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Tetrahedron Letters
Volume 27, Issue 2, 1986, Pages 135-138

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Peptide fluoromethyl ketones have been synthesized for the first time. The inhibitor 3-(N-benzyloxycarbonylphenylalanylamido)-

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doi:10.1016/S0040-4039(00)83960-X

A versatile synthesis of peptidyl fluoromethyl ketones

Barbara Imperiali and Robert H. Abeles, ^*

Department of Biochemistry Brandeis University Waltham. Mass. 02254 U.S.A.

Received 8 October 1985.

Available online 8 March 2001.

Abstract

A versatile synthesis of peptidyl fluoromethyl ketones with potential as serine protease inhibitors is described.

References

The term “fluoromethyl ketone” is applied generally to mono-, di, and trifluoromethyl ketones.

M.H. Gelb, J.P. Svaren and R.H. Abeles Biochemistry 24 (1985), p. 1813. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (133)

For examples see E. Reich, D.B. Rifkin and E.S. Shaw, Editors, Proteases and Biological Control 2, Cold Spring Harbor Conferences on Cell Proliferation (1975).
N. Katumuna, H. Umezawa and H. Holzer Proteinase Inhibitors; Medical and Biological Aspects, Springer Verlag (1983).

Although treatment of N-blocked amino acids with acetic anhydride and pyridine results in good yields of the corresponding methyl ketones, similar treatment with trifluoroacetic anhydride (in the presence or absence of catalytic 4-dimethylaminopyridine) affords only ketone products with the unsubstituted amino acid glycine. E.J. Bourne, J. Burdon, V.C.R. McLoughlin and J.C. Tatlow J. Chem. Soc. (1961), p. 1771. Full Text via CrossRef

Because of the instability of CF₃Li and CF₃gMgI we have found the corresponding zinc reagent CF₃ZnI useful in the preparation of simple trifluoromethyl ketones au]T. Kitazume N. Ishikawa Chem. Lett. (1981), p. 1679 However, the use of such organometallic reagents is problematic in the preparation of peptidyl products. .

D.J. Cook, O.R. Pierce and E.T. McBee J. Am. Chem. Soc. 76 (1954), p. 83. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (3)

At this time, the diastereomers have not been separated or resolved, however, in order to obtain optically pure peptides, the stage of the β-amino alcohol would be an appropriate point at which to resolve the intermediate since protocols for the resolution of numerous β-amino alcohols are available. P. Newman Optical Resolution Procedures for Chemical Compounds; Vol. 1, Amines and Related Compounds, Optical Resolution Center, N.Y. (1978) Published by .

The yield in the case of the trifluoromethyl compound is slightly lower than that for the di- and monofluoromethyl alcohols. This is due to the reactivity of the secondary alcohol (pK_a 12.4) causing side reactions in the peptide coupling.

G.I. Poos, G.E. Arth, R.E. Beyler and L.H. Sarett J. Am. Chem. Soc. 75 (1953), p. 422 The Sarett oxidation is a chromium trioxide/pyridine oxidation with the active complex generated in situ. In this case double the normal equivalents of pyridine and chromium trioxide and longer reaction times (i.e., 2h, 25°) are necessary to ensure complete oxidation. . Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (40)

The only literature procedures available for the oxidation of trifluoromethyl carbinols employ very harsh conditions which are unsuitable for these peptidyl compounds. M. Hudlicky In: (2nd edition ed.),Chemistry of Organic Fluorine Compounds, Ellis Horwood Ltd. (1976), pp. 208–213 For examples see .

If optically active materials were subjected to the oxidation procedure, the following points are pertinent. Method A has been frequently used to oxidize α-chiral aldehydes without racemizatlon, and therefore should proceed in a similar manner for the preparation of optically active mono- and difluoromethyl ketones. In the oxidation of the trifluoromethyl compounds (Method B) since the oxidation is carred out under aqueous conditions, it is hoped that the ketone in its hydrated form will not be prone to racemization, even in base.

Both ¹H NMR and ¹³C NMR were obtained for all intermediates and final products, all were completely consistent with the designated structures.¹³C NMR (75.5 MH₃) proton decoupled, of final products. (Acetone-d₆)δ: 22.4, 23.4, 25.5, 34.5, 41.4, 52.8, 57.0, 94.4 (q, J = 28.8Hz), 123.0(q, J = 270Hz), 127.2, 129.2, 130.3, 139.5, 171.2, 175.3. (Acetone-d₆ + 20% D₂O)δ: 22.4, 23.0, 23.1, 25.5, 34.8, 41.4, 53.5, 55.0, 94.6 (t, J = 25Hz ), 115.4 ( t, J = 245Hz), 127.3, 129.3, 130.7, 139.5, 173.3, 174.2 (CDCl₃δ: 22.3, 22.6, 22.9, 24.5, 36.1, 36.4, 41.0, 51.3, 51.7. 56.3, 84. 27 (d, J = 185.3Hz), 84.41 (d, J = 183.8Hz), 127.2, 128.7, 129.2, 135.7, 136.1, 170.6, 170.8, 172.9, 173.2, 203.9 (d, J = 17.9Hz).

Compounds , , and were all specific inhibitors for bovine chymotrypsin, as were compounds and towards porcine pancreatic elastase. Full details of these results will be reported elsewhere.

Tetrahedron Letters
Volume 27, Issue 2, 1986, Pages 135-138

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