Chiral Phosphoric Acid-Catalyzed Stereoselective Transformations of Vinyl Ethers and Acetals.

Few methods exist for asymmetric nucleophilic addition to reactive oxocarbenia-like systems. A direct, chiral-catalyst controlled method to perform such transformations would simplify the task of synthesizing moieties such as nonthermodynamic spiroketals and chiral piperidines. We have developed a chiral phosphoric acid-mediated spiroketalization reaction yielding spiroketals with 54-96%ee. Lower enantioselectivities were observed when nucleophile sterics were decreased. Hammett analysis is consistent with a concerted mechanism that does not involve a significant amount of charge development in the transition state of the reaction (ro = -1.3). In addition, a deuterium labeling study suggests the acidic proton from the catalyst and the hydroxy nucleophile add to the enol ether from the same face of the molecule. This syn addition was observed in a range of solvents as well as with a variety of achiral, strong Bronsted acids. These findings raise the possibility that even achiral acids can provide stereocontrol in an underappreciated manner. Computational analysis found agreement with a concerted pathway being the lowest in energy. Direct dynamics assist us in concluding that oxocarbenia are not stable intermediates in this reaction, nor are they long-lived transition states, with collapse of the transition state to spiroketal occurring in an average of 519 fs in model systems. Finally, the mechanism of an aza-Michael reaction yielding chiral piperidines was investigated computationally. A new transacetilization/SN2’-like pathway involving a chiral phosphate acetal intermediate was identified as the lowest energy pathway. The validity of this pathway was reinforced upon investigation of the formation of the minor enantiomer of the product, the pathway for which was 3.2 kcal/mol higher than that of the major stereoisomer. This difference in energy is in agreement with the propensity of the reaction to favor the observed major product, and stems from the ability of the major isomer to form an H-bond between the N-H and a phosphate oxygen present in the catalyst. These findings call for a recategorization of the mechanism of strong Bronsted acid-catalyzed spiroketalization reactions and chiral pipieridine formations from operating through an oxocarbenium ion intermediate to a concerted, asynchronous reaction mechanism, and a transacetilization/SN2’-like mechanism, respectively.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113427/1/gwinsche_1.pd