Asymmetric total synthesis of vindoline.
A concise asymmetric total synthesis of (-)-vindoline (1) is detailed based on a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which the tether linking the initiating dienophile and oxadiazole bears a chiral substituent that controls the facial selectivity of the initiating Diels-Alder reaction and sets absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduces three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. Implementation of the approach also required the development of a unique ring expansion reaction to provide a six-membered ring suitably functionalized for introduction of the Delta (6, 7)-double bond found in the core structure of vindoline and defined our use of a protected hydroxymethyl group as the substituent used to control the stereochemical course of the cycloaddition cascade.
Kato
Daisuke
D
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Sasaki
Yoshikazu
Y
Boger
Dale L
DL
D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry; D010069:Oxadiazoles / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D001688:Biological Products; D010069:Oxadiazoles; C009667:vindoline; D014747:Vinblastine