Natural Product-Guided Synthesis of a Spiroacetal Collection Reveals Modulators of Tubulin Cytoskeleton Integrity

Abstract

The spiro[5.5]ketal moiety forms the underlying structural skeleton of numerous biologically active natural products. Since simplified but characteristic spiroketals derived from the parent natural products retain biological activity, the spiro[5.5]ketal unit can be regarded as a biologically prevalidated framework for the development of natural product-derived compound collections. We report an enantioselective synthesis of spiro[5.5]ketals on solid support. The reaction sequence employs asymmetric boron enolate aldol reactions with the enolate bound to the polymer or in solution as the key enantiodifferentiating step. It proceeds in up to 12 steps on solid support, makes the desired spiroketals available in high overall yields and with high stereoselectivities and is amenable to structural variation of the products. The small spiroketal collection synthesized contains phosphatase inhibitors and compounds that modulate the formation of the tubulin cytoskeleton in human cancer cells without directly targeting microtubules.