Computational Analysis of the Selective Formation of the C4α-C8' Bond in the Intermolecular Coupling of Catechin Derivatives.

Procyanidin B3 is a natural flavonoid composed of two catechins connected via a C4α-C8' bond. The couplings of catechin derivatives, promoted by Lewis acids, have been widely applied to the syntheses of procyanidin B3 and related flavonoids because the reactions construct the C4α-C8' bond in a highly stereo- and regioselective manner. However, the structural complexity of the catechin derivatives has complicated the exploration of a detailed mechanism for this selectivity. Here, we report the results of a computational study to provide plausible origins for the selective C4α-C8' bond formation of catechin derivatives and by using models and . Although a systematic search did not provide S2-like transition states, we successfully identified transition states , , and for the S1-type C4α-C8', C4β-C8', and C4α-C6' bond formations, respectively, from a total of 233 transition states to justify the stereo- and regioselectivity of the experimental results. The analysis of these structures by NCIPLOT mapping and the distortion/interaction strain model suggests that the eclipsed interaction at the forming C-C bond between the electrophile and the nucleophile destabilizes , while the strain of the electrophile destabilizes . Consequently, the C4α-C8' bond is formed via the lowest energy transition state .