An Aza-Enolate Alkylation Strategy for the Synthesis of α-Alkyl-δ-amino Esters and α-Alkyl Valerolactams

Abstract

Alkylation of the aza-enolate of valerolactim methyl ether with electrophiles affords a-alkyl lactims that may be hydrolysed under mild acidic conditions to afford their corresponding a-alkyl-d-amino esters as their hydrochloride salts. Neutralisation of these salts with base results in smooth intramolecular cyclisation to afford their corresponding a-alkyl lactams in excellent yield.Key words: lactim ether, aza-enolate, alkylation, a-alkyl-d-amino ester, a-alkyl lactams a-Alkyl-d-amino acid derivatives constitute an important class of synthetic building blocks for the development of medicinally active compounds, 1 which have also been employed as monomers for probing the conformation of derived peptide isosteres. 2 This type of d-amino acid may also be used to prepare a-alkyl lactams that are useful for the preparation of drug-like molecules. 3 As part of studies directed towards developing asymmetric methodology for their syntheses, we required access to a series of racemic a-alkyl-d-amino esters, 4 as well as to their corresponding a-alkyl valerolactams. 5 Consequently, we now report on the development of highly efficient aza-enolate alkylation methodology that employs valerolactim methyl ether 1 as a substrate for the preparation of both classes of compound.A review of the literature revealed that Trost et al. had reported that lithium aza-enolates of valerolactim ether (1) could be alkylated with electrophiles to afford a-substituted lactim ethers 2-4 in moderate 37-60% yields (Scheme 1). 6 Lactim ether bonds are easily hydrolysed using mild aqueous acid, 7 and as a consequence we reasoned that hydrolysis of a-alkyl lactim ethers 5 would also afford a route to their corresponding a-alkyl-d-amino methyl ester hydrochloride salts 6. Subsequent neutralisation of these hydrochloride salts with base would then result in intramolecular cyclisation to give their corresponding a-alkyl lactams 7 (Scheme 2).

Geometry-Constrained N,N,O-Nickel Catalyzed α-Alkylation of Unactivated Amides via a Borrowing Hydrogen Strategy

“…1, 140.9, 128.5, 128.4, 126.2, 48.1, 38.8, 33.1, 31.9, 25.5, 24.8. 3-Benzylpiperidin-2-one (6e). 37 The title compound was isolated by column chromatography following the general procedure to give the product as a white solid. Yield: 79%, 148.8 mg. 1 3-Benzylindolin-2-one (6f).…”