Convergent synthesis of (1→2)- and (1→4)-C-linked imino disaccharides

Article abstract of DOI:10.1039/a905310g

A convergent synthesis of (1→2)- and (1→4)-C-linked imino disaccharides was achieved by applying Nozaki-Kishi coupling of a hydroxyproline-derived carbaldehyde with isolevoglucosenone or levoglucosenone derived enol triflates.

Full text of DOI:10.1039/a905310g

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Convergent synthesis of (1 2)- and (1 4)-C-linked imino disaccharides†
Yao-Hua Zhu and Pierre Vogel*
Section de Chimie de l’Université de Lausanne, BCH, CH-1015 Lausanne-Dorigny, Switzerland.
E-mail: pierre.vogel@ico.unil.ch
Received (in Liverpool, UK) 30th June 1999, Accepted 13th August 1999
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A convergent synthesis of (1 2)- and (1 4)-C-linked imino
disaccharides was achieved by applying Nozaki–Kishi
coupling of a hydroxyproline-derived carbaldehyde with
isolevoglucosenone or levoglucosenone derived enol triflates.
Hydroboration of 9 with BH3·SMe2 in THF at 50 °C followed
by H2O2/NaOH work-up furnished the d-glucose derivative 12
in 57% yield. Desilylation with Bu4NF in THF gave triol 13
(97%), which was debenzylated to give tetrol 14 (94%).
Treatment of 14 in refluxing MeOH saturated with gaseous HCl
for 2 days produced a 2+1 mixture of 15a and 15b in 83%
yield.
Carbohydrate mimetics are potentially useful tools to study
cellular interactions,1 the biosynthesis of glycoproteins, the
metabolism of glycoconjugates,2 and the mechanisms of
digestion.3 Inhibitors of the enzymes involved in these proc-
esses such as the glycosidases and the glycosyltransferases are
potential anti-cancer, antiviral, and antidiabetic agents, as well
as insect antifeedant agents.4 Disaccharide mimetics such as C-
disaccharides and dideoxyiminoalditol C-linked to mono-
saccharides have emerged as a new class of specific glycosidase
inhibitors and may represent non-hydrolyzable epitopes.5–7
Recently we disclosed an efficient and versatile approach to the
The d-gluco configuration of the methyl pyranosides 15a and
15b was determined from their 1H NMR spectra.13 The
configuration of the hydroxymethano linker was established by
converting diol 12 into the corresponding acetonide 16
[(MeO)2CMe2, acetone, TsOH, Drierite, 25 °C, 68% yield], the
structure of which was established by its NOESY and 1H NMR
spectra. The coupling constants, 3J(H-3, H-4) = 10.9 Hz, 3J(H-
3
4, H-1A) = 11.2 Hz and J(H-2, H-3) = 7.2 Hz, show the
antiperiplanar orientation between these proton pairs. Fur-
thermore, NOEs were observed between signals attributed to
Hsyn-6, H-2, H-4, and between those attributed to Meaxial, H-1A,
H-3. Thus, the Re face of aldehyde 8 is preferred for the
alkenylchromium addition, which is in accord with the Felkin–
Anh Model.14
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syntheses of (1 3)-C-disaccharides and (1 3)-C-linked imino
disaccharides 5 based on the cross-aldolisation of the aldehydes
3 with the nucleophile 1,4-adducts 2 of isolevoglucosenone 1
(Scheme 1).8,9 We report here that (1 4)- and (1 2)-C-
disaccharides can be prepared starting from 1 and levoglucose-
none 17 with 3, respectively.
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Adduct 6 of benzyl alcohol with isolevoglucosenone was
enolized, without elimination of benzylate anion, on treatment
with LiHMDS in 95+5 THF–HMPA at 278 °C (Scheme 2).9
Quenching of the corresponding lithium enolate with 2-[bis(tri-
fluoromethylsulfonyl)amino]-5-chloropyridine provided the
enol triflate 7 in 87% yield.10 Nozaki–Kishi coupling of 7 and
aldehyde 8 led to allylic alcohols 9 and 10 isolated in 62 and
17% yield, respectively.11,12‡ Interestingly, the reaction was
accelerated by ultrasound and O2. Under N2 atmosphere,
ultrasound shortened the reaction time from 30 to 2 h. While in
the presence of a catalytic amount of O2 (5 mol% with respect
to CrCl2, concentration of O2 lower than 10%), the reaction time
was reduced further to less than 1 h. Moreover, O2 suppressed
the formation of 11, resulting from H2O quenching of the
alkenylchromium species, from 36 to less than 10%.
Scheme 2 Reagents and conditions: i, BnOH, Et3N, 25 °C; ii, LiHMDS,
HMPA–THF,
2-[bis(trifluoromethylsulfonyl)amino]-5-chloropyridine,
Scheme 1
278 °C, 87%; iii, 8, CrCl2, NiCl2, O2, DMF, ultrasound, 25 °C; iv,
BH3·SMe2, THF, 50 °C, v, H2O2, NaOH, 57% for 2 steps; vi, Bu4NF, THF,
97%; vii, H2, 10% Pd-C, MeOH, 25 °C, 94%; viii, MeOH, HCl, reflux, 2
days, 83%.
† Spectral data for 15a, 15b and 29 are available from the RSC web site, see
http://www.rsc.org/suppdata/cc/1999/1873/
Chem. Commun., 1999, 1873–1874
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disaccharides, and thus make possible the exploration of their
structure–activity relationships.17
This work was supported by the Swiss National Science
Foundation. We thank also the European COST D13 action
programme for encouragement.
Notes and references
‡ Selected data for 9: colorless oil; [a]2D5 2107 (c 1.2, CHCl3); dH(400 MHz,
CDCl3, 323 K) 7.38–7.25 (m, 5H, Ph), 5.54 (m, 2H, H-1, H-3), 4.76 [d, 3J
(H-5, Hexo-6) 3.6, H-5], 4.65 and 4.62 (2d, 2H, 2J 11.5, PhCH2O), 4.38 (p,
3J 3.6, H-4A), 4.37 (m, H-1A), 4.31 (m, H-2A), 3.71 (m, 2H, H-6), 3.55 [d,
3J(H-2, H-3) 3.9, H-2), 3.48 (d, 2J 11.2 , H-5Aa), 3.35 [dd, 2J 11.2 , 3J(H-4A,
H-5Ab) 4.2, H-5Ab] 1.92 (m, 2H, H-3A), 1.48 [s, 9H, (CH3)3CO], 0.86 [s, 9H,
(CH3)3CSi], 0.04 [s, 6H, (CH3)3Si]. For 20: [a]2D5+24 (c 0.94, CHCl3);
dH(400 MHz, CDCl3, 323 K) 7.44–7.26 (m, 5H, Ph), 5.69 (m, H-3), 5.64 (s,
H-1), 4.77 [dtd, 3J(H-5, Hexo-6) 6.6, 4J(H-3, H-5) = 3J(H-5, Hendo-6) = 1.7,
3J(H-4, H-5) 1.1, H-5), 4.68 (s, 2H, PhCH2O), 4.52 (m, H-1A), 4.32 (m, H-
4A), 4.20 (m, H-2A), 3.87 (dd, 2J 7.6, 3J 6.6, Hexo-6), 3.58 [dt, 3J(H-3, H-4)
3.9, 3J(H-4, H-5) = 5J (H-4, H-1A) = 1.1, H-4], 3.46 (m, H-5Aa), 3.36 (dd,
2J 11.2, 3J 4.2, H-5Ab), 3.31 (dd, 2J 7.6 ,3J 1.7, Hendo-6), 1.89 (m, 2H, H-3A),
1.49 [s, 9H, (CH3)3CO], 0.88 [s, 9H, (CH3)3CSi], 0.06 [s, 6H, (CH3)2Si].
1 See, e.g.: A. Varki, Glycobiology, 1993, 3, 97; P. R. Crocker and T.
Feizi, Curr. Opin. Struct. Biol., 1996, 6, 679; A. Varki, Proc. Natl. Acad.
Sci. U.S.A., 1994, 91, 7390; K. W. Moremen, R. B. Trimble and A.
Herscovics, Glycobiology, 1994, 4, 113; B. Ganem, Acc. Chem. Res.,
1996, 29, 340 and references cited therein.
2 R. Kornfeld and S. Kornfeld, Annu. Rev. Biochem., 1985, 54, 631; A.
Lai, P. Pang, S. Kalelkar, P. A. Romero, A. Herscovics and K. W.
Moremen, Glycobiology, 1998, 8, 981 and references cited therein.
3 J. Marshall, J. Adv. Carbohydr. Chem. Biochem., 1974, 30, 257; D. D.
Schmidt, W. Frommer, B. Junge, L. Müller, W. Wingender, E. Truscheit
and D. Schefer, Naturwissenschaften, 1977, 64, 535.
4 A. D. Elbein and R. J. Molyneux, in Iminosugars as Glycosidase
Inhibitors, ed. A. E. Stütz, Wiley-VCH, Weinheim, 1999, pp. 216–251;
C. W. Ekhart, M. H. Fechter, P. Hadwiger, E. Mlaker, A. E. Stütz, A.
Tauss and T. M. Wrodnigg, in Iminosugars as Glycosidase Inhibitors,
ed. A. E. Stu¨tz, Wiley-VCH, Weinheim, 1999, pp. 253–390; M. Bols,
Acc. Chem. Res., 1998, 31, 1; E. Fenouillet, M. J. Papandreou and I. M.
Jones, Virology 1997, 231, 89; T. Kolter, Angew. Chem., Int. Ed. Engl.,
1997, 36, 1955 and references cited therein.
Scheme 3 Reagents and conditions: i, 8, CrCl2, NiCl2, O2, DMF,
ultrasound, 25 °C; ii, BH3·SMe2, THF, reflux; iii, H2O2, NaOH, 37% for 2
steps; iv, MeOH, TsOH, 25 °C; v, BH3·SMe2, THF; vi, H2O2, NaOH, 46%
for 2 steps; vii, MeOH, HCl, reflux, 92%; viii, H2, 10% Pd-C, MeOH, 25 °C,
95%.
5 C. Pasquarello, R. Demange and P. Vogel, Bioorg. Med. Chem. Lett.,
1999, 9, 793.
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In parallel with the synthesis of (1 4)-C-disaccharides,
(1 2)-C-disaccharides and analogues can be obtained starting
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6 B. A. Jones, Y. T. Pan, A. D. Elbein and C. R. Johnson, J. Am. Chem.
Soc., 1997, 119, 4856; K. Kraehenbuehl, S. Picasso and P. Vogel, Helv.
Chim. Acta, 1998, 81, 1439; M. A. Leeuwenburgh, S. Picasso, H. S.
Overkleeft, G. A. van der Marel, P. Vogel and J. H. van Boom, Eur. J.
Org. Chem., 1999, 1185.
7 See, e.g.: G. D. MacLean, M. B. Bowen-Yacyshyn, J. Samuel, A.
Meikle, G. Stuart, J. Nation, S. Poppema, M. Jerry, R. Koganty, T.
Wong and B. M. Longenecker, J. Immunother., 1992, 11, 292; P. D.
Rye, N. V. Bovin, E. V. Vlasova and R. A. Walker, Glycobiology, 1995,
5, 385.
8 Y.-H. Zhu and P. Vogel, Tetrahedron Lett., 1998, 39, 31.
9 Y.-H. Zhu and P. Vogel, J. Org. Chem., 1999, 64, 666.
10 D. L. Comins and A. Dehghani, Tetrahedron Lett., 1992, 33, 6299.
11 S. Mori, T. Ohno, H, Harada, T. Aoyama and T. Shioiri, Tetrahedron,
1991, 47, 5051.
from levoglucosenone 17 (Scheme 3). Benzyl alcohol adduct 18
was converted (as above) into triflate 19 in 90% yield.15 In the
Nozaki–Kishi coupling reaction, 19 was found to be less
reactive than triflate 7. It required activation with ultrasound
and a catalytic amount of O2 to react (best results with 5 mol%
O2 with respect to CrCl2, 0.3 mol% NiCl2). This led to alcohol
20 isolated in 48% yield, together with dehydroxylated product
21 (5% yield) and side product 22 (8% yield).‡ Hydroboration
of 20 followed by oxidative work-up provided diol 23 in modest
yield (37%). The 1H NMR and NOESY spectra of acetonide 24
(obtained under the same conditions as those for 16) showed
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coupling constants J(H-2, H-3) = 10.7 Hz, J(H-1A, H-2) =
3
10.7 Hz, J(H-3, H-4) = 3.6 Hz, and NOEs between proton
pairs Hsyn-6/H-3, H-3/H-1A H-3/Meaxial and H-1A/Meaxial. These
establish the d-altro configuration of the anhydrohexose moiety
and the (R) configuration of the hydroxymethano linker
demonstrating again that the Re face of 8 was preferred for the
nucleophilic addition.16 Hydroboration took place from the exo
face of the bicyclic system probably because of steric hindrance
from the endo hydrogen at C6. The allylic acetal was readily
opened by acidic methanolysis, which provided glycosides 25a
and 25b isolated in 85 and 12% yield, respectively. Hydro-
boration of 25a gave alcohol 26 (46%) and the anhydroglucitol
derivative 27 (10%).16 Under reflux in MeOH saturated with
HCl, 28 was obtained in 92% yield. Hydrogenation liberated the
12 K. Takai, M. Tagashira, T. Kuroda, K. Oshima, K. Vtimoto and H.
Nozaki, J. Am. Chem. Soc., 1986, 108, 6048; D. P. Stamos, X. C. Sheng,
S. S. Chen and Y. Kishi, Tetrahedron Lett., 1997, 38, 6355 and
references cited therein.
13 Y. Wang, P. G. Goekjian, D. M. Ryckman, W. H. Miller, S. A. Babirad
and Y. Kishi, J. Org. Chem., 1992, 57, 482.
14 F. Rübsam, S. Seck and A. Giannis, Tetrahedron, 1997, 53, 2823; P.
Ciapetti, M. Falorni and M. Taddei, Tetrahedron, 1996, 52, 7379.
15 For the preparation of 18, see: T. Kawai, M. Isobe and S. C. Peters, Aust.
J. Chem., 1995, 48, 115.
16 J. Cossy, V. Bellosta and M. C. Müller, Tetrahedron Lett., 1992, 33,
5045.
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17 An example of the synthesis of the b-C(1 4)glucopyranoside of
3-deoxy-d-glucose from levoglucosenone was reported by Witczak and
co-workers: Z. J. Witczak, R. Chhabra and J. Chojnacki, Tetrahedron
Lett., 1997, 38, 2215.
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(1 2)-C-linked imino disaccharide 29 (95%).
The stereoselective methods presented above should be
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applicable to the preparation of a large variety of (1 2)- and
(1 4)-C-disaccharides and analogues employing the same
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starting materials as those for the synthesis of (1 3)-C-
Communication 9/05310G
1874 Chem. Commun., 1999, 1873–1874