Synthesis of (−)-mesembrine using the quaternary carbon-constructing allylic substitution

Abstract

Synthesis of (−)-mesembrine was studied by using the allylic substitution for construction of quaternary carbons. The required allylic picolinate 6 (R = TBS) with the three substituents on the olefin was synthesized by hydromagnesiation of propargylic alcohol (S)-13 followed by iodination, Pd-catalyzed coupling of the resulting vinyl iodide (S)-14 with CH2CH(CH2)2MgBr and esterification with PyCO2H. The substitution proceeded stereo- and regioselectively to afford SN2′ product 9, which was transformed to keto aldehyde 29 by substitution with NsMeNH, Wacker oxidation and ozonolysis. Finally, aldol reaction and subsequent de-nosylation afforded the title compound. During the synthesis, the coupling of the vinyl iodide with alkylmetals was investigated under the Negishi conditions.