title: Synthesis of a Potent Vinblastine: Rationally Designed Added Benign Complexity.
abstract: Many natural products, including vinblastine, have not been easily subjected to simplifications in their structures by synthetic means or modifications by late-stage semisynthetic derivatization in ways that enhance their biological potency. Herein, we detail a synthetic vinblastine that incorporates added benign complexity (ABC), which improves activity 10-fold, and is now accessible as a result of advances in the total synthesis of the natural product. The compound incorporates designed added molecular complexity but no new functional groups and maintains all existing structural and conformational features of the natural product. It constitutes a member of an analogue class presently inaccessible by semisynthetic derivatization of the natural product, by its late-stage functionalization, or by biosynthetic means. Rather, it was accessed by synthetic means, using an appropriately modified powerful penultimate single-step vindoline-catharanthine coupling strategy that proceeds with a higher diastereoselectivity than found for the natural product itself.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Oliver
authors.initials: O
authors.lastname: Allemann
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Manuela
authors.initials: M
authors.lastname: Brutsch
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Lukesh
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Brody
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D001688:Biological Products / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D013237:Stereoisomerism; D014747:Vinblastine / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D001688:Biological Products; D014747:Vinblastine