Highly Enantioselective Synthesis of β‐Amino Acid Derivatives by the Lewis Base Catalyzed Hydrosilylation of β‐Enamino Esters

Abstract

Optically active b-amino acids are very important chiral building blocks for the synthesis of b-peptides, b-lactams, natural products, and physiologically active substances. [1] Therefore, efficient methods for the synthesis of optically active b-amino acids would be of great value for drug discovery and organic synthesis. Among the approaches to chiral b-amino acids, [2] the most straightforward and atom economic one is catalytic asymmetric reduction of b-enamino esters. Pioneered by Noyori et al., [3a] many chiral transition-metal complexes were developed to catalyze high-pressure hydrogenation of N-acyl b-enamino esters, [3] N-aryl benamino esters, [4] or N-unprotected b-enamino esters [5] with high enantioselectivities. However, transition-metal-catalyzed hydrogenation cannot get rid of the problems of metal leaching, high pressure, the cost of the catalyst, and its regeneration.Recently, asymmetric reactions involving the strategy of Lewis base activation of Lewis acids attracted much attention.[6] Among these reactions, Lewis base catalyzed enantioselective hydrosilylation of ketimines has become an important alternative to transition-metal catalysis in synthesis of chiral amines.[7] However, there is only limited examples of enantioselective hydrosilylation of b-enamino esters. [7b, 8] To our knowledge, a general, highly enantioselective Lewis base organocatalyzed hydrosilylation of b-enamino esters has not been reported, and thus remains an important challenge.Herein, we describe the first general, highly enantioselective organocatalytic hydrosilylation of b-enamino esters. Matsumura and co-workers reported the hydrosilylation of unprotected b-enamino ester 1 a catalyzed by N-picolinoylpyrrolidine derivative 2 a that resulted in poor yield and enantioselectivity (Scheme 1).[7b] However, to our delight, we found that the same catalyst 2 a and its analogues displayed excellent activities and enantioselectivities in promoting hydrosilylation of N-aryl b-enamino esters.First, N-picolinoylpyrrolidine derivatives 2 a-2 e and N-picolinoylephedrine (4) [7m] were evaluated in hydrosilylation of (Z)-methyl 3-phenyl-3-(phenylamino)acrylate.[9] As can be seen in

Asymmetric Organocatalysis

“…Zhang and co-workers developed an elegant asymmetric hydrosilylation of b-enamine esters using chiral Lewis base 194 as a catalyst (Scheme 66) [151]. High yields and enantioselectivities (up to 96% ee) were obtained for a diverse scope of b-amino acid derivatives.…”

The First Highly Enantioselective Lewis Base Organocatalyzed Hydrosilylation of α‐Imino Esters

“…As can be seen in Table 1, we found that catalysts 1a and 1b (Figure 1), which gave good results in the enantioselective hydrosilylation of N-aryl β-enamino esters, [9] exhibited only moderate enantioselectivities in the hydrosilylation of ethyl 2-(4-methoxyphenylimino)-2-phenylacetate (2a) at -10°C in chloroform (Table 1, Entries 1 and 2). Afterwards, we were very gratified to find that catalysts 1c and 1d, which delivered poor ee values in the enantioselective hydrosilylation of N-aryl β-enamino esters, [9] gave much higher enantioselectivities in this case (Table 1, Entries 3 and 4). Inversion of the configuration at C4 of the pyrrolidine ring from R to S only caused a slight drop in ee.…”

A New Motif for Lewis Base Catalysis: Asymmetric Reduction of β‐Enamino Esters

“…(S)-2, Scheme 2). [5] At around the same time, the Malkov and Kočovský group were able to significantly extend the substrate scope to a-substituted b-enamino esters (3!4, Scheme 3). As shown later by Zhang and coworkers, the identical Lewis base LB1 catalyzes the reduction of monoprotected 1, e.g., with a PMP group at the nitrogen atom, with superb levels of enantiocontrol ( 96 % ee, not shown).…”

“…As shown later by Zhang and coworkers, the identical Lewis base LB1 catalyzes the reduction of monoprotected 1, e.g., with a PMP group at the nitrogen atom, with superb levels of enantiocontrol ( 96 % ee, not shown). [5] At around the same time, the Malkov and Kočovský group were able to significantly extend the substrate scope to a-substituted b-enamino esters (3!4, Scheme 3). [6,9,10] The a substituent added a stereochemical complication to this reduction but several monoprotected b 2, 3 -amino acids 4 were obtained with excellent syn diastereoselectivity.…”

“…The area of Lewis base-catalyzed reduction of b-enamino esters was initiated by Matsumura [4] (PG = H, Scheme 1, left) and later elaborated by others [5,6] (PG = PMP, not shown). These asymmetric syntheses of b 3 -amino acids were then complemented by a diastereocontrolled and enantioselective access to b 2,3 -amino acids by Malkov, Kočovský, and coworkers (PG = PMP, Scheme 1, middle).…”