Development of a catalytic cycle for the generation of C1-glycosyl carbanions with Cp2TiCl2: Application to glycal synthesis

Article abstract of DOI:10.1016/S0040-4039(00)01514-8

A catalytic cycle has been developed for the conversion of glycosyl halides to their corresponding glycals using Cp₂TiCl₂. This process can be effectively used with only 30% of the in situ generated single electron reducing agent in contrast to the 2 equivalents normally employed. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01514-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8645–8649
Development of a catalytic cycle for the generation of
C1-glycosyl carbanions with Cp2TiCl2: application to glycal
synthesis
Thomas Hansen, Kim Daasbjerg and Troels Skrydstrup*
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
Received 11 July 2000; revised 25 August 2000; accepted 7 September 2000
Abstract
A catalytic cycle has been developed for the conversion of glycosyl halides to their corresponding
glycals using Cp2TiCl2. This process can be effectively used with only 30% of the in situ generated single
electron reducing agent in contrast to the 2 equivalents normally employed. © 2000 Published by Elsevier
Science Ltd.
Keywords: electron transfer; glycosyl halides; anomeric radicals; anions; titanium.
The single electron reducing agent, bis(cyclopentadienyl)titanium chloride (Cp2TiCl), has
currently attracted much interest due to its ability to promote a variety of selective radical and
anionic reactions, such as highly diastereoselective pinacol coupling,1 reductive epoxide opening
and subsequent radical addition reactions,2 as well as reduction of glycosyl halides3 and
vic-dibromides.4 Particularly attractive for the radical based reactions are the recent develop-
ments of catalytic protocols with respect to the low valent metal complex. Gansa¨uer and
co-workers have nicely demonstrated that both pinacol coupling and reductive epoxide opening
may effectively be achieved with 5 mol% Cp2TiCl2 employing a stoichiometric reductant such as
manganese, and either a trialkylsilyl chloride or collidinium chloride for the liberation of the
TiIV species from the product.1d–h,2g–j,5 Whereas such a protocol works well for radical reactions,
it may be anticipated that in reactions where the corresponding anion is of interest, the second
reduction step would be less favored owing to competitive hydrogen abstraction, rearrangement
and fast dimerization reactions.6 This is explained by the increased effective lifetime of the
generated radical due to the decreased quantities and hence low concentration of the titaniumIII
reagent compared to the stoichiometric version.
* Corresponding author. Tel: (45) 89 42 39 32; fax: (45) 86 19 61 99; e-mail: ts@kemi.aau.dk
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01514-8

8646
In this communication, we show that counterintuitively glycosyl C1-carbanions are effectively
prepared employing only 30 mol% of Cp2TiCl2 with manganese as the metal reductant
compared to the two equivalents of the TiIV complex, which has previously been reported. This
catalytic cycle has been adapted to the preparation of the synthetically useful glycals7 from
protected glycosyl halides.8
Initial experiments were carried out with acetobromoglucose (1) as shown in Table 1.
Reactions were run exactly as described earlier with manganese as the stoichiometric reductant9
though with varying quantities of Cp2TiCl2 and the addition of 1.3 equivalents of Me3SiCl or
collidinium chloride. Best results were obtained with Me3SiCl as the regenerating agent (entry 2),
as in its absence or with collidinium chloride (entries 3 and 4) the yield of triacetylglucal 2 was
low, suggesting that regeneration of Cp2TiCl was slow or not taking place. As expected, the
catalyst loading has a clear effect on the efficiency of the glycal formation. The yields of the
glycal steadily improved with increasing mol% of Cp2TiCl2 reaching a plateau at approximately
40 mol% (entry 6).10 The importance of the catalyst is shown in entry 9, as in its absence no
glycal formation was obtained.11
Table 1
Effect of the catalyst loading on the formation of triacetylglucala
Entry
Quantity of Cp2TiCl2 (mol%)
Regenerating agent
Yield of triacetylglucal
1
2
3
4
5
6
7
8
9
10
20
20
20
30
40
80
160
0
Me3SiCl
Me3SiCl
–
Collidinium chloride
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
Me3SiCl
59%
62%
17%
31%
65%
77%
83%
82%
0%
a Isolated yields after chromatography on silica gel.
In order to diminish the quantity of the titanium catalyst without effecting the yield, the
solvent volume was reduced by two-fold.12 In this way, the catalyst loading could be decreased
to 30% without a noteworthy influence on the product yield. The results are shown in Table 2
with a variety of glycosyl bromides and one chloride. The reaction with the monosaccharide and
disaccharide derivatives in entries 1–8 work well and are basically as good as seen with that
employing stoichiometric amounts of Cp2TiCl2.3e Even the less reactive glycosyl chloride could
be used affording the tri-O-benzylglucal in 72% yield (entry 8).13

8647
Table 2
Glycal synthesis using 30 mol% Cp2TiCl2a
In Scheme 1, we propose a mechanism for the catalytic cycle developed to generate
carbohydrate C1-carbanions. Reduction of Cp2TiCl2 with manganese powder affords Cp2TiCl
which participates in a dissociative electron transfer step with the glycosyl halide 1. This
produces the anomeric radical 3 and Cp2TiBrCl, which is reduced to Cp2TiCl with the excess
manganese. Further reduction of 3 then gives the anomeric anion 4, which undergoes concomi-
tant b-elimination with the C2-substituent affording the glycal 2 and Cp2TiCl(OAc). Liberation
of the TiIV complex from acetate with Me3SiCl then completes the catalytic cycle.
In conclusion, we have successfully applied the catalytic protocol with Cp2TiCl2, previously
employed in radical reactions, for the generation of C1-sugar anions. Although the amount of
catalyst is still higher than for other TiIII-catalyzed radical reactions, the above-described work
has lowered the amount of Cp2TiCl2 required for glycal formation from 200 to 30 mol%, which
is a considerable reduction. Further work is now in progress to employ such anions in other
reactions.

8648
Scheme 1. A mechanistic proposal for the catalytic cycle with Cp2TiCl2
Acknowledgements
Financial support from the Danish National Science Foundation (THOR program), the
Carlsberg Foundation and the University of Aarhus is gratefully acknowledged.
References
1. (a) Handa, Y.; Inanaga, J. Tetrahedron Lett. 1987, 28, 5717. (b) Barden, M. C.; Schwartz, J. J. Am. Chem. Soc.
1996, 118, 5484. (c) Barden, M. C.; Schwartz, J. J. Org. Chem. 1997, 62, 7520. (d) Gansa¨uer, A. Chem. Commun.
1997, 457. (e) Gansa¨uer, A.; Bauer, D. J. Org. Chem. 1998, 63, 2070. (f) Gansa¨uer, A.; Moschioni, M.; Bauer,
D. Eur. J. Org. Chem. 1998, 1923. (g) Gansa¨uer, A.; Bauer, D. Eur. J. Org. Chem. 1998, 2673. (h) Dunlap, M.
S.; Nicholas, K. M. Synth. Commun. 1999, 29, 1097.
2. (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110, 8561. (b) Nugent, W. A.; RajanBabu, T. V.
J. Am. Chem. Soc. 1989, 111, 4525. (c) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986. (d)
Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc., Chem. Commun. 1990, 843. (e) Yadav, J. S.;
Shekharam, T.; Srinivas, D. Tetrahedron Lett. 1992, 33, 7973. (f) Maiti, G.; Roy, S. C. J. Chem. Soc., Perkin
Trans 1 1996, 403. (g) Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed. 1998, 37, 101. (h)
Gansa¨uer, A.; Bluhm, H. Chem. Commun. 1998, 2143. (i) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.
Soc. 1998, 120, 12849. (j) Gansa¨uer, A.; Lauterbach, T.; Bluhm, H.; Noltemeyer, M. Angew. Chem., Int. Ed. 1999,
38, 2909.
3. (a) Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1995, 60, 7055. (b) Spencer, R. P.; Schwartz, J. Tetrahedron Lett.
1996, 37, 4357. (c) Spencer, R. P.; Schwartz, J. J. Org. Chem. 1997, 62, 4204. (d) Spencer, R. P.; Cavallaro, C.
L.; Schwartz, J. J. Org. Chem. 1999, 64, 3987. (e) Hansen, T.; Krintel, S. L.; Daasbjerg, K.; Skrydstrup, T.
Tetrahedron Lett. 1999, 40, 6087.

8649
4. Davies, S. G.; Thomas, S. E. Synthesis 1984, 1027.
5. Gansa¨uer, A. Synlett 1998, 801.
6. For example, Cavallaro and Schwartz have previously attempted the preparation of glycals from glycosyl halides
using catalytic Cp2TiCl2 with aluminum or zinc. In both cases, the product obtained from direct reduction of the
halide was observed as the major product, see Ref. 3d.
7. For recent reviews on the use of glycals in organic synthesis, see: (a) Danishefsky, S. J.; Bilodeau, M. T. Angew.
Chem., Int. Ed. 1996, 35, 1380. (b) Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685.
8. For a recent account on the different methods used for the preparation of glycals, see: Spencer, R. P.; Schwartz,
J. Tetrahedron 2000, 56, 2103.
9. Replacement of the manganese metal, by aluminum or zinc led to reduced or no yield of the expected glycals,
respectively (Ref. 3e).
10. The major byproduct in the reactions with low catalyst loading is the compound of simple reduction;
1-deoxy-2,3,4,6-tetra-O-acetyl-D-glucopyranose.
11. Several attempts to reduce the catalyst loading by the syringe pump addition of the glycosyl halide to the
Cp2TiCl2/Mn/Me3SiCl mixture lead to a low yield of the glycal in addition to the 1-deoxy derivative (Ref. 10).
12. Further reduction of the solvent volume led to a slurry which afforded reduced yields of the triacetylglucal.
13. Representative example: a solution of acetobromocellobiose (170 mg, 0.24 mmol), Cp2TiCl2 (18 mg, 0.073 mmol),
Mn (50 mg, 0.91 mmol) and Me3SiCl (40 ml, 0.31 mmol) in THF (1 ml) was stirred for 12 h at 20°C under argon.
The reaction was evaporated to dryness and the residue was purified by column chromatography
(CH2Cl2:acetone, 24:1). This afforded the corresponding glycal as a colorless syrup (128 mg, 94%).
.