Synthesis of novel, potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal

The synthesis of novel, potent, diol-based HIV-1 protease inhibitors, havin g phenethyl groups (-CH2CH2Ph) in P1/P1' position is described. An intermol ecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanaI 16 wa s the key step in the synthesis. From this reaction sequence four carba ana logues, compounds 8a, 8b, 9a, and 9b, were prepared, having the inverted co nfiguration of one or both of the stereogenic centers carrying the diol hyd roxyls as compared to the parent series represented by inhibitors 6 and 7. Inhibitor 8b was found to be a potent inhibitor of HIV-1 protease (PR), sho wing excellent antiviral activity in the cell-based assay and in the presen ce of 40% human serum. The absolute stereochemistry of the central diol of the potent inhibitor (8b) was determined from the X-ray crystallographic st ructure of its complex with HIV-1 PR.