Open AccessPreparation of cyclohexene isotopologues and stereoisotopomers from benzene
Author(s) -
Jacob Smith,
Katy B. Wilson,
Reilly E. Sonstrom,
Patrick J. Kelleher,
Kevin D. Welch,
Emmit K. Pert,
Karl S. Westendorff,
Diane A. Dickie,
Xiaoping Wang,
Brooks H. Pate,
W. Dean Harman
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2268-y
Subject(s) - deuterium , cyclohexene , kinetic isotope effect , chemistry , isotopologue , benzene , hydrogen , tritium , radiochemistry , computational chemistry , combinatorial chemistry , organic chemistry , catalysis , molecule , nuclear physics , physics
The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine 1 . Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules 1 . Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease 2 , was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial 1,3,4 . The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound 5 , improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug 6,7 , these processes are often unselective and the stereoisotopic purity can be difficult to measure 7,8 . Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.