Computational investigation on the mechanism and stereochemistry of guanidine-catalyzed enantioselective isomerization of 3-alkynoates to allenoates

The mechanism of guanidine-catalyzed enantioselective isomerization of 3-alkynoates to allenoates is investigated using density functional theory methods. The calculations predict that the isomerization reaction includes two hydrogen-transfer steps and one conformational change mediated by the TBO catalyst. The first hydrogen-transfer step corresponds to the migration of hydrogen from C(4) of the substrate to the guanidine catalyst, and the second one to the transfer of this hydrogen from the guanidine catalyst to C(6) of the substrate forming the product. The calculations predict that the first hydrogen-transfer step (deprotonation of the substrate) might be the rate-determining step for the overall reaction. In the chiral system, the evolution of IM1s is crucial for the enantioselectivity of the reaction, which is more relevant to the second hydrogen-transfer step via TS2. In TS2, the N-H···O hydrogen bond between the guanidine catalyst and the substrate, sensitive to the chiral environment, might account for the enantioselectivity of the isomerization reaction. The larger size of the substituted group at the chiral site of guanidine could selectively make one of the competing transition states unstable in terms of significantly decreasing the strength of the N-H···O hydrogen bond in the disfavored TS, which results in a high ee value.