Solid-Phase Synthesis of β-Lactam Analogues

Significance

The solid-phase synthesis of β-lactam analogues of cholesterol absorption inhibitors was achieved via Staudinger reaction and olefin cross-metathesis. The resin-bound aniline 3 was prepared from N-Fmoc p-aminophenol 1 and Wang resin 2 using TMAD and Bu₃P as coupling reagents. After Fmoc deprotection, the resulting resin-bound aniline was condensed with aldehyde 4 to give aldimine 5. Construction of the β-lactam ring was performed by the solid-supported Staudinger reaction using Mukaiyama’s reagent as an acid-activating agent to give 3-vinyl-β-lactam 6 with high trans selectivity. Olefin cross-meta­thesis of the resin-bound 3-vinyl-β-lactam 6 proceeded with complete E-selectivity with allylbenzene in the presence of the second-generation Grubbs precatalyst. The resulting β-lactam 7 was converted into the desired inhibitor 8 via cleavage of the resin supports, hydrogenation and methylation.