Investigations on the intramolecular (4+3) cycloadditions of epoxy enolsilanes, and applications towards the asymmetric synthesis of himandrine

Abstract

The intramolecular (4+3) cycloadditions of epoxy enolsilane substrates 1.89 generated polycyclic cycloadducts 1.90 having bicyclo[5.3.0]decane frameworks, a skeleton which is common among terpenoid natural products (Scheme 1). Each cycloadduct has been fully characterized, and two cycloaddition models have been proposed to rationalize their formation. Epimerization has been observed to generate an additional diastereomer which did not directly result from cycloaddition. Cycloaddition of optically enriched (+)-1.89b produced 1.90b with conserved ee. Tethered pyrroles having a range of N-protecting groups and substituents have been synthesized and their cycloadditions examined (Scheme 2). The intramolecular (4+3) cycloadditions of pyrrolyl enolsilanes such as 2.171 has been observed to proceed with good yields and diastereoselectivities. The endo cycloadducts (type i) were the major diastereomers in all cycloadditions, except when the pyrrole is substituted at C3. Cycloaddition models have been proposed to explain the stereochemical outcomes. Cycloaddition of enantiomerically pure (+)-2.106 also provided (–)-2.113a and (+)-2.114 with conserved ee. Based on these results, we have pursued the asymmetric synthesis of 3.77, the BCDEF rings of himandrine, a Type II Galbulimima alkaloid. The intramolecular (4+3) cycloaddition of optically enriched pyrrole (+)-3.127 to generate cycloadduct (–)-3.138ii, was the key step to construct the BCF ring system of the himandrine core (Scheme 3). From (–)-3.138ii, the methoxycarbonyl group was introduced by a palladium-catalyzed carbonylation, and further transformations provided cyclic amine (–)-3.159. Ring E was formed by the aza-Michael/Mukaiyama aldol sequence, and the resultant alcohols 3.167 were reduced by a Barton-McCombie deoxygenation. For constructing ring D, a metal-halogen exchange and intramolecular carbonyl addition were employed. Finally, the target molecule (–)-3.77 has been successfully achieved in 19 (or 20) steps.