Asymmetric synthesis of 4-amino-γ-butyrolactones via lithium amide conjugate addition

Abstract

Upon treatment with homochiral lithium ( R)- N-benzyl- N-(α-methylbenzyl)amide, γ-benzyloxy but-2-enoates undergo competitive conjugate addition and γ-deprotonation, while γ- tert-butyldimethylsilyloxy but-2-enoates undergo exclusive conjugate addition. Treatment of γ-benzyloxy or γ- tert-butyldimethylsilyloxy but-2-enamides with lithium ( R)- N-benzyl- N-(α-methylbenzyl)amide furnishes exclusively the γ-benzyloxy- or γ- tert-butyldimethylsilyloxy-β-amino amide products of conjugate addition in high de. The γ- tert-butyldimethylsilyloxy-β-amino butanoate products of conjugate addition readily undergo O-desilylation and concomitant cyclisation to furnish 4-[ N-benzyl- N-(α-methylbenzyl)amino]-γ-butyrolactone, which may be stereoselectively functionalised via deprotonation and alkylation to give the corresponding trans-3-alkyl-4-amino-γ-butyrolactones. Alternatively, stereoselective alkylation of γ-benzyloxy- or γ- tert-butyldimethylsilyloxy-β-amino butanoates and butanamides through enolate formation and alkylation following a tandem (via the ( Z)-lithium enolate) or stepwise (via the ( E)-lithium enolate) protocol gives a range of separable syn- and anti-α-alkyl-β-amino esters and amides. O-Silyl deprotection of the syn- and anti-α-alkyl-β-amino butanoates with TBAF and concomitant cyclisation provide trans-3-alkyl-4-amino-γ-butyrolactones, consistent with epimerisation to the thermodynamically favoured trans-lactone occurring upon deprotection.