Chemical & biochemistry

The transannular oxidative cycliration of I-methylcyclooct-4-en-l-o1 and cyclooct-4en-l-01 was studied using hypervalent iodine reagents. The regioselectivity for the [3.3.1] vs. 14.2.11 9-oxabicyclononane skeletom is low, but the addition is highly ~-selective; the results are rationalized in terms of a tricyclic oxonium ion intermediate.

The bicycloannulation reaction between cyclohexenone and indolyl enamines yields trans-3-(cyclic amino)-2-(3'indolyl)bicyclo[ 2.2.2]octan-5-ones, and these adducts are conformationally restricted analogues of indolylethylamine (tryptamine) which exhibit structure-dependent affinity for the serotonin 5HT2 and 5HT1, receptors. The stereochemistry of the isomeric endo and exo adducts obtained is assigned from the 'H NMR spectra of the specifically deuterated alkenes prepared from the ketones by the Bamford-Stevens reaction. Molecular mechanics calculations indicate that the conformational flexibility of the amino and indolyl groups is restricted through van der Waals interactions with the bridges of the bicyclic unit. These compounds inhibit the binding of [3H]ketanserin to 5HT2 sites in mouse cerebrocortical membranes, and the binding of [3H]-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]-8-OH-DPAT) to 5HT1, sites in mouse hippocampal membranes. The endo compounds are the most potent, and molecular mechanics calculations indicate that these isomers have a less bulky bicyclo bridge proximate to the amine group and more conformational freedom about the C,-C,-N+-H bridge of the bicycla[ 2.2.2loctane ~keleton.~ These adducts bear a carbonyl group on one of the two remaining ethano bridges, giving rise to geometric isomers: endo when the carbonyl is syn to the amine moiety and exo when the carbonyl is syn to the indole group.5 This structure provides a framework from which additional analogues can be made by changing the amine substituent (different sized cyclic amines), the indole substituent (substituted indole, phenyl, substituted phenyl), and the (1) For recent work in this area, see: (a) Taylor, E. W.; Nikam, S.; Weck, B.; Martin, A,; Nelson, D. Life Sci. 1987, 41, 1961. (b) Tuomisto, J.; Tuomisto, L. J . Neural Transm. 1987, 68, 191. (c) Cannon, J. G.; Mohan, P.; Bojarski, J.; Long, J. P.; Bhatnagar, R. K.; Leonard, P. A.; Flynn, J. R.; Chatterjee, T. K. J. Med. Chem. 1988, 31, 313. (d) Glennon, R. A.; Titeler, M.; Lyon, R. A.; Slusher, R. M. J. Med. Chem. 1988,31, 867. (e) Hogberg, T.; Svante, B. R.; Strom, P.; Grunewald, G. L.; Creese, M. W.; Bunce, J. D. Engel, G.; Feniuk, W.; Fozard, J. R.; Humphrey, P. P. A.; Middlemiss, D. N.; Mylecharane, E. J.; Richardson, B. P.; Saxena, P. R. Neuropharmacology 1987, 25, 563. (3) (a) Leysen, J. E.; Niemegeers, C. J. E.; Van Nueten, J. M.; Laudron, P. M. Mol. Pharmacol. 1981,21,301. (b) Reith, M. E. A.; Sershen, H.; Lajtha, A. Biochem. Pharmacol. 1984,33, 4101. (4) Schlecht, M. F.; Giandinoto, S. Heterocycles 1987, 25, 485. The spectral data for compounds 4b and 4c in this earlier paper (9a and 9b in the present work) should be reversed. ( 5 ) For this series we define endo and exo on the basis of which substituent (indole or amine) is syn to the carbonyl. We assign a higher priority to the amine group since the carbon of the bicyclic skeleton is bonded to nitrogen for this substituent, versus a bond to carbon for the indole substituent. Thus the isomers 9a, loa, and 11 are endo isomers, with the carbonyl syn to the higher priority substituent, and 9b and 10b are exo isomers. Analogous assignments are used for the corresponding alkenes.