Stereoselective synthesis of bis-β-lactam grafted macrocycles

Article abstract of DOI:10.1016/j.tetlet.2006.10.076

The synthesis of a series of macrocyclic bis-β-lactam derivatives via a highly stereoselective (2+2) cycloaddition is described.

Full text of DOI:10.1016/j.tetlet.2006.10.076

Tetrahedron Letters 47 (2006) 8855–8857
Stereoselective synthesis of bis-b-lactam grafted macrocycles
Natarajan Arumugam and Raghavachary Raghunathan*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 29 July 2006; revised 5 October 2006; accepted 12 October 2006
Abstract—The synthesis of a series of macrocyclic bis-b-lactam derivatives via a highly stereoselective (2+2) cycloaddition is
described.
ꢀ
2006 Elsevier Ltd. All rights reserved.
b-Lactam antibiotics are widely employed in the treat-
ment of bacterial infections. Unfortunately, resistance
compound with an N-methylthio group was able to
induce DNA damage and inhibit DNA replication in
Jurkat T cells within a 2 h treatment. Moreover, Ojima
has shown the utility of bis-b-lactams for the synthesis
of peptides. The synthesis of bis-b-lactams in general has
1
is usually developed by the target bacteria, mainly
through the expression of lactamases, which eliminate
or strongly reduce the effectiveness of the therapeutic
8
2
agent. On the other hand, b-lactams show anti-elastase
been reported by stepwise construction of b-lactam
9
–11
activity against enzymes, for example human leucocyte
rings.
Recently, b-lactams linked with an ethylene
3
12
elastase. In recent years, several natural b-lactams have
bridge have been reported.
been shown to exhibit a high antibacterial activity. 1,3,4-
Trisubstituted b-lactams were found to be new, potent
Motivated by these results we were interested in synthe-
sizing novel b-lactam grafted macrocycles. Herein, we
describe the synthesis of macrocyclic bis-b-lactams.
Incorporation of a b-lactam in a macrocyclic ring could
be easily accomplished by Staudinger reaction using the
4
cholesterol absorption inhibitors human cytomegalovi-
5
6
rus protease inhibitors, and thrombin inhibitors. Fur-
thermore, many anticancer drugs in current use are toxic
and thus limited in their efficacy. It is therefore essential
to develop novel chemotherapeutic agents with lower
levels of toxicity. The b-lactam antibiotics have been
used for many years with limited or no toxicity. Smith
0
appropriate macrocyclic imine. Thus treatment of a,a -
xylene dibromide 1a with salicylaldehyde and K CO
2
3
in dry acetone at room temperature afforded dialdehyde
2a (Scheme 1).
7
et al. discovered and characterized the apoptosis indu-
cing properties of a family of novel b-lactam antibiotics
against human leukemia breast, prostate and head and
neck cancer cells. They found that one particular lead
Dialdehyde13 2a, when treated with ethylene diamine in
ethanol, at room temperature afforded bis-imine 3a in
1
4
N
N
Br
CHO
O
OHC
O
CHO
OH
i
ii
O
O
Br
a-c (m,o,p)
1
2
a-c (m,o,p)
3a-c (m,o,p)
2 3
Scheme 1. Reagents and conditions: (i) anhydrous K CO , dry acetone, rt, 3 h; (ii) ethylene diamine, ethanol, rt, 12 h.
*
Corresponding author. Tel.: +91 44 09444333883; e-mail: ragharaghunathan@yahoo.com
040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
0
doi:10.1016/j.tetlet.2006.10.076

8856
N. Arumugam, R. Raghunathan / Tetrahedron Letters 47 (2006) 8855–8857
O
O
O
O
O
H
H
H
H
N
N
O
N
H
N
O
O
N
H
N
H
O
H
i
O
O
O
O
O
5
a-b m,o
3a-b
4a-b m,o
Scheme 2. Reagents and conditions: (i) phenoxy acetyl chloride, dry dichloromethane, Et
3
N, 0 ꢁC to rt, 12 h.
a 75% yield. Bis-imine 3a so prepared was used for the
next step without further purification. Crude imine 3a
was treated with phenoxy acetyl chloride in the presence
of triethylamine in dichloromethane for 12 h to give a
diastereomeric mixture of cis macrocyclic bis-b-lac-
equivalent methylenes joining the two b-lactam rings.
The C-3 and C-4 protons resonated as two doublets at
5.54 and 5.58 (J = 4.4 Hz) and the O-methylene protons
attached to the m-xylene unit appeared as two doublets
1
3
at d 5.04 and 5.12 (J = 13.6 Hz). In the C NMR spec-
trum, the peaks at d 166.8 and 164.9 were due to the
amide carbonyl carbons of bis-b-lactams 4a and 5a,
respectively. Similarly, the synthesis of diastereomeric
bis-lactams 4b and 5b could be achieved by the same
synthetic sequence as discussed earlier. The structure
of 5a was further confirmed by single crystal X-ray anal-
1
5
tams in a 50% yield (diastereomeric ratio was 58:42).
1
TLC and H NMR spectral analysis of the crude reac-
tion mixture showed the presence of two diastereomers.
These diastereomers were separated by flash column
chromatography. The IR spectrum of bis-b-lactam 4a
ꢀ
1
showed a sharp band at 1749 cm and the ether linkage
ꢀ1
18
appeared at 1600 cm . The C -symmetric structure of
ysis (Fig. 1). The reaction time and the yield were
2
macrocyclic bis-b-lactam 4a was assigned on the basis
found to be far better with a chlorinated solvent rather
than benzene (Table 1). However, the synthesis of the
p-isomer of bis-b-lactams 4c and 5c could not be
achieved due to the poor solubility of bis-imine 3c in
organic solvents.
1
1
of H NMR analysis. The H NMR spectrum of 4a
showed two doublets at d 3.41 and 3.68 with geminal
couplings of 12.0 Hz for the protons of the methylene
1
6
groups joining the two b-lactam rings. The C-3 and
C-4 protons resonated as two doublets at d 5.37 and
4
.82 with coupling constants of J = 4.4 Hz. The O-meth-
In summary, the synthesis of a series of macrocyclic
bis-b-lactam derivatives was achieved in a good yield
by a stereoselective (2+2) cycloaddition reaction.
ylene protons attached to the m-xylene unit appeared
as two doublets at d 4.94 and 5.13 (J = 13.2 Hz)
(
Scheme 2).
1
17
The H NMR spectrum of meso structure 5a showed
two multiplets at d 3.02 and 4.08 due to the two non-
Acknowledgements
N.A. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi, for award of JRF and
SRF. R.R. thanks the CSIR, New Delhi, for financial
assistance. The Department of Science and Technology
(DST-FIST) is also thanked for NMR spectra.
References and notes
1
2
. Samarendra, C. I.; Maiti, N.; Micetich, R.; Daneshtalab,
M.; Atchison, K.; Phillips, O. A.; Kunugita, C. J. Antibiot.
1
994, 47, 1030.
. Kotra, L. P.; Mobashery, S. Bull. Inst. Pasteur 1998, 96,
139.
Figure 1. ORTEP diagram of compound 5a.
Table 1. Synthesis of macrocyclic bis-b-lactams using different solvents
Entry
Dry dichloromethane
Time (h) Yield (%)
Dry chloroform
Dry benzene
Time (h)
Yield (%)
Time (h)
Yield (%)
4
4
5
5
a
b
a
b
12
12
12
12
50
52
45
45
12
12
12
12
40
45
38
43
15
15
15
15
35
38
30
35

N. Arumugam, R. Raghunathan / Tetrahedron Letters 47 (2006) 8855–8857
8857
3
4
. For reviews, see: (a) Mascaretti, O. A.; Boschetti, C. E.;
Danelon, G. O.; Mata, E. G.; Roveri, O. A. Curr. Med.
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Med. Res. Rev. 1994, 14, 127.
. (a) Vaccaro, W. D.; Davis, H. R., Jr. Bioorg. Med. Chem.
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D. A. Tetrahedron Lett. 1994, 35, 7339.
14. Representative experimental procedure for compound 3a
A mixture of dialdehyde (1 mmol), ethylene diamine
(1 mmol) and ethanol (100 ml) was stirred for 12 h at
room temperature. After completion of the reaction the
solvent was removed under reduced pressure to give the
required bis-imine.
15. Representative experimental procedure for compound 4a
A solution of phenoxy acetyl chloride in dry dichloro-
methane (20 ml) was slowly added to a solution of bis-
imine (1 mmol) and triethylamine (3.5 mmol) in dichloro-
methane (20 ml) at 0 ꢁC and then the mixture was stirred
for 12 h at room temperature. It was then washed with
5
6
7
8
. Borthwick, A. D.; Weingarte, G.; Haley, T. M.; Toma-
szewski, M.; Wang, W.; Hu, Z.; Bedard, J.; Jin, H.; Yuen,
L.; Mansour, T. S. Bioorg. Med. Chem. Lett. 1998, 8, 365.
. Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Federici, M.
E.; Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem.
water (2 · 20 ml), saturated NaHCO
3
(15 ml) and brine
1
995, 3, 1123.
(15 ml) then dried over anhydrous Na SO . The removal
2
4
. Smith, D. M.; Kazi, A.; Smith, L.; Long, T. E.; Heldreth,
of the solvent by distillation under reduced pressure gave
the crude product as a diastereomeric mixture. The
diastereomers were separated by column chromatography
(hexane:ethyl acetate 7:3) to give pure b-lactam in a good
yield. The product was recrystallized from ethyl acetate.
16. 8,14-Dioxa-1,4-diaza-4,16(1,2)-dibenzene-9,13(1,3) benzene-
B.; Turos, E.; Ping dou, Q. Mol. Pharmacol. 2002, 61,
1
348.
. (a) Ojima, I.; Hatanaka, N.; Yoda, N.; Abe, R.; Yatabe,
M.; Yanashita, M. In Peptide Chemistry; Sakakibara, S.,
Ed.; Protein Research Foundation: Osaka, 1983; pp 29–
0
0
3
4; (b) Yamashita, M.; Abe, R.; Hatanaka, N.; Ojima, I.
4,5,17,1-bis-(3 -phenoxy azetidin-2 -one) cycloheptadeca-
phane 4a: White solid; yield: 50% mp: 238 ꢁC IR (KBr):
In Peptide Chemistry; Sakakibara, S., Ed.; Protein
Research Foundation: Osaka, 1983; pp 85–90.
ꢀ
1 1
1749, 1600 cm
3
H NMR (400 MHz, CDCl ) d 3.41 (d,
9
. (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.;
Yamashita, M.; Abe, R. J.Org. Chem. 1991, 56, 5263;
J = 11.9 Hz, 2H), 3.68 (d, J = 12.0 Hz, 2H), 4.82 (d, J =
4.4 Hz, 2H), 4.94 (d, J = 13.2 Hz, 2H), 5.13 (d,
J = 13.2 Hz, 2H), 5.37 (d, J = 4.4 Hz, 2H), 6.48–7.77 (m,
22H), C NMR (100 MHz, CDCl ): d 39.95, 56.53, 68.10,
3
81.10, 81.49, 111.22, 115.26, 120.81, 121.60, 125.03,
(
b) Ojima, I.; Nakahashi, K.; Branstadter, S. M.; Hata-
1
3
naka, N. J. Am. Chem. Soc. 1987, 109, 1798; (c) Bose, A.
K.; Womensdors, J. F.; Krishnan, L.; Urbanczyk-Lip-
kowska, Z.; Shelly, D. C.; Manhas, M. S. Tetrahedron
128.82, 129.03, 129.55, 137.76, 155.94, 156.71, 166.85.
+
1
991, 47, 5379; (d) Jayaram, M.; Puranik, V. G.; Bhawal,
B. M. Tetrahedron 1996, 52, 9005.
0. Jayaram, M.; Puranik, V. G.; Bhawal, B. M. Tetrahedron
996, 52, 9005.
1. Jayaram, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
J. Org. Chem. 1994, 59, 932.
MS (EI) m/z = 638 [M ]. Anal. Calcd for C40
H
34
2
N O
6
: C,
75.21; H, 5.32; N, 4.38. Found: C, 75.22; H, 5.30; N,
4.40.
1
1
1
1
1
17. 7,13-Dioxa-3,17-diaza-4,16(1,2)-dibenzene-8,12(1,3) benzene-
3,4,16,17-bis-(3 -phenoxy azetidin-2 -one) cycloheptadeca-
0
0
phane 5a: White solid yield 45% mp: 248 ꢁC IR (KBr):
ꢀ
1 1
2. Karupaiyan, K.; Puranik, V. G.; Deshmukh, A. R. A. S.;
Bhawal, B. M. Tetrahedron 2000, 56, 8555.
1749, 1600 cm
H NMR (400 MHz, CDCl ) d 3.02 (m,
3
2H), 4.08 (m, 2H), 5.04 (d, J = 13.6 Hz, 2H), 5.12 (d,
3. Representative experimental procedure for compound 2a
A mixture of freshly distilled salicylaldehyde (2 mmol),
m-xylene dibromide (1 mmol), anhydrous potassium car-
bonate (2 mmol) and dry acetone (20 ml) was stirred for
J = 13.2 Hz, 2H), 5.54 (d, J = 4.4 Hz, 2H), 5.58 (d,
J = 4.4 Hz, 2H), 6.62–7.41 (m, 22H), C NMR (100
1
3
MHz, CDCl ): d 36.45, 55.19, 66.65, 80.99, 110.26, 114.23,
3
119.31, 119.34, 120.50, 121.00, 123.36, 127.05, 127.31,
3
h at room temperature. The reaction mixture was then
127.54, 128.37, 130.38, 154.84, 155.41, 164.93. MS (EI)
+
washed with water and extracted with chloroform. The
organic layer was concentrated by distillation under
reduced pressure to give the required dialdehyde in an
excellent yield.
m/z = 638 [M ]. Anal. Calcd for C40
H
34
2
N O
6
: C, 75.21;
H, 5.32; N, 4.38. Found: C, 75.24; H, 5.30; N, 4.39.
18. Gayathri, D.; Latha, D.; Velmurugan, D.; Ravikumar, K.;
Arumugam, N. Acta Cryst. 2006, E62, o3082–o3084.