Configuration ethers, cyclic

Ether cleavage and further functionalization afforded the intermediate 268. The [5+2]-cycloaddition provided the hydroazulene 267 with the correct relative configuration at and C. Tracing back the synthesis of the pyryli-um ylide 266 leads to the astonishing realization that 2-methyl cyclopent-2-enone (90) was the original cyclic starting material and that the methyl as well as the isopropyl group were introduced by a sequence of cuprate addition and enolate alkylation (see Schemes 15, 31 and 36 for comparison). 

Homoallylic coupling (5,/nn) is closely related to allylic coupling in its stereochemical dependence. In cyclic compounds the existence of homoallylic couplings can be used for configurational assignments. For example, tru s-2,5-disubstituted bislactim ethers show a 4 Hz difference in the couplings between H-2 and H-5200. 

Cyclic cyanohydrin ethers, 6-alkyl-2,2-dimethyl-l,3-dioxane-4-carbonitriles 1, are easily available from silylated aldols. Deprotonation of 1 and subsequent alkylation gives, v+ -4,6-disubsti-tuted 2,2-dimethyl-l,3-dioxane-4-carbonitriles 2 in good yields in a highly diastereoselective reaction48. Primary bromoalkanes and oxiranes have been used as alkylating reagents. Reduction of the alkylation products 2 afforded the protected, vj. -l,3-diols 3 with complete retention of configuration (see Section D.2.I.). 

A similar set of reactions has been carried out with cyclic allyl ethers and alkylmagnesium halides using the same nickel catalyst, however, the optical yields are generally low (< 60 %)21 with the exception of the following example213. The optical purity and configuration of the product was established by chemical correlation with 3-ethvlhexanedioic acid. 

Distal C-C bond formation can also be used to construct cyclic ethers, but this demands that methods be developed for the enantioselective assembly of complex acyclic ethers. P. Andrew Evans of Indiana University has demonstrated (Angew. Chem. Jnt. Ed. 2004, 43,4788) that Rh-mediated coupling of secondary allylic carbonates such as 7 with secondary alcohols such as 8, both enantiomerically pure, proceeds with clean retention (double inversion) of absolute configuration. Alkene metathesis then delivers the cyclic ether 9 in high diastereomeric and enantiomeric purity. 

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