Stereocontrolled Construction of Cyclic Ethers

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 (/ Org. Chem. 2005, 70, 829) 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) that such an epoxide is reduced with Ti(UT) 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 Et,SiH conditions, and to the free radical removal of the xanthate derived from the alcohol. 

Synthesis of the Proteasome Inhibitors Salinosporamide A, Omuralide and Lactacystin 

The structurally-related y-lactams salinosporamide A I, omuralide 2 and lactacystin 3, of bacterial origin, inhibit proteasome activity, and so are of interest as lead compounds for the development of anticancer agents. Barbara C. M. Potts of Nereus Pharmaceuticals in San Diego has reported (7. Med. Chem. 2005, 48, 3684) a detailed structure-activity studies in this series, and E.J. Corey of Harvard University has prepared (7. Am. Chem. Soc. 2005,127, 8974, 15386) several interesting structural analogues. Susumi Hatakeyama of Nagasaki University, building on previous work in this area, has reported (7. Org. Chem. 2004, 69, 7765) a synthesis of 2 and 3 from Tris. 

In cell culture, 1 is by far the most active of these three natural products. The challenge in the synthesis of 1 is not closing the (3-lactone, but rather the stereocontrolled assembly of the y-lactam 9. 

---

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. 

Bicyclic Ketals Versatile Intermediates for the Stereocontrolled Construction of Cyclic Ether Derivatives. Kotsuki, H. Synlett 1992, 97. 

Stereocontrolled syntheses of macrolides and macrolactams are well developed. Much remains to be done toward the efficient enantioselective construction of five and suc-membered cyclic ethers and amines. Four recent natural product syntheses illustrate the current state of the art. 

---