Short and convergent synthesis of (1→3)-C-linked imino disaccharides (aza-C-disaccharides)

Full text of DOI:10.1021/jo981781d

666
J . Org. Chem. 1999, 64, 666-669
We have prepared the first examples of “branched”
Sh or t a n d Con ver gen t Syn th esis of
(1f3)-C-Lin k ed Im in o Disa cch a r id es
(Aza -C-d isa cch a r id es)
disaccharides.4,9 Further examples were reported by
J ohnson and co-workers.5 The current syntheses of
“branched” disaccharide mimetics are rather lengthy,
which limits their development and the search for better
glycosidase inhibitors from among highly diverse candi-
dates. We report here a new approach which condenses
a dideoxyiminoaldose with an isolevoglucosenone-derived
enolate.10 The aldol so obtained can be transformed
readily into C-linked iminodisaccharides in which L-glyc-
ero-1,2,4-trideoxy-1,4-iminotetritol is linked through a
CH(OH) moiety at position C(3) of methyl D-gluco- or
methyl D-galacto-pyranoside.
Yao-Hua Zhu and Pierre Vogel*
Section de chimie, Universite´ de Lausanne,
BCH, CH-1015 Lausanne-Dorigny, Switzerland
Received September 1, 1998
Glycosidases and glycosyltransferases are key enzymes
in the biosynthesis and processing of glycoproteins, which
are molecules involved in recognition (cell-cell, host-
pathogen interactions) and in control of biological mech-
anisms and structures.1 Thus, substances able to inhibit
these enzymes have become potential antibacterial,
antiviral, antimetastatic, antidiabetes, antihyperglyce-
Conjugate addition of benzyl alcohol to isolevoglucose-
none 1 (derived in four steps from D-glucose11) afforded
ketone 2 in 90% yield with high stereoselectivity. The
enolates of ketone 2 did not induce â-elimination at low
temperature, probably because of the rigid bicyclic sys-
tem.10 The dichlorozinc enolate of 2, generated by depro-
tonation with (Me3Si)2NK followed by treatment with
anhydrous ZnCl2, added to aldehyde 3.12 This produced
a single aldol 4 which partially decomposed during
attempts at purification (chromatography on silica gel or
Florisil).13,14 Therefore, the crude aldol 4 was directly
reduced with L-Selectride into the D-galactose derivative
5 (53% based on 2).15 Desilylation of 5 with n-Bu4NF
afforded triol 6 in 96% yield. Debenzylation of 6 gave 7
in 96% yield, which was refluxed in anhydrous methanol
saturated with gaseous HCl, producing a 3:2 mixture of
methyl R- and â-D-galacto-pyranosides 8r and 8â, re-
spectively, in 82% yield.
mic, antiadhesive, or immunostimulatory agents.2,3
A
new class of selective glycosidase inhibitors has emerged
with the C-linked imino disaccharides (aza-C-disaccha-
rides)4,5 which contains not only the steric and charge
information of the glycosyl moiety, which is liberated
during the enzyme-catalyzed hydrolysis, but also that of
the aglycon to which the glycon is attached. The first
example of a C-linked imino disaccharide (1,5-dideoxy-
1,5-imino-D-mannitol linked at C(6) of D-galactose through
a CH2 unit) was prepared by J ohnson and co-workers.6
Other examples of “linear” C-linked imino disaccharides
were obtained by the groups of Martin7 and Van Boom.8
(1) See, e.g.: (a) Schauer, R. Adv. Carbohydr. Chem. Biochem. 1982,
40, 131. (b) Stu¨tz, A. E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1926.
(c) Rademacher, T. W.; Parekh, R. B.; Dwek, R. A. Annu. Rev. Biochem.
1988, 57, 785. (d) Hindsgaul, O.; Khare, D. P.; Bach, M.; Lemieux, R.
U. Can. J . Chem. 1985, 63, 2653. (e) Feizi, T. Carbohydrate Recognition
in Cellular Function, Ciba Geigy Symposium 145; Wiley: Chichester,
1989; p 62. (f) Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985,
54, 631. (g) Moremen, K. W.; Trimble, R. B.; Herscovics, A. Glycobiology
1994, 4, 113. (h) Rice, G. E.; Bevilacqua, M. P. Science 1989, 246, 1303.
(i) Smith, C. A.; Davis, T.; Anderson, D.; Solam, L.; Beckmann, M. P.;
J erzy, R.; Dower, S. K.; Cosman, D.; Goodwin, R. G. Science 1990, 248,
1019. (j) Varki, A. Glycobiology 1993, 3, 97. (k) Dwek, R. A. Chem.
Rev. 1996, 96, 683.
(2) (a) Ganem, B. Acc. Chem. Res. 1996, 29, 340 and references cited
therein. (b) van de Broek, L. A. G. M.; Vermaas, D. J .; Heskamp, B.
M.; van Boeckel, C. A. A.; Tan, M. C. A. A.; Bolscher, J . G. M.; Ploegh,
H. L.; van Kemenade, F. J .; de Goede, R. E. Y.; Miedema, F. Recl. Trav.
Chim. Pays-Bas 1993, 112, 82. (c) Look, G. C.; Fotsch, C. H.; Wong,
C.-H. Acc. Chem. Res. 1993, 26, 182. (d) Winchester, B.; Fleet, G. W.
J . Glycobiology 1992, 2, 199. (e) Zheng, Y.; Pan, Y. T.; Asano, N.; Nash,
R. J .; Elbein, A. D. Glycobiology 1997, 7, 297 and references cited
therein.
Reduction of the crude aldol 4 with Me4NBH(OAc)3,16
on the other hand, formed the D-glucose derivative 9 (59%
based on 2) which was deprotected as above, giving first
10 in 94% yield, then 11 in 93% yield, and finally a 7:3
mixture of methyl R- and â-D-gluco-pyranosides 12r and
12â, respectively, in 90% yield.
The structures of the new compounds were given by
their mode of formation and their spectral data. Further
proof was given by the vicinal coupling constants and the
NOE’s (Figure 1) measured in the 1H NMR spectra of
acetonides 13 and 14 derived from diols 5 and 9,
respectively, under standard conditions (Me2C(OMe)2,
acetone, TsOH, and Drierite). The δC(Me) ) 24.8 and 24.2
ppm observed in the 13C NMR spectrum of 13 suggest a
twist-boat conformation for the acetonide.17 Coupling
(3) See, e.g.: (a) Pal, R.; Hoke, G. M.; Sarngadharan, M. G. Proc.
Natl. Acad. Sci. U.S.A. 1989, 86, 3384. (b) J ohnson, V. A.; Walker, B.
D.; Barlow, M. A.; Paradis, T. J .; Chou, T. C.; Hirsch, M. S. Antimicrob.
Agents Chemother. 1989, 33, 53. (c) Mehta, A.; Lu, X.; Block, T. M.;
Blumberg, B. S.; Dwek, R. A. Proc. Natl. Acad. Sci. U.S.A. 1997, 94,
1822. (d) Fischer, P. B.; Karlsson, G. B.; Dwek, R. A.; Platt, F. M. J .
Virol. 1996, 70, 7153. (e) Fenouillet, E.; Papandreou, M. J .; J ones, I.
M. Virology 1997, 231, 89. (f) White, S. L.; Nagai, T.; Akijama, S. K.;
Reeves, E. J .; Grzegorzewski, K.; Olden, K. Cancer Commun. 1991, 3,
83. (g) Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause,
B. L.; Oredipe, O. A.; Newton, S. A.; White, S. L. Pharmacol. Ther.
1991, 50, 285. (h) Goss, P. E.; Baptiste, J .; Fernandes, B.; Baker, M.;
Dennis, J . W. Cancer Res. 1994, 54, 1450.
(4) (a) Kraehenbuehl, K.; Picasso, S.; Vogel, P. Bioorg. Med. Chem.
Lett. 1997, 7, 893; (b) Helv. Chim. Acta 1998, 81, 1439.
(5) J ohns, B. A.; Pan, Y. T.; Elbein, A. D.; J ohnson, C. R. J . Am.
Chem. Soc. 1997, 119, 4856.
(6) J ohnson, C. R.; Miller, M. W.; Golebiowski, A.; Sundram, H.;
Ksebati, M. B. Tetrahedron Lett. 1994, 35, 8991.
(7) Martin, O. R.; Liu, L.; Yang, F. Tetrahedron Lett. 1996, 37, 1991.
(8) Leeuwenburgh, M. A.; Picasso, S.; Overkleeft, H. S.; van der
Marel, G. A.; Vogel, P.; Van Boom, J . H. Manuscript in preparation.
(9) (a) Baudat, A.; Vogel, P. Tetrahedron Lett. 1996, 37, 483. (b)
Fre´rot, E.; Marquis, C.; Vogel, P. Tetrahedron Lett. 1996, 37, 2023. (c)
Baudat, A.; Vogel, P. J . Org. Chem. 1997, 62, 6252.
(10) This approach has been reported by us for the synthesis of
(1f3)-C-disaccharides: Zhu, Y.-H.; Vogel, P. Tetrahedron Lett. 1998,
39, 31.
(11) Horton, D.; Roski, J . P.; Norris, P. J . Org. Chem. 1996, 61, 3783.
(12) Mori, S.; Ohno, T.; Harada, H.; Aoyama, T.; Shioiri, T. Tetra-
hedron 1991, 47, 5051.
(13) Zinc enolates gave the best results among the enolates tried.
Applying lithium enolates, retro-aldol products were formed during
aqueous workup or during in situ reduction of the aldols (DIBALH,
-78 °C); with alumium enolates, â-elimination of BnOH took place
during in situ reduction of the aldols (DIBALH, -78 °C).
(14) For examples of cross-aldolisations with sugar-derived ketones,
see, e.g.: Yu, K. L.; Handa, S.; Tsan, R.; Fraser-Reid, B. Tetrahedron
1991, 47, 189.
(15) No formation of diol 9 was observed; NaBH4 (THF/MeOH, 0
°C) gave a 10:1 mixture of diols 5 and 9.
(16) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
10.1021/jo981781d CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/29/1998

Notes
J . Org. Chem., Vol. 64, No. 2, 1999 667
Sch em e 1
It will now be applied to a large number of iminodideoxy-
aldoses and sugar-derived carbaldehydes in order to
generate a large variety of C-disaccharides and ana-
logues.
Exp er im en ta l Section
General remarks, see ref 4b.
1,6-An h yd r o-2-O-ben zyl-3-d eoxy-D-er yth r o-h exop yr a n o-
4-u lose (2). A mixture of isolevoglucosenone 1 (185 mg, 1.47
mmol),11 benzyl alcohol (8.2 mL), and triethylamine (0.1 mL, 0.72
mmol) was stirred at 20 °C for 15 h. Et3N was then eliminated
by evaporation. Excess of BnOH was recovered by bulb-to-bulb
distillation in vacuo. The residue was chromatographed on silica
gel (15:85 EtOAc/light petroleum ether), affording a colorless
syrup (310 mg, 90%). [R]25D ) -57 (c 1.2, CHCl3). IR (film): 1736
cm-1. 1H NMR (400 MHz, CDCl3): δ 7.45-7.22 (m, 5H), 5.62 (s,
1H), 4.63 and 4.57 (2d, J ) 12.0 Hz, 2H), 4.55 (d, J ) 5.0 Hz,
1H), 3.92 (d, J ) 8.0 Hz, 1H), 3.84 (dd, J ) 8.0, 5.0 Hz, 1H),
3.78 (ddd, J ) 6.5, 3.5, 1.2 Hz, 1H), 2.68 (dd, J ) 12.5, 6.5 Hz,
1H), 2.61 (dd, J ) 12.5, 3.5 Hz, 1H). 13C NMR (100.6 MHz,
CDCl3): δ 204.1, 137.2, 128.6, 128.1, 127.7, 101.5, 79.1, 75.5,
71.6, 66.8, 39.2. MS (CI, NH3): 252 ([M + NH4]+). Anal. Calcd
for C13H14O4: C, 66.66; H, 6.02. Found: C, 66.56; H, 6.01.
1,6-An h yd r o-2-O-b en zyl-3-d eoxy-3-[(1′R)-4′-O-ter t-b u -
tyld im eth ylsilyl-N-ter t-bu tyloxyca r bon yl-2′,3′,5′-tr id eoxy-
2′,5′-im in o-L -er yt h r o-p e n t it ol-1′-C-yl]-â-D -ga la ct op yr a -
n ose (5).A solution of potassium bis(trimethylsilyl)amide (0.75
M in toluene, 0.24 mL, 0.18 mmol) was added to a solution of 2
(32 mg, 0.14 mmol) in anhydrous THF (1.3 mL) stirred at -50
°C under a nitrogen atmosphere. After being stirred at this
temperature for 1 h, the mixture was cooled to -78 °C and a 1
M solution of ZnCl2 in ether (0.18 mL, 0.18 mmol) was added
dropwise. After being stirred for 15 min, a solution of aldehyde
312 (58 mg, 0.18 mmol) in anhydrous THF (0.3 mL) was added.
The reaction mixture was warmed to -45 °C and stirred at this
temperature for 5 h. A saturated aqueous solution of NH4Cl (0.6
mL) was added, and the mixture was allowed to warm to 20 °C
with stirring. EtOAc (2 mL) was added. The aqueous phase was
separated and extracted with EtOAc (3 mL, three times). The
combined organic phases were dried (anhydrous Na2SO4), and
F igu r e 1. Selected 1H NMR data for 13 and 14.
constants between vicinal protons at C(2,3,4) suggest a
boat conformation for the tetrahydropyran ring (O-C1-
C2-C3-C4-C5) in which H-2 and H-3 are axial. For 14,
the 13C NMR spectrum displays δC(Me) ) 29.9 and 19.9
ppm for the acetonide moiety, suggesting a chair confor-
mation for it. Coupling constants between vicinal protons
at C2, C3, and C4 also confirm a boat conformation for
the tetrahydropyran ring as shown in Figure 1. This also
appears to be the case for the 1,6-anhydro-â-glucopyra-
nose derivatives 9, 10, and 11 for which vicinal coupling
constants 3J (H3, H4) ) 8.7, 9.8, and 10.5 Hz, respectively,
were measured. These data confirmed that the cross-
aldolization between 2 and 3 follows the Zimmerman-
Traxler model.10,18
An expedient method for the stereoselective synthesis
of (1f3)-C-linked imino disaccharides has been realized.
(17) (a) Buchanan, J . G.; Chaco´n-Fuertes, M. E.; Edgar, A. R.;
Moorhouse, S. J .; Rawson, D. I.; Wightman, R. H. Tetrahedron Lett.
1980, 21, 1793. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J . Org.
Chem. 1993, 58, 3511.
(18) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.

668 J . Org. Chem., Vol. 64, No. 2, 1999
Notes
the solvent was removed in vacuo to yield the crude aldol product
4, the H NMR spectrum of which showed 75% conversion. This
crude product was used for the following reaction without further
purification.
tography on silica gel (5% aqueous NH3:i-PrOH ) 1:2.5) to afford
1
a colorless oil (7.4 mg, 82%). [R]25 ) +38 (c 0.15, H2O). IR
D
(film): 3375 cm-1. H NMR (400 MHz, D2O): δ 4.72 (d, J ) 3.6
1
Hz, 0.6H, H-1 of 8r), 4.56 (m, 1H), 4.30 (d, J ) 7.9 Hz, 0.4H,
H-1 of 8â), 4.24 (ddd, J ) 10.3, 7.3, 4.5 Hz, 1H), 4.18 (m, 0.4 H),
4.15 (dd, J ) 7.9, 4.5 Hz, 0.6 H), 4.12 (m, 0.6 H), 4.08 (d, J ) 2.7
Hz, 0.4 Hz), 3.96 (dd, J ) 11.5, 3.6 Hz, 0.6H), 3.82 (dd, J ) 7.3,
4.8 Hz, 0.6H), 3.73-3.65 (m, 1.4H), 3.61 (dd, J ) 11.2, 7.9 Hz,
0.4H), 3.55 (s, 1.2H), 3.41 (s, 1.8H), 3.18 (dd, J ) 11.5, 4.5 Hz,
0.6 H), 3.15 (dd, J ) 10.6, 4.5 Hz, 0.4H), 3.10 (d, J ) 11.5 Hz,
0.6H), 3.07 (d, J ) 10.6 Hz, 0.4H), 2.12 (dd, J ) 13.3, 7.3 Hz,
1H), 2.04 (ddd, J ) 13.3, 10.3, 4.2 Hz, 1H), 1.95 (ddd, J ) 11.2,
7.9, 2.7 Hz, 0.6 H), 1.81 (ddd, J ) 10.6, 6.0, 3.0 Hz, 0.4H). 13C
NMR (100.6 MHz, D2O): δ 106.5 (d, 1J (C, H) ) 157 Hz, C1 of
8â), 99.9 (d, 1J (C, H) ) 171 Hz, C1 of 8r),19 79.0, 72.6, 71.8,
71.7, 71.3, 71.1, 68.0, 67.2, 67.1, 66.0, 62.4, 62.1, 61.7, 61.5, 58.3,
56.0, 54.3, 48.5, 44.0, 36.3, 35.9. MS (CI, NH3): 294 ([M + H]+).
Anal. Calcd for C12H23O7N‚1.8H2O: C, 44.25; H, 8.23; N, 4.30.
Found: C, 44.26; H, 8.53; N, 4.44.
A solution of L-Selectride (1 M in THF, 0.69 mL, 0.69 mmol)
was added dropwise to a THF (2 mL) solution of above crude
product at -78 °C under a nitrogen atmosphere. The resulting
yellow solution was stirred at this temperature for 1 h. After
being warmed to 20 °C, MeOH (0.5 mL), followed by 3 M aqueous
NaOH (1 mL) and 35% H2O2 (1 mL), was added to the reaction
mixture. The mixture was stirred vigorously at 20 °C for 1 h.
MeOH (2 mL) was added, and the mixture was extracted with
CH2Cl2 (6 mL, three times). The combined organic phases were
dried (anhydrous Na2SO4), and the solvent was removed in
vacuo. The residue was purified by flash chromatography on
silica gel (35:65 EtOAc/light petroleum ether), giving a colorless
oil (41 mg, 53%). [R]25 ) -29 (c 1.73, CHCl3). IR (film): 3364,
D
1673 cm-1. 1H NMR (400 MHz, CDCl3, 323 K): δ 7.37-7.15 (m,
5H), 5.40 (s, 1H), 4.60 (s, 2H), 4.54 (dd, J ) 5.8, 4.8 Hz, 1H),
4.51 (t, J ) 6.1 Hz, 1H), 4.43-4.28 (m, 3H), 4.20 (m, 1H), 3.62-
3.50 (m, 2H), 3.40 (d, J ) 4.5 Hz, 1H), 3.23 (dd, J ) 11.4, 4.2
Hz, 1H), 2.15 (ddd, J ) 13.0, 7.9, 5.1 Hz, 1H), 2.05 (ddd, J )
7.6, 6.1, 4.5 Hz, 1H), 1.89 (dddd, J ) 13.0, 7.7, 3.0, 1.6 Hz, 1H),
1.43 (s, 9H), 0.88 (s, 9H), 0.05 (s, 6H). 13C NMR (100.6 MHz,
CDCl3, 323 K): δ 156.3, 137.8, 128.6, 128.0, 127.7, 100.9, 80.5,
77.2, 74.7, 73.3, 71.6, 70.5, 66.6, 62.8, 60.7, 56.3, 41.0, 35.4, 28.4,
25.8, 18.0, -4.7, -4.8. MS (CI, NH3): 566 ([M + H]+). Anal.
Calcd for C29H47O8NSi: C, 61.56;; H, 8.37; N, 2.48.. Found: C,
61.66; H, 8.42; N, 2.45.
1,6-An h yd r o-2-O-b en zyl-3-d eoxy-3-[(1′R)-4′-O-ter t-b u -
tyld im eth ylsilyl-N-ter t-bu tyloxyca r bon yl-2′,3′,5′-tr id eoxy-
2′,5′-im in o-L-er yth r o-pen titol-1′-C-yl]-â-D-glu copyr an ose (9).
A solution of crude aldol product 4 derived from 32 mg (0.14
mmol) of 2 (see above) in MeCN (0.3 mL) was added to a stirred
solution of Me4NBH(OAc)3 (330 mg, 1.3 mmol) in CH3CN (1 mL)
and AcOH (1 mL) at -40 °C. The flask containing 4 was rinsed
with CH3CN (0.3 mL, twice). The mixture was warmed to -20
°C and stirred at this temperature for 20 h. A 1 M aqueous
potassium sodium tartrate solution (1 mL) was added, and the
mixture was warmed to 20 °C. The phases were separated. The
aqueous phase was extracted with CH2Cl2 (3 mL, three times).
The combined organic phases were washed with a saturated
aqueous solution of NaHCO3 (5 mL), which was counter-
extracted with CH2Cl2 (3 mL, four times). The washing and
extraction procedure was repeated once more. The combined
organic phases were dried (anhydrous Na2SO4), and the solvent
was evaporated in vacuo. Chromatography on silica gel (2:3
EtOAc/light petroleum ether) afforded a colorless oil (32 mg,
1,6-An h ydr o-2-O-ben zyl-3-deoxy-3-[(1′R)-N-ter t-bu tyloxy-
ca r bon yl-2′,3′,5′-tr id eoxy-2′,5′-im in o-L-er yth r o-p en titol-1′-
C-yl]-â-D-ga la ctop yr a n ose (6). A tetrabutylammonium fluo-
ride solution (1 M in THF, 0.40 mL, 0.40 mmol) was added to a
solution of 5 (60 mg, 0.11 mmol) in THF (2.5 mL) at 20 °C. After
being stirred at 20 °C for 15 h, the solvent was evaporated and
the residue purified by chromatography on silica gel (1% MeOH
in EtOAc), affording a colorless oil (48 mg, 96%). [R]25 ) -17
D
(c 0.48, CHCl3). IR (film): 3374, 1668 cm-1. 1H NMR (400 MHz,
CDCl3, 323 K): δ 7.40-7.25 (m, 5H), 5.38 (s, 1H), 4.62 (d, J )
11.9 Hz, 1H), 4.53 (d, J ) 11.9 Hz, 1H), 4.54 (dd, J ) 6.4, 4.8
Hz, 1H), 4.50 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 4.28 (d, J )
7.6 Hz, 1H), 4.07 (m, 1H), 3.60 (d, J ) 11.8 Hz, 1H), 3.54 (dd, J
) 7.3, 4.8 Hz, 1H), 3.35 (d, J ) 4.8 Hz, 1H), 3.30 (dd, J ) 11.8,
4.2 Hz, 1H), 2.22 (ddd, J ) 13.6, 7.6, 4.8 Hz, 1H), 2.00 (ddd, J )
8.8, 6.4, 4.8 Hz, 1H), 1.81 (dddd, J ) 13.3, 7.8, 3.0, 2.1 Hz, 1H),
1.43 (s, 9H). 13C NMR (100.6 MHz, CDCl3, 323K): δ 156.0, 137.8,
128.6, 128.0, 100.7, 80.7, 77.9, 74.6, 72.8, 71.7, 70.0, 66.3, 62.7,
60.3, 56.1, 41.1, 34.6, 28.5. MS (CI, NH3): 452 ([M + H]+). Anal.
Calcd for C23H33O8N‚H2O: C, 58.84; H, 7.51; N, 2.98. Found:
C, 58.96; H, 7.42; N, 3.35.
59%). [R]25 ) -32 (c 1.5, CHCl3). IR (film): 3428, 1674 cm-1
.
D
1H NMR (400 MHz, CDCl3, 323 K): δ 7.39-7.26 (m, 5H), 5.42
(s, 1H), 4.60 (s, 2H), 4.49 (d, J ) 5.2 Hz, 1H), 4.33 (p, J ) 3.9
Hz, 1H), 4.14 (td, J ) 7.5, 3.0 Hz, 1H), 3.98 (dd, J ) 8.1, 2.6 Hz,
1H), 3.84 (m, 2H), 3.66 (dd, J ) 7.3, 5.2 Hz, 1H), 3.55 (d, J )
11.5 Hz, 1H), 3.26 (dd, J ) 11.5, 3.9 Hz, 1H), 3.16 (d, J ) 3.9
Hz, 1H), 2.11 (ddd, J ) 13.3, 7.7, 3.9 Hz, 1H), 1.93 (dddd, J )
13.3, 7.7, 3.9, 1.8 Hz, 1H), 1.87 (ddd, J ) 8.7, 8.5, 3.9 Hz, 1H),
1.44 (s, 9H), 0.86 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR
(100.6 MHz, CDCl3, 323 K): δ 156.1, 137.7, 128.5, 127.9, 127.7,
100.4, 80.3, 77.6, 77.3, 73.8, 71.3, 70.6, 68.9, 66.3, 59.7, 56.3,
45.4, 35.2, 28.5, 25.8, 18.0, -4.8, -4.9. MS (CI, NH3): 566 ([M
+ H]+). Anal. Calcd for C29H47O8NSi: C, 61.56; H, 8.37; N, 2.48.
Found: C, 61.51; H, 8.35; N, 2.44.
1,6-An h yd r o-3-d eoxy-3-[(1′R)-N-ter t-b u t yloxyca r b on yl-
2′,3′,5′-t r id eoxy-2′,5′-im in o-L-er yth r o-p en t it ol-1′-C-yl]-â-D-
ga la ctop yr a n ose (7). A degassed mixture of 6 (48 mg, 0.10
mmol), 10% Pd on charcoal (12 mg, 0.011 mmol), and MeOH (5
mL) was stirred under H2 at 20 °C for 15 h. The catalyst was
filtered off and solvent evaporated in vacuo. The residue was
chromatographed (5% MeOH in EtOAc) to afford a white solid
1,6-An h ydr o-2-O-ben zyl-3-deoxy-3-[(1′R)-N-ter t-bu tyloxy-
ca r bon yl-2′,3′,5′-tr id eoxy-2′,5′-im in o-L-er yth r o-p en titol-1′-
C-yl]-â-D-glu cop yr a n ose (10). The same procedure as for the
preparation of 6 was used, starting from 9 (119 mg, 0.211 mmol),
yielding a colorless oil (93 mg, 94%) which crystallized from CH2-
Cl2. Mp 80-81 °C. [R]25D ) -49 (c 1.75, MeOH). IR (KBr): 3414,
(37 mg, 96%). Mp 209-210 °C. [R]25 ) -47 (c 0.75, MeOH). IR
D
(KBr): 3495, 3397, 3254, 1650 cm-1
.
1H NMR (400 MHz, CD3-
1656 cm-1 1H NMR (400 MHz, CD3OD, 323 K): δ 7.45-7.28
.
OD, 323 K): δ 5.22 (d, J ) 1.2 Hz, 1H), 4.64 (m, 1H), 4.56-4.38
(m, 3H), 4.30 (d, J ) 7.6 Hz, 1H), 4.22 (dd, J ) 8.2, 5.7 Hz, 1H),
3.60 (m, 2H), 3.56 (d, J ) 11.4 Hz, 1H), 3.40 (dd, J ) 11.4, 4.2
Hz, 1H), 2.35 (dt, J ) 13.3, 5.7 Hz, 1H), 1.95 (dddd, J ) 13.3,
8.2, 3.3, 1.8 Hz, 1H), 1.96-1.88 (m, 1H), 1.52 (s, 9H). 13C NMR
(100.6 MHz, CD3OD, 323 K): δ 156.7, 103.9, 81.5, 76.8, 73.8,
70.7, 68.3, 63.9, 60.9, 56.5, 44.7, 34.4, 28.9. MS (CI, NH3): 362
([M + H]+). Anal. Calcd for C16H27O8N: C, 53.18; H, 7.53; N
3.88. Found: C, 53.23; H, 7.64; N, 3.83..
Met h yl 3-Deoxy-3-[(1′R)-2′,3′,5′-t r id eoxy-2′,5′-im in o-L-
er yth r o-p en titol-1′-C-yl]-r(a n d â)-D-ga la ctop yr a n osid e (8r,
8â). A mixture of 7 (10.0 mg, 0.0277 mmol) and anhydrous
MeOH saturated with gaseous HCl (1 mL) was refluxed under
N2 for 20 h. After cooling, the solution was poured onto a column
(5 cm length) of Dowex 50WX8 (100-200 mesh). The column
was washed sequentially with MeOH (20 mL), H2O (5 mL), and
5% NH3‚H2O (40 mL). The fractions containing products 8r and
8â were concentrated in vacuo and purified by flash chroma-
(m, 5H), 5.45 (s, 1H), 4.64 (s, 2H), 4.45 (m, 1H), 4.43 (m, 1H),
4.10-3.98 (m, 1H), 4.03 (d, J ) 9.8 Hz, 1H), 3.93 (m, 1H), 3.82
(d, J ) 7.6 Hz, 1H), 3.67 (dd, J ) 7.6, 5.9 Hz, 1H), 3.52 (d, J )
11.3 Hz, 1H), 3.43 (dd, J ) 11.3, 4.9 Hz, 1H), 3.22 (br s, 1H),
2.33 (br s, 1H), 1.89 (ddd, J ) 13.3, 7.9, 3.0 Hz, 1H), 1.75 (dt, J
) 9.8, 3.0 Hz, 1H), 1.44 (s, 9H). 13C NMR (100.6 MHz, CD3OD,
323 K): δ 156.6, 139.3, 129.6, 129.1, 129.0, 101.5, 81.3, 78.8,
75.8, 73.1, 72.2, 70.8, 68.3, 66.3, 60.7, 56.2, 47.2, 34.4, 28.8. Anal.
Calcd for C23H33O8N‚H2O: C, 58.84; H, 7.51; N, 2.98. Found:
C, 59.16; H, 7.40; N, 2.73.
1,6-An h yd r o-3-d eoxy-3-[(1′R)-N-ter t-b u t yloxyca r bon yl-
2′,5′-im in o-2′,3′,5′-t r id eoxy-L-er yth r o-p en t it ol-1′-C-yl]-â-D-
glu cop yr a n ose (11). The same procedure as for the preparation
(19) (a) Bock, K.; Thøgersen, H. Annu. Rep. NMR Spectrosc. 1982,
13, 1. (b) Bock, K.; Pedersen, C. Adv. Carbohydr. Chem. Biochem. 1983,
41, 27. (c) J ones, C. In Advances in Carbohydrate Analysis; J AI Press:
Greenwich, CT, 1991; Vol. 1, p 145.

Notes
J . Org. Chem., Vol. 64, No. 2, 1999 669
of 7 was used, starting from 10 (50 mg, 0.11 mmol): white solid
MHz, CDCl3, 333 K): δ 7.40-7.22 (m, 5H), 5.42 (s, 1H), 4.63 (s,
2H), 4.57 (dd, J ) 7.9, 5.6 Hz, 1H), 4.45 (p, J ) 5.2 Hz, 1H),
4.38 (t, J ) 8.2 Hz, 1H), 4.36-3.98 (m, 2H), 4.22 (d, J ) 7.5,
1H), 3.52 (dd, J ) 7.5, 5.6 Hz, 1H), 3.41 (dd, J ) 10.7, 5.4 Hz,
1H), 3.43-3.21 (m, 2H), 2.23 (dt, J ) 12.6, 5.4 Hz, 1H), 1.90
(ddd, J ) 10.3, 8.2, 6.3 Hz, 1H), 1.79 (ddd, J ) 12.4, 8.6, 5.6 Hz,
1H), 1.49 (s, 9H), 1.32 (s, 3H), 1.31 (s, 3H), 0.88 (s, 9H), 0.06 (s,
3H), 0.04 (s, 3H). 13C NMR (100.6 MHz, CDCl3, 333K): δ 154.3,
137.8, 128.4, 127.8, 127.7, 101.8, 80.4, 79.4, 71.3, 70.6, 70.5, 70.2,
62.5, 61.9, 57.3, 55.1, 40.0, 34.9, 28.7, 25.8, 24.8, 24.2, 18.0, -4.8,
-4.9. MS (CI, NH3): 606 ([M + H]+). Anal. Calcd for C32H51O8-
NSi: C, 63.44; H, 8.48; N: 2.31. Found: C, 63.53; H, 8.56; N,
2.41.
(37 mg, 93%). Mp 164-165 °C. [R]25 ) -74 (c 1.2, MeOH). IR
D
(KBr): 3463, 3379, 1649 cm-1. 1H NMR (400 MHz, CD3OD, 323
K): δ 5.27 (s, 1H), 4.45 (d, J ) 5.4 Hz, 1H), 4.42 (m, 1H), 4.24
(m, 1H), 4.07 (dd, J ) 10.4, 1.5 Hz, 1H), 3.92 (m, 1H), 3.82 (d, J
) 7.6 Hz, 1H), 3.67 (dd, J ) 7.6, 5.4 Hz, 1H), 3.55 (d, J ) 11.5
Hz, 1H), 3.42 (dd, J ) 11.5, 4.6 Hz, 1H), 3.40 (d, J ) 3.1 Hz,
1H), 2.32 (dt, J ) 13.4, 6.0 Hz, 1H), 1.96 (dddd, J ) 13.3, 8.1,
3.1, 1.5 Hz, 1H), 1.59 (dt, J ) 10.5, 3.1 Hz, 1H), 1.52 (s, 9H).13
C
NMR (100.6 MHz, CD3OD, 323 K): δ 156.8, 104.2, 81.2, 78.8,
73.3, 70.8, 69.2, 68.8, 66.5, 60.6, 56.4, 49.8, 34.3, 28.9. MS (CI,
NH3): 362 ([M + H]+). Anal. Calcd for C16H27O8N: C, 53.18; H,
7.53; N, 3.88. Found: C, 53.02; H, 7.68; N, 3.83.
Met h yl 3-Deoxy-3-[(1′R)-2′,5′-im in o-2′,3′,5′-t r id eoxy-L-
er yth r o-p en titol-1′-C-yl]-r (a n d â)-D-glu cop yr a n osid e (12r,
12â). The same procedure as for the preparation of 8r and 8â
was used, starting from 11 (10.0 mg, 0.0277 mmol), chromatog-
raphy on silica gel (5% aqueous NH3:MeOH ) 1:12): colorless
1,6-An h yd r o-2-O-ben zyl-3-d eoxy-1′,4-O-isop r op ylid en e-
3-[(1′R)-4′-O-ter t-bu tyld im eth ylsilyl-N-ter t-bu tyloxyca r bo-
n yl-2′,3′,5′-t r id eoxy-2′,5′-im in o-L-er yth r o-p en t it ol-1′-C-yl]-
â-D-glu cop yr a n ose (14). The same procedure as for the
preparation of 13 was used, starting from 9 (32 mg, 0.057
oil (7.8 mg, 90%). [R]25 ) +43 (c 0.29, H2O). IR (film): 3354
D
mmol): colorless oil (29 mg, 85%). [R]25 ) -11 (c 1.45, CHCl3).
D
cm-1 1H NMR (400 MHz, D2O): δ 4.71 (d, J ) 3.7 Hz, 0.7H,
.
IR (film): 1690 cm-1
.
1H NMR (400 MHz, CDCl3, 323 K):
δ
H-1 of 12r), 4.59 (t, J ) 4.2 Hz, 1H), 4.35 (d, J ) 7.9 Hz, 0.3H,
H-1 of 12â), 4.26 (dd, J ) 6.0, 2.6 Hz, 1H), 4.14 (dt, J ) 11.4,
6.0 Hz, 1H), 3.88 (dd, J ) 12.1, 2.1 Hz, 0.3H), 3.83 (dd, J ) 12.1,
2.1 Hz, 0.7H), 3.70 (d, J ) 12.1, 0.3H), 3.67 (d, J ) 12.1, 0.7H),
3.68-3.58 (m, 2H), 3.65 (dd, J ) 10.6, 3.7 Hz, 0.7 H), 3.54 (s,
0.9H), 3.41 (s, 2.1H), 3.34 (dd, J ) 12.8, 4.2 Hz, 1H), 3.28 (d, J
) 7.7, 0.3H), 3.21 (d, J ) 12.6, 1H), 2.18 (dd, J ) 14.0, 6.0 Hz,
1H), 1.98 (ddd, J ) 14.0, 11.4, 4.2 Hz, 1H), 1.96 (td, J ) 10.9,
3.5 Hz, 0.7H), 1.80 (td, J ) 10.3, 2.3 Hz, 0.3H). 13C NMR (100.6
7.40-7.28 (m, 5H), 5.32 (s, 1H), 4.60 (s, 2H), 4.44 (p, J ) 5.6
Hz, 1H), 4.42 (m, 1H), 4.23 (m, 1H), 4.18 (m, 1H), 3.63 (m, 1H),
3.48 (m, 2H), 3.38 (dd, J ) 10.7, 5.4 Hz, 1H), 3.25 (m, 1H), 3.19
(m, 1H), 2.23 (ddd, J ) 12.8, 5.6, 4.4 Hz, 1H), 1.77 (m, 1H), 1.60
(q, J ) 10.3 Hz, 1H), 1.46 (s, 9H), 1.39 (s, 6H), 0.86 (s, 9H), 0.03
(s, 3H), 0.01 (s, 3H). 13C NMR (100.6 MHz, CDCl3, 323 K): δ
154.3, 137.5, 128.5, 127.9, 102.0, 79.0, 78.8, 75.7, 73.1, 71.7, 70.7,
69.3, 58.1, 55.1, 38.7, 34.5, 29.9, 28.6, 25.9, 19.9, 18.0, -4.8, -4.9.
MS (CI, NH3): 606 ([M + H]+). Anal. Calcd for C32H51O8NSi:
C, 63.44; H, 8.48; N, 2.31. Found: C, 63.48; H, 8.46; N, 2.37.
1
MHz, D2O): δ 105.7 (d, J (C, H) ) 163 Hz, C1 of 12â), 99.4 (d,
1J (C, H) ) 167 Hz, C1 of 12r),19 79.3, 72.8, 70.8, 70.0, 69.9,
69.9, 68.1, 64.9, 64.5, 62.4, 62.1, 61.9, 61.7, 58.1, 55.9, 54.1, 49.5,
45.4, 37.2, 37.0. MS (CI, NH3): 294 ([M + H]+). Anal. Calcd for
Ack n ow led gm en t . We thank the Swiss National
Science Foundation and the Fonds Herbette (Lausanne)
for financial support. We thank also Mr. F. Sepulveda
and Mr. Rey for their technical assistance.
C
12H23O7N‚1.2H2O: C, 45.76; H, 8.13; N, 4.45. Found: C, 45.83;
H, 7.99; N, 4.53.
1,6-An h yd r o-2-O-ben zyl-3-d eoxy-1′,4-O-isop r op ylid en e-
3-[(1′R)-4′-O-ter t-bu tyld im eth ylsilyl-N-ter t-bu tyloxyca r bo-
n yl-2′,3′,5′-t r id eoxy-2′,5′-im in o-L-er yth r o-p en t it ol-1′-C-yl]-
â-D-ga la ctop yr a n ose (13). A mixture of 5 (39 mg, 0.069 mmol),
2,2-dimethoxypropane (2 mL), Drierite (2 g, powder), dry acetone
(4 mL), and p-toluenesulfonic acid (1 mg) was stirred at 20 °C
for 15 h. After addition of K2CO3 (10 mg), the precipitate was
filtered off and the solvent evaporated in vacuo. The residue was
purified by chromatography on silica gel (8:92 EtOAc/light
petroleum ether), affording a colorless oil (37 mg, yield 89%).
1
Su p p or tin g In for m a tion Ava ila ble: Detailed H and 13C
NMR spectra and signal assignments, further optical rotation
data, and UV, IR, and MS spectra (12 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
[R]25 ) +5 (c 1.65, CHCl3). IR (film): 1694 cm-1. 1H NMR (400
J O981781D
D