Intramolecular Diels-Alder Synthesis of Yohimbe Alkaloids.

Abstract

Our goal was to determine the feasibility of a stereospecificsynthesis of yohimbine 1 and like alkaloids by an intramolecularDiels-Alder construction of rings D and E with a precursor such as10. Of particular theoretical and practical interest was the geometry of the D/E ring fusion of the product(s) of this reaction. Would the "Endo rule" apply? Two synthetic approaches to a key model intermediate 10a were investigated. The first approach converted tryptamine by a multistep sequencethrough the intermediate 146 to betaine 79. An attempt todecarboxylatively eliminate betaine 79 thermally to 10a failed. A byproduct of this synthetic approach was converted to model compound 152. This intramolecularly cyclized to a mixture of yohimbane and alloyohimbane derivatives, 160 and 161, whose stereochemistry was assigned by combined spectral methods with detailed consideration of their carbon-13 magnetic resonance spectra. The second approach to 10a proposed the addition of carbanionic reagents to N-norharmalanium salts. The feasibility of this approach was demonstrated by synthesis of 173 and its intramolecular cyclization to a mixture of (DELTA)18,19 yohimbene 177 and (DELTA)18,19 alloyohimbene 178, which were identified by spectral means and conversion to ((+OR-)) yohimbane and ((+OR-)) alloyohimbane. The selectivity of the reactions of 152 and 173 for products with only the normal and allo stereochemistry is rationalized by non-bonded interactions of the diene and dienophile with atoms of the connecting chain. A brief discussion of recent relevant literature on the factors affecting the geometry of the ring fusion formed in intramolecular Diels-Alder reactions is presented. Carbon-13 magnetic resonance data are reported and assigned for most intermediates. Previous syntheses of yohimbine are briefly and critically reviewed.