α-fluoromethyl tryptophans via imino ene reaction

Article abstract of DOI:10.1055/s-2001-16054

A preparative simple synthesis of α-fluoromethyl tryptophans is described. The new method is based on a non-catalytic imine ene reaction of highly electrophilic imines derived from methyl bromodifluoro- and trifluoropyruvate, and 1-sulfonyl-3-methylene in

Full text of DOI:10.1055/s-2001-16054

LETTER
1287
-Fluoromethyl Tryptophans via Imino Ene Reaction
Sergej N. Osipov,a Natalia M. Kobel´kova,a Alexey F. Kolomiets,a Ksenia Pumpor,b Beate Koksch,b Klaus Burgerb,*
a A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Science, Vavilov str. 28, 117813 Moscow, GSP-1, Russia
bDepartment of Organic Chemistry, University of Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax (49) 341 9736599; E-mail: burger@organik.chemie.uni-leipzig.de
Received 18 May 2001
ly constrained -amino acids.14 In connection with these
Abstract: A preparative simple synthesis of -fluoromethyl tryp-
studies, we wish to report herein a short, efficient access
to -bromodifluoromethyl and -trifluoromethyl tryp-
tophans is described. The new method is based on a non-catalytic
imine ene reaction of highly electrophilic imines derived from me-
tophan derivatives, unknown so far. The high electron
density of the trifluoromethyl group may be important in
the formation of strong hydrogen bonds with enzymes,
thereby blocking enzymatic metabolism of the natural
substrates. This group is also attractive since it is relative-
ly nontoxic and more stable than the mono- and difluo-
romethyl analogues.15
thyl bromodifluoro- and trifluoropyruvate, and 1-sulfonyl-3-meth-
ylene indolines.
Keywords: -fluoromethyl substituted -amino acids, tryptophans,
3-methylene indoles, fluorinated imines, ene reactions
Indole amine 2,3-dioxygenase (IDO) is an interferon- -
induced protein which is the first enzyme in the degrada-
tion pathway of tryptophan in macrophages and other
cells.1 Many inflammatory processes and neurodegenera-
tive diseases have been linked to aberrant L-tryptophan
metabolism effected by IDO hyperactivity.2 It was found,
that one class of competitive IDO inhibitors are tryp-
tophan analogues, e.g. -(3-benzofuranyl)- and -[3-ben-
zo(b)thienyl] alanines are exhibiting moderate inhibitory
activity towards rabbit intestine IDO.3 Recently it was
demonstrated that 1-methyl-L-tryptophan is the most ac-
tive inhibitor of IDO, known so far, being more active
than its D-isomer.3,4
Scheme 1 Reaction conditions: (i) PhSO2Cl/Py, THF, 80 C, 2 h;
(ii) NaH/DMF, 0 C, 2 h; (iii) propargyl bromide/DMF, r.t., 8 h; (iv)
Bu3SnH/AIBN, benzene, 80 C, 4-5 h.
Aromatic L-amino acid decarboxylase (AADC) is a pyri-
doxal phosphate dependent enzyme responsible for the fi-
nal step in the biosynthesis of both dopamine and
seretonin via decarboxylation of L-dopa and L-5-hydrox-
ytryptophan, respectively. In this context, the develop-
ment of new effective antagonists of serotonin-producing
enzymes (tryptophan hydroxylase and AADC), e.g. for
chemotherapy of carcinoid tumors, caused by an overpro-
duction of serotonin, is of current interest.5 During the last
two decades a number of -fluoromethyl -amino acids,
like -difluoromethyl ornithine,6 attracted considerable
attention of bioorganic and medicinal chemists, due to
their ability to inhibit selectively pyridoxal phosphate de-
pendent enzymes via a suicide-type mechanism.7
3-Methylene-1-(phenylsulfonyl)indolines 1a16 and 1b17
(Scheme 1) obtainable in good yields in a three-step pro-
cedure starting from ortho-bromoanilines, which are com-
mercially available with a vast variety of substituents at
the aromatic ring, readily react with highly electrophilic
imines derived from methyl bromodifluoro and
trifluoropyruvates18 in an ene-type reaction (Scheme 2,
Table).
The N-phenylsulfonyl amines 1 easily react with sulfo-
nylimines 2 derived from methyl trifluoropyruvate19 at
room temperature to give the protected tryptophan deriv-
atives 3a-c, f.20 The progress of the reaction was moni-
tored by 19F NMR spectroscopy, to obtain optimal yields.
Heteroaromatization of the indoline moiety to give the in-
dole system is the driving force of the ene reaction. Since
the starting material 3-methylene-1-(phenylsulfonyl)in-
doline 1 itself is susceptible to heteroaromatization,21 pro-
tic solvents have to be avoided, because they readily
catalyze this process. So far, best results were obtained us-
ing dry benzene.
A number of methods for the synthesis of fluoroalkyl sub-
stituted tryptophans have been already reported.5,8-11
On the other hand, peptidomimetics bearing -alkylated
-amino acids in strategical positions have recently
emerged as important synthetic targets. They are used for
the design of highly potent, proteolitically stable, confor-
mationally restricted enzyme inhibitors.12
As part of our current investigations directed to the syn-
thesis of new types of peptido-mimetics, we are develop-
ing general and highly efficient synthetic routes to non-
natural,13 especially fluorine-containing, conformational-
Synlett 2001, No. 8, 1287–1289 ISSN 0936-5214 © Thieme Stuttgart · New York

1288
LETTER
(5) Schirlin, D.; Gerhart, F.; Hornsperger, J.M.; Hamon, M.;
Wagner, J.; Jung, M.J. J. Med. Chem. 1988, 31, 30.
Zembower, D.E.; Gilbert, J.A.; Ames, M.M. J. Med. Chem.
1993, 36, 305.
(6) Di Bari, C.; Pastore, G.; Roscigno, G.; Schechter, P.J.;
Sjoerdsma, A. Ann. Intern. Med. 1986, 105, 803. Schirlin, D.;
Ducep, J.B.; Baltzer, S.; Bey,P.; Piriou, F.; Wagner, J.;
Hornsperger, J.M.; Heydt, J.G.; Jung, M.J.; Danzin, C.;
Weiss, R.; Fischer, J.; Mitschler, A.; De Cian, A. J. Chem.
Soc. Perkin Trans. 1 1992, 1053. Bey, P.; Danzin, C.; Jung,
M.J. in: McCann, P.P.; Pegg, A.E.; Sjoerdsma, A. Inhibition
of Polyamine Metabolism: Biological Significance and Basis
for New Therapies; Ed.; Academic: Orlando, FL, 1987; p 1.
(7) Kollonitsch, J.; Perkins, L.M.; Patchett, A.A.; Doldouras,
G.A.; Marburg, S.; Duggan, D.E.; Maycock, A.L.; Aster, S.D.
Nature 1978, 274, 906. Bey, P. Ann. Chim. Fr. 1984, 9, 695.
(8) Soloshonok, V.A.; Kukhar, V.P. J. Org. Chem. USSR (Engl.
Transl.) 1990, 26, 358.
Scheme 2
Table Synthesis of -Fluoromethyl Tryptophans 3
(9) Lee, M.; Phillips, R.S. Bioorg. Med. Chem. Lett. 1991, 1, 477.
(10) Gebler, J.C.; Woodside, A.B.; Poulter, C.D. J. Am. Chem. Soc.
1992, 114, 7354.
(11) Gong, Y.; Kato, K.; Kimoto, H. Tetrahedron Lett. 1999, 40,
5743
(12) Giannis, A.; Kolter, T. Angew. Chem. Ent. Ed. Engl. 1993, 32,
1244. Schiller, W.P. In Medicinal Chemistry for the 21st
Century; Wermuth, C.G., Ed.; Oxford Blackwell Scientific
Publications, 1992; Chap. 15, 215. Marshal, G.R.; Clarc, J.D.;
Dunbar, J.B. jr., Smith, G.D.; Zabrocki, J.;Redlinski, A.S.;
Leplawy, M.T. Int. J. Pept. Protein Res. 1988, 32, 544. Hruby,
V.J.; Al-Obeidi, F.; Klazmierski, W. Biochem. J. 1990, 268,
249. Toniolo, C.; Benedetti, E. Macromolecules 1991, 24,
4004. Hanessian, S.; McNaughton-Smith, G.; Lubell, W.D.
Tetrahedron 1997, 53, 12789.
As expected, less electrophilic imines like 2d and 2e and
1 react only at elevated temperatures (80 °C). However,
yields were low (18 24%), especially when equimolar
amounts of the starting materials were used. Under these
reaction conditions, N-phenylsulfonyl-3-methylindole,
formed on heteroaromatization from 1 was the main prod-
uct of the reaction. When starting materials 2d/2e and 1
were treated in a 2:1 ratio at 60 °C and the progress of the
reaction was carefully monitored by 19F NMR spectrosco-
py, yields could be improved to 39-50%.
(13) Pires, R.; Fehn, S.; Golubev, A.S.; Winkler, D.; Burger, K.
Amino Acids 1996, 11, 301.
(14) Osipov, S.N.; Burger, K. Tetrahedron Lett. 2000, 41, 5659.
Koksch, B.; Mütze, K.; Osipov, S.N.; Golubev, A.S.; Burger,
K. Tetrahedron Lett. 2000, 41, 3825. Osipov, S.N.; Bruneau,
C.; Picquet, M.; Kolomiets, A.F.; Dixneuf, P.H. J. Chem. Soc.
Chem. Commun. 1998, 2053. Koksch, B.; Sewald, N.;
Jakubke, H.-D.; Burger, K. In Biomedical Frontiers of
Fluorine Chemistry, ACS Symposium Series 639; Ojima, I.;
McCarthy, J.R.; Welch, J.T., Ed.; 1996; p 42 and literature
cited therein.
In conclusion, we have demonstrated that the imino ene
reaction is a useful tool for the construction of -trifluo-
romethyl and -bromodifluoromethyl tryptophan deriva-
tives. Experiments to adapt this methodology for the
synthesis of a series of -fluoroalkyl substituted heterocy-
clic -amino acids as building blocks for the construction
of new types of peptidomimetics and for modification of
natural products are in progress.
(15) Welch, J.T. In Selective Fluorination in Organic and
Bioorganic Chemistry, ACS Symposium Series 456; Welch,
J.T., Ed.; 1991; p 1.
(16) Boger, D.L.; Coleman, R.S. J. Am. Chem. Soc. 1988, 110,
4798.
Acknowledgement
(17) 5-Fluoro-3-methylene indoline 1b was unknown. 1H NMR
(CDCl3) = 4.56 (t, J = 3.0 Hz, 2H, NCH2), 5.02 (t, J = 2.4
Hz, 1H, trans-C = CH), 5.34 (t, J = 3.0 Hz, 1H, cis-C = CH),
7.0-7.9 ppm (m, 8H, Ar). 19F NMR (CDCl3) = -42.4 ppm (m,
1F).
We thank the Deutsche Forschungsgemeinschaft (Innovationskol-
leg), the Stiftung Volkswagenwerk, and the Fonds der Chemischen
Industrie for financial support.
References and Notes
(18) Osipov, S.N.; Golubev, A.S.; Sewald, N.; Michel, T.;
Kolomiets, A.F.; Fokin, A.V.; Burger, K. J. Org. Chem. 1996,
61, 7521.
(1) Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J.M. Tetrahedron Lett.
2000, 41, 2781.
(2) Brown, R.R.; Ozaki, Y.; Datta, S.P.; Borden, E.C.; Sondel,
P.M.; Malone, D.S. Adv. Exp. Med. Biol. 1991, 294, 425.
Blight, A.R.; Saito, K.; Heyes, M.P. Brain Res. 1993, 632,
314.
(3) Cady, S.G.; Sono, M. Arch. Biochem. Biophys. 1991, 291,
326.
(4) Peterson, A.C.; Migawa, M.T.; Martin, M.J.; Hamaker, L.K.;
Czerwinski, K.C.; Zhang, W.; Arend, R.A.; Fisette, P.L.;
Ozaki, J.; Will. J.A.; Brown, R.R; Cook, J.M. Med. Chem.
Res. 1994, 3, 531.
(19) Osipov, S.N.; Chkanikov, N.D.; Kolomiets, A.F.; Fokin, A.V.
Bull. Acad. Sci. USSR Chem. Sect. (Engl.) 1986, 1256.
(20) General procedure for the preparation of 3:
A mixture of 3-methylidene-N-(phenylsulfonyl)indoline 1
(0.4 mmol) and N-protected imine of pyruvate 2 (0.4 mmol) in
5 mL of benzene was stirred at r.t. (80 C for 3d, e). The
solvent was removed in vacuo, and the crude product was
purified by flash chromatography (ethyl acetate/petroleum
ether). Selected data for 3a: 1H NMR (D6-acetone) = 3.32 (s,
3H, OMe), 3.61 (dAB, J = 12.4 Hz, 1H, CH2), 3.65 (dAB
,
Synlett 2001, No. 8, 1287–1289 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
J = 12.4 Hz, 1H, CH2), 7.29 (t, J = 3.6 Hz, 1H, arom.), 7.34
-Fluoromethyl Tryptophans via Imino Ene Reaction
1289
CH2), 5.86 (s, 1H, NH), 7.08-7.16 (m, 2H, arom.), 7.33 (d,
J = 8.2 Hz, 2H, arom.), 7.47-7.59 (m, 3H, arom.), 7.76-7.82
(m, 2H, arom.), 7.92 (d, J = 8.2 Hz, 2H, arom.), 7.96-8.00
ppm (m, 2H, arom.). 19F NMR (CDCl3) = -41.36 (s, 1F, F),
5.50 ppm (s, 3F, CF3).
(t, J = 3.6 Hz, 1H, arom.), 7.48 (d, J = 4.0 Hz, 1H, arom.),
7.61 (m, 7H, arom.), 7.81 (s, 1H, NH), 7.92 ppm (m, 5H,
arom.). 19F NMR (D6-acetone) = 6.03 ppm (s, 3F, CF3). 3c:
1H NMR (D6-acetone) = 3.06 (s, 3H, Me), 3.42 (s, 3H,
OMe), 3.63 (dAB, J = 12.3 Hz, 1H, CH2), 3.65 (dAB, J = 12.3
Hz, 1H, CH2), 7.18 (s, 1H, NH), 7.30 (t, J = 3.4 Hz, 1H,
arom.), 7.36 (t, J = 3.4 Hz,1H, arom.), 7.57 (m, 3H, arom.),
7.64 (m, 1H, arom.), 7.86 (s, 1H, arom.), 8.00 ppm (m, 3H,
arom.). 19F NMR (D6-acetone) = 5.61 ppm (s, 3F, CF3). 3f:
1H NMR (CDCl3) = 2.47 (s, 3H, Me), 3.60 (s, 3H, OMe),
3.47 (dAB, J = 15.3 Hz, 1H, CH2), 4.02 (dAB, J = 15.3 Hz, 1H,
(21) Murphy, J.A.; Scott, K.A.; Sinclair, R.S.; Martin, C.G.;
Kennedy A.R.; Lewis, N. J. Chem. Soc. Perkin Trans. 1 2000,
2395.
Article Identifier:
1437-2096,E;2001,0,08,1287,1289,ftx,en;G08901ST.pdf
Synlett 2001, No. 8, 1287–1289 ISSN 0936-5214 © Thieme Stuttgart · New York