Total Synthesis of Proanthocyanidin A1, A2, and Their Stereoisomers

The first novel stereoselective synthesis of naturally occurring A1 (<b>1</b>) and A2 proanthocyanidins (<b>2</b>) has been achieved. The key synthetic steps involved (a) the formation of a coupled product (<b>13</b> or <b>14</b>) between an open chain C-ring C-4 hydroxyethoxy analogue of either (+)-catechin or (−)-epicatechin with 5,7,3′,3′-tetra-<i>O</i>-benzyl-(+)-catechin/-(−)-epicatechin in the presence of bentonite clay K-10, (b) removal of benzyl protecting groups under mild catalytic hydrogenation conditions to form the desired A-type compound <i>in situ</i> as a mixture of diastereomers via ketal/oxonium ion/carbonium ion formation, and (c) separation of the diasteromers via silica gel column chromatography. The structures of A1 and A2 proanthocyanidins were unequivocally established by analytical comparison to the natural products. Following this methodology, an additional six diastereomers of proanthocyanidins A1 and A2 have been synthesized. A plausible mechanism for the formation of the A-type linkage in proanthocyanidins has been proposed

Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926

The formation of the d-homocyclopamine ring system in IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective cyclopropanation followed by a stereoselective acid-catalyzed carbocation rearrangement. In order to perform large-scale cyclopropanation reactions, we developed new iodomethylzinc bis­(aryl)­phosphate reagents that were found to be both effective and safe. These soluble reagents can be prepared under mild conditions and are stable during the course of the reaction. Importantly, they have favorable energetics relative to other cyclopropanating agents such as EtZnCH₂I. Herein, we describe the process optimization studies that led to successful large-scale production of the d-homocyclopamine core necessary for IPI-926