Synthesis of Sulfur-Containing Olefinic Peptide Mimetic Farnesyl Transferase Inhibitors Using the Nozaki-Hiyama-Kishi Reaction and Cuprate S(N)2' 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(N)2' reactions. Normal syn NHK reaction and substrate-dependent syn and anti-S(N)2' 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(N)2' reaction (7b --> 11). Deprotection conditions were optimized to ensure high purity and yield of the final aminothiol compounds.
Yang
Hu
H
Eisai Research Institute, 4 Corporate Drive, Andover, Massachusetts 01810.
Sheng
Xiaoning C.
XC
Harrington
Edmund M.
EM
Ackermann
Karen
K
Garcia
Ana Maria
AM
Lewis
Michael D.
MD