A general strategy for the stereoselective synthesis of l-1-deoxyallonojirimycin and d-1-deoxygulonojirimycin

Article abstract of DOI:10.1016/j.tetlet.2006.06.110

A general strategy for the synthesis of deoxyazasugars from d-glucose is described. Ring-closing metathesis and stereoselective dihydroxylation reactions were used as key steps.

Full text of DOI:10.1016/j.tetlet.2006.06.110

Tetrahedron Letters 47 (2006) 6041–6044
A general strategy for the stereoselective synthesis
of L-1-deoxyallonojirimycin and D-1-deoxygulonojirimycinI
Subhash Ghosh,* J. Shashidhar and Samit Kumar Dutta
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 1 April 2006; revised 14 June 2006; accepted 22 June 2006
Abstract—A general strategy for the synthesis of deoxyazasugars from D-glucose is described. Ring-closing metathesis and stereo-
selective dihydroxylation reactions were used as key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
Polyhydroxylated piperidines, commonly known as
azasugars (iminosugars), are a class of compounds in
which the ring oxygen of the sugar ring is replaced by
nitrogen. At physiological pH, this nitrogen can be pro-
tonated and mimics a glycopyranosyl cation. In recent
years, these polyhydroxylated compounds have
attracted a great deal of attention, mainly due to their
special structural features and promising biological
activities.1 Polyhydroxylated piperidines have the ability
to inhibit glycosidases and glycosyl transferases, the car-
bohydrate processing enzymes, which are responsible
for the cleavage of glycosidic bonds.2 Thus, this family
of compounds have the potential to provide leads for
the treatment of numerous diseases associated with car-
bohydrate-related metabolic disorders like diabeties,3
cancer,4 AIDS,5 and viral infections.6 Due to these
promising biological activity profiles, a large number
of strategies have been developed for their syntheses.7
Here, we report a protocol (Scheme 1), which allows
the total synthesis of the deoxyazasugars L-1-deoxyallono-
jirimycin 18 and D-1-deoxygulonojirimycin 29 (Fig. 1).
OH
HO
O
O
5
4
1, 2
7
3
1
O
O
2
N
N
Cbz
O
Cbz
O
5: C-3 (
S)
3: C-6 (
R
), C-5 (
), C-5 (
R), C-3 (S)
S
6: C-3 (
R
)
4: C-6 (
S
), C-3 (
R
)
O
O
O
O
O
D-Glucose
O
O
N
Cbz
O
HO
7: C-3 (
8: C-3 (
S)
9
R)
Scheme 1. Retrosynthetic analysis.
OH
OH
HO
OH
OH
HO
OH
OH
N
N
H
H
Our retrosynthetic analysis is shown in Scheme 1. Deoxy
azasugars 1 and 2 could be synthesized from 3 and 4,
respectively, by cleavage of the sugar unit. Compounds
3 and 4 in turn could be obtained by stereoselective
dihydroxylation of piperidines 5 and 6, which would
be prepared by ring-closing metathesis of bis-alkenes 7
D-1-deoxygulonojirimycin
L-1-deoxyallonojirimycin
2
1
Figure 1.
and 8. Compounds 7 and 8 could be synthesized from
9, which in turn, would be derived from D-glucose
according to the literature procedure.10
Keywords: Azasugar; Allylation; Ring-closing metathesis; Dihydroxyl-
ation; D-Glucose.
q IICT Communication No. 060340.
*
The synthesis started from 9, which was converted into
1011 in two steps, involving the formation of an imid-
azoyl sulfate with sulfuryl chloride and imidazole in
Corresponding author. Fax: +91 40 27193108;
subhashbolorg3@yahoo.com
e-mail:
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.110

6042
S. Ghosh et al. / Tetrahedron Letters 47 (2006) 6041–6044
CH2Cl2, followed by azide displacement. Selective
deprotection of the 5,6-O-isopropylidene group using
50% acetic acid in water at room temperature, followed
by azide reduction with H2 under atmospheric pressure
in the presence of Pd/C, gave an intermediate amine,
which on treatment with CbzCl afforded 11 in good
yield. Compound 11 on treatment with imidazole,
Ph3P, and iodine in toluene at 50 °C afforded 12.12 N-
Allylation of 12 using allyl bromide and NaH in DMF
at 0 °C afforded the desired bis-alkene 7 in 88% yield.
Next, the crucial ring-closing metathesis (RCM) of 7,
using Grubbs’ first generation catalyst Cl2(PCy3)2Ru@
CHPh (10 mol %) in CH2Cl2 under argon at 50 °C affor-
ded piperidine 5 in 90% yield.13 Stereoselective dihydr-
hydroxyl groups of 3 were protected as benzyl ethers using
BnBr, NaH, and TBAI (cat) in THF at 0 °C to afford 13.
Acetonide deprotection of 13 with 50% TFA in water at
0 °C afforded 14 in good yield. Cleavage of the diol in 14
using NaIO4 in 50% ethanol, followed by NaBH4 reduc-
tion, gave 15 in 80% yield. Finally, global deprotection
by hydrogenation using Pd/C with under atmospheric
pressure afforded L-1-deoxyallonojirimycin 1 in 90%
yield, the physical properties of which were shown to
be identical with previously reported spectral and ana-
lytical data.8a,16
For the synthesis of D-1-deoxygulonojirimycin, we
started from 16, which was prepared from 9 according
to the reported procedure.17 The key building block 6 re-
quired for the synthesis of 2 was synthesized in good
yield using similar transformations to those used for
the synthesis of 5 from 9 (Scheme 2). Stereoselective
dihydroxylation of 6 using OsO4 gave exclusively one
oxylation of
5 using catalytic OsO4 with two
equivalents of NMO in acetone:water (2:1) at 0 °C for
12 h, afforded a separable diastereomeric mixture of
4:1 in favor of the required isomer 3.14 The structure
of 3 was confirmed by extensive NMR study.15 The
HO
O
O
O
O
O
O
O
O
i, ii
O
O
iii, iv; v
HO
O
O
O
HO
vi
CbzHN
N
3
9
11
10
O
O
O
viii
vii
O
O
O
NCbz
CbzHN
O
12
7
OH
OBn
O
ix
HO
O
x
BnO
O
N
O
O
Cbz
O
N
N
Cbz
O
Cbz
O
5
3
13
OBn
OH
OBn
BnO
xii
HO
OH
OH
xiii
O
xi
BnO
OH
OH
OH
N
N
H
N
Cbz
OH
Cbz
14
15
1
Scheme 2. Reagents and conditions: (i) SO2Cl2, imidazole, CH2Cl2, rt, 5 h; (ii) NaN3, DMF, 70 °C, 3 h, 50% in two steps; (iii) 50% aq AcOH, rt, 5 h;
(iv) H2, Pd/C, MeOH, 1 h; (v) CbzCl, Et3N, CH2Cl2, 30 min, 60% in three steps; (vi) Ph3P, imidazole, I2, toluene, 50 °C, 90%; (vii) NaH, DMF, allyl
bromide, 0 °C, 2 h, 88%; (viii) 10 mol % (PCy3)2RuCl2@CHPh, CH2Cl2, 24 h, 90%; (ix) NMO, NaIO4, OsO4, acetone:water (2:1), 0 °C, 12 h, 72%; (x)
NaH, BnBr, TBAI (cat), THF, 0 °C to rt, 4 h, 95%; (xi) 50% TFA in water, 0 °C, 8 h; (xii) NaIO4, 50% aq EtOH, 45 min, followed by NaBH4,
10 min, 80% in two steps; (xiii) Pd/C, H2 under atmospheric pressure, 12 h, 90%.
O
O
O
O
O
O
iii
O
O
i, ii
O
O
O
N
O
O
HO
Cbz
O
HO
iv
16
9
6
OH
OH
HO
OH
OH
HO
v
O
N
H
N
Cbz
O
4
2
Scheme 3. Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C; (ii) NaBH4, MeOH, 0 °C, 85% in two steps; (iii) same as in Scheme
2 for the conversion 9 to 5, 49% in eight steps; (iv) OsO4, NMO, acetone:water (2:1), 50 °C, 12 h, 80%; (v) same as in Scheme 2 for the conversion 3 to
1, 43% in four steps.

S. Ghosh et al. / Tetrahedron Letters 47 (2006) 6041–6044
6043
Ramsden, N. G.; Witty, D. R. Tetrahedron 1989, 45, 319–
326; (c) Altenbach, H. J.; Himmeldirk, K. Tetrahedron:
Asymmetry 1995, 6, 1077–1080; (d) Koulocheri, S. D.;
Pitsinos, E. N.; Haroutounian, S. A. Synthesis 2002, 1707–
1710; (e) Knight, J. G.; Tchabanenko, K. Tetrahedron
2003, 59, 281–286.
diol 4, as expected, since the b-face is blocked by the
bulky NCbz group as well as the adjacent C4-b oxy-
gen.15 Finally, diol 4 was converted into D-1-deoxy-
gulonojirimyan 2 following the same set of reactions
as in Scheme 3 (for 3 to 1). The spectroscopic and
analytical data of 2 were in good agreement with the
literature data.9g,i,18
8. For recent syntheses, see: (a) Kato, A.; Kato, N.; Kano,
E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto, T.; Banba, Y.;
Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005,
48, 2036–2044; (b) also see Ref. 1g.
In conclusion, we have devised a strategy for the synthe-
sis of deoxyazasugars from the commercially available,
cheap starting material D-glucose. Making library
synthesis and a study of their biological activities are
currently under progress and will be reported in due
course.
9. For the first synthesis of deoxygulonojirimycin, see: (a)
Leontein, K.; Lindberg, B.; Lonngren, J. Acta Chem.
Scand. B 1982, 36, 515–518; For more recent synthesis,
see: (b) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.;
Dosbaa, I.; Geoffroy, S.; Foglietti, M.-J. Bioorg. Med.
Chem. 1997, 5, 519–533; (c) Liao, L.-X.; Wang, Z.-M.;
Zhou, W.-S. Tetrahedron: Asymmetry 1999, 10, 3649–
3657; (d) Haukaas, M. H.; O’Doherty, G. A. Org. Lett.
2001, 3, 401–404; (e) Ruiz, M.; Ojea, V.; Ruanova, T. M.;
Quintela, J. M. Tetrahedron: Asymmetry 2002, 13, 795–
799; (f) Singh, O. V.; Han, H. Tetrahedron Lett. 2003, 44,
2387–2391; (g) Takahata, H.; Banba, Y.; Ouchi, H.;
Nemoto, H. Org. Lett. 2003, 5, 2527–2529; (h) Amat, M.;
Acknowledgments
We are thankful to CSIR (S.K.D.) and UGC (J.S.), New
Delhi, for research fellowships. We are also thankful to
Dr. T. K. Chakraborty, Dr. A. C. Kunwar and the
Director, IICT for their support and encouragement.
´
Huguet, M.; Llor, N.; Bassas, O.; Gomez, A. M.; Bosch,
J.; Badia, J.; Baldomab, L.; Aguilar, J. Tetrahedron Lett.
2004, 45, 5355–5358; (i) Pyun, S.-J.; Lee, K.-Y.; Oh, C.-H.;
Joo, J.-E.; Cheon, S.-H.; Ham, W.-H. Tetrahedron 2005,
61, 1413–1416.
References and notes
10. Schmidt, O. T. Methods Carbohydr. Chem. 1962, 2, 318–
325.
11. Yoshimura, Y.; Endo, M.; Miura, S.; Sakata, S. J. Org.
Chem. 1999, 64, 7912–7920.
12. Garegg, P. G.; Samuclson, B. Synthesis 1979, 813–814.
13. (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–
2238; (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res.
2001, 34, 18–19; (c) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012–3043.
14. (a) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett.
1983, 24, 3943–3946; For recent review, see: (b) Cha, J. K.;
Kim, N.-S. Chem. Rev. 1995, 95, 1761–1795.
1. Reviews: (a) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep.
1994, 135–162, and references cited therein; (b) Ganem, B.
Acc. Chem. Res. 1996, 29, 340–347; (c) Sears, P.; Wong,
C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300–2324; (d)
Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed.
1999, 38, 750–770; (e) Meyers, A. I.; Anders, C. J.; Resek,
J. E.; Woodall, C. C.; McLaughlin, M. A.; Lee, P. H.;
Price, D. A. Tetrahedron 1999, 55, 8931–8952; (f) Asano,
N. Glycobiology 2003, 13, 93; (g) Kamyar, A.; Akmal, B.
Tetrahedron: Asymmetry 2005, 16, 1239–1287.
2. Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000,
100, 4683–4696.
15. The structures of 3 and 4 were confirmed by extensive
NMR studies at 500 MHz in DMSO-d6 at 30 °C. The
assignments were carried out with the help of 1H and
double quantum filtered correlation spectroscopy (DQF-
COSY) experiments. Nuclear Overhauser effect spectros-
copy (NOESY) experiments provided information about
3. (a) Yoshikuni, Y.; Ezure, Y.; Seto, T.; Mori, K.; Wata-
nabe, M.; Enomoto, H. Chem. Pharm. Bull. 1989, 37, 106–
109; (b) Kimura, M.; Chen, F.-J.; Nakashima, N.;
Kimura, I.; Asano, N.; Koya, S. J. Trad. Med. 1995, 12,
214–219; (c) Horii, S.; Fukase, H.; Matsuo, T.; Kameda,
Y.; Asano, N.; Matsui, K. J. Med. Chem. 1986, 29, 1038–
1046; (d) Robinson, K. M.; Begovic, M. E.; Reinhart,
B. L.; Heineke, E. W.; Ducep, J.-B.; Kastner, P. R.;
Marshall, F. N.; Danzin, C. Diabetes 1991, 40, 825–830.
4. (a) Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575–
591; (b) Hakomori, S. Cancer Res. 1985, 45, 2405–2414;
(c) Nishimura, Y. In Studies in Natural Products Chem-
istry; Atta-ur-Rahman, Ed.; Elsevier Science: B.V.:
Amsterdam, 1995; Vol. 16, pp 75–121; (d) Gross, P. E.;
Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935–944.
3
the proximity of the protons. In 3, JH4–H5 = 2.6,
3
3
3
0
JH5–H6 = 3.0, JH6ꢀH7 ¼ 5:8, and JH6–H7 = 10.5Hz,
and characteristic NOE correlations between H3–C5OH,
H7–C5OH, H3–H7, H4–H6, and H4–CH3proR confirm
the structure in Figure A. The six-membered ring adopts a
3C6 chair form. For 4, JH4–H5 = 4.0, JH6–H7 = 3.8, and
3
3
3
0
JH6–H7 ¼ 7:8 Hz and characteristic NOE correlations
between H3–H70, H3–C5OH, H70–C5OH, H1–H6, H2–
H6, H3–CH3proR, and H4–CH3proR confirm the struc-
ture given in Figure B. The nuclear Overhauser correla-
tions for 3 and 4 are shown in Figures A and B,
respectively.
5. (a) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M.
¨
Curr. Top. Med. Chem. 2003, 3, 513–523; (b) Taylor, D.
L.; Sunkara, P.; Liu, P. S.; Kang, M. S.; Bowlin, T. L.;
Tyms, A. S. AIDS 1991, 5, 693–698.
H1
1
H
3
H
6. Fleet, G. W. J.; Karpas, A.; Dwek, R. A.; Fellows, L. E.;
Tyms, A. S.; Petursson, S.; Namgoong, S. K.; Ramsden,
N. G.; Smith, P. W.; Son, J. C.; Wilson, F.; Witty, D. R.;
Jacob, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237,
128–132.
7. For syntheses of azasugars and analogues, see for exam-
ple: (a) Fleet, G. W. J.; Ramsden, N. G.; Witty, D. R.
Tetrahedron Lett. 1988, 29, 2871–2874; (b) Fleet, G. W. J.;
H2
O
CH3pro-S
CH3
pro-S
OH
O
H6
O
O
2
H
H5
N
H7
H4
H5
HO
HO
pro-R
O
O
CH3
pro-R
CH3
H7
N-CBz
CBz
'
H7
OH
'
4
H
H3
H7
H6
Figure A
Figure B

6044
S. Ghosh et al. / Tetrahedron Letters 47 (2006) 6041–6044
27
1
Spectral data of 3: ½aꢁD +66.7 (c 1.54, CHCl3); H NMR
(500 MHz, DMSO-d6): d 7.42–7.31 (m, 5H, aromatic
protons), 5.72 (d, 1H, H1, J = 3.3 Hz), 4.98 (m, 1H, H2),
4.95 (d, 1H, C5–OH, J = 3.5 Hz), 4.91 (d, 1H, C6–OH,
J = 6.2 Hz), 4.06 (ddd, 1H, H5, J = 2.6, 3.0, 3.5 Hz), 3.70
(dd, 1H, H4, J = 2.6, 10.0 Hz), 3.68 (dd, 1H, H70, J = 5.8,
11.6 Hz), 3.61 (dddd, 1H, H6, J = 3.0, 5.8, 6.2, 10.5 Hz),
3.14 (dd, 1H, H3, J = 3.7, 10.7 Hz), 2.86 (dd, 1H, H7,
J = 10.5, 11.6 Hz), 1.41 (s, 3H, CH3proR), 1.21 (s, 3H,
CH3proS); 13C NMR (CDCl3, 75 MHz) d 156.4, 136.0,
128.5, 128.2, 128.1, 112.8, 105.0, 79.0, 76.3, 67.9, 66.4,
66.8, 55.1, 46.4, 26.4, 26.0; HRMS (ESI) calcd for
C18H23NO7Na [M+Na]+ 388.1372, found 388.1387. Spec-
128.3, 128.0, 127.7, 111.9, 103.7, 85.1, 77.9, 67.6, 66.2,
64.2, 58.5, 44.0, 26.7, 26.2; HRMS (ESI) calcd for
C18H23NO7 [M+1]+ 366.155, found 366.1562.
16. Mio, S. M. Tetrahedron 1991, 47, 2133–2144.
27
1
17. Spectral data of 1: ½aꢁD ꢀ29.6 (c 0.24, MeOH); H NMR
(500 MHz, D2O): d 4.08 (t, 1H, H5, J = 2.8 Hz), 3.90
(ddd, 1H, H6, J = 2.8, 5.0, 11.5 Hz), 3.85 (dd, 1H, H2,
J = 3.3, 12.6 Hz), 3.77 (dd, 1H, H20, J = 5.5, 12.6 Hz),
3.73 (dd, 1H, H4, J = 2.8, 10.4 Hz), 3.23 (ddd, 1H, H3,
J = 3.3, 5.5, 10.4 Hz), 3.17 (dd, 1H, H7, J = 5.0, 12.1 Hz),
3.03 (dd, 1H, H70, J = 11.5, 12.1 Hz); 13C NMR (D2O,
100 MHz) d 69.0, 67.6, 63.0, 59.4, 55.9, 42.8; HRMS (ESI)
calcd for C6H13NO4 [M+1]+ 164.0922, found 164.0924.
27
27
tral data of 4: ½aꢁD ꢀ39.7 (c 1.1, CHCl3); 1H NMR
18. Spectral data of 2: ½aꢁD ꢀ13.07 (c 0.5, H2O); 1H NMR
(500 MHz, DMSO-d6): d 7.41–7.30 (m, 5H, aromatic
protons), 5.76 (d, 1H, H1, J = 3.8 Hz), 5.13 (m, 1H, C5–
OH), 4.83 (d, 1H, C6–OH, J = 5.0 Hz), 4.76 (d, 1H, H2,
J = 3.8 Hz), 4.25 (dd, 1H, H4, J = 4.0, 5.4 Hz), 3.99 (d,
1H, H3, J = 5.4 Hz), 3.76 (m, 1H, H6), 3.74 (m, 1H, H5),
3.40 (dd, 1H, H70, J = 7.5, 12.5 Hz), 3.25 (dd, 1H, H7,
J = 3.8, 12.5 Hz), 1.41 (s, 3H, CH3proR), 1.24 (s, 3H,
CH3proS); 13C NMR (CDCl3, 75 MHz) d 157, 136, 128.4,
(500 MHz, D2O): d 4.29 (ddd, 1H, H6, J = 3.0, 5.0,
11.4 Hz), 4.16 (dd, 1H, H4, J = 2.0, 4.6 Hz), 4.09 (dd, 1H,
H5, J = 3.0, 4.6 Hz), 3.94 (dd, 1H, H2, J = 4.7, 12.3 Hz),
3.85 (dd, 1H, H20, J = 9.0, 12.3 Hz), 3.58 (ddd, 1H, H3,
J = 2.0, 4.8, 9.0 Hz), 3.35 (dd, 1H, H7, J = 5.0, 12.0 Hz),
3.17 (dd, 1H, H70, J = 11.4, 12.0 Hz); 13C NMR (D2O,
150 MHz) d 70.4, 65.1, 63.2, 58.2, 53.3, 42.7; HRMS (ESI)
calcd for C6H13NO4 [M+1]+ 164.0920, found 164.0926.