A general and facile synthetic approach to Nα-Boc ureidoalanine derivatives

Article abstract of DOI:10.1055/s-2006-939044

We report a new and facile synthetic approach to N^α-Boc ureidoalanine derivatives from commercially available Boc-L-aspartic acid. Not only N′-substituted but also N′,N′-disubstituted ureidoalanine derivatives may be obtained by this method. Th

Full text of DOI:10.1055/s-2006-939044

LETTER
877
A General and Facile Synthetic Approach to Na-Boc Ureidoalanine Derivatives
a
Synthetic
A
pproac
a
h to
N
-Boc
n
U
reidoalani
b
ne
D
erivativ
i
e
s
ng Teng, Yunjiao He, Lamei Wu, Jiangtao Su, Xichun Feng, Guofu Qiu, Shucai Liang, Xianming Hu*
State Key Laboratory of Virology, College of Pharmacy, Wuhan University, Wuhan 430072, P. R. of China
Fax +86(27)68754629; E-mail: xmhu@whu.edu.cn
Received 14 December 2005
or that use of a secondary amine is desired, a different syn-
thetic strategy must be considered.10
a
Abstract: We report a new and facile synthetic approach to N -Boc
ureidoalanine derivatives from commercially available Boc-L-as-
partic acid. Not only N¢-substituted but also N¢,N¢-disubstituted ure-
idoalanine derivatives may be obtained by this method. The key
aspect of this method is the employment of a 5-oxazolidinone to
provide proper protection of the a-nitrogen of L-aspartic acid. This
ensures successful obtainment of the corresponding isocyanate by a
Curtius rearrangement.
a
Our ongoing goal is to synthesize N -Boc ureidoalanine
derivatives and we need a safe and economical access to
these compounds. Retrosynthetic analysis suggests there
is another possible route. This alternative strategy
(Scheme 1, route B) makes use of isocyanate 4, which can
be prepared from an L-aspartic acid derivative by a Cur-
tius rearrangement. This may react directly with primary
and secondary amines to give the target ureido com-
pounds. This approach has an advantage over route A be-
cause it avoids preparation of various isocyanates
R1NCO, some of which can be extremely unstable, even
hazardous. Moreover, the synthesis of 2 becomes feasible
using NH3 (R1 = R2 = H) and secondary amine (R1 ≠ H,
R2 ≠ H) in route B.
Key words: ureidoalanine, amino acids, protecting groups, 5-ox-
azolidinone, Curtius rearrangement
The biological importance of nonproteinogenic a-amino
acids continues to foster immense interest in their synthe-
sis and design.1 L-Albizziine (1), a non-protein amino
acid, which bears an ureido group in its side chain, was
first isolated from the seeds of Albizzia juibrissin2 and
shows activity against Newcastle disease and herpes viral
infections along with other biological activities.3 A simi-
lar structural motif is found in ureidoalanine derivatives 2,
which have been widely used in many medicinally impor-
tant entities (Figure 1).4
O
3 + R1NCO
H2N
OR
NHPG
3
2
O
R1
R2
OCN
OR3
NHPG
+
HN
O
O
O
O
R1
PG = protecting group
R1, R2 = H, alkyl, aryl, etc.
R3 = H, Me, Bn
H2N
N
OH
N
N
OH
HN PG
H
R2
H
NH2
1
2
PG = protecting group
R1, R2 = H, alkyl, aryl, etc.
Scheme 1
Figure 1
However, the N-monoprotected L-aspartic acid derivative
5 does not afford expected isocyanate 4; it directly gives
cyclic urea 6 after a Curtius rearrangement (Scheme 2).11
The synthesis of these compounds5 conventionally
involves reaction of N -protected 2,3-diaminopropionic
a
O
O
acid ester (3) with isocyanates (Scheme 1, route A). The
most common synthesis of important intermediate 3 in-
volves a Hoffman rearrangement of protected aspar-
agines. However, the rearrangement often requires an
expensive reagent like bis[trifluoroacetoxy]phenyliodine6
and is sometimes accompanied by low yields when Boc-
protected asparagine is used.7 The Ts- or Cbz-protected
compound 3 can be obtained by Hoffman rearrangement
in good yield,8 but these two protecting groups are highly
restrictive, especially in solid-phase peptide synthesis.9
Moreover, for the cases that R1 = H (Scheme 1, route A)
Curtius
HO
OR
OCN
OR
rearrangement
O
NHBoc
NHBoc
5
4
H
N
intramolecular
trapping
O
OR
N
Boc
O
6
R = Bn, Me
Scheme 2
In order to prevent the intermolecular trapping of the
isocyanate, a strategy of dual Boc-protection of the reac-
tive nitrogen has been put forward and this leads to the tar-
get isocyanate successfully.11 We conceived that use of a
N-Boc-5-oxazolidinone moiety could also provide com-
plete protection of a-amino group and the corresponding
SYNLETT 2006, No. 6, pp 0877–0880
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939044; Art ID: W10805ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
4.
2
0
0
6

878
H. Teng et al.
LETTER
O
1) EtOCOCl
NMM, NaN3
O
O
O
O
(CH2O)n, p-TsOH
R1
R2
HO
HO
R1NHR2
OCN
OH
O
O
N
N
O
H
NH
benzene, reflux, 72%
O
N
N
O
2) toluene, 75°C
N
Boc
Boc
Boc
Boc
8
7
9
R1, R2 = H, alkyl, aryl,
etc.
Scheme 3
isocyanate would be obtained similarly. The desired 5-ox- NaN3.13 Isocyanate 8 (strong absorption at 2223–2255
azolidinone 7 is prepared from Boc-L-aspartic acid in cm–1 in IR) is successfully generated in situ upon heating
good yield in benzene with paraformaldehyde and a cata- acyl azide in toluene at 75 °C. On allowing isocyanate 8
lytic amount of p-toluenesulfonic acid.12 This is then con- to react with amines, the desired ureas 9 are readily ob-
verted to corresponding acyl azide (strong absorption at tained (Scheme 3).14
2145 cm–1 in IR) by reaction of the mixed anhydride with
Table 1 Synthesis of Compounds 9 by the Reaction of Isocyanate 8 and Amines
Entry Amine
Solvent
Temp
Time
Yield (%)a
62
Productb
O
O
c
H2N
N
O
1
2
NH3
THF
r.t.
15 min
H
N
Boc
9a
O
O
O
NH2
CH2Cl2
r.t.
30 min
57
N
N
H
H
N
Boc
9b
O
O
N
N
H
O
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
r.t.
r.t.
30 min
30 min
30 min
61
58
57
NH2
H
N
Boc
9c
O
O
H3CO
N
N
O
H3CO
NH2
H
H
N
Boc
9d
F
O
O
F
O
N
N
H
H
NH2
N
Boc
9e
O
O
MeO2C
N
H
N
O
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
r.t.
r.t.
30 min
12 h
55
32
60
MeOOC
NH2
H
N
Boc
9f
O
O
O2N
N
N
H
O
O2N
NH2
H
N
Boc
9g
9h
O
O
O
NH
30 min
N
N
H
N
Boc
O
O
O
N
N
9
CH2Cl2
r.t.
30 min
57
H
N
N
H
Boc
9i
Synlett 2006, No. 6, 877–880 © Thieme Stuttgart · New York

a
LETTER
Synthetic Approach to N -Boc Ureidoalanine Derivatives
879
Table 1 Synthesis of Compounds 9 by the Reaction of Isocyanate 8 and Amines (continued)
Entry Amine
Solvent
THF
Temp
r.t.
Time
Yield (%)a
61
Productb
O
O
d
N
N
O
10
11
12
CH3NH2
15 min
H
H
N
Boc
9j
O
O
O
CH2Cl2
CH2Cl2
r.t.
r.t.
15 min
30 min
59
55
N
N
NH2
H
H
N
Boc
9k
9l
O
O
O
N
N
14
NH2
14
H
H
N
Boc
COOMe
O
O
COOMe
NH2
13
14
CH2Cl2
CH2Cl2
r.t.
r.t.
30 min
15 min
57
60
N
H
N
O
H
N
Boc
9m
O
HO
O
O
OH
N
N
H
Boc
H
N
NH2
9n
a Isolated yields according to compound 7.
b All products were characterized by IR, NMR and MS spectra.
c 28–30% aq NH3.
d 30% aq CH3NH2.
O
O
As shown in Table 1, not only primary but also secondary
amines (entries 8 and 9) react rapidly with isocyanate 8 to
give the corresponding ureido derivatives 9.
R1
R2
1 N NaOH
MeOH
9
N
N
OH
NHBoc
H
(a, b, h, k)
10
Entries 2–6 show the results of use of aromatic amines.
These observations suggest that isocyanate 8 is highly
reactive and that electronic factors have little effect al-
though on use of amines with strongly electron-
withdrawing group such as nitro poorer results are
obtained (entry 7). Attempts to promote the reaction (en-
try 7) by prolonging the reaction time or employing a base
like N-methyl morpholine (NMM)15 failed. Entry 9 sug-
gests that the effects of steric factors can be insignificant.
(a, b, h, k)
yield ≥90%
Scheme 4
The hydrolysis of 9m under these conditions proved to be
non-selective. Electrospray MS indicates two hydrolysis
products are formed: one is from the hydrolysis of 5-ox-
azolidinone ring and the other is from the hydrolysis of the
amino acid methyl ester moiety. The long reaction time
(overnight) leads to the hydrolysis of both. An attempt to
hydrolyze selectively the 5-oxazolidinone moiety in aque-
ous methanolic sodium hydrogen carbonate19 was unsuc-
cessful.
It is noteworthy that isocyanate 8 also reacts more readily
with amino groups even in the presence of H2O (entries 1
and 10) or hydroxyl groups (entry 14).
In order to avoid the ring-cleavage of 5-oxazolidinone,16
highly reactive amines (entries 1, 9–11, 14) should be
added slowly and the reaction should be quenched imme-
diately when it is finished.
In conclusion, we describe here a new and facile approach
to synthesize N -Boc ureidoalanine derivatives. The key
a
aspect of this method is the use of the intermediate 7,
which provides proper protection of a-nitrogen and
allows obtainment of isocyanate 8 on Curtius rearrange-
ment. This method has been applied to synthesize not only
3-[N¢-substituted ureido]propionic acids, but also 3-
[N¢,N¢-disubstituted ureido]propionic acids and Boc-L-al-
bizziine. Furthermore, this simple method does not make
use of expensive reagents and good results are obtained.
Saponification of the 5-oxazolidinone moiety is accom-
plished by using 1 N NaOH or LiOH.17 Four representa-
tive compounds (9a,b,h,k) have been chosen for
a
hydrolysis and the corresponding N -Boc ureidoalanines
are obtained in high yield (Scheme 4).18
Synlett 2006, No. 6, 877–880 © Thieme Stuttgart · New York

880
H. Teng et al.
LETTER
(d, 1 H, J = 3.9 Hz), 5.38 (br s, 1 H), 5.90 (br s, 1 H, NH).
13C NMR (150 MHz, CDCl3): d = 28.24, 40.22, 56.09,
78.43, 82.53, 152.12, 159.29, 171.99. MS: m/z = 259 [M+].
Anal. Calcd for C10H17N3O5: C, 46.33; H, 6.61; N, 16.21.
Found: C, 46.57; H, 6.56; N, 16.11.
References and Notes
(1) (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013.
(b) Ghost, A. K.; Xu, C. X.; Kulkarni, S. S.; Wink, D. Org.
Lett. 2005, 7, 7.
(2) Gmelin, R.; Strass, G.; Hasenmaier, G. Z. Naturforsch. B:
Chem. Sci. 1958, 13, 252.
(3) (a) Fukuyasu, H.; Kawakami, K.; Sato, Y.; Ohya, Z.;
Kikuchi, T.; Tsuruoka, T.; Inouye, S. Meiji Seika Kenkyu
Nenpo 1983, 22, 9. (b) Singh, R. P.; Srivastava, H. S. Curr.
Sci. 1987, 56, 93.
(4) (a) Piper, J. R.; McCaleb, G. S.; Montgomery, J. A.; Schmid,
F. A.; Sirotnak, F. M. J. Med. Chem. 1985, 28, 1016.
(b) Itoh, F.; Yoshioka, Y.; Yukishige, K.; Yoshida, S.;
Ootsu, K.; Akimoto, H. Chem. Pharm. Bull. 2000, 48, 1270.
(c) Lherbet, C.; Morin, M.; Castonguay, R.; Keillor, J. W.
Bioorg. Med. Chem. Lett. 2003, 13, 997. (d) Ishigaki, T.;
Taniguchi, K.; Ito, T.; Ono, H.; Kaino, M.; Meguro, H. JP
2003277340, 2003. (e) Bernareggi, A.; Cassara, P. G.;
Chatterjee, S.; Ferreti, E.; Iqbal, M.; Menta, E.; Messina
Mclaughlin, P. A.; Oliva, A. WO 2005021558, 2005.
(5) Sargent, D. R.; Skinner, C. G. J. Med. Chem. 1971, 14, 465.
(6) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266.
(7) Lee, E. S.; Jurayj, J.; Cushman, M. Tetrahedron 1994, 50,
9873.
(8) (a) Hartner, F. W.; Cvetovich, R. J.; Tsay, F.; Amato, J. S.;
Pipik, B.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem.
1999, 64, 7751. (b) Khayer, K.; Jenn, T.; Akhtar, M.; John,
R.; Gani, D. Tetrahedron Lett. 2000, 41, 1637.
(9) Arttamangkul, A. S.; Murray, T. F.; DeLander, G. E.;
Aldrich, J. V. J. Med. Chem. 1995, 38, 2410.
20
Compound 9h: white foam; Rf = 0.6 (PE–EtOAc, 1:1); [a]D
+114.4 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): d = 1.48
(s, 9 H), 3.24 (s, 3 H), 3.58–3.76 (m, 1 H), 4.19 (s, 1 H),
4.64–4.80 (m, 1 H, NH), 5.09 (d, 1 H, J = 3.6 Hz), 5.38 (br
s, 1 H), 7.21–7.42 (m, 5 H). 13C NMR (150 MHz, CDCl3):
d = 28.44, 37.50, 40.95, 55.05, 78.28, 82.51, 127.54, 127.83,
130.30, 143.09, 152.27, 157.09, 171.96. MS: m/z = 349
[M+]. Anal. Calcd for C17H23N3O5: C, 58.71; H, 6.70; N,
12.25. Found: C, 58.44; H, 6.64; N, 12.03.
20
Compound 9k: white foam; Rf = 0.4 (PE–EtOAc, 1:1); [a]D
+140.2 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): d = 1.46
(s, 9 H), 3.50–3.72 (m, 2 H), 4.15–4.26 (m, 3 H), 5.06 (br s,
1 H), 5.32 (br s, 1 H), 5.53–5.64 (m, 2 H, NH), 7.19–7.25 (m,
5 H). 13C NMR (150 MHz, CDCl3): d = 27.19, 39.29, 43.16,
54.51, 77.29, 81.31, 126.07, 126.28, 127.45, 138.36, 151.06,
157.33, 170.94. MS: m/z = 349 [M+]. Anal. Calcd for
C17H23N3O5: C, 58.44; H, 6.64; N, 12.03. Found: C, 58.63;
H, 6.34; N, 11.96.
(15) Patil, B. S.; Vasanthakumar, G. R.; Suresh Babu, V. V. J.
Org. Chem. 2003, 68, 7274.
(16) (a) Lee, K. I.; Kim, J. H.; Ko, K. Y.; Kim, W. J. Synthesis
1991, 935. (b) Park, M.; Lee, J.; Choi, J. Bioorg. Med.
Chem. Lett. 1996, 6, 1297.
(17) (a) Olsen, R. K.; Ramasamy, K. J. Org. Chem. 1985, 50,
2264. (b) Ducrot, P.; Rabhi, C.; Thal, C. Tetrahedron 2000,
56, 2683. (c) Esslinger, C. S.; Cybulski, K. A.; Rhoderick, J.
F. Bioorg. Med. Chem. 2005, 13, 1111.
(18) Typical Procedure for the Preparation of Compounds
10.
(10) (a) Rudinger, J.; Poduska, K.; Zaoral, M. Collect. Czech.
Chem. Commun. 1960, 25, 2022. (b) Denis, J. N.;
Tchertchian, S.; Vallée, Y. Synth. Commun. 1997, 27, 2345.
(c) Martinez, J.; Oiry, J.; Imbach, J. L.; Winternitz, F. J.
Med. Chem. 1982, 25, 178.
(11) (a) Englund, E. A.; Gopi, H. N.; Appella, D. H. Org. Lett.
2004, 6, 213. (b) Deng, J.; Hamada, Y.; Shioiri, T.
Tetrahedron Lett. 1996, 37, 2261.
Compound 9 (5 mmol) was dissolved in MeOH (20 mL) and
1 N NaOH (10 mL) was added. The mixture was stirred at
r.t. till TLC indicated 9 was exhausted. Then, MeOH was
removed under reduced pressure and the solution was
washed with EtOAc (2 ꢀ 10 mL). The aqueous solution was
then acidified to pH 2 with 1 N HCl and extracted with
EtOAc (4 ꢀ 20 mL). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and
concentrated to give 10.
(12) Scholtz, J. M.; Bartlett, P. A. Synthesis 1989, 542.
(13) Guichard, G.; Semetey, V.; Didierjean, C.; Aubry, A.;
Briand, J. P.; Rodriguez, M. J. Org. Chem. 1999, 64, 8702.
(14) Typical Procedure for the Preparation of Compounds 9.
Compound 7 (10 mmol) was dissolved in dry THF (30 mL)
and cooled to –15 °C. After addition of EtOCOCl (11 mmol)
and NMM (12 mmol), the mixture was stirred for 20 min. A
solution of NaN3 (25 mmol) in H2O (5 mL) was added and
stirred for 1 h at –10 °C. The solution was then diluted with
H2O and extracted with EtOAc (150 mL). The organic layers
were washed with brine (2 ꢀ 10 mL), dried over Na2SO4 and
concentrated under reduced pressure to give crude acyl
azide. This crude acyl azide can be further purified by a flash
column chromatography (PE–EtOAc, 2:1, Rf = 0.7). Purified
acyl azide was dissolved in toluene (30 mL) and the resulting
solution was heated to 75 °C under stirring. After gas
evolution had stopped the toluene was removed under
reduced pressure to afford isocyanate 8 as clear oil. This
isocyanate 8 was directly used in the next step without
further purification. Amine (8 mmol) was added to a stirred
suspension of isocyanate in CH2Cl2 (40 mL) at r.t. (when
highly reactive amines are used, they should be dissolved in
solvent and added dropwise). The solvent was removed
under reduced pressure when the reaction was complete
(detected by TLC) and the products were purified by a
column chromatography.
Compound 10a: white foam; yield 90%; [a]D20 –13.2 (c 1,
MeOH). 1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H),
3.49–3.74 (m, 2 H), 4.30 (br s, 1 H), 6.27 (br s, 2 H, NH2),
6.66 (br s, 1 H, NH). 13C NMR (150 MHz, CDCl3):
d = 28.32, 41.86, 54.42, 80.45, 156.22, 161.25, 174.20.
MS: m/z = 247 [M+]. Anal. Calcd for C9H17N3O5: C, 43.72;
H, 6.93; N, 17.00. Found: C, 43.97; H, 6.68; N, 17.23.
Compound 10h: white foam; yield 92%; [a]D20 –1.3 (c 1,
MeOH). 1H NMR (300 MHz, CDCl3): d = 1.42 (s, 9 H), 3.25
(s, 3 H), 3.48–3.63 (m, 2 H), 4.20 (br s, 1 H), 5.02 (br s, 1 H,
NH), 5.92 (br s, 1 H), 7.23–7.43 (m, 5 H). 13C NMR (150
MHz, CDCl3): d = 28.51, 37.75, 43.13, 55.18, 80.45, 127.53,
127.95, 130.34, 142.76, 156.39, 158.43, 172.90. MS:
m/z = 337 [M+]. Anal. Calcd for C16H23N3O5: C, 56.96; H,
6.87; N, 12.46. Found: C, 60.24; H, 7.16; N, 12.23.
Compound 10k: white foam; yield 95%; [a]D20 –1.4 (c 1,
MeOH). 1H NMR (300 MHz, CDCl3): d = 1.37 (s, 9 H),
3.45–3.54 (m, 2 H), 4.16–4.30 (m, 3 H), 6.05–6.32 (br, 2 H,
NH), 7.21–7.26 (m, 5 H), 8.19 (br, 1 H, NH). 13C NMR (150
MHz, CDCl3): d = 28.27, 42.33, 44.29, 55.08, 80.53, 127.18
127.35, 128.53, 138.83, 156.37, 159.77, 173.63. MS:
m/z = 337 [M+]. Anal. Calcd for C16H23N3O5: C, 56.96; H,
6.87; N, 12.46. Found: C, 60.17; H, 7.13; N, 12.65.
(19) Allevi, P.; Anastasia, M. Tetrahedron Lett. 2003, 44, 7663.
Compound 9a: white foam; Rf = 0.3 (EtOAc). [a]D20 +65.8
(c 1, MeOH). 1H NMR (300 MHz, CDCl3): d = 1.48 (s, 9 H),
3.62–3.82 (m, 2 H), 4.21 (br s, 1 H), 5.05 (s, 2 H, NH2), 5.19
Synlett 2006, No. 6, 877–880 © Thieme Stuttgart · New York