Preparation of cyclohexene isotopologues and stereoisotopomers from benzene.

Abstract

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools of 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 The deuterium kinetic isotope effect (DKIE), which compares the rate of a chemical reaction for a compound to its deuterated counterpart, can be dramatic.1–3 The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and distribution of metabolites for a compound,4 improving the efficacy and safety of the drug. Deutetrabenazine, a promising treatment for Huntington’s disease,5 recently became the first deuterated drug to win FDA-approval.The pharmacokinetics of a deuterated compound depend on the location(s) of D. While methods currently exist for deuterium incorporation at both early and late stages of a drug’s synthesis,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 D incorporation, as bound to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions can be precisely controlled on the cyclohexene ring. 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 pharmacological and toxicological properties of drugs and provide new mechanistic information related to their distribution and metabolism in the body.