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Recent Synthetic Approaches Toward Non-anomeric Spiroketals in Natural Products
Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne, Batochime, CH-1015 Lausanne, Switzerland
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Received: 18 July 2008; in revised form: 29 September 2008 / Accepted: 15 October 2008 / Published: 17 October 2008
Abstract: Many natural products of biological interest contain [6,5]- and [6,6]-spiroketal moieties that can adopt various configurations, benefiting or not from anomeric conformation stabilizing effects. The spiroketal fragments are often important for the biological activity of the compounds containing them. Most stable spiroketal stereoisomers, including those benefiting from conformational anomeric effects (gauche conformers can be more stable than anti conformers because of a contra-steric stabilizing effect), are obtained easily under acidic conditions that permit acetal heterolysis (formation of tertiary oxycarbenium ion intermediates). The synthesis of less stable stereoisomers requires stereoselective acetal forming reactions that do not permit their equilibration with their most stable stereoisomers or, in the case of suitably substituted derivatives, concomitant reactions generating tricyclic products that quench the less stable spiroketal conformers. Ingenuous approaches have been recently developed for the synthesis of naturally occurring [6,6]- and [5,6]-nonanomeric spiroketals and analogues. The identification of several parameters that can influence the stereochemical outcome of spirocyclization processes has led to seminal improvements in the selective preparation of the non-anomeric isomers that are discussed herein. This review also gives an up-dated view of conformational anomeric effect which represents a small fraction of the enthalpic anomeric effect that makes gem-dioxy substituted compounds much more stable that their 1,n-dioxy substituted isomers (n > 1). Although models assuming sp3-hybridized oxygen atoms have been very popular (rabbit ears for the two non-bonding electron pairs of oxygen atom), sp2-hybridized oxygen atoms are used to describe the conformational anomeric effect.
Keywords: Spiroketal; anomeric interaction; non-anomeric interaction; thermodynamic equilibration; kinetic control; spirocyclization; anomeric effect; gauche effect
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Favre, S.; Vogel, P.; Gerber-Lemaire, S. Recent Synthetic Approaches Toward Non-anomeric Spiroketals in Natural Products. Molecules 2008, 13, 2570-2600.
Favre S, Vogel P, Gerber-Lemaire S. Recent Synthetic Approaches Toward Non-anomeric Spiroketals in Natural Products. Molecules. 2008; 13(10):2570-2600.
Favre, Sylvain; Vogel, Pierre; Gerber-Lemaire, Sandrine. 2008. "Recent Synthetic Approaches Toward Non-anomeric Spiroketals in Natural Products." Molecules 13, no. 10: 2570-2600.