C-Arylglucoside synthesis: Triisopropylsilane as a selective reagent for the reduction of an anomeric C-phenyl ketal

Article abstract of DOI:10.1016/j.tetasy.2003.08.007

Reduction of tetra-O-benzyl-protected 1C-phenylglucoside using triethylsilane and BF₃·OEt₂ has been reported (Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610-612) to give exclusively 2,3,4,6-tetra-O-benzyl-β-1C-phenyl-1-deoxyglucoside. We have determined that this reduction actually gives a 4:1 mixture of anomers (β:α). We observed that the selectivity of the reduction is influenced by the steric bulk of the silane. The use of triisopropylsilane as a reducing agent gives >35:1 ratio (β:α) of 2,3,4,6-tetra-O-benzyl-β-1C-phenyl-1- deoxyglucoside.

Full text of DOI:10.1016/j.tetasy.2003.08.007

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3243–3247
C-Arylglucoside synthesis: triisopropylsilane as a selective
reagent for the reduction of an anomeric C-phenyl ketal
Bruce A. Ellsworth,a,* Abigail G. Doyle,a,† Manorama Patel,a Janet Caceres-Cortes,b Wei Meng,a
Prashant P. Deshpande,c Annie Pullockaranc and William N. Washburna
aDepartment of Metabolic Disease Discovery Chemistry, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543, USA
bDepartment of Preclinical Candidate Optimization, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543, USA
cDepartment of Process Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543, USA
Received 18 July 2003; accepted 1 August 2003
Abstract—Reduction of tetra-O-benzyl-protected 1C-phenylglucoside using triethylsilane and BF3·OEt2 has been reported
(Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610–612) to give exclusively 2,3,4,6-tetra-O-benzyl-b-1C-phenyl-1-deoxyglucoside.
We have determined that this reduction actually gives a 4:1 mixture of anomers (b:a). We observed that the selectivity of the
reduction is influenced by the steric bulk of the silane. The use of triisopropylsilane as a reducing agent gives >35:1 ratio (b:a)
of 2,3,4,6-tetra-O-benzyl-b-1C-phenyl-1-deoxyglucoside.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
with carbon nucleophiles to selectively generate b-C-
glucosides via the general route outlined in Figure 1.6–13
Although reductions of the intermediate ketal (structure
2) generally provide glycosides with the alkyl- or aryl
substituents in the b-configuration, Kishi et al. reported
that the reduction of alkyl-glycoside 4 proceeded with
modest selectivity (Scheme 1). The reduction of hemike-
tal 4 gave 3:1 ratio of equatorial (b) and axial products
(a) with Et3SiH; whereas, substitution of tri-n-propylsi-
lane increased the b:a selectivity to 7:1, demonstrating
that these reductions are sensitive to the steric bulk of
the reducing agent.14,15 During the synthesis of C-thia-
zoylglycosides, Dondoni et al. observed that the tri-
ethylsilane reduction of ketal 7 generated a 1:1 ratio of
equatorial (b) to axial (a) products (Scheme 2). They,
too, demonstrated that more sterically demanding
We were interested in a versatile, selective synthesis of
b-C-aryl glucosides, an important class of natural prod-
ucts.1,2 Among the many synthetic methods for prepa-
ration of b-C-arylglucosides,3,4 we utilized the addition
of an aryllithium reagent to an appropriately protected
gluconolactone followed by reduction of the intermedi-
ary lactol. However, during these gram-scale syntheses
of C-arylglucosides,5 a lower level of selectivity was
observed than anticipated based on published reports
of the silane-mediated reduction of 2,3,4,6-tetra-O-ben-
zyl-1C-phenylglucoside (Fig. 1, compound 2 R=Ph).6
This finding was unexpected since protected glucono-
lactone is often used as a glycosyl-donor in conjunction
Figure 1. Synthesis of b-C-arylglucosides via organometallic addition to gluconolactone.
* Corresponding author. Tel.: 1-609-818-4965; fax: 1-609-818-3460.; e-mail: bruce.ellsworth@bms.com
† Current address: Dept. of Chemistry, Mudd Building Box 151, Stanford University, Stanford, CA 94305-5080, USA
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.007

3244
B. A. Ellsworth et al. / Tetrahedron: Asymmetry 14 (2003) 3243–3247
Scheme 1. Synthesis of alkylglycosides. Reagents: (a) n-Pr3SiH, BF3·OEt2, CH3CN, −20°C gives a 7:1 ratio of 5 (b) to its
a-isomer.14,15
Scheme 2. Synthesis of 1-C-thiazoylglucosides.16 Reaction conditions: (a) 2-lithiothiazole, Et2O/THF; (b) TEA, CH2Cl2, Ac2O; (c)
TMS-OTf (10 equiv.), Et3SiH, CH2Cl2.
reducing agents can influence the outcome, since the
substitution of phenyldimethylsilane increased selectiv-
ity to 2:1 b:a linked products.16
tion outcome (Fig. 2) via spectra corresponding to the
individual a- and b-deoxyglucoside spin systems. In
conclusion, reduction of phenylketal 9 with BF3·OEt2
and Et3SiH unambiguously generates a 4:1 (b:a) mix-
ture of products.
2. Results and discussion
Having established product identity and analytical con-
ditions, the dependence of product composition on the
reducing agent was determined. The results, obtained
with a set of ten silanes as well as DIBAL, are summa-
rized in Table 1. Yields were essentially invariant (ca.
95%); however, composition ranged from 2:1 to 45:1.
The critical factor promoting beta selectivity appears to
be the steric bulk surrounding the silyl hydride center.
Of all the common, commercially available silane
reagents evaluated, the highest beta selectivity (45:1
b:a) was obtained with triisopropylsilane. This ability
to dramatically enhance formation of the beta anomer
by reduction of 2,3,4,6-tetra-O-benzyl-1C-arylglu-
cosides provides a practical means to prepare pure
b-1C-aryl-1-deoxyglucoside on multigram-scale without
necessitating difficult chromatographic separations or
crystallizations of modestly enriched anomeric
mixtures.
To delineate better the factors controlling the stereo-
chemical course of formation of b-arylglucosides, we
investigated the reduction of phenyl ketal 9 (Scheme 3)
which was prepared as an undetermined diastereotopic
mixture by addition of phenyllithium to 2,3,4,6-tetra-O-
benzylgluconolactone 1, as previously reported.6 Treat-
ment with BF3·OEt2 and Et3SiH converted ketal 9 in
99% yield to glucoside 10; however, HPLC analysis in
conjunction with LC-MS revealed 10 to be a 4:1 iso-
meric mixture. When this product mixture was hydro-
genated over Pd/C and exhaustively acetylated,
following the procedure of Czernecki and Ville,6 only
pure 2,3,4,6-tetra-O-acetyl-b-1C-phenyl-1-deoxyglucose
was obtained. More careful analysis revealed that the
minor component was preferentially lost during the
hydrogenolysis step, thereby producing the appearance
of a completely stereoselective ketal reduction.
Although separation of the mixture 10b,a was very
difficult by silica chromatography, the minor product,
upon isolation via semi-preparative reverse-phase
HPLC, was determined to be 2,3,4,6-tetra-O-benzyl-a-
1C-phenyl-1-deoxyglucoside 10a. NOESY experiments
confirmed the configuration of the minor product, as
10a. Selective 1D TOCSY experiments of the product
mixture 10 provided further confirmation of the reac-
We propose that, in the case of C-alkyl- and C-arylglu-
cosides, the usual anomeric influence on the facial
reactivity of oxocarbenium ions is mitigated by substi-
tution. Although we have not probed the electronic- or
steric contributions of the aryl-glycoside in depth, com-
parable selectivity patterns have been obtained using
triethylsilane and triisopropylsilane on a large number
of C-arylglucoside substrates.5

B. A. Ellsworth et al. / Tetrahedron: Asymmetry 14 (2003) 3243–3247
3245
Scheme 3. Synthesis of a- and b-C-phenylglucosides. Reaction conditions: (a) PhLi 1.8 M in hexanes, THF, −78°C; (b) BF3·OEt2,
Et3SiH, CH3CN/CH2Cl2 (3:1), −40°C; (c) (i) H2 (atm.), Pd(OH)2, EtOAc, (ii) Ac2O, pyridine, DMAP, CH2Cl2, 0°C.
3. Conclusion
We have discovered that the reduction of 2,3,4,6-tetra-
O-benzyl-1C-phenylglucoside is moderately selective
using triethylsilane. The use of triisopropylsilane in the
reduction of C-arylglucosides gives higher selectivity
for b-arylglucoside product, thereby facilitating the iso-
lation and characterization of intermediates toward the
synthesis of b-C-arylglucosides on multigram scale.
4. Experimental
4.1. 2,3,4,6-Tetra-O-benzyl-1C-phenylglucose 9
Figure 2. NMR spectra of the reduction product mixture and
Synthesis according to previous reports.6 [h]D25=+19.5
purified phenyldeoxyglucoside 10; A. Proton spectra of the
1
(c 1.0, CHCl3) H NMR (CDCl3, 400 MHz) l 7.64 (dd,
product mixture containing both a and b deoxyglucosides 10;
2H, J=1.6, 8.3 Hz), 7.41–7.16 (m, 21H), 6.98 (dd, 2H,
B. and C. 1D-TOCSY spectra of 10b and 10a deoxyglucoside,
J=1.5, 5.3 Hz), 4.94–4.86 (m, 3H), 4.65 (d, 2H, 9.0
respectively, upon selective excitation of the anomeric proton;
Hz), 4.55 (d, 1H, J=12.3 Hz), 4.39 (d, 1H, 10.1 Hz),
D. Proton spectra of the purified a-deoxyglucoside. Note:
4.18 (ddd, 1H, J=1.7, 6.1, 10.1 Hz), 4.08 (t, 1H, J=9.2
Benzylic protons are visible in spectra A and D, whereas
Hz), 3.88–3.83 (m, 2H), 3.80 (d, 1H, 10.5 Hz), 3.73 (dd,
selective excitation does not reveal these proton signals in
1H, J=1.7, 11.0 Hz), 3.07 (s, 1H) 13C (CDCl3, 100
spectra B and C.
MHz) l 142.2, 138.8, 138.7, 138.3, 137.2, 128.6, 128.4,
128.2, 127.9, 127.7, 127.6, 126.1, 97.9, 85.1, 83.4, 78.3,
75.7, 75.5, 73.3, 72.1, 69.0.
4.2. General procedure for ketal reductions
Anal. calcd for C40H40O6 theoretical: C, 77.89; H, 6.53
observed: C, 77.67; H, 6.50
To a cooled (−40°C) solution of 2,3,4,6-tetra-O-benzyl-
1C-phenylglucose (0.1 mmol) and silane (2 equiv.) in

3246
B. A. Ellsworth et al. / Tetrahedron: Asymmetry 14 (2003) 3243–3247
Table 1. Results of the reduction of ketal 9 to deoxyglu-
coside 10 (Scheme 3)
4.4. (1S)-2,3,4,6-Tetra-O-benzyl-1C-phenyl-1-deoxyglu-
cose 10b
Silane
Ratio (b-a)
PhSiH3
2:1
3:1
4:1
n-Pr3SiH
Me2PhSiH
Et3SiH
4:1
(Me3Si)3SiH
i-Bu3SiH
Ph3SiH
t-BuMe2SiH
DIBAL
4:1
7:1
16:1
24:1
25:1
45:1
[h]2D5=+11.1 (c 0.38, CHCl3) 1H NMR (CDCl3, 400
MHz), l 7.52–7.14 (m, 23H), 6.93–6.91 (m, 2H), 4.98–
4.86 (m, 3H), 4.68–4.55 (m, 3H), 4.36 (d, 1H, J=10.1
Hz), 4.25 (d, 1H, J=9.3 Hz, H-1), 3.82–3.73 (m, 5H),
3.61–3.60 (m, 1H), 3.55–3.50 (m, 1H). 13C NMR
(CDCl3, 100 MHz) l 139.0, 138.7, 138.4, 138.2, 137.6,
128.4, 128.3, 128.2, 128.0, 127.7, 86.7, 84.4, 81.7, 79.3,
78.3, 75.6, 75.1, 74.9, 73.4, 69.1. Anal. calcd for
C40H40O5 theoretical: C, 79.97; H, 6.71, found: C,
79.80; H, 6.82.
i-Pr3SiH
acetonitrile/CH2Cl2 (3:1) was added BF3·OEt2. Upon
stirring for 1 h at −40°C, an aliquot was removed for
HPLC analysis of reaction progress. When the reduc-
tion was complete, the solution was stirred at room
temp. for 30 min with 1 mL of saturated aqueous
potassium carbonate. The solution was extracted twice
with 50 mL of ethyl acetate. The combined organic
layers were washed with 50 mL of brine, dried over
MgSO4 and evaporated to give the product as an oil.
4.5. NMR characterization 10a, 10b
Proton and TOCSY-1D experiments were collected on
a Varian INOVA 500 MHz spectrometer in CDCl3 at
25°C. Proton spectra were acquired with 6.6 ms pulse at
55dB, 1s relation delay, 16 transients, 16384 complex
points and 5204.94 Hz spectral width. TOCSY-1D
experiments were acquired with 6.6 ms pulse at 55dB,
1.5 s relaxation delay, 512 transients, 16384 complex
points, 5204.94 Hz spectral width, MLEV spin lock
mixing array between 0 and 195 ms in 15 ms incre-
ments, selective 180° shaped pulse for anomeric protons
as follows: a at 5.28ppm, 127.2 ms at −7 dB and b at
4.29ppm, 134.4 ms at −7 dB.
HPLC analysis was performed at
1 mg/mL in
methanol. Column: YMC S-3 ODS (C-18) 6.0×150
mm. Solvent program: 100% solvent B (isocratic). Sol-
vent B: 90% methanol/water+0.2% H3PO4. Flow rate:
1.5 mL/min. Monochrome detection at 220 nm. Reten-
tion time: a isomer 10a 7.0 min, b isomer 10b 7.5 min.
Product ratios (Table 1) are reported as the average of
duplicate reductions.
4.3. (1R)-2,3,4,6-Tetra-O-benzyl-1C-phenyl-1-deoxyglu-
cose 10a
Acknowledgements
We thank Dr. David Floyd and Dr. Scott Biller for
support of the internship for A.G.D. We also thank Dr.
Richard Mueller for his support of an interdepartmen-
tal collaboration.
References
[h]2D5=+95.5 (c 0.02, CHCl3) 1H NMR (CDCl3, 400
MHz) l 7.74 (d, 2H, J=7.8 Hz), 7.35–7.22 (m, 21H),
7.11–7.09 (m, 2H), 5.24 (d, 1H, J=5.2 Hz, H1), 4.97
(app. d, 1H, J=11.1 Hz), 4.80 (d, 1H, J=2.0 Hz), 4.77
(d, 1H, J=1.7 Hz), 4.70–4.61 (m, 3H), 4.48 (m, 2H),
4.10–4.01 (m, 2H, H-2+H-3), 3.77–3.73 (m, 1H, H-4),
3.70–3.61 (m, 2H, H-6+H-6%), 3.53–3.49 (m, 1H, H-5).
13C NMR (CDCl3, 100 MHz) l 138.6, 138.2, 138.1,
138.0, 137.8, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6,
127.4, 82.0, 81.3, 78.3 (C-4), 75.0, 74.7, 73.6, 73.4 (C-1),
73.1, 72.3 (C-5), 69.0 (C-6) Anal. calcd for C40H40O5
HRMS [M+NH4] 618.3219, found m/z 618.3240.
1. Suzuki, K.; Matsumoto, T. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed. Synthesis of Glycosylare-
nes; Marcel Dekker, Inc: New York, 1997; pp. 527–542.
2. Hacksell, U.; Daves, G. D., Jr. In Prog. Med. Chem.;
Ellis, G. P.; West, G. B., Eds. The Chemistry and Bio-
chemistry of C-Nucleosides and C-Arylglycosides;
Elsevier Science Publishers, 1985; pp. 19–65.
3. Jaramillo, C.; Knapp, S. Synthesis 1994, 1–20.
4. Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998,
54, 9913–9959.
5. Ellsworth, B.; Washburn, W. N.; Sher, P. M.; Wu, G.;
Meng, W. US patent US 6,414,126B1, 2002

B. A. Ellsworth et al. / Tetrahedron: Asymmetry 14 (2003) 3243–3247
3247
6. Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54 (3), 610–612.
7. Bihovsky, R.; Selick, C.; Giusti, I. J. Org. Chem. 1988, 53,
4026–4031.
12. Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem. 2002,
67, 4475–4486.
13. Daly, S. M.; Armstrong, R. W. Tetrahedron Lett. 1989, 30,
5713–5716.
8. Kraus, G. A.; Molina, M. T. J. Org. Chem. 1988, 53,
752–753.
14. Babirad, S. A.; Wang, Y.; Kishi, Y. J. Org. Chem. 1987,
52, 1370–1372.
9. Lancelin, J.-M.; Zollo, P. H. A.; Sinay, P. Tetrahedron Lett.
15. Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992,
1983, 24, 4833–4836.
57, 468–481.
10. Fuganti, C.; Serra, S. Synlett 1999, 1241–1242.
11. Dondoni, A.; Mariotti, G.; Marra, A.; Massi, A. Synthesis
2001, 2129–2137.
16. Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59,
6404–6412.