Conformational analysis of some type XII bisbenzyltetrahydroisoquinoline alkaloids from Thalictrum alpinum assisted by quantitative noe, j coupling constants analysis and anisotropic NMR parameters

Abstract

Northalrugosidine (1), a type XII bisbenzyltetrahydroisoquinoline alkaloid, exhibits in vivo efficacy in a murine model of visceral leishmaniasis (J. Nat. Prod., 2015, 78, 552 – 556). The conformational space of the macrocyclic moiety in compounds within the same subgroups of this class should provide more clues on their structure-activity relationships, which will be very beneficial for the potential future medicinal chemistry optimization of 1. The solution-state conformation of this molecule was investigated by conducting NMR spectroscopic studies on two naturally occurring analogues in the same subclass, thalrugosidine (2) and thalidasine (3). Residual dipolar couplings (RDCs), collected in compressed PMMA gel, were employed for the determination of relative spatial orientation of 1H-13C bonds, whereas 1H-1H inter-atomic distances were determined by measurement of quantitative nuclear Overhauser effects (qNOEs). The conformation of the studied molecules in solution was determined by simultaneous fitting of these NMR data and 3 J H,H coupling constants with computed molecular models.