Enantioselective Organocatalytic Transfer Hydrogenation of α‐Imino Esters by Utilization of Benzothiazoline as Highly Efficient Reducing Agent

Abstract

Benzothiazoline was employed as an efficient and versatile reducing agent for the chiral phosphoric acid-catalyzed transfer hydrogenation of a-imino esters. The corresponding a-amino esters were furnished with excellent enantioselectivities. Novel and readily removable benzothiazolines bearing a hydroxy group were also investigated.Keywords: amino esters; benzothiazolines; imino esters; organocatalysis; transfer hydrogenation a-Amino acids are found widely in natural products and biological systems. They are broadly utilized in biochemistry and pharmaceutical chemistry because of their intriguing biological activities.[1] The synthesis of a-amino acids and their derivatives in the optically pure form has attracted much attention in the last decade.[2] The reduction of a-imino esters is one of the most direct approaches to afford the a-amino esters. In addition to the transition metal-catalyzed method reported by Zhang, [3] Antilla and You independently reported the asymmetric reduction of aimino esters by means of a chiral Brønsted acid catalyst [4] and Hantzsch esters, [5] which are the most wellused cofactors in biochemical hydrogenation reactions. Although Hantzsch esters have been extensively employed as a hydrogen source, in asymmetric organocatalyzed reactions lately, [6,7] the development of novel hydrogen sources has been expected. We have recently reported that benzothiazoline [8] functioned as a novel reducing agent in the asymmetric transfer hydrogenation of ketimines, [9] giving rise to the corresponding amines with excellent enantioselectivities. As a result of our continuing efforts towards the development of chiral Brønsted acid-catalyzed reactions, [10,11,12] we wish to report herein the phosphoric acid-catalyzed asymmetric transfer hydrogenation of a-imino esters using benzothiazoline as the reducing agent. Preliminary experiments were carried out with the combination of ethyl imino ester 2a and benzothiazoline 4 (Table 1). We examined the effects of a variety ee [%][c]

Frustrated Lewis Pair Catalyzed Hydrogenations

“…(1-naphth) 3 P (9)] 30 This phenomenon was identified by NMR spectroscopy, revealing that the H 2 activation readily occurs at temperatures as low as -60 °C to -80 °C for the simple, less electron-releasing phosphine C 6 F 5 P(C 6 H 5 ) 2 (7) in combination with B(C 6 F 5 ) 3 (6). The low temperature for the loss of hydrogen is an indication for the high Brønsted acidity of the phosphonium cation.…”

“…Also metal-free hydrogenations using hydrogen surrogates, for example, Hantzsch's ester, 5 thiazolines, 6 as stoichiometric reducing agent have been developed. High yield and high chemo-and enantioselectivies were achieved with a diversity of substrates.…”

Mimicking Nature to Make Unnatural Amino Acids and Chiral Diamines

“…Very recently, Shi [47] reported a highly stereoselective transamination reaction (up to 92 %ee) for making α-amino acids in excellent yield (100 %) using cinchona alkaloid as a general base catalyst (10 mol-%). Stereoselective catalytic reduction [48] or alkylation [49] of α-keto ester imines are also efficient routes to amino acids.…”

Chemo‐ and Enantioselective Brønsted Acid‐Catalyzed Reduction of α‐Imino Esters with Catecholborane

“…Among these methods the most direct approach to enantiomerically enriched α‐arylglycines is the catalytic asymmetric direct reduction of prochiral α‐enamides and α‐imino esters, employing both metal‐based catalysts and organocatalysts. Although only few examples of metal‐catalyzed hydrogenation reactions of α‐imino esters are known due to the low reactivity of these substrates,11 some organocatalytic protocols have been developed employing Hantzsch esters,12 benzothiazolines13 or trichlorosilane14 as hydride source. However, the reduction with Hantzsch esters as well as with benzothiazolines occasionally suffers from difficulties in the purification of the products, albeit, in the latter case these problems have been overcome by developing novel benzothiazolines bearing hydroxy groups 13.…”

“…Although only few examples of metal‐catalyzed hydrogenation reactions of α‐imino esters are known due to the low reactivity of these substrates,11 some organocatalytic protocols have been developed employing Hantzsch esters,12 benzothiazolines13 or trichlorosilane14 as hydride source. However, the reduction with Hantzsch esters as well as with benzothiazolines occasionally suffers from difficulties in the purification of the products, albeit, in the latter case these problems have been overcome by developing novel benzothiazolines bearing hydroxy groups 13. In contrast, the use of achiral boron hydrides as reducing agents in organocatalysis is less investigated.…”