Application of carbodiimide mediated Lossen rearrangement for the synthesis of α-ureidopeptides and peptidyl ureas employing N-urethane α-amino/peptidyl hydroxamic acids

Article abstract of DOI:10.1039/b905790k

Application of the Lossen rearrangement to the synthesis of N-urethane protected α-peptidyl ureas and ureidopeptides is reported. The carbodiimide mediated rearrangement of N-Boc/Z/Fmoc protected α-amino/peptide hydroxamic acids into isocyanates and coupling of the latter with the amino acid esters/peptide esters have been accomplished in a single-pot to obtain good yields of urea products. Synthesis of the ureidoalanine derivatives via the hydroxamate derivatives of N-protected aspartic acid has also been carried out using the same procedure.

Full text of DOI:10.1039/b905790k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Application of carbodiimide mediated Lossen rearrangement for the synthesis
of a-ureidopeptides and peptidyl ureas employing N-urethane a-amino/
peptidyl hydroxamic acids†
N. Narendra, Gundala Chennakrishnareddy and Vommina V. Sureshbabu*
Received 24th March 2009, Accepted 20th May 2009
First published as an Advance Article on the web 7th July 2009
DOI: 10.1039/b905790k
Application of the Lossen rearrangement to the synthesis of N-urethane protected a-peptidyl ureas and
ureidopeptides is reported. The carbodiimide mediated rearrangement of N-Boc/Z/Fmoc protected
a-amino/peptide hydroxamic acids into isocyanates and coupling of the latter with the amino acid
esters/peptide esters have been accomplished in a single-pot to obtain good yields of urea products.
Synthesis of the ureidoalanine derivatives via the hydroxamate derivatives of N-protected aspartic acid
has also been carried out using the same procedure.
For preparation of peptidyl ureas through Curtius rearrange-
Introduction
ment, the N-protected a-amino acid azides are heated at re-
Research in peptide therapeutics has been revisited during
flux in toluene and the resulting isocyanates are coupled with
amino acid/ester.25 The isocyanates obtained from N-protected
a/b amino acid azides are also converted into methyl/ethyl
carbamates26 that are in turn used as activated monomers for urea
synthesis. Synthesis of a-peptidyl ureas through diphenylphos-
phoryl azide (DPPA) mediated modified Curtius rearrangement
has been recently reported27 (Scheme 1). b-Peptidyl ureas are also
synthesized in solution and solid phase by using the monomers
obtained by coupling the amines resulting from reduction of the
N-protected a-amino nitriles/amides or b-amino alkyl azides or
by other methods.28 The bis[trifluroacetoxy]phenyliodine (PIFA)
mediated oxidative Hoffmann rearrangement of N-urethane pro-
tected amino amides also yields peptidyl ureas.29 Both main chain
and side chain primary amide groups have been transformed into
isocyanate moiety via this method in a single step and coupled
with amino component.30
In spite of their routine use, both the Curtius and Hoffmann
rearrangements present their own limitations. The azide method,
although compatible with common N-protecting groups,31 is syn-
thetically less attractive—particularly for large scale reactions—
due to the instability of acyl azides and their explosive nature
under the high temperature conditions used for accomplishing the
rearrangement. Furthermore, this method furnishes impressive
yields of ureas with Fmoc chemistry while it does not quantita-
tively yield Boc protected ureas mainly due to the instability of
Boc-amino acid azides. The PIFA mediated conversion of amides
to isocyanates uses stable amides as starting materials and involves
milder conditions. But, in addition to the high cost of PIFA,
the reaction requires higher equivalents of a base and therefore
becomes incompatible with Fmoc chemistry. Consequently, its
application to Fmoc chemistry has resulted in describing limited
examples with invariably less yields.29 Moreover, when PIFA is
used, the trifluoroacetic acid byproduct formed during the reaction
can catalyze the hydrolysis of isocyanate thus reducing the yields
of urea and can also deprotect the Boc group.32
recent years following the developments in the chemistry of
peptidomimetics. Chemical modification of the peptide backbone
has turned into a powerful tool to overcome the intrinsic
inadequacies of peptide drugs.1 The urea linkage is one of the
common types of amide-bond surrogate to be inserted into
the peptide backbone. N,N-Substituted ureas, N,N¢-linked ureas
and ureidopeptoids are being explored for novel applications in
medicinal2 as well as structural chemistry.3 Ureido analogs of
angiotensin,4 [Leu]enkephaline,5 gasrtin antagonists,6 Tat derived
oligomers binding TAR RNA7, aspartic peptidases8 and protease
inhibitors like microbial alkaline protease,9 HIV-1 protease,10
aspartic acid proteases,11 g-secretase12 and several other classes of
enzyme inhibitors13 have been prepared and studied for improved
biological properties. Urea functionality has been utilized to create
highly organized hydrogen bonded molecular assemblies including
protein secondary structure mimics14–16 and hydrogen bonded
molecular self-assemblies.17,18 Non-proteinogenic amino acids like
L-albizziine contain urea linkages.19 Consequently, it is important
that efficient methods to synthesize peptides bearing a ureido bond
are available.
Currently, ureidopeptides are synthesized using the follow-
ing methods: a) Coupling of amine with isocyanates that are
obtained by the reaction of a-amino acid esters with phosgene
or triphosgene.20 Alternatively, several coupling agents like
N,N¢-carbonyldiimidazole,21 N,N¢-disuccinimido carbonate,22
1,1¢-carbonylbisbenzotriazole23 and also treatment of the primary
amines with PPh3-CCl4-TEA system24 have been used for the
insertion of ureido bond into peptide backbone; b) Curtius or
oxidative Hoffmann rearrangement for insertion of the ureido
bonds at the C-terminus of N-protected a- or b-amino acid.
Peptide Research Laboratory, Department of Studies in Chemistry, Central
College Campus, Bangalore University, Dr B. R. Ambedkar Veedhi,
Bangalore, 560001, India. E-mail: hariccb@rediffmail.com
† Electronic supplementary information (ESI) available: General exper-
imental procedure for the preparation of Na-protected amino/peptide
hydroxamic acid and characterization data. See DOI: 10.1039/b905790k
The isocyanates, on the other hand, can also be produced
through the Lossen rearrangement of hydroxamic acids. Here,
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Scheme 1 Outline of the present methods followed for urea bond insertion.
the isocyanates are generated from the activated hydroxamates
through the displacement of N-hydroxyl group followed by
the C→N migration. Reagents such as p-toluenesulfonyl
chloride,33N,O-bis-(ethoxycarbonyl)hydroxylamine,34 methane-
sulfonyloxycarbamate,35 several acylating agents36 and carbodi-
imides37 have been used to accomplish the rearrangement. The
reported applications of this rearrangement include degradation
of the carboxyl group of oligosaccharide derivatives via an
isocyanate intermediate.38 In peptide chemistry, the application
of this reaction is limited to very few early reports on carboxyl
terminal determination in peptides39 and mechanistic studies
relating to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (EDC) mediated conversion of hydroxamic acid into
amines.40 The formation of an isocyanate as a common byproduct
through the Lossen rearrangement of the N-hydroxy succinimidyl
esters and carbonates has been documented.41
of cyanuric chloride,46 tetramethylfluoroformamidinium hexaflu-
orophosphate (TFFH)47 and alkyl chloroformates.48 Coupling of
N-protected amino acids with O-benzylhydroxylamine followed
by hydrogenolysis has also yielded hydroxamic acids.49 The N-Boc
and Z-a-amino hydroxamic acids employed as starting materials
in the present study were prepared as stable solids in high yields
by treating the corresponding mixed anhydride solutions with
a neutral methanolic solution of hydroxyl amine prepared by
neutralizing NH2OH.HCl with methanolic KOH (Table 1). Out
of the two Fmoc protected hydroxamic acids, Fmoc-Val-NHOH
was prepared starting from stable Fmoc-Val-Cl,50 while the Fmoc-
Glu(OtBu)-NHOH was obtained through the mixed anhydride
method (Table 1). The easy and quantitative preparation of
hydroxamic acids from amino acid and peptide acids and their
long shelf-life place them as better starting materials compared to
the amino acid azides.
A feature of this reaction, especially suited for peptide
chemistry is its ability to be executed under mild and neu-
tral conditions when the rearrangement is effected using
N,N-dicyclohexylcarbodiimide (DCC) or EDC. Consequently,
the reaction becomes compatible with all the three urethanes,
Boc, Z and Fmoc and tolerable by most side chain protecting
groups that are labile towards either acid or base. In spite of
these inherent advantages, the application of this rearrangement
to the synthesis of peptidomimetics has not been explored.31
With the intention of developing a new and facile method to
a-peptidyl urea synthesis, we considered demonstrating the
application of Lossen rearrangement in the peptidomimetic
chemistry.
Studies on the reaction were initiated with the preparation of
the hydroxamic acid from the corresponding N-protected a-amino
acids. The amino acid derived hydroxamic acids, apart from being
synthetically useful compounds, are also biologically active in and
of themselves.42 Several procedures have been reported for the
synthesis of N-protected amino/peptide hydroxamic acids. These
include hydroxaminolysis of N-protected amino acid esters,43
resin bound amino/peptide acids44 and N-protected amino acid
derived oxazolidinones.45 Hydroxamates have also been prepared
by the reaction of hydroxyl amine with amino acids in presence
Rearrangement of the hydroxamic acid was effected by treating
Boc-Phe-NHOH (chosen as model compound) with a solution
of EDC in CH2Cl2 at rt for about 30 min. This was followed by
the addition of amino acid ester (H-Val-OMe) and continuing the
stirring for another 4–5 h provided the dipeptidyl urea 1c in 72%
yield. The effect of the two carbodiimides, EDC and DCC on the
yield of the urea could be observed with EDC producing about
5–10% higher yield than DCC. Also, during purification, while the
urea adduct of EDC could be removed by aqueous work up, DCU
was tediously removed either through column chromatography or
repeated recrystallization with DMSO-water.
However with both the carbodiimides, addition of a cat-
alytic amount of 4-dimethylaminopyridine (DMAP) increased the
yields. For instance, when the reaction of Boc-Phe-NHOH was
carried out in the presence of 0.1 equivalent of DMAP, the yield
of 1c rose to 82%. Once the optimized reaction condition was
described, the reaction was repeated by using EDC to obtain the
Boc and Z protected dipeptidyl ureas, 1a–g and 2a–d in good
yields. However, when the reaction was carried out using N-Fmoc
protected hydroxamic acids, comparably less yields of the peptidyl
ureas 3a and 3b were observed. This was reasoned out to the
reduced solubility of the N-Fmoc protected a-amino hydroxamic
acids in CH2Cl2 (Table 2).
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Table 1 Preparation of Na-protected amino/peptide hydroxamic acids
R-CONHOH
Yield (%)
Ref.
R-CONHOH
Yield (%)
Boc-Val-NHOH
Boc-Phe-NHOH
Boc-Ser(OBzl)-NHOH
Z-Ala-NHOH
92
96
91
95
91
93
90
90
46b
Z-Ala-Ile-NHOH, 4a
92
88
94
90
84
91
81
89
43a,44a,46a–b,47
49
43b,46a
46a,47
New compd.
New compd.
50
Z-Leu-Phe-NHOH, 4b
Z-Phe-Leu-NHOH, 4c
Boc-Val-Leu-NHOH, 4d
Boc-Val-Pro-NHOH, 4e
Boc-Phe-Phg-NHOH, 4f
Boc-Val-Ala-Leu-NHOH, 4g
Boc-Phg-Phe-NHOH, 4i
Z-Val-NHOH
Z-Phg-NHOH
Fmoc-Glu(OtBu)-NHOH
Fmoc-Val-NHOH
Table 2 Preparation of peptidyl ureas from Na-protected amino acid hydroxamates and various amino acid esters
Entry
R
R1
Yield (%)
1a
1b
1c
1d
1e
1f
1g
2a
2b
2c
2d
3a
3b
CH(CH3)2
CH2C6H5
CH2C6H5
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH2OBzl
CH3
CH(CH3)2
(L)-C6H5
(L)-C6H5
CH(CH3)2
C2H4COOtBu
H
79
78
82
81
81
79
76
79
77
80
79
68
69
CH2CH(CH3)2
CH(CH3)2
CH3
CH2C6H5
C(CH3)C6H5
H
H
CH3
R-C(CH3)C6H5
S-C(CH3)C6H5
CH2CH(CH3)2
H
The reaction was explored for the inclusion of the ureido
bond in between the oligopeptide sequences. The dipeptides, Boc-
Val-Leu-OH, Z-Phe-Leu-OH, Z-Leu-Phe-OH and Z-Ala-Ile-OH
were converted into their hydroxamate derivatives by following
the procedure outlined in Table 1, and reacted with amino acid
methyl esters in the presence of EDC to obtain the ureido bond
linked tripeptide esters 5a–d in about 75% yield. Boc-Val-Leu-
NHOH and Boc-Val-Pro-NHOH were coupled respectively to
dipeptide and tripeptide esters in the presence of EDC to afford the
corresponding ureido analogs of tetrapeptide 5e and pentapeptide
5f. Finally, the hexapeptide sequence Boc-Val-Ala-Leu-y[NH-
CO-NH]-Val-Ala-Leu-OMe was synthesized. For this, Boc-Val-
Ala-Leu-NHOH was subjected to the rearrangement using EDC
and coupled with the amino free tripeptide ester to yield the ureido
bond possessing oligopeptides 5g in 68% yield (Table 3).
pure R and S 1-phenylethylamine. The 1H-NMR analysis of
the crude sample of the dipeptidyl urea Z-L-Phg-y(NHCONH)-
R-(+)-phenylethylamine 2c and Z-L-Phg-y(NHCONH)-S-(-)-
phenylethylamine 2d containing R-1-phenylethylamine and S-1-
phenylethylamine residues revealed the methyl group peaks at d
values 1.36, 1.38 and 1.38 and 1.39 ppm respectively. Further, the
NMR spectrum of the epimeric mixture of 2c and 2d (Fig. 1)
prepared by using the racemic mixture of 1-phenylethylamine
contained the methyl group resonances at d values 1.36, 1.38
and 1.39. Optical purities of the oligopeptidyl ureas synthesized
from peptide hydroxamic acids were also evaluated. The 1HNMR
spectrum of the two tripeptidyl ureas 5h and 5i, obtained by
reacting Boc-L-Phe-L-Phg-NHOH 4f separately with (R) and (S)
1-phenylethylamine, contained single methyl groups at d values
1.38, 1.40; and 1.47 and 1.49 respectively, while the equimolar
mixture of the epimers 5h and 5i, prepared by reacting racemic
1-phenylethylamine with 4f, showed the methyl group doublets
at 1.46 and 1.38. Further, the 1HNMR of tripeptidyl ureas
To study the possibility of epimerization during the reaction,
two epimeric dipeptidyl ureas were synthesized via the present
method by reacting Z-L-Phg-NHOH, separately with optically
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Table 3 Synthesis of peptidyl ureas from Na-protected peptide hydroxamic acids
Entry
R2
R3
R4
R5
Yield (%)
5a
5b
5c
5d
5e
5f
Z-Ala
Z-Leu
Z-Phe
Boc-Val
Boc-Val
Boc-Val
Boc-Val-Ala
CH(CH3)C2H5
CH2C6H5
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
-(CH2)3-
CH2CH(CH3)2
CH3
CH(CH3)C2H5
CH2C6H5
CH(CH3)2
CH(CH3)2
CH(CH3)2
OMe
OMe
OMe
OMe
Leu-OMe
Ala-Leu-OMe
Ala-Leu-OMe
78
80
74
71
75
71
68
5g
CH2CH(CH3)2
Fig. 1 Peptidylureas studied for epimerization.
5j and 5k containing (R) and (S) 1-phenylethylamine residues
respectively, synthesized similarly from Boc-L-Phg-L-Phe-NHOH
4i contained distinct doublets at d values 1.25, 1.27; and 1.21 and
1.23 respectively. Again the equimolar mixture of the epimers 5j
and 5k, obtained by reacting racemic 1-phenylethylamine with 4g
had two doublets at 1.22 and 1.26. The appearance of only one
distinct doublet for each sample of the compounds 2c and 2d; 5h
and 5i; 5j and 5k, and the methyl group resonances separated by
0.04–0.09 ppm for the equimolar mixtures of the epimers in the
1HNMR spectra confirmed that the compounds analyzed were
optically pure and the synthesis of peptidyl ureas through the
present protocol proceeds with retention of configuration.
Ureidoalanine derivatives which are structurally similar to
L-albizziine in possessing an ueriodo group in the side chain
are widely used as drug components.51 Conventionally they are
prepared by coupling of the isocyanates with Na-protected 2,3-
diaminopropionic acid ester,52 or coupling w-isocyanates from
N-Boc-5-oxazolidinones with different amines.53 We envisioned
that the application of the afore-described Lossen rearrangement
conditions would lead to simple and practical synthesis of
ureidoalanine derivatives via a safe and simple method devoid
of the use of acid azides. Accordingly, the Z-Asp-oxazolidinone
6 was prepared in 91% yield through the reported method.54
It was then converted into the hydroxamate 7 by treating the
corresponding mixed anhydride solution with hydroxyl amine.
The resulting hydroxamic acid, obtained in 80% yield, was found
to be stable at ambient temperature for a very long time. It was
then subjected to the rearrangement using the EDC and coupled
with amino acid ester under similar reaction conditions described
above. The ureido compound 8 was isolated in about 70% yield and
was completely characterized. Saponification of the oxazolidinone
with 1 N LiOH for 30 min yielded the Na-Z-ureidoalanine 9
(Scheme 2).
In conclusion, we have demonstrated that N-urethane protected
a-amino acid and peptide acid derived hydroxamic acids easily
undergo Lossen rearrangement effected by carbodiimide to yield
isocyanates which in presence of a-amino acid/peptide esters
produce good yields of peptidyl ureas. The reaction is carried out
under mild conditions, neutral reaction medium, and applicable
to all commonly employed urethane type N-protecting groups.
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Scheme 2 Synthesis of ureidoalanine derivative.
Ureido bonds can also be easily inserted in the amino acid
side chains by reacting the corresponding hydroxamates with
amines under the same protocol. The reaction can be easily scaled
up.
Z-Val-w[NH-CO-NH]-Ala-OMe, 2b. Mp 182–184 ◦C; 1H
NMR (DMSO-d6, 200 MHz): d 0.89–1.05 (m, 6H), 1.40 (d, J =
5.6 Hz, 3H), 2.10 (m, 1H), 3.75 (s, 3H), 4.22 (m, 1H), 5.10 (s, 2H),
5.41 (br, 1H), 6.45 (br, 1H), 7.30–7.45 (m, 5H); 13C NMR (DMSO-
d6, 100 MHz): d 17.7, 18.2, 18.8, 19.1, 31.2, 48.8, 52.4, 53.6, 60.3,
63.7, 67.0, 128.2, 128.5, 136.2, 154.1, 156.3, 170.8; HRMS m/z
374.1685 (M + Na+), calcd for C17H25N3O5Na 374.1692.
Experimental section
General procedure for the preparation of peptidyl ureas
Fmoc-Glu(OtBu)-w[NH-CO-NH]-Gly-OMe, 3b. Mp 196–
◦
1
198 C; H NMR (DMSO-d6, 200 MHz) 1.35 (s, 9H), 2.02 (m,
2H), 2.23 (t, 2H), 3.67 (s, 3H), 4.01 (s, 2H), 4.38 (t, 1H), 4.66 (d,
2H), 5.54 (t, 1H), 6.05 (s, 2H); 13C NMR (DMSO-d6, 100 MHz)
27.7, 30.3, 31.1, 41.2, 46.7, 51.5, 57.8, 65.3, 79.6, 120.1, 125.2,
127.0, 127.6, 140.7, 143.8, 155.0, 156.6, 171.5, 171.6; MALDI-
TOF m/z 534.3 (M + Na+), calcd for C27H33N3O7Na 534.2.
To
a
solution of 201.3 mg (1.05 mmol) of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
and 12.2 mg (0.1 mmol) of 4-dimethylaminopyridine (DMAP)
in dry CH2Cl2 or tetrahydrofuran was added the finely ground
powder of Na-urethane protected amino/peptide hydroxamic
acid (1.0 mmol) in small portions at rt. The reaction mixture was
stirred for 20 min and then amino-free amino acid/peptide acid
ester (1.0 mmol) was added. The resulting mixture was stirred at
rt for 4–5 h until completion (as monitored by TLC). The solvent
was removed in vacuo and the residue was dissolved in EtOAc.
The organic layer was washed with 10% citric acid solution, brine
and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure to afford the product, which was purified
by column chromatography using CHCl3/MeOH.
◦
1
Z-Ala-Ile-w[NHCONH]-Leu-OMe, 5a. Mp 190–192 C; H
NMR (CDCl3, DMSO-d6, 200 MHz) d 0.85–1.05 (m, 12H), 1.26
(d, J = 6.6 Hz 3H), 1.44–1.87 (m, 4H), 3.64 (s, 3H), 4.05–4.12 (m,
1H), 4.23–4.29 (m, 1H), 4.92–4.96 (m, 1H), 5.03 (s, 2H), 6.27–6.37
(m, 1H), 6.76–6.80 (br, 2H), 7.31 (br, 5H), 7.84–7.88 (br, 2H); 13
C
NMR (CDCl3, DMSO-d6, 100 MHz) d 11.0, 14.0, 18.5, 21.5, 22.5,
24.4, 24.9, 40.1, 41.5, 50.1, 50.8, 51.5, 60.5, 66.5, 127.1, 127.5,
128.1, 136.8, 155.5, 156.7, 171.5, 174.2; HRMS m/z 501.2684
(M + Na+), calcd for C24H38N4O6Na 501.2689.
Boc-Val-Ala-Leu-NHOH, 4g. Mp 158–159 ◦C; 1H NMR
(CDCl3, DMSO-d6, 200 MHz) d 0.81–1.01 (m, 12H), 1.20–1.31
(m, 4H), 1.45 (s, 9H), 1.62–1.95 (m, 3H), 4.25 (m, 1H), 4.42–4.55
(m, 1H), 7.20 (br, 1H); 13C NMR (CDCl3, DMSO-d6, 100 MHz)
18.4, 19.0, 22.0, 22.9, 28.6, 32.0, 41.3, 48.9, 51.2, 52.5, 79.6, 158.2,
169.8, 172.2, 173.4 6; HRMS m/z 439.2528 (M + Na+), calcd for
C19H36N4O6Na 439.2533.
Acknowledgements
The authors thank Professor Fred Naider, CUNY, New York for
useful discussions and the Department of Science and Technology,
New Delhi for financial support (grant no. SR/S1/OC-26/2008).
GC thanks CSIR, New Delhi for a Senior Research Fellowship.
◦
1
Boc-Val-w[NH-CO-NH]-Gly-OMe, 1a. Mp 165–167 C; H
NMR (CDCl3, 400 MHz) d 1.00 (m, 6H), 1.46 (s, 9H), 2.05 (m,
1H), 3.69 (s, 3H), 4.05 (m, 1H), 4.32–4.50 (br, 2H), 5.10 (br, 1H),
6.00 (br, 1H), 9.50 (br, 1H); 13C NMR (CDCl3, 100 MHz) d
15.4, 28.2, 30.8, 41.7, 42.0, 52.1, 60.0, 72.1, 79.7, 156.6, 158.8,
172.2; HRMS m/z 326.1698 (M + Na+), calcd for C13H25N3O5Na
326.1692.
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