Effective pathway to the α-CF3-substituted azahistidine analogues

Article abstract of DOI:10.1055/s-2006-956492

An efficient method for the preparation of functionalized α-trifluoromethyl-substituted azahistidine analogues has been developed. The method is based on the regioselective addition of allenylmagnesiumbromide to highly electrophilic imines of trifluoropyr

Full text of DOI:10.1055/s-2006-956492

136
LETTER
Effective Pathway to the a-CF3-Substituted Azahistidine Analogues
a
-C
F
Azahistidinerigorii T. Shchetnikov, Alexander S. Peregudov, Sergej N. Osipov*
3
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, 119991 Moscow, Russia
Fax +7(495)1355085; E-mail: osipov@ineos.ac.ru
Received 16 October 2006
proach to functionalized aza analogues of a-CF3-histidine
Abstract: An efficient method for the preparation of functionalized
which is based on the ‘click chemistry’ conception recent-
a-trifluoromethyl-substituted azahistidine analogues has been
ly introduced by Sharpless and co-workers.9 The replace-
developed. The method is based on the regioselective addition of
ment of the C(2) atom by nitrogen in the imidazole ring to
allenylmagnesiumbromide to highly electrophilic imines of tri-
fluoropyruvates and subsequent 1,3-dipolar Huisgen cycloaddition give 1,2,3-triazole could be interesting from the biological
between a-propargyl-a-trifluoromethyl-a-amino esters and organic
activity point of view. This heterocycle functions as a rig-
id linking unit that can mimic the atom placement and
electronic properties of a peptide bond without the same
susceptibility to hydrolytic cleavage. Both the N(2) and
N(3) triazole atoms can act as hydrogen-bond acceptors,
the strong dipole may polarize the C(5) proton to such de-
azides.
Key words: fluorinated imines, amino acids, histidine, click reac-
tion, organic azides
Synthetic a-amino acids play an important role in the area gree that it can function as a hydrogen-bond donor, like
of peptide research and are extensively incorporated into the amide proton.10 Perhaps due to their ability to mimic
biologically active peptides to restrict their conformation- certain aspects of a peptide bond, many 1,2,3-triazoles
al flexibility, enhance proteolytic stability, increase selec- possess varied biological activity, including anti-HIV
tivity and improve pharmacokinetics and bioavailability activity,11 selective b3-adrenergic receptor inhibition,12
properties of the potential drugs.1 At the same time, it is antibacterial activity,13 potent antihistamine activity14 and
known, that the incorporation of a-trifluoromethyl-a-ami- more.15
no acids (a-CF3-AA) into strategically important posi-
The synthesis of starting a-propargyl-a-CF3-AA deriva-
tions of peptides retards proteolytic degradation, induces
tives 216 has been accomplished via addition of Grignard
secondary structure motif, and improves lipophilicity2 en-
reagent generated from propargyl bromide17 to electro-
philic imines 1 under mild conditions. Reactions proceed-
ed in anhydrous diethyl ether or THF at –78 °C to give
hancing in vivo absorption, thus improving permeability
through certain body barriers. Furthermore, 19F NMR
spectroscopy represents an efficient tool for conforma-
corresponding amino esters in moderate to good yields
tional studies of fluorine-containing peptides as well as
(Scheme 1, Table 1).
for the elucidation of metabolic processes.3 The spectra
can be recorded even in water and under cell-like condi-
F3C
CO2R
PG
F3C
tions. Therefore, the synthesis of new members of this
special class of Ca,a-disubstituted amino acids as building
blocks for peptide modification and as suicide inhibitors
irreversibly blocking pyridoxal phosphate-dependent
enzymes4 is of current interest.
1. H2C=C=CHMgBr
2. H+, H2O
PG
OR
N
H
N
O
2
1
Scheme 1 Synthesis of a-propargyl-a-CF3-AA derivatives
Table 1 a-Propargyl-a-CF3-AA Derivatives
In previous papers we described the syntheses of a-CF3-
AA derivatives (e.g. such as CF3-ornithine,5a CF3-argin-
ine,5b CF3-thalidomide5c) based on addition of C-nucleo-
philes to acylimines of 3,3,3-trifluoropyruvates.6
Unsaturated a-CF3-AA obtained by this methodology
were successfully applied further in ruthenium-mediated
metathesis-type reactions to afford a new family of the
corresponding proline and pipecolic acid derivatives.7
Taking into consideration that synthetic design of histi-
dine is not a trivial task and any modification of both
imidazole moiety and its amino acid backbone currently
represents a great challenge in synthetic biomedicinal
chemistry,8 we wish to disclose herein an efficient ap-
Entry
R
PG
Product
2a
Yield (%)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Et
Cbz
Boc
Ts
69
54
74
55
41
40
61
2b
2c
SO2Ph
CO2Et
Cbz
Boc
2d
2e
2f
Et
2g
SYNLETT 2007, No. 1, pp 0136–0140
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-956492; Art ID: G30706ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
a-CF3-Azahistidine
137
The usual procedure for regioselective Cu(I)-catalyzed
alkyne–azide coupling, that is the best ‘click’ reaction to
date, involves the use of a copper salt in conjugation with
an added organic or inorganic base. The catalyst can be
directly introduced as a Cu(I) salt or generated in situ by
reduction of Cu(II) salts,10 usually in organoaqueous sys-
tems. Application of these protocols to amino acid and
peptide chemistry has recently begun,18 but to the best of
our knowledge fluorinated amino acids have not been
utilized for such kind of transformations.
CF3
CO2Me
N
NH PG
F3C
Method A
Method B
R1
PG
OMe
+
N3
N
N
H
R1
N
O
Scheme 2 Synthesis of a-CF3 azahistidine derivatives. Reagents
and conditions: Method A: CuI (10 mol%), DIPEA (3 equiv), THF;
Method B: CuSO4 (5 mol%), Na-ascorbate (30 mol%), H2O–t-BuOH.
presence of organic base (DIPEA); B) the generation of
Cu(I) in situ from CuSO4 and sodium ascorbate in water–
alcohol media (Scheme 2, Table 2).
For the synthesis of the CF3-substituted azahistidines 3 we
applied both of above-mentioned methods, namely: A) the
usage of CuI as a catalyst in organic solvent (THF) in the
Table 2 a-CF3-Histidine Derivatives
Entry
1
R1-N3
Product
Method
B
Yield (%)
89
CF3
CO2Me
N3
N
N
N
N
N
N
H
H
SO2Ph
3a
2
3
4
5
6
7
A
79
CF3
N3
CO2Me
O
N
Ph
N
3b
O
A
77
CF3
CO2Me
N3
N
N
O
N
N
H
3c
O
N
A
85
CF3
O
HO
O
CO2Me
O
N3
N
N
Ph
HO
N
H
3d
O
A
83
CF3
CO2Me
O
HO
O
N3
N
N
N
O
N
HO
N
N
H
H
3e
O
A/B
A/B
78/84
82/92
CF3
O
HO
O
CO2Me
O
N3
N
N
HO
3f
O
AcO
CF3
AcO
O
CO2Me
O
AcO
AcO
N3
O
AcO
AcO
N
N
N
OAc
N
H
OAc
3g
O
Synlett 2007, No. 1, 136–140 © Thieme Stuttgart · New York

138
G. T. Shchetnikov et al.
LETTER
Table 2 a-CF3-Histidine Derivatives (continued)
Entry
8
R1-N3
Product
Method
B
Yield (%)
89
AcO
CF3
CO2Me
AcO
O
AcO
AcO
N3
O
AcO
AcO
N
N
N
OAc
N
H
SO2Ph
OAc
3h
9
B
B
80
88
CF3
O
O
N3
CO2Me
O
O
N
N
N
Ph
N
O
O
N
H
3i
O
O
O
10
CF3
CO2Me
N3
O
N
N
N
H
SO2Ph
3j
Thus, we found that 1,3-dipolar Huisgen cycloaddition Finally, the Cbz protective group of 5 was quantitatively
reaction of propargyl-containing amino esters 2 with removed via Pd-catalyzed hydrogenation in methanol to
various available azides at room temperature for 6–8 afford the desired free amino acid 620 (Scheme 3).
hours readily provided functionalized a-CF3 azahistidines
In conclusion, we have developed an effective pathway to
3.19 In spite of the fact that both methods give good to ex-
functionalized aza analogues of a-CF3-histidine via Cu(I)-
cellent results, route B is preferable due to a simpler
catalyzed ‘click’ reaction of a-propargyl substituted a-
isolation procedure (in all cases column chromatography
CF3-AA derivatives with different azides. The free amino
was not needed).
acid can be easily synthesized by step-wise deprotection
To obtain free a-CF3 azahistidine 6, N-pivaloylmethyl de- of the corresponding cycloadduct bearing the pivaloyl-
rivative 3j was selected as the most suitable precursor. We methyl moiety.
found that the pivaloylmethyl group could be selectively
removed under basic conditions within few minutes at
room temperature in methanol; more prolonged exposure
Acknowledgment
This work was supported by Russian Foundation of Basic Research
(Grant 04-03-32644).
of 3j in 5% KOH–MeOH solution resulted in simul-
taneous ring and carboxylic function deprotection.
CF3
2% KOH/MeOH
CO2Me
20 min, 89%
N
N
NHCbz
H
N
4
CF3
CO2Me
O
N
N
NHCbz
N
CF3
CO2H
NHCbz
3
O
5% KOH/MeOH
24 h, 96%
N
N
Cbz = C(O)OCH2Ph
H
N
5
CF3
H2, Pd/C
CO2H
5
N
N
NH2
MeOH
H
N
6
98%
Scheme 3 Deprotection of a-CF3 azahistidine
Synlett 2007, No. 1, 136–140 © Thieme Stuttgart · New York

LETTER
a-CF3-Azahistidine
139
(14) (a) Buckle, D. R.; Rockell, C. J. M. J. Chem. Soc., Perkin
Trans. 1 1982, 627. (b) Buckle, D. R.; Outred, D. J.;
Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem.
1983, 26, 251. (c) Buckle, D. R.; Rockell, C. J. M.; Smith,
H.; Spicer, B. A. J. Med. Chem. 1986, 29, 2262.
References and Notes
(1) (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl.
1993, 32, 1244. (b) Seebach, D.; Sting, A. R.; Hoffmann, M.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. (c) Cativiela,
C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517. (d) Link, A. J.; Mock, M. L.; Tirrell, D. A. Curr.
Opin. Biotechnol. 2003, 14, 603.
(2) (a) Sewald, N.; Burger, K. In Synthesis of b-Fluoro-
Containing Amino Acids; Kukhar’, V. P.; Soloshonok, V. A.,
Eds.; John Wiley and Sons Ltd.: New York, 1995, 139.
(b) Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31, 335.
(c) Jaeckel, C.; Salwiczek, M.; Koksch, B. Angew. Chem.
Int. Ed. 2006, 45, 4198.
(3) (a) Gregory, D. H.; Gerig, J. T. Biopolymers 1991, 31, 845.
(b) Cushmann, M.; Patel, H. H.; Scheuring, J.; Bacher, A. J.
Org. Chem. 1992, 57, 5630.
(4) Kollonitsch, J. In Biomedicinal Aspects of Fluorine
Chemistry; Filler, R.; Kobayashi, Y., Eds.; Kondasha, Tokyo
and Elsevier Biomedical Press: Amsterdam, 1982, 93; and
references cited therein.
(5) (a) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Burger, K.
Tetrahedron Lett. 1997, 38, 5965. (b) Moroni, M.; Koksch,
B.; Osipov, S. N.; Crucianelli, M.; Triderio, M.; Bravo, P.;
Burger, K. J. Org. Chem. 2001, 66, 130. (c) Osipov, S. N.;
Tsouker, P.; Hennig, L.; Burger, K. Tetrahedron 2004, 60,
271.
(6) Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel, T.;
Kolomiets, A. F.; Fokin, A. V.; Burger, K. J. Org. Chem.
1996, 61, 7521.
(7) (a) Osipov, S. N.; Bruneau, C.; Picquet, M.; Kolomiets, A.
F.; Dixneuf, P. H. Chem. Commun. 1998, 2053.
(b) Semeril, D.; Le Notre, J.; Bruneau, C.; Dixneuf, P. H.;
Kolomiets, A. F.; Osipov, S. N. New J. Chem. 2001, 16.
(c) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.;
Bruneau, C.; Dixneuf, R. H. Synlett 2000, 1031. (d)Osipov,
S. N.; Kobel’kova, N. M.; Shchetnikov, G. T.; Kolomiets, A.
F.; Bruneau, C.; Dixneuf, P. H. Synlett 2001, 621.
(e) Osipov, S. N.; Artyushin, O. I.; Kolomiets, A. F.;
Bruneau, C.; Picquet, M.; Dixneuf, P. H. Eur. J. Org. Chem.
2001, 3891. (f) Osipov, S. N.; Dixneuf, P. Russ. J. Org.
Chem. 2003, 39, 1211. (g) Eckert, M.; Monnier, F.;
Shchetnikov, G. T.; Titanyuk, I. D.; Osipov, S. N.; Dérien,
S.; Dixneuf, P. H. Org. Lett. 2005, 7, 3741.
(8) (a) Faden, A. I.; Labroo, V. M.; Cohen, L. A. Neurotrauma
1993, 10, 101. (b) Vonhof, S.; Paakkari, I.; Feuerstein, G.;
Cohen, L. A.; Labroo, V. M. Eur. J. Pharmacol. 1989, 164,
77. (c) Narayanan, S.; Vangapandu, S.; Jain, R. Bioorg.
Med. Chem. Lett. 2001, 11, 1133.
(9) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(10) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2006, 51.
(11) Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De
Clercq, E.; Perno, C.-F.; Karlsson, A.; Balzarini, J.;
Carmarasa, M. J. J. Med. Chem. 1994, 37, 4185.
(12) Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M.
R.; Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.;
Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med.
Chem. Lett. 2000, 10, 2111.
(13) Genin, M. J.; Allwine, D. A.; Anderson, D. J.; Barbachyn,
M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grege,
K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer,
R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt, R.
D.; Stapert, D.; Yagi, B. H. J. Med. Chem. 2000, 43, 953.
(15) For cytokine inhibition, see: Kim, D.-K.; Park, H. J. Bioorg.
Med. Chem. Lett. 2004, 14, 2401.
(16) General Procedure for the Preparation of 2.
Allenylmagnesiumbromide17 (solution in THF, 10.0 mmol)
was added dropwise to a stirred solution of an imine (10.0
mmol) in dry THF (25 mL) at –78 °C. After 1 h at –78 °C the
reaction mixture was allowed to warm to r.t. within 2 h. The
reaction was quenched with 1 N HCl and extracted with
Et2O (2 × 25 mL). The combined organic layer was washed
with brine (25 mL), dried over MgSO4 and filtered. The
solvent was removed under reduced pressure and the crude
product was purified by flash chromatography (EtOAc–PE).
Data for Compounds 2a,b.
Compound 2a: oil. 1H NMR (300 MHz, CDCl3): d = 2.09 (s,
1 H, ≡CH), 3.10 (d, JAB = 16.6 Hz, 1 H, CH2), 3.71 (d,
JAB = 16.6 Hz, 1 H, CH2), 3.96 (s, 3 H, OCH3), 5.22 (m, 2 H,
OCH2), 6.10 (s, 1 H, NH), 7.43 (m, 5 H, Ph). 19F NMR (282
MHz, CDCl3): d (TFA) = 3.38 (s, 3 F, CF3). Anal. Calcd for
C15H14F3NO4 (%): C, 54.71; H, 4.29; F, 17.33. Found: C,
55.02; H, 4.38; F, 16.99.
Compound 2b: mp 70–71 °C. 1H NMR (300 MHz, CDCl3):
d = 1.46 [s, 9 H, C(CH3)3], 2.06 (s, 1 H, ≡CH), 3.10 (d,
J = 16.9 Hz, 1 H, CH2), 3.71 (m, 1 H, CH2), 3.90 (s, 3 H,
OCH3), 5.70 (s, 1 H, NH). 19F NMR (282 MHz, CDCl3):
d (TFA) = 3.44 (s, 3 F, CF3). Anal. Calcd for C12H16F3NO4:
C, 48.81; H, 5.47; N, 4.74. Found: C, 48.74; H, 5.47; N, 4.68.
(17) Brandsma, L.; Verkrujsse, H. Preparative Organometallic
Chemistry, Vol. 1; Springer: Berlin, 1987, 63.
(18) See, for example: (a) Kuijpers, B. H. M.; Groothuys, S.;
Keereweer, A. R.; Quaedflieg, P. J. L. M.; Blaauw, R. H.;
Van Delft, F. L.; Rutjes, F. P. J. T. Org. Lett. 2004, 6, 3123.
(b) Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem.
Soc. 2003, 125, 9372. (c) Dondoni, A.; Giovannini, P. P.;
Massi, A. Org. Lett. 2004, 6, 2929. (d) Angelo, N. G.;
Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134. (e) Paul,
A.; Bittermann, H.; Gmeiner, P. Tetrahedron 2006, 62,
8919.
(19) Typical Procedure for the Preparation of 3.
Method A. A mixture of organic azide (1.0 mmol), amino
ester 2 (1.0 mmol), DIPEA (3.0 mmol) and CuI (0.1 mmol)
in THF (10 mL) was stirred at r.t. for 6–8 h. The resulted
reaction mixture was treated with 1 N HCl (15 mL), and
extracted with Et2O (3 × 15 mL). Combined organic layers
were dried over MgSO4 and filtered. The solvent was
removed under reduced pressure and the crude product was
purified by flash chromatography on silica gel (EtOAc–PE).
Method B. Organic azide (2.0 mmol) and amino ester 2 (2.0
mmol) were suspended in 1:1 H2O–t-BuOH (8 mL). To this
was added CuSO4·5H2O (5 M solution, 0.1 mmol, 5 mol%)
and sodium ascorbate (0.6 mmol). The mixture was stirred at
r.t. for 24 h, at which time TLC (silica, PE–EtOAc) indicated
complete conversion. The resulted solution was
concentrated under reduced pressure (rotary evaporator).
The residue was dissolved in 30 mL of brine and then
extracted with CH2Cl2 (3 × 30 mL). Combined organic
layers were washed with 5% aq NH4OH (2 × 10 mL), dried
over MgSO4, filtered and solvent was removed under
vacuum to give analytically pure product.
Data for Compounds 3a,g.
Compound 3a: mp 158–159 °C. 1H NMR (300 MHz,
CDCl3): d = 3.80 (d, 1 H, CH2, JAB = 15.0 Hz), 4.03 (s, 3 H,
OCH3), 4.16 (d, 1 H, CH2, JAB = 15.0 Hz), 6.18 (s, 1 H, NH),
Synlett 2007, No. 1, 136–140 © Thieme Stuttgart · New York

140
G. T. Shchetnikov et al.
LETTER
7.53–7.90 (m, 10 H, Ar), 8.22 (s, 1 H, H-triazole). 19F NMR
(282 MHz, CDCl3): d (TFA) = 5.38 (s, 3 F, CF3). Anal.
Calcd for C19H17F3N4O4S (%): C, 50.22; H, 3.77; N, 12.33.
Found: C, 50.07; H, 3.84; N, 12.28.
Anal. Calcd for C29H33F3N4O13: C, 49.58; H, 4.73; N, 7.97.
Found: C, 49.12; H, 4.57; N, 7.57.
(20) Data for Compound 6.
Mp 216–217 °C. 1H NMR (300 MHz, D2O): d = 3.38 (d,
Compound 3g: mp 78–79 °C. 1H NMR (300 MHz, CDCl3):
d = 1.84 and 1.88 (2 × s, 3 H, OAc), 2.12 (m, 9 H, 3 × OAc),
3.67 (dd, J = 14.8, 2.5 Hz, 1 H, CH), 3.95 and 3.98 (2 × s, 3
H, OMe), 4.02 (m, 1 H, CH), 4.26 (m, 3 H, CH, CH2), 5.11–
5.51 (m, 5 H, 3 × CH, OCH2), 5.78 (t, 2JH–H = 8.9 Hz, 1 H),
JAB = 15.3 Hz, 1 H), 3.64 (d, JAB = 15.3 Hz, 1 H), 7.73 (s, 1
H, H-triazole). 19F NMR (282 MHz, D2O): d (TFA) = 3.55
(s, 3 F, CF3). 13C NMR (150.9 MHz, D2O): d = 26.5, 65.3 (q,
2JC–F = 25.4 Hz), 123.5 (q, 1JC–F = 228.9 Hz), 128.1, 137.9,
166.0. Anal. Calcd for C6H7F4N4O2: C, 32.15; H, 3.15; N,
25.00. Found: C, 32.12; H, 3.04; N, 24.67.
6.09 (br s, 1 H, NH), 7.45 (m, 6 H, 1 H-triazole, 5 H-Ar). 19
F
NMR (282 MHz, CDCl3): d (TFA) = 3.87 (br s, 3 F, CF3).
Synlett 2007, No. 1, 136–140 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.