An ester enolate-Claisen rearrangement route to substituted 4-alkylideneprolines. studies toward a definitive structural revision of lucentamycin A.

Substituted 4-alkylideneprolines represent a rare class of naturally occurring amino acids with promising biological activities. Lucentamycin A is a cytotoxic, marine-derived tripeptide that harbors a 4-ethylidine-3-methylproline (Emp) residue unique among known peptide natural products. In this paper, we examine the synthesis of Emp and related 4-alkylideneprolines employing a versatile ester enolate-Claisen rearrangement. The scope and selectivity of the key rearrangement reaction are described with a number of diversely substituted glycine ester substrates. Treatment of the allyl esters with excess NaHMDS at ambient temperature gives rise to highly substituted α-allylglycine products with good to excellent diastereoselectivities. Resolution of dipeptide diastereomers and cyclization to form the pyrrolidine rings provide rapid access to stereopure prolyl dipeptides. We have applied this strategy to the synthesis of four Emp-containing isomers of lucentamycin A in pursuit of a definitive stereochemical revision of the natural product. Our studies indicate that the Emp stereogenic centers are not the source of structural misassignment. The current strategy should find broad utility in the synthesis of additional natural product analogues and related 3-alkyl-4-alkylidene prolines.