Design of an optimized synthesis for N-methylated cyclodepsipeptide cotransin

Cotransin is a cyclic heptadepsipeptide with interesting bioactivity.  Like the fungal-derived natural product, HUN-7293, cotransin has high pharmacological potential because it selectively and reversibly represses VCAM-1 expression.  However, the current method of synthesizing cotransin is laborious and gives a low percent yield.  We propose an alternative method that will alleviate the three main problems in the current synthetic scheme for cotransin.  In the previously reported synthesis, Fmoc deprotection caused the N-terminal amine to initiate diketopiperazine (DKP) formation in large quantity.  Here, we decreased propensity for DKP formation by adjusting which residue is bound to the resin, thereby never placing a free amine six atoms following the ester bond. Previous synthetic efforts employed a solution-phase cyclization that produced poor yields.  We addressed this problem by attaching the peptide via tyrosine side chain phenol, using orthogonal protecting groups on the N- and C-termini, thus effecting cyclization on-resin. Finally, N-methylated amino acids previously shown a decrease in the overall percent yield because of the difficulty in coupling to a sterically hindered secondary amine. We will avoid this problem by N-methylating after cyclization. Our research could lead to a time and cost effective method for synthetically accessing the myriad challenging scaffolds represented by N-methylated cyclic depsipeptide natural products.