Titanium-Mediated Cyclization of omega-Vinyl Imides in Alkaloid Synthesis: Isoretronecanol, Trachelanthamidine, 5-Epitashiromine, and Tashiromine.

A new method for the stereocontrolled synthesis of pyrrolizidine and indolizidine alkaloids by means of titanium-mediated cyclization of omega-vinyl imides is described. The general procedure involves treatment of readily available omega-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 (H(2), PtO(2), EtOAc) and NaCNBH(3) reduction (TFA, MeOH), respectively. Finally, treatment of the resulting lactams with LAH or diborane afforded the target alkaloids 1-8 in good yields.