Synthesis of a trihydroxylated aminoazepane from D-glucitol by an intramolecular aziridine ring opening

Article abstract of DOI:10.1055/s-0028-1083569

Transformation of D-glucitol into its 1,6-diazido derivative allowed its conversion into the polyhydroxylated aminoazepane ring in a one-pot reaction using Ph₃P and H₂O. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083569

2874
LETTER
Synthesis of a Trihydroxylated Aminoazepane from D-Glucitol by an
Intramolecular Aziridine Ring Opening
Synthesis of
a
T
rihydro
a
xylatedA
m
r
inoazep
c
ane elo Siqueira Valle, Raquel Marques Braga*
Instituto de Química, Universidade Estadual de Campinas, P.O. Box 6154, Campinas, SP 13084-971, Brazil
Fax +55(19)35213023; E-mail: raquel@iqm.unicamp.br
Received 1 May 2008
NH2
O
OH
Abstract: Transformation of D-glucitol into its 1,6-diazido deriva-
tive allowed its conversion into the polyhydroxylated amino-
azepane ring in a one-pot reaction using Ph3P and H2O.
HO
OH
OH
HO
NH2
O
HO
OH
OH
OBn
Key words: azepanes, 1-deoxynojirimycin, iminosugars, aziridine
N
H
HN
OH
trihydroxylated aminoazepane
D-glucitol
3
4
Polyhydroxylated piperidine derivatives are very interest-
ing synthetic targets due to their potent and diverse bio-
logical activities, related to their inhibition of
glycosidases.1 These compounds are considered to be imi-
nosugars because they have the capacity to mimic carbo-
hydrate structures and have thus found applications in the
treatment of diabetes and other metabolic diseases,2 in ob-
structing microbial infection,3 and as antiviral agents, in
particular against the human immunodeficiency virus
(HIV).4 1-Deoxynojirimycin (DNJ, 1, Figure 1), a potent
naturally occurring glycosidase inhibitor, is an example of
this class of compounds. Another class of nitrogen hetero-
cycles having similar biological activities are the polyhy-
droxylated azepanes, some of these being superior
homologues of DNJ.5 Because of their highly substituted
peculiar seven-membered ring and interesting biological
properties, various strategies for azepane syntheses have
been described over the last years.6
Scheme 1 Retrosynthetic scheme for polyhydroxylated nitrogen
heterocycles
only 31% yield.7 We have optimized the conditions to
produce 5 as the major product of a mixture of acetonides
using 2,2-dimethoxypropane in DMF in the presence of
TsOH as catalyst (Scheme 2). Theoretical studies using
Spartan 4.1 indicate that 5 is the acetonide with the lowest
energy (291.3 kcal/mol) when compared to 6 and 7 (dif-
ference of 0.4 and 14.3 kcal/mol with respect to 5, respec-
tively).8
Tosylation of the primary hydroxyl group of 5 was carried
out using TsCl and Et3N in CH2Cl2 to produce 8 in quan-
titative yield (Scheme 2). Protection of the remaining free
hydroxyl group was obtained by treatement of 8 with NaH
and benzyl bromide in the presence of Bu4NI in THF af-
fording 9 in a satisfactory yield (65%). For the selective
deprotection of the acetonide in the C5–C6 positions, we
applied two methodologies: TsOH/MeOH and I2/MeOH
(Table 1). Using the first method, compound 10 was ob-
tained in low yields (entries 1 and 2). Using the I2/MeOH
method, decomposition of 9 was observed after 24 hours
of reaction at room temperature (entry 3) while 27% of 10
could be obtained by reducing reaction time to 20 hours
(entry 4). Increasing the reaction temperature to 35 °C or
40 °C while simultaneously diminishing reactions times
to 3 hours or 4 hours afforded acceptable yields of 10
(43% and 45%, respectively, entries 5 and 6). When the
temperature was raised to 60 °C however, a drastic de-
crease of the yield (45% to 19%) was observed despite a
very short reaction time (0.5 h, entry 7). In general, the
starting material could be recovered.
OH
HO
OH
HO
OH
OH
HO
OH
N
H
N
H
1-deoxynojirimycin (1)
polyhydroxylated azepane (2)
Figure 1 Polyhydroxylated nitrogen heterocycles
We present herein our efforts to prepare the trihydroxylat-
ed aminoazepane 3 via intramolecular aziridine opening
of an intermediate 4 obtained stereospecifically from D-
glucitol (Scheme 1).
The latter is an interesting starting material because it is
accessible commercially, is inexpensive, and has the cor-
rect configuration at the asymmetric centers required for
our synthetic objectives. The literature relates the use of
ZnCl2 in acetone to form the desired acetonide 5 but in
Diol 10 was then treated with TsCl and Et3N in CH2Cl2 to
furnish the ditosylated compound 11 in 86% yield
(Scheme 3). Both tosyl groups of 11 were replaced by azi-
do groups using NaN3 in DMF to give 12 (quant).
Alternatively, we could also access the diazide 12 from 9
with NaN3 in DMF and afforded 13 in quantitative yield
(Scheme 3). Diacetonide 13 was treated with I2/MeOH af-
fording the monoacetonide 14 in 48% yield which was se-
SYNLETT 2008, No. 18, pp 2874–2876
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083569; Art ID: S04108ST
© Georg Thieme Verlag Stuttgart · New York
1
4
.1
1
.2
0
0
8

LETTER
Synthesis of a Trihydroxylated Aminoazepane
2875
1
2
1
2
OH
OH
OH
O
O
O
O
O
Me2C(OMe)2
TsOH, DMF
3
3
HO
O
HO
O
+
+
4
5
6
4
5
6
OH
OH
OH
OH
O
OH
O
O
O
O
O
O
D-glucitol
5 54%
6 7%
7 5%
OTs
O
OTs
O
NaH, TBAI
TsCl, Et3N
O
O
5
4
OH
O
BnBr, THF
18 h
65%
OBn
O
CH2Cl2, 12 h
quant
O
O
8
9
Scheme 2 Preparation of diacetonide 9
lectively tosylated at C6 to give 15 in 54% yield (65%
based on the recovery of 14). The desired product 12
could be isolated in quantitative yield when 15 was treated
with NaN3 in DMF.
Table 1 Selective Deprotection of 9 by TsOH/MeOH and I2/MeOH
Methods
Entry Reagent
Temp
(°C)
Time
(h)
Yield
of 10 (%) of 9 (%)
Recovery
Conversion of 12 into the azepane 16 was performed us-
ing four-step sequence encompassing: (i) reduction of the
both azide groups to the corresponding iminophosphorane
12a, (ii) formation of aziridine 12b, (iii) hydrolysis of the
second iminophosphorane to the amine 4, and (iv) in-
tramolecular attack of the aziridine at C6. These consecu-
tive steps were performed using Ph3P in MeCN at 50 °C
followed by addition of water to produce the desired
azepane 16, isolated as the major product in 29% yield
(Scheme 4). There was no evidence of the product arising
from attack of the amine at C5.
1
2
3
4
5
6
7
TsOH/MeOH
0
0
6
9
29
45
60
–
TsOH/MeOH
I2/MeOH
I2/MeOH
I2/MeOH
I2/MeOH
I2/MeOH
12
r.t.
r.t.
35
40
60
24
20
3
–
27
33
12
21
13
43
4
45 (54)a
19
In conclusion, a new partially protected trihydroxy ami-
noazepane 16 was synthesized from D-glucitol in seven
steps (5% overall yield) having as the key step the one-pot
transformation of diazide 12 to azepane 16. Compound 16
0.5
a Yield calculated on the basis of recovered starting material.
1
was unequivocally characterized by H NMR and NOE
analysis (Figure 2).9
N3
N3
O
N3
O
I2, MeOH
TsCl, Et3N
O
O
O
O
40 °C
48%
CH2Cl2, 12 h
54%
OBn
OBn
OH
OBn
OH
(20%
NaN3, DMF
O
recovered 10)
70 °C, 12 h
quant
OTs
O
O
OH
OTs
15
13
14
O
NaN3, DMF
70 °C, 12 h
quant
OBn
O
Table 1
N3
O
OTs
O
OTs
O
9
TsCl, Et3N
CH2Cl2, 12 h
NaN3, DMF
70 °C, 12 h
O
O
O
O
quant
86%
OBn
OH
N3
OBn
OH
OH
10
OBn
OH
OTs
11
12
Scheme 3 Synthesis of diazide intermediate 12
Synlett 2008, No. 18, 2874–2876 © Thieme Stuttgart · New York

2876
M. S. Valle, R. M. Braga
LETTER
N3
O
Ph3P
MeCN
O
OBn
O
50 °C
3
4
then H2O
NH2
O
OBn
OH
N3
5
2
1
6
29%
N
H
12
16
NH2
O
N=PPh3
O
N=PPh3
1. Ph3P
MeCN
O
H2O
– Ph3PO
O
O
O
50 °C
16
a
12
OBn
OBn
OH
OBn
– Ph3PO
2. H2O
5
6
5
b
HN
HN
N=PPh3
6
12a
12b
4
Scheme 4 Pathway proposed for formation of product 16
Jimenez-Barbero, J.; Sinay, P. Org. Biomol. Chem. 2004, 2,
1492. (c) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.;
PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760.
(6) (a) Andreana, P. R.; Sanders, T.; Janczuk, A.; Warrick, J. I.;
Wang, P. G. Tetrahedron Lett. 2002, 43, 6525. (b) Moutel,
S.; Shipman, M.; Martin, O. R.; Ikeda, K.; Asano, N.
Tetrahedron: Asymmetry 2005, 16, 487. (c) Li, H.-Q.; Liu,
T.; Zhang, Y. M.; Favre, S.; Bello, C.; Vogel, P.; Butters,
T. D.; Oikonomakos, N. G.; Marrot, J.; Bleriot, Y.
ChemBioChem. 2008, 9, 253.
0.58%
4'
3'
NH2
H
H
5'
2'
H
2
5
N
H
1
H
4
1'
6
6'
3
H
H
O
O
O
H
H
H3C
H
0.26%
0.30%
H 1.01%
H3C
1.43%
1.00%
(7) Kuszmann, J.; Sohár, P. Carbohydr. Res. 1979, 74, 187.
(8) (a) Kato, L. Dissertação de Mestrado; Universidade de
Campinas: Brazil, 1996. (b) Kato, L.; Braga, R. M. Magn.
Reson. Chem. 1999, 37, 447. (c) Braga, R. M.; Kato, L.
J. Braz. Chem. Soc. 2003, 14, 822.
Figure 2 NOE of 16
(9) Spectroscopic Data for (5S)-Amino-(4R)-O-benzyl-1,5,6-
trideoxy-(2S,3R)-O-isopropylidene-1,6-imino-D-glucitol
(16, Figure 2)
Acknowledgment
The authors thank CNPq/FAPESP and FAEP-UNICAMP for finan-
cial support. Thanks also are due to Dr. Carol Collins (Instituto de
Química, UNICAMP) and Robert H. Dodd (ICSN-CNRS, France)
for linguistic and grammatical corrections.
Rf = 0.2 (CHCl3–MeOH, 9:1; 2×). IR (KBr): 3360, 3291
(NH), 2851 (CH), 1070 (CN) cm–1. MS: m/z (%) = 57 (16),
71 (21), 84 (26), 91 (100), 98 (49), 110 (8), 126 (34), 141 (7),
149 (10), 167 (14), 184 (27), 201 (23), 227 (3), 277 (10), 292
(2). 1H NMR (500 MHz, CDCl3): d = 1.43, 1.44 [6 H, 2 s,
C(CH3)2], 2.13–2.18 (3 H, br s, NH aliphatic and cyclic),
2.71 (1 H, dd, 2J = 11.7 Hz, 3J = 9.0 Hz, H1-a), 2.81 (1 H,
dd, 2J = 14.4 Hz, 3J = 6.8 Hz, H6-a), 2.89 (1 H, dd, 2J = 14.4
Hz, 3J = 2.2 Hz, H6-b), 3.00 (1 H, ddd, 3J = 6.8 Hz, 3J = 4.6
Hz, 3J = 2.2 Hz, H5), 3.37 (1 H, dd, 3J = 9.0 Hz, 3J = 4.6 Hz,
H4), 3.40 (1 H, dd, 2J = 11.7 Hz, 3J = 4.8 Hz, H1-b), 3.89
(1 H, td, 3J = 9.0 Hz, 3J = 4.8 Hz, H2), 4.01 (1 H, t, 3J = 9.0
Hz, H3), 4.68 (1 H, d, 2J = 11.7 Hz, OCHH¢C6H5), 4.93 (1 H,
d, 2J = 11.7 Hz, OCHH¢C6H5), 7.29 (1 H, t, 3J = 7.4 Hz, H4¢),
7.35 (2 H, t, 3J = 7.4 Hz, H3¢, H5¢), 7.39 (2 H, d, 3J = 7.4 Hz,
H2¢, H6¢). 13C NMR (125 MHz, CDCl3): d = 27.0, 27.2
[C(CH3)2], 49.2 (C6), 49.8 (C1), 55.9 (C5), 72.9
References and Notes
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138.6 (C1¢).
Synlett 2008, No. 18, 2874–2876 © Thieme Stuttgart · New York

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