The Carbon-Skeleton Rearrangement in Tropane Alkaloid Biosynthesis

High-level quantum chemistry calculations have been performed to examine the carbon-skeleton rearrangement of the tropane alkaloid littorine to hyoscyamine. Two pathways involving radical and carbocation intermediates have been investigated in this regard, namely, stepwise (or fragmentation−recombination) and concerted. The fragmentation products are calculated to be of high energy for both the radical- and carbocation-based mechanisms (136.3 and 170.9 kJ mol−1, respectively). Similarly, the rearrangement barrier for the radical-based concerted pathway is calculated to be quite high (135.6 kJ mol−1). In contrast, the carbocation-based concerted pathway is found to be associated with a relatively low barrier (47.4 kJ mol−1). The ionization energy of the substrate-derived radical 3a is calculated to be 7.01 eV, suggesting that its oxidation to generate the substrate-derived carbocation 3b ought to be facile. In an attempt to investigate how an enzyme might modulate the rearrangement barriers, the separate a...