Fluorination reactions are essential to modern medicinal chemistry, thus providing a means to block site-selective metabolic degradation of drugs and access radiotracers for positron emission tomography imaging. Despite current sophistication in fluorination reagents and processes, the fluorination of unactivated CH bonds remains a significant challenge. Reported herein is a convenient and economic process for direct fluorination of unactivated CH bonds that exploits the hydrogen abstracting ability of a decatungstate photocatalyst in combination with the mild fluorine atom transfer reagent N-fluorobenzenesulfonimide. This operationally straightforward reaction provides direct access to a wide range of fluorinated organic molecules, including structurally complex natural products, acyl fluorides, and fluorinated amino acid derivatives.
Late-stage C-H fluorination is an appealing reaction for medicinal chemistry. However, the application of this strategy to process research appears less attractive due to the formation and necessary purification of mixtures of organofluorines. Here we demonstrate that γ-fluoroleucine methyl ester, an intermediate critical to the large-scale synthesis of odanacatib, can be accessed directly from leucine methyl ester using a combination of the decatungstate photocatalyst and N-fluorobenzenesulfonimide in flow. This efficient C-H fluorination reaction compares favorably with several generations of classical γ-fluoroleucine process syntheses.
The late-stage fluorination of common synthetic building blocks and drug leads is an appealing reaction for medicinal chemistry. In particular, fluorination of benzylic C-H bonds provides a means to attenuate drug metabolism at this metabolically labile position. Here we report two complimentary strategies for the direct fluorination of benzylic C-H bonds using N-fluorobenzenesulfonimide and either a decatungstate photocatalyst or AIBN-initiation.
Fluorination reactions are essential to modern medicinal chemistry, thus providing a means to block site‐selective metabolic degradation of drugs and access radiotracers for positron emission tomography imaging. Despite current sophistication in fluorination reagents and processes, the fluorination of unactivated CH bonds remains a significant challenge. Reported herein is a convenient and economic process for direct fluorination of unactivated CH bonds that exploits the hydrogen abstracting ability of a decatungstate photocatalyst in combination with the mild fluorine atom transfer reagent N‐fluorobenzenesulfonimide. This operationally straightforward reaction provides direct access to a wide range of fluorinated organic molecules, including structurally complex natural products, acyl fluorides, and fluorinated amino acid derivatives.
An auxiliary strategy has been developed for asymmetric reactions of aldehydes in which the auxiliary itself is not chiral, but a single chlorine atom introduced via organocatalytic α-chlorination. The stereodirecting influence of the chlorine atom is then exploited prior to its removal by radical reduction. This strategy is demonstrated in the synthesis of several aldols (92-99% ee) and the natural products (+)-dihydroyashabushiketol and (+)-solistatin.
A one‐step photocatalytic fluorination of (S)‐leucine methyl ester (I) is thoroughly elaborated which allows for the multi‐gram preparation of (S)‐γ‐fluoroleucine methyl ester (II) under continuous flow conditions, thus representing a straightforward access to the critical intermediate (II) of odanacatib (III).
The growing proportion of drugs reaching the market as single enantiomers has placed an increasing demand on the discovery of robust asymmetric methods for their synthesis. Consequently, chiral catalysis, separations, salt resolutions, and auxiliary‐controlled reactions have now largely replaced the chiral‐pool approach to synthesizing enantiomerically pure drugs. Although chiral auxiliaries may seem antiquated in light of the increasing scope of asymmetric catalysis, the chiral auxiliary approach is still optimal for a variety of key synthetic transformations and continues to play an important role in both drug discovery and development. This chapter provides a survey of chiral auxiliaries used in the synthesis of drugs, with examples chosen based on their demonstrated utility on scale.
A Convenient Photocatalytic Fluorination of Unactivated C-H Bonds. -A straightforward method for fluorination of unactivated C-H bonds is described. Alkyl fluorides of natural products and amino acids are obtained in moderate yields. Furthermore, aldehydes react to amides in the presence of amines. -(HALPERIN, S. D.; FAN, H.; CHANG, S.; MARTIN, R. E.; BRITTON*, R.; Angew. Chem., Int. Ed. 53 (2014) 18, 4690-4693, http://dx.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.