A new route to 1,4-oxazepanes and 1,4-diazepanes from Garner aldehyde

Article abstract of DOI:10.1016/j.tetlet.2010.01.035

A highly efficient and convenient method for the synthesis of substituted chiral 1,4-oxazepanes and 1,4-diazepanes have been described from Garner aldehyde through reductive amination with amino ester hydrochlorides followed by intramolecular cyclization as the key steps.

Full text of DOI:10.1016/j.tetlet.2010.01.035

Tetrahedron Letters 51 (2010) 1483–1485
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Tetrahedron Letters
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A new route to 1,4-oxazepanes and 1,4-diazepanes from Garner aldehyde
*
Sanjit Kumar Das, Ajay Kumar Srivastava, Gautam Panda
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, M G Marg, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient and convenient method for the synthesis of substituted chiral 1,4-oxazepanes and 1,4-
diazepanes have been described from Garner aldehyde through reductive amination with amino ester
hydrochlorides followed by intramolecular cyclization as the key steps.
Received 7 December 2009
Revised 30 December 2009
Accepted 9 January 2010
Available online 18 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Due to their diverse biological properties1, oxazepanes and dia-
zepanes have been the major synthetic targets to synthetic and
medicinal chemists.2 1,4-Oxazepanes could be found as important
structural framework in natural products like neurotoxin batrach-
otoxin.3 The analog of Microline A 1 showed potent efficiency as
immunosuppressant than the parent compound.4 Recently Shank-
aran et al. have reported synthesis and biological evaluation of oxa-
zepanes, diazepanes, and thiazepanes as nitric oxide synthase
inhibitor.5 1,4-Diazepane scaffold is also frequently encountered
in several marketed drugs like tetrazepam, dilazep, chlorproma-
zine etc.6 The group of Wattanasin reported a new class of diaze-
panes as LFA-1 inhibitors.7 Diazepane and its derivatives are also
known as CGRP receptor antagonists.8 Complex nucleoside antibi-
otics Liposidomycin B 2 and C 3 inhibit bacterial peptidoglycan
synthesis (Fig. 1).9
all stereoisomers of natural products such as Balanol, Ophiocor-
din,13d and Epiquinamide.13e To further diversify our methodology,
we were interested to find a new and easy synthetic access to ami-
no acid-based chiral oxazepanes and diazepanes. Incorporation of
different amino acids in the ring generates structural as well as ste-
reochemical diversity due to their wide availability and diversity in
their structures. The amino acid based-diazepanes and oxazepanes
are also important as they can be used as building blocks for the
synthesis of peptide nucleic acids (PNAs) to control the biological
function in the desired manner.15
To the best of our knowledge, there is no report for chiral
3-substituted 1,4-oxazepane and 2-substituted 1,4-diazepane
derivatives. Herein we present a simple and scalable approach
for the synthesis of 3,6-disubstituted 1,4-oxazepanes and 2,6-
disubstituted 1,4-diazepanes from L
-Garner aldehyde14 in enantio-
Despite wide occurrence and importance of oxazepane and dia-
zepane core, very few synthetic routes have been reported till date.
Clark and Osborn reported a synthetic strategy with moderate
overall yield for substituted and functionalized 7-methoxy [1,4]-
oxazepanes10 through careful control of sodium periodate ring
merically pure form. The methodology is highly diverse from the
R1
R2
cleavage of methyl a-D-glucopyranoside followed by condensation
with amine in the presence of NaCNBH3. Recently, Bedurftig and
Wunsch published a four- step sequence involving high tempera-
ture, long reaction time with harsh conditions for chiral non-race-
mic 2-hydroxymethyl-substituted 1,4-diazepanes11 from methyl
ester of (S)-serine. Wlodarczyk et al. also reported 1,4-diazepanes
along with byproducts through microwave-assisted cyclization
and LiAlH4 reduction of cyclic lactams.12 Crestey et al. have
recently described a protocol to chiral 1,4-diazepanes utilizing
HO
O
O
O
O
O
O
O
H
N
O
O
N
NH
N
N
O
O
O
O
H
O
N
OH
Microline A analog; 1
activated aziridines ring opening with
a-amino alcohols followed
HO
by Fukuyama–Mitsunobu cyclization.6
OH
OSO3H
N
O
O
In our ongoing research program, we are engaged in the synthe-
sis and bioevaluation of amino acid-based polycycles13a–h in chiral-
ly pure form using inter and intramolecular Mitsunobu reactions.
Amino acid-derived Garner aldehyde14 was used for synthesis of
O
OH
NH2
liposidomycin B; R1=H, R2=CH3;
liposidomycin C; R1=CH3, R2=H; 3
2
* Corresponding author.
E-mail address: gautam.panda@gmail.com (G. Panda).
Figure 1. Some bioactive 1,4-oxazepane and 1,4-diazepanes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.035

1484
S. K. Das et al. / Tetrahedron Letters 51 (2010) 1483–1485
Table 1
O
O
Ts
Synthesized 3,6-disubstituted chiral 1,4-oxazepanes
Ts
N
a
N
N
CH2OTs
HO
CH2N3
N
½
a 2D5
ꢀ
Boc
Boc
Entry
Product
R
Overall yield (%)
7a-c
R
10a-c
R
1
2
3
4
9a
9b
9c
9d
–CH3
–CH2Ph
–CH2(C6H4)OBn
–CH2CH(CH3)2
60
55
62
59
50.1
46.3
54.2
48.4
b
Ts
N
c
CH2N3
BocHN
R
11a-c
H
N
TsO
Ts
d
R
N
CH2N3
synthetic point of view and can be applied for the synthesis of sev-
eral chiral 1,4-oxazepane and diazepane series.
BocHN
N
BocHN
Ts
R
12a-c
13a-c
The synthesis of oxazepanes 9a–d (Table 1) started from the
reductive amination of L-Garner aldehyde with amino acid methyl
Scheme 2. Synthesis of 2-alkyl-6-amino-1,4-diazepanes. Reagents and conditions:
(a) NaN3, DMF, 70 °C, (84–88%); (b) cat. p-TsOH, MeOH, 0 °C, (82–84%); (c) p-TsCl,
Et3N, DCM, 0 °C, 2 h, (76–81%); (d) (i) H2, Pd/C, MeOH, (ii) K2CO3, rt, (66–72% over
two steps).
ester hydrochlorides using NaCNBH3 to give the products 5a–d in
very good yields (95–97%). The coupled products were exposed
to lithium aluminum hydride reduction at 0 °C to furnish Boc-pro-
tected amino alcohols 6a–d in excellent yields (85–88%) (see
Scheme 1).
The amino alcohols were further converted into their tosyl
derivatives 7a–d (88–92%) using TsCl/Et3N in dry DCM and then
acetonides were cleaved by catalytic amount of p-TSA in methanol
at 0 °C to provide compounds 8a–d (84–89%). In the final step, with
the compounds 8a–d in hand, we examined the kinetically unfa-
vorable seven-membered ring cyclization via simple intramolecu-
lar nucleophilic substitution (SN2) under mild reaction condition
(K2CO3/CH3OH/rt). Surprisingly, we found that the cyclization pro-
ceeded very efficiently yielding chiral oxazepanes 9a–d (ee’s >99%,
90–93%)16 in very good overall yields (55–62%).
After successful exploration of our methodology, we targeted to
synthesize the nitrogen counterpart of the above-mentioned oxa-
zepanes by utilizing the intermediates 7a–c. The ditosyl deriva-
tives 7a–c were then reacted with sodium azide in DMF at 70 °C
for 4 h to obtain the azido products 10a–c in good yields (84–
88%). The acetonide group was cleaved using catalytic amount of
p-TSA in methanol at 0 °C to produce azido alcohols 11a–c (82–
84%) which were then converted into tosyl derivatives 12a–c in
good yields (76–81%). With the tosyl derivatives in hand, reduction
of the azides using 10% Pd–C in methanol followed by K2CO3-med-
iated cyclization was found to be effective to afford diazepanes
13a–c (ee’s >99%, 66–72% over two steps)17 in good overall yields
(22–24%) (see Scheme 2 and Table 2).
Table 2
Synthesized 2,6-disubstituted chiral 1,4- diazepanes
½ ꢀ
a 2D5
Entry
Product
R
Overall yield (%)
1
2
3
13a
13b
13c
–CH3
–CH2Ph
–CH2(C6H4)OBn
24
22
22
148.3
106.3
80.6
for the generation of new bioactives which can be utilized as pep-
tidomimetics. Biological testing of these molecules is currently
underway and will be reported elsewhere.
Acknowledgments
Financial support from ICMR is highly acknowledged. S.K.D. and
A.K.S. thank CSIR for providing fellowships. The CDRI Communica-
tion No. is 7883.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.035.
In conclusion, we have described a new method for the synthe-
sis of chiral amino acid-based oxazepane and diazepane scaffolds
from easily available Garner aldehyde. The methodology is quite
diverse with incorporation of natural and unnatural amino acids
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Scheme 1. Synthesis of 3-alkyl-6-amino-1,4-oxazepanes. Reagents and conditions:
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5 h, (84–89%); (e) K2CO3, MeOH, rt, (90–93%).

S. K. Das et al. / Tetrahedron Letters 51 (2010) 1483–1485
1485
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