Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.

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Abstrakt

Tytuł:: Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.
Autorzy:: Smith JA; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Wilson KB; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Sonstrom RE; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Kelleher PJ; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Welch KD; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Pert EK; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Westendorff KS; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Dickie DA; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Wang X; Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA.
Pate BH; University of Virginia Department of Chemistry, Charlottesville, VA, USA.
Harman WD; University of Virginia Department of Chemistry, Charlottesville, VA, USA. .
Źródło:: Nature [Nature] 2020 May; Vol. 581 (7808), pp. 288-293. Date of Electronic Publication: 2020 May 20.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
MeSH Terms:: Chemistry Techniques, Synthetic*
Benzene/*chemistry
Cyclohexenes/*chemical synthesis
Cyclohexenes/*chemistry
Deuterium/*chemistry
Pharmaceutical Preparations/*chemical synthesis
Pharmaceutical Preparations/*chemistry
Databases, Chemical ; Kinetics ; Molecular Structure ; Stereoisomerism ; Tetrabenazine/analogs & derivatives ; Tetrabenazine/chemical synthesis ; Tetrabenazine/chemistry ; Tungsten/chemistry
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Grant Information:: R01 GM132205 United States GM NIGMS NIH HHS; 1R01GM132205-01 United States NH NIH HHS
Substance Nomenclature:: 0 (Cyclohexenes)
0 (Pharmaceutical Preparations)
12L0P8F7GN (cyclohexene)
AR09D82C7G (Deuterium)
J64922108F (Benzene)
P341G6W9NB (deutetrabenazine)
V9306CXO6G (Tungsten)
Z9O08YRN8O (Tetrabenazine)
Entry Date(s):: Date Created: 20200521 Date Completed: 20200629 Latest Revision: 20210325
Update Code:: 20240105
PubMed Central ID:: PMC7250047
DOI:: 10.1038/s41586-020-2268-y
PMID:: 32433618
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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.

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