Ring-closing olefin metathesis of prearranged C-allyl saccharides for the synthesis of C-butenyl linked homo- and hetero-disaccharides

Article abstract of DOI:10.1016/S0040-4039(00)01122-9

Synthesis of C-butenyl-linked homo- and hetero-disaccharides was achieved via ring-closing olefin metathesis employing the Grubb's catalyst. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01122-9

Tetrahedron Letters 41 (2000) 6593±6597
Ring-closing ole®n metathesis of prearranged C-allyl
saccharides for the synthesis of C-butenyl linked
homo- and hetero-disaccharides
Gang-Ting Fan, Tzu-Sui Hus, Chang-Ching Lin and Chun-Cheng Lin*
Institute of Chemistry, Academia Sinica, Nankang, Taipei, ROC 11529, Taiwan
Received 27 April 2000; revised 25 May 2000; accepted 30 June 2000
Abstract
Synthesis of C-butenyl-linked homo- and hetero-disaccharides was achieved via ring-closing ole®n
metathesis employing the Grubb's catalyst. # 2000 Elsevier Science Ltd. All rights reserved.
Oligosaccharides have been found to play a vital role in intercellular communication and cell-
mediated processes.1 This ®nding has directed many chemists to design and synthesize glyco-
conjugates for the study of glycobiology as well as therapeutic and pharmaceutical development.2
However, like proteins and nucleic acids, carbohydrates are susceptible to biodegradation, thus
limiting their therapeutic potential and use in biological studies. C-Glycosides,3 one of the
glycomimetics which constitute potential non-hydrolysable epitopes, have therefore attracted
considerable interest.
After the development of ruthenium benzylidene catalyst 1,4 the ring-closing metathesis (RCM)
reaction has become a powerful tool for organic synthesis5 due to its compatibility with a variety
of functional groups and commercial availability.6 Most applications of catalyst 1 in carbohydrate
chemistry are ring-closing metathesis for the synthesis of fused or spiro monosaccharide derivatives.7
Although the use of catalyst 1 in the synthesis of a,a0-O- and C-alkenyl-linked disaccharides has
been reported,5a most of the examples are the synthesis of homodimeric pyranosides using cross-
metathesis (CM).8 Surprisingly, to our knowledge, there are only two examples of the synthesis of
C/O-alkenyl-linked hetero-disaccharides using CM.8b This limitation is due to the synthesis of
heterodimers by CM of two di€erent terminal ole®ns often encountering the problem of obtaining
undesired homodimers, as shown in Fig. 1. To avoid this formidable self-metathesis problem, we
designed and used RCM in conjunction with prearranged C-allyl saccharides. By switching the
reaction from intermolecule (CM) to intramolecule (RCM), many C-butenyl-linked hetero-
disaccharides were easily obtained.
* Corresponding author. Fax: 886-2-27831237; e-mail: cclin@chem.sinica.edu.tw
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01122-9

6594
Figure 1.
To study the e€ects of spacers on the Z:E ratios of RCM products, three di€erent spacers,
glutaryl, succinyl, and phthaloyl, were used for the synthesis of spacer-linked C-allyl mannosides,
6, 7, and 8, respectively, as shown in Scheme 1. Compound 3 was chosen as starting material due
to its having an orthogonal protecting group at the primary hydroxyl that spacer can be inserted
through. It was obtained by a one-pot synthesis method9 from readily available a-methyl
mannopyranoside 2, followed by hydrolysis of the acetyl group to give 4. The glutaryl spacer was
introduced into the primary hydroxyl group by acylation of 4 with glutaric anhydride.10 The
resulting carboxyl acid 5 was then coupled with 4 in the presence of EDC and DMAP to give 6.
Compounds 7 and 8 were obtained by using similar methods as mentioned above. RCM reactions
of these C-allyl mannosides were proceeded in CH2Cl2 (0.06 M) with 10 mol% of catalyst 1 at
re¯uxing temperature for 10 h. The Z- and E-isomers were determined 1H NMR and 13C NMR.
For these homo-disaccharides, the coupling constant of the vinyl proton with the allyl protons of
the Z-isomer was ca. 4.2 Hz, and that of the E-isomer was ca. 3.5 Hz. The allyl carbon of the
Z-isomer appeared at ca. 26 ppm and that of the E-isomer at ca. 31 ppm. As shown in Table 1,
while the use of di€erent spacers did not in¯uence reaction yields, it changed the Z:E ratios.
When a more rigid spacer, phthaloyl group, was used, the ratio of Z-isomer increased.
Scheme 1.
In order to extend this method for the synthesis of C-butenyl-linked disaccharides, more glutaric
linked C-allyl saccharides were synthesized and tested, as shown in Table 2.11 These results
showed excellent yields (80±94%) with the Z-isomers as the favoured product. It should be noted
that in the cases of homodimers, the orientation of hydroxyl groups of glycosides in¯uenced the
Z:E ratios (Entry 1 of Table 1, and Entries 1 and 2 of Table 2). The Z- and E-isomers of butenyl

6595
Table 1
Table 2
linked hetero-disaccharides showed di€erent vinyl proton splitting patterns in 1H NMR spectrum,
which were used for their identi®cation. The splitting patterns of the vinyl protons in the E-isomer
were the AB type (Áꢀ/J ꢀ3.1) and the coupling constant was ca. 14 Hz; those of the Z-isomers
were very closed (Áꢀ/J ꢀ2.3) and could not be distinguished.12 It should be noted that `head to
tail' type 1,60 butenyl linked diglucoside, 23, was also obtained.

6596
In conclusion, we have demonstrated in this work a straightforward method for the synthesis of
C-butenyl-linked hetero-disaccharides. The strategy is based on the Grubbs' catalyst for RCM, used
in conjunction with prearranged C-allyl saccharides. By changing the spacer, the diastereoisomers
Z:E ratio could be modulated.
Acknowledgements
We thank the National Science Council (NSC89-2113-M001-009) and Academia Sinica for
their ®nancial support.
References
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Tetrahedron 1998, 54, 4413±4450. (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371±388.
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Baeker, W. D.; Jenkins, P. R.; Davies, D. L.; Garratt, S.; Fawcett, J.; Russell, D. R.; Ghosh, S. ibid. 1998, 37,
3298±3300. (c) Oguri, H.; Tanaka, S.-I; Oishi, T.; Hirama, M. Tetrahedron Lett. 2000, 41, 975±978. (d) van Hooft,
P. A. V.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van Boeckel Constant, A. A.; van Boom,
J. H. ibid. 1998, 39, 6061±6064. (e) Leeuwenburgh, M. A; Kulker, C.; Overlkeeft, H. S.; van der Marel, G. A.; van
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Marel, G. A.; van Boom, J. H. Tetrahedron 1999, 55, 8253±8262. (h) Delgado, M.; Martin, J. D. J. Org. Chem.
1999, 64, 4834±4839. (i) Rainier, J. D.; Allwein, S. P. ibid 1998, 63, 5310±5311.
8. (a) Blackewll, H. E.; O'Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussman, D. A.; Grubbs, R. H.
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Lett. 1999, 40, 4755±4759. (e) Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999, 64, 1770±1771. (e)
Dominidue, R. S.; Das, K; Roy, R. Chem. Commun. 1998, 2437±2438. (f) Schurer, S. C.; Blechert, S. Chem.
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1
11. Selected data for compound 19Z: H NMR (CDCl3, 400 MHz) ꢁ 1.97 (ddd, J=7.5 Hz, 2H), 1.97±2.06 (m, 2H),
2.29 (ddd, J=15.2, 7.6, 7.6 Hz, 2H), 2.33±2.38 (m, 2H), 2.44 (ddd, J=15.2, 7.6, 7.6 Hz, 2H), 3.49±3.56 (br, 2H),
3.77 (dd, J=5.1, 3.0 Hz, 2H), 2.93±4.03 (m, 6H), 4.10±4.18 (m, 2H), 4.44 (d, J=12.0 Hz, 2H), 4.48 (d, J=12.0 Hz,
2H), 4.52 (d, J=12.0 Hz, 2H), 4.57 (d, J=12.0 Hz, 2H), 4.61 (d, J=12.4 Hz, 2H), 4.66 (d, J=12.4 Hz, 2H), 5.09
(t, J=11.4 Hz, 2H), 5.43 (t, J=4.7 Hz, 2H), 7.15±7.50 (m, 30H). HRMS (FAB) calcd for C63H69O12 (M+H+):
1017.4789. Found: 1017.5023. Compound 20Z: 1H NMR (CDCl3, 400 MHz) ꢁ 1.91±2.06 (m, 1H), 1.96 (q, J=7.2
Hz, 2H), 2.15±2.35 (m, 4H), 2.35±2.55 (m, 3H), 3.52±3.63 (m, 3H), 3.78 (dd, J=6.4, 3.2 Hz, 2H), 3.86±4.16 (m,
7H), 4.43±4.73 (m, 13H), 5.05 (t, J=11.6 Hz, 1H), 5.40±5.52 (m, 2H), 7.15±7.45 (m, 30H). Calcd for C63H69O12
(M+H+): 1017.4789. Found: 1017.4882. Compound 21Z: 1H NMR (CDCl3, 400 MHz) ꢁ 1.85±2.05 (m, 2H), 2.22±
2.55 (m, 8H), 3.28 (dd, J=9.6, 8.7 Hz, 1H), 3.44 (dd, J=4.7, 3.1 Hz, 1H), 3.57 (dd, J=7.9, 2.8 Hz, 1H), 3.68 (dd,
J=12.1, 2.6 Hz, 1H), 3.71 (dd, J=9.2, 5.7 Hz, 1H), 3.75±3.88 (m, 2H), 3.77 (dd, J=4.4, 2.7 Hz, 1H), 3.96 (dt,

6597
J=10.6, 2.4 Hz, 1H), 4.06 (td, J=8.4, 3.2 Hz, 1H), 4.12±4.23 (m, 2H), 4.26 (dd, J=11.3, 2.5 Hz, 1H), 4.41 (s, 2H),
4.48 (s, 2H), 4.49 (d, J=11.5 Hz, 1H), 4.41±4.50 (m, 5H), 4.56 (d, J=11.0 Hz, 1H), 4.57 (d, J=11.0 Hz, 1H), 4.63
(d, J=11.5 Hz, 1H), 4.66 (d, J=11.0 Hz, 1H), 4.77 (d, J=10.9 Hz, 1H), 4.87 (d, J=11.0 Hz, 1H), 4.95 (d, J=10.9
Hz, 1H), 5.05 (t, J=11.4 Hz, 1H), 5.47±5.62 (m, 2H), 7.05±7.14 (m, 2H), 7.23±7.45 (m, 28H). Calcd for C63H69O12
(M+H+): 1017.4789. Found: 1017.4637. Compound 23Z:1H NMR (CDCl3, 400 MHz) ꢁ 1.33 (s, 3H), 1.46 (s, 3H),
1.75±2.08 (m, 3H), 2.17±2.55 (m, 6H), 2.55±2.66 (m, 1H), 3.22 (dd, J=9.6, 8.4 Hz, 1H), 3.63±3.74 (m, 1H), 3.74±
3.86 (m, 2H), 3.88 (dd, J=7.6, 3.2 Hz, 1H), 3.98±4.10 (m, 2H), 4.21 (dd, J=9.6, 3.0 Hz, 1H), 4.34±4.44 (m, 2H),
4.50±4.70 (m, 5H), 4.72±4.79 (m, 1H), 4.80±4.95 (m, 2H), 5.19 (dt, J =9.6, 3.6 Hz, 1H), 5.43±5.69 (m, 2H), 5.92 (d,
J=3.6 Hz, 1H), 7.20±7.40 (m, 20H). Calcd for C51H59O12 (M+H+): 863.4028. Found: 863.4028.
12. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identi®cation of Organic Compounds, 6th ed.; John
Wiley & Sons: New York, 1998.