Intramolecular (3+2) cycloaddition reactions of epoxy and aziridinyl enolsilanes

Abstract

Epoxy and aziridinyl enolsilanes that engaged in (4+3) cycloaddition reactions with dienes, have now been demonstrated to undergo (3+2) cycloaddition reactions with alkenes and indoles to form fused five-membered rings bearing up to four contiguous stereocenters. Epoxy/aziridinyl enolsilanes tethered with alkyl-, aryl- and vinyl-substituted alkenes, underwent intramolecular (3+2) cycloaddition reactions to generate 6,5-fused cycloadducts as single diastereomers with up to 97% yield. The conformations of dienes affected the course of the cycloaddition. The open dienes that were locked in the s-cis conformation underwent (4+3) cycloaddition as the major pathway. However, dienes which are found predominantly in the s-trans conformation, produced only the corresponding (3+2) cycloadducts by cycloaddition with one of the double bonds. The use of more bulky silyl groups on the enolsilane required a longer time to complete the reaction without affecting the yields. Different protecting groups on the aziridines, including Ts, Bz, Piv are compatible in the cycloaddition. Enolsilanes with a substituent on the double bond failed to undergo cycloaddition, probably because this led to the formation of highly reactive oxyallyl cations, which tended to decompose under these conditions. The intramolecular (3+2) cycloadditions were also limited to substrates whose tethers led to the formation of intervening 6- membered-rings. Optical purity was conserved from epoxides and aziridines to the corresponding (3+2) cycloadducts which provides a new asymmetric strategy for the synthesis of hydrindanes. Experimental results were consistent with the computational studies, showing that the cycloaddition proceeded by stepwise bond formations with the activated epoxide or aziridine, to form a carbocationic intermediate. A second C-C bond formation culminated in a formal (3+2) cycloaddition. Intramolecular (3+2) cycloaddition reactions of epoxy and aziridinyl enolsilanes tethered to indoles have also been found to afford highly functionalized cyclopentaindoline compounds in yields of up to 88%. A total of fourteen indole substrates tethered to the epoxide or aziridine at C3 were studied. Cycloaddition occurred only to provide cycloadducts with an intervening 6-membered ring. Those that are N-protected with electron-donating and electronwithdrawing protecting groups underwent intramolecular (3+2) cycloadditions with similar reactivity and selectivity. The nature of C5 substituents also had minimal effects on the yield and diastereoselectivity. Generally, endo and exo cycloadducts are possible. When R´ = H, the diastereoselectivity is low. However, when R´ = Me or Et, the indole substrates underwent highly endo-selective intramolecular (3+2) cycloadditions. All of the endo cycloadducts tended to undergo epimerization to afford a more stable polycyclic framework. Cycloaddition of enantiomerically pure (–)-3.68 and (+)-3.74 also provided cycloadducts with conserved ee. The reactions of indoles tethered to the epoxide at C2 and at N1 were also studied. Intramolecular (3+2) cycloadditions proceeded, but with significantly decreased yields (< 20%). Many of these substrates underwent one C-C bond formation to generate Friedel–Crafts products. Nevertheless, the successful cycloadditions of these indoles constructed fused indolines that show a skeletal diversity.