An approach to the synthesis of the phomoidrides.
The phomoidrides are a structurally fascinating family of natural products which possess moderate inhibitory activity against Ras farnesyl transferase and squalene synthase. Since their discovery they have inspired a great deal of attention from synthetic chemists. Our own work, culminating in an efficient synthesis of the fully elaborated tetracyclic core of phomoidrides B and D, is described herein. The synthesis relies on a late stage tandem reaction involving a novel carbonylation reaction that delivers the strained bicyclic pseudoester system, which strain in turn drives a highly efficient silyloxy-Cope rearrangement that delivers the tetracyclic core of phomoidrides B and D. Several examples of this powerful tandem reaction are presented that document its tolerance of significant structural variation. The application of this methodology to the synthesis of a phomoidride D precursor lacking only the maleic anhydride is described, and the prospects for the completion of a total synthesis are discussed.
Bio
Matthew M
MM
Department of Chemistry, Columbia University, New York, New York, 10027, USA.
Leighton
James L
JL
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001685:Biological Factors / Q000032:analysis / Q000138:chemical synthesis*; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000032:analysis / Q000138:chemical synthesis*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D051231:Farnesyltranstransferase; D007202:Indicators and Reagents; D008299:Maleic Anhydrides / Q000032:analysis / Q000138:chemical synthesis*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism
D001685:Biological Factors; C104957:CP 263114; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D008299:Maleic Anhydrides; C438971:phomoidride D; D019883:Alkyl and Aryl Transferases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D051231:Farnesyltranstransferase