Synthesis of Sulfur-Containing Olefinic Peptide Mimetic Farnesyl Transferase Inhibitors Using the Nozaki−Hiyama−Kishi Reaction and Cuprate S_N2‘ Displacements

Syntheses of the potent sulfur-containing tetrapeptide mimetic farnesyl transferase inhibitors B956 (22) and B957 (23) are described. The two double bonds in 22 and 23 were constructed by application of iterative NHK and cuprate S_N2‘ reactions. Normal syn NHK reaction and substrate-dependent syn and anti-S_N2‘ diastereoselectivities accompanied by exclusive E-olefin selectivity were observed for the first NHK iteration (1 → 4). In the second iteration, unexpected epimerization and a strong preference for syn diastereoselectivity was observed for the NHK reaction (5b → 7a + 9a) while an unusual Z-olefin was observed for the S_N2‘ reaction (7b → 11). Deprotection conditions were optimized to ensure high purity and yield of the final aminothiol compounds.