Physical constraints on sesquiterpene diversity arising from cyclization of the eudesm-5-yl carbocation

The biogenic origins of complex cyclic terpenes derive from the interplay of enzymes and the intrinsic reactivity of carbocation species at major branch-points along intramolecular cyclization pathways to ultimately determine the distribution of terpene skeletal types in nature. Solanaceous plants biosynthesize chemical defense compounds, largely derived from the eremophilane and spirovetivane-type sesquiterpenes. These hydrocarbon skeletons share a common biogenic origin, stemming from alternative Wagner-Meerwein rearrangements of the eudesm-5-yl carbocation during the cyclization of farnesyl pyrophosphate (FPP) catalyzed by sesquiterpene synthases. While the spirojatamane skeleton shares the same carbocation intermediate, this class of sesquiterpenes has not been reported in the Solanaceae and is exceedingly rare in nature. To investigate the physical basis for alternative rearrangements of the eudesm-5-yl carbocation, we carried out quantum mechanics (QM) analyses to calculate the allowable conformations, energies, and transition states linking conformers of the eudesm-5-yl carbocation to the eremophilene, spirovetivane, and spirojatamane skeletons. Additionally, we conducted parallel investigations on simplified decalin carbocation systems to examine the contribution of ring substituents to allowable conformations and rearrangement pathways. Our study reveals that ring substituents expand the conformational space accessible to the eudesm-5-yl carbocation while sterically blocking rearrangements in certain contexts. From our analysis, we define a conformational threshold for each possible rearrangement based on dihedral angles describing transition state geometry. Further, our calculations indicate that methylene migration rearrangements leading to spiro compounds are thermodynamically dominant in the eudesm-5-yl and simpler decalin carabocation systems. Interestingly, the theoretical abundance of sesquiterpene skeletal types arising from the intrinsic reactivity of the eudesm-5-yl carbocation stands in sharp contrast to their currently known natural abundance. The implications of these results for the catalytic tragectories catalyzed by sesquiterpene synthases are discussed.