Questioning the γ-gauche effect: stereoassignment of 1,3-disubstituted-tetrahydro-β-carbolines using 1H–1H coupling constants

Abstract

The Pictet–Spengler reaction of tryptophan esters and aldehydes has been widely applied in natural product synthesis and medicinal chemistry. To date, the trans- or cis-configuration of 1,3-disubstituted tetrahydro-β-carbolines (THβCs) formed in this reaction has most often been assigned based on the relative ¹³C chemical shifts of C1 and C3 in the diastereomers. Although the upfield shifts of C1 and C3 in trans-THβCs relative to cis-THβCs has been attributed to steric compression associated with the “γ-gauche” effect, we show that this effect is not borne out experimentally for other carbons that should suffer this same compression. Thus we developed a robust alternative method for stereochemical assignment based on ¹H NMR coupling constants (31 examples) and supported by extensive DFT-based conformational analysis and calculation of ¹H–¹H coupling constants. DFT calculations of ¹³C NMR chemical shifts also cast doubt upon the role of the “γ-gauche” effect on C1 and C3 chemical shifts in trans-THβCs.