Molecular Rearrangements of (-)-Modhephene and (-)-Isocomene to a (-)-Triquinane Pedro Joseph-Nathan, † Benito Reyes-Trejo, ‡ and Martha S. Morales-Rı ´os* ,† Departamento de Quı ´mica, Centro de InVestigacio ´ n y de Estudios AVanzados del Instituto Polite ´ cnico Nacional, Apartado 14-740, Me ´ xico, D. F., 07000 Me ´ xico, and Laboratorio de Productos Naturales, A Ä rea de Quı ´mica, UniVersidad Auto ´ noma Chapingo, Apartado 74, Oficina de Correos Chapingo, Texcoco, Me ´ xico, 56230 Me ´ xico smorales@cinVestaV.mx ReceiVed February 7, 2006 The preparation and further rearrangement of (-)-modhephene (1) to a (-)-triquinane 5 has been assessed through acid catalysis. The rearrangement involved protonation, 1,2 σ-bond and methyl shifts, and deprotonation. Monitored experiments by 1 H NMR spectroscopy suggested the intermediate (-)-isocomene (3), which was further evidenced when a sample of natural (-)-3 undergoes acid-catalyzed conversion to the (-)-triquinane 5. In addition, deuterated (-)-modhephene (1-d) labeled stereospecifically at the 14 geminal methyl group at C4 was synthesized, through the corresponding chiral deuterated primary alcohol, in 5 steps, starting from natural (-)-14-hydroxymodhephene (8), and rearranged under acid catalysis to elucidate the stereochemical factors that control the methyl shift at this position. The final deuterium-labeled (-)-triquinane, 5-d, obtained from [14- 2 H 1 ]-1-d was established to have deuterium in the methyl group at C5 by 13 C NMR spectroscopy. This stereoselective methyl migration is in accordance with the molecular orbital demand formulated by the quantum chemical calculations performed in the present study. Introduction A small class of tricyclopentenoid compounds known as triquinanes have received considerable attention in recent years as a result of their unique architecture, which presents significant synthetic challenges as well as a wide range of biological activity exhibited by some of them. 1 Although triquinanes are found in relatively abundant plants, they are present in only minute amounts as complex volatile mixtures of structurally similar isomers, thus, isolation of the pure components represents a major challenge. (-)-Modhephene (1), isolated from Isocoma wrigthii, 2 (Chart 1) was the first reported triquinane possessing the [3.3.3]propellane nucleus. The relative structure of (-)-1 was determined by single-crystal X-ray analysis of a derived diol, 2a and the absolute stereochemistry was established through the stereospecific rearrangement of (+)- and (-)-dispirounde- canol 2. 3 From Isocoma wrigthii was also isolated (-)- isocomene (3), 4 a triquinane possessing a cyclopenta[c]pentalene framework. (-)-Modhephene (1) has been the subject of a number of total racemic, diasteroselective, and enantioselective syntheses. 5 Within the strategies used, a new approach involves cationic cascade rearrangements of (()-dispiroundecanol 2. 6 Under † Centro de Investigacio ´n y de Estudios Avanzados del IPN. ‡ Universidad Auto ´noma Chapingo. (1) (a) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671-719. (b) Dobner, M. J.; Schwaiger, S.; Jenewein, I. H.; Stuppner, H. J. Ethnophar- macol. 2003, 89, 301-303. (2) (a) Zalkow, L. H.; Harris, R. N., III; Van Derveer, D. J. Chem. Soc., Chem. Commun. 1978, 420-421. (b) Bohlmann, F.; Zdero, C.; Bohlmann, R.; King, R. M.; Robinson, H. Phytochemistry 1980, 19, 579-582. (3) Fitjer, L.; Monzo ´-Oltra, H.; Noltemeyer, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1492-1494. (4) (a) Zalkow, L. H.; Harris, R. N., III; Van Derveer, D.; Bertrand, J. A. J. Chem. Soc., Chem. Commun. 1977, 456-457. (b) Bohlmann, F.; Le Van, N.; Pickardt, J. Chem. Ber. 1977, 110, 3777-3781. 10.1021/jo060258t CCC: $33.50 © 2006 American Chemical Society J. Org. Chem. 2006, 71, 4411-4417 4411 Published on Web 05/16/2006