Asymmetric (4+3) Cycloadditions of Enantiomerically Enriched Epoxy Enolsilanes

Abstract

The (4+3) cycloaddition reaction is a direct and efficient method to construct seven-membered carbocycles. [1] Isoelectronic with the Diels-Alder reaction, the classical mechanistic understanding of this reaction is that an allyl cation dienophile, contributing two electrons, undergoes cycloaddition with the diene (Scheme 1). Cyclic dienes are commonly employed, thus resulting in bicyclic adducts which are useful synthetic intermediates. [2] Compared with the (4+2) reaction, however, asymmetric (4+3) cycloadditions remain underdeveloped. [3] Other than two examples of asymmetric catalysis, [4] the majority of asymmetric versions of (4+3) cycloadditions rely on chiral auxiliaries or incorporate chiral elements into the reacting cation or the diene. [5,6] On the basis of the seminal work by Eguchi et al., [7] we have developed a silyl-triflate-catalyzed intramolecular (4+3) cycloaddition reaction of furan-tethered epoxy enolsilanes such as 1, and it affords the cycloadduct 2 in excellent yield and diastereoselectivity (Scheme 2). [8] The corresponding intermolecular (4+3) cycloadditions with epoxy enolsilanes such as 3 a have also been observed to generate endo and exo cycloadducts with facial selectivity (Scheme 2). [9] In both cases, the reactions with optically active epoxy enolsilanes generate cycloadducts with high conservation of the enantiomeric excess. [8,10] Each of these cycloadducts has inherited one stereocenter (* in Scheme 2) from the epoxide precursor, so the observed selectivity could be understood as a diastereoselective cycloaddition of chiral oxyallyl cations, similar to the previously reported asymmetric (4+3) cycloadditions involving chiral cations. [5] In contrast, for intermolecular (4+3) cycloadditions of simpler enolsilanes such as the optically pure 5 a (Scheme 3), the corresponding oxyallyl cation would be expected to be devoid of any stereochemical elements, and should engender racemic cycloadducts. However, we have observed that the enantiomeric purity was, in fact, highly conserved in the cycloaddition. The treatment of 5 a, having a 99 % ee, with a catalytic amount of TESOTf in the presence of furan and a subsequent Et 3 N·3 HF desilylative workup resulted in endo and exo diastereomers with 92 and 97 % ee, respectively. [11] Cycloaddition with the more reactive cyclopentadiene afforded products with even higher enantiomeric excesses, thus showing essentially a complete retention of chirality.The absolute stereochemistry of the cycloadducts a-6 a and b-6 a were determined by X-ray crystallographic analysis of their (À)-camphanoyl and p-bromobenzoyl ester derivatives, 7 a and 7 b, respectively (see the Supporting Information for structures). [12] The observed absolute stereochemistry implies that carbon-carbon bond formation occurred with inversion of stereochemistry at the epoxide. The high degree of enantiomeric excess observed in this (4+3) cycloaddition shows that the reaction did not proceed through the putative achiral oxyallyl cation intermediate, which would necessitate that mos...

Dearomative Intramolecular (4+3) Cycloadditions of Arenes with Epoxy and Aziridinyl Enolsilanes

“…[10] In some cycloadditions with furan derivatives,F riedel-Crafts (FC) alkylation products were also observed as minor products.E xperiments and computational studies are consistent with an activated epoxide or aziridine as the dienophile,which undergoes cycloaddition to effectively transfer chirality to the cycloadduct. [11] When these aziridinyl enolsilanes were subjected to intermolecular reactions with arenes,F Calkylation products were produced, as expected. [12] However,wewere intrigued to find that in the triethylsilyl triflate (TESOTf) catalyzed reaction of the benzene-tethered epoxy enolsilane 1a,i n addition to the FC product, 3a,t he dearomatized (4+ +3) cycloadduct 2a,r esulting from ipso attack, was observed under these mild reaction conditions (Scheme 1).…”

Concerted Ring Opening and Cycloaddition of Chiral Epoxy Enolsilanes with Dienes

“…Experimentally, however, cycloadditions of 1 with furan display small losses of enantioselectivity (Scheme 2c). Moreover, the major diastereomer (2b) is isolated with a 4-16% lower ee than the minor diastereomer (3b) [7] (see also the Supporting Information). The losses of ee cannot be attributed to epimerization of the products.…”

“…However, we recently discovered that monosubstituted epoxy enolsilanes 1 (Scheme 2c) also undergo cycloaddition with excellent enantioselectivity. [7] Complete conservation of enantiomeric purity is obtained in the cycloaddition of 1 (R = Et) with cyclopentadiene, while a small (2-7%) erosion of ee is observed in the cycloaddition with furan. In the reaction with furan, the major (endo) diastereomer has a lower ee.…”

“…Thes ilyl-triflate-catalyzed reactions of epoxy enolsilanes with dienes (Scheme 2) [5,6] constitute am ild and chemoselective approach to (4+ +3) cycloadditions.T hese reactions have previously been understood to involve the intermediate oxyallyl cations C (Scheme 2), derived from ring opening of the silylated epoxide.H igh levels of diastereoselectivity are obtained in the inter-a nd intramolecular cycloadditions of disubstituted epoxy enolsilanes (Scheme 2a,b), and could formally be attributed to facially selective reactions of C (R 1 ¼ 6 H) with the diene.H owever, we recently discovered that monosubstituted epoxy enolsilanes (1;S cheme 2c) also undergo cycloaddition with excellent enantioselectivity. [7] Complete conservation of enantiomeric purity is obtained in the cycloaddition of 1 (R = Et) with cyclopentadiene,w hile as mall (2-7 %) erosion of the ee value is observed in the cycloaddition with furan. In the reaction with furan, the major (endo)d iastereomer has al ower ee value.T he high enantioselectivities obtained in the cycloadditions of 1 rule out any major role for oxyallyl cation C,which is achiral (R 1 = H), but Scheme 1.…”

“…Asymmetric (4+ +3) cycloadditions of disubstituted (a,b) and monosubstituted (c) epoxy enolsilanes. [6,7] TES = triethylsilyl, Tf = trifluoromethanesulfonyl.…”