title: The carbon-skeleton rearrangement in tropane alkaloid biosynthesis.
abstract: 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 and combined influences of partially protonating the migrating group and partially deprotonating the spectator OH group of the substrate were investigated. Such interactions can lead to significant reductions in the rearrangement barrier for both the radical- and carbocation-based concerted pathways, although the carbocation pathway continues to have significantly lower energy requirements. Also, the relatively high (gas-phase) acidity of the OH group of the product-related carbocation 4b indicates that the direct formation of hyoscyamine aldehyde (6) is a highly exothermic process. Although we would not wish to rule out alternative possibilities, our calculations suggest that a concerted rearrangement mechanism involving carbocations constitutes a viable low-energy pathway for the carbon-skeleton rearrangement in tropane alkaloid biosynthesis.
authors.affiliation: School of Chemistry and ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, University of Sydney, Sydney, NSW 2006, Australia. sandala@chem.usyd.edu.au
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Sandala
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.forename: Leo
authors.initials: L
authors.lastname: Radom
mesh_terms: D001285:Atropine / Q000096:biosynthesis* / Q000737:chemistry*; D001286:Atropine Derivatives / Q000737:chemistry* / Q000378:metabolism*; D002244:Carbon / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D015394:Molecular Structure; D010088:Oxidoreductases / Q000737:chemistry
chemical_list: D001286:Atropine Derivatives; C063158:littorine; D002244:Carbon; D001285:Atropine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases