Optical Rotation Computation, Total Synthesis, and Stereochemistry Assignment of the Marine Natural Product Pitiamide A

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 (7 S,10 R )- and (7 R,10 R )-isomers of pitiamide A in a CHCl 3 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 (7 R,10 R ). 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.