Rapid entry to 1,4-diazepane-2,5-dione from β-amino acids

Article abstract of DOI:10.1246/cl.2006.86

A versatile method for the synthesis of conformationally constrained 1,4-diazepane-2,5-dione from β-amino acids is described. These heterocyclic compounds will be useful as a new platform for the synthesis of conformationally constraint peptidomimetics. C

Full text of DOI:10.1246/cl.2006.86

86
Chemistry Letters Vol.35, No.1 (2006)
Rapid Entry to 1,4-Diazepane-2,5-dione from ꢀ-Amino Acids
Manisha Sathe, Ramarao Ghorpode, and Mahabir Parshad Kaushikꢀ
Process Technology Development Division, Defence R & D Establishment, Jhansi Road, Gwalior-474002 (MP), India
(Received September 20, 2005; CL-051199; E-mail: mpkaushik@rediffmail.com)
A versatile method for the synthesis of conformationally
PPh3 (1:1) in THF at room temperature. Cyclization occurred
after 24 h and the product 4c could be isolated in 30% yield after
column chromatography. The other compound recovered in
reaction mixture was unreacted 2-(2-amino-3-methylbutyryl-
amino)cyclopentanecarboxylic acid methyl ester (6). The pres-
ence of 6 was also confirmed even when hindered di-tert-butyl
azodicarboxylate (DTAD) was used, suggested that dipeptide
3c was reluctant to cyclization probably because of the preferen-
tial transoid conformation assumed by the peptide bond. Excel-
lent yields (70–87%) of the final products, however, could
be obtained by using N,N-diisopropylethylamine DIPEA.10 4c
was achieved in 73% yield with the formation of smaller amount
of 6 which could also be recharged further (Scheme 2). Under
these conditions, several compounds were effectively and quan-
titatively cyclized to give functionalized 1,4-diazepane-2,5-
diones (4a–4e and 5a–5e) (Table 1).
Effect of the nature of tertiary amines on cyclization was
also studied. It was found that all esters described racemises
more slowly in the presence of hindered amine i.e. DIPEA in
comparison to that of less hindered amine i.e. triethylamine.
Understandably, removal of amide proton is less susceptible to
steric hindrance then the removal of the proton from the ꢁ
carbon atom of the ester. Moreover, it provides an expedient
route for the stereoselective synthesis of the desired products
constrained 1,4-diazepane-2,5-dione from ꢀ-amino acids is
described. These heterocyclic compounds will be useful as a
new platform for the synthesis of conformationally constraint
peptidomimetics.
The development of new approaches for the construction of
number of heterocycles continues to be essential for accessing
natural products and their structural analogues. Among them,
1,4-diazepane-2,5-dione1 scaffolds have gained over the years
an ongoing interest for synthetic and clinical studies mainly as
novel inhibitors of LFA-12 and HDM2 antagonists.3 In this
regard, use of ꢀ-amino acids are well known for the synthesis
of various class of bioactive compounds.4 Although several
methods have been reported for designing and synthesis of six
member diketopiperazine5 rings, but there are very few reports
concerning the seven member diazepane ring.6 As a part of
our ongoing efforts directed towards the synthesis of bioactive
molecules and heterocyclic compounds, our attention was direct-
ed towards the synthesis of constrained 1,4-diazepane-2,5-dione
using ꢀ-amino acids. Herein, we present a new general and ver-
satile synthesis of 1,4-diazepane-2,5-dione from ꢀ-amino acids.
Our synthetic approach is illustrated in Scheme 1. ꢀ-Amino
ester hydrochloride salt has been synthesized by the reported
method,7 which was further coupled with N-protected amino
acids to afford 4a–4e and 5a–5e in excellent yields. The reaction
was monitored by TLC (CCl4:MeOH (6:4)). Under the condi-
tions described several N-protected amino acids were effectively
and quantitatively coupled with amino ester hydrochloride prov-
ing the efficiency of the coupling reaction. Further to optimize
the reaction conditions for cyclization various methods8 have
been tried, using 2-(2-tert-butoxycarbonylamino-3-methylbu-
tyrylamino)cyclopentanecarboxylic acid methyl ester (3c) as
a model compound to give 3-isopropyloctahydrocyclopenta-
[e][1,4]diazepine-2,5-dione (4c). The first attempt was made
with the use of classical Mitsunobu condition9 using DEAD/
H
N
OCH3
HN
O
O
O
O
R
(i) TFA, CH Cl
2
2
NH
NH2
O
NH
H CO
3
NH
O
(ii) DIPEA, CH Cl
2
2
O
(CH )n
2
O
(3c) n = 3, R = CH(CH3)2
(4c)
(6)
Scheme 2. Synthesis of 1,4-diazepane-2,5-dione core.
Table 1. Synthesis of 1,4-diazepane-2,5-dione (4a–4e and
5a–5e)
Entry
Productsa
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
5a
5a
5b
5c
5d
5e
24
24
24
24
23
18
18
18
18
18
18
70
70
73
75
70
85
80
86
85
84
87
O
O
R
OH
NH
O
H3CO
(ii)
OCH3
O
NH
(i)
NH2. HCl
O
(CH2)n
(3)
NH2
(1)
O
n(H2C)
n(H2C)
(2)
(iii)
R
4a n = 3, R = H
4b n = 3, R = CH3
4c n = 3, R = CH(CH3)2
4d n = 3, R = CH2-CH(CH3)2
4e n = 3, R = CH2-C6H5
H
N
5a n = 6 R = H
5b n = 6 R = CH3
5c n = 6 R = CH(CH3)2
5d n = 6, R = CH2-CH(CH3)2
5e n = 6, R = CH2-C6H5
O
O
NH
10
11
n(H2C)
(4) / (5)
aAll compounds have been characterized by IR, NMR, and
MS. Isolated yields after purification by column chroma-
tography.
Scheme 1. Reagents and conditions (i) SOCl2, anhydrous
MeOH. (ii) (C2H5)3N, EDC, HOBT, CH3CN, BocNH–R(CH)–
COOH. (iii) TFA, DIPEA, CH2Cl2.
b
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.1 (2006)
87
with excellent yield and purity. It is well evident from the Table 1
that the reactivity of the substrate increases with the ring size,
this may be essentially because of the ring strain present in the
eight member ring which results in less stability and more
reactivity (5a–5e) then five member rings (4a–4e). Most of the
reactions proceeded smoothly and excellent yield were obtained
in appropriate reaction time. Typical experimental procedures
for the synthesis of 4a–4e and 5a–5e and the spectroscopic data
for the selected compounds are summarized in references.11,12
In summary, a simple and an efficient method for the synthe-
sis of 1,4-diazepane-2,5-diones from ꢀ-amino acids have been
developed. This strategy may also be employed for the elonga-
tion of peptide chain or to increase the molecular diversity. Fur-
ther elaboration of these products to potentially useful building
block is actually underway in our laboratory and will be reported
in due course.
Org. Chem. 2003, 68, 7893.
O. Mitsunobu, Synthesis 1981, 1.
10 B. M. Antony, A. P. Mehrotra, D. Gani, J. Chem. Soc.,
Perkin Trans. 1 1997, 2513.
9
11 Typical procedures for the synthesis of 4c. To a stirred solu-
tion of the N-tert-butoxycarbonyl protected ꢀ-amino ester
(13.3 mmol) in CH2Cl2, TFA was added (2 mL). The reac-
tion mixture was stirred at room temperature for 45 min
and concentrated under reduced pressure to give oil, which
was redissolved in minimum quantity of CH2Cl2 (10 mL)
and DIPEA (diisopropylethylamine 2 mL) was added, the
mixture was stirred at rt for 24 h. The reaction mixture was
concentrated under reduced pressure to give brown viscous
liquid. Purification by flash chromatography on silica and
elution with CCl4:MeOH (6:4) gave pure product in 73%
yield.
12 All compounds described gave satisfactory analytical and
spectroscopic data. Analytical data for selected compounds
have been reported here. 5e, viscous oil, IR 3213, 1735
cmꢁ1 1H NMR (CDCl3, 400 MHz) ꢂ 1.29 (m, 8H), 1.51
(m, 2H), 1.53 (m, 2H), 3.02 (td, J ¼ 9 Hz, 4 Hz, 1H), 3.60
(m, 1H), 3.98 (dd, J ¼ 16 Hz, 7 Hz, 1H), 4.46 (dd, J ¼ 16
Hz, 7.1 Hz, 1H), 4.92 (m, 1H), 7.06 (m, 1H), 7.12 (m, 2H),
7.21 (m, 2H) 8.1 (br, NH, 2H). 13C NMR (CDCl3, 100
MHz) ꢂ 24.51, 25.02, 26.82, 29.61, 30.03, 32.91, 37.61,
45.61, 49.11, 58.12, 125, 127.11, 127.32, 128.1, 128.4,
140.2, 175, 178.55. ESI-MS m=z 301 (M þ H)þ. 4c, viscous
oil, IR 3218, 1737 cmꢁ1 1H NMR (CDCl3, 400 MHz) ꢂ 0.93
(d, J ¼ 7:1 Hz, 3H), 0.95 (d, J ¼ 6:7 Hz, 3H), 1.51 (m, 2H),
1.73–1.75 (m, 4H), 2.68 (m, 1H), 3.07 (td, J ¼ 9 Hz, 5 Hz,
1H), 3.80 (m, 1H), 4.56 (m, 1H), 8.02 (br, NH, 2H).
13C NMR (CDCl3, 100 MHz) ꢂ 16.21, 16.24, 17.3, 20.6,
28.01, 28.5, 48.02, 46.31, 62.81, 174.4, 178.5. ESI-MS
m=z 211 (M þ H)þ. 4b, viscous oil, IR 3211, 1731 cmꢁ1
1H NMR (CDCl3, 400 MHz) ꢂ 1.48 (d, J ¼ 7 Hz, 3H), 1.50
(m, 2H), 1.73–1.75 (m, 4H), 3.08 (td, J ¼ 9 Hz, 5 Hz, 1H),
3.83 (m, 1H), 4.72 (m, 1H), 8.01 (br, NH, 2H). 13C NMR
(CDCl3, 100 MHz) ꢂ 17.21, 17.34, 20.6, 28.01, 46.21,
48.05, 52.81, 175.4, 178.2. ESI-MS m=z 183 (M þ H)þ.
We thank Shri K. Sekhar, Director, DRDE. Gwalior, for his
keen interest, and encouragement.
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Published on the web (Advance View) December 10, 2005; DOI 10.1246/cl.2006.86