Oxazolidine molecules undergo the aza-Cope Mannich reaction (ACM) to yield acyl pyrrolidines in a diastereoselective fashion.  We model the ACM reaction for oxazolidines with different substituents at their respective carbinol carbon using density functional methods. Experimental data indicates that the stereoselectivity of the methylated oxazolidine is much higher than that of the unsubstituted substrate. We calculate activation barriers for the rate-determining step in the ACM reaction and for a series of C-C bond rotations that can erode the stereoselectivity. Results indicate that in the case of the methylated oxazolidine barriers to C-C bond rotation are significantly higher than those for the ACM reaction, suggesting that little scrambling of stereoselectivity will occur.  The reverse is true in the case of the unsubstituted substrate.  In order to separate electronic from steric effects we also use a trifluoromethyl substituent at the carbinol carbon.

Effect of carbinol substituents on product stereoselectivity in an aza-Cope - Mannich reaction

246th National Meeting (2013)

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