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

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.