Total synthesis of proanthocyanidin A1, A2, and their stereoisomers.

The first novel stereoselective synthesis of naturally occurring A1 (1) and A2 proanthocyanidins (2) has been achieved. The key synthetic steps involved (a) the formation of a coupled product (13 or 14) between an open chain C-ring C-4 hydroxyethoxy analogue of either (+)-catechin or (-)-epicatechin with 5,7,3',3'-tetra-O-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 in situ 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.

Synthesis and in vitro pharmacological studies of C(4) modified salvinorin A analogues.

Salvinorin A is the most potent naturally occurring opioid agonist with a high selectivity and affinity for kappa-opioid receptor. To explore its structure-activity relationships, modifications at the C(4) position have been studied and a series of salvinorin A derivatives were prepared. These C(4)-modified salvinorin A analogues were screened for binding and functional activities at the human kappa-opioid receptor and several potent new agonists have been identified.

Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues.

Salvinorin A is the most potent naturally occurring opioid agonist yet discovered with high selectivity and affinity for kappa-opioid receptor. To explore its structure and activity relationships, a series of salvinorin A derivatives modified at the C2 position were prepared and studied. These salvinorin A derivatives were screened for binding and functional activities at the human kappa-opioid receptor.