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

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 β-branched primary alkyl halides, which provides impressive levels of
kinetic resolution and double stereodifferentiation during the alkylation, allowing for two α- and γ-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 α-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 α-amino ketone into both syn and anti α-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 α-amino amides including Weinreb amides readily available
with enormous structural variation and also establishes a general and practical route to vicinal diamines,
α-amino ketones, and α-amino alcohols with the desired stereochemistry.