Computational Analysis of the Selective Formation of the C4α—C8′ Bond in the Intermolecular Coupling of Catechin Derivatives

Abstract

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 1 and 2 by using models 5 and 7. Although a systematic search did not provide SN2-like transition states, we successfully identified transition states TS-A, TS-B, and TS-C for the SN1-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 TS-B, while the strain of the electrophile destabilizes TS-C. Consequently, the C4αC8′ bond is formed via the lowest energy transition state TS-A.