Synthesis of Sulfur-Containing Olefinic Peptide Mimetic Farnesyl Transferase Inhibitors Using the Nozaki−Hiyama−Kishi Reaction and Cuprate S<sub>N</sub>2‘ Displacements
1998-12-10T00:00:00Z (GMT) by
Syntheses of the potent sulfur-containing tetrapeptide mimetic farnesyl transferase inhibitors B956 (<b>22</b>) and B957 (<b>23</b>) are described. The two double bonds in <b>22</b> and <b>23</b> were constructed by application of iterative NHK and cuprate S<sub>N</sub>2‘ reactions. Normal <i>syn</i> NHK reaction and substrate-dependent <i>syn</i> and <i>anti</i>-S<sub>N</sub>2‘ diastereoselectivities accompanied by exclusive <i>E</i>-olefin selectivity were observed for the first NHK iteration (<b>1</b> → <b>4</b>). In the second iteration, unexpected epimerization and a strong preference for <i>syn</i> diastereoselectivity was observed for the NHK reaction (<b>5b</b> → <b>7a</b> + <b>9a</b>) while an unusual <i>Z</i>-olefin was observed for the S<sub>N</sub>2‘ reaction (<b>7b</b> → <b>11</b>). Deprotection conditions were optimized to ensure high purity and yield of the final aminothiol compounds.
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