Organic Chemistry Portal
Organic Chemistry Highlights

Monday, May 16, 2005
Douglass Taber
University of Delaware

Diastereoselective and Enantioselective Construction of Cyclic Ethers

Because the stereocontrolled construction of cyclic ethers has been difficult and expensive, the use of cyclic ethers as pharmaceuticals has not been fully explored. With the development of powerful new methods for the diastereoselective and enantioselective construction of cyclic ethers, this situation is changing. The best of the recently developed methods for stereocontrolled cyclic ether construction are highlighted here.

Often, ethers are constructed by alkoxide displacement of a stereodefined leaving group. Hirakazu Arimoto of Nagoya University has found (Chem. Commun. 2004, 1220. DOI: 10.1039/b402391a) that it is possible to effect diastereocontrolled construction of cyclic benzylic ethers such as 2 by oxidation of 1 to the o-quinone methide. The more stable equatorial C-glycoside product 2 is formed in near quantitative yield.

Triply-convergent “linchpin” construction is a powerful approach to organic synthesis. Tarun Sarkar of the Indian Institute of Technology, Kharagpur reports (Angew. Chem. Int. Ed. 2004, 43, 1417. DOI: 10.1002/anie.200353184) the preparation of the valuable bis-silane 5. Condensation of 5 with 3 and 4 proceeded in a highly diastereoselective fashion, to give the five-membered ring ether 6.

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. Int. Ed. 2004, 43, 4788. DOI: 10.1002/anie.200460612) 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.

We (J. Org. Chem. 2004, 69, 7234. DOI: 10.1021/jo048863o) used the power of the Sharpless oxidations (epoxidation, dihydroxylation) to convert the prochiral 10 into the epoxy diol 11. Base-catalyzed cascade cyclization then converted 11 into crystalline 12, again with high diastereomeric and enantiomeric purity. An advantage of this approach is that by changing the absolute sense of the epoxidation and/or the dihydroxylation, it should be possible to selectively prepare each of the four enantiomerically-pure diastereomers of 12.

Amir Hoveyda of Boston College has developed (J. Am. Chem. Soc. 2004, 126, 12288. DOI: 10.1021/ja0458672) an elegant series of Ru catalysts for enantioselective alkene metathesis. The power of this approach is illustrated by the direct conversion of the easily-prepared prochiral alkene 13 into the enantiomerically-enriched cyclic ether 15.

D. F. Taber, Org. Chem. Highlights 2005, May 16.