A short and efficient synthesis of 1,5-dideoxy-1,5-imino-D-galactitol (1-deoxy-D-galactostatin) and 1,5-dideoxy-1,5-imino-L-altritol (1-deoxy-L- altrostatin) from D-galactose

Article abstract of DOI:10.1055/s-1999-3158

A short and efficient route is described for the synthesis of 1-deoxy- D-galactostatin and 1-deoxy-L-altrostatin starting from D-galactose.

Full text of DOI:10.1055/s-1999-3158

LETTER
593
A Short and Efficient Synthesis of 1,5-Dideoxy-1,5-imino-D-galactitol (1-
deoxy-D-Galactostatin) and 1,5-Dideoxy-1,5-imino-L-altritol (1-deoxy-L-
Altrostatin) from D-Galactose
Clara Uriel, Francisco Santoyo-González*
Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
Fax: +34-958-243186; E-mail: fsantoyo@goliat.ugr.es
Received 16 February 1999
(+)-Galactostatin (also named galacto-nojirimicin or 1,5-
imino-D-galactitol) is a natural product isolated14 from the
culture broth of Streptomyces lydicus PA-5725 and it has
been reported to be a potent and specific inhibitor of sev-
eral a- and b-galactosidases. Its reduced product, 1-
deoxy-D-galactostatin (1,5-dideoxy-1,5-imino-D-galacti-
Abstract: A short and efficient route is described for the synthesis
of 1-deoxy-D-galactostatin and 1-deoxy-L-altrostatin starting from
D-galactose.
Key words: galactostatin, altrostatin, azasugars, galactose, trifla-
tion
tol) is also a strong galactosidase inhibitor14-17
.
Different strategies have been described for the synthesis
of (+)-galactostatin using D-glucose15, L-tartaric acid18, L-
serine19, D-serine20, L-quebrachitol21 and (+)-diethyl
tartrate22 as starting materials. On the other hand, the first
reported synthesis of (+)-deoxygalactostatin started from
1,6-anhydro-a-D-galactofuranose23. In addition, it has
also been synthesised from D-glucose15, L-tartaric acid18,
L-quebrachitol21, benzene24, L-arabino-hexos-5-ulose25,
5-azido-1,4-lactones26, methyl a-D-galactopyranose16,
Polyhydroxypiperidines (also called azasugars, amino
sugars or imino alditols) are sugar analogues in which an
NH group replaces the oxygen ring. They have become in-
creasingly important targets since they have been shown
to possess potent glycosidase inhibitory activity1-7 and
thus have the potential of becoming useful agents for the
treatment of several diseases8-13 such as cancer, viral in-
fections (HIV), inflammation or disorders related to car-
bohydrate metabolism (diabetes). There is, in fact,
considerable efforts in either chemical or enzymatic syn-
thetic procedures to synthesise natural azasugars and their
unnatural analogues.
deoxynojirimicin27,
tetrazole28 and by enzymatic synthesis29.
N-acetylglucosamine-derived
Synlett 1999, No. 5, 593–595 ISSN 0936-5214 © Thieme Stuttgart · New York

594
C. Uriel, F. Santoyo-González
LETTER
(10) Robinson, K. M.; Begovic, M. E.; Rhinehart, B. L.; Heineke,
E. W.; Ducep, J. B.; Kastner, P. R.; Marshall, F. N.; Danzin,
C. Diabetes 1991, Vol 40, 825.
(11) Kajimoto, T.; Liu, K. K.; Pederson, R. L.; Zhong, Z. Y.;
Ichikawa, Y.; Porco, J. A.; Wong, C.-H. J. Am. Chem. Soc.
1991, 113, 6187.
This paper reports the synthesis of 1-deoxy-galactostatin
7 and its L-altro analogue 10 from D-galactose in seven
and five steps, respectively, with good overall yields. We
envisaged the synthesis of these azasugars from the partly
protected galactofuranoside derivative 1, that is easily ob-
tained in one step from D-galactose following the method-
ology previously described by us30, by reaction with N-
pìvaloyl imidazole. Compound 1, having the hydroxyl
group at C-5 unprotected, allows easy access to the 5-azi-
do-5-deoxy-D-galacto and L-altro derivatives.
(12) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res.
1993, 26, 182.
(13) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 11, 135.
(14) Miyake, Y.; Ebata, M. Agric. Biol. Chem. 1988, 52, 153.
(15) Legler, G.; Pohl, S., Carbohyd. Res. 1986, 115, 119.
(16) Bernotas, R. C.; Pezzone, M. A.; Ganem, B. Carbohyd. Res.
1987, 167, 305.
(17) Miyake, Y.; Ebata, M. Agric. Biol. Chem. 1988, 52, 1649.
(18) Aoyagi, S.; Fujimaki, S.; Yamazaki, N.; Kibayashi, C. J. Org.
Chem. 1991, 56, 815.
(19) Dondoni, A.; Merino, P.; Perrone, D. J. Chem. Soc.,Chem.
Commun. 1991, 1576.
(20) Dondoni, A.; Perrone, D. J. Org. Chem. 1995, 60, 4749.
(21) Chida, N.; Tanikawa, T.; Tobe, T.; Ogawa, S. J. Chem. Soc.,
Chem. Commun. 1994, 1247.
For the synthesis of 1-deoxy-L-altrostatin 10 we have fol-
lowed the route summarised in Scheme 1. Triflation of the
free 5-OH group of compound 1 gave 231 in quantitative
yield. Subsequent treatment with sodium azide in DMF
led to the 5-azido-L-altrofuranose derivative 832 in 85%
yield. Removal of the pivaloyl groups from 8 was accom-
plished by using NaOMe in MeOH (Zémplen conditions)
affording 5-azido-5-deoxy-L-altrofuranose 933 in 90%
yield34. Catalytic hydrogenation of this compound in the
presence of palladium black in methanol gave the piperi-
dine derivative 1035 in quantitative yield.
(22) Kirihata, M.; Nakao, Y.; Mori, M.,Ichimoto, I. Heterocycles
1995, 41, 2271.
(23) Paulsen, H.; Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980,
113, 2601.
For the synthesis of the potent inhibitor 1-deoxy-D-galac-
tostatin 7 a similar approach to that described above could
be used but a previous inversion of the configuration at C-
5 in 1 is needed. This inversion was achieved by treatment
of the triflate derivative 2 with sodium nitrite in DMF af-
fording the L-altro derivative 336 in 55% yield from 1.
Compound 437 was obtained in quantitative yield by reac-
tion of 3 with triflic anhydride-pyridine. Treatment of 4
with sodium azide in DMF gave the 5-azido-5-deoxy-D-
galactofuranose derivative 538 in 75% yield. De-O-piv-
aloylation of this compound using NaOMe in MeOH gave
639 (97%) which was hydrogenated under the same condi-
tions as used for 8 leading to the expected 1-deoxy-D-ga-
lactostatin 740 being isolated as a hygroscopic solid in
quantitative yield.
(24) Johnson, C. R.; Golebiowski, A.; Sundram, H.; Miller, M. W.;
Dwaihy, R. L. Tetrahedron Lett. 1995, 36, 653.
(25) Barili, P. L.; Berti, G.; Catelani, G.; D'Andrea, F.; De Rensis,
F.; Puccioni, L. Tetrahedron 1997, 3407.
(26) Shilvock, J. P.; Fleet, G. W. J. Synlett 1998, 554.
(27) Takahashi, S.; Kuzuhara, H. J. Carbohyd. Chem. 1998, 17,
117.
(28) Heightman, T. D.; Ermert, P.; Klein, D.; Vasella, A. Helv.
Chim. Acta 1995, 78, 514.
(29) Lees, W. J.; Whitesides, G. M. Bioorg. Chem. 1992, 20, 173.
(30) Santoyo-González, F.; Uriel, C.; Calvo-Asín, J. A. Synthesis
1998, 1787.
(31) Trific anhydride (0.41 ml, 2.48 mmol) in anhydrous CH2Cl2 (5
ml) was added to a solution of pyridine (1.25 ml, 15.5 mmol)
in anhydrous CH2Cl2 and the solution was stirred under N2 at
15ºC. After 15 min., a solution of 1 (1.63 gr, 3.1 mmol) in
anhydrous CH2Cl2 was added, and stirring was continued for
45 min., the temperature being allowed to rise gradually to
0ºC. After this time, TLC (hexane-AcOEt, 7:3) showed
complete disappearance of the starting material. CH2Cl2 (100
ml) was added and the solution washed successively with 5%
HCl solution (100 ml), aq satd NaHCO3 solution (100 ml) and
H2O (50 ml). The organic phase was dried (Na2SO4) and
evaporated to give 2 that could be used without purification
for the next step.1H NMR (CDCl3, 300 MHz): d 1.18, 1.20,
1.22, 1.24 (4 s, 36H, 4 C(CH3)3), 4.11 (dd, 1H, J = 13.1 and
J = 6.6 Hz, H-6), 4.30 (t, 1 H, J = 7.2 Hz, H-4), 4.53 (dd, 1 H,
J = 13.1 and 2.8 Hz, H-6'), 5.14 (m, 1 H, H-5), 5.46 (dd, 1 H,
J = 7.2 and 4.3 Hz, H-2), 5.55 (t, 1 H, J = 7.2 Hz, H-3), 6.40
(d, 1 H, J = 4.3 Hz, H-1)
Acknowledgement
We thank the Comisión Asesora de Investigación Científica y Téc-
nica for financial support (Proyect nº PB97/1207).
References and Notes
(1) Legler, G., Adv. Carbohydr. Chem. Biochem. 1990, 48, 3.
(2) Sears, P.; Wong, C.-H. Chem. Commun. 1998, 1161.
(3) Sinnott, M. L. Chem. Rev. 1990, 90, 1171.
(4) Bols, M. Acc. Chem. Res. 1998, 31, 1.
(5) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. Rev.
1996, 96, 443.
(6) Martin, O. R. In Carbohydrate Mimics; Concepts and
Methods; Chapleur, Y.,Ed.; Wiley-VCH: Weinheim, 1998; p
259.
(7) Depezay, J. C. In Carbohydrate Mimics; Concepts and
Methods; Chapleur, Y.,Ed.; Wiley-VCH: Weinheim, 1998; p
307.
(8) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497.
(9) Reitz, A. B.; Baxter, E. W. Tetrahedron Lett. 1990, 31, 6777.
(32) Compound 2 (2.5 g, 3.86 mmol) was dissolved in anhydrous
DMF (50 ml) and then NaN3 (1.75 g, 27 mmol) was added.
After 2h the solution was diluted with Et2O (150 ml) and
toluene (50 ml) and washed with water (150 ml). The aqueous
layer was extracted three times with Et2O-toluene (150:50
ml). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The resulting crude product was
purified by column chromatography using hexane-ether, 9:1
to give 8 (1.77 g, 85%); mp 62-64 ºC; [a]D+21º (c 0.13,
chloroform). 1H NMR(CDCl3, 300 MHz): d 1.14, 1.16, 1.18,
1.20 (4 s, 36 H, 4C(CH3)3), 3.74 (dt, 1 H, J = 7.6 and 3.2 Hz,
H-5), 3.99 (t, 1 H, J = 7.4 Hz, H-4), 4.03 (dd, 1 H, J = 11.7 and
Synlett 1999, No. 5, 593–595 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Short and Efficient Synthesis of 1,5-Dideoxy-1,5-imino-D-galactitol
595
7.6 Hz, H-6), 4.29 (dd, 1 H, J = 11.7 and 3.2 Hz, H-6’), 5.33
J = 4.6 Hz, H-1). 13C NMR(CDCl3, 300 MHz): d 26.9, 27.0,
27.2 (C(CH3)3), 38.7, 38.8, 38.9 (C(CH3)3), 64.6 (C-6), 71.4,
75.4, 75.6, 81.0 (C-2,3,4,5), 93.5 (C-1), 176.3, 177.1, 178.3,
178.6 (4 CO). HRMS (FAB): m/z calcd for C26H44O10Na:
539.2832, found: 539.2830
(dd, 1 H, J = 7.3 and 4.7 Hz, H-2), 5.63 (t, 1 H, J = 7.3 Hz, H-
3), 6.29 (d, 1 H, J = 4.7 Hz, H-1). 13C NMR(CDCl3, 300
MHz): d 26.8, 26.9, 27.0, 27.1 (4 C(CH3)3), 62.8 (C-5), 63.6
(C-6), 74.4, 75.2, 78.6 (C-2, 3, 4), 93.7 (C-1), 176.4, 176.9,
177.0, 177.7 (4 CO). Anal. Calcd. for C26H43N3O9: C, 57.64;
H, 8.01. Found: C, 57.88; H, 8.27.
(37) Triflation of 3 under the same conditions as described for 1
gave 4 wich was used in the next step without purification. 1H
NMR(CDCl3, 300 MHz):1.19, 1.20, 1.24, 1.27 (s, 36 H,
4C(CH3)3), 4.26 (dd, 1 H, J = 13.2 and 6.6 Hz, H-6), 4.34 (t, 1
H, J = 7.2 Hz, H-4), 4.56 (dd, 1 H, J = 2.3 Hz, H-6), 5.23 (m,
1 H, H-5), 5.44 (dd, 1 H, J = 7.2 and 4.4 Hz, H-2), 5.54 (t, 1
H, J = 7.2 Hz, H-3), 6.38 (d, 1 H, J = 4.4 Hz, H-1)
(38) Compound 4 (650 mg, 1 mmol) was treated with NaN3 (455
mg, 7 mmol) in anhydrous DMF as described for 8 to give 5
(406 mg, 75% from 1); mp 101-102ºC; [a]D+24º (c 0.1,
chloroform); IR: nmax (Nujol) 2098 cm-1. 1H NMR(CDCl3, 300
MHz): d 1.19, 1.20, 1.22, 1.25, (s, 36 H, 4 C(CH3)3), 3.81
(ddd, 1 H, J = 7.8, 4.7 and 4.1 Hz, H-5), 4.03 (dd, 1 H, J = 6.7
and 4.7 Hz, H-4), 4.15 (dd, 1 H, J = 11.7 and 7.8 Hz, H-6'),
4.31 (dd, 1 H, J = 11.7 and 4.1 Hz, H-6), 5.40 (dd, 1 H, J = 7.9
and 4.6 Hz, H-2), 5.59 (m, 1 H, H-3), 6.32 (d, 1 H, J = 4.6 Hz,
H-1). 13C NMR(CDCl3, 300 MHz): d 27.0, 27.1, 27.1 (4
C(CH3)3), 38.9, 41.7 (4 C(CH3)3), 61.6 (C-5), 63.4 (C-6), 74.1,
74.6, 79.8 (C-2,3,4), 93.0 (C-1), 172.2, 177.8 (4 CO). Anal.
Calcd. for C26H43N3O9: C, 57.64; H, 8.01; N, 7.76. Found: C,
57.41; H, 8.39; N, 7.52.
(39) Compound 5 (325 mg, 0.6 mmol) was de-O-pivaloylated as
described for 9. The crude product was purified by column
chromatography (CH2Cl2-MeOH, 4:1) to give 6 (119 mg,
97%). IR: nmax (Nujol) 2118 cm-1; 1H NMR(300 MHz, D2O)
selected signals: d 5.24 (d, 1 H, J = 3.1 Hz, H-1), 5.30 (d, 1 H,
J = 4.6 Hz, H-1);13C NMR (300 MHz, D2O): d 62.4, 63.0 (C-
6), 65.1, 66.7, 76.6, 77.6, 78.1, 81.5, 82.8, 82.9 (C-2,3,4,5),
96.8, 102.5 (C-1)
(40) A solution of 6 (185 mg, 0.9 mmol) was hydrogenated as
described for 10 to give 7 as a hygroscopic solid (quantitative
yield). [a]D+61.3º (c 0.4, H2O); (lit18[a]D+52.6º (c 1.3, H2O);
lit21[a]D+52º (c 0.4, H2O); lit24[a]D+53.7º (H2O); lit25
[a]D+40.5º (c 1.5, H2O); 1H NMR(300 MHz, D2O): d 2.39 (dd,
1 H, J = 12.6 and 10.8 Hz, H-1), 2.77 (dt, 1 H, J = 6.7 and 1.4
Hz, H-5), 3.13 (dd, 1 H, J = 12.6 and 5.3 Hz, H-1'), 3.47 (dd,
1 H, J = 9.7 and 3.2 Hz, H-3), 3.59 (dd, 1 H, J = 11.2 and 6.7
Hz, H-6), 3.64 (dd, 1 H, J = 6.7 and 1.2 Hz, H-6'), 3.75 (ddd,
1 H, J = 10.8, 9.7 and 5.3 Hz, H-2), 3.99 (dd, 1 H, J = 3.2 and
1.4 Hz, H-4); 13C NMR(300 MHz, D2O): 49.1 (C-1), 61.5 (C-
6), 59.2, 68.2, 69.3, 75.2 (C-2,3,4,5).
(33) A solution of 8 (800 mg, 1.48 mmol) in 0.1M NaOMe in
MeOH (10 ml) was stirred for 12h at room temperature. The
solution was diluted with MeOH, neutralised with Amberlite
IR-120 (H+) filtered and evaporated. The crude was purified
by column chromatography (CH2Cl2-MeOH, 9:1) to give 9
(272 mg, 90%) isolated as a syrup.1H NMR (D2O, 300 MHz)
selected signals: d 5.26 (d, 1 H, J = 2.6 Hz, H-1), 5.28 (d, 1 H,
J = 4.7 Hz, H-1).13C NMR (D2O, 300 MHz): d 63.4 (C-6),
66.9, 67.9, 77.4, 78.7, 82.0, 83.9, 84.5 (C-2,3,4,5), 97.9, 103.6
(C-1).
(34) When the reaction time and/or the amount of sodium
methoxide are increased, a minor product appears (<10%),
that tentatively was assigned as 5-azide-5-deoxy-a,b-L-
arabino-2-hexo-2-ulopyranose as a result of a Lobry de
Bruyn-Van Ekenstein rearrangement. 1H NMR(D2O, 300
MHz) (selected signals): d 3.50 (d, 1 H, J = 10.4 Hz, H-6),
3.71 (d, 1 H, J = 11.7 Hz, H-1'), 3.60 (t, 1 H, J = 10.4 Hz, H-
6), 3.92 (dd, 1 H, J = 9.6 and 3.3 Hz, H-4); 13C NMR(D2O,
300 MHz): d 59.9 (C-5), 62.0, 65.4 (C-1, 6), 70.9, 71.5 (C-
3,4), 99.8 (C-2).
(35) A solution of 9 (220 mg, 1.07 mmol) in MeOH (5 ml) and Pd/
C (180 mg), was hydrogenated for 12 h at 25ºC and 50-80 bar.
The catalyst was removed by filtering over Celite and
evaporated to give 10 (100%) as a hygroscopic solid. [a]D -
7.0º (c 0.4, methanol); lit25 [a]D -6.8º (c 0.9, methanol). 1H
NMR(D2O, 300 MHz): d 2.91 (d, 1 H, J = 13.0 Hz, H-1), 2.99
(m, 1 H, H-5), 3.08 (dd, 1 H, J = 13.0 and 1.4 Hz, H-1’), 3.87
(dd, 1 H, J = 9.8 and 2.3 Hz), 3.79, 3.96 (m, 4 H, H-2, 4, 6, 6’);
13C NMR(D2O, 300 MHz): d 44.6 (C-1), 55.9 (C-5), 60.2 (C-
6), 65.5 (C-4), 68.6 (C-2), 70.2 (C-3).
(36) Compound 2 was obtained from 1 (3.1 mmol) and used
directly without purification. It was dissolved in anhydrous
DMF (8 ml) and then NaNO2 (1 g, 15 mmol) was added. After
18h the reaction mixture was diluted with Et2O (75 ml) and
toluene (25 ml) and then washed with a saturated solution of
NaHCO3 (50 ml) and water (50 ml). The organic layer was
dried (Na2SO4) and concentrated. The resulting crude product
was purified by column chromatography (Et2O-hexane, 3:1)
to give 3 (880 mg, 55% yield from 1) isolated as a white solid;
mp 117 ºC; [a]D+33º (c 1, chloroform). 1H NMR(CDCl3, 300
MHz): d 1.18, 1.20, 1.21, 1.22 (s, 36 H, 4 C(CH3)3), 4.00, 4.09,
4.27 (m, 4 H, H-4, 5, 6, 6'), 5.43 (dd, 1 H, J = 7.2 and 4.6 Hz,
H-2), 5.59 (dd, 1 H, J = 7.2 and 4.6 Hz, H-3), 6.37 (d, 1 H,
Article Identifier:
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Synlett 1999, No. 5, 593–595 ISSN 0936-5214 © Thieme Stuttgart · New York