Preparation of cyclohexene isotopologues and stereoisotopomers from benzene

doi:10.1038/s41586-020-2268-y

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2268-y
	Preparation of cyclohexene isotopologues and stereoisotopomers from benzene
	Shimazaki, Yuya 1; Schwartz, Ido 1; Watanabe, Kenji 2; Taniguchi, Takashi 2; Kroner, Martin 1; Imamoglu, Atac 1
	2020-04-13
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	581 期号:7808 页码:288-+
文章类型	Article
语种	英语
国家	USA
英文关键词	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. Cyclohexene isotopologues and stereoisotopomers with varying degrees of deuteration are formed by binding a tungsten complex to benzene, which facilitates the selective incorporation of deuterium into any position on the ring.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000534818200012
WOS关键词	HETEROGENEOUS CATALYSTS ; ACTIVATION ; HYDROGENATION ; DEUTERIUM ; TRITIATION ; COMPLEXES ; MECHANISM ; FORM
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281288
专题	地球科学资源环境科学气候变化
作者单位	1.Swiss Fed Inst Technol, Inst Quantum Elect, Zurich, Switzerland; 2.Natl Inst Mat Sci, Tsukuba, Ibaraki, Japan
推荐引用方式 GB/T 7714	Shimazaki, Yuya,Schwartz, Ido,Watanabe, Kenji,et al. Preparation of cyclohexene isotopologues and stereoisotopomers from benzene[J]. NATURE,2020,581(7808):288-+.
APA	Shimazaki, Yuya,Schwartz, Ido,Watanabe, Kenji,Taniguchi, Takashi,Kroner, Martin,&Imamoglu, Atac.(2020).Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.NATURE,581(7808),288-+.
MLA	Shimazaki, Yuya,et al."Preparation of cyclohexene isotopologues and stereoisotopomers from benzene".NATURE 581.7808(2020):288-+.