Yannick Geiger

Thierry Achard

Aline Maisse-François

Stéphane Bellemin- Laponnaz

Observation of hyperpositive non

Keywords: asymmetric catalysis, non-linear effect, homogeneous catalysis, zinc chemistry

teaching and research institutions in France or abroad, or from public or private research centers.

Introduction

Non-linearity between the enantiomeric excess of a product and of a chiral auxiliary in asymmetric synthesis or catalysis is the result of interactions between the two enantiomers of the chiral auxiliary (i.e. diastereomeric perturbations). [START_REF] Guillaneux | Nonlinear effects in asymmetric catalysis[END_REF][START_REF] Girard | Nonlinear Effects in Asymmetric Synthesis and Stereoselective Reactions: Ten Years of Investigation[END_REF][START_REF] Satyanarayana | Nonlinear Effects in Asymmetric Catalysis[END_REF][START_REF] Kagan | Non-linear effects and autocatalysis[END_REF][START_REF] Girard | On diastereomeric perturbations[END_REF][START_REF] Kagan | Nonlinear Effects in Enantioselective Organometallic Catalysis[END_REF] A non-linear effect that gives an asymmetric amplification (positive non-linear effect, (+)-NLE) is believed to play a key role in the emergence of biological chirality. [START_REF] Blackmond | The origin of biological homochirality[END_REF] In addition, understanding these nonlinear effects is of great importance for asymmetric catalysis; it allows to clarify the mechanism and the nature of the species that are involved in the catalytic cycle.

Since the first comprehensive studies on asymmetric synthesis using scalemic chiral catalysts by Kagan and collaborators in 1986, several models have been proposed and verified by mathematical argumentation. [START_REF] Puchot | Nonlinear effects in asymmetric synthesis. Examples in asymmetric oxidations and aldolization reactions[END_REF] In particular, Kagan proposed a model where the formation of catalytic species involving the combination of several chiral ligands is inducing the non-linearity: the model is based on a metal M bearing n ligands and thus is called MLn model. [START_REF] Guillaneux | Nonlinear effects in asymmetric catalysis[END_REF] All these MLn complexes, which are homo-or hetero-chiral species -depending on the enantiomers that are present around the metal -will then react simultaneously to give the product. Interestingly, it has been proposed for the ML3 model that chiral catalysts, when not enantiopure, may be more enantioselective than their enantiopure counterparts, though such a case has never been observed experimentally until very recently. [START_REF] Geiger | Hyperpositive nonlinear effects in asymmetric catalysis[END_REF] We discuss here the first example of such hyperpositive nonlinear effect, which was observed while studying the addition of dialkylzinc reagents to aromatic aldehyde substrates with partially resolved chiral N-benzyl-ephedrine ligands. A rationalization of the effect was possible by studying the concentration, temperature and aggregation effect on the catalyst. The reaction scope was also studied using various para-substituted substrates with electron-donating and electronattracting groups. Overall, our results point toward a twocomponent catalysis, where a mononuclear catalyst is in equilibrium with a dinuclear catalyst, both systems being in competition to give the chiral product.

Materials and Methods

All reagents were purchased from commercial chemical suppliers and used without further purification, except for liquid benzaldehyde substrates that were distilled and stored under argon over 4 Å molecular sieves prior to use. (1R,2S)-Nbenzylephedrine was prepared according to a literature procedure. [START_REF] Coote | Enantiospecific Stereodivergent Synthesis of trans-and cis-N(2),3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolines[END_REF] The ligand ee was adjusted by preparing appropriate mixtures of the (1R,2S)-and (1S,2R)-enantiomers. Enantiomeric excesses were determined on a Varian 3900 gas chromatograph equipped with a CP-8400 autosampler and a Chiraldex G-TA capillary column (25 m long, 250 µm in diameter) with helium as carrier gas.

General procedure -N-benzylephedrine-catalysed addition of dialkylzinc to aromatic adehyde. The procedure is identical to what has been published previously. [START_REF] Geiger | Hyperpositive nonlinear effects in asymmetric catalysis[END_REF] In a N2-filled glovebox, (1R,2S)-N-benzylephedrine (23.7 mg, 20 mol%, 92.6 µmol) and a magnetic stirring bar were placed in an oven-dried vial, which was then closed with a septum-containing screwcap. The vial was put out of the glovebox and a 15% ZnEt2 solution in toluene (0.5 mL, 1.2 equiv., 560 µmol) was added via syringe; gas evolution occurred. After 10 min stirring, the mixture was cooled to 0 °C and benzaldehyde (47 µL, 1 equiv, 460 µmol) was added via syringe. The yellow solution was stirred overnight at 0 °C and turned colourless, then was quenched carefully with 3 M aqueous Abstract: Asymmetric amplification is a phenomenon that is believed to play a key role in the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been investigated to provide an understanding of how chiral amplification is possible, in particular based on non-linear effects. Interestingly, it has been proposed a quarter century ago that chiral catalysts, when not enantiopure might even be more enantioselective than their enantiopure counterparts.

We show here that such hyperpositive non-linear effect in asymmetric catalysis is indeed possible. An in-depth study into the underlying mechanism was carried out and the scheme we derive differs from the previous proposed models.

HCl in an ice-water bath under vigorous stirring. The organic phase was isolated, dried over Na2SO4 and analysed by chiral stationary phase GC. ZnMe2 was used as a 1.0 M solution in toluene (0.5 ml, 1.2 equiv., 500 µmol) with adapted ligand (21.3 mg, 20 mol%, 83.3 µmol) and benzaldehyde quantities (1 equiv., 420 µmol). Reaction media with ZnMe2 stayed colorless and were let to stir for 4 days. The procedures were identical for the use of para-substituted benzaldehydes, except for those which are solid (CN, I, Br, Cl). Those were weighed and added into the vial inside of the glovebox, together with the ligand.

Results and Discussion

Alkylation of benzaldehyde

Because of the weak knowledge of NLEs with ephedrine-based ligands, we investigated the behaviour of N-benzyl ephedrine derivatives (NBE) in the zinc-catalysed alkylation of benzaldehyde. The reaction conditions have been fixed as displayed in Scheme 1. A key point to be made is the catalyst loading which was deliberately fixed at 20 mol%, thus promoting potential catalyst aggregation. The reaction temperature was fixed at 0 °C to minimize the achiral background reaction [START_REF] Sung | Reactions of aldehydes with diethylzinc catalysed by polymer-supported ephedrine and camphor derivatives: comparisons of enantiomeric excesses achieved with various supports: optimisation of support parameters to enable high enantiomeric excesses to be obtained[END_REF] and the formation of benzyl alcohol as side-product. 12 SCHEME 1. Enantioselective addition of dimethyl-or diethyl-zinc to benzaldehyde, catalysed by chiral (-)-N-Benzylephedrine (NBE).

Figure 1 (a) displays the correlation between the enantiomeric excess of the product (eeP) and the enantiomeric excess of the ligand (eeL) with diethylzinc as reagent (red triangles). When the enantiopure ligand was used, the product was isolated in 76% ee. Interestingly, variation of eeL lead to a very strong (+)-NLE: eeP stays at high level down to an eeL of only 3%, which is an unprecedented strong amplification in a non-autocatalysed reaction. Even more interesting is the shape of the curve: starting at 76% eeP with the enantiopure ligand, the enantiomeric excess of the product eeP increased up to 81% in the presence of (-)-NBE ligand of only 10% ee. Thus, the scalemic, enantio-impure catalyst lead to a more stereoselective reaction than the enantiopure one: this is a case of hyperpositive non-linear effect.

An even more significant hyperpositive non-linear effect was observed with dimethylzinc as reagent. Figure 1 (b) displays the result of our investigations (red triangles). While the enantiopure NBE induced a very low enantioselectivity of only 16%, the progressive decrease of eeL lead to a seemingly exponential growth of the eeP, with a maximum of 53% in presence of only 5% ligand ee. [START_REF] Geiger | Hyperpositive nonlinear effects in asymmetric catalysis[END_REF] Green squares: superimposition of eeP as function of catalyst loading using either ZnEt2 (a) or ZnMe2 (b), which was previously converted to eeP vs. simulated ligand ee (from Figure 2). Each point is the mean of three different experiments; the vertical bars depict standard deviations. The 2 nd -order polynomial fits (dotted lines) serve as visual guidelines.

Mechanistic investigations

Given the importance of these experimental results, we decided to conduct in-depth investigations to determine the origin of such hyperpositive effect. The ML3 model proposed by Kagan implies that the NLE curve can be hyperpositive in the upper half of the ligand ee scale and obviously, such a case cannot be considered here. Therefore, the ML3 model is not applicable and we had to search for another model for this peculiar phenomenon.

A notable fact during our catalytic investigations is that upon addition of the dialkylzinc reagent, a precipitate was observed when the scalemic ligand was used, whereas the solution stayed clear with the enantiopure one. Further analyses of the hydrolysed precipitate obtained from 50% ee ligand samples gave the free ligand in its racemic form. This result suggests that the precipitate is most likely a meso aggregate of the zinc catalyst. Thus, the precipitation of an inactive heterochiral aggregate is in accordance with the emergence of a positive (+)-NLE, pushed by the presence of an active enantioenriched Zn complex in solution. We can reasonably apply here the "reservoir effect" model from Henri Kagan, which implies that part of the ligand is stored in a reservoir. [START_REF] Guillaneux | Nonlinear effects in asymmetric catalysis[END_REF] This implies also that decreasing the enantiomeric excess of the ligand would thus generate more heterochiral inactive aggregates and therefore less catalytically active species. Reducing the eeL thus induces a decrease of the active catalyst concentration. We assumed that the observed hyperpositive nonlinear effect could be linked to the effective catalyst concentration. Therefore, the enantioselective reaction was evaluated by varying The results revealed that a decrease of the catalyst loading led to an increase of the enantiomeric excess of the product (from 76% to 84% ee with ZnEt2, and from 16% to 49% ee with ZnMe2). Moreover, the shape of the two curves are identical with the one seen in our NLE investigations. Thus, it would seem possible to link the observed non-linear effects to the experiments from Figure 2. Indeed, if we assume that the heterochiral aggregate is fully precipitated, a catalytic system with e. g. 20 mol% catalyst loading of a ligand of 50% ee should be equivalent to a 10 mol% catalyst loading of enantiopure catalyst. Thus, we could correlate all data points from Figure 2 with a virtual enantiomeric excess if a scalemic ligand was used. The resulting graphs were superimposed with the hyperpositive NLE curves and are displayed in Figure 1 (green squares). In both cases, an excellent agreement was observed.

Based on these observations, it seems plausible that the catalytic system is composed of two independent catalysts that are in equilibrium and in competition: a monomeric species and a possible dimeric species that operate at a steady state. Alkylzinc aminoalkoxides are known to form dimers (and even higher aggregates) [START_REF] Coates | Reactions between some organozinc compounds and 2-dimethylaminoethanol, acetoxime, phenylisocyanate, and benzophenone. Some observations on the methylzinc methoxide tetramer[END_REF][START_REF] Boersma | Investigations on organozinc compounds X. Coordination chemistry of organozinc compounds RZnX: organozinc-oxygen derivatives of potentially bidentate ligands[END_REF][START_REF] Van Der Schaaf | Organozinc complexes with monoanionic chelating phenolates or 2-pyridylmethanolates. Molecular structure of [Zn(CH2SiMe3){OCH2(2-Py)}]4[END_REF][START_REF] Fitzpatrick | Thiol and disulfide derivatives of ephedra alkaloids 2: A mechanistic study of their effect on the addition of diethyl zinc to benzaldehyde[END_REF] which are at the origin of strong NLEs with the DAIB ligand in dialkylzinc additions. [START_REF] Kitamura | Enantioselective addition of dialkylzincs to aldehydes promoted by chiral amino alcohols. Mechanism and nonlinear effect[END_REF][START_REF] Kitamura | Quantitative Analysis of the Chiral Amplification in the Amino Alcohol-Promoted Asymmetric Alkylation of Aldehydes with Dialkylzincs[END_REF][START_REF] Noyori | Self and nonself recognition of chiral catalysts: The origin of nonlinear effects in the amino-alcohol catalyzed asymmetric addition of diorganozincs to aldehydes[END_REF] Assuming that the enantiomeric excess produced by the monomer catalyst (eem) is higher than with the dimer (eed), then decreasing the catalyst concentration leads to an increase of the overall eeP as the equilibrium is shifted to the more enantioselective catalyst (i.e. monomeric species). In the same way, decreasing eeL would have the same effect as it causes the lowering of the effective catalyst in solution and therefore gives rise to a hyperpositive non-linear effect.

Several additional experiments have been carried out to support this hypothesis. [START_REF] Geiger | Hyperpositive nonlinear effects in asymmetric catalysis[END_REF] These experiments include the investigation of the impact of the reaction temperature on the eeP, where an unusual inverse temperature dependence was observed. Indeed, the product eeP increases with the reaction temperature, consistent with a monomer/dimer-equilibrium shifted towards the monomer at higher temperature. Additionally, [START_REF] Guillaneux | Nonlinear effects in asymmetric catalysis[END_REF] H DOSY NMR experiments were conducted to evaluate the degree of aggregation of the catalysts as function of the temperature. Finally, Visual Time-Normalised Analyses (VTNA) of kinetic profiles resulted in an unusual U-shaped catalyst order vs. catalyst loading plot, which was found to be consistent with a model in which both monomer and homochiral dimer catalyse simultaneously.

Proposed model

A mechanism that is coherent with the experimental investigations is displayed in Figure 3. It describes a catalytic system that operates with both a monomeric catalyst and a dimeric catalyst that operate at a steady state. If we assume that the enantiomeric excess produced by the monomer catalyst is higher than with the dimer (eem > eed), then decreasing the ee of the ligand induces a lower effective concentration of catalyst and therefore the equilibrium between monomer and dimer is shifting toward the more enantioselective monomeric species, which induces an increase of the overall product ee. This mechanistic proposal stands in contrast to the Noyori model for DAIB-catalysed dialkylzinc additions, which excludes the participation of dimers in the catalytic step. [START_REF] Kitamura | Enantioselective addition of dialkylzincs to aldehydes promoted by chiral amino alcohols. Mechanism and nonlinear effect[END_REF]

Substrate screening

As for now, there is a lack of information about the structure of the dimeric catalyst and how it catalyses the reaction. One way to obtain such information is to study the catalytic reaction with substrates that differ in their electronic or steric properties. Upon a change in the substrate, the monomeric and dimeric catalytic cycles may react differently: the reaction rate, enantioselectivity and affinity of the catalyst for the substrate -or for the productmay vary to different extents for both catalysts. This has been exploited for example by Noyori and collaborators in the case of DAIB-catalysed ZnMe2 reactions, where they built Hammett plots using enantiopure and racemic (-)-DAIB. [START_REF] Kitamura | Asymmetric addition of dialkylzincs to benzaldehyde derivatives catalyzed by chiral βamino alcohols. Evidence for the monomeric alkylzinc aminoalkoxide as catalyst[END_REF] As the plots turned out to be linear and identical, the authors concluded that in both cases the reaction was catalysed by an identical species. Since catalysis by homochiral dimeric [DAIB-ZnMe]2 had been ruled out, they deduced that the catalytic species was a monomeric zinc complex. and catalysis by heterochiral dimers could also be excluded. This led us to investigate several para-substituted benzaldehydes and study the influence of the electronic effects on the substrate. Substitution in para position was chosen to avoid any steric influence of the substituent onto the reaction mechanism. We performed a series of catalytic runs using either enantiopure or 20% eeL-(-)-NBE. The results are shown in Figure 4 (a) for ZnMe2 and Figure 4 (b) for ZnEt2 as reagent (for conversions, see Figure S1 and Table S1; for the data from Figure 4 see Tables S2 andS3). With ZnMe2, all substrates showed a hyperpositive non-linear relationship (i. e. eeP from scalemic ligand is higher than from the enantiopure one), except those bearing an -OCF3 or -SF5 substituent. The eeP difference between scalemic and enantiopure ligand (ΔeeP) lies mostly between 18 and 25% (details can be found in the Supporting Information). With the scalemic ligand, eeP increases when going from electrondonating (σP < 0) to neutral substituents (σP ≈ 0), then reaches a plateau of ca. 40-45% eeP. The enantiopure ligand roughly follows the same trend. -OMe, -OCF3 and -SF5 stand out as exceptions: they show overall lower eeP than observed in the global trend; the eeP yielded from enantiopure para-OMe-benzaldehyde even broke down to almost 0%.

Using ZnEt2 as the dialkylzinc reagent leads to overall high eeP values of ca. 70-80%, with both scalemic and enantiopure (-)-NBE (Figure 4 b). This leads to small ΔeeP values of only few percent, and a hyperpositive NLE is clearly achieved only using substituents with σP ≈ 0 (H, F, 2-naphtaldehyde), except for electron-donating -OiPr which also gives a hyperpositive NLE. Otherwise, there are no general trends to read from these results.

-OMe again stands out as an exception, giving a much lower eeP of ca. 50% with both 100 and 20% eeL; -OCF3 too, but only when using scalemic ligand (29% eeP), same goes for -CN and -SF5 in a less pronounced way (ca. 60% eeP).

The fact that the reactions with ZnEt2 show only small differences in eeP between the different substrates, when compared their ZnMe2 counterparts, may indicate that the dimeric catalyst plays a minor role with ZnEt2 -either because of a low dimer/monomer ratio or because the monomer is significantly more active than the dimer. This is further supported by the overall high eeP values obtained with ZnEt2, which also suggest a stronger participation of the monomeric catalyst. Another possible factor might be the increase of the catalysts' enantioselectivities eem and/or eed when switching from ZnMe2 to ZnEt2. However in case of Noyori's system, the monomeric DAIB yields similar eeP values with both dialkylzinc reagents (ZnEt2: 98% at 0 °C; ZnMe2: 95% at 40 °C). [START_REF] Kitamura | Enantioselective addition of dialkylzincs to aldehydes promoted by chiral amino alcohols. Mechanism and nonlinear effect[END_REF][START_REF] Kitamura | Quantitative Analysis of the Chiral Amplification in the Amino Alcohol-Promoted Asymmetric Alkylation of Aldehydes with Dialkylzincs[END_REF] This indicates that the nature of the alkyl group has only minor influence on the enantioselectivity of the catalytic step. Therefore, with NBE a significant change in enantioselectivity seems unlikely when switching from ZnMe2 to ZnEt2, at least for the monomeric (-)-NBE-ZnMe complex. In turn, it seems that the ZnMe2-system is more adapted for this study as the overall lower eeP and higher ΔeeP values indicate that both monomer and dimer participate significantly in the reaction. Therefore, possible changes in the catalytic system upon substrate variation are more likely to be observed with ZnMe2, and the remarkably low eeP values yielded by electronrich substrates might be caused by such a change. A decrease of eem and/or eed or a faster achiral background reaction (which may be accelerated by the coordinating -OMe and -OiPr groups) are possible but not sufficient to explain this behaviour, as the DAIB ligand gives only slightly lower eeP with OMe-substituted benzaldehyde (88%) than with the unsubstituted one (95%). [START_REF] Kitamura | Asymmetric addition of dialkylzincs to benzaldehyde derivatives catalyzed by chiral βamino alcohols. Evidence for the monomeric alkylzinc aminoalkoxide as catalyst[END_REF] Therefore, an increased dimer/monomer ratio or dimer/monomer relative reaction rate in presence of electron-rich substrates seems to be more likely to lower eeP. It should be noted that the electron-rich substrates react only sluggishly and gave only low conversion values after 4 days (cf. Supporting Information for detailed conversion data). We have reported before that eeP increases over time, at least in the early stage of the NBEcatalysed reaction with ZnMe2. [START_REF] Geiger | Hyperpositive nonlinear effects in asymmetric catalysis[END_REF] However, the low conversion cannot account alone for the low eeP since certain electron-rich substrates do also reach only low conversions, although their eeP stays high.

Conclusion

The study of dialkylzinc addition to benzaldehyde, catalysed by chiral (-)-NBE, has allowed us to find the first example of a hyperpositive NLE. This fulfils Kagan's 25 years-old prediction of a scalemic catalyst being able to be more enantioselective than its enantiopure counterpart, even though the mechanism turned out to be different from what Kagan proposed at that time. Instead of the ML3 model, we have found (-)-NBE to follow a model in which both monomeric and homochiral dimeric (-)-NBE-ZnR (R = Me, Et) catalyse, the aggregate being less enantioselective than the discrete complex. Precipitation of an insoluble mesoaggregate allows to trap the minor enantiomer catalyst and to generate an enantioenriched monomer/dimer equilibrium that induces a hyperpositive NLE. Evidence for this model has been found by varying the catalyst loading, the reaction temperature, by DOSY NMR investigations and by kinetic analyses (catalyst order vs. catalyst loading and eeP vs. time). Furthermore, we have started to study the influence of para-substituents on the benzaldehyde substrate on the overall catalytic outcome. Preliminary results suggest that electronic effects from the substituents may induce changes in the relative reaction parameters (dimer/monomer concentration ratio, dimer/monomer reaction rate ratio) and thus give information about the distinct monomeric and dimeric catalytic cycles. A more advanced study including the analysis of Hammett plots is underway.

FIGURE 1 .

 1 FIGURE 1. Red triangles: optical purity of the product as a function of the ligand ee in the (-)-NBE-catalysed addition of ZnEt2 (a) or ZnMe2 (b) to benzaldehyde.[START_REF] Geiger | Hyperpositive nonlinear effects in asymmetric catalysis[END_REF] Green squares: superimposition of eeP as function of catalyst loading using either ZnEt2 (a) or ZnMe2 (b), which was previously converted to eeP vs. simulated ligand ee (from Figure2). Each point is the mean of three different experiments; the vertical bars depict standard deviations. The 2 nd -order polynomial fits (dotted lines) serve as visual guidelines.

  the catalyst loading of the enantiopure NBE ligand with diethylzinc (Figure 2 a) or dimethylzinc (Figure 2 b) as reagent.

FIGURE 2 .

 2 FIGURE 2. Optical purity of the product ee as a function of the catalyst loading in the addition of ZnEt2 (a) or ZnMe2 (b) to benzaldehyde, catalysed by enantiopure (-)-NBE. 9 Each point is the mean of three different experiments; the vertical bars depict standard deviations. The 2 nd -order polynomial fits (dotted lines) serve as visual guidelines.

- 19 FIGURE 3 .

 193 FIGURE 3. Proposed enantiodivergent model for the NBE-catalyzed addition of dialkylzinc to benzaldehyde which explains the hyperpositive non-linear effect.

FIGURE 4 .

 4 FIGURE 4. Product ee of NBE-catalysed additions of a) ZnMe2 and b) ZnEt2 to para-substituted benzaldehydes using (-)-NBE with 100% (blue dots) or 20% eeL (orange triangles). The results are sorted according to the substituent's σP values. Outliers (OMe, OCF3, SF5) are depicted by hollow dots and triangles. Each point is the mean of three different experiments; the vertical bars depict standard deviations.

Acknowledgements

This work was funded by the French National Research Agency (ANR) through the Programme d'Investissement d'Avenir under contract ANR-11-LABX-0058_NIE within the Investissement d'Avenir program ANR-10-IDEX-0002-02.


Ewan Goligher

Annemijn Jonkman

Jose Dianti

Katerina Vaporidi

Jeremy Beitler

Bhakti Patel

Takeshi Yoshida

Samir Jaber

Martin Dres

Tommaso Mauri

Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.


Basi V Subba Reddy
email: basireddy@iict.res.in

] Preethi

Narayanan Nair

Aneesh Antony

Claudia Lalli
email: claudia.lalli@univ-rennes1.fr

René Grée
email: rene.gree@univ-rennes1.fr

P N Nair

MICROREVIEW Aza-Prins Reaction in the Synthesis of Natural Products and Analogues

Keywords: aza-Prins cyclization, natural products, piperidine, iminium ion, acyliminium ion

Classical Prins cyclization reaction is one of the most studied reactions during the last two decades and it has found many applications in the key steps of natural product syntheses, especially for those having pyrans and related structures in their core skeleton. Nitrogen-based version of the Prins reaction, aza-Prins cyclization, found its own relevance in organic synthesis owing to the fact that it gives direct access to piperidines which are even more widespread in natural products and in drugs. Even though the potential scope of the reaction is very vast and despite it afforded significant progress in the synthesis of various aza heterocycles, its applications in the field of natural product synthesis is by far under developed compared to the classical Prins reaction. A compilation of the applications of aza-Prins reaction in the preparation of natural products and selected analogues, especially the molecules of potential biological interest, is presented by giving emphasis on the key role of this reaction during the total synthesis of these products.

Introduction

The Prins cyclization reaction (Scheme 1) is one of the most powerful methods for generating oxygen-containing heterocycles through concomitant carbon-heteroatom and carbon-carbon bond formation, showing great potential in the synthesis of natural and/or bioactive compounds. [START_REF] Arundale | For reviews on the Prins cyclization reaction see: a)[END_REF] The aza-Prins cyclization is the nitrogen version of the reaction, which permits a rapid access to aza heterocycles. 2 This reaction is mediated by a variety of Brønsted and Lewis acids and further, a large number of nucleophiles, compatible with the acid reaction conditions, have also been used. Various types of solvents have been employed as well, including more recently ionic liquids. The mechanism of this reaction has been also well investigated, including by high level computational studies. The classical aza-Prins, as well as three more recent variants of this reaction considered in this review, are indicated in Figure 1. Scheme 1. Prins cyclization (X=O) and related reactions aza-Prins (X=N-PG) and thia Prins (X=S).

The aza-Prins gives a direct access, often with a good stereocontrol, to the piperidine skeleton with introduction of the nucleophile in position 4 (Figure 1,a). On the other hand, the alkyne aza-Prins provides similar molecules but with a double bond in position 3-4 (Figure 1,b), while in the case of aza-silyl-Prins, the reaction occurs with loss of the silicon group and 3,4dehydropiperidines are obtained directly (Figure 1,c). Finally, the aza-acyliminium-Prins affords piperidines, equivalent to the first series, but in an N-protected format (Figure 1,d). It is possible to combine this acyliminium version with the previous ones, as demonstrated in this review. Since the piperidine core is abundant in natural products, as well as in various types of bioactive non-natural molecules, the aza-Prins reaction has been already often used for the preparation of this type of products. To date and to the best of our knowledge, there is no review in the literature devoted specifically to the aza-Prins cyclization. 1d Therefore, this publication is focused on the comprehensive compilation of the recent applications of the aza-Prins cyclization as key step in the synthesis of natural products and/or biologically relevant compounds. We will consider first the simplest derivatives with a piperidine core and then more complex molecules with bicyclic structures and finally polyheterocycles. In each case, we will highlight the impact of the aza-Prins cyclization on the total synthesis of corresponding molecules.

Synthesis of natural products and bioactive molecules

Piperidine derivatives

We will start by describing the synthesis of the natural products showing the simplest architecture, ie the piperidine or tetrahydropyridine cores. In that case, the preparation of natural products or biologically active compounds comes as a direct application of the synthetic methodology. In this context Dobbs and co-workers reported a novel aza-silyl-Prins cyclization between an aldehyde and a silylated homoallylic amine in the presence of InCl3 as mild Lewis acid. 3 This methodology exhibited a perfect diastereocontrol since when a substituent was introduced at the α-carbon atom to the nitrogen atom, only the 2,6-trans-substituted product was obtained. To illustrate the ((Author Portrait)) synthetic utility of this reaction, expedient syntheses of (-)-Solenopsin A 6 and (+)-epi-Dihydropinidine 7, drugs candidates for the treatment of Alzheimer's disease, were successfully carried out. The key step in both cases was a one-pot multicomponent aza-silyl-Prins condensation involving the N-benzyl silylated secondary amine 1. In a first attempt the syntheses were performed with racemic 1 and aldehydes 2 and 3 which gave the trans-substituted tetrahydropyridines 4, in 72% yield, and 5, in 58% yield respectively. Deprotection of the benzyl group together with the concomitant reduction of the double bond proceeded quantitatively and completed the synthesis of the target molecules Solenopsin A and epi-Dihydropinidine (Scheme 2). The enantiopure version of the syntheses was then achieved by using each enantiomer of amine 1. Latter intermediates were obtained through a short sequence starting by the ring opening of (R)-(+) or (S)-(-)propylene oxide with trimethylsilylacetylene and BF3·Et2O.

Scheme 2. Solenopsin A and epi-Dihydropinidine synthesis via aza-silyl-Prins cyclization.

As an extension of this work the same group reported a rapid access to trifluoromethylated piperidines, with a large variety of substituents, molecules which are of great interest in the synthetic and medicinal chemistry field. 4 Therefore the authors prepared the vinylsilane 8 with a CF3 group on the carbon-α to the nitrogen, as a E:Z=1:1 mixture. This homoallylic amine undergoes aza-silyl-Prins cyclization with aliphatic aldehydes to afford tetrahydropyridines 9 in modest yields and as trans major or unique diastereomers (Scheme 3, a). Moreover they observed that the Z-alkene was always consumed during the reaction while the E-alkene was recovered from the reaction mixture. Further manipulations on the compound 10 obtained from ethyl glyoxylate consisted in the bishydroxylation in the presence of NMO and catalytic amounts of osmium tetroxide, followed by acetylation to complete the synthesis of CF3containing pipecolate derivatives such as 11 (Scheme 3, b). Scheme 3. Synthesis of CF3-containing pipecolate derivatives via aza-silyl-Prins cyclization.

In an attempt to solve the problem of the deprotection of the tosyl group, very often present on the final piperidine products, the group of Martín and Padrón studied the reactivity of N-nosyl and N-mesyl homoallyl and homopropargyl amines in the presence of Fe(III) salts. 5 In this context they developed a short synthesis, in racemic form, of the alkaloid Coniine, used in ancient Greece as poison. They designed two different three steps routes (Scheme 4). For the first approach an alkyne aza-Prins cyclization of homopropargyl(mesyl)amine 12 with butanal 3 was evoked. Stoichiometric amount of FeCl3 were required to promote the reaction and recover the tetrahydropyridine 14 in 85% yield. Hydrogenation by treatment with Pd(OH)2/C and ammonium formate as H2 source delivered the piperidine 16 in 90% yield. The second approach reposed on a classical aza-Prins with homoallyl(mesyl)amine 13 with butanal 3, in the presence of FeCl3/TMSCl as catalytic system. The 4-Clpiperidine 15 was recovered in 72% yield and the chlorine atom removed in the presence of Bu3SnH and AIBN, to get the same intermediate 16 in 90% yield. The desired Coniine 17 was obtained in 85% yield after deprotection of the mesyl group with Red-Al in toluene. Thomassigny and co-workers reported a very short synthesis of the tobacco alkaloid Anabasine 21, as an extension of the method they developed for the aza-Prins cyclization of pyridine carbaldehydes. 6 The two step sequence involved an In(OTf)3promoted aza-Prins reaction between the homoallylic amine 19 and the pyridine-3-carbaldehyde 18, affording a mixture of the two regioisomers of the pyridyl-dehydropiperidine 20 in 44% yield. A final selective hydrogenation with PtO2 and H2 ended up with the racemic target molecule in 93% yield (Scheme 5). Scheme 5. Aza-Prins cyclization of pyridine carbaldehydes: synthesis of rac-Anabasine.

Subba Reddy and co-workers reported an efficient synthesis of several piperidine and indolizidine natural products such as (±)-Coniine 17, (±)-Pipecolic acid 26, (±)-Hydroxypipecolic acid 30, (±)-4-Hydroxy-2-hydroxymethylpiperidine 31 and (±)-Coniceine 27. The common strategy involved a highly diastereoselective aza-Prins cyclization to construct the key 4-iodo 25 (Scheme 6) and 4-hydroxy piperidine 29 cores (Scheme 7) of these alkaloids. 7 The iodo piperidines 25 were obtained by using GaI3 and I2 as promoters of the aza-Prins process between homoallylamine 22 and aldehydes 23, 24 and 3 in 85%-92% yields. Further manipulations of the ring substituents (2-3 steps) completed the route to targets molecules (Scheme 6). An indolizidine core was also obtained by intramolecular cyclization of the N atom onto the leaving group in terminal position of the side chain to give (±)-Coniceine 27. This molecule is known as a blocker for nicotinic receptor. Scheme 6. Synthesis of (±)-Coniine, (±)-Pipecolic acid and (±)-Coniceine via a GaI3/I2 mediated aza-Prins cyclization.

On the other hand, the hydroxy piperidines 29 were synthesized by a phosphomolybdic acid (PMA)-catalyzed aza-Prins cyclization between homoallylamine 22 and aldehydes 23 and 28 in 85% and 65% yield respectively. Starting with 29a, oxidative cleavage of the olefin to give the corresponding carboxylic acid and deprotection of the tosyl group delivered racemic Hydroxypipecolic acid 30 in 54% yield over 2 steps, while racemic 4-Hydroxy-2-hydroxymethyl-piperidine 31 was obtained from 29b by a simple deprotection of the Ts group in 70% yield (Scheme 7). With the aim of synthesizing new antibiotics against drug resistant bacteria, Ichikawa's group designed simplified analogues of a nucleoside antibiotic, caprazamycin A 32 (Scheme 8). 8 The N atom in the C-6' position is critical for the activity of the natural product, thus the authors thought to replace the central diazepanone core with a piperidine ring. A three component aza-Prins-Ritter sequence seemed to be the most step economic way to have access to piperidinylaminoribosyluridines. The aldehydes 33 and 34, diastereomers at the 5' stereocenter, were synthesized and reacted with N-Cbz homoallylic amine 35 in the presence of TfOH in acetonitrile at 0 °C to give the desired uridine derivatives containing the piperidine core. Aldehyde 33 furnished three diastereomers in 53% overall yield and in a ratio 7:2:1 but only 36 and 37 were characterized and used for the next steps. On the other hand, from aldehyde 34 only compounds 38 and 39 were obtained in 22% and 19% yield respectively (Scheme 8). Scheme 8. Aza-Prins-Ritter sequence for the direct synthesis of piperidinylaminoribosyluridines.

Simple manipulations, including deprotection of the acetyl and Cbz groups and reduction of the azide to amine, delivered compound 40, the other analogues were obtained after grafting the different lipophilic side chains (Scheme 9). Biological tests on phosphor-MurNAc-pentapeptide translocase (MraY) indicated the importance of the stereochemistry at 5'-and 6'-position and the need of a lipophilic side chain. Compounds 43-44-45 and 46 were found to be more potent inhibitors than 40-41-42 and 47 while the best analogues were identified to be 43 and 46. Scheme 9. Simplified analogues of the nucleoside antibiotic caprazamycin A.

Aza bicycles

The synthesis of azabicyclic core in concise routes attracts great attention since this motif is found in several biologically active natural products. In particular various alkaloid families with a wide range of activities possess an aza-bicyclic skeleton, for example indolizidine alkaloids such as Castanospermine and Swainsonine that are glycosidase inhibitors and Martinelline which is a bradykinin receptor antagonist, among others. In this section we will describe the methodological efforts made by the community to reach azabicyclic skeletons in one operation step, and then the application to the natural products synthesis. To achieve the indolizidine core two approaches have been developed, the aza-Prins cyclization from allylpyrrolidines and the intramolecular aza-silyl-Prins cascade that can eventually afford even the quinolizidine skeleton. Waters's group described the synthesis of functionalized indolizidines from 2allylpyrrolidines 48. 9 The reaction of the endocyclic amine with formaldehyde or highly activated aldehydes such as glyoxylate derivatives led to the formation of an iminium ion 49 that undergoes nucleophilic attack from the embedded allyl substituent (Scheme 10). Thus the fused bicycle was formed together with two, or eventually three, new stereogenic centers. The reaction proceeded in a complete diastereoselective way, dictated by the equatorial position occupied by the pyrrolidine ring and the axial attack on the resulting carbocation in the transition state. When formaldehyde 50 was employed, the reaction was conducted in aqueous media thus the nucleophile was water and products 51 were formed. When glyoxylic acid 52 was used, the carbocation was trapped by the carboxylic acid and therefore an extra lactone ring 53 was formed and the substituents were in the 1,3-diaxial position of the piperidine ring. In a recent report Dobbs and co-workers presented their studies toward the azabicyclic cores of the indolizidines and quinolizidines. This time both rings were formed in a single intramolecular one-pot cascade initiated by the formation of an acyliminium ion and terminated by an aza-silyl-Prins cyclization. 10 The amide precursors 57 and 58 were synthesized to this end, with the aldehyde function masked as acetal. Treatment with the appropriate Lewis acid, Sc(OTf)3 and FeCl3 respectively, delivered the desired indolizidines 59 and quinolizidines 60 in good yields showing that both the aza-silyl-Prins and the aza-acyliminium-Prins reactions may be combined for the preparation of such azabicycles. (Scheme 11). Scheme 11. Intramolecular aza-silyl-and aza-acyliminium-Prins cyclizations for indolizidines and quinolizidines synthesis.

The synthesis of the octahydro pyrrolo- [3,2-c]pyridine skeleton of Martinelline and Martinellinic acid, molecules that show activities as inhibitor for bradykinin, histaminergic and muscarinic receptors, among others, has been studied by Yadav and Subba Reddy. 11 The authors proposed an intramolecular aza-Prins cyclization between styrene epoxides 62, as phenyl acetaldehyde equivalents, and homoallylic amines containing a tethered amine nucleophile 61, catalyzed by p-TSA at 10 mol% (Scheme 12). The reaction proceeded smoothly with the Ealkene to give the trans-fused azabicycles 63 while cis selectivity was observed with the Z olefin, thus the origin of the selectivity comes from the double bond geometry in bistosylamides 61.

Scheme 12. Synthesis of the octahydro pyrrolo- [3,2-c]-pyridine skeleton of Martinelline and Martinellinic acid via aza-Prins cyclization with epoxides. The Krasavin's group reported a concise route to aza-biandtricycles, found in the skeleton of various natural products including Lycopodium alkaloids, by condensation of amine 64 with aromatic aldehydes or ethyl glyoxylate, in the presence of BF3.Et2O and under MW irradiations. 12 Playing on the amount of aldehyde employed, namely 1 or 2 equivalents, the aza-Prins cyclization led to the formation of 3-azabicyclo[3.3.1]non-6-enes 65 or 1-azatricyclo [3.3.1.1]decanes 66 via a second aza-Prins. Compound 65 was obtained as single endo-diastereomer and as single double bond regioisomer. This regioselectivity was explained by the nitrogen assisted intramolecular deprotonation (Scheme 13). Unsymmetrical substituted 1-azaadamantanes could also be obtained by this methodology through a sequential double aza-Prins cyclization with two different aldehydes. Very recently Reisman and co-workers succeeded in the enantioselective synthesis of complex functionalized indolines in a one operational step starting from indoles, through a conjugate addition/asymmetric protonation/aza-Prins cascade. 13 Indoles with an embedded homoallyl on the 1 or 3 positions, compounds 67 and 68 respectively, undergo smoothly conjugate addition to amidoacrylate, followed by an enantioselective protonation catalyzed by a chiral ZrCl4-BINOL complex and in the presence of 2,6-dibromophenol and TMSCl as HCl source (Scheme 14). The chloride anion played the role of nucleophile source, thus it trapped the carbocation formed after the aza-Prins cyclization and allowed the catalyst turnover. The indolines products were obtained in high yields, high enantioselectivity thanks to the chiral Lewis acid-assisted Brønsted acid, and good diastereoselectivity during the aza-Prins cyclization dictated by the nucleophilic attack of the chloride. Indeed this occurred on the equatorial position for products 69 and on the axial for compounds 70. Armstrong's group detailed a concise synthesis of the bicyclic alkaloid (±)-Epibatidine 76 and its analogue (±)-Epiboxidine 74 (Scheme 16), poisons extracted from the skin of frogs, and using 7-azabicyclo[2.2.1]heptane 72 as a key intermediate. 14 This latter was obtained from substituted pyrrolidine 71 in the presence of equimolar amount of SnCl4. 15 The authors observed the formation of only the exo 72 product with respect to the aldehyde function, and this diastereoselectivity could be explained by an unusual aza-Prins-pinacol sequence (Scheme 15). She and co-workers reported the asymmetric syntheses of two alkaloids clinically used in the place of morphine, as narcotic analgesics with reduced effects of addiction, namely (-)-Pentazocine 91 and (-)-Eptazocine 96 (Scheme 19 and 20), via a common strategy involving an aza-Prins cyclization/intramolecular Friedel-Crafts domino reaction as the key step. 17 This cascade was first validated on a racemic model substrate 82 with formaldehyde (Scheme 18). In the presence of camphorsulfonic acid (CSA) as promoter the desired piperidine 83 was obtained in 95% yield as a mixture of regioisomers, while with other Lewis or Brønsted acids complex mixtures of products were obtained. The Friedel-Crafts reaction proceeded well in the presence of AlCl3 or CF3SO3H to give the bicycle 84. The formal total synthesis of (-)-Pentazocine started with the preparation of intermediate 87, obtained in 28% yield over 9 steps from aldehyde 85 and the chiral auxiliary 86, as shown in Scheme 19. By applying the best reaction conditions for the aza-Prins/Friedel-Crafts reaction, compound 87 delivered the desired piperidine 88 and then the benzobicyclo [3.3.1] 89 in good yields and as a mixture of diastereomers at the C-9 position in a ratio α:β=3:1. After deprotection and prenylation of the N atom, the two diastereomers were separated at this stage to keep only the β-Me 90. The synthesis of (-)-Pentazocine 91 could be completed, after a final demethylation step, as described by Trost 18 (Scheme 19).

Scheme 19. She's formal total synthesis of (-)-Pentazocine.

Towards Eptazocine, the enantiopure intermediate 94 was synthesized from 92 and 93 in 5 steps and 60% overall yield, again using a thiazolidinethione as chiral auxiliary. The key intermediate 94 was submitted to the tandem aza-Prins/Friedel-Crafts this time by treatment with CF3SO3H and then AlCl3 to give bicycle 95 in 80% yield on the overall domino reaction. A final protection/deprotection sequence furnished (-)-Eptazocine 96 in 3 steps and 57% yield from 95 (Scheme 20). Scheme 20. Total synthesis of (-)-Eptazocine.

Very recently Maison's group has reported a domino aza-Prins/Friedel-Crafts reaction for the synthesis of a library of benzomorphanes, including the skeleton of (-)-Pentazocine 91. ref This represent actually the shortest formal synthesis of this opioid analgesic, obtained in only 6 steps starting from the commercially available 3-buten-2-one 97, while the previous described synthesis by She was accomplished in 13 steps. The author's prepared the homoallylic amine 98 in 2 steps and 58% yield, including the formation of the α-aminoketone and a Wittig olefination (Scheme 21). The aza-Prins/Friedel-Crafts domino reaction was performed in the presence of aldehyde 85 and in a one-pot fashion, by treatment with 10 mol% of TMSOTf, followed by addition of 1.2 eq. of CF3SO3H. The desired adduct 99 was obtained in 49% yield in a ratio α:β=4.3:1, and it can be converted according to reported procedures, 17,18 into the desired (-)-Pentazocine. Scheme 21. Maison's formal total synthesis of (-)-Pentazocine.

Hanessian's group has developed an intramolecular Nacyliminium carbocyclization with different embedded carbon nucleophiles, such as alkene, alkynes and even allenes in order to get aza bi-and tricyclic scaffolds. 19 This methodology has been applied as key step in the first total synthesis and structural confirmation of the antithrombotic marine natural product Oscillarin 102, also called D-Pla-D-Phe-L-Choi-Adc. 20 The synthesis started from N-Boc-L-glutamate 97 which has been transformed into the hemiaminal 98 in five steps and 64% overall yield. Treatment of 98 with SnBr4 afforded the desired octahydroindole 101 in 78% yield through the formation of the Nacyliminium ion 99 and intramolecular trapping by the tethered alkene (Scheme 21). The stereochemical control can be explained by a chair like transition state 99 in which the ω-olefinic nucleophilic carbon and the iminium ion are antiperiplanar, in order to minimize the allylic strain, and the bromide attacks the incipient carbocation 100 from the equatorial position. To complete the synthesis, the Dphenyllactyl-D-phenylalanine and the pyrrolino-guanidine chains needed to be installed on the L-Choi unit. Thus oscillarin 102 was obtained in 8 steps from the key 1-aza[4. Saikia and co-workers established a very efficient protocol for the synthesis of azabicyclic hexahydroindolizinones and hexahydroquinolizinones via a tandem aza-Prins/Friedel-Crafts or aza-Prins/Ritter sequences of cyclic N-acyliminium ions mediated by BF3.Et2O. 21 The extension of this methodology to the use of p-toluenesulphonic acid as promoter led to the synthesis of O-tosyl hexahydroquinolizinones were p-TSA acts as Brønsted acid and nucleophile. This method was successfully applied to the total synthesis of (±)-epi-Indolizidine 167B and 209D, member of a class of alkyl indolizidine alkaloids, known to be blockers of neuromuscular transmission. 22 The authors synthesized in two steps starting from succinimide 103, the carbinols 104 and 105 in 63% and 65% yield respectively. Those later underwent aza-Prins cyclization and trapping with tosylate to deliver the tosylated azabicyclic products 108 and 109 in 79% and 84% respectively, as single isomers (Scheme 22). The stereocontrol was due to the more favored transition state 106 in which the alkyl R chain was axial in order to minimize the angular strain with the C=O group of the lactam ring, followed by equatorial attack of the tosylate nucleophile on the carbocation 107. The target alkaloids (±)-epi-Indolizidine 167B 110 and 209D 111 were finally obtained after removal of the OTs group in the presence of NaBH4 and reduction of the lactam with LiAlH4, in 56% and 62% yield respectively over 2 steps. Scheme 22. Synthesis of alkaloids (±)-epi-Indolizidine 167B and 209D via aza-Prins cyclization and trapping with tosylate anion.

Complex polycyclic heterocycles

This section is devoted to the synthesis of complex skeletons of natural products, in particular Lycopodium alkaloids which possess a tetracyclic core and have been used for long time in traditional Chinese medicine and homeopathic therapies. In this part we will discuss the synthesis of Huperzine A, Nankakurines, Lycopodines, Lycospidine A and Lyconadines, belonging to this alkaloid family; then the synthesis of Cilindricines, Crepidines analogues and Cortistatin A will be detailed. White's group reported the formal total synthesis of the alkaloid (-)-Huperzine A 119, an acetylcholinesterase inhibitor, exploiting as key step a tandem sequence including an intramolecular aza-Prins cyclization followed by a cyclobutane fragmentation for the construction of the bicyclo [3.3.1]nonene core of the natural product. 23 Overman and co-workers attempted the total synthesis of Nanakakurine A. Kobayashi's group proposed, in 2004 123 for the structure and relative stereochemistry of the spiranic stereocenter of the isolated molecule, 25 but two years later they revised the original structure into compound 124 (Scheme 24). 26 In order to elucidate the structure and absolute configuration of Nanakakurine and because of the scarce availability of this alkaloid and its congeners potentially useful in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease, the authors have undertaken the synthesis of these alkaloids. The proposed synthetic plan was based on an unprecedented amino-terminated aza-Prins cyclization to construct the tetracyclic core of the natural product. 27 For this goal, the authors synthesized the cis-fused decalin amine 120 that was readily converted into the corresponding carbamate 121 in 80% yield. Reaction of this carbamate with one equivalent of paraformaldehyde in the presence of TFA furnished a tetracyclic product intermediate 122 through a sulfonamideterminated aza-Prins cyclization, albeit in low yield (10-20%), together with a complex mixture of other cyclic products. At this stage all efforts to increase the yield of the aza-Prins cyclization failed, thus the author terminated the synthesis after removal of the tosyl group with Na/NH3 (98% yield) and reduction of the carbamate by treatment with LiAlH4 (65% yield). They obtained a product 123 corresponding to the first proposed structure, namely (±)-5-epi-Nankakurine A (Scheme 24). Therefore this synthetic work allowed to unambiguously establishing the structure of the natural product. Finally, Nankakurine A 124 was synthesized via another route, involving an intramolecular [3+2] cycloaddition.

Scheme 24. Sulfonamide-terminated aza-Prins cyclization towards the synthesis of (±)-5-epi-Nankakurine A.

The N-benzyl cis-fused decalin amine 125 was the key intermediate also in the Fukuyama's syntheses of the tetracyclic skeleton of Lyconadins A-C 130-132. 28 These molecules exhibit various activities including, among others, cytotoxicity against carcinoma cells in rats and enhanced mRNA expression for nerve growth factor. In this case, treatment of 125 with formaldehyde in acetic acid and in the presence of SiO2 gave the desired aza-Prins tricycle 126 in 81% yield (Scheme 25). After a deprotection/protection sequence, the dibromocyclopropanation gave, in 61% overall yield, the compound 127 which is the common intermediate for the synthesis of the three congeners of lyconadins. Indeed electrocyclic ring opening upon cleavage of the dibromocyclopropane and deprotection of the Boc group, afforded 128 that was further manipulated to complete the synthesis Lyconadin C 130. When the expansion was accompanied by the of C-N bond, then the tetracyclic compound 129 was obtained and this could be finally transformed into the desired Lyconadin A 131 and B 132. Very recently She's group succeeded in the asymmetric total synthesis of two Lycopodium alkaloids, having a tetracyclic core, (-)-Lycopodine 140 and (-)-Lycospidine 141, which have been used in Chinese folk medicine as analgesic for example. 29 The main difference between the core structure of the two natural products resides in the A ring, where for (-)-Lycopodine it is a 6 membered-, while for (-)-Lycospidine it is a 5 membered-ring (Scheme 26). The authors designed a synthesis for both alkaloids starting from the commercially available (R)-pulegone as chiral source, and as D ring. They easily obtained the intermediate 133 that was transformed into the bicyclic alkyneamide 134, through amidation reaction followed by cyclization. In this way the C ring was formed. The intramolecular alkyne aza-Prins cyclization proceeded in the presence of formic acid and 85% phosphoric acid via the formation of the N-acyliminium ion 135 that undergoes cyclization to give 136 and then tautomerization of the enol to give the BCD tricyclic skeleton 137 in 99% yield. The same intermediate can be obtained in a onepot procedure starting from 133 and allylamine, in the presence of acetic acid and 85% phosphoric acid in 90% yield. Thus in a single operation consisting in the amidation/cyclization/alkyne aza-Prins, three bonds and the C and B rings were formed, together with two contiguous stereogenic centers, including a quaternary one (Scheme 26). This key intermediate 137 was the starting point for the last cyclization, achieved by aldol condensations, leading on one hand to the tetracyclic 138, containing a newly formed piperidine ring, and on the other hand to the unique five membered A ring of 139. To complete the synthesis of (-)-Lycopodine 140, reduction of both the lactam to amine and the ketone to alcohol, followed by re-oxidation of the alcohol were necessary. (-)-Lycospidine 141 was obtained after a late stage oxidation on the B ring, followed by a reduction/reoxidation sequence.

Scheme 26. Acyliminium alkyne aza Prins for the enantioselective synthesis of (-)-Lycopodine and (-)-Lycospidine.

The synthesis of other natural products, beyond that of the Lycopodium alkaloids, has also been attempted via the aza-Prins cyclization as key step. Hsung and co-workers successfully carried out the total syntheses of (-)-Lepadiformine 149 and (+)-Cylindricines C-E 150-152 (Scheme 27), 30 which show moderate cytotoxicity against tumor cell lines in vitro. These were performed a common intermediate, the aza tricyclic compond 147, derived from an aza-Prins cyclization and Wharton's rearrangement (Scheme 28). This intermediate was synthesized through a multistep sequence starting from butyrolactam 142 which, on addition of the appropriate lithium derivative, led to the amino ketone 143. This latter was submitted to a formic acid-promoted aza-acyliminium-Prins cyclization to give the aza spirocyclic skeleton 144 as formyl protected allylic alcohol. After in situ deprotection by K2CO3 in MeOH, the bicyclic derivative 145 was obtained in 64% yield over 2 steps. Further transformations on this intermediate, including a Warthon's rearrangement to transpose the allylic alcohol, led to the compound 146. Finally treatment with TFA to cleave the Boc group allowed the cyclization to deliver the key tricycle 147 in 72% yield. The synthesis of (-)-Lepadiformine 149 was completed after deoxygenation of the C-4 carbonyl. This could be achieved after the selective reduction with NaBH4, leading exclusively to the β hydroxyl group, then transformation into xanthate 148 (Scheme 28). Deoxygenation and desilylation furnished the desired target molecule 149. To achieve the synthesis of (+)-Cylindricines the epimerization at the C-5 level was necessary (Scheme 28). Fortunately, the authors observed spontaneous epimerization of intermediate 147 already on silica gel, thus they optimized this process and by using TBAF they obtained concomitant desilylation, affording (+)-Cylindricine C 150 in 91% yield. Further manipulations delivered also (+)-Cylindricines D 151 and E 152.

Scheme 28. Synthesis of (-)-Lepadiformine and (+)-Cylindricines C-D-E starting from the common aza-tricyclic intermediate.

Another approach to those natural products involved a tandem Mannich strategy. Kibayashi was the first to succeed in the synthesis of (-)-Lepadiformine 149 thanks to an N-acyliminium intramolecular spirocyclization of compound 154 directly synthesized from (S)-153 with the appropriate Grignard reagent. 31 Treatment of 154 with formic acid gave in 88% yield the spiranic bicyclic intermediate 156 with a good regiocontrol, dictated by the stability of the chairlike transition state 155 (Scheme 29). Further transformations including the hydrolysis of the formate, the oxidation and diastereoselective reduction, and finally the cyclization to give the tricyclic amine, were necessary to obtain the target natural product.

Scheme 29. Mannich strategy for the synthesis of (-)-Lepadiformine Nacyliminium intramolecular spirocyclization.

Shair's group reported an enantioselective synthesis of (+)-Cortistatin A 164, a potent and selective inhibitor of endothelial cell proliferation, through an aza-Prins/transannular cyclization as the key sequence to construct the A ring of the natural product (Scheme 30). 32 The synthesis started from optically pure Hajos-Parrish ketone 157 that was transformed into tricyclic β,γ-unsaturated enone 158 in 8 steps. Further manipulations included a ring expansion to afford compound 159. This latter was the precursor of the aldehyde 160 that was obtained after removal of the TES group and oxidation with Dess-Martin periodinane. This key intermediate was readily engaged in the aza-Prins cyclization with 3 equivalents dimethylamine in the presence of ZnBr2. The following cascade reactions started with the construction of the A ring via diastereoselective aza-Prins cyclization (Scheme 30). The formation of the C-3 stereocenter was controlled by the boat conformation of the iminium ion 161, the H and the iminium were coplanar to avoid 1,3 allylic strain, while the OAc group blocked the Re face allowing the addition on the Si face. Simultaneously the transannular cyclization initiated by the ether in C-8 position occured to afford the oxabicylo [3.2.1]octane 162. The sequence was terminated by the deprotection of MEM protecting group, thus the oxonium ion release delivered directly compound 163. The synthesis was completed in further five steps including the installation of the isoquinoline group.

Scheme 30. Synthesis of (+)-Cortistatin A through an aza-Prins/transannular cyclization.

In their efforts towards the synthesis of Alkaloid (-)-205B 165, extracted as traces from the frog skin, Delair and co-workers reported a new stereoselective approach to the 8bazaacenaphthylene core via a domino partial reduction/aza-Prins cyclization. 33 The authors prepared lactam 166 that was subjected to vinylogous Mannich to lead to the pyrrolidine 167 (Scheme 31). This latter delivered the indolizinone 168 through lactamization. The strategy aimed to reduce the lactam in order to form an iminium ion that undergoes attack from the double bond. Unfortunately attempts to cleanly get the tricyclic skeleton of Alkaloid (-)-205B failed. Indeed the reduction of 168 with LiAlH4 followed by addition of formic acid and saponification of the formate intermediate, afforded a mixture of diastereomers at the C-4 center together with a product of over reduction, in 62% yield. The diastereomers were separated and disappointingly the analysis of major product 169 revealed an epimerization at the C-6 stereocenter. Scheme 31. Domino partial reduction/aza-Prins cyclization approach to the azaacenaphthylene core of Alkaloid (-)-205B.

New aza-Prins-type cyclizations

In recent years, chemists have developed new strategies, inspired from aza-Prins reaction, in which iminium intermediates are generated by completely different routes. This includes acidmediated cleavage of heterocycles such as aminals, or protonation of various aza-heterocycles, to give iminiums different from those obtained in previous sections. These aza-Prins-derived approaches allowed the synthesis of natural products with complex skeletons, as described in the following examples. This section is devoted to, via strategies that rely on inspired aza-Prins cyclization as key step. Li's group reported the total synthesis of the drimentine alkaloids A, F and G xx-xx, which show anticancer, antibacterial as well as antifungal activities. Moreover they reported the bioinspired synthesis of Indotertine A xx, simply by treatment of Drimentine F xx with Bi(OTf)3 and in presence of KPF6, in 78% yield (Scheme xx). 34 The pathway should go through the formation of the iminium specie xx, followed by iminium-olefin cyclization to give the cationic intermediate xx, which undergoes proton elimination to yield the desired Indotertine A.

Scheme xx. Bioinspired synthesis of Indotertine A.

The same group reported bioinspired total synthesis of Sespenine xx, an indolosesquiterpenoid showing a spirotetrahydroquinoline moiety exhibiting antimicrobial activities against several bacteria. The key step of this synthesis includes an aza-Prins/Friedel-Crafts/retro Friedel-Crafts cascade. 35 The authors synthesized the indosespene-type intermediate xx with a methoxycarbonyl substituent in the C-2 position and they optimized the reaction conditions for the oxidation on the position C-3. Treatment of xx with oxone/acetone gave an inseparable mixture of two hydroxyindolenine gg and yy, epimers on the C-3 (Scheme xx). These latter were treated with AcOH to yield in only 1h the desired spirocycle zz in 58% yield over 2 steps. The overall sequence includes the activation of the imine by the acid, followed by aza-Prins cyclization to deliver the cationic specie ww, this undergoes Friedel-Crafts reaction to afford the spirocyclic intermediate vv, which re-aromatizes through a retro Friedel-Crafts fragmentation to give compound xx. Three more steps, including demethoxycarbonylation, hydrolysis and deacetylation yielded Sespenine in 78% overall yield.

Scheme xx. Bioinspired total synthesis of Sespenine via an aza-Prins/Friedel-Crafts/ retro Friedel-Crafts cascade.

Li, Sun and co-workers reported the total synthesis of Notoamides F, I and R aa-cc, members of the prenylated indole alkaloids family, as well as Sclerotiamide, biosynthetically related to Notoamide R dd. 36 Their strategy rests on an oxidative aza-Prins cyclization to construct the bicyclo[2.2.2]diazaoctane ring, starting from the dipeptide xx. Optimization of reaction conditions for the oxidation-cyclization step was necessary and finally treatment with FeCl3 in CH3CN/CH2Cl2 afforded the desired bicycle yy in 67% yield, via the imine ww (Scheme xx). With this compound in hands the authors successfully achieved the total synthesis of (+)-Notoamide I bb in 22% yield over five steps including a Grignard reaction followed by a Co catalyzed cycloisomerization to form the central 6 membered ring, and a Cu catalyzed propargylation followed by an allenyl Claisen rearrangement for the formation of the est oxygenated 6 membered ring. Reduction of Notoamide I in the presence of DIBAL-H furnished (+)-Notoamide R cc in 85% yield, treatment of this latter with AcOH/MeOH delivered (+)-Notoamide F aa in 95% yield. The rearrangement of (+)-Notoamide R in the presence of an oxaziridine as oxidant afforded (-)-Sclerotiamide dd in 55% yield.

Conclusion

Aza-Prins and related cyclization reactions are now well established methods in organic synthesis. They can easily be used, directly, for the synthesis of simple piperidines as well as for bicyclic alkaloids for instance. This has been already demonstrated by excellent examples in this review article. For the natural products, as well as for the molecules designed as drugs or pharmacological tools, their preparation of optically pure form is required. The possible use of asymmetric synthetic methodologies, by using chiral pool approaches for instance, has been also clearly established in aza-Prins cyclization reactions. However, the asymmetric catalysis route remains to be developed, although the first successful entries in the catalytic asymmetric Prins reactions have appeared recently. [37][38] The other fascinating aspect of the most recent research is this area is the evolution towards more and more complex molecules. This was made possible by the combination of aza-Prins cyclization with other reactions. Such tandem/ cascade/domino Prins-based reactions allowed the efficient preparation, in very few steps, of polycyclic very complex structures. It can be anticipated that this type of combination will be develop also in the future since it offers extremely powerful possibilities towards the synthesis of very challenging and important molecules. Therefore, we expect this review would trigger more developments in the utilization of these reactions in the total synthesis of natural, as well as non natural, bioactive molecules.

MICROREVIEW Text for Table of Contents

Aza-Prins Reaction in the Synthesis of Natural Products and Analogues

Aza-Prins, and related reactions, have demonstrated high efficiencies in the direct synthesis of piperidine-, indolizidine-and quinolizidine-type alkaloids. More recently, new strategies combining aza-Prins in sequence with other reactions have proved to be very powerful in the preparation of complex polyheterocyclic natural products and bioactive molecules.

Figure 1 .

 1 Figure 1. Aza-Prins and related reactions.

Scheme 4 .

 4 Scheme 4. Alkyne aza-Prins and classical aza-Prins cyclizations for the synthesis of rac-Coniine.

  Scheme7.(±)-Hydroxypipecolic acid and (±)-4-Hydroxy-2hydroxymethylpiperidine synthesis via a PMA promoted aza-Prins cyclization.

FinallyScheme 10 .

 10 Scheme 10. Indolizidine synthesis from allylpyrrolidines.

Scheme 13 .

 13 Scheme 13. Synthesis of azabicyclononene and azaadamantane skeletons of biological interest.

Scheme 14 .

 14 Scheme 14. Enantioselective Lewis acid-assisted Brønsted acid synthesis of functionalized indolines.

Scheme 15 .

 15 Scheme 15. Aza-Prins-pinacol sequence for the synthesis of the key intermediate towards (±)-Epibatidine and (±)-Epiboxidine.

  Scheme 17. Intramolecular aza-Prins-type cyclization/oxidative C-H activation for the synthesis of Tetrabenazine and its metabolite.

Scheme 18 .

 18 Scheme 18. Aza-Prins cyclization/intramolecular Friedel-Crafts domino reaction en route to (-)-Pentazocine and (-)-Eptazocine skeleton.

Scheme 21 .

 21 Scheme 21. Synthesis of Oscillarin via N-acyliminium carbocyclization.

24 Scheme 23 .

 2423 Scheme 23. Intramolecular aza-Prins cyclization/cyclobutane fragmentation for the synthesis of (-)-Huperzine A.

Scheme 25 .

 25 Scheme 25. Synthesis of the tricyclic skeleton of Lyconadins A-B-C via an aza-Prins cyclization.

Scheme 27 .

 27 Scheme 27. Synthesis of the common aza-tricyclic intermediate towards (-)-Lepadiformine and (+)-Cylindricines C-D-E, via aza-Prins cyclization and Wharton's rearrangement.

  Scheme xx.Oxidative aza-Prins cyclization strategy for the synthesis of Notoamides F, I and R and Sclerotiamide.

Scheme 16. Synthesis of (±)-Epibatidine and (±)-Epiboxidine from the common intermediate 72.

Acknowledgements

This research has been performed as part of the Indo-French "Joint Laboratory for Natural Products and Synthesis toward Affordable Health". We thank CNRS, CSIR and University of Rennes 1 for support of this research.


Julien Braire

Vincent Dorcet

Joëlle Vidal
email: joelle.vidal@univ-rennes1.fr

Claudia Lalli
email: claudia.lalli@univ-rennes1.fr

François Carreaux
email: francois.carreaux@univ-rennes1.fr

BINOL derivatives-catalysed enantioselective allylboration of isatins: application to the synthesis of (R)-chimonamidine

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The catalytic formation of carbon quaternary stereogenic centers from privileged structure such as isatins 1 continues to be a very challenging task for the organic chemistry community since the 3-substituted-3-hydroxyoxindole scaffold is widely found in natural products 2 and pharmacologically active molecules. 3 More specifically, 3-allyl-3-hydroxyoxindole structures can be versatile intermediates to access various alkaloids such as convolutamydine derivatives (1), 4 donaxaridine (2), [4][5] CPC-1 (3), 6 leucolusine (4) 7 and (R)chimonamidine (5) 8 resulting from an oxindole rearrangement 9 (Fig. 1). Moreover, due to the presence of the double bond which can be engaged in several intramolecular cyclization reactions, this class of compounds can serve as a platform for the synthesis of fused spirooxindole scaffolds of great interest in the medicinal chemistry area 10 such as spiroether 6. 11 In addition to the asymmetric hydroxylation of 3-allyl-2-oxindoles 12 or allylation of 3-hydroxy-2-oxindoles, 13 efficient enantioselective preparations of 3-allyl-3-hydroxyoxindoles have been mainly realized by allylation of isatins with allylstannanes, catalysed by chiral metal complexes (Sc, 14 In [14][15] and Pd 16 ) or organocatalysts. 6a, 17 The reactivity of the less toxic allylsilanes with isatins in the presence of Hg, 18 Sc 19 or Ag 20 chiral complexes was also explored with success. Other allyl donors such as allylic alcohols in the presence of chiral phosphoramidite-palladium complexes as catalyst led to moderate enantioselectivities, 21 while better results were obtained from allyl acetates and chiral iridium catalysts. 22 As 3allyl-3-hydroxyoxindoles have a great potential for the synthesis of bioactive compounds, there is a need to avoid metals in their preparation. 23 Allylboron derivatives are key reagents in the development of metal-free procedures for the catalytic enantioselective allylation of carbonyl compounds. 24 While numerous organocatalysts have been reported for the efficient enantioselective allylboration of aldehydes, 24a-e very few are valuable for non-activated ketones 25 or activated ketones. 26 In the case of N-substituted isatins, to the best of our knowledge, only one report describes the use of catalysts derived from aminophenol coupled to valine, to produce the expected 3-allyl-3-hydroxyoxindoles in good yields and with excellent enantiomeric excess (ee). 27 In view of our research programs targeted to the development of organoboron methodology leading to biologically active molecules, 28 and in line with our efforts directed towards the development of enantioselective transformations catalysed by BINOL-derived organocatalysts, 29 we speculated that chiral biphenols, prepared from commercially available BINOL enantiomers in both enantiomeric forms, 30 could efficiently catalyse an asymmetric allylation of isatins. In this paper, we describe our experimental findings related to this reaction. A convenient and efficient method was implemented with a wide range of isatin derivatives, including N-unprotected substrates. As this catalytic process can be performed on a gram-scale, a synthesis of (R)-chimonamidine is also depicted. As a starting point to find optimized reaction conditions, several allyl boronic esters 7 were screened for the allylation of N-benzylindoline-2,3-dione 9a in toluene at room temperature and in the presence of (R)-3,3'-Br2-BINOL 8a as chiral catalyst because of its known efficiency when reacted with ketones (Table 1). 25a, 25b The use of allylpinacol boronate 7a under these conditions led to the product 10a in good yield (75%) after 48 h. However, no enantioselectivity was detected (entry 1). The reaction with allyldiisopropoxyborane 7b, a more reactive boronate, allowed to obtain a greater yield after only 16 h but with a low enantiomeric excess (entry 2). The S absolute configuration at the C3-position has been assigned by comparing the specific rotation and HPLC chromatographic analysis of 10a described in the literature. 22 Based on Schaus's work concerning the enantioselective allylboration of ketones using 7b, 25b, 25c we added isopropyl alcohol in the catalytic process in order to improve the enantioselectivity. A better enantiomeric excess (77%) was obtained using 5 equivalents of i-PrOH (entry 3). Nevertheless, result was disappointing when compared with those obtained with ketones. 25b, 25c Moreover, the replacement of i-PrOH by t-BuOH caused a significant drop of the enantioselectivity justifying the development of a new catalytic system for this kind of substrates (entry 4). In the light of this facts, other cyclic boronates 7c-e having an intermediary reactivity with carbonyl compounds have been attempted. 31 Reactions were completed after 16 h except for 7d-e (entries 8 and 9). In terms of enantioselectivity, satisfactory results were obtained with 7c and 7e using an alcohol additive such as t-BuOH. Taking the reactivity difference into account, the fivemembered allylboronate 7c was selected for the further studies in which different chiral BINOL-derived catalysts 8a-f were evaluated as well as other parameters such as temperature and solvents (Table 2). The replacement of 3,3'-Br2-BINOL 8a by other organocatalysts was briefly screened.

The importance of a halogen substituent at the 3,3'-positions of BINOL for the enantioselectivity was clearly demonstrated by the evaluation of parent BINOL 8c and the phenyl-BINOL derivative 8d for which a drop in the enantioselectivity was observed (entries 3-4). The result with iodo-BINOL 8b was almost similar to the one obtained with the bromo analogue 8a (entries 1-2). The use of H8-BINOL catalysts 8e-f led to a strong drop of selectivity (entries 5-6). The enantiomeric excess using 3,3'-Br2-BINOL 8a can be slightly increased by adding molecular sieves in the catalytic procedure (91% ee instead of 88% ee, entry 7). Using this catalyst, we focused on improving enantioselectivity by modifying solvent and temperature. Lower ee was obtained using CH2Cl2 and cyclohexane (entries 8-9). In the latter case, the allylboration reaction was slower (24h) due to the weak solubility of 9a in cyclohexane. Higher ee was reached when decreasing the temperature up to -10° C (entries 10-11). 32 Under these conditions, the complete consumption of starting material 9a required a longer reaction time (24 h instead of 16 h). At this stage, it is interesting to note that the catalyst loading is not an issue for this reaction since 8a can easily be recovered during the chromatographic purification of homoallylic alcohol 10a. d) In the presence of molecular sieves (5Å). e) Cyclohexane.

Despite this, we showed that the yield and enantioselectivity were maintained using only 5 mol% of 3,3'-Br2 BINOL (R)-8a (98%, 94% ee, entry 12).

Please do not adjust margins

Please do not adjust margins These latter conditions were selected to explore the synthetic scope of this enantioselective allylboration process using an assortment of diversely substituted isatins (Table 3). The protecting group on the nitrogen did not show a crucial influence on the reactivity of isatins 9a-f except with the Nacetyl derivative 9f. In this case, the slower reaction rate as well as the dramatic drop of enantioselectivity could be mainly explained by two factors: the weaker solubility of 9f under the reaction conditions and the presence of an additional carbonyl group in the molecule which could any way affect the mechanism of the reaction. As expected the use of the (S)-8a catalyst delivered the (R)-hydroxyoxindoles 10g-h in the same range of yield and enantiomeric excess. More interestingly, we also showed that the asymmetric allylboration process is effective with N-unprotected isatin 9i. In spite of a longer reaction time for an almost complete conversion (6 days instead of 24 h), the excellent enantiomeric excess (94%) was preserved. The single crystal X-Ray analysis of 10i and 10h confirmed the absolute configuration above-mentioned. 33 Whatever the electronic nature of substituents (e.g 10j-n and 10p-s) as well as their positions in the aromatic ring (10j-k compared with 10p-r), high yields and no significant erosion of enantiopurity were obtained demonstrating the good level of reliability of this catalytic process. At this stage of our study, the mechanism of the reaction with this type of substrates does not seem to be conventional, 34 in light of the result obtained with a non-activated ketone such as indan-1-one (Scheme 1). Indeed, under similar conditions with the chiral catalyst (R)-8a, the allylboronate 7c adds to the face of the carbonyl group opposite to the one attacked with isatins. This experimental observation suggests a different mechanistic pathway for the formation of 3-allyl-3hydroxyindoles 10 which will be the subject of a further work.

In order to highlight the synthetic interest of our methodology, we planned the gram-scale synthesis of the key intermediate 10h for the preparation of (R)-chimonamidine 5 since the catalytic asymmetric allylboration approach was never employed to access this natural product. 35 We were pleased to observe that starting from 6.5 mmol of N-methyl isatin 9b and using (S)-8a as catalyst, the homoallyl alcohol 10h was obtained in 98% yield and with an excellent enantiomeric excess (94%) (Scheme 2). The oxidative cleavage of the double bond by OsO4-NaIO4 followed by NaBH4 reduction gave the alcohol 12 in 40% yield. After treatment of 12 with tosyl chloride, tosylate 13 underwent a nucleophilic substitution reaction by methylamine followed by a spontaneous transamidation reaction that afforded the expected natural product 5. (R)-Chimonamidine 5 was obtained with an enantiomeric excess of 94% in 19% overall yield from 10h.

After several hours in CDCl3 we observed the apparition of a new compound coming from the transformation of 5, whose structure was firstly attributed to 14. As the acidic salts of 3-(aminoethyl)oxindoles are stable, 3c, 9 lactam 5 was reacted with TFA to generate the oxindole isomer 14 after extraction from a basic water phase. The two isomers 5 and 14 slowly equilibrated at room temperature in CDCl3 solution (c = 45 mM), to reach a 5/14 ratio of 78:22 determined by 1 H NMR. In summary, we reported a new catalytic procedure for the enantioselective allylboration of isatins employing the easy-tohandle cyclic allyl boronate reagent 7c. In addition, the enantiopure catalyst, 3,3'-Br2 BINOL 8a can be easily prepared and is also commercially available.

Scheme1 Face differentiation by the catalytic system in the case of indan-1-one Scheme 2 Application to the synthesis of (R)-chimonamidine 5 and its isomer 14.

The reaction is suitable for a large range of isatins including Nunprotected compounds which means a significant This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins improvement compared with the only method using a boronbased reagent described to date for these substrates. 27 In order to demonstrate the synthetic utility of this asymmetric allylboration, a synthesis of (R)-chimonamidine and its isomer 14 was carried out. Further investigations concerning the application of this catalytic process to other cyclic activated ketones as well as mechanistic studies are ongoing and will be report in due course.

Fig. 1

 1 Fig. 1 Synthetic utility of 3-allyl-3-hydroxyoxindoles.

  a) Unless otherwise stated, all reactions were performed with 9 (0.2 mmol), boronate 7c (0.3 mmol), catalyst (R)-8a (5 mol%) in toluene (1 mL) under Ar. Isolated yields are shown. Enantiomeric excess was determined by chiral HPLC.b) Catalyst (S)-8a was used.c) The reaction was run starting from 6.5 mmol of 9h. d) 6 days instead of24 h.

Table 1

 1 Asymmetric allylboration of isatin 9a

	entry a)	boronate	additive	time	yield	ee c)
			(5 equiv)	(h)	(%) b)
	1	7a	-	48	75	0
	2	7b	-	16	98	32
	3	7b	i-PrOH	16	98	77
	4	7b	t-BuOH	16	97	18
	5	7c	-	16	98	53
	6	7c	i-PrOH	16	97	2
	7	7c	t-BuOH	16	98	88
	8	7d	t-BuOH	22	98	74
	9	7e	t-BuOH	22	98	84
	a) All reactions were performed with isatin 9a (0.2 mmol), boronate 7 (0.3 mmol)
	and 3,3'-Br2-BINOL (R)-8a (0.1 equiv) under Ar at room temperature.

b)

Isolated yield after chromatography purification on silica. c) Determined by chiral HPLC.

Table 2

 2 Optimization of the reaction conditions

	entry a)	Cat.	Solv.	T (°C)	time	yield	ee c)
		(mol%)			(h)	(%) b)
	1	8a (10)	toluene	r.t.	16	98	88
	2	8b (10)	toluene	r.t.	16	98	84
	3	8c (10)	toluene	r.t.	24	97	46
	4	8d (10)	toluene	r.t.	24	95	30
	5	8e (10)	toluene	r.t.	24	98	10
	6	8f (10)	toluene	r.t.	24	98	40
	7 d	8a (10)	toluene	r.t.	16	98	90
	8 d	8a (10)	CH2Cl2	r.t.	16	98	78
	9 d	8a (10)	C6H12 e	r.t.	24	97	86
	10 d	8a (10)	toluene	0	24	98	92
	11 d	8a (10)	toluene	-10	24	98	94
	12 d	8a (5)	toluene	-10	24	98	94
	a) All reactions were performed with isatin 9a (0.2 mmol), boronate 7c (0.3 mmol)
	under Ar at the temperature indicated. b) Isolated yield after chromatography
	purification on silica.

c)

Determined by chiral HPLC.

Table 3

 3 Asymmetric allylboration of various isatins and ORTEP diagram of compound 10h and 10i a)

Acknowledgements

This work was supported by the University of Rennes 1 and the "Centre National de la Recherche Scientifique" (CNRS). J. B thanks "Ecole doctorale 3M" and University of Rennes 1 for a research fellowship.

Conflicts of interest

There are no conflicts to declare.