Ribe, S and Kondru, RK and Beratan, DN and Wipf, P
(2000)
Optical rotation computation, total synthesis, and stereochemistry assignment of the marine natural product pitiamide A.
Journal of the American Chemical Society, 122 (19).
4608 - 4617.
ISSN 0002-7863
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Abstract
We report the joint application of ab initio computations and total synthesis to assign the absolute configuration of a new natural product. The expected specific rotations of the (7S,10R)- and (7R,10R)-isomers of pitiamide A in a CHCl3 solvent continuum model were determined as +8 and - 39, respectively, by CADPAC calculations of the electric-dipole-magnetic- dipole polarizability tensor. Total syntheses of these two stereoisomers of the marine metabolite were achieved by a convergent strategy that utilized Evans' oxazolidinone alkylation, a novel water-accelerated modification of Negishi's zirconocene-catalyzed asymmetric carbometalation as well as an unusual segment condensation via Mitsunobu alkylation of a nosyl-activated amide. The experimental optical rotation measurements confirmed the results of the computational optical rotation predictions. On the basis of NMR comparisons, the configuration of pitiamide A was assigned as (7R,10R). These studies highlight the considerable structural significance of [α](D) data, but, because the optical rotation of the natural product was different from either synthetic diastereomer, our work serves also as an illustration of potential problems with obtaining accurate experimental [α](D) data for natural samples.
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