Hélène Pellissier is a Researcher at the Centre National de la Recherche Scientifique (CNRS), where she focuses in organic synthesis.

Recent Developments in Asymmetric Organocatalysis

By Hélène Pellissier

The Royal Society of Chemistry

Copyright © 2010 Hélène Pellissier
All rights reserved.
ISBN: 978-1-84973-054-9

Contents

Chapter 1 Nucleophilic Additions to Electron-deficient C=C Double Bonds, 1,
Chapter 2 Nucleophilic Additions to C=O Double Bonds, 77,
Chapter 3 Nucleophilic Additions to C=N Double Bonds, 123,
Chapter 4 Nucleophilic Additions to Unsaturated Nitrogen, 150,
Chapter 5 Nucleophilic Substitutions at Aliphatic Carbon, 158,
Chapter 6 Cycloaddition Reactions, 172,
Chapter 7 Oxidations, 192,
Chapter 8 Reductions, 202,
Chapter 9 Kinetic Resolutions and Desymmetrisations, 213,
Chapter 10 Miscellaneous Reactions, 220,
General Conclusion, 232,
Subject Index, 234,

CHAPTER 1

Nucleophilic Additions to Electron-deficient C=C Double Bonds

The conjugate addition of nucleophiles to electron-poor alkenes is one of the most frequently used C–C and C–heteroatom bond-forming reactions in organic synthesis. The catalytic asymmetric version of this reaction employing chiral catalysts has been widely developed over the last few years. In particular, the use of chiral organocatalysts has been subjected to a spectacular development in recent years. In the Michael addition, a nucleophile Nu- is added to the β-position of an α,β-unsaturated acceptor. The active nucleophile Nu- is usually generated by deprotonation of the precursor NuH. The mechanistic scheme implies that enantioface differentiation in the addition to the β-carbon atom of the acceptor can be achieved in two ways, either deprotonation of NuH with a chiral base, resulting in a chiral ion pair, which can be expected to add to the acceptor asymmetrically, or phase-transfer catalysis, in which deprotonation of NuH is achieved in one phase with an achiral base and the anion Nu- is transported into the organic phase by a chiral phase-transfer catalyst, also resulting in a chiral ion pair from which asymmetric β-addition may proceed. These methods of providing a chiral environment for the attacking nucleophile can be regarded as the classical ways of approaching asymmetric organocatalysis of Michael additions (Scheme 1.1).

Two highly efficient and very practical alternatives have emerged in recent years (Scheme 1.2). One of these approaches consists of activating the acceptors by reversible conversion into a chiral iminium ion. Thus, the reversible condensation of an α,β-unsaturated carbonyl compound with a chiral secondary amine provides a chiral α,β-unsaturated iminium ion. A face-selective reaction with the nucleophile provides an enamine, which can be either reacted with an electrophile and then hydrolysed, or just hydrolysed to a β-chiral carbonyl compound. The second approach is the enamine pathway. If the nucleophile is an enolate anion, it can be replaced by a chiral enamine, formed reversibly from the original carbonyl compound and a chiral secondary amine. It is apparent that enamine and iminium catalysis are based on the same origin. Enamine catalysis proceeds via iminium ion formation and almost always results in iminium ion formation. In an opposing but complementary fashion, iminium catalysis typically results in the formation of an enamine intermediate. The two catalytic intermediates are opposite, yet interdependent, and they consume and support each other.

1.1 Intermolecular Michael Additions of C-Nucleophiles

1.1.1 Intermolecular Michael Additions of C-Nucleophiles Catalysed by Proline Derivatives

The first part of this chapter deals with Michael additions of C-nucleophiles evolving via enamine or iminium ion intermediates. The most successful catalyst for enamine-type reactions is the cheap, natural, simple and readily available amino acid, L-proline, which has been defined in the recent past as a “universal catalyst”. Proline can react as a nucleophile with carbonyl groups or Michael acceptors to form iminium ions or enamines. The high enantioselectivities generally observed in proline-mediated reactions can be rationalised by the capacity of this molecule to promote the formation of highly organised transition states with extensive hydrogen-bonding networks. There are several reasons why proline has become an important molecule in asymmetric catalysis, e.g. it is an abundant chiral molecule which is inexpensive and available in both enantiomeric forms. A wide series of modifications of the structure of proline have been accomplished with the aim of improving the solubility and/or enhancing the acidity of the directing acid proton. Many successes have been achieved by applying organocatalysts such as proline derivatives to highly reactive Michael donors or acceptors. In contrast, Michael additions of simple aldehydes to enones have received little attention. In this context, Cordova et al. have employed an α,α-diarylprolinol ether to promote the first highly enantioselective catalytic conjugate addition of aldehydes to both aliphatic and aromatic alkylidenemalonates. The reaction gave access to β-formyl-substituted malonates with high yields combined with diastereoselectivities of up to 86% de and enantioselectivities of up to 99% ee, as shown in Scheme 1.3.

This organocatalyst and the corresponding trifluoromethyl-substituted derivative have been applied by Zhu and Lu to the asymmetric Michael reaction of aldehydes with other Michael acceptors, such as vinyl sulfones, providing the corresponding Michael products with exceptional enantioselectivities and excellent yields (Scheme 1.4). In order to make this methodology more useful, the authors extended its scope to 2-aryl-substituted vinyl sulfones as acceptors, which yielded the corresponding Michael products in excellent yields, good diastereoselectivities and nearly perfect enantioselectivities, as shown in Scheme 1.4.

In order to explain the stereoselectivity of this reaction, the authors have proposed a plausible transition-state model depicted in Scheme 1.5, in which the bulky biaryl silyl ether moiety exerted steric shielding, resulting in the formation of the observed stereoisomer. This enantioselective addition to vinyl sulfones, in combination with desulfonation, offered a unique, asymmetric entry to α-alkylated aldehydes and their derivatives.

Similar Michael additions of various aldehydes to vinyl sulfones to some of those depicted above have also been developed by Alexakis et al. in the presence of an aminal-pyrrolidine organocatalyst derived from proline, albeit leading to both lower enantioselectivities (≤ r91%) and yields (Scheme 1.6). In general, the best enantioselectivities were obtained with the more substituted aldehydes with the exception of the more bulky 3,3-dimethylbutyraldehyde, which gave only 75% ee probably due to a strong interaction between the tert-butyl group and the catalyst. Moreover, a poor enantiocontrol (16% ee) was observed in the case of using an α,α-disubstituted aldehyde.

In addition, aldehydes have been added by Jorgensen et al. to ethyl 2-(di-ethoxyphosphoryl)acrylate in the presence of 2-[bis(3, 5-bistrifluoromethylhenyl)trimethylsilylanyloxymethyl]pyrrolidine as the organocatalyst. The obtained Michael products were not purified, but submitted directly to a chemoselective reduction with NaBH4 in methanol, affording the corresponding δ-hydroxyalkanoates, which were cyclised to the corresponding α-diethoxyphosphoryl-δ-lactones under acidic conditions. These lactones, obtained in good yields as mixtures of epimers, were finally submitted to a Horner–Wadsworth–Emmons olefination process by treatment with formaldehyde, affording the target α-methylene-δ-lactones in good yields and excellent enantioselectivities (Scheme 1.7). As an extension of this methodology, the Michael products could be converted into the corresponding α-methylene-δ-lactams by a reductive amination with benzylamine. The formed δ-aminoalkanoates underwent a spontaneous lactamisation, yielding α-diethoxyphosphoryl-δ-lactams as mixtures of epimers. These products led to the final α-methylene-δ-lactams via a Horner–Wadsworth–Emmons olefination process with formaldehyde in high enantioselectivities of up to 94% ee (Scheme 1.7).

On the other hand, most organocatalysed Michael additions of stabilised carbon nucleophiles have involved either nucleophiles or electrophiles that are highly activated. As an example, Michael additions of highly activated nucleophiles, such as malonates, to α,β-unsaturated aldehydes have been reported. Therefore, Ma et al. have reported the Michael addition of malonates to α,β-unsaturated aldehydes catalysed by O-TMS protected diphenylprolinol combined with acetic acid in water. A wide range of aldehydes including β-aryl, β-alkyl and β-alkenyl acroleins were found to be compatible with these conditions, providing the corresponding adducts in good yields and with good to excellent enantioselectivities, as shown in Scheme 1.8. It must be noted that the short reaction time (less than 24 h) used was remarkable. These advantages presumably resulted from the combination of Brønsted acids as promoters and water as the reaction medium.

In 2008, Barbas et al. developed the first enantioselective thioester Michael addition of simple trifluoroethyl thioesters, thereby establishing a new class of nucleophiles for direct catalytic reactions. Indeed, these nucleophiles were condensed onto a series of α,β-unsaturated aldehydes in the presence of 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilylanyloxymethyl]pyrrolidine as an organocatalyst, and benzoic acid as a co-catalyst, providing the corresponding Michael products in good yields and moderate to high enantioselectivities of up to 98% ee, albeit in modest diastereoselectivities in favour of the anti-product (Scheme 1.9).

In 2009, these authors applied this methodology to other nucleophiles, such as N-tosylimidates. Indeed, N-tosylimidates were highly enantioselectively added to α,β-unsaturated aldehydes in the presence of 2-[bis(3,5-bistri-fluoromethylphenyl)trimethylsilylanyloxymethyl]pyrrolidine as the organocatalyst, yielding the corresponding Michael products in high enantioselectivities of up to 98% ee, albeit in low diastereoselectivities, as shown in Scheme 1.10. In particular, α-phenyl-substituted N-tosylimidate showed the best reactivity. In addition, these authors have demonstrated that the kinetic acidity of the α-proton of α-phenyl N-tosylimidate as measured by proton/deuterium NMR exchange experiments was correlated with the potential of N-tosylimidates to act as nucleophiles in organocatalytic reactions.

Other nucleophiles, such as dicyanooleffins, have been submitted to organocatalysed Michael additions with α,β-unsaturated aldehydes by Loh et al., in 2008. Therefore, a pool of water-compatible catalysts, namely dialkyl-(S)-prolinols, was developed for the enantioselective direct vinylogous Michael addition of vinylmalononitriles to α,β-unsaturated aldehydes in aqueous medium. In all the reactions tested, only the anti-Michael addition products were obtained. Notably, the best results in both yields and enantioselectivities were obtained by using the catalyst bearing a hexyl group, as shown in Scheme 1.11.

In addition, Jorgensen et al. have shown that racemic oxazolones were excellent reagents for the synthesis of chiral quaternary amino acids by nucleophilic addition to α,β-unsaturated aldehydes catalysed by diarylprolinol silyl ethers. This novel organocatalytic reaction proceeded with a good diastereoselectivity and an excellent enantioselectivity of up to 96% ee for a broad range of aldehydes and oxazolones, as shown in Scheme 1.12. The synthetic potential of this process was demonstrated by the conversion of the formed chiral products into various chiral products, such as α,α-disubstituted α-amino acids, α-quaternary proline derivatives, amino alcohols, lactams and tetrahydropyranes. Furthermore, the authors have shown by DFT calculations of transition states that the stereoselectivity for one class of compounds was due to hydrogen-bonding interactions between an acceptor in the ortho-position of the aromatic α,β-unsaturated aldehyde interacting with the enolate-form of oxazolone, and, in a more general manner, the selectivity could be controlled by a benzhydryl-protecting group in the oxazolone.

On the other hand, a number of asymmetric Michael additions of C-nucleophiles involving acceptors other than α,β-unsaturated aldehydes and catalysed by a proline derivative have recently been reported. As an example, Ley et al. have demonstrated that the pyrrolidinyl tetrazole catalyst, depicted in Scheme 1.13, could be used to efficiently induce the enantioselective Michael addition of malonates to α,β-unsaturated enones. Cyclic, acyclic and aromatic enones could be involved in this process, and the reaction with the most efficient ethyl malonate provided, in the presence of piperidine as an additive, the corresponding Michael products in high yields with good to excellent enantioselectivities, as shown in Scheme 1.13.

Nitroalkanes are a particularly useful source of stabilised carbanions for the asymmetric addition to electron-poor alkenes. This type of nucleophiles has been added to cyclic and acyclic α,β-unsaturated enones in the presence of a novel class of organocatalysts, such as chiral α-aminophosphonates. This study revealed that the hydrate salt of a pyrrolidine-based catalyst bearing a phosphonate group, depicted in Scheme 1.14, was found to be the best catalytic species, providing, in the presence of trans-2,5-dimethylpiperazine as an additive, moderate to good results for a range of substrates, as summarised in Scheme 1.14.

In the course of synthesising enantioenriched γ-keto gem-bisphosphonates having anti-arthritic and anti-inflammatory activities, Barros and Phillips have finalised organocatalytic asymmetric Michael additions of cyclic ketones to vinyl gem-bisphosphonates. The reactions were performed in the presence of (S)-(+)-1-(2-pyrrolidininylmethyl)pyrrolidine as an organocatalyst and benzoic acid as an additive, leading to the expected Michael products in high yields, excellent diastereoselectivities (≥ 98% de) combined with enantioselectivities of up to 99% ee, as shown in Scheme 1.15. In order to extend the scope of this methodology, these authors have tried to involve linear ketones, β-keto esters or β-ketophosphonates as the Michael donors albeit unsuccessfully, since no reaction occurred with propiophenone, while the formed Michael products derived from either β-keto esters or β-ketophosphonates were obtained in a racemic form.

1.1.2 Intermolecular Michael Additions of C-Nucleophiles Catalysed by Non-proline Derivatives

A number of other-than-proline-derived organocatalysts have been involved to induce chirality in Michael additions of various C-nucleophiles onto a range of Michael acceptors. Among them, bifunctional organocatalysts possessing a thiourea moiety and a tertiary amino group were designed by Takemoto et al. in order to be investigated as catalysts for the asymmetric Michael addition of malononitrile to α,β-unsaturated carboxylic acid derivatives having an imide moiety. As shown in Scheme 1.16, the corresponding Michael adducts bearing various β-substituents were obtained in high yields combined with high enantioselectivities of up to 93% ee.

Among other-than-proline-derived organocatalysts, the modified cinchona alkaloids have been the most employed in the last two years. These tunable bifunctional organocatalysts have emerged in the last four years as robust and tunable bifunctional organocatalysts for a range of synthetically useful transformations. In contrast with chiral secondary amine catalysts, little attention has been paid to the development of chiral primary amine catalysts. In 2009, Ye et al. developed a novel type of primary amine thiourea organocatalysts derived from 1,2-diaminocyclohexane and 9-amino (9-deoxy) cinchona alkaloid for the asymmetric Michael addition of malonates to α,β-unsaturated enones. A series of cyclic and acyclic enones could react very well with different malonates in the presence of the catalyst derived from epiquinine, affording the corresponding Michael products with excellent yields and enantioselectivities, as shown in Scheme 1.17.

A closely related catalyst to the above was applied by the same workers to the asymmetric Michael addition of nitroalkanes to both cyclic and acyclic α,β-unsaturated enones, allowing the corresponding Michael products to be obtained in good yields and excellent enantioselectivities of up to 98% ee (Scheme 1.18). This process offered a new way to construct quaternary stereocentres from enones and nitroalkanes.

Another member of the epi-cinchona-based thiourea organocatalyst family, depicted in Scheme 1.19, was applied by Vakulya et al. to the asymmetric Michael addition of nitroalkanes to chalcones, giving excellent yields and enantioselectivities of up to 98% ee. The extension of this methodology was further explored to encompass α,β-unsaturated N-acylpyrroles, as a chalcone mimic. The corresponding Michael products were obtained in high yields and enantioselectivities of up to 94% ee, as shown in Scheme 1.19. This simple novel approach allowed a concise stereoselective synthesis of (R)-rolipram to be accomplished.

(Continues…)Excerpted from Recent Developments in Asymmetric Organocatalysis by Hélène Pellissier. Copyright © 2010 Hélène Pellissier. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.