Despite being largely absent from natural products and biological processes, fluorine plays a conspicuous and increasingly important role within pharmaceuticals and agrochemicals, as well as in materials science.1a−1c Indeed, as many as 35% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.1d Fluorine is the most electronegative element in the periodic table, and the introduction of one or more fluorine atoms into a molecule can result in greatly perturbed properties. Fluorine substituents can potentially impact a number of variables, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability. The multitude of effects that can arise from the introduction of fluorine in small molecules in the context of medicinal chemistry has been extensively discussed elsewhere.2

For these reasons, methods to introduce fluorine into small organic molecules have been actively investigated for many years by specialists in the field of fluorine chemistry. However, particularly in the past decade, a combination of the increasing importance of fluorine-containing molecules and the successful development of bench stable, commercially available fluorine sources has brought the expansion of fluorine chemistry into the mainstream organic synthesis community. This has resulted in an acceleration in the development of new fluorination methods and consequently in methods for the asymmetric introduction of fluorine.3 Catalytic asymmetric fluorination methods have inevitably lagged somewhat behind their nonasymmetric counterparts as understanding of the modes of reactivity of new fluorinating reagents must generally be developed and understood before they can be extended to enantioselective catalysis.3b Indeed, the last special issue of Chemical Reviews dedicated to fluorine chemistry, in 1996, contained no articles addressing asymmetric fluorine chemistry, and the editor of the issue noted that “although fluorine chemistry is much less abstruse now than when I entered the field a generation ago, it remains a specialized topic and most chemists are unfamiliar, or at least uncomfortable, with the synthesis and behavior of organofluorine compounds.”4 The field has undoubtedly undergone great change within the last two decades.

As with the incorporation of the fluorine atom, the introduction of the trifluoromethyl (CF3) group into organic molecules can substantially alter their properties. As with fluorine, the prevalence of CF3 groups in pharmaceuticals and agrochemicals coupled with the development of new trifluoromethylating reagents also has led to a recent surge in the development of asymmetric trifluoromethylation and perfluoroalkylation. Although the fluorine and trifluoromethyl moieties are often found on the aromatic rings of many pharmaceutical and agrochemicals rather than in aliphatic regions, this may be a result of the lack of efficient methods for the asymmetric introduction of C–F and C–CF3 bonds into molecules; it could be the case that lack of chemical methods is restricting useful exploration of such molecules. However, there are still encouraging examples of drug candidates containing chiral fluorine and trifluoromethyl-bearing carbons (Figure ​(Figure11).



Figure 1

Molecules of medicinal interest bearing C–F and C–CF3 stereocenters.

Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: A review of the last 20 years (1989–2009)

Fluorinated organic compounds have received considerable attention because they possess unique properties such as greater stability, higher electronegativity, and water and oil repellency, which are potentially beneficial in terms of the development of novel pharmaceutical agents and advanced materials. Such extreme behaviors of fluoro-organic compounds however, often make their syntheses all the more complicated, especially when the synthesis of target compounds requires an enantiocontrolled methodology. Many strategies can be employed for introducing chirality into organic molecules, but enantioselective fluorination and trifluoromethylation reactions are especially attractive because non-fluorinated prochiral substrates can be directly transformed to chiral fluoro-organic compounds with a control of absolute configuration. Significant progress has been made in the development of the asymmetric fluorination reaction in recent years; however, the direct enantioselective trifluoromethylation reaction remains a challenge. In this report, we discuss recent developments in the enantioselective trifluoromethylation reactions, including nucleophilic, electrophilic, and radical approaches. Although the emphasis of this report is on the enantioselective trifluoromethylation reaction, the less-studied enantioselective difluoromethylation and monofluoromethylation reactions are also covered.

Recent advances in enantioselective trifluoromethylation reactions

Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates.

This invention provides Compounds I having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. Compound I is 
wherein:
 Q is selected from the group consisting of: m is 1 or 2; —W— is 
A is selected from the group consisting of C 1-6 alkoxy, aryl and heteroaryl; in which said aryl is phenyl or napthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C 1-6 alkoxy, —C(O)NH 2 ; and C 1-6 alkyl, —NHC(O)CH 3 , halogen and trifluoromethyl.

Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are promising drugs for the treatment of HIV when used in combination with other anti-HIV drugs such as nucleoside reverse transcriptase (RT) inhibitors and protease inhibitors. The first generation of NNRTIs have, however, suffered from the rapid development of resistance. This review discusses the properties of the FDA-approved NNRTI drugs and focuses on the recent efforts being made to produce second generation inhibitors that circumvent this resistance problem.

https://journals.sagepub.com/doi/pdf/10.1177/095632029901000601

Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom.

The Flourishing Syntheses of Non-Nucleoside Reverse Transcriptase Inhibitors

New S-DABOs with a long alkylating S-alkyl substituent showing antiretroviral activity against HIV-1 in the micromolar range were prepared from 5,6-disubstituted 4-oxo-2-thiopyrimidines and 1,7-dibromo-3,5-dioxaheptane. The analogues with an ethyl group in position 5 also showed activity in the micromolar range against a Tyr/8/Cys mutant strain of HIV-1. The S-DABO analogues showing activity against the HIV-1 RT mutant strain were transformed to the N-3 and N-1 ring closed 7-oxo-pyrimidino-1,3,5-oxathiazepines which surprisingly all showed activity against HIV-1 in the micromolar range, as well as against a Tyr/8/Cys mutant strain of HIV-1. Some analogues of S-DABO with a thien-2-ylmethyl residue in position 6 were synthesized and tested against HIV-1 wild type, but they showed less or comparable activities to those of the corresponding 6-benzyl analogues.

Synthesis of 5-Alkyl-6-arylmethyl-2-(7-bromo-3,5-dioxaheptylthio)-pyrimidin-4(1H)-ones and 7-Oxopyrimidino-1,5,3-oxathiazepines as NewS-DABO Analogues with Anti-HIV Activity

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are of increasing importance in the treatment of HIV-1 infected persons. In this review the focus is on the syntheses of the approved NNRTI drugs efavirenz, delavirdine, nevirapine, and their analogues. This review also deals with the syntheses of the most promising NNRTI candidates in clinical testing and with the syntheses of subclasses of NNRTIs with known crystal structures when complexed with the reverse transcriptase enzyme.

Ole S. Pedersen

Papers

Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom.

The Flourishing Syntheses of Non-Nucleoside Reverse Transcriptase Inhibitors

Synthesis of 5-Alkyl-6-arylmethyl-2-(7-bromo-3,5-dioxaheptylthio)-pyrimidin-4(1H)-ones and 7-Oxopyrimidino-1,5,3-oxathiazepines as NewS-DABO Analogues with Anti-HIV Activity

The Flourishing Syntheses of Non-nucleoside Reverse Transcriptase Inhibitors