Current Organic Chemistry - Volume 14, Issue 9, 2010

The chemistry of organic fluorine compounds is a rapidly developing area of research because of their importance in biochemical and medicinal applications and material science. Introduction of fluorine atom into biologically active compounds often leads to improvement of chemical, physical properties and biological activity, metabolic stability and selectivity of the parent compounds due to the unique properties of the fluorine atom. Chiral organofluorine compounds are interesting and important materials with applications in analytical, biological and medicinal chemistry as well as chiral building blocks, chiral derivatization reagents and synthetic intermediates for organic synthesis. This special Hot Topic issue highlights the substantial progresses on the electrophilic asymmetric fluorination methodologies, the synthesis and applications of some important chiral nonracemic fluoro-containing organic compounds. In the past twenty years, we have witnessed the truly intense efforts in the development of asymmetric fluorination reactions for the synthesis of chiral nonracemic fluoro-organic molecules with a fluorine atom on a stereogenic center. Electrophilic asymmetric fluorination has proven to be a particularly effective method for the synthesis of optically active fluoro compounds. In the first review provided by us (L.- L. Cao, B.-L. Gao, S.-T. Ma and Z.-P. Liu, School of Pharmaceutical Sciences, ShandongUniversity, China), the substrate-mediated diastereoselective electrophilic fluorinations for the synthesis of chiral organofluorine compounds is discussed, followed by chiral reagentcontrolled stoichiometric asymmetric electrophilc fluorination of achiral compounds, with emphasis on the developments and applications of neutral chiral N-F agents based on the sultam templates, including our contributions to this field, and the charged chiral [N-F]+ reagents derived from the fluorinated cinchona alkaloids or the alkaloids/Selectfluor combination. The recently developed catalyst-controlled enantioselective fluorination is a more elegant and attractive method for the synthesis of chiral organofluorine compounds. The second review, provided by Y. K. Kang and D. Y. Kim, Department of Chemistry, Soonchunhyang University, Korea, focus on the recent advances in catalytic enantioselective fluorination of active methane compounds like β-ketoesters, α- chloro-β-ketoesters, malonates, α-cyanoacetate, β-ketophosphonates, α-cyanophosphonates, etc. Catalytic fluorination mediated by various metal complexes, organocatalysts and chiral phase-transfer catalysts are discussed. The third review was written by J. L. Acena, A. Simon-Fuentes and S. Fustero, Departamento de Quimica Organica, Facultad de Famacia, Universidad de Valencia, Spain and Laboratorio de Moleculas Organicas, Centro de Investigacion Principe Felipe. They presented an overview on the recent developments in the synthesis of fluorinated β-amino acids, including 69 references covering the reported literatures from 2004. They comprehensively summarized the diverse methods for the synthesis of fluorinated acyclic β-amino acids, cyclic β-amino acids and β-peptides. The fourth review came from T. Fujiwara and Y. Takeuchi, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan. They focused mainly on their excellent work in the synthesis of chiral fluorothalidomide and 2-aryl-2- fluoropropionic acids and their applications in medicinal chemistry, in the developments of chiral α-monofluorocarbonyl compounds as chiral derivatizing agents for the determination of enantiomeric excess and absolute configuration of chiral alcohols and amines by 19F NMR spectroscopy. T. Fujishima, S. Fujii and H. Harayama, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University (Japan), contribute to the fifth review, including 67 references, which deals with the synthesis and biological activity of fluorinated vitamin D. Due to the special features of fluorine, the fluorinated vitamin D analogues exhibited unique activity profiles and metabolism stability. The use of fluorinated analogues as tools for the structural analysis of the flexible hormone 1α,25-dihydroxyvitamin D3 was also discussed. The last review was contributed by Y. Cheng, A.-L. Guo and D.-S. Guo, Department of Chemistry, Shandong Normal University, China. The current review comprises 72 references and highlights the major advancement of fluorinated carbohydrates since 2000. The diverse approaches for the synthesis of fluorinated carbohydrates and those functionalized analogues that contain the N, P, S and halogen moieties and their applications in bioorganic chemistry are summarized. Finally, as a guest editor for this special issue, I would like to thank all of the authors from different parts of the world for their valuable and excellent contributions. I also sincerely thank all the referees for their valuable comments on the papers submitted.

In the past twenty years, the development of efficient methods for asymmetric fluorination is one of the most fascinating aspects of modern organofluorine chemistry. Among the many approaches towards the construction of chiral organofluorine compounds containing a fluorine atom bonded directly to a stereogenic center, electrophilic asymmetric fluorination has proven to be particularly effective. In this review, substrate-mediated diastereoselective electrophilic fluorinations for the synthesis of chiral organofluorine compounds is first discussed, followed by chiral reagent-controlled stoichiometric asymmetric electrophilc fluorination of achiral compounds, with emphasis on the developments and applications of neutral chiral N-F agents based on the sultam templates and charged chiral [N-F]+ reagents derived from the fluorinated cinchona alkaloids or the alkaloids/Selectfluor combination.

Organofluorine compounds are central importance in the pharmaceutical and agrochemical industries because the replacement of a hydrogen with a fluorine atom in biologically active molecules can be beneficial in terms of physicochemical properties and biological activities. Thus, the development of effective methodologies for the preparation of chiral organic fluorine compounds through C-F bond formation is still a highly desirable goal in synthetic organic chemistry. In this account, we review latest progresses in the area of catalytic enantioselective electrophilic fluorination of active methine compounds.

Synthetic studies on fluorinated β-amino acids and β-peptides have expanded rapidly in recent years, and particularly significant are those methods giving access to the target compounds in enantiomerically pure form. Two main strategies have been investigated, namely selective fluorination of appropriate functional groups in β-amino acid frameworks, and exploitation of already fluorinated small molecules for their use as synthetic building blocks. In addition, fluorine-containing β-lactams have often been employed as synthetic intermediates for the preparation of the corresponding β-amino acids. A large variety of acyclic β-amino acids has been reported, containing one or two fluorine atoms at the α-position, as well as α- or β-fluoroalkyl substituents. In contrast, fluorinated cyclic derivatives are much more unusual. Furthermore, the first examples of peptidic molecules containing fluorinated β-amino acids in combination with non fluorinated α- or β-amino acids have recently appeared. These compounds have been studied in terms of structure, proteolytic stability and biological activity.

Chiral α-monofluorocarbonyl compounds have recently received much attention and have been often employed as targets for asymmetric synthesis. However, there are relatively few reports describing applications of such compounds compared to other types of organofluorine compounds such as trifluoromethylated compounds and fluoroaromatics in spite of the many potential applications of such compounds. We describe here our recent results regarding examination of use of several chiral α-monofluorocarbonyl compounds for determination of absolute configurations of chiral compounds and clarification of biological roles of stereochemistry of important medicinal agents.

The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1), has a wide range of biological activities, making its analogues promising therapeutic agents for the treatment of cancer, psoriasis and osteoporosis. In particular, the stability of the carbonfluorine bond to oxidation has aided in the development of fluorinated vitamin D analogues as catabolism inhibitors. The analogues were synthesized either by classical steroidal approaches or by convergent methods, depending on the sites of fluorination. The incorporation of fluorine has provided numerous advantages for studying the structurally flexible hormone 1α,25-dihydroxyvitamin D3 1, including helping to define its molecular mode of actions. Biological evaluation of the fluorinated analogues suggested that fluorine substitution would not only change the metabolism, but also have direct effects on the vitamin D receptor, resulting in compounds with unique activity profiles.

The biological importance and activity of fluorinated carbohydrates is a focus of numerous investigations to date. The introduction of fluorine atom(s) can be achieved by a few means such as the classical fluorination, the building block strategy and the radical addition. This is a mini review of carbohydrates containing fluorine atom(s) developed in the past decade. General preparative methods to the fluorinated carbohydrates are organized according to the type of fluorine atom(s) in their molecular structures. The aspects concerning their N-, P-, S- and halogen-containing derivatives and some potential applications in bioorganic chemistry are also discussed.