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J Am Chem Soc. 2005 Oct 12;127(40):13796-7.

Stereocontrolled synthesis of spiroketals via a remarkable methanol-induced kinetic spirocyclization reaction.

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Pharmacology Program, Weill Graduate School of Medical Sciences of Cornell University, 1275 York Avenue, Box 422, New York, New York 10021, USA.


A methanol-induced kinetic spiroketalization reaction has been developed for the stereocontrolled target- and diversity-oriented synthesis of spiroketals. In contrast to existing methods for spiroketal synthesis, this reaction does not depend on thermodynamic product stability or require axial attack of an oxygen nucleophile. Stereodiverse glycals are alkylated at the C1 position with side chains bearing protected hydroxyl groups. After alcohol deprotection, the glycal is epoxidized stereoselectively, then the side chain hydroxyl is spirocyclized with inversion of configuration at the anomeric carbon by addition of excess MeOH at -63 degrees C. This spirocyclization reaction appears to proceed by MeOH hydrogen-bonding catalysis and has been used to form five- and six-membered rings with stereoisomeric substituents. In some cases, the stereocomplementary spiroketals can be also obtained by classical acid-catalyzed equilibration.

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