TY - JOUR
T1 - Asymmetric Total Synthesis of (−)-Phaeocaulisin A
AU - Péter, Áron
AU - Crisenza, Giacomo E.M.
AU - Procter, David J.
N1 - Funding Information:
This work was supported by the University of Manchester (Dean’s Award to Á.P. and Lectureship to G.E.M.C.). Additionally, we thank Dr. Ralph Adams and Mr. Carlo Bawn for their assistance with NMR spectroscopic measurements and analysis, Dr. George Whitehead and Dr. Inigo J. Vitorica-Yrezabal for assistance with X-ray crystallographic analysis, and Dr. Derren Heyes for help with the circular dichroism measurements. We also acknowledge the Leigh group (600 MHz NMR) and the Leonori group (CV measurements) for their assistance.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/4/27
Y1 - 2022/4/27
N2 - The therapeutic properties of Curcuma (ginger and turmeric’s family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI2), the lactone intermediate was submitted to two sequential SmI2-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from Curcuma phaeocaulis - as well as their synthetic derivatives - for medicinal chemistry and drug design.
AB - The therapeutic properties of Curcuma (ginger and turmeric’s family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI2), the lactone intermediate was submitted to two sequential SmI2-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from Curcuma phaeocaulis - as well as their synthetic derivatives - for medicinal chemistry and drug design.
UR - http://www.scopus.com/inward/record.url?scp=85128586482&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/32665026-a169-3c04-9b70-07f2d5ea9aac/
U2 - 10.1021/jacs.2c02188
DO - 10.1021/jacs.2c02188
M3 - Article
SN - 0002-7863
VL - 144
SP - 7457−7464
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 16
ER -