	CH3), 17.5 (CH3).
	HRMS (ESI) calc´d for [C28H32N2O3+H] + : 445.2486, found: 445.2485.
	Template for SYNTHESIS © Thieme Stuttgart • New York	2016-05-24	page 16 of 23

HPLC Chiralpak AZ-H, Heptane/ethanol 90:10, 25°C, 1.0 mL/min, λ = 254 nm, τmajor = 11.47 min, τminor = 9.83 min.

Ethyl (6aS,7R,8S,8aR,14aS)-8-(methoxy(methyl)carbamoyl)-2,8a- dimethyl

	1 H NMR (400 MHz, CDCl3) δ (ppm) Most aromatic protons and NH could
	not be attributed unambiguously to one diastereomer or the other: major
	diastereomer 7.34 -7.27 (m, 2H), 7.23 -7.08 (m, 2 or 3H), 7.00 -6.85 (m,
	3 or 4H), 6.74 -6.66 (m, 2H), 6.65 -6.52 (m, 2H), 5.33 (d, J = 5.8 Hz, 1H),
	4.32 or 3.98 (s, 1H, NH), 4.29 -4.00 (m, 1H), 3.68 (s, 3H), 3.63 -3.50 (m,
	3H), 3.14 -3.04 (m, 1H), 2.99 (dd, J = 11.3, 5.7 Hz, 1H), 2.68 (s, 3H), 2.24
	(s, 3H), 1.46 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H); minor diastereomer 7.34 -7.27
	(m, 2H), 7.23 -7.08 (m, 2 or 3H), 7.00 -6.85 (m, 3 or 4H), 6.74 -6.66 (m,
	2H), 6.65 -6.52 (m, 2H), 5.06 (d, J = 5.7 Hz, 1H), 4.32 or 3.98 (s, 1H, NH),
	4.29 -4.00 (m, 3H), 3.66 (s, 3H), 3.44 (t, J = 11.9 Hz, 1H), 3.36 (d, J = 2.6 Hz,
	1H), 2.84 (ddd, J = 11.9, 5.9, 2.7 Hz, 1H), 2.76 (s, 3H), 2.22 (s, 3H), 1.54 (s,
	3H), 1.22 (t, J = 7.1 Hz, 3H).
	13 C NMR (101 MHz, CDCl3): The complexity of the structure, its existence
	as two diastereomers, which causes overlaps between some signals, and
	its moderate stability made it difficult to obtain a complete 13 C NMR
	description. For each diastereomer, 30 signals are expected: 2 carbonyls,
	6 aromatic C, 10 aromatic CH (including two accounting for two carbon
	atoms), 1 aliphatic C (aminal), 5 aliphatic CH, 1 aliphatic CH2 and 5
	aliphatic CH3. δ (ppm): 173.
	). A mixture of
	product 23 (64 mg, 0.182 mmol, 1 equiv), potassium
	phenylethynyltrifluoroborate (24) (99 mg, 0.436 mmol, 2.4 equiv) and
	scandium (III) triflate (17.9 mg, 0.036 mmol, 0.2 equiv) was dissolved in
	dry CH2Cl2 (2 mL) under argon atmosphere. The reaction mixture was
	stirred at room temperature during 40 h. After filtration on celite, the
	CH2Cl2 was removed under vacuum. Purification by flash column
	chromatography over silica gel (cyclohexane/EtOAc 75:25) yielded
	product 25 as a colorless oil (35 mg, 0.077 mmol, 42% yield, >20:1 dr).
	TLC (Cyclohexane/EtOAc 75:25) Rf 0.47 (UV, p-anisaldehyde).
	HRMS (ESI) calc´d for [C29H30N2O3+H] + : 455.2329, found: 455.2328.
	1 H NMR (400 MHz, CDCl3) δ (ppm) 9.00 (s, 1H), 7.62 -7.57 (m, 2H), 7.55
	(dd, J = 7.8, 1.4 Hz, 1H), 7.43 -7.37 (m, 3H), 7.35 -7.17 (m, 5H), 7.11 (td, J
	= 7.9, 1.4 Hz, 1H), 6.95 (dd, J = 8.1, 1.2 Hz, 1H), 6.79 (td, J = 7.6, 1.3 Hz, 1H),
	3.77 -3.62 (m, 2H), 3.56 (d, J = 4.4 Hz, 1H), 3.08 -2.95 (m, 2H), 3.01 (s, 3H),
	2.94 (s, 3H), 1.74 -1.64 (m, 1H), 1.22 (s, 3H).
	13 C NMR (101 MHz, CDCl3) δ (ppm) 172.9 (C), 155.8 (C), 143.3 (C), 135.5
	(C), 131.9 (2 CH), 128.6 (2 CH), 128.52 (CH), 128.50 (2 CH), 128.3 (2 CH),
	127.7 (CH), 127.1 (CH), 126.1 (CH), 123.2 (C), 119.2 (CH), 114.4 (CH), 90.7
	(C), 86.5 (C), 60.7 (CH3), 57.9 (C), 50.8 (CH), 50.5 (CH2), 43.4 (CH3), 31.9
	(CH), 27.5 (CH2), 24.8 (CH3).
	[α]D 20 = +162 (c 1.0, CHCl3).
	-7-phenyl-5,6a,7,8,8a,14a-hexahydro-6H-
	benzo[h]benzo[4,5]oxazolo[3,2-a][1,6]naphthyridine-6-carboxylate
	(28). 4Å molecular sieves (ca. 600mg) and Sc(OTf)3 (9.8 mg, 0.020 mmol,
	0.2 equiv) were added to a solution of ethyl glyoxalate (26) (50% in
	toluene, 13 µL, 0.100 mmol, 1 equiv) and p-toluidine (27) (10.7 mg, 0.100
	mmol, 1 equiv) in dry CH3CN (2 mL), and the mixture as stirred at room
	temperature. After 5 min, the three-component product 16a (35 mg,
	0.100 mmol, 1 equiv) was added, and the resulting suspension was stirred
	under argon atmosphere at the same temperature for 48 h. An aqueous
	saturated NaHCO3 solution (5 mL) was added, and the resulting mixture
	was extracted with CH2Cl2 (3 x 5 mL). The organic layer was dried over
	Na2SO4, filtered and the solvent was removed under vacuum. The residue
	was purified by flash chromatography on silica gel (PE/EtOAc 70:30) to
	afford the desired piperidine 28 as a colorless oil (41 mg, 0.076 mmol,
	76% yield, 1.6:1 dr).
	TLC (PE/EtOAc 70:30) Rf 0.47 (UV, p-anisaldehyde).
	HRMS (ESI) calc´d for [C32H35N3O5+H] + : 542.2649, found: 542.2650.

  ) calc´d for [C21H21FN2O3+H] + : 369.1609, found: 369.1606.

	1 H NMR (400 MHz, CDCl3) δ (ppm) 7.22 (dd, J = 8.3, 5.6 Hz, 2H), 6.93 (t, J
	= 8.7 Hz, 2H), 6.83 (td, J = 7.4, 1.6 Hz, 1H), 6.75 -6.57 (m, 4H), 4.89 (dd, J
	= 7.6, 1.7 Hz, 1H), 3.99 (d, J = 11.6 Hz, 1H), 3.60 (d, J = 11.6 Hz, 1H), 3.32
	(s, 3H), 3.01 (s, 3H), 1.74 (s, 3H).

13 C NMR (75 MHz, CDCl3): δ

	1 H NMR (300 MHz, CDCl3): δ (ppm) ketone tautomer: 9.88 (br s, 1H), 8.05
	-7.84 (m, 2H), 7.49 -7.22 (m, 5H), 7.17 (d, J = 7.2 Hz, 2H), 3.29 (app t, J =
	9.8 Hz, 1H), 2.99 (ddt, J = 17.6, 9.1, 2.7 Hz, 1H), 2.78 (ddd, J = 17.6, 8.6, 3.1
	Hz, 1H), 2.42 (s, 3H), 2.39-2.21 (m, 2H); enol tautomer: 10.92 (br s, 1H),
	8.05 -7.84 (m, 2H), 7.78 (br s, 1H), 7.49 -7.22 (m, 6H), 6.89 (s, 1H), 2.88
	(br s, 2H), 2.61 (br s, 2H), 2.46 (s, 3H).
	(ppm) ketone tautomer: 202.2 (C), 165.2 (C),
	145.2 (C), 138.0 (C), 137.7 (C), 135.4 (CH), 134.8 (C), 133.1 (C), 132.2 (2
	CH), 129.7 (2 CH), 129.4 (2 CH), 128.7 (2 CH), 53.9 (CH), 26.6 (CH2), 21.8
	(CH2), 21.6 (CH3); enol tautomer: 172.5 (C), 166.8 (C), 145.4 (C), 137.7 (C),
	135.8 (C), 134.8 (C), 133.9 (C), 130.6 (2 CH), 129.8 (2 CH), 129.0 (2 CH),
	125.4 (2 CH) 124.8 (CH), 105.1 (C), 29.8 (CH2), 26.2 (CH2), 21.9 (CH3).
	m.p. = 174-176 °C.

  Prepared according to the general procedure C using 3bromo-2-oxo-N-tosylcyclopentanecarboxamide (42) (72.0 mg, 0.200 mmol, 1 equiv), acrolein(32) (27 µL, 0.400 mmol, 2 equiv) and 2aminophenol (12a) (32.7 mg, 0.3 mmol, 1.5 equiv) with a reaction time of 72 h. Purification by flash chromatography over silica gel (pure CH2Cl2 then CH2Cl2/EtOAc 98:2) afforded product 45 as a yellowish solid (49.2 mg, 0.101 mmol, 50% yield, >20:1 dr, 39% ee). (ppm) 7.42 (dd, J = 7.2, 1.7 Hz, 1H), 7.17(d, J = 8.1 Hz, 2H), 7.15 -6.98 (m, 4H), 6.60 (dd, J = 7.4, 1.4 Hz, 1H), 6.01 (d, J = 1.6 Hz, 1H), 4.44 (dd, J = 8.6, 3.3 Hz, 1H), 2.88 (dt, J = 14.3, 9.3 Hz, 1H), 2.46 -2.28 (m, 3H), 2.34 (s, 3H), 2.24 -2.00 (m, 2H), 1.91 -1.77(m, 2H).

	1 H NMR (400 MHz, d 6 -DMSO): δ (ppm) 12.37 (br s, 1H, 1 diastereomer),
	10.76 (br s, 1 diastereomer), 7.86 (d, J = 8.4 Hz, 2H, 1 diastereomer), 7.47
	-7.39 (m, 2H, 2 diastereromers), 5.08 -5.02 (m, 1H, 1 diastereromer),
	4.75 -4.63 (m, 1H, 1 diastereromer), 3.45 (d, J = 8.5 Hz, 1H, 1
	diastereomer), 3.34 (d, J = 8.5 Hz, 1H, 1 diastereomer), 2.48 -1.94 (m, 4H,
	2 diastereromers), 2.39 (s, 3H, 2 diastereomers).
	Because of solubility and stability issues, conjugated with the presence of
	diastereomers and ketone-enol tautomerism, no clear 13 C NMR
	description could be obtained.
	m.p. = 143-145 °C.
	(1R,3aS,6S,12aS)-1-bromo-13-tosyl-1,2,3,4,5,6-hexahydro-6,3a-
	(epiminomethano)benzo[4,5]oxazolo[3,2-a]cyclopenta[b]pyridin-
	14-one (45).

TLC (CH2Cl2/EtOAc 95:5) Rf 0.93 (UV, p-anisaldehyde). HRMS (ESI) calc´d for [C22H21BrN2O4S+H] + : 489.0478, found: 489.0480. 1 H NMR (300 MHz, d 6 -DMSO): δ

  Rf 0.92 (UV, p-anisaldehyde).HRMS (ESI) calc´d for [C31H31N3O4S+H]+ : 542.2108, found: 542.2106. (ppm) 7.99(d, J = 8.4 Hz, 2H), 7.32(d, J = 8.2 Hz, 2H), 7.27 (dd, J = 8.2, 1.4 Hz, 1H), 7.10 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 7.04 (br d, J = 7.5 Hz, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.87 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H), 6.81 (dd, J = 8.2, 1.5 Hz, 1H), 6.17 (dd, J = 3.7, 1.8 Hz, 1H), 3.14 (ddd, J = 13.6, 9.9, 2.3 Hz, 1H), 2.55 -2.45 (m, 2H), 2.43 (s, 3H), 2.33 -1.76 (m, 12H), 1.04 -0.92 (m, 1H).

	TLC (CH2Cl2/EtOAc 98:2)

1 H NMR (400 MHz, CDCl3): δ

/EtOAc 70:30) Rf

0.43 (UV, p-anisaldehyde)

.

HRMS (ESI) calc´d for [C23H22N2O2+H]

+ : 359.1754, found: 359.1754.

1 H

NMR (400 MHz, CDCl3): δ

  (ppm) 7.61 (br s, 1H), 7.51 -7.43 (m, 2H), 7.38 -7.29 (m, 4H), 7.07 (td, J = 7.7, 1.5 Hz, 1H), 7.02 (s, 1H), 6.95 (dd, J = 8.1, 1.6 Hz, 1H), 6.72 (td, J = 7.7, 1.6 Hz, 1H), 4.61 (dd, J = 4.7, 3.3 Hz, 1H), 2.64 (ddd, J = 12.8, 9.1, 3.6 Hz, 1H), 2.58 -2.47 (m, 2H), 2.11 -2.01 (m, 1H), 1.95 -1.84 (m, 3H), 1.78 -1.70 (m, 2H), 1.68 -1.58(m, 1H).

TLC (PE/EtOAc 60:40)

  Rf 0.46 (UV, p-anisaldehyde).HRMS (ESI) calc´d for [C21H19N3O6S+H]+ : 442.1067, found: 442.1070. (ppm) 8.03 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.9 Hz, 2H), 7.18 -7.13 (m, 1H), 7.04 -6.94 (m, 2H), 6.39 -6.29(m, 1H), 5.81 (t, J = 2.6 Hz, 1H), 2.44 -2.31 (m, 2H), 2.26 -2.16 (m, 1H), 2.15 -2.06 (m, 1H), 2.03 -1.87 (m, 5H),1.74 -1.66 (m, 1H).

1 H NMR (400 MHz, CDCl3): δ

H NMR (400 MHz, CDCl3) δ (ppm) ketone form: 3.92 (s,

2H), 3.79 (t, J = 7.2 Hz, 2H), 2.51 (t, J = 8.1 Hz, 2H), 2.20 (s, 3H), 2.06 -1.95(m, 2H). NMR signals are in accordance with literature.44

Acknowledgment

We warmly thank Dr. Nicolas Vanthuyne and Marion Jean for HPLC analyses on chiral stationary phase, and the whole team of the Spectropole (www.spectropole.fr). Alban Falconnet is acknowledged for the preparation of starting materials and Didier Wilhelm (Clariant) for a gift of ethyl 4-oxobut-2-enoate. Financial support from Aix Marseille Université, Centrale Marseille, the CNRS, the Agence Nationale de la Recherche (ANR-07-CP2D-06, scholarship for M.M.S.D.; ANR-11-BS07-0014, scholarship for S. G.) and the China Scholarship Council is acknowledged (scholarship for H.Y.D.) is acknowledged.

Primary Data

NO (this text will be deleted prior to publication)

Supporting Information

YES (this text will be updated with links prior to publication)