We have discovered a novel two-step route to cis- and trans-fused bicyclic amines with multiple substitution and functionality. A double Michael reaction between a tethered carbon diacid and an alkynone gives a cyclopentane, cyclohexane, or piperidine ring with pendant functionality. A piperidine, pyrroline, or cyclohexane ring is then trans-annulated or a piperidine ring is then cis-annulated onto the first ring to give an azabicyclic compound with multiple functionality and well-defined stereochemistry. Protecting groups are not required for these highly chemo-, regio-, and stereoselective reactions, despite the densely functionalized nature of the intermediates. The method is distinguished from existing ones by its wide scope and by the highly substituted and functionalized nature of the products, which have heretofore been available only with difficulty.
Our specific aims are to expand the scope of the double annulation route to bicyclic amines, including, trans-perhydroisoquinolines, trans-perhydroindoles, and cis-perhydroisoquinolines, and to apply it to the synthesis of biologically active molecules. We will prepare a series of tethered diacids and alkynones and explore the kinds of structures we can create, paying special attention to the preparation of rigid, cyclic alpha- and beta-amino acids. Our route to trans-perhydroisoquinolines will be used to prepare yohimbine, an alpha2-adrenoceptor antagonist, corynanthine an alpha1-adrenoceptor antagonist, and codeine, a mu-opioid receptor agonist, by unique and efficient routes that are amenable to the preparation of bioactive analogs. The yohimbine and corynanthine analogs will be tested for alpha-adrenoceptor antagonist activity.
| Blankenship, Jimmy D; Houseknecht, Justin B; Pal, Sitaram et al. (2005) Biosynthetic precursors of fungal pyrrolizidines, the loline alkaloids. Chembiochem 6:1016-22 |
| Ciochina, Roxana; Grossman, Robert B (2003) A new synthetic approach to the polycyclic polyprenylated acylphloroglucinols. Org Lett 5:4619-21 |
| Holeman, Derrick S; Rasne, Ravindra M; Grossman, Robert B (2002) Trimethylsilylethynyl ketones as surrogates for ethynyl ketones in the double Michael reaction. J Org Chem 67:3149-51 |
