A Computational Study on the Stereo- and Regioselective Formation of the C4α-C6' Bond of Tethered Catechin Moieties by an Exhaustive Search of the Transition States.

We previously reported the total synthesis of procyanidin B6 by using the stereo- and regioselective C-C bond formation of tethered catechin moieties as the key step. The reaction afforded the product bearing a new C4α-C6' bond linkage instead of the inherently preferable C4α-C8' bond. However, the origin of this selectivity remained unclear due to the complex structure of the substrate. Here we report the results of computational exploration of this C-C bond formation to gain mechanistic insights into the selectivity. The computational study of highly flexible compounds was realized by an exhaustive search of transition states. A large library of candidate transition states was generated by a conformational search of constrained models using molecular mechanics simulations and semiempirical molecular orbital calculations. Subsequent DFT-based transition state calculations provided 367 transition states for C4-C6' and C4-C8' bond formations. Comparison of the geometries and energies showed that the C4α-C6' linkage is preferentially formed via two competing transition states, leading to a C6'-diastereomeric mixture. Interactive atomic distances and visualization of the nonbonding interactions suggest the importance of nonclassical hydrogen bonding and CH-π, π-π, and lone pair-π interactions in stabilizing the two transition states. The present study supports preferential C4α-C6' bond formation of the tethered catechins.