Optical rotation computation, total synthesis, and stereochemistry assignment of the marine natural product pitiamide A

Wr report the joint application of ab initio computations and total synthes is to assign the absolute configuration of a new natural product. The expec ted 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, respect ively, by CADPAC calculations of the electric-dipole-magnetic-dipole polari zability tensor. Total syntheses of these two stereoisomers of the marine m etabolite were achieved by a convergent strategy that utilized Evans' oxazo lidinone alkylation, a novel water-accelerated modification of Negishi's zi rconocene-catalyzed asymmetric carbometalation as well as an unusual segmen t condensation via Mitsunobu alkylation of a nosyl-activated amide. The exp erimental optical rotation measurements confirmed the results of the comput ational optical rotation predictions. On the basis of NMR comparisons, the configuration of pitiamide A was assigned as (7R,10R). These studies highli ght the considerable structural significance of [alpha](D) data, but, becau se the optical rotation of the natural product was different from either sy nthetic diastereomer, our work serves also as an illustration of potential problems with obtaining accurate experimental [alpha](D) data for natural s amples.