Organofluorine Chemistry


Organopentafluorosulfonyl Chemistry

The pentafluorosulfanyl (SF5) group is one of only a very few truly new functional groups to be introduced to the armentarium of the synthetic organic chemist in the last 100 years. The pseudooctahedral symmetry of the SF5 group, presenting a square pyramid of electron density, as defined by the fluorine ligands, is not otherwise known to the medicinal or pharmaceutical chemist. However only with the recent availability of the necessary reagents and building blocks has this functional group found applications as an aromatic substituent in agrochemicals, pharmaceuticals and liquid crystals. In aliphatic chemistry, pentafluorosulfanylated materials are even more rarely encountered with applications largely limited to polymer or oligomer preparations. The SF5 group is profoundly electron withdrawing but with the highly polarizable carbon-sulfur bond may directly influence reactivity in a manner different from that associated with the trifluoromethyl group.


Treflan Analogs

The synthesis of 2,6-dinitro-4-pentafluorosulfanyl-N,N-dipropylaniline, 2, was achieved in a straightforward manner from commercially available 1-nitro-4-pentafluorosulfanylbenzene. In post-emergence screening 2 was found to be approximately twice as potent as trifluralin with the same general spectrum of activity. In contrast, in pre-emergence tests, 2 was nearly 5 fold more potent against quackgrass and crabgrass.

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Serotonin Analogs

The trifluoromethyl group of fluoxetine and fenfluramine and norfenfluramine was substituted by the pentafluorosulfanyl group. On examination of the efficacy of the pentafluorosulfanyl containing compounds as inhibitors of 5-hydroxytryptamine receptors, it was found that substitution could lead to enhanced selectivity and in the case of the pentafluorosulfanyl analog of fenfluramine, led to significantly enhanced potency against the 5-HT2b, 5-HT2c and 5-HT6 receptors.

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Fluoroolefin Peptidomimetics

The fluoroolefin dipeptide isostere (peptidomimetic) has been found to be a superior isoelectronic and isosteric replacement for the peptide amide bond on the basis of its planar geometry and direction of polarization. The fluoroolefin isoster not only possesses similar steric demand, bond lengths and bond angles to those of the amide bond but also a fixed conformation. The high electronegativity of fluorine can introduce a pronounced polarity in an olefin unit, in a direction similar to that created by the carbonyl oxygen of the amide bond. Fluoroolefin can efficiently mimic the electronic features of the amide bond. We have described the synthesis of a series of fluoroolefin containing dipeptide isosteres, as inhibitors of Dipeptidyl peptidase IV (DPP IV, CD26), with Ki in the submicromolar range and as components of tetrapeptide substrates for the cyclosporin binding protein cyclophilin.

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Dipeptidyl Peptidase IV (CD26) Inhibitors

Dipeptidyl-peptidase IV (DPP IV, EC 3.4.14.5, CD26), designated CD26, is an extracellular membrane-bound enzyme expressed on the surface of several cell types, in particular CD4+ T-cells,as well as on kidney, placenta, blood plasma, liver, and intestinal. On T-cells, DPP IV has been shown to be identical to the antigen CD26. CD26 is expressed on a fraction of resting T cells at low density but is strongly upregulated following T-cell activation. Recent results indicate that CD26 is a multifunctional molecule that may have an important functional role in T-cells and in overall immune system modulation. CD26 is associated with other receptors of immunological significance found on the cell suface such as the protein tyrosine phosphatase CD45 and adenosine deaminase (ADA). In our laboratories we have prepared several DPPIV inhibitors as shown below with excellent potency yet retaining sufficient stability for ready investigation.

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