Concise and practical synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars

Article abstract of DOI:10.1016/S0040-4020(03)00177-7

The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from D-glucose are described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed

Full text of DOI:10.1016/S0040-4020(03)00177-7

Tetrahedron 59 (2003) 1873–1876
Concise and practical synthesis of (2S,3R,4R,5R) and
(2S,3R,4R,5S)-1,6-dideoxy-1,6-iminosugars
*
Jayant N. Tilekar, Nitin T. Patil, Harishchandra S. Jadhav and Dilip D. Dhavale
Department of Chemistry, Garware Research Center, University of Pune, Ganeshkhind Road, Pune 411 007, India
Received 1 November 2002; revised 26 December 2002; accepted 30 January 2003
Abstract—The syntheses of (2S,3R,4R,5R) and (2S,3R,4R,5S)-1,6-dideoxy-1,6 iminosugars 1a and 1b, respectively, from D-glucose are
described. The key transformations in this reaction sequence include regio-selective epoxide ring opening with N-benzylamine followed by
intramolecular reductive amination of amino-aldehyde. q 2003 Published by Elsevier Science Ltd.
1. Introduction
of azepane molecules therefore is mainly concerned with
the different positional and stereochemical orientation of
the –OH functionality at C-2/C-3/C-4/C-5. In view of this, a
variety of di-, tetra-hydroxylazepane analogues were
synthesized and are being evaluated for their biological
properties.2c,4 In the continuation of our interest in the
synthesis of polyhydroxylated piperidine and indolizidine
alkaloids,5 we are now describing a divergent synthetic
route to (2S,3R,4R,5R)-1,6-dideoxy-1,6-imino-D-glucitol
1a6 and (2S,3R,4R,5S)-1,6-dideoxy-1,6-imino-L-iditol 1b.
In recent years, much attention has been focused on the
preparation and evaluation of glycosidase inhibitory
activities of various five- and six-member iminosugars
namely polyhydroxy pyrrolidine and piperidine alkaloids.1
However, only a few reports have appeared on the syntheses
of seven-member iminosugars-azepanes 1 (Fig. 1), despite
their promising glycosidase inhibitory activity.2 Azepanes
are also potentially useful as DNA minor groove binding
ligands (MGBL).3 The hydroxyl groups in azepanes adopt
different conformations due to the flexibility of the seven-
member ring (compared with five- or six-member rings),
thereby increasing the probability of forming hydrogen
bonds with the nitrogen bases thus rendering their ability to
point into the minor groove of the DNA. The high water
solubility, allowing them to circumvent the problem of poor
bio-availability seen with many other MGBL’s, is an
additional advantage of these compounds. The designing
2. Results and discussion
D-Glucose was converted to 5,6-dideoxy-1,2-O-isopropyl-
idene-3-O-benzyl-a-D-xylo-hex-5-enofuranose (2) by the
known method7 (Scheme 1). Epoxidation of 2 with mCPBA
in dichloromethane at room temperature afforded a
diastereomeric mixture of 5,6-epoxides 3a and 3b in the
ratio 55:45, respectively.8
The regio-selective nucleophilic attack of N-benzylamine,
at the terminal carbon of the epoxy ring, in 3a afforded
6-deoxy-6-N-benzylamino-1,2-O-isopropylidene-3-O-ben-
zyl-a-D-gluco-furanose (4a).9 Hydrogenolytic removal of
the N and O-benzyl protecting groups in 4a, with
ammonium formate, 10% Pd–C in methanol under reflux
gave an aminoalcohol, that was directly subjected to
selective N-Cbz protection with benzylchloroformate, in
the presence of sodium bicarbonate in methanol–water, to
give 5a. Removal of the 1,2-acetonide group in 5a with
triflouroacetic acid–water (3:2) followed by catalytic
hydrogenation using 10% Pd–C in methanol afforded
(2S,3R,4R,5R)-1,6-dideoxy-1,6-imino-D-glucitol 1a.10
Similar sequence of reactions was repeated with 5,6-
anhydro-b-L-ido-furanose 3b. Thus, epoxide ring opening
Figure 1.
Keywords: carbohydrates; imino sugars; enzyme inhibitors;
D-glucoazepane; L-idoazepane.
*
Corresponding author. Tel.: þ91-20-560-1225; fax: þ91-20-569-1728;
e-mail: ddd@chem.unipune.ernet.in
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00177-7

1874
J. N. Tilekar et al. / Tetrahedron 59 (2003) 1873–1876
were recorded on a Perkin–Elmer 1600 FTIR spectro-
photometer as a thin film or in nujol mull. NMR spectra
were recorded on a Varian Mercury instrument (300 MHz
for 1H and 75 MHz for 13C) in CDCl3 solvent, unless
otherwise stated, with reference to TMS as an internal
standard. Elemental analyses were carried out on a Hosli C,
H-analyser. Optical rotations were measured using a
Bellingham Stanley-ADP 220 digital polarimeter at 258C.
As and when required, the reactions were carried out in
oven-dried glassware under dry N2. Thin layer chromato-
graphy was performed on pre-coated plates (0.25 mm, silica
gel 60 F254). After work up, the organic rotavapor layer was
washed with water, dried over anhydrous sodium sulphate
and evaporated under reduced pressure using a rotavapor.
Visualization was by absorption of UV light, or by thermal
development after spraying with 2,4-dinitrophenyl-
hydrazine solution and with basic aqueous potassium
permanganate solution. Column chromatography was
carried out on silica gel (100–200 mesh). Diethyl ether,
dichloromethane, ethyl acetate and THF were purified and
dried before use. Petroleum ether (PE) was the distillation
fraction between 40 and 608C. N-Benzylamine, benzyloxy-
carbonyl chloride and 10% Pd–C were purchased from
Aldrich and/or Fluka.
3.1.1. 5,6-Anhydro-1,2-O-isopropylidene-3-O-phenyl
methyl-a-D-gluco-1,4-furanose (3a) and 5,6-anhydro-
1,2-O-isopropylidene-3-O-phenylmethyl-b-L-ido-1,4-
furanose (3b). To a 08C cooled solution of alkene 2 (2.0 g,
7.25 mmol) in CH2Cl2 (30 mL) was added m-chloro-
perbenzoic acid (3.75 g, 21.7 mmol) in two portions with
an interval of 10 min. The stirred reaction mixture was
warmed to room temperature and after 36 h diluted with
CH2Cl2 (50 mL). The organic layer was washed with 1 M
NaOH (20 mL£2), water (10 mL£2), was dried over
anhydrous sodium sulphate and evaporated on rotovapor
under reduced pressure. The crude oil thus obtained was
purified by column chromatography, elution first with
PE/ethyl acetate, 98/2 afforded 3a (0.95 g, 45%) as a thick
liquid: Rf (60% n-hexane/ethyl acetate) 0.52; [a]D¼250.9
(c 4.79, CHCl3), lit.8 [a]D¼251.2 (c 4.77, CHCl3). Further
elution with PE/ethyl acetate (95/5) afforded 3b (0.85 g,
40%) as a thick liquid; Rf (60% n-hexane/ethyl acetate)
0.42; [a]D¼279.5 (c 6.45, CHCl3), lit.8 [a]D¼278.7 (c
6.50, CHCl3). The spectral data of 3a and 3b were found to
be in good agreement with that reported.
Scheme 1. Reagents and conditions: (i) Ref. 7; (ii) mCPBA, CH2Cl2, 258C,
36 h; (iii) for 3a, BnNH2, neat, 258C, 12 h; for 3b, BnNH2, 808C, 12 h; (iv)
(a) HCOONH4, 10% Pd–C, MeOH, reflux, 40 min; (b) ClCOOBn,
MeOH–H2O, 0–258C, 2 h; (v) (a) TFA–H2O, 258C, 2 h; (v) (a) TFA–
H2O, 258C, 2 h; (b) 10% Pd–C, MeOH, H2, 80 psi, 258C, 24 h.
of 3b with N-benzylamine at 808C gave 4b,11 which on
hydrogenolysis followed by N-Cbz protection afforded 5b.
Removal of the 1,2-acetonide group with TFA–water and
catalytic hydrogenation with 10% Pd–C in methanol gave
(2S,3R,4R,5S)-1,6-dideoxy-1,6-imino-L-iditol 1b. The
spectral and analytical data of 1b were in consonance with
that reported in the literature.
3.1.2. 6-Deoxy-6-N-phenylmethylamino-1,2-O-iso-
propylidene-3-O-phenylmethyl-a-D-gluco-1,4-furanose
(4a). A solution of 3a (1.4 g, 4.7 mmol) and N-benzylamine
(0.56 g, 5.27 mmol) was stirred at room temperature under
N2 for 12 h and directly loaded on a silica gel column.
Elution with PE/ethyl acetate, 4/1 afforded 4a (1.2 g, 82%)
as a thick liquid; (Found: C, 69.29; H, 7.49. C23H29NO5
requires C, 69.16; H, 7.31%); Rf (40% ethyl acetate/
n-hexane) 0.35; [a]D¼þ15.32 (c 0.19, CHCl3); nmax (neat)
3300–3000 (broad) cm21; dH (300 MHz, CDCl3) 1.35 (3H,
s, Me), 1.50 (3H, s, Me), 1.91 (1H, bs, exchanges with D2O,
OH/NH), 2.78 (1H, dd, J¼12.3, 8.5 Hz, CH2HBn), 2.99
(1H, dd, J¼12.3, 3.0 Hz, CH2HBn), 3.84 (2H, s, NCH2Ph),
4.01 (1H, dd, J¼8.5, 3.0 Hz, C4–H), 4.08 (1H, d, J¼3.0 Hz,
C3–H), 4.15 (1H, dt, J¼8.5, 3.0 Hz, C5–H), 4.57 (1H, d,
J¼3.5 Hz, C2–H), 4.62 (2H, AB quartet J¼11.8 Hz,
In conclusion, we have presented an efficient and straight-
forward chiron approach for the syntheses of tetrahydroxy-
azepane derivatives 1a and 1b that can be reproduced on
multi-gram scale. The concept that we have shown herein
clearly indicates a design strategy for the development of
new analogues of this class of compounds.
3. Experimental
3.1. General
Melting points were recorded with Thomas Hoover melting
point apparatus and are uncorrected. IR spectra (n, cm21
)

J. N. Tilekar et al. / Tetrahedron 59 (2003) 1873–1876
1875
OCH2Ph), 4.77 (1H, bs, exchanges with D2O, OH/NH), 5.88
(1H, d, J¼3.5 Hz, C1–H), 7.3 (10H, bs, Ph); dC (75 MHz,
CDCl3) 26.1, 26.7, 51.4, 52.9, 65.8, 72.3, 81.6, 81.7, 82.2,
105.1, 111.6, 127.6, 127.7, 128.4, 128.5, 137.3, 137.4.
(1.01 g, 5.96 mmol), as stated in case of 4a, afforded 5b
(0.78 g, 81%) as a thick liquid; (Found: C, 57.90; H, 6.77.
C17H23NO7 requires C, 57.79; H, 6.55%); Rf (20%
methanol/chloroform) 0.55; [a]D¼29.75 (c 0.20, CHCl3);
nmax (neat) 3350, 1699 cm21; dH (300 MHz, CDCl3) 1.32
(3H, s, Me), 1.48 (3H, s, Me), 1.60–1.85 (2H, bs, exchanges
with D2O, OH/NH), 3.29 (1H, dd, J¼14.3, 6.1 Hz, H2-
CNHCbz), 3.48 (1H, dd, J¼14.3, 3.3 Hz, H2CNHCbz),
4.00–4.07 (1H, m, C4–H), 4.10–4.17 (1H, m, C5–H), 4.30
(1H, d, J¼2.8 Hz, C3–H), 4.50 (1H, d, J¼3.3 Hz, C2–H),
5.10 (2H, s, OCH2Ph), 5.46–5.58 (1H bs, exchanges with
D2O, OH/NH), 5.95 (1H, d, J¼3.3 Hz, C1–H), 7.30–7.42
(5H, s, Ph); dC (75 MHz, CDCl3) 26.2, 26.8, 44.9, 67.1,
70.3, 76.3, 79.9, 85.3, 104.8, 111.8, 128.0, 128.1, 128.4,
135.9, 157.2.
3.1.3. 6-Deoxy-6-N-phenylmethylamino-1,2-O-iso-
propylidene-3-O-phenylmethyl-b-L-ido-1,4-furanose
(4b). A solution of 3b (1.5 g, 1.53 mmol) and N-benzyl-
amine (0.62 g, 1.67 mmol) was heated at 808C for 5 h and
the crude product on cooling was loaded on a silica gel
column. Elution with PE/ethyl acetate (4/1) afforded 4b
(1.3 g, 85%) as a thick liquid; (Found: C, 69.01; H, 7.35.
C23H29NO5 requires C, 69.16; H, 7.31%); Rf (40% ethyl
acetate/n-hexane) 0.39; [a]D¼250.07 (c 0.20, CHCl3); nmax
(neat) 3300–3000 (broad) cm21 1H NMR (300 MHz,
;
CDCl3), d 1.32 (3H, s, Me), 1.48 (3H, s, Me), 1.58–2.01
(1H, bs, exchanges with D2O, OH/NH), 2.58–2.78 (2H, m,
CH2NHBn), 3.72 (2H, AB quartet, J¼11.8 Hz, NHCH2Ph),
3.95 (1H, d, J¼3.5 Hz, C3–H), 4.05–4.15 (2H, m, C4–H,
C5–H), 4.37 (1H, d, J¼11.5 Hz, OCH2Ph), 4.53 (1H, d,
J¼3.5 Hz, C2–H), 4.58 (1H, d, J¼11.5 Hz, OCH2Ph), 4.82
(1H, bs, exchanges with D2O, OH/NH), 5.98 (1H, d,
J¼3.5 Hz, C1–H), 7.25–7.35 (10H, m, Ph); 13C NMR
(75 MHz, CDCl3), d 26.2, 26.7, 50.9, 53.6, 67.1, 71.7, 81.0,
82.2, 104.7, 111.7, 126.9, 127.7, 128.2, 128.52, 128.5,
128.8, 128.9, 136.7, 136.9.
3.1.6. 1,6-Dideoxy-1,6-imino-(2S,3R,4R,5R)-D-glucitol
(1a). A solution of 5a (0.5 g, 1.41 mmol) in TFA–H2O
(5 mL, 3/2) was stirred at 258C and after 2 h TFA was
co-evaporated with benzene to furnish the hemiacetal as a
thick liquid. A solution of hemiacetal in methanol and
10% Pd/C (0.1 g) was hydrogenated at 80 psi. After 18 h,
the catalyst was filtered, washed with methanol (5 mL£2)
and the filtrate concentrated to a sticky solid. The sticky
solid was washed with chloroform and loaded on
DOWEX-Hþ resin. Elution with 5% ammonia–methanol
and evaporation of methanol afforded 1a (0.17 g, 76%) as
3.1.4. 6-Deoxy-6-N-benzyloxycarbonyl-1,2-O-isopropyl-
idene-3-O-phenylmethyl-a-D-gluco-1,4-furanose (5a). A
solution of 4a (1.1 g, 2.75 mmol), ammonium formate
(0.92 g, 15.1 mmol) and 10% Pd–C (0.2 g) in methanol
(10 mL) was refluxed for 40 min. The catalyst was filtered
through celite and washed with methanol (5 mL£2). To the
filtrate, cooled to 08C, was added sodium bicarbonate
(0.725 g, 8.61 mmol) and benzyloxycarbonyl chloride
(0.47 g, 2.70 mmol) and the stirred reaction mixture
warmed to room temperature. After 2 h, methanol was
removed under reduced pressure and the residue was
extracted with ethyl acetate (5 mL£3). Combined extract
was washed with brine, dried over anhydrous sodium
sulphate and concentrated on rotovapor to afford a residue
which was purified by column chromatography (chloro-
form/methanol, 9/1) to get 5a (0.81 g, 84%) as a thick
liquid; (Found: C, 58.02; H, 6.67. C17H23NO7 requires C,
57.79; H, 6.55%); Rf (20% methanol/chloroform) 0.6;
[a]D¼þ18.02 (c 0.20, CHCl3); nmax (neat) 3421,
1685 cm21; dH (300 MHz, CDCl3) 1.29 (3H, s, Me), 1.46
(3H, s, Me), 2.10–2.25 (1H, broad, exchanges with D2O,
OH/NH), 3.22–3.40 (1H, m, CH2NHCbz), 3.50–3.65 (1H,
m, CH2NHCbz), 3.70–4.0 (1H, broad, exchanges with D2O,
OH/NH), 4.02 (2H, bs, C3–H and C5H), 4.33 (1H, bs, C4–
H), 4.50 (1H, d, J¼3.6 Hz, C2–H), 5.09 (2H, s, OCH2Ph),
5.55 (1H, bs, exchanges with D2O, OH/NH), 5.92 (1H, d,
J¼3.6 Hz, C1–H), 7.30–7.45 (5H, m, Ph); dC (75 MHz,
CDCl3) 26.0, 26.7, 44.5, 67.1, 69.6, 74.8, 80.4, 85.0, 104.9,
111.7, 127.8, 128.0, 128.1, 128.5, 136.0, 158.0.
a
sticky solid; (Found: C, 36.47; H, 8.90.
C6H13NO4.2H2O requires C, 36.18; H, 8.59%); Rf (20%
methanol/chloroform) 0.11; nmax (neat) 3555–3340,
1592, 1194 cm21; dH (300 MHz, D2O) 2.65–2.87 (4H,
m, H2CNHCH2), 3.40–3.52 (1H, m), 3.53–3.65 (2H, m),
3.78–3.88 (1H, m); dC (75 MHz, D2O) 49.3, 49.6, 71.2,
73.3, 74.7, 75.2.
A solution of 1a (0.1 g) in methanol (5 mL) and two drops
of concentrated hydrochloric acid was stirred at room
temperature for 24 h. The solution was concentrated and the
residue was dissolved in water (10 mL) and extracted with
ether (2£10 mL). The aqueous layer was concentrated and
residue washed with methanol-ether to give white gummy
solid (0.085 g, 70%); [a]D¼219.5 (c 0.6, H2O); lit.10
[a]D¼215 (c 1, H2O).
3.1.7. 1,6-Dideoxy-1,6-imino (2S,3R,4R,5S)-L-iditol (1b).
Reaction of 5b (0.2 g, 0.56 mmol) with TFA–H2O, as in
case of 5a, followed by hydrogenation with 10% Pd–C in
methanol gave 1b (0.06 g 65%) as a thick liquid;
(Found: C, 36.43; H, 8.77. C6H13NO4·2H2O requires
C, 36.18; H, 8.59%); Rf (20% methanol/chloroform)
0.15; [a]D¼þ20.1 (c 0.2, H2O); lit.4e [a]D¼þ19.9 (c 2,
H2O); nmax (neat) 3560–3367, 1577, 1179 cm21; dH
(300 MHz, D2O) 2.95–3.07 (2H, dd, J¼8.2, 13.8 Hz,
H2NHCH2, 3.12–3.24 (2H, dd, J¼1.9, 13.8 Hz,
H2CNHCH2), 3.46–3.55 (2H, m, C2–H and C5–H),
3.84–3.96 (2H, m, C3–H and C4–H); dC (75 MHz, D2O)
47.0, 67.8, 76.7.
3.1.5. 6-Deoxy-6-N-benzyloxycarbonyl-1,2-O-isopropyl-
idene-3-O-phenylmethyl-b-L-ido-furanose
(5b).
A
reaction of 4b (1.5 g, 3.75 mmol), ammonium formate
(1.25 g, 19.1 mmol) and 10% Pd–C (0.3 g) in methanol
(10 mL), followed by reaction with sodium bicarbonate
(1.59 g, 18.9 mmol) and benzyloxycarbonyl chloride
Acknowledgements
We are grateful to DST (SP/S1/G23-2000), New Delhi for
the financial support. J. N. T. is thankful to CSIR, New

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J. N. Tilekar et al. / Tetrahedron 59 (2003) 1873–1876
Schwabenlander, F.; Tesler, J. Tetrahedron: Asymmetry 1999,
10, 4521.
Delhi for the senior research fellowship. We gratefully
acknowledge UGC for the grant to procure high field
(300 MHz) NMR facility.
5. (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. J. Chem. Soc., 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.
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