Insights into the regioselectivity and diastereoselectivity of the Nazarov cyclization of 3-alkenyl-2-indolylmethanol with tryptophol

Abstract

The reaction mechanism of the Nazarov cyclization of 3-alkenyl-2-indolylmethanol with tryptophol was investigated in the presence and absence of 3 Å molecular sieves (MS), while insight was gained on the regioselectivity and diastereoselectivity. Density functional theory (DFT) calculations indicated that, whether in the presence or absence of the MS, the mechanism first involved cyclization to form a cyclic carbocation after the dehydration of 3-alkenyl-2-indolylmethanol with TsOH, and then a regioselective reaction with tryptophan. However, in the presence of the MS, π–π stacked binary complexes of tryptophan and TsO⁻ formed while the N1 position of tryptophan was activated to attack the cyclic carbocation and hence form C–N bond products—but in its absence, the formation of ternary complexes of tryptophan, TsO⁻ and trace H₂O with π–π stacking interactions were favored, and activated the C2 of tryptophan to attack the cyclic carbocation and hence generate C–C bond products. The transition state energy barrier of the cyclic carbocation and TsO⁻ with the (R)-configuration was lower than that with the (S)-configuration, so the diastereoselectivity of the final products were determined. This mechanism based on computational data was found to be quite consistent with the experimental results and is expected to provide theoretical guidance for follow-up work.