A cycloaddition cascade approach to the total synthesis of (-)-FR182877.
An asymmetric synthesis of the cytotoxic natural product, (-)-FR182877 (1), has been achieved. Chirality for the entire structure was established using two (4R)-4-benzyl-2-oxazolidinone-mediated boron aldol reactions. A 19-membered macrocarbocycle was synthesized by the coupling of two fragments using a regioselective Suzuki coupling (17 + 23 --> 26; 84%) and macrocyclization of a beta-keto ester (30 --> 31; 77%). Oxidation of 31 triggered a sequence of stereoselective transannular Diels-Alder reactions (32 -->34; 63%) forming four new rings and seven new stereocenters in the pivotal construction event. This pentacyclic intermediate was subsequently transformed to (-)-FR182877. Semiempirical calculations of the transannular Diels-Alder cycloaddition cascade were carried out to determine the origins of asymmetric induction.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. evans@chemistry.harvard.edu
David A
DA
Evans
Jeremy T
JT
Starr
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; C408303:FR 182877; D011083:Polycyclic Compounds