TY - JOUR
T1 - Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship
AU - Bemis, Christopher Y.
AU - Ungarean, Chad N.
AU - Shved, Alexander S.
AU - Jamieson, Cooper S.
AU - Hwang, Taehwan
AU - Lee, Ken S.
AU - Houk, K. N.
AU - Sarlah, David
N1 - Funding Information:
Financial support for this work was provided by the University of Illinois and National Institute of General Medical Sciences, National Institute of Health (GM 124480 to K.N.H.). Bristol Myers Squibb, Amgen, Eli Lilly, and FMC are also acknowledged for unrestricted research support. The Bruker 500-MHz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, Iowa, USA. We also thank Dr. D. Olson and Dr. L. Zhu for NMR spectroscopic assistance, Dr. D. L. Gray and Dr. T. Woods for X-ray crystallographic analysis assistance, and F. Sun for mass spectrometric assistance. We thank Dr. Patrick S. Fier (Merck Research Laboratories) for providing us with an authentic sample of pycnidione and Dr. Russel G. Kerr (University of Prince Edward Island) for sharing their NMR data of dehydroxypycnidione. Finally, we would like to thank Matthew Bock and Yingzhe Yang for assistance with this work and Christopher J. Huck for critical proofreading of this paper. We dedicate this work in memory of Sir Jack Baldwin.
Publisher Copyright:
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PY - 2021/4/21
Y1 - 2021/4/21
N2 - The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.
AB - The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.
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U2 - 10.1021/jacs.1c02150
DO - 10.1021/jacs.1c02150
M3 - Article
C2 - 33825475
AN - SCOPUS:85104969932
SN - 0002-7863
VL - 143
SP - 6006
EP - 6017
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 15
ER -