An Ester Enolate–Claisen
Rearrangement Route to Substituted 4-Alkylideneprolines. Studies toward
a Definitive Structural Revision of Lucentamycin A
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Abstract
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