Titanium-mediated cyclization of ω-vinyl imides in alkaloid synthesis: Isoretronecanol, trachelanthamidine, 5-epitashiromine, and tashiromine

Article abstract of DOI:10.1021/jo9907383

A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means of titanium-mediated cyclization of ω-vinyl imides is described. The general procedure involves treatment of readily available ω-vinyl imides 9 and 10 with 2.5 equiv of cyclopentylmagnesium chloride in the presence of ClTi(O-i-Pr)₃ (1.1 equiv) and subsequent stereoselective reduction of the N-acylaminal group. The cis and trans ring junction stereoisomers can be stereoselectively prepared by catalytic hydrogenation (H₂, PtO₂, EtOAc) and NaCNBH₃ reduction (TFA, MeOH), respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target alkaloids 1-8 in good yields.