Synthesis of difluorinated pseudopeptides using chiral α,α- difluoro-β-amino acids in the Ugi reaction

Article abstract of DOI:10.1016/j.tetlet.2003.11.019

2,2-Difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenylpropionic acid 3, obtained by a Reformatsky-type reaction of ethyl bromodifluoroacetate with (4R)-2,4-diphenyloxazolidine, was used as a classical carboxylic acid in the Ugi reaction to prepare various difluorinated pseudopeptides 5a-n. Compounds 5 were then deprotected by hydrogenolysis to furnish difluorinated pseudopeptides 6.

Full text of DOI:10.1016/j.tetlet.2003.11.019

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 773–776
Synthesis of difluorinated pseudopeptides using chiral a,a-difluoro-
b-amino acids in the Ugi reaction
Vanessa Gouge, Philippe Jubault and Jean-Charles Quirion*
Laboratoire d’Heꢀteꢀrochimie Organique associeꢀ au CNRS, IRCOF, INSA de Rouen, 1 rue Tesniꢁere,
76821 Mont Saint-Aignan cedex, France
Received 21 August 2003; revised 3 November 2003; accepted 10 November 2003
In memory of Miss Anne-Laure Janer who passed away in January 2003
Abstract—2,2-Difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenylpropionic acid 3, obtained by a Reformatsky-type reaction
of ethyl bromodifluoroacetate with (4R)-2,4-diphenyloxazolidine, was used as a classical carboxylic acid in the Ugi reaction to
prepare various difluorinated pseudopeptides 5a–n. Compounds 5 were then deprotected by hydrogenolysis to furnish difluorinated
pseudopeptides 6.
Ó 2003 Elsevier Ltd. All rights reserved.
Multicomponent condensation (MCC) reactions and in
particular the Ugi four-component coupling reaction,1
have recently appeared as efficient methods for the
synthesis of diverse libraries of small molecules such as
benzodiazepines, lactams, pyrroles, C-glycoside peptide
ligands and diketopiperazines.2 As a synthetic tool for
creating diverse compound libraries, the Ugi reaction
accepts a wide range of components although the range
of available isocyanides is limited. To overcome the
limited commercial availability of isocyanides, several
new isocyanides have been recently introduced.3
tides7 as well as building blocks for b-lactam antibiot-
ics.8 We have recently described9 the enantioselective
synthesis of a,a-difluoro-b-amino acids via the Refor-
matsky-type reaction of ethyl bromodifluoroacetate
with chiral 1,3-oxazolidines (Scheme 1).
This article describes the application of these a,a-diflu-
oro-b-amino acids in the Ugi reaction. Due to the
bifunctionality encountered in the a,a-difluoro-b-amino
acids 4, subsequent transformations of these compounds
were necessary to block either the amine or carboxylic
acid terminus before their use in the Ugi reaction to
avoid the formation of lactams. We decided to block the
amine function in order to use the highly reactive car-
boxyl terminus in the Ugi reaction. Several protecting
groups were tested such as Boc, Cbz, Ses and tosyl. In
the case of the Boc protection, we observed a very low
yield and rapid deprotection because of the intrinsic
acidity of the a,a-difluoro-b-amino acid. For Ses and
Cbz, very low yields were again obtained. Tosyl pro-
tection was efficiently realized (50%) but its removal
requires drastic conditions, which are not compatible
with peptide bonds. Finally we decided to test com-
pound 3 directly in the Ugi reaction and used the chiral
auxiliary as a nitrogen protecting group, even though
it contains a hydroxyl moiety and does not eliminate
the reactivity of that secondary nitrogen. In a first
attempt,10 methanolic solutions of benzylamine, benz-
aldehyde, commercially available ethyl isocyanoacetate
and compound 3 were mixed at room temperature for
Furthermore, fluoro compounds have raised a great deal
of interest. Indeed, the presence of a fluorine atom
introduces modifications to the physiological activity of
bioactive compounds.4 In particular gem-difluoro amino
acids and derivatives have been the subject of an
important area of research as the CH2/CF2 transposition
has been recognized as a valuable tool in the blockage of
metabolic processes. Replacement of various functional
groups by a gem-difluoromethylene moiety has gener-
ated potent transition-state-type inhibitors.5 Addition-
ally, b-amino acids are now recognized as valuable tools
for the generation of new derivatives6 such as b-pep-
Keywords: Ugi reaction; a,a-Difluoro-b-amino acids; Pseudopeptides;
Phenylglycinol.
* Corresponding author. Tel.: +33-2-35-52-24-26; fax: +33-2-35-52-29-
59; e-mail: quirion@insa-rouen.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.019

774
V. Gouge et al. / Tetrahedron Letters 45 (2004) 773–776
Ph
Ph
Ph
BrZn
F
CO2Et
F
O
HO
NH
HO
N
HN
HCl 6M
71%
O
CO2H
THF
70%
F
Ph
F
F
Ph
Ph
F
1
3
2
H2, Pd/C, MeOH
90%
NH2
CO2H
Ph
F
F
4
Scheme 1.
R1
NH2
R1
O
H
F
H
N
F
F
F
+
R3
N
N
HO
O
CH3OH, r.t.
24 h
N
H
OH
OH
R2
R3
C
+
R2
H
O
Ph
Ph
O
Ph
Ph
+
3
5a-n
N
C
Scheme 2.
Table 1. Synthesis of difluorinated pseudopeptides 5a–n
Compound
R1
R2
Ph
R3
Yield (%)
5a
5b
5c
5d
5e
5f
Ph–CH2
Ph–CH2
Ph–CH2
Ph–CH2
Ph
EtOC(O)CH2
EtOC(O)CH2
EtOC(O)CH2
EtOC(O)CH2
EtOC(O)CH2
EtOC(O)CH2
EtOC(O)CH2
EtOC(O)CH2
2-TBSO-C6H4
2-TBSO-C6H4
2-TBSO-C6H4
2-TBSO-C6H4
2-TBSO-C6H4
95
73
63
55
68
40
61
81
67
57
50
54
34
46
CH3–(CH2)4
trans-Ph–CH@CH
4-Pyridyl
Ph
Ph
Ph
CH3–(CH2)4
trans-Ph–CH@CH
4-Pyridyl
5g
5h
5i
Ph
Ph–CH2
Ph–CH2
Ph–CH2
Ph–CH2
2-BocNH–C6H4
BnOC(O)CH2
Ph
5j
CH3–(CH2)4
trans-Ph–CH@CH
4-Pyridyl
5k
5l
5m
5n
Ph
Ph
C2H5OC(O)CH2
24 h leading to difluoro pseudopeptide 5a in 95% yield.
As previously noted, no diastereoselectivity was
observed. Indeed, in early work, Bock and Ugi11 deter-
mined that use of a chiral acid or isonitrile in the Ugi
MCC reaction did not provide any degree of diastereo-
selectivity. We then applied this methodology by
changing each of the three components in the Ugi
reaction in order to generate a small library of difluo-
rinated pseudopeptides (Scheme 2). For the amine
component, we used benzylamine, aniline, O-benzylated
glycine and N-Boc-phenylenediamine; benzaldehyde,
hexanal, 4-pyridylcarboxaldehyde and trans-cinnamal-
dehyde were used as the aldehyde source. For the iso-
nitrile component, we used ethyl isocyanoacetate and
the isonitrile developed by Linderman et al.3c Finally,
for compound 3, (R)-phenylglycinol was used in each
case as chiral auxiliary. All the results obtained for the
generation of this small library are collected in Table 1.
In most cases, the Ugi reaction occurred smoothly,
affording difluorinated pseudopeptides 5 with satisfac-
tory yields of the purified product. In most cases, dia-
stereoisomers were easily separated by column
chromatography on silica gel. We then turned our
attention towards the removal of (R)-phenylglycinol
(Scheme 3). In the case of 5a, hydrogenolysis of the

V. Gouge et al. / Tetrahedron Letters 45 (2004) 773–776
775
Ph
Ph
Ph
Ph
O
H
F
F
O
F
F
EtO
N
N
H2, Pd/C
EtO
N
NH2
N
H
OH
N
H
MeOH
75%
O
O
Ph
Ph
O
O
Ph
5a
6a
O
O
N
BnO
O
HO
O
H
F
F
F
F
EtO
N
N
EtO
NH2
H2, Pd/C
N
OH
N
H
MeOH
65%
O
H
Ph
O
Ph
Ph
O
Ph
O
Ph
5n
6n
Scheme 3.
W. J. Org. Chem. 1996, 61, 8935–8939; (c) Linderman, R.
J.; Binet, S.; Petrich, S. R. J. Org. Chem. 1999, 64, 336–
337.
nitrogen appendage cleaved the phenylglycinol part
selectively (75% yield) furnishing 6a without elimination
of fluorine. In the case of 5n, hydrogenolysis cleaved the
phenylglycinol part and the benzylic ester (65% yield)
leading to 6n.
4. Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical
Frontiers of Fluorine Chemistry. In ACS Symposium
Series 369; American Chemical Society: Washington, DC,
1996.
In conclusion, we have performed the Ugi reaction using
an a,a-difluorocarboxylic acid leading to difluorinated
pseudopeptides in moderate to high yields. Further
investigations, especially solid-phase applications,
removal of the isonitrile moiety (using the ÔconvertibleÕ
isonitrile), post-condensation and cyclization leading to
heterocyclic rings (e.g., benzodiazepines, azepanes) are
currently in progress in our laboratory and will be
reported in due course.
5. (a) Iseki, K. Tetrahedron 1998, 54, 13887–13914; (b) Tozer,
M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619–8683.
6. Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; VCH-Wiley: New York, 1997.
€
7. Matthews, J. L.; Overhand, M.; Kuhnle, F. N. M.; Ciceri,
P. E.; Seebach, D. Liebigs Ann. Recl. 1997, 1371–1381.
8. (a) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447–1465;
(b) Van der Steen, F. H.; Van Koten, G. Tetrahedron 1991,
47, 7503–7524.
9. (a) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion,
J.-C. J. Org. Chem. 1999, 64, 8461–8464; (b) For recent
modified approaches, see: Staas, D. D.; Savage, K. L.;
Homnick, C. F.; Tsou, N. N.; Ball, R. G. J. Org. Chem.
2002, 67, 8276–8279; Vidal, A.; Nefzi, A.; Houghten, R. A.
J. Org. Chem. 2001, 66, 8268–8272.
References and notes
10. (2-{{[2-(tert-Butyl-dimethyl-silanyloxymethyl)-phenylcar-
bamoyl]-phenyl-methyl}-[2,2-difluoro-3-(2-hydroxy-1
R-phenylethylamino)-3 S-phenylpropionyl]-amino}-phenyl)-
carbamic acid tert-butyl ester 5m: All compounds were
diluted in dry MeOH to afford a concentration of approxi-
mately 1 M. N-Boc-phenylenediamine (112 mg, 0.54mmol,
1.2 equiv) and benzaldehyde (0.069 mL, 0.675 mmol,
1.5 equiv) were combined and the reaction was stirred
for 2 h. Isonitrile (167 mg, 0.675 mmol, 1.5 equiv) and 2,2-
difluoro-3-(2-hydroxy-1 R-phenylethylamino)-3 S-phenyl-
propionic acid (286 mg, 0.45 mmol, 1 equiv) were added,
and the reaction was stirred for 24 h. After the solvent had
been evaporated, the residue was purified on silica gel,
eluting with cyclohexane/ethyl acetate gradient (9/1 to 7/3).
1H NMR (CDCl3) (300 MHz). Mixture of rotamers (ratio,
3/1); for clarity only one rotamer is described; 1st diaste-
reoisomer: 0.0 (s, 6H), 0.8 (s, 9H), 1.6 (s, 9H), 3.7–4.0 (m,
2H), 4.6–5.0 (m, 4H), 6.2 (s, 1H), 6.7 (s, 1H), 6.72 (s, 1H),
7.0–7.6 (m, 21H), 8.05 (m, 1H), 8.5 (m, 1H), 9.1 (s, 1H),
10.0 (s, 1H); 2nd diastereoisomer: 0.0 (s, 6H), 0.8 (s, 9H),
1.6 (s, 9H), 3.7–4.0 (m, 2H), 4.6–5.0 (m, 4H), 6.2 (s, 1H), 6.7
(s, 1H), 6.72 (s, 1H), 7.0–7.6 (m, 21H), 8.1 (m, 1H), 8.4 (m,
1H), 9.2 (s, 1H), 10.1 (s, 1H).
1. (a) Ugi, I. Angew. Chem., Int. Ed. 1982, 21, 810–819; (b)
€
Ugi, I. J. Prakt. Chem. 1997, 339, 499–516; (c) Domling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
3210.
2. (a) Mjalli, A. M. M.; Sarshar, S.; Baiga, T. J. Tetrahedron
Lett. 1996, 37, 2943–2946; (b) Hanusch-Kompa, C.; Ugi,
I. Tetrahedron Lett. 1998, 39, 2725–2728; (c) Short, K. M.;
Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359–362; (d)
Short, K. M.; Ching, B. W.; Mjalli, A. M. M. Tetrahedron
Lett. 1998, 39, 7489–7492; (e) Bienayme, H.; Bouziuo, K.
Tetrahedron Lett. 1998, 39, 2735–2738; (f) Hulme, C.;
Morissette, M. W.; Volz, F. A.; Burns, C. J. Tetrahedron
Lett. 1998, 39, 1113–1116; (g) Hulme, C.; Ma, L.;
Cherrier, M.-P.; Romano, J. J.; Morton, G.; Duquenne,
C.; Salvino, J.; Labaudiniere, R. Tetrahedron Lett. 2000,
41, 1883–1887; (h) Hulme, C.; Ma, L.; Vasant Kumar, N.;
Krolikowski, P. H.; Allen, A. C.; Labaudiniere, R.
Tetrahedron Lett. 2000, 41, 1509–1514; (i) Nixey, T.;
Tempest, P.; Hulme, C. Tetrahedron Lett. 2002, 43, 1637–
1639; (j) Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org.
Lett. 2002, 4, 1167–1170.
3. (a) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc.
1995, 118, 2574–2583; (b) Keating, T. A.; Armstrong, R.
19F NMR (CDCl3) (282 MHz). 1st diastereoisomer: )98.3
2
(d, 1F, JF–F ¼ 271:9 Hz), )98.8 (d, minor rotamer,

776
V. Gouge et al. / Tetrahedron Letters 45 (2004) 773–776
2
2JF–F ¼ 270:8 Hz), )119.4 (dd, minor rotamer, JF–F
¼
121.0, 122.2, 124.4, 127.4, 127.5, 127.6, 128.0, 128.2,
3
2
259 Hz, JF–H ¼ 19:3 Hz), )119.5 (dd, JF–F ¼ 270:8 Hz,
128.3, 128.4, 128.5, 128.6, 128.9, 129.1, 129.4, 129.6,
130.6, 130.7, 131.0, 135.1, 137.5, 141.7, 153.5, 168.7.
Rf . 1st diastereoisomer: 0.58 (ethyl/cyclohexane 3/7); 2nd
diastereoisomer: 0.47 (ethyl/cyclohexane 3/7).
3JF–H ¼ 23:6 Hz); 2nd diastereoisomer: )98.9 (d, 1F,
2JF–F ¼ 278:3 Hz), )112.3 (dd, 1F, JF–F ¼ 278:3 Hz,
2
3JF–H ¼ 19:3 Hz).
13C NMR (CDCl3) (75.4 MHz). Only one rotamer of the
2nd diastereoisomer is described: )5.4, )5.2, 18.2, 25.8,
25.9, 27.0, 28.4, 28.5, 30.3, 43.6, 62.6, 65.4, 66.4, 68.7, 80.2,
117.5 (dd, JC–F ¼ 208:9 Hz, JC–F ¼ 198:6 Hz), 119.1,
Mass spectrometry (FAB+): M ¼ 865:3.
11. (a) Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 339, 385–389;
(b) Ziegler, T.; Schlomer, R.; Koch, O. Tetrahedron Lett.
1998, 39, 5957–5960.
1
1