A General Synthesis of Iminosugars

Article abstract of DOI:10.1021/jo035763u

1-Deoxynojirimycin, 1-deoxymannojirimycin, and 1-deoxygalactostatin have been synthesized by epoxidation of tri-O-acetyl-6-deoxyhex-5-enopyranosyl azides followed by methanolysis, deacetylation, and catalytic hydrogenation. 1,6-Dideoxygalactostatin was obtained by the reaction of 2,3,4-tri-O-acetyl-6-deoxy-β-L-arabino-hex-5-enopyranosyl azide with NIS in methanol followed by deacetylation and catalytic hydrogenation. The overall yields were 4.4-23.5% over seven to nine steps.

Full text of DOI:10.1021/jo035763u

of synthetic routes to azasugars published to date.7
Herein, we describe a general approach for the synthesis
of 1-deoxyazasugars.8 More specifically, the synthesis of
1-deoxynojirimycin 1, 1-deoxymannojirimycin 2,9 1-deoxy-
galactostatin 3, and 1,6-dideoxygalactostatin 410 has been
achieved from the corresponding 6-deoxyhex-5-enopy-
ranosyl azide.11
A Gen er a l Syn th esis of Im in osu ga r s
Ciaran McDonnell, Linda Cronin, J ulie L. O’Brien, and
Paul V. Murphy*
Centre for Synthesis and Chemical Biology, Chemistry
Department, Conway Institute of Biomolecular and
Biomedical Research, University College Dublin,
Belfield, Dublin 4, Ireland
paul.v.murphy@ucd.ie
Received December 2, 2003
Retr osyn th etic An alysis. We have studied the prepa-
ration and reactions of epoxides derived from 6-deoxyhex-
Abstr a ct: 1-Deoxynojirimycin, 1-deoxymannojirimycin, and
1-deoxygalactostatin have been synthesized by epoxidation
of tri-O-acetyl-6-deoxyhex-5-enopyranosyl azides followed by
methanolysis, deacetylation, and catalytic hydrogenation.
1,6-Dideoxygalactostatin was obtained by the reaction of
2,3,4-tri-O-acetyl-6-deoxy-â-L-arabino-hex-5-enopyranosyl
azide with NIS in methanol followed by deacetylation and
catalytic hydrogenation. The overall yields were 4.4-23.5%
over seven to nine steps.
(6) Asano, N.; Nishida, M.; Kato, A.; Kizu, H.; Matsui, K.; Shimida,
Y.; Itoh, T.; Baba, M.; Watson, A. A.; Nash, R. J .; de Q. Lilley, P. M.;
Watkin, D. J .; Fleet, G. W. J . J . Med. Chem. 1998, 41, 2565.
(7) For selected reviews on synthesis of glycosidase inhibitors, see:
(a) Tatsuta, K. In Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-
VCH: Weinheim, 1998; pp 283-305. (b) Fechter, M. H.; Stu¨tz, A. E.;
Tauss, A. Curr. Org. Chem. 1999, 3, 269.
(8) For general approaches to iminosugars, see: (a) Kajimoto, T.;
Chen, L. R.; Liu, K. K. C.; Wong, C. H. J . Am. Chem. Soc. 1991, 113,
6678. (b) LeMerrer, Y.; Poitout, L.; Depezay, J . C.; Dosbaa, I.; Geoffroy,
S.; Foglietti, M. J . Bioorg. Med. Chem. 1997, 5, 519. (c) Singh, O. V.;
Han, H. Tetrahedron Lett. 2003, 44, 2387. (d) Baxter, E. W.; Reitz, A.
B. J . Org. Chem. 1994, 59, 3175.
The iminosugars (“azasugars”) are a family of polyhy-
droxylated heterocycles containing an endocyclic nitrogen
atom, and some are naturally occurring. 1-Deoxynojiri-
mycin 1 is an example of a naturally occurring azasugar,1
and derivatives have found clinical application.2 In
general, these compounds are among the most promising
lead compounds for treatment of HIV infection, hepatitis
C virus infection, diabetes, and other metabolic dis-
orders.3 The substitution of the ring oxygen of the
corresponding pyranose with the nitrogen renders the
azasugar metabolically inert but does not prevent their
recognition by glycosidases4 and glycosyltransferases,5
and they can therefore inhibit glycoprocessing. The
carbohydrate mimicry displayed by azasugars has re-
sulted in their use as tools in the investigation of
glycoprotein maturation and in the study of certain
biochemical pathways. The mechanism of inhibition of
glycosidases displayed by these derivatives is due to their
binding in the enzyme active site. The azasugars are
charged at physiological pH, and the interaction of the
charged nitrogen with carboxylates involved in catalysis
is important. There is evidence that the anti HIV-1
activity displayed by some of these molecules may be due
to inhibition by the azasugars at novel and as yet
undetermined sites of action.6 There have been a number
(9) For previous syntheses of 1 and/or 2, see refs 3 and 7 and: (a)
Rudge, A. J .; Collins, I.; Holmes, A. B.; Baker. R. R. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 3, 2320. (b) Schaller, C.; Vogel, P.; J a¨ger, V.
Carbohydr. Res. 1998, 314, 25. (c) J ohnson, C. R.; Nerurkar, B. M.;
Golebiowski, A. Sundram, H.; Esker, J . L. J . Chem. Soc. Chem.
Commun. 1995, 1139. (d) Lindstrom, U. M.; Somfai, P. Tetrahedron
Lett. 1998, 39, 7173. (e) Comins, D. L.; Fulp, A. B.; Tetrahedron Lett.
2001, 42, 6839. (f) Matos, C. R. R.; Lopes, R. S. C.; Lopes, C. C.
Synthesis 1999, 571. (g) Kajimoto, T.; Liu, K. K. C.; Pederson, R. L.;
Zhong, Z. Y.; Ichikawa, Y.; Porco, J . A.; Wong, C. H. J . Am. Chem.
Soc. 1991, 113, 6187. (h) Cook, G. R.; Beholz, L. G.; Stille, J . R. J .
Org. Chem. 1994, 59, 9, 3575. (i) Xu, Y.-M.; Zhou, W.-S. J . Chem. Soc.,
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Lett. 2001, 3, 401. (k) J ohnson, C. R.; Golebiowski, A.; Schoffers, E.;
Sundram, H.; Braun, M. P. Synlett, 1995, 313. (l) Furneaux, R. H.;
Tyler, P. C.; Whitehouse, L. A. Tetrahedron Lett. 1993, 34, 3613. (m)
Zhous, P. Z.; Salleh, H. M.; Chan, P. C. M.; Lajoie, G.; Honek, J . F.;
Nambiar, P. T. C.; Ward, O. P. Carbohydr. Res. 1993, 239, 155. (n)
Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.; Yamaguchi,
S.; Hirai, Y. Org. Lett. 2000, 2, 2427. (o) Mart´ın, R.; Moyano, A.;
Pericas, Riera, A. Org. Lett. 2000, 2, 93. (p) Knight, J . G.; Tchabanenko,
K.; Tetrahedron 2003, 59, 281. (q) Meyers, A. I.; Andres, C. J .; Resek,
J . E.; Woodall, C. C.; McLaughlin M. A.; Lee, P. H.; Price, D. A.
Tetrahedron 1999, 55, 8931. (r) Spreitz, J .; Stutz, A. E.; Wrodnigg, T.
M. Carbohydr. Res. 2002, 337, 183. (s) Straub, A.; Effenberger, F.;
Fischer, P. J . Org. Chem. 1990, 55, 3929.
(10) For previous syntheses of 3 and/or 4, see: (a) Paulsen, H.;
Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2001. (b) Lees, W.
J .; Whitesides, G. M.; Bioorg. Chem. 1992, 20, 173. (c) Kajimoto, T.;
Chen, L.; Liu, K. C.; Wong, C. H. J . Am. Chem. Soc. 1991, 113, 6678.
(d) Liu, K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong,
C. H. J . Org. Chem. 1991, 56, 6280. (d) Aoyagi, S.; Fujimaki, S.;
Yamazaki, N.; Kibayashi, C. J . Org. Chem. 1991, 56, 815. (e) Furneaux,
R. H.; Tyler, P. C.; Whitehouse, L. A., Tetrahedron. Lett. 1993, 34, 22,
3609. (f) Asano, K.; Hakogi, T.; Iwama, S.; Katsumura, S., Chem.
Commun. 1999, 1, 41. (g) Uriel, C.; Santayo-Gonzalez, F. Synlett 1999,
5, 593. (h) Ruiz, M.; Ruanova, T. M.; Ojea, V.; Quintela, J . M.
Tetrahedron. Lett. 1990, 40, 2021. (j) Barilli, P. L.; Berti, G.; Catelani,
G.; D’Andrea, F.; De Rensis, F.; Puccioni, L. Tetrahedron 1997, 53,
3407. (k) Chida, N.; Tanikawa, T.; Tobe, T. Ogawa, S. J . Chem. Soc.,
Chem. Commun. 1994, 1247. (l) Shivlock, J . P.; Fleet, G. W. J . Synlett
1998, 554. Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron
2000, 56, 5819. (m) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.
Org. Lett. 2003, 5, 2527. (n) Defoin, A. Sarazin, H.; Streith, J . Synlett
1995, 1187. (o) Defoin, A.; Sarazin, H.; Streith, J . Tetrahedron 1997,
53, 13783.
(1) Asano, N.; Nash R. J .; Molyneaux, R. J .; Fleet, G. W. J .
Tetrahedron: Asymmetry 2000, 11, 1645.
(2) Kingma, P. J .; Menheere, P. P.; Sels, J . A.; Nieuwenhuijzen
Kruseman, A. C. Diabetes Care 1992, 15, 478.
(3) (a) Hughes, A. B.; Rudge, A. J . Nat. Prod. Rep. 1994, 135. (b)
Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199.
(4) For reviews on glycosidase inhibition see refs 1 and 3 and: (a)
Ganem, B. Acc. Chem. Res. 1996, 29, 340. (b) Heightman, T. D.; Vasella
A. T. Angew. Chem., Int. Ed. 1999, 38, 750. (c) Lillelund V. H.; J ensen,
H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515. (d) Greimel, P.;
Spreitz, J .; Stutz, A. E.; Wrodnigg, T. M. Curr. Topics. Med. Chem.
2003, 3, 513.
(5) For a recent review on iminosugar based glycosyltransferase
inhibitors, see: Compain, P.; Martin, O. R. Curr. Top. Med. Chem.
2003, 3, 541.
(11) A preliminary account of the work described herein has been
published. See: Tosin M.; O’Brien, J .; Murphy, P. V. Org. Lett. 2001,
3, 3353.
10.1021/jo035763u CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/07/2004
J . Org. Chem. 2004, 69, 3565-3568
3565

SCHEME 1. Retr osyn th etic An a lysis
SCHEME 2. Syn th esis of 1 a n d 2
5-enopyranosides (similar to 8) and found they are
hydrolyzed to give 1,5-dicarbonyl sugars.12 Baxter and
Reitz have previously converted such 1,5-dicarbonyl
sugars to azasugars by a double-reductive amination
strategy.4d It seemed reasonable that the imine 6, which
is presumably related to intermediates generated by the
Baxter and Reitz approach, would be generated in situ
by catalytic hydrogenation of 7 and that further reduction
in situ would give 1-deoxyazasugars via the cyclic imine
5 (Scheme 1).13 It was anticipated that 7 would be
accessible from the alkene 8 and its epoxide derivatives.
Syn t h esis of 1-Deoxym a n n ojir im ycin a n d 1-
Deoxyn ojir im ycin . The alkene 10a , required for syn-
thesis of 1-deoxymannojirimycin, was obtained after the
acetolysis of 9a 14 followed by reaction of the product with
azidotrimethylsilane and tin(IV) chloride and subsequent
elimination of hydrogen iodide using DBU.15 A similar
sequence from the corresponding glucopyranoside 9b
gave the alkene 10b. It was possible to isolate in good
yields mixtures of epoxides 11a and 11b16 from reactions
of methyl(trifluoromethyl)dioxirane, generated in situ,17
with 10a and 10b. Prolonged reaction times or attempts
to separate the diastereoisomeric epoxides by chroma-
tography led to the formation and isolation of hexos-5-
uloses 15,12 resulting from the hydrolysis of the epoxide
and subsequent elimination of hydrogen azide. The
reaction of methanol with epoxides 11a gave, with high
stereoselectivity, the intermediate 13; this results from
attack by the nucleophile at C-5 and subsequent migra-
tion of the acetate group from O-4 to O-6 during chro-
matography. The product adopts the 1C4 conformation
SCHEME 3
(12) (a) Enright, P. M.; O’Boyle, K. M.; Murphy, P. V. Org. Lett. 2000,
2, 3929. (b) Enright, P. M.; Tosin, M.; Nieuwenhuyzen, M.; Cronin, L.;
Murphy, P. V. J . Org. Chem. 2002, 67, 3733.
1
(determined by H NMR in CDCl3) placing the electron-
(13) The cyclic imine has been used in synthesis of 1. Paulsen, H.;
Sangster, I.; Heyns, K. Chem. Ber. 1967, 100, 802.
(14) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1980, 2866.
withdrawing methoxy group in an axial orientation,
fitting the anomeric effect, and the hydroxymethyl group
in an equatorial orientation to minimize 1,3-diaxial
interactions. Catalytic hydrogenation (40 psi) of 14,
prepared by removal of acetates from 13, gave 1-deoxy-
mannojirimycin 2 (23% for three steps) (Scheme 2).
A sequence identical to that described for the synthesis
of 2 did not, however, give 1 from 11b. Only 18 (Scheme
3) was obtained when the glucose-derived epoxide 11b
was reacted with methanol. This is a result of nucleo-
philic attack at C-6 to give 16, which is followed by
elimination of hydrogen azide to give 17 and further
reaction with methanol. The acetylation of 18 gave the
acyclic compound 19. The diverging behavior of 11a when
compared to 11b can be explained by a stereoelectronic
(15) The synthesis of 6-deoxyhex-5-enopyranosides by elimination
of halogenated carbohydrates has been introduced. (a) Semeria, D.;
Phillipe, M.; Delaumeny, J .-M.; Sepulchre, A.-M.; Gero, S. D. Synthesis
1983, 710. (b) Sakairi, N.; Kuzuhara, H. Tetrahedron Lett. 1982, 23,
5327. (c) Takeo, K.; Fukatsu, T.; Yasato, T. Carbohydr. Res. 1982, 107,
71. (d) Ferrier, R. J .; Prasit, P. Carbohydr. Res. 1980, 82, 263. (e)
Sugawara, F.; Kuzuhara, H.; Agric. Biol. Chem. 1981, 45, 301. (f)
Defaye, J .; Gadelle, A.; Wong, C. C. Carbohydr. Res. 1981, 94, 131.
(16) A 1.4:1 mixture of epoxides was obtained. The major stereo-
isomer has been assigned the R configuration at C-5 on the basis of
chemical shift and NOE data.
(17) For the in situ generation of the fluorinated dioxirane, see:
Yang, D.; Wong, M.-K.; Yip, Y.-C. J . Org. Chem. 1995, 60, 3887.
Distilled dimethyldioxirane has been used provide epoxides from a
similar alkene in good yields. See: Hartman, M. C. T.; Coward, J . K.
J . Am. Chem. Soc. 2002, 124, 10036.
3566 J . Org. Chem., Vol. 69, No. 10, 2004

SCHEME 4
effect. The reaction to give the product of methanol attack
at C-5 is most likely to proceed via a carbocation/oxonium
ion intermediate, and the rate will depend on the stability
of this intermediate. Bols and co-workers18 have provided
evidence that rates of hydrolysis of glycopyranosides are
dependent on whether the substituents are axial or
equatorial. They suggest that an electronegative group
is more electron withdrawing when it is equatorial;
positive charge formation at the anomeric center during
the hydrolysis reaction is thus destabilized to a greater
degree when there are more equatorial substituents. In
the case of 11a , there are axial groups at C-1 and C-2
whereas for the glucose isomer 11b all substituents (from
C-1 to C-4) have equatorial orientation. Also, the man-
nose isomer has the possibility of stabilization of positive
charge formation at C-5 through participation by the
axial 2-acyl group or through electrostatic interactions
of axial groups. Presumably, carbocation/oxonium ion
formation is therefore slower for 11b than for 11a and
methanolysis proceeds for 11b via faster nucleophilic
attack at C-6. The regioselectivity of the epoxide ring
opening reaction of 11b was altered in the presence of
camphorsulfonic acid, ensuring the efficient generation
of the required carbocation/oxonium ion so that the
desired ketal 12 was obtained. The acetate protecting
groups were removed from 12, and subsequent catalytic
hydrogenation at 500 psi gave 1.19 The overall isolated
yields (over nine steps) were 4.4% for 1 and 10% for 2.
The main reason for depletion of yields was the difficulty
in purifying the final product by chromatography; in our
hands, substantial losses were incurred. The analytical
data for 1 and 2 (hydrochloride salt and amine) agreed
with those of an authentic sample (Sigma) and with
literature data.20
Syn t h esis of 1-Deoxyga la ct ost a t in a n d 1,6-Di-
d eoxyga la ctosta tin . The reactions of alkene 2021 with
methyl(trifluoromethyl)dioxirane, generated in situ, and
with buffered m-CPBA in dichloromethane did not give
mixtures from which the expected epoxide(s) could be
isolated; the epoxidation reactions were slow, and hy-
drolysis of the desired epoxide occurred. Epoxidation with
m-CPBA in methanol as described by Catelani and co-
workers22 gave the desired ketal derivatives 22 after
acetylation in a low yield (26%). Deacetylation of 22 gave
23, and its subsequent hydrogenation at 500 psi gave
1-deoxygalactostatin as the major product in a mixture
with the C-5 epimer 24 (ratio 4:1). The synthesis of 1,6-
dideoxygalactostatin was also achieved from 20; its
reaction with NIS in methanol gave the iodo derivative
21, which was converted to 4 with high stereoselectivity
(97:3)23 after deacetylation and catalytic hydrogenation.
The analytical data for 3 and 4 were identical with
authentic samples and with literature data.24 The iso-
lated yields (seven steps) were 7% for 3 and 24 and 23.5%
for 4. As for the synthesis of 1 and 2 there is room for
further improvement, particularly in the route to 3 where
epoxidation was a problem.
6-Deoxyhex-5-enopyranosyl azides have been used as
intermediates for the synthesis of a range of iminosugars.
The methodology may have future application in areas
such as the synthesis of oligosaccharides that incorporate
a terminal iminosugar residue or for medicinally inter-
esting compounds based on iminosugar scaffolds.25 In
addition the synthesis of the enantiomer of 4, 1-deoxy-
L-fuconojirimycin, which is a potent fucosidase inhibitor
and relevant to the development of cell adhesion inhibi-
tors,26 will be amenable from L-galactose which has been
made available by chemical synthesis.27
Exp er im en ta l Section
2,3,4,6-Tetr a -O-a cetyl-5-C-m eth oxy-â-D-glu cop yr a n osyl
Azid e a n d 2,3,4,6-Tet r a -O-a cet yl-5-C-m et h oxy-r-L-id o-
p yr a n osyl Azid e 12. Epoxide mixture 11b (1.69 g, 4.5 mmol)
was dissolved in MeOH (50 mL), and camphorsulfonic acid (0.51
g, 2.2 mmol) was added. This solution was stirred at room
temperature under nitrogen for 10 min, diluted with CH2Cl2 (50
mL), washed with NaHCO3 (4 × 100 mL) and water (2 × 100
mL), and dried (MgSO4). The solvent was removed, and pyridine
and acetic anhydride (1:1) were added to the residue. The
mixture was stirred for 20 min, and the volatile components were
then removed. Xylene (100 mL) was added and distilled from
the residue in vacuo. The residue was purified by chromatog-
raphy (EtOAc/petroleum ether (3:1) as eluant) to give the title
compounds 12 (major isomer, 0.85 g, 48%; minor isomer 0.27 g,
15%). Analytical data for the major isomer: [R]D -51.8 (c 0.6,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.28 (apparent t, 1H, J )
8.2), 5.18-5.22 (overlapping signals, 2H), 5.14 (d, 1H, J ) 8.4),
4.41 (d, 2H, J ) 12.5), 4.14 (d, 1H, J ) 12.5), 3.44 (s, 3H), 2.04,
2.08 (2s), 2.10 (each s, 12H); 13C NMR (125 MHz, CDCl3) δ 169.8,
169.7, 169.2, 168.6 (each s, each CdO), 100.3 (s, C-5), 85.6, 71.9,
(18) Bols, M.; Liang, X.; J ensen, H. H. J . Org. Chem. 2002, 67, 8970.
(19) Catalytic hydrogenation at 40 psi did not give the desired
product.
(20) See ref 9s and: Fleet, G. W. J .; Ramsden, N. G.; Witty, D. R.
Tetrahedron Lett. 1989, 30, 327.
(21) Gyo¨rgydea´k, Z.; Szilagyi, L. Liebigs Ann. Chem. 1987, 235.
(22) Catelani, G.; Corsaro, A.; D′Andrea, F.; Mariani, M.; Pistara`
V.; Vittorino, E. Carbohydr. Res. 2003, 338, 2349.
(23) The presence of 1,6-dideoxy-L-altronojirimycin in the product
mixture was supported by the presence of a doublet at δ 1.31 in the
1H NMR. See ref 24b.
(25) Chery, F.; Murphy, P. V. Tetrahedron Lett. 2004, 45, 2067.
(26) Simanek, E. E.; McGarvey, G. J .; J ablonski, J . A.; Wong, C.-H.
Wong, Chem. Rev. 1998, 98, 833.
(24) (a) Uriel C.; Santoyo-Gonza´lez, F.; Synlett 1999, 593. (b) Pistia,
G.; Hollingsworth, R. I. Carbohydr. Res. 2000, 328, 467.
(27) Kim, K. S.; Cho, B. H.; Shin, I. Bull. Kor. Chem. Soc. 2002, 23,
1193; Chem. Abstr. 2002, 138, 170409.
J . Org. Chem, Vol. 69, No. 10, 2004 3567

71.0, 70.4 (each d), 60.0 (t, C-6), 49.6 (q, OMe), 20.5 (q, CH3); IR
(KBr) 2900, 2111 (N3), 1754 (CdO), 1378, 1170, 1047 cm-1; CI-
HRMS found 421.1570, required 421.1571 (M + NH4)+. Analyti-
cal data for the minor isomer: [R]D -79.4 (c 0.33, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 5.50 (apparent t, 1H, J ) 9.5), 5.33
(d, 1H, J ) 9.5), 5.06 (apparent t, 1H, J ) 9.5), 4.79 (d, 1H, J )
9.5), 4.30 (d, 1H, J ) 12.0), 4.22 (d, 1H, J ) 12.0), 3.45 (s, 3H),
2.13, 2.10, 2.08, 2.02 (each s, 12H); 13C NMR (125 MHz,
CDCl3): δ 170.3, 170.0, 169.6, 169.5 (each s, each CdO), 99.1
(s, C-5), 83.5, 71.0, 69.9, 69.7 (each d), 61.6 (t, C-6), 49.7, (q,
OMe), 20.8 (2s), 20.7, 20.75 (each q, each CH3); IR (KBr) 2963,
2120 (N3), 1754 (CdO), 1370, 1226, 1041; CI-HRMS found
421.1574, required 421.1571 (M + NH4)+.
1-Deoxyn ojir im ycin 1. The isomers 12 (0.12 g, 0.3 mmol)
were dissolved in MeOH (3 mL), a solution of sodium methoxide
in MeOH (1 mL of 0.1 M) was added, and the mixture was stirred
until the reaction was judged complete by TLC analysis. Am-
berlite IR-120 (H+) ion-exchange resin was added, and stirring
was continued for 10 min. The residue (44 mg, 0.27 mmol) was
dissolved in ethanol (50 mL) and stirred in a high-pressure
reactor (Parr) under an atmosphere of hydrogen at 500 psi in
the presence of Pd(OH)2 (20 mg) for 24 h. The mixture was
filtered and the solvent removed. The residue was dissolved in
MeOH (5 mL), and HCl (1 M in Et2O, 0.44 mL) was added. The
solvent was evaporated and the residue chromatographed (elut-
ing with MeOH-chloroform-triethylamine, 100:100:1), to give
the title compound (11 mg, 19%). The NMR and other analytical
data agreed with those previously reported21 and with those of
an authentic sample (Sigma).
2,3,4,6-Tet r a -O-a cet yl-5-C-m et h oxy-r-L-a lt r op yr a n osyl
Azid e a n d 2,3,4,6-Tetr a -O-a cetyl-5-C-m eth oxy-â-D-ga la cto-
p yr a n osyl Azid e 22. To 20 (0.50 g, 1.61 mmol) in dry MeOH
(5 mL) and dry CH2Cl2 (5 mL) at 0 °C under a N2 atmosphere
was slowly added a solution of m-CPBA (77% purity, 0.772 g,
3.22 mmol) in dry MeOH (5 mL), and the resulting mixture was
allowed to warm to rt and stirred for 16 h. The mixture was
then diluted with CH2Cl2 (50 mL), washed with aq NaHCO3 (4
× 50 mL), dried (MgSO4), and filtered, and solvent was removed
in vacuo. The residue was stirred in acetic anhydride (5 mL),
pyridine (5 mL), and DMAP (cat.) for 2 h. Water (10 mL) was
added, and the product was extracted into EtOAc (3 × 10 mL).
The combined organic portions were dried (MgSO4) and filtered,
and solvent was removed in vacuo. Chromatography (6:1 petro-
leum ether-EtOAc) gave the title compounds (6:1, 0.168 g, 26%)
as a yellow oil. Analytical data for the major isomer: Rf 0.48
(1:1 petroleum ether-EtOAc); [R]D -54.8 (c 0.5 CHCl3); 1H NMR
(300 MHz, CDCl3) δ 5.42-5.46 (overlapping signals, 2H), 5.24
(apt t, 1H, J ) 10.4, 8.9 Hz), 4.73 (d, 1H, J ) 8.9 Hz), 4.29 (br
s, 2H), 3.43 (s, 3H), 2.16, 2.13 2.12, 2.10 (each s, 12H); 13C NMR
(125 MHz, CDCl3) δ 170.0, 169.9, 169.6, 169.6 (each s, each Cd
O), 100.6 (s, C-5), 74.1 (d, C-1), 68.7, 68.1, 67.6 (each d, C-2_4),
57.8 (t, C-6), 49.1 (q, OCH3), 20.8, 20.7 (each q, each CH3); CI-
HRMS found 421.1574 required 421.1571 [M + NH4]+. Analyti-
cal data for the minor isomer: Rf 0.45 (1:1 petroleum ether-
EtOAc); [R]D -17.2 (c 0.5 CHCl3); 1H NMR (300 MHz, CDCl3) δ
5.53 (d, 1H, J ) 3.8 Hz), 5.33 (dd, 1H, J ) 8.0, 3.8 Hz), 5.26 (dd,
1H, J ) 8.0, 5.0 Hz), 5.13 (d, 1H, J ) 5.0 Hz), 4.39 (d, 1H, J )
12.2 Hz), 4.33 (d, 1H, J ) 12.2 Hz), 3.53 (s, 3H, OCH3), 2.21,
2.17, 2.10 (each s, 12H); 13C NMR (125 MHz, CDCl3) δ 170.3,
170.1, 170.1, 169.6 (each s, each CdO), 98.5 (s, C-5), 87.0 (d,
C-1), 69.8, 67.8, 67.3, (each d, C-2_4), 62.0 (t, C-6), 50.6 (q, OCH3),
20.9, 20.8 (each q, each CH3); IR (film) ν 2964, 2114 (N3), 1746
(CdO), 1372, 1226, 1042 cm-1; CI-HRMS found 421.1573,
required 421.1571 [M + NH4]+.
C-5), 86.5 (d, C-1), 69.9, 69.7, 68.5 (each d, C-2_4), 56.6 (t, C-6),
48.2 (q, OCH3); CI-HRMS found 253.1148, required 253.1148
[M + NH4]+. The azide 23 (22 mg, 0.094 mmol) was dissolved in
EtOH (40 mL) and was stirred for 2 days under an atmosphere
of hydrogen at a pressure of 500 psi in the presence of palladium
hydroxide (22 mg). The reaction mixture was filtered through
Celite, and the solvent was removed in vacuo. Chromatography
(1:1 CHCl3-MeOH and 1% aq NH3) gave, as an inseparable
mixture, the title compound and 1-L-deoxyaltronojirimycin 24
(ratio 3/24 ) 4:1, 10.5 mg, 70%). The NMR data for 3 and 24
were in agreement with those reported previously.24a
6-Deoxy-6-iod o-5-C-m eth oxy-â-D-ga la ctop yr a n osyl Azid e
21. To 20 (0.5 g, 1.6 mmol) stirring in dry MeOH (5 mL) under
a N2 atmosphere was added NIS (1.08 g, 4.8 mmol) dissolved in
dry MeOH (5 mL). The reaction was stirred for 2 h, diluted with
CH2Cl2 (50 mL), washed with 10% sodium thiosulfate solution
(2 × 50 mL) and aq NaHCO3 solution (50 mL), dried (MgSO4),
and filtered and the solvent removed in vacuo. Chromatography
(4:1 petroleum ether-EtOAc) gave 2,3,4-tri-O-acetyl-6-deoxy-6-
iodo-5-C-methoxy-â-D-galactopyranosyl and 2,3,4-tri-O-acetyl-6-
deoxy-6-iodo-5-C-methoxy-R-L-altropyranosyl azide (galactose
isomer, 0.52 g, 69%; altrose isomer, 0.11 g, 15%). Analytical data
for the galactose isomer; Rf 0.55 (1:1 petroleum ether-EtOAc):
[R]D -5.9 (c 0.4 CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.50 (d,
1H, J ) 3.4 Hz), 5.33 (dd, 1H, J ) 10.4, 3.4 Hz), 5.09 (apparent
t, 1H, J ) 8.9 Hz), 4.61 (d, 1H, J ) 8.9 Hz), 3.28 (overlapping
signals, 5H), 2.11, 2.01, 1.91 (each s, 9H, each CH3); 13C NMR
(125 MHz, CDCl3) δ 169.8, 169.6, 169.2 (each s, each CdO), 100.7
(s, C-5), 84.9, 69.4, 68.9, 67.7 (each d, C-1-4), 48.3 (q, OCH3),
20.9, 20.8, 20.7 (each q, each CH3), 0.2 (t, C-6); IR (film) υ 2985,
2118 (N3), 1753 (CdO), 1370, 1218 cm-1; CI-HRMS found
489.0486, required 489.0485 [M + NH4]+. Analytical data for
the altrose isomer: Rf 0.53 (1:1 petroleum ether-EtOAc); [R]D
1
-11.4 (c 0.4 CHCl3); H NMR (300 MHz, CDCl3) δ 5.69 (d, 1H,
J ) 3.4 Hz), 5.20-5.23 (overlapping signals, 2H), 4.95 (d, 1H, J
) 6.4 Hz), 3.56 (d, 1H, J ) 11.9 Hz), 3.49 (s, 3H), 3.45 (d, 1H, J
) 11.9 Hz), 2.19, 2.13, 2.07 (each s, 9H); 13C NMR (125 MHz,
CDCl3) δ 170.0, 169.8, 169.4 (each s, each CdO), 97.8 (s, C-5),
85.9 (C-1), 69.1, 68.7, 68.0 (each d, C-2-4), 50.3 (q, OCH3), 20.8,
20.8, 20.7 (each q, each CH3), 3.3 (t, C-6); IR (film) ν 2986, 2115
(N3), 1753 (CdO), 1641, 1371, 1220, 1021 cm-1; CI-HRMS found
489.0483, required 489.0482 [M + NH4]+. Deacetylation of the
galactose isomer (0.36 g, 0.77 mmol) as described for 22 and
purification of the residue by chromatography (6:1 CH2Cl2-
EtOH as eluant) gave 21 as a yellow oil (0.168 g, 93%): Rf 0.22
(3:2 CH2Cl2-EtOAc); [R]D -2.2 (c 0.6 MeOH); 1H NMR (D2O,
300 MHz) δ 4.72 (d, 1H, J ) 8.8 Hz), 4.08 (d, 1H, J ) 3.4 Hz),
3.82 (dd, 1H, J ) 10.0, 3.4 Hz), 3.47-3.53 (overlapping signals,
3H), 3.31 (s, 3H); 13C NMR (D2O, 300 MHz) δ 100.2 (s, C-5),
86.0 (d, C-1), 68.7, 68.5, 68.3 (each d, C-2_4), 46.8 (q, OCH3), 1.1
(t, C-6); IR (film) ν 3421 (O-H), 1363, 1220, 1027 cm-1
;
CI-HRMS found 363.0165, required 363.0166 [M + NH4]+.
1,6-Did eoxy-D-ga la ctosta tin 4. A solution of 21 (26 mg,
0.075 mmol), in EtOH (40 mL) was stirred for 2 days under a
hydrogen atmosphere at 500 psi in the presence of palladium
hydroxide (26 mg). The reaction was filtered through Celite, IR-
67 (weakly basic) ion-exchange resin was added, the solution
was stirred for 10 min and filtered, and the solvent was removed
in vacuo. Chromatography (3:1 CH2Cl2-MeOH) gave the title
compound 4 (8 mg, 73%). The analytical data were agreement
with those of an authentic sample (Sigma) and with data in the
literature.24b
Ack n ow led gm en t. We thank Pfizer Pharmaceuti-
cals Ltd. Ringaskiddy, Co. Cork ,and Enterprise Ireland
for funding (SC/2002/0225).
1-D-Deoxyga la ctosta tin 3. A solution of the major isomer
of 22 (60 mg, 0.15 mmol) was stirred in MeOH containing sodium
methoxide (0.1 M, 5 mL) for 2 h. Solid CO2 was then added, and
the solvent was removed in vacuo. Chromatography (6:1 CH2-
Cl2-EtOH) gave 23 as a yellow oil (30 mg, 86%): Rf 0.84 (3:2
EtOAc-MeOH); [R]D -62.4 (c 0.5 MeOH); 1H NMR (D2O, 300
MHz) δ 4.74 (d, overlapping with HOD, 1H), 3.86 (dd, 1H, J )
10.8, 3.4 Hz), 3.86 (d, 1H, J ) 3.4 Hz), 3.72 (d, 1H, J ) 12.3 Hz,
H-6), 3.66 (d, 1H, J ) 12.3 Hz), 3.48 (apparent t, 1H, J ) 10.8
Hz), 3.31 (s, 3H, OCH3); 13C NMR (D2O, 300 MHz) δ 102.3 (s,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data for all other compounds and 1H
and 13C spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O035763U
3568 J . Org. Chem., Vol. 69, No. 10, 2004