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Monday, October 24, 2005
Douglass Taber
University of Delaware

O-Heterocyclic Construction by Alkene Metathesis

In the preparation of enantiomerically-pure starting materials, it is not uncommon for the early low molecular weight intermediates to require special handling. Often, the initial stereogenic centers are derived from carbohydrate precursors. Bastien Nay of the Muséum National d’Histoire, Paris has developed (Tetrahedron Lett. 2005, 46, 3867. ) an elegant approach that takes advantage of alkene cross metathesis. Enantiomerically-pure diols such as 1, readily prepared from mannitol, are easy to handle. Exposure of the derived acrylate to the second generation Grubbs catalyst gives clean transformation to two equivalents of the γ-lactone 3. The corresponding δ-lactones are formed even more efficiently from the vinyl acetate esters of 1.

Kevin J. Quinn of the College of the Holy Cross chose (Org. Lett. 2005, 7, 1243. ) a complementary approach in his synthesis of rollicosin. The symmetrical diol 4 is also available from carbohydrate precursors. Monosilylation followed by esterification with acryloyl chloride gave 5. Exposure of 5 to the Grubbs catalyst in the presence of 6 led, by ring-closing metathesis and cross metathesis, to the γ-lactone 7. Note that δ-lactone formation did not compete!

En route to a synthesis of (+)-peluroside A, Mikhail S. Ermolenko of the Institut de Chemie, Gif-sur-Yvette, envisioned (Org. Lett. 2005, 7, 2225. ) selective construction of the trisubstituted alkene by ring-closing metathesis of the ester 8. Unfortunately, preparation of 8 was accompanied by substantial racemization, to give 9. In fact, this proved to be an advantage, because it led to the observation that 8 participated in ring-closing metathesis about 50 times as rapidly as 9, delivering 10 contaminated with only a trace of the diastereomeric δ-lactone. Thus, the mixture of 8 and 9 was prepared using the racemic acid choride, and the unreacted 9 was recycled to the mixture of 8 and 9 by brief exposure to LDA.

Stereodefined spiroketals are a common structural motif in physiologically-active natural products. Richard P. Hsung of the University of Minnesota recently reported (Org. Lett. 2005, 7, 2273. ) that Tf2NH is a particulary effective Brønsted acid mediator for the stereoselective coupling of vinyl lactols such as 11 with homoallylic acids such as 12. The axial ethers so produced undergo smooth ring-closing metathesis to the spiroketals.

Ring-closing metathesis can also be used to close larger rings. In the course of a total synthesis of (-)-dactylolide, Michael P. Jennings of the Unversity of Alabama described (Org. Lett. 2005, 7, 2321. ) the preparation of the diol 15. Despite the presence of four other alkenes in 15, brief exposure to the second generation Grubbs’ catalyst (1 h, rt) delivered 16 in excellent yield. Both of the diastereomers of 15 appeared to participate with equal efficiency in the cyclization.

D. F. Taber, Org. Chem. Highlights 2005, October 24.