Oxygen-Directed Carbocyclizations of 2,3-Epoxy Alcohols:  Stereoselective Construction of Polyfunctionalized Seven-Membered Rings by 7-Endo-Tet Ring Closures

Abstract

The stereocontrolled construction of cycloheptanoid ring systems, relevant to sesquiterpenes and diterpenes of biological activity, is described. A new and highly efficient cyclization methodology provides stereocontrolled routes to polyfunctionalized and hydroxylated cycloheptanoid (and cyclohexanoid) rings. An alkyne or alkene terminus is shown to cyclize onto a 2,3-epoxy alcohol unit to give a cycloheptanoid ring incorporating syn-1,2-dihydroxylated functionality. Unusually, these carbocyclizations take place at the less substituted epoxide carbon atom of 2,3-epoxy alcohols, to the effective exclusion of alternative modes of cyclization. Chelation control is invoked to account for the highly efficient 7-endo-tet processes. Those processes occur at the expense of the normally more favored 6-exo-tet cyclizations. The little used Lewis acids SnBr4 and Sn(OTf)2 are shown to be effective in promoting acetylenic epoxy alcohol cyclizations. The effect of the relative configuration of the epoxy alcohol unit upon the outcome of the cyclization was studied.

Stereocontrolled Formation of Epoxy Peroxide FunctionalityAppended to a Lactam Ring

“…Recently we employed diastereoselective epoxidations as part of new methodology for the stereocontrolled construction of polyoxygenated bicyclic systems (Scheme , eqs. i and ii) . We have also shown that such epoxidations take a markedly different course when the carbocyclic backbone is replaced by a lactam system (Scheme , eqs.…”

“…The diastereoselective epoxidations (eqs. i and ii) shown in Scheme are prerequisite to Lewis acid mediated cyclizations that furnish polyfunctionalized fused carbocycles . The π-face selectivity exhibited by 1 and 3 is notable and in both cases the syn epoxy alcohols 2 and 4 result (in this context, we have found it useful to define the configuration by orienting the carbon framework as prior to a cyclization as in Scheme , and then to apply the terms syn and anti).…”

Asymmetric Catalytic Routes to Dialkyl Peroxides and Oxaziridines

“…The stereochemical outcome and the nature of the products of this reaction differ from the VO­(acac) 2 /TBHP-catalyzed epoxidation of the analogous carbocycles, in which the sole syn -epoxy alcohols were the preferentially observed diastereoisomers . Hence, epoxidation via hydroxyl coordination to the tin metal would not appear a likely route.…”

“…The stereochemical outcome and the nature of the products of this reaction differ from the VO(acac) 2 /TBHP-catalyzed epoxidation of the analogous carbocycles, in which the sole syn-epoxy alcohols were the preferentially observed diastereoisomers. 23 Hence, epoxidation via hydroxyl coordination to the tin metal would not appear a likely route. Although the mechanism was not investigated, a Lewis acid-catalyzed acyl iminium ion formation was hypothesized, followed by a Weitz− Scheffer nucleophilic epoxidation.…”

Synthesis of Single-Enantiomer 6-Hydroxy-7-phenyl-1,4-oxazepan-5-ones

“…A direct epoxide opening would be a 7-endo-tet ring closure. While 5-endo-tet ring and 6-endo-tet ring closures are disfavored 4 7-endo-tet ring closures are allowed and can even be facile under conditions of chelation control, 5 a condition, in this case, possibly provided by the magnesium ion. The uncertainty around the diastereomeric purity of 11df prevented accurately deducing why only the two cis oriented 2,7-diphenyl derivatives 1f and 2d were obtained.…”