Total synthesis of HUN-7293

The first total synthesis of the cyclic heptadepsipeptide HUN-7293 (1), a potent inhibitor of cell adhesion molecule expression exhibiting anti-inflammatory properties, is detailed. The most effective approach relied on an unusually efficient macrocyclization with the formation of the MLEU3-LEU4 secondary amide that potentially benefits from intramolecular H-bonding preorganization of the acyclic Substrate. The requisite linear depsipeptide was convergently assembled with the late stage introduction of the linking ester enlisting a Mitsunobu esterification that occurs with inversion of the DGCN alpha-center permitting the utilization of a readily available L-amino acid precursor to the D or-hydroxy carboxylic acid residue. An alternative and similarly attractive approach of direct macrolactonization of a substrate necessarily incorporating a D-DGCN subunit proved viable albeit less effective. Biological evaluation in cellular assays for vascular adhesion molecule expression confirmed that synthetic HUN-7923 (1) is essentially indistinguishable from the naturally occurring cyclodepsipeptide.