Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin.

ABSTRACT

Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl4 and CrCl3, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19-C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one-pot ketone synthesis to form the macrocyclic ketone.