Internal Nucleophilic Termination in Biomimetic Acid Mediated polyene Cyclizations: Stereochemical and Mechanistic Implications. Synthesis of (+/-)-Ambrox and Its Diastereoisomers

Article abstract of DOI:10.1021/jo00029a031

Treatment of 10 structurally releted trienols and dienols 5-8 with an excess of fluorosulfonic acid in 2-nitropropane at -90 deg C afforded, in 74-87percent yield, diastereoisomeric mixtures of the odoriferous norlabdane oxides 9-15 ((-)-9 (Ambrox) is a naturally occuring ambergris odorant).These tranformations represent examples of efficientbiomimetic acid-mediated cyclizations in which the hydroxyl group serves as the internal nucleophilic terminator.The stereochemical outcome of these kinetically controlled processes has been analysed in detail, and mechanistic hypotheses consistent with the results have been proposed.For the four acyclic trienols 5, the major reaction pathway can be rationalized by a totally synchronous process involving three internal anti additions via chair or skew-boat conformations of the nascent cyclohexane rings.An alternative explanation postulates a nonsynchronous process in which ring closure to an intermediate cyclohexyl cation is followed by rapid cyclization, directed by a strong kinetic preference for equatorial C-C and C-O bond formation.In contrast, for the monocyclic dienols 6-8 only a nonsynchronous process, involving prior protonation of the cyclohexenyl bond, is fully consisitent with the results.In the nonsynchronous processes, the orientation of the side chain vicinal to the cyclohexyl cation directs the stereochemical course of the cyclization.For the acyclic trienols, this factor is predetermined by the configuration of the C(7)=C(8) bond, whereas, for the monocyclic dienols, this orientation is determined by the stereoselective axial protonation of the cyclohexenyl bond in 6, or by the distribution of cyclohexene and cyclohexane conformers in 7 and 8, respectively.In the cases studied, it is clear that conformational inversion of the six-membered ring is slower than cyclization and thus ensures that an equatorial side chain leads to a trans A/B ring junction in the cyclization product, whereas an axial side chain affords a cis A/B ring junction.