Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B

Macrocycles with bent pi-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent pi-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland-Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2-13.3 mu M and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.

Automated summary

This article presents a new synthetic strategy for the asymmetric total synthesis of spirohexenolides A and B. By designing ring-closing metathesis and double dehydration reactions, the C15 macrocycle with deformed nonplanar 1,3,5-triene conjugation was achieved. In vitro studies demonstrated cytotoxicity of both spirohexenolides against human cancer cells, with spirohexenolide A exhibiting higher activity.