Highly Enantioselective Phase-Transfer-Catalyzed Alkylation of Protected α-Amino Acid Amides toward Practical Asymmetric Synthesis of Vicinal Diamines, α-Amino Ketones, and α-Amino Alcohols

Abstract

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its ability to recognize the chirality of beta-branched primary alkyl halides, which provides impressive levels of kinetic resolution and double stereodifferentiation during the alkylation, allowing for two alpha- and gamma-stereocenters to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether (CPME), this system offers a facile access to structurally diverse optically active vicinal diamines. Furthermore, the optically active alpha-amino acid Weinreb amide 11 can be efficiently converted to the corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and alkylation of the optically active alpha-amino ketone into both syn and anti alpha-amino alcohols with almost complete relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the present approach renders both enantiomers of alpha-amino amides including Weinreb amides readily available with enormous structural variation and also establishes a general and practical route to vicinal diamines, alpha-amino ketones, and alpha-amino alcohols with the desired stereochemistry.

Synthesis and Synthetic Applications of α-Amino Ketones Derived from Natural α-Amino Acids

“…In this case, the authors employed a phase-transfer-catalysed asymmetric alkylation of differently protected glycine amides using a chiral quaternary ammonium bromide as the catalyst [51].…”

Recent Developments in Enantioselective Phase Transfer Catalysis Using Chiral Ammonium Salts

“…For instance, secondary, tertiary and Weinreb amides were used successfully in combination with catalysts of type 3 (Fig. 10) [84][85][86][87]. It was then even possible to perform an iterative process to generate a small peptidic side chain [88].…”

Recent approaches towards the asymmetric synthesis of α,α-disubstituted α-amino acids

“…41 Shibasaki et al introduced the tartrate-derived diammonium salt (TaDiAS) 41 as phase transfer-catalyst for the alkylation of alanine-derived Schiff bases 40 (Scheme 15). 42 Interestingly, the tetrafluoroborate catalyst proved to be considerably more powerful than the originally employed iodide in the alkylation of both glycine-and alanine-derived Schiff bases.…”