Total Synthesis and Anticancer Activity of (+)‐Hypercalin C and Congeners

Abstract

The hypercalins are dearomatized acylphloroglucinols with a pendant complex cyclopentane ring that exhibit activity against several cancer cell lines. We report the first total synthesis of (+)-hypercalin C employing a convergent strategy that enabled the dissection of the essential structural features required for the observed anticancer activity. A strategic disconnection involving an unusual C <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:mrow><mml:mi>sp</mml:mi><mml:msup><mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:mrow></mml:msub></mml:math> -C <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:mrow><mml:mi>sp</mml:mi><mml:msup><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup></mml:mrow></mml:mrow></mml:msub></mml:math> Suzuki-Miyaura coupling with an α-bromo enolether also revealed an unexpected C-H activation. This strategy targeted designed analogues along the synthetic route to address particular biological questions. These results support the hypothesis that hypercalin C may act as a proton shuttle with the dearomatized acylphloroglucinol moiety being essential for this activity.