| Abstract
| - We report the joint application of ab initio computations and total synthesis to assign the absoluteconfiguration of a new natural product. The expected specific rotations of the (7S,10R)- and (7R,10R)-isomersof pitiamide A in a CHCl3 solvent continuum model were determined as +8 and −39, respectively, by CADPACcalculations of the electric-dipole−magnetic-dipole polarizability tensor. Total syntheses of these twostereoisomers of the marine metabolite were achieved by a convergent strategy that utilized Evans' oxazolidinonealkylation, 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. Theexperimental optical rotation measurements confirmed the results of the computational optical rotationpredictions. 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 rotationof the natural product was different from either synthetic diastereomer, our work serves also as an illustrationof potential problems with obtaining accurate experimental [α]D data for natural samples.
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