Understanding diastereofacial selection in carbohydrate-based domino cycloadditions: Semiempirical and DFT calculations

The sequential cycloaddition of nitroalkenes with methyl vinyl ether was in vestigated by semiempirical (PM3) and density functional methods (B3LYP/6-3 1G*). The asymmetric version was also examined with a threo-configured carb ohydrate auxiliary. This produces a larger, more flexible system that compl icates the calculation. Most transition structures were then fully optimize d at the: PM3 level and further refinement was done at ab initio levels. Th is study represents a model case that enables the rationalization of the hi gh facial selectivity observed in carbohydrate-based nitrone- and nitronate -alkene cycloadditions. The selective endo orientation of the [4+2] pathway results from Coulombic attraction and secondary orbital interactions in th e transition state. The stereochemical outcome is largely influenced by a c ombination of steric shielding from the bulky chiral substituent at C4 and the anomeric effect that places the nitronate C6-alkoxy group in a pseudoax ial arrange ment. The resulting conformation favors the subsequent exo appr oach of methyl vinyl ether to the less hindered re face of the nitronate. I t is also remarkable to note that solvation energies stabilize significantl y a particular transition structure, thereby explaining the marked stereose lection observed in a polar medium.