Enantioselective synthesis of N1999A2.
An enantioselective synthetic route to the enediyne antibiotic N1999A2 (1) is described, proceeding in 21 steps (0.4% yield, 77% average yield per step) from (R)-(+)-glycidol. The route involves the convergent assembly of three components: a (1-iodovinyl) stannane (2), a 1,5-hexadiyne-3,4-diol derivative (3), and a substituted naphthoic acid (4). Important transformations in the synthetic sequence include the palladium-catalyzed coupling of 2 and 3, an intramolecular oxidative cyclization of a terminal bisacetylene, and a transannular anionic (bi)cyclization of a cyclic bromoenetriyne. The careful selection and manipulation of protective groups throughout the sequence proved to be critical to the development of the synthetic route, where all late-stage intermediates were unstable and could not be concentrated. In the final step of the sequence, three protective groups were removed in a single operation, providing synthetic N1999A2 (1) in 76% yield. Conditions were found that, for the first time, led to the precipitation of 1 as a solid.
Ji
Nan
N
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
O'Dowd
Hardwin
H
Rosen
Brad M
BM
Myers
Andrew G
AG
D053281:Enediynes / Q000138:chemical synthesis* / Q000737:chemistry; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D053281:Enediynes; D004852:Epoxy Compounds; C437375:N1999-A2; D009281:Naphthalenes