Yixin Lu

Primary amino acids: privileged catalysts in enantioselective organocatalysis.

Despite the recent spectacular advances in asymmetric organocatalysis, proline and its analogues have been predominantly employed as organocatalysts in reactions utilizing enamine intermediates. Recent studies of enantioselective organocatalytic reactions promoted by primary amino acids and their derivatives are described in this account. The primary amino functions, rather than the secondary pyrrolidine moiety, have been shown to provide unique reactivity and stereoselectivity in asymmetric aldol and Mannich reactions.

Asymmetric Synthesis of Spiropyrazolones through Phosphine‐Catalyzed [4+1] Annulation

An enantioselective synthesis of spiropyrazolones from allenoate-derived MBH acetates and pyrazolones through a phosphine-mediated [4+1] annulation process has been developed. Spiropyrazolones were readily prepared in good chemical yields and good to high enantioselectivities. This is the first asymmetric example in which α-substituted allenoates were utilized as a C4 synthon for phosphine-catalyzed [4+1] annulation.

Asymmetric Mannich Reaction of Fluorinated Ketoesters with a Tryptophan-Derived Bifunctional Thiourea Catalyst†

Small organic molecules capable of hydrogen-bonding interactions with substrates have found widespread application in asymmetric catalysis. In particular, thiourea-based organic molecules have become the most prominent hydrogen-bonddonor catalysts in a wide variety of organic reactions. In this context, bifunctional organic molecules containing a tertiary amino functionality and a thiourea moiety are remarkably useful organic catalysts. Despite their tremendous utility, these bifunctional catalysts are derived from a very limited range of chiral structural scaffolds, including cyclohexane-1,2diamine, 1,1’-binaphthyl-2,2’-diamine, and cinchona alkaloids. The development of readily accessible novel bifunctional catalysts of this nature would be highly desirable. As part of our research program towards the development of practical organocatalysts based on primary amino acids, we were intrigued by the possibility of designing novel tertiary amine– thiourea catalysts on the basis of simple amino acids. The facile conversion of natural amino acids into 1,2-diamines and the availability of structurally diverse side chains make this method very attractive. To investigate the validity of this approach, we selected l-tryptophan as the chiral precursor. We reasoned that the indole moiety would be capable of engaging in aromatic and hydrogen-bonding interactions with substrates, and these effects may result in efficient chiral induction (Scheme 1). Fluorinated molecules are of high importance in the pharmaceutical industry, and their asymmetric preparation has drawn great attention. The catalytic construction of fluorinated quaternary carbon stereocenters is a formidable synthetic challenge. A number of excellent methods based on metal catalysis have been reported; however, organocatalytic approaches for the creation of fluorinated quaternary centers are rather limited. Recently, organocatalytic synthetic methods with fluorinated substrates have become an alternative and viable option for accessing chiral fluorinated molecules. In such approaches, racemic fluorinated nucleophiles are used as substrates. A C C bond is formed rather than a C F bond, and full advantage is taken of the high electronegativity and small molecular radius of the fluorine atom. We and others have used fluorinated substrates in this way in organocatalytic Michael and alkylation reactions for the construction of fluorinated chiral molecules. To assess the utility of tryptophan-based bifunctional catalysts, we chose to focus on the direct asymmetric Mannich reaction of a-fluorinated b-ketoesters, as such reactions yield structurally demanding and biologically important a-fluorob-amino acids. Organocatalytic asymmetric Mannich reactions of b-ketoesters and malonates were reported recently by the research groups of Schaus, Deng, and Dixon, all of whom employed organic catalysts derived from cinchona alkaloids. Herein, we report that tryptophan-based bifunctional thiourea derivatives promote the asymmetric Mannich reaction of fluorinated substrates to afford highly optically enriched fluorine-containing molecules containing adjacent quaternary and tertiary stereocenters. We selected the Mannich reaction of a-fluoro-b-ketoester 1a with N-Boc imine 2a as a model reaction and examined the catalytic effects of various bifunctional catalysts (Table 1). Quinidine-derived thioureas and a quinidine-derived sulfonamide gave disappointing results (Table 1, entries 1–3). On the other hand, the tryptophan-based thiourea derivatives Trp-1–Trp-3 were found to be good catalysts. They afforded the Mannich product 3a in quantitative yield and with good diastereoselectivity and enantioselectivity (Table 1, entries 4– 6). Under optimized reaction conditions, the fluorinated product containing adjacent quaternary and tertiary stereoScheme 1. Thiourea catalyst based on a primary amino acid (tryptophan).

Highly enantioselective [4 + 2] annulations catalyzed by amino acid-based phosphines: Synthesis of functionalized cyclohexenes and 3-spirocyclohexene-2-oxindoles

Highly enantioselective [4 + 2] annulation of activated alkenes with α-substituted allenoates catalyzed by amino acid-based bifunctional phosphines has been developed for the first time, which provides an easy access to optically enriched functionalized cyclohexenes. In particular, 3-spirocyclohexene-2-oxindoles were prepared in high yields and with excellent enantioselectivities.

Asymmetric Michael addition mediated by novel cinchona alkaloid-derived bifunctional catalysts containing sulfonamides.

Novel cinchona alkaloid-derived bifunctional organocatalysts containing sulfonamide groups were utilized to promote Michael addition of bicyclic alpha-substituted beta-ketoesters to nitroolefins. The desired Michael adducts with all-carbon quaternary centers were constructed in high yield and with excellent enantioselectivity, demonstrating the great potential of cinchona alkaloid-derived sulfonamides in asymmetric catalysis.

Direct asymmetric three-component organocatalytic anti-selective Mannich reactions in a purely aqueous system

The direct three-component Mannich reactions of O-benzyl hydroxyacetone with p-anisidine and aromatic or aliphatic aldehydes in the presence of an L-threonine-derived catalyst afforded anti-1,2-amino alcohols in good-to-excellent yields and with enantioselectivities of up to 97%. This study is the first demonstration that direct three-component Mannich reactions can be promoted by a primary amino acid in water.

Highly enantioselective synthesis of 3,4-dihydropyrans through a phosphine-catalyzed [4+2] annulation of allenones and β,γ-unsaturated α-keto esters.

A phosphine-catalyzed novel [4+2] annulation process was devised employing allene ketones as C2 synthons and β,γ-unsaturated α-keto esters as C4 synthons. In the presence of an L-threonine-derived bifunctional phosphine, 3,4-dihydropyrans were obtained in high yields and with virtually perfect enantioselectivities. The synthetic value of the dihydropyran motif was demonstrated by a concise preparation of an anti-hypercholesterolemic agent.

The Direct Asymmetric Vinylogous Aldol Reaction of Furanones with α‐Ketoesters: Access to Chiral γ‐Butenolides and Glycerol Derivatives

The creation of quaternary stereogenic centers is still a challenge in organic synthesis even though significant progress has been made in the past few decades. As part of our ongoing research efforts towards the efficient generation of quaternary stereogenic centers, we were interested in organic molecules containing a tertiary hydroxy group. Structures that contain tertiary alcohols are very important in the biological sciences and pharmaceutical industry. In particular, enantiomerically pure glycerol derivatives having a quaternary center are key chiral structural motifs that are present in many pharmaceuticals, and they are also versatile synthetic intermediates. Although many excellent methods have been devised for the synthesis of chiral tertiary alcohols, the asymmetric preparation of glycerol derivatives having a quaternary center is still a formidable task. To the best of our knowledge, only two examples have been reported in the literature. In 1992, Harada, Oku, and co-workers reported a synthetic approach utilizing menthone as a chiral auxiliary. Very recently, Kang and co-workers elegantly employed chiral copper complexes to carry out the enantioselective desymmetrization of meso-2-substituted glycerols, and obtained 2-substituted 1,2,3-propanetriols with excellent enantioselectivity. It is thus our goal to develop an efficient organocatalytic variant to allow easy access to 2-substituted chiral glycerol derivatives. We focused on the vinylogous aldol reaction between furanones and a-ketoesters (Scheme 1). The g-butenolides that would result from these reactions are common structural motifs in bioactive molecules. Moreover, they can be readily converted into tertiary-alcohol-containing glycerol derivatives. The vinylogous aldol reaction has been investigated intensively in the past few decades, and although it is commonplace to employ 2-silyloxyfurans as nucleophiles, the direct utilization of 2-furanone derivatives in the vinylogous aldol reactions is rare, probably because of their low reactivity. Zhang and co-workers first utilized a,b-dichloro-gbutenolides in the direct vinylogous aldol reaction. Recently, Terada and co-workers reported an enantioselective vinylogous aldol reaction of furanone derivatives with aldehydes catalyzed by a chiral guanidine. Feng and coworkers subsequently disclosed a thiourea-catalyzed direct vinylogous aldol reaction of furanones with aldehydes. Herein, we document the first direct asymmetric vinylogous aldol reaction of 3,4-dichlorofuran-2(5H)-one with a-ketoesters, catalyzed by an l-tryptophan-derived bifunctional catalyst, that leads to an efficient synthesis of chiral gbutenolides and 2-substituted glycerol derivatives. We recently introduced a novel tertiary amine/thiourea bifunctional catalyst derived from l-tryptophan, and showed its effectiveness in the Mannich reaction of fluorinated ketoesters. To extend the applications of these aminoacid-based bifunctional catalysts, we prepared a number of l-tryptophan-derived organic catalysts and examined their catalytic effects in the vinylogous aldol reaction of 3,4dichlorofuran-2(5H)-one (1a) with the phenylglyoxylates 2 (Table 1). The reaction was quite slow in the presence of Trp-1 alone (Table 1, entry 1), but the rate of the reaction could be substantially improved with the addition of molecular sieves (4 ; Table 1, entry 2). An examination of the ester moieties in the different a-ketoesters revealed that tert-butyl phenylglyoxylate (2c) offered the best diastereoselectivity and enantioselectivity (Table 1, entry 4). Changing the concentration of the reaction mixture yielded the product with a 91% ee (Table 1, entry 6). Notably, in contrast to the high stereoselectivity induced by the tryptophan-derived organic catalysts, quinidine QD-1, 6’-demethylated quinidine QD2, quinidine-derived sulfonamide QD-3, and quinidineScheme 1. Construction of g-butenolides and glycerol derivatives through the vinylogous aldol reaction.

Enantioselective conjugate addition of nitroalkanes to vinyl sulfone: an organocatalytic access to chiral amines.

Organocatalytic asymmetric conjugate addition of nitroalkanes to vinyl sulfone mediated by cinchona alkaloid-derived thiourea catalyst afforded the desired Michael product with good enantioselectivity. The described method, in combination with ready desulfonation, represents a novel approach to access alpha-alkylated chiral amines.

Asymmetric construction of functionalized bicyclic imides via [3 + 2] annulation of MBH carbonates catalyzed by dipeptide-based phosphines.

A highly enantioselective [3 + 2] annulation of MBH carbonates and maleimides catalyzed by chiral phosphines has been developed. In the presence of 5 mol % of L-Thr-L-Val-derived phosphine 6, functionalized bicyclic imides were prepared in excellent yields, and with high diastereoselectivities and nearly perfect enantioselectivities.