Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 21, 2005
Douglass Taber
University of Delaware

Stereocontrolled Construction of Cyclic Ethers

While N-heterocycles have dominated pharmaceutical synthesis from its inception, the increasing facility with which complex cyclic ethers can be assembled suggests that such cyclic ethers could also be suitable pharmaceutical platforms.

Martin E. Fox of Dowpharma Chiratech in Cambridge, UK, has described (J. Org. Chem. 2005, 70, 1227. DOI: 10.1021/jo048035v) a concise route to enantiomerically-pure tetrahydrofuran derivatives such as 3, starting from methyl D-malate. The alkylation of 1 proceeded with 20:1 diastereoselectivity, leading to the lactone 2. Reduction followed by exposure to Me3SiBr activated the lactol for coupling with the alkenyl cuprate, to give 3, again with high diastereoselectivity. The ether 3 is of interest as a prostaglandin analogue.

Sugars are also useful starting materials for the preparation of cyclic ethers. Maarten H.D. Postema, now at the Josephine Ford Cancer Center, Detroit, prepared (J. Org. Chem. 2005, 70, 829. DOI: 10.1021/jo040254t) the ester 4 from D-galactal. Methylenation of the ester carbonyl followed by ring-closing metathesis returned 5. Hydroboration of the enol ether then delivered the C-glycoside 6 in high diastereomeric purity.

Cyclic enol ethers such as 8 are also easily epoxidized. R. Daniel Little of the University of California, Santa Barbara has found (J. Org. Chem. 2005, 70, 5249. DOI: 10.1021/jo050465d) that such an epoxide is reduced with Ti(III) regioselectively to the radical, that adds with remarkable diastereocontrol to enones such as 7 to give the adduct 9. Reductive cyclization converted 9 to the tricyclic ether 10. The C-Br bond of 10 was stable both to the Et3SiH conditions, and to the free radical removal of the xanthate derived from the alcohol.

Medium rings can also be formed by ring-closing metathesis. Kenshu Fujiwara of Hokkaido University has demonstrated (Tetrahedron Lett. 2005, 46, 3465. DOI: 10.1016/j.tetlet.2005.03.114) that the ester 12 undergoes Claisen rearrangement to give 13 as a single diastereomer. Exposure to the second-generation Grubbs catalyst then delivers the eight-membered ring ether 14.

(-)-Zampanolide shows IC50 values of 1-5 nanomolar against several cell lines. The immediate precursor to zampanolide is dactylolide (19). Paul Floreancig of the University of Pittsburgh has developed (Angew. Chem. Int. Ed. 2005, 44, 3485. DOI: 10.1002/anie.200500564) a powerful approach to the macrocyclic ring system of 19. Attempted homologation of 15 to the allyl silane led directly to the cyclic ether 16, with high diastererocontrol. The stereodefined six-membered ring of 16 then served as a scaffold for assembling the macrolactone 19.

D. F. Taber, Org. Chem. Highlights 2005, November 21.