Total synthesis of spiroketal containing natural products: kinetic vs. thermodynamic approaches

Abstract

This review details part of a lecture delivered at the 20 th ICHC in Palermo Italy, July 31-August 5 2005. The published total syntheses of reveromycin A (1) and the assigned structure for spirofungin B (26) are described. The approach to 1 utilized a hetero-Diels-Alder reaction to construct the spiroketal fragment in a kinetic stereocontrolled manner. The synthesis of the proposed spirofungin B (26) spiroketal fragment utilized a thermodynamically controlled cyclization of a protected dihydroxyketone precursor. This allowed for the reassignment of the structure of spirofungin B as epi-spirofungin A (48).

Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions

“…In view of the fact that natural spiroketals prevalently possess the thermodynamically most stable configuration, the majority of synthetic approaches to natural spiroketals rely on catalyst-promoted cyclization under equilibrating conditions. , At the same time, similar conditions cannot be employed when a less stable nonthermodynamic configuration is desired (cf. pectenotoxin 1; Figure ).…”

Discovery of a Phosphine-Mediated Cycloisomerization of Alkynyl Hemiketals: Access to Spiroketals and Dihydropyrazoles via Tandem Reactions

“…A number of methods for the synthesis of spiroketals have been developed. − They were inspired by the challenge of natural product total synthesis, physical investigations into the fundamental principles governing spiroketal configuration, and the biological activities associated with spiroketal-containing natural products. Representative examples of natural product spiroketals are oligomycin B ( 1 ), − berkelic acid ( 2 ), − and reveromycin A ( 3 ) (Figure ). − Among the structures in Figure , oligomycin B is noteworthy because it contains a ketone α to the spiroketal which parallels the organization of functionality that develops in the new tandem reaction reported here.…”

Chiral Phosphoric Acid-Catalyzed Enantioselective and Diastereoselective Spiroketalizations

“…However, a stereoselective synthesis of this functionality becomes significantly more challenging in cases where the conformational and stereoelectronic factors prevent the formation of the desired configuration under equilibrating conditions or when the spiroketal moiety is the only source of stereoisomerism in the natural product (Figure ) . While having flexibility in the syntheses of stereodefined spiroketals would be beneficial to many areas of organic chemistry, including target- − and diversity-oriented syntheses, only a few general methods are available. Typically, these methods rely on substrate- or auxiliary-directed stereoinduction to form the spiroketal stereocenter .…”