Synthesis of chiral α-amino-diazoketones on solid support: An access to β-homologated amino acid derivatives

Article abstract of DOI:10.1055/s-2004-835639

Diazoketone derivatives were obtained on solid support from their corresponding α-amino acids anchored by their N-terminus to the resin. A complete study was performed to optimize the two steps process of this synthesis on solid support: activation of the carboxylic acid function followed by reaction with diazomethane. The obtained diazoketones were then submitted to Wolff rearrangement in the presence of an amine to yield the corresponding homologated amides or in the presence of water to yield the corresponding β-homologated amino acids.

Full text of DOI:10.1055/s-2004-835639

LETTER
2791
Synthesis of Chiral a-Amino-diazoketones on Solid Support: An Access to
b-Homologated Amino Acid Derivatives
Synthesis of
C
o
hiral
a
-Amin
n
o-diazoketo
ines on
a
Solid
S
upport Cantel, Jean Martinez, Jean-Alain Fehrentz*
Laboratoire des Aminoacides, Peptides et Protéines (LAPP), UMR 5810 CNRS Universités Montpellier I et II, Faculté de Pharmacie,
15 Avenue Charles Flahault, BP 14491, 34093 Montpellier Cédex 5, France
Fax +33(4)67548651; E-mail: fehrentz@colombes.pharma.univ-montp1.fr
Received 31 August 2004
Various experimental conditions were used for this acti-
Abstract: Diazoketone derivatives were obtained on solid support
vation step. The obtained activated carboxylic acid func-
tion was then placed in the presence of a large excess of
nucleophile (benzylamine) in DMF and after classical
from their corresponding a-amino acids anchored by their N-termi-
nus to the resin. A complete study was performed to optimize the
two steps process of this synthesis on solid support: activation of the
carboxylic acid function followed by reaction with diazomethane. washings, compounds were released from support under
The obtained diazoketones were then submitted to Wolff rearrange-
acidic conditions and the crude producta were analyzed by
ment in the presence of an amine to yield the corresponding
HPLC and mass spectrometry (Scheme 1). IBCF, BOP,
homologated amides or in the presence of water to yield the corre-
HATU, TOTU, SOCl2, TFFH, HBTU, HCTU, TCTU,
sponding b-homologated amino acids.
BTC and DIC/pentafluorophenol7 were evaluated in the
same reaction conditions: 5 equivalents of activating re-
agents were used and allowed to react for 30 minutes. Af-
Key words: a-amino-diazoketone, Wolff rearrangement, solid-
phase synthesis, inverse anchoring
ter washing with anhydrous DMF, 10 equivalents of
benzylamine were added to the swollen resin for one hour.
Diazoketones of a-amino acids are interesting starting
materials for medicinal chemistry. They can be used for
homologation of a-amino acids, yielding b-amino acids
through Wolff rearrangement via the Arndt–Eistert ap-
proach,1 for the synthesis of amino acid derived
imidazoles2 or thiazoles3 or for the preparation of haloge-
nated a-amino ketones.4 This versatility prompted us to
demonstrate that generation of these intermediates was
possible on solid support. For this purpose, it was neces-
sary to anchor the a-amino acid to a solid support by its
amino function, leaving the carboxylic acid function free.
This was achieved using a-amino esters via an activated
carbonate Wang resin as previously described.5 After sa-
ponification of the ester,6 the carboxylic acid function
could be activated to react with diazomethane. We report
in this paper the optimization of these two steps leading to
a-amino diazoketones. For this study, phenylalanine was
chosen as model as it presents the advantage to be UV de-
tectable, allowing easy HPLC and mass spectrometry
(MS) analysis. These compounds were then involved in
the Wolff rearrangement in the presence of an amine com-
ponent or of water to yield, respectively, the correspond-
ing homologated amide or acid derivatives.
After cleavage, the crude products were analyzed by
HPLC. With this stoichiometry, the best results were ob-
tained with BOP, HBTU and DIC/pentafluorophenol with
comparable purity and yield. SOCl2 and BTC yielded to
crudes containing by-products and low yields of benzyl-
amide derivatives. HATU, TOTU, TFFH, HCTU and
TCTU were found effective to prepare the benzylamide
derivatives on support but with formation of minor by-
products, which were not analyzed. As it can be seen in
Table 1, three successive activations with 10 equivalents
of IBCF were necessary to yield quantitative acylation of
benzylamine. The best solvent for this step was DMF
compared to CH2Cl2 and DME. Optimized experimental
conditions were the following: activation of the resin with
10 equivalents IBCF in the presence of 10 equivalents
NMM for 3 minutes and filtration of the resin. This oper-
ation was repeated twice and then the resin was briefly
washed with anhydrous DMF. Benzylamine (5 equiva-
lents) was then added to the resin swollen in DMF and
allowed to react for 30 minutes.
The synthesis of a-amino diazoketones is a two steps pro-
cess involving first, preparation of activated carboxylic
acids and second, reaction with diazomethane to yield the
desired compounds. We needed to ensure the complete
activation of the carboxylic acid function on solid support.
This activation has to be quantitative to avoid esterifica-
tion of the remaining carboxylic acid by diazomethane.
OX
activating
benzylamine
COOH
NH
NH
agent/base
O
H
N
H
N
cleavage and
analysis
TFA, H2N
NH
O
1
O
SYNLETT 2004, No. 15, pp 2791–2793
Advanced online publication: 08.11.2004
0
7
.1
2
.2
0
0
4
Scheme 1 Synthetic scheme for the activation study.
DOI: 10.1055/s-2004-835639; Art ID: G25404ST
© Georg Thieme Verlag Stuttgart · New York

2792
S. Cantel et al.
LETTER
Table 1 Activation of the N-Terminal Linked Amino Acid
Carboxylic Acid Function with IBCF in DMF
When the activated resin was rinsed and suspended in
THF, formation of the methyl ester was not observed
(Figure 1) but the non-homologated benzylamide was ob-
tained as a by-product, even using a large excess of diazo-
methane (50 equivalents) or longer reaction time.
Generation of diazomethane from diazald® (N-methyl-N-
nitroso-p-toluenesulfonamide, Aldrich) in ethereal alco-
holic or alcohol-free ethereal solutions, generation of dia-
zomethane from 1-methyl-3-nitro-1-nitrosoguanidine in
ethereal or dichloromethane solution gave the same re-
sults. Using commercially available (trimethylsilyl)diazo-
methane solution in hexane yielded complex mixtures.
IBCF (equiv)
2
5
3 × 5
3 × 10
Amide 1 (yield, %)
50
80
89
100
We then started to investigate formation of the diazoke-
tone on solid support. Three activating methods were used
in parallel: BOP reagent, IBCF and pentaflurophenyl
esters which were described to react vigorously with
diazomethane.8,9 After activation, a solution of diazo-
methane in diethyl ether (from diazald®) was allowed to
react with the resin suspended in DMF. Completion of the
diazoketone formation was checked by HPLC and MS on
released compounds obtained after homologation with
benzylamine in the presence of silver benzoate
(Scheme 2) or by IR analysis of beads (disappearance of
the 2105 cm–1 band). To ensure completion of the activa-
tion step, an aliquot of the same activated resin was
always aminolyzed in parallel with benzylamine. Final
compounds were then cleaved by TFA from the support
and analyzed.
As a control, we prepared in parallel the same compounds
in solution from Boc-phenylalanine using standard exper-
imental conditions with IBCF as activating agent
(Scheme 3). While HPLC analysis of crude Boc-b-h-Phe-
benzylamide revealed only one peak, HPLC analysis of
crude TFA, H-b-h-Phe-benzylamide after removal of Boc
with TFA revealed two peaks. However LC-MS analysis
of these two crudes revealed the presence of two com-
pounds which were identified as the non-homologated
(about 17%) and the homologated benzylamide (about
83%) derivatives. These compounds were approximative-
ly obtained in the same proportions than on solid support.
O
N
H
TFA, H2N
b,c
1
OX
a
CHN2
NH
NH
O
O
COOMe
TFA,
H2N
F
F
F
F
2
X = -Bt, -COOiBu,
F
H
N
TFA,
H2N
O
3
Figure 1 HPLC analysis at 214 nm of the crudes after cleavage.
Scheme 2 Formation of the diazoketone using various activation
methods. Reagents and conditions: (a) Diazomethane; (b) Ag+/Et3N,
benzylamine; (c) TFA cleavage and analysis.
a) IBCF/NMM
CHN2
BocNH
COOH
BocNH
While the activation step was complete (checked by the
aminolysis of the activated aliquots of resin with benzyl-
amine), we always observed formation of small amounts
of by-products during the Arndt–Eistert homologation.
Use of BOP or DIC/pentafluorophenol as activating agent
did not yield clean compounds. With mixed anhydride,
two compounds were obtained and identified by LC-MS
as the desired homologated amide (83%) and the phenyl-
alanine methyl ester. The formation of methyl ester im-
plied hydrolysis of the activated species by water and
esterification of the acidic function by diazomethane or
could be explained by the presence of a H2O···CH2N2
adduct reacting with the activated species.10 This could
not be avoided by drying the diazomethane solution over
sodium sulfate for 10–15 minutes.
b) CH2N2
O
c) Ag+, benzylamine
d) TFA
1
+
2
+
3
MH+ 269
MH+ 180 MH+ 255
Scheme 3 Solution Arndt–Eistert homologation of Boc-phenylala-
nine.
The best experimental conditions were found to be as fol-
lows: 1) activation of the carboxylic function with 10
equivalents IBCF in DMF at room temperature in the
presence of 10 equivalents NMM for 3 minutes and filtra-
tion of the resin. This operation was repeated twice and
then the resin was briefly washed with and suspended in
anhydrous THF; 2) diazomethane (4 equivalents) in
CH2Cl2 or diethyl ether was then added for one hour at
Synlett 2004, No. 15, 2791–2793 © Thieme Stuttgart · New York

LETTER
Synthesis of Chiral a-Amino-diazoketones on Solid Support
2793
0 °C; 3) the diazoketone linked to the support was sus-
pended in anhydrous THF, 5 equivalents of amine and sil-
ver benzoate (0.9 equivalents) in TEA (9 equivalents)
were added for two hours at room temperature and in dim
light. Resin was successively washed with THF, MeOH
and CH2Cl2 before TFA cleavage.
References
(1) Penke, B.; Czombos, J.; Balaspiri, L.; Peters, J.; Kovacs, K.
Helv. Chim. Acta 1970, 53, 1057.
(2) Groarke, M.; McKervey, M. A.; Nieuwenhuyzen, M.
Tetrahedron Lett. 2000, 41, 1275.
(3) Groarke, M.; McKervey, M. A.; Moncrieff, H.;
Nieuwenhuyzen, M. Tetrahedron Lett. 2000, 41, 1279.
(4) Umezawa, H.; Nakamura, T.; Fukatsu, S.; Aoyagi, T.;
Tatsuta, K. J. Antibiot. 1983, 36, 1787.
(5) Gouilleux, L.; Fehrentz, J.-A.; Winternitz, F.; Martinez, J.
Tetrahedron Lett. 1996, 37, 7031.
(6) Cantel, S.; Desgranges, S.; Martinez, J.; Fehrentz, J.-A. J.
Pept. Sci. 2004, 10, 326.
(7) For a revue of activating reagents see: Synthesis of Peptides
and Peptidomimetics, In Houben-Weyl, Methods of Organic
Chemistry, Vol. E22c; Goodman, M.; Felix, A.; Moroder,
L.; Toniolo, C., Eds.; Thieme: Stuttgart, 2002.
(8) Babu, V. V. S.; Gopi, H. N. J. Pept. Res. 1999, 53, 308.
(9) Babu, V. V. S.; Gopi, H. N. Lett. Pept. Sci. 1999, 6, 173.
(10) Plucinska, K.; Liberek, B. Tetrahedron Lett. 1987, 15, 3509.
The Wolff rearrangement was then performed in the opti-
mized conditions from diazoketones with various amines
(Table 2) to exemplify this new reaction on solid support.
In conclusion, we report in this paper the first synthesis of
a-amino diazoketones on solid support with a-amino
acids linked by their amine function on the resin. This
synthesis leads to useful intermediates as diazoketones
can be used further in different reactions to yield various
interesting chemical entities linked to the support, which
can be used in a parallel combinational chemistry.
Table 2 Synthesis of b-Homologated Amino Acid Amide Deriva-
tives on Solid Support
Linked
Amines
Yield of 1 Yield of 3
residues
(%)
83
60
56
85
79
77
92
85
(%)
17
13
15
15
21
9
Phe
Phe
Phe
Phe
Phe
Trp
Leu
Val
Benzylamine
H-Phe-OMe
H-Phe-NH2
Diphenylethylamine
p-methoxybenzylamine
Benzylamine
Benzylamine
8
Benzylamine
15
Synlett 2004, No. 15, 2791–2793 © Thieme Stuttgart · New York