An expeditious synthesis of a (3S,4S,5R)-trihydroxyazepane

Article abstract of DOI:10.1016/S0040-4039(03)01870-7

A practical approach for the synthesis of the (2S,3S,4R)-trihydroxyazepane 1d has been reported. Starting from α-D-xylo-pentodialdose, readily available from D-glucose, the sequence involves Wittig olefination and reductive amination as key steps.

Full text of DOI:10.1016/S0040-4039(03)01870-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7321–7323
An expeditious synthesis of a (3S,4S,5R)-trihydroxyazepane
Dilip D. Dhavale,* Vinod D. Chaudhari and Jayant N. Tilekar
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
Received 15 July 2003; revised 25 July 2003; accepted 31 July 2003
Abstract—A practical approach for the synthesis of the (2S,3S,4R)-trihydroxyazepane 1d has been reported. Starting from
a-D-xylo-pentodialdose, readily available from D-glucose, the sequence involves Wittig olefination and reductive amination as key
steps.
© 2003 Elsevier Ltd. All rights reserved.
Amongst polyhydroxylated imino-sugars, the seven-
membered azepane compounds 1 play an important
role as DNA minor groove binding ligands (MGBL)
and as glycosidase inhibitors.1 The primary advantage
of these compounds is their high water solubility, allow-
ing them to circumvent the problem of poor bio-
availability seen with many other MGBL’s. In addition,
the pseudo-rotating conformations in the seven-mem-
bered ring (as compared to five or six-membered imino-
sugars) render the ability of azepanes to point into the
minor groove of DNA. This effect of adopting different
conformations is augmented due to the probability of
hydrogen bonding between the hydroxyl groups with
the nitrogen of various bases. In the search for struc-
ture–activity relationship, attempts are being made to
correlate the MGBL and glycosidase inhibitory activi-
ties for each hydroxyl substituent in azepanes.2 This has
led to the discovery of di-, tri- and tetra-hydroxylated
azepane derivatives 1a, 1b and 1c (Fig. 1), respectively,
polyhydroxylated imino-sugars using the chiron
approach,4 we describe here a new efficient method for
the synthesis of trihydroxyazepane 1d.5 Our approach
hinges on the reductive amination of suitably protected
5-amino-5-deoxy-a-
D-xylo-hexodialdo-1,4-furanose
which can be obtained by a one carbon homologation
of a- -xylo-pentodialdose 2 using the Wittig olefina-
D
tion.
Thus, reaction of 3-O-benzyl-1,2-O-isopropylidene-a-
-xylo-pentodialdose6 2 with the Wittig reagent, pre-
pared from methoxymethyltriphenylphosphonium
D
chloride and potassium-t-butoxide in t-butanol–THF,
afforded a geometrical mixture of 3 (E:Z=3:1) which
on mild acid hydrolysis gave 5-deoxy-3-O-benzyl-1,2-
O-isopropylidene-a-
-xylo-hexodialdo-1,4-furanose 47
D
in 82% yield (Scheme 1).8 Reductive amination of 4
using N-benzylamine and sodium cyanoborohydride
afforded amino derivative 5.8 Hydrogenolytic removal
of the N- and O-benzyl protecting groups in 5 with
ammonium formate and 10% Pd–C in methanol gave
an amino alcohol, which was directly subjected to
selective N-Cbz protection with benzyl chloroformate
to give 5,6-dideoxy-6-(N-benzyloxycarbonyl) amino-
either by chemoenzymatic or chemical synthesis.1,3
A
number of synthetic approaches to tetrahydroxy-
azepanes are known, however only limited synthetic
strategies are reported for the trihydroxy derivatives.
As a part of our ongoing interest in the synthesis of
1,2-O-isopropylidene-a- -gluco-furanose 6. Treatment
D
of 6 with TFA–water afforded an anomeric mixture of
hemiacetals, which on hydrogenation using 10% Pd–C
in methanol afforded trihydroxyazepane 1d as a thick
1
oil. The H and 13C NMR spectra and analytical data
were in agreement with the proposed structure 1d. The
compound 1d was treated with acetic anhydride in
pyridine for three days to obtain the tetra-acetyl deriva-
tive 1e as a solid. The melting point, analytical data and
the optical rotation value8 of 1e was found to be in
good agreement with those reported.5
Figure 1.
* Corresponding author. Fax: +91 20 569 1728; e-mail: ddd@
chem.unipune.ernet.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01870-7

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D. D. Dha6ale et al. / Tetrahedron Letters 44 (2003) 7321–7323
Scheme 1. Reagents and conditions: (a) Ref. 4; (b) potassium t-butoxide (1.5 equiv.), H3COCH2PPh3Cl (1.2 equiv.), t-BuOH–
THF, −40°C, 2 h, 78%; (c) 3N HCl–THF (1:10), 25°C, 3 h, 88%; (d) BnNH2 (1.1 equiv.), NaCNBH3 (1.5 equiv.), cat. CH3COOH,
MeOH, −78°C, 2 h then 25°C, 24 h, 86%; (e) i. HCOONH4 (7 equiv.), 10% Pd–C, MeOH, reflux, 40 min, ii. ClCOOBn (1.5
equiv.), NaHCO3 (2.8 equiv.), MeOH–H2O, 0–25°C, 2 h, 76%; (f) i. TFA–H2O (3:2), 25°C, 2 h, ii. 10% Pd–C, MeOH, H2, 80 psi,
25°C, 24 h, 85%; (g) Ac2O, pyridine, 25°C, 72 h, 45%.
In summary, we have developed a simple and concise
synthesis of trihydroxyazepane 1d. The readily available
starting material, low cost of reagents and high yields
make our synthetic route practicable and workable on
multigram scale.
1999, 10, 4521; (e) Lohray, B. B.; Bhushan, V.; Prasuna,
G.; Jayamma, Y.; Raheem, M. A.; Papireddiy, P.;
Umadevi, B.; Premkumar, M.; Lakshmi, N. S.;
Narayanreddy, K. Indian J. Chem. 1999, 38B, 1311–1321;
(f) Painter, G. F.; Falshaw, A. J. Chem. Soc., Perkin
Trans. 1 2000, 1157; (g) Armbruster, J.; Stelzer, F.; Lan-
denberger, P.; Wieber, C.; Hunkler, D.; Keller, M.;
Prinzbach, H. Tetrahedron Lett. 2000, 41, 5483.
Acknowledgements
4. (a) Dhavale, D. D.; Desai, V. N.; Sindkhedkar, M. D.;
Mali, R. S.; Castellari, C.; Trombini, C. Tetrahedron:
Asymmetry 1997, 9, 1475; (b) Dhavale, D. D.; Saha, N. N.;
Desai, V. N. J. Org. Chem. 1997, 62, 7482; (c) Dhavale, D.
D.; Desai, V. N.; Saha, N. N. Chem. Commun. 1999, 1719;
(d) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org.
Chem. 2001, 66, 1065; (e) Saha, N. N.; Desai, V. N.;
Dhavale, D. D. Tetrahedron 2001, 57, 39; (f) Patil, N. T.;
Tilekar, J. N.; Dhavale, D. D. Tetrahedron Lett. 2001, 42,
747; (g) Patil, N. T.; John, S.; Sabharwal, S. G.; Dhavale,
D. D. Bioorg. Med. Chem. 2002, 10, 2155.
We thank the Department of Science and Technology
(SP/S1/G-23/2000) for financial support and the Uni-
versity Grants Commission for a grant to procure a
High Field NMR spectrometer. One of us (J.N.T.) is
thankful to CSIR for a Senior Research Fellowship.
We are grateful to Professor M. S. Wadia for helpful
suggestions.
5. For the first synthesis of the tetra-acetylated derivative 1e
see: Paulsen, H.; Todt, K. Chem. Ber. 1967, 100, 512. No
other synthesis of 1d has been reported so far.
6. Wolfrom, M. L.; Hanessian, S. J. Org. Chem. 1962, 27,
1800.
References
1. (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021; (b) Winchester,
B.; Fleet, G. W. J. Glycobiology 1992, 2, 199; (c) Wong, C.
H.; Halcomb, R. L.; Ichikawa, Y.; Kajimato, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 521; (d) Moris-Varas, F.;
Qian, X.; Wong, C. H. J. Am. Chem. Soc. 1996, 118, 7647;
(e) Qian, X.; Moris-Varas, F.; Fitzgerald, M. C.; Wong, C.
H. Bioorg. Med. Chem. 1996, 4, 2055; (f) Le Merrer, Y.;
Poitout, L.; Depazy, J.-C.; Dosbaa, I.; Geoffroy, S.; Fogli-
etti, M. Bioorg. Med. Chem. 1997, 5, 519.
7. Compound 4 is reported as unpublished results: Tronchet,
J. M. J.; Bonenfant, A. P. Helv. Chim. Acta 1980, 63, 1644.
8. All new compounds were obtained in analytically pure
form. Data of significant chemical shifts of major E-iso-
1
mer 3: H NMR (300 MHz, CDCl3): l 1.33 (s, 3H), 1.52
(s, 3H), 3.59 (s, 3H), 3.78 (d, J=3.0 Hz, 1H), 4.54–4.75
(m, 4H), 5.05 (dd, J=12.9 and 9.4 Hz, 1H), 5.92 (d, J=3.9
Hz, 1H), 6.67 (d, J=12.9 Hz, 1H), 7.25–7.36 (m, 5H).
Anal. calcd for C17H22O5: C, 66.65%; H, 7.23%. Found C,
66.43%; H, 7.37%. Data for 4: [h]2D5 −40.21 (c 0.15,
2. Johnson, H. A.; Thomas, N. R. Bioorg. Med. Chem. Lett.
2002, 12, 237.
3. (a) Poitout, L.; Le Merrer, Y.; Depazy, J.-C. Tetrahedron
Lett. 1994, 35, 3293; (b) Lohray, B. B.; Jayamma, Y.;
Chatterjee, M. J. Org. Chem. 1995, 60, 5958; (c) Poitout,
L.; Merrer, Y. L.; Depazy, J.-C. Tetrahedron Lett. 1996,
37, 1613; (d) Herdeis, C.; Mohareb, R. M.; Neder, R. B.;
Schwabenlander, F.; Tesler, J. Tetrahedron: Asymmetry
1
CHCl3). IR (neat): 2733, 1722 cm−1; H NMR (300 MHz,
CDCl3): l 1.33 (s, 3H),1.51 (s, 3H), 2.85 (m, 2H), 3.99 (d,
J=3.02 Hz, 1H), 4.53 (d, J=11.8 Hz, 1H), 4.50–4.73 (m,
3H), 5.90 (d, J=3.57 Hz, 1H), 7.25–7.36 (m, 5H), 9.73 (t,
J=1.3, 1H); 13C NMR (75 MHz CDCl3): l 26.26, 26.80,

D. D. Dha6ale et al. / Tetrahedron Letters 44 (2003) 7321–7323
7323
42.61, 71.95, 75.39, 82.07, 82.25, 104.57, 111.57, 127.66,
127.96, 128.39, 128.41, 137.01, 199.71. Anal. calcd for
C16H20O5: C, 65.75%; H, 6.85%. Found C, 65.83%; H,
6.72%. Data for 5: [h]2D5 −25.05 (c 0.2, CHCl3). IR(neat):
C, 60.87%; H, 7.05%. Data for 1d: [h]2D5 16.36 (c 0.33,
MeOH). H NMR (300 MHz, D2O): l 1.72–2.20 (m, 2H),
1
2.95–3.20 (m, 2H), 3.27–3.37 (m, 2H), 3.40–3.52 (m, 1H),
3.55–3.70 (m, 1H), 3.72–3.87 (m, 1H); 13C NMR (75 MHz,
D2O): l 27.8, 53.0, 53.4, 68.0, 72.5, 78.7. Anal. calcd for
C6H13NO3·H2O: C, 43.63%; H, 9.14%. Found C, 43.87%;
H, 9.35%. Data of 1e: mp=108–110°C, lit.5 112–114°C,
[h]D25 4.0 (c 0.5, CHCl3), 4.6 (c 1, MeOH), lit.5 [h]2D5 4.8 (c
1
3600–3300 cm−1; H NMR (300 MHz, CDCl3): l 1.32 (s,
3H), 1.49 (s, 3H), 1.72–1.92 (broad, 2H), 1.96–2.10 (m,
1H), 2.62–2.80 (m, 2H), 3.75 (AB quartet, J=11.7 Hz,
2H), 3.78 (d, J=3.02 Hz, 1H), 4.16–4.27 (m, 1H), 4.43 (d,
J=11.8 Hz, 1H), 4.60 (d, J=3.9 Hz, 1H), 4.68 (d, J=11.8
Hz, 1H), 5.90 (d, J=3.9 Hz, 1H), 7.25–7.36 (m, 10H); 13C
NMR (75 MHz, CDCl3): l 26.17, 26.66, 28.48, 46.35,
53.85, 71.56, 78.95, 82.03, 82.17, 104.53, 111.11, 126.74,
127.57, 127.73, 127.96, 128.20, 128.28, 128.37, 128.41,
137.29, 140.02. Anal. calcd for C23H29NO4: C, 72.06%; H,
7.57%. Found C, 72.33%; H, 7.21%. Data for 6: [h]2D5 13.33
(c 0.15, CHCl3). IR (neat): 3354, 1701 cm−1; 1H NMR (300
MHz, CDCl3): l 1.32 (s, 3H), 1.47 (s, 3H), 1.70–1.98 (m,
2H), 2.62–2.80 (broad 1H, exchangeable with D2O), 3.18–
3.40 (m, 2H), 3.95–4.20 (m, 2H), 4.50 (d, J=3.9 Hz, 1H),
5.06 (bs, 2H), 5.31 (broad 1H, exchangeable with D2O),
5.87 (d, J=3.9 Hz, 1H), 7.25–7.40 (m, 5H); 13C NMR (75
MHz, CDCl3): l 26.16, 26.67, 28.10, 66.78, 75.47, 77.18,
78.72, 85.15, 104.27, 111.40, 128.02, 128.40, 136.29, 157.48.
Anal. calcd for C17H23NO6: C, 60.53%; H, 6.82%. Found
1, MeOH). IR (Nujol): 1740, 1642 cm−1 1H NMR (300
;
MHz, CDCl3): l 1.80–2.62 (m, 14H), 3.32–3.65 (m, 2H),
3.67–3.82 (dd, J=3.8, 15.3 Hz, 1H), 3.84–4.02 (m, 1H),
4.84–4.96 (m, 1H), 4.96–5.08 (m, 1H), 5.13–5.28 (m, 1H);
13C NMR (75 MHz, CDCl3): l 20.6, 20.8, 21.3, 21.6, 28.8,
41.7, 47.1, 72.6, 74.2, 74.3, 169.4 (strong), 169.8, 171.0.
1
The H and 13C NMR spectra of 1e showed doubling of
signals. This was due to the isomerisation by restricted
rotation around CꢀN in the N-COCH3 group. see: Appli-
cations of NMR Spectroscopy in Organic Chemistry; Jack-
man, L. M.; Sternhell, S., Eds.; Pergamon Press: Elmsford,
NY, 1978; p. 361. An analogous observation was also
noticed by us and others (Ref. 4d). Anal. calcd for
C14H21NO7: C, 53.34%; H, 6.70%. Found C, 53.63%; H,
7.01%.