α-Glucosaminide synthesis: Exercising stereocontrol at C1 or C2 via torsional effects or DeShong nucleophiles

Article abstract of DOI:10.1016/S0040-4039(00)01329-0

The synthesis of α-glucosaminides may be carried out by installing synthons for the cis-related C1 and C2 functionalities in either order. When the C2 azide is installed first, α-glycosidation can be induced by using a 4,6-O-benzylidene ring to provide torsional control of anomeric selectivity. In the alternative option, the C1 linkage can be established by use of an n-pentenyl-manno-1,2-orthoester, the C2-oxygen of the resulting α-mannoside being replaced with inversion by use of DeShong's hypervalent silicon azide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01329-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7605–7608
a-Glucosaminide synthesis: exercising stereocontrol at C1 or
C2 via torsional effects or DeShong nucleophiles
G. Anilkumar, Latha G. Nair, Lars Olsson,† Jacquitta K. Daniels and Bert Fraser-Reid*
Natural Products and Glycotechnology Research Institute, Inc.,‡ 4118 Swarthmore Road, Durham, NC 27707, USA
Received 26 May 2000; revised 31 July 2000; accepted 1 August 2000
Abstract
The synthesis of a-glucosaminides may be carried out by installing synthons for the cis-related C1 and
C2 functionalities in either order. When the C2 azide is installed first, a-glycosidation can be induced by
using a 4,6-O-benzylidene ring to provide torsional control of anomeric selectivity. In the alternative
option, the C1 linkage can be established by use of an n-pentenyl-manno-1,2-orthoester, the C2ꢀoxygen
of the resulting a-mannoside being replaced with inversion by use of DeShong’s hypervalent silicon azide.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: hypervalent silicon azido nucleophiles; n-pentenyl glycosides; n-pentenyl orthoesters.
The laboratory synthesis of cis-1,2-glucosaminides, 2, presents problems with respect to both
the C1 and C2 stereocenters.1,2 Option A of Scheme 1 relates to C1, and in this connection,
Paulsen and co-workers introduced a C2 azido group as the 2-amino precursor, e.g. 1, in the
expectation that being a non-participating entity, it would facilitate a-glycosidation.3 This
seminal contribution has inspired novel synthetic approaches to C2 azido sugars,4 one of the
most recent being Vasella’s facile procedure for diazo transfer to amines.5 That development
enabled us to employ pent-4-enoyl6 and tetrachlorophthaloyl (TCP)7 as protecting groups for
preparing a variety of C2 azido sugars including 4a and 7.8
* Corresponding author. E-mails: dglucose@aol.com, werowdies@hotmail.com
† Present address: Astra Zeneca, Stockholm, Sweden.
‡ A non-profit organization at Centennial Campus (NC State University), Raleigh, NC, USA.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01329-0

7606
Scheme 1.
We were interested to determine the best donor-partner for the partially protected inositols 5(a9
or b)10 to obtain an a-product with good yield and selectivity. As indicated in Scheme 2a, the
NPG 4a failed to undergo appreciable coupling with 5a; the material was therefore converted into
glycosyl bromide, 4b, and trichloroacetimidate, 4c (Scheme 1), by standard procedures.11,12 With
4b, excellent a-selectivity was achieved by the Lemieux-halide assisted protocol,13 although the
yield was disappointing.14 On the other hand, the yield of coupled products with the trichloroace-
timidate 4c was very good; but the anomeric selectivity was problematic.15
Scheme 2.
Theoretical16 and experimental17 studies have shown that torsional factors strongly influence
reactions at the anomeric center, and Crich and co-workers have applied this chemistry elegantly
for controlling anomeric selectivities.18 In light of the abject failure with 4a (Scheme 2a) the
torsionally constrained benzylidene analog 7 was tested with acceptor 5b and, in contrast to 4a,
was found to give a satisfactory yield of 8 with complete a-selectivity (Scheme 2b). Notably,
N-bromosuccinimide had to be used as promoter, since the more potent combination (NIS/
TESOTf)11 caused cleavage of the benzylidene ring.
The routes in Scheme 2 are based upon the retrosynthetic strategy, option A, Scheme 1. The
alternative, option B, could (a) take advantage of the ready formation of a-mannosides, e.g. 3,
if (b) the resulting C2ꢀOR could be replaced by an amino group with inversion of configuration.
In order to explore option B, the n-pentenyl orthoester 9a19 was coupled with the inositol 5a to
provide the a-mannoside 10a (Scheme 3). The strategy of Lemieux and Gunner for stereocontrolled
reduction of C2-oximo glycosides20 was investigated with the derived oxime 10c, but the borane
reduction step proved too drastic for the substrate.

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Scheme 3. Reaction conditions: i. 9a (1.3 equiv.), NIS (1.3 equiv.), TBDMSOTf (0.3 equiv.), rt, 20 min, 78%; ii.
NaOMe, MEOH/CH2Cl2, 14 h, 94%; iii. (a) DMSO/Ac2O, rt, 24 h. (b) NH2OH, HCl, NaOAc·3H2O, H2O/EtOH, rt,
14 h; iv. 9 (1.3 equiv.), NIS (1.3 equiv.), BF3·OEt2 (0.3 equiv.), 0°C, 20–30 min; v. (a) Tf2O, DMAP, Pyr, CH2Cl2,
−75°C–rt, 3 h; vi. TMSN3 (1.5 equiv.), TBAF (1.5 equiv.), THF, 65°C, 14–24 h.
Nucleophilic displacement at C2 of a-mannosides is traditionally difficult,21 and so the complete
failure of Mitsunobu displacement22 on alcohol 10b was not surprising.
Binkley’s triflate displacement procedure23 has been successful elsewhere,2 and in order to test
this, the orthoesters 9a–c were coupled with inositol 5b to give 11a–c in excellent yields, and without
detectable contamination of b anomers (Scheme 3). Unfortunately, treatment of compound 12a
with sodium azide in DMF at room temperature gave only elimination products.
The recent report on the use of hypervalent silicon nucleophiles by DeShong and co-workers24
was therefore timely. Particularly impressive were the quantitative displacements with b-phenethyl
bromide, without b-elimination to give styrene. The triflates, 12a–c were subjected to the
hypervalent silicon azide as described by DeShong and co-workers. The TMSN3/tetra-
butylammonium triphenyldifluorosilicate (TBAT) reagent combination was problematic in that
the product was contaminated with aromatic impurities. This outcome was avoided by use of the
TMSN3/TBAF combination, 14, leading to the displacement products 13a–c in good yields. These
1
transformations could be easily monitored by analyzing the appropriate signals in the H NMR
spectra, (the parameters shown in Scheme 3 for 12a and 13a being typical) and the IR spectra,
which showed the required absorption for the azido group at 2104 cm−1.
In light of the widespread use of silicon protecting groups in carbohydrate transformations,
success in obtaining the tert-butyl diphenylsilyl (TBDPS)25 protected analogue 13c is noteworthy.
In summary, the C2 and C1 stereocenters of a-glucosaminides can be cleanly established either
by retrosynthetic option A or B (Scheme 1). For the former, the restraining effect of a
4,6-O-benzylidene ring can be used to induce a-coupling. For the latter, a manno NPOE ensures
(a) clean a-coupling and (b) a convenient C2ꢀester ready to be replaced with a triflate leaving
group for displacement with DeShong’s hypervalent silicon azide.

7608
Acknowledgements
We are grateful to the Research in Tropical Diseases (TDR) program of the World Health
Organization, Affymax Research Institute, and the NIH (GM40171) for financial assistance.
References
1. Vos, J. N.; van Boom, J. H.; van Boeckel, C. A. A.; Beetz, T. J. Carbohydr. Chem. 1984, 3, 117–129.
2. Pavliak, V.; Kovac, P. Carbohydr. Res. 1991, 210, 33–337.
3. Paulsen, H.; Stenzel, W.; Kolar, C. Tetrahedron Lett. 1977, 2785–2788. Paulsen, H.; Richter, A.; Stenzel, W.
Carbohydr. Res. 1978, 64, 339–364. Paulsen, H.; Stentzel, W. Chem. Ber. 1978, 111, 2334–2347.
4. Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244–1251. Kloosterman, M.; de Nijs, M. P.; van
Boom, H. J. Carbohydr. Chem. 1986, 5, 215. Pavliak, V.; Kovac, P. Carbohydr. Res. 1991, 210, 333–337.
5. Vasella, A.; Witzig, C.; Chiara, J. L.; Martin-Lomas, M. Helv. Chim. Acta 1991, 74, 2073–2077.
6. Madsen, R.; Roberts, C.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 7920–7926.
7. Debenham, J. S.; Debenham, S. D.; Fraser-Reid, B. Bioorg. Med. Chem. 1996, 4, 1909–1918.
8. Olsson, L.; Jia, J. J.; Fraser-Reid, B. J. Org. Chem. 1998, 63, 3790–3792.
9. Anilkumar, G.; Jia, Z. J.; Kraehmer, R.; Fraser-Reid, B. J. Chem. Soc., Perkin 1, 1999, 3591–3596.
10. Elie, C. J. J.; Verduyn, R.; Dreef, C. E.; van der Marel, G. A.; van Boom, J. H. J. Carbohydr. Chem. 1992, 11,
715–739.
11. Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt, R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett,
1992, 927–942.
12. Schmidt, R. R. In Modern Methods in Carbohydrate Synthesis; Khan, S. H.; O’Neill, R. A. Eds.; Harwood
Academic Publishers: The Netherlands, 1996; Chapter 2.
13. Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem. Soc. 1975, 97, 4056–4062.
14. However for another assessment see: Baeschlin, D. K.; Chaperon, A. R.; Green, L. G.; Hahn, M. G.; Ince, S. J.;
Ley, S. V. Chem. Eur. J. 2000, 6, 172–186.
15. However for another assessment see: Mayer, T. G.; Kratzer, B.; Schmidt, R. R. Angew. Chem., Int. Ed. Engl.
1994, 33, 2171–2181.
16. Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.; Bowen, J. P. J. Am. Chem. Soc. 1991, 113, 1434–1435.
17. Andrews, C. W.; Rodebaugh, R.; Fraser-Reid, B. J. Org. Chem. 1996, 61, 5280–5289.
18. Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291–1297. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120,
435–436.
19. Roberts, C.; May, C. L.; Fraser-Reid, B. Carbohydr. Lett. 1994, 1, 89–93.
20. Lemieux, R. U.; Gunner, S. W. Can. J. Chem. 1968, 46, 405–411.
21. Richardson, A. C. Carbohydr. Res. 1969, 10, 395–402.
22. Mitsunobu, O. Synthesis 1981, 1–64.
23. Binkley, E. R.; Binkley, R. W. In Preparative Carbohydrate Chemistry; Hanessian, S., Ed; Marcel Dekker: New
York, 1997; pp. 87–104.
24. Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P.; Favor, D. A.; Hirschmann, R.; Smith III, A. B. J.
Am. Chem. Soc. 1998, 120, 435–436.
25. Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975–2977.
.