The thioenamide functional group features in several natural products with promising biological activity, including some penicillins, linaridins, and lantibiotics. Notwithstanding its potential importance, the functional group is understudied, with limited methods for synthesis and virtually no information on the functional group’s tolerance to assorted chemically and physiologically relevant conditions. We have reported an acid-promoted route to thioenamides via condensation of an aldehyde (bearing a b-thioether) and a primary amide, to afford moderate yields and high Z-stereoselectivity. Collaborative computational work confirmed our rationale for the Z-stereoselectivity, viz. a preferred conformation during the dehydration step. Optimization of reactions conditions and a study of protecting group compatibilities, preceded application of the condensation reaction to peptidyl examples en route to the C-terminal macrocycles of several natural product peptides.

Thioenamide synthesis inspired by peptide macrocycles

2019 Spring National Meeting

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