Synthesis of the Verapamil Intermediate through the Quaternary Carbon-Constructing Allylic Substitution

In the present study, the key secondary allylic picolinate was synthesized via Pd(PPh 3 ) 4 -catalyzed coupling of the TBS ether of ( R , Z )-4-iodo-5-methylhex-3-en-2-ol with allyl-MgBr. Allylic substitution of the picolinate with the copper reagent derived from 3,4-(MeO) 2 C 6 H 3 MgBr and Cu(acac) 2 in a 2:1 ratio afforded the anti S N 2′ product with complete chirality transfer and 91% regioselectivity. Synthetic manipulation of the olefin moiety led to the nitrile group, generating the intermediate for the synthesis of ( S )-verapamil.