Regioselective de-O-benzylation of monosaccharides

Article abstract of DOI:10.1016/S0040-4039(01)02306-1

Poly-O-benzylated sugars are regioselectively debenzylated using CrCl₂/LiI in moist EtOAc. A predictive, three-point coordination model is proposed.

Full text of DOI:10.1016/S0040-4039(01)02306-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 963–966
Regioselective de-O-benzylation of monosaccharides
J. R. Falck,a,* D. K. Barma,a Sylesh K. Venkataraman,a Rachid Baatib and Charles Mioskowskib
aDepartments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas,
TX 75390-9038, USA
bUniversite´ Louis Pasteur de Strasbourg, Faculte´ de Pharmacie, Laboratoire de Synthe`se Bio-Organique (UMR 7514),
67401 Illkirch, France
Received 21 September 2001; accepted 29 November 2001
Abstract—Poly-O-benzylated sugars are regioselectively debenzylated using CrCl2/LiI in moist EtOAc. A predictive, three-point
coordination model is proposed. © 2002 Elsevier Science Ltd. All rights reserved.
Benzyl ethers are widely utilized as alcohol protecting
groups.1 They are easily installed, stable to a wide range
of reagents, and readily removed in the presence of
many common functionalities via catalytic hydrogen-
olysis, dissolving metals or Lewis/Bro¨nsted acids. How-
ever, in the context of labile or polybenzylated
compounds, e.g. carbohydrates,2 the traditional de-O-
benzylation conditions show poor regioselectivity and/
or are too harsh.3 A variety of elaborated benzyl ether
protecting groups has been introduced to address these
limitations, but they lack the robustness of unsubsti-
tuted benzyl ethers and often introduce an additional
level of complexity.1,4 In continuation of our studies of
CrCl2/LiI,5 we report herein the utility of this reagent
combination for the regioselective deprotection of poly-
benzylated carbohydrates (Eq. (1)) and propose a three-
point coordination3b,c of the carbohydrate with Cr(II)
or Cr(III) for optimal selectivity.
1). This remarkable selectivity can be explained by
prior complexation3b,c of Cr with the oxygens of the
ring and the C(5) and C(6) side chain substituents (Fig.
1). SN2 attack at the C(5)-benzyl by iodide along path-
way ‘a’ is comparatively unhindered and leads to the
observed differential product 2. Displacement at the
C(6)-benzyl via trajectory ‘b’ is more sterically con-
gested since it traverses the top face of the ring. While
alternative three-point complexes are possible, e.g.
between the C(3)-, C(5)-, and C(6)-oxygens, they
appear less likely. This is evident in the reactivity of
C(3)-acetyl derivative 37 (entry 2) and allose 58 (entry
3), the C(3)-epimer of 1, both of which lose their
C(5)-protecting group resulting in
respectively.
4
and 6,9
The strict regioselectivity observed above can be over-
come in some cases by intramolecular chelation; thus,
alcohol 8 is smoothly generated from 7 (entry 4) via
specific rupture of the 2,6-dimethoxybenzyl (DOB)
ether. When there is more than one possibility for
intramolecular chelation, the more accessible ether is
favored. For example, 9 gave rise to 10 (entry 5) at
room temperature. Inspection of 2,4,6-tri-O-benzyl-
myo-inositol orthoformate10 (11) reveals only the side
encompassing the C(1)-, C(2)-, and C(3)-oxygens can
simultaneously coordinate to chromium and, in accor-
dance with the predictive model, only the C(2)-benzyl
ether is cleaved providing alcohol 1210 in good yield
(1)
The scope and regioselectivity of the de-O-benzylation
were evaluated using a panel of representative polyben-
zylated monosaccharides and the results are compiled
in Table 1. Treatment of 3,5,6-tri-O-benzyl-1,2-O-iso-
propylidene-a-
-glucofuranose6 (1) with CrCl2 and LiI
D
at 75°C gave 23b as the sole product in good yield (entry
(entry 6). For 1,6-anhydro-a-
-glucopyranose 13,11
D
only the a-face (encompassing the ring, C(2)-, and
C(4)-oxygens) can form a three-point chelate. In this
case, exposure to 1 equivalent of CrCl2 trimmed just the
C(4)-benzyl ether to give 14,12 whereas 4 equivalents of
CrCl2 led to diol 1512 in excellent overall yield (entry 7).
Keywords: chromium; protecting groups; cleavage reactions; deblock-
ing; carbohydrates.
* Corresponding author. Tel.: 214-648-2406; fax: 214-648-6455;
e-mail: j.falck@utsouthwestern.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02306-1

964
J. R. Falck et al. / Tetrahedron Letters 43 (2002) 963–966
Table 1. Regioselective de-O-benzylation using CrCl2/Li

J. R. Falck et al. / Tetrahedron Letters 43 (2002) 963–966
965
References
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd Ed.; John Wiley & Sons: New
York, 1999; Chapter 2.
2. Zeigler, T. Carbohydr. Chem. 1998, 21–45.
3. For examples of differential cleavage of benzyl ethers,
see: (a) Madsen, J.; Viuf, C.; Bols, M. Chem. Eur. J.
2000, 6, 1140–1146; (b) Hori, H.; Nishida, Y.; Ohrui, H.;
Meguro, H. J. Org. Chem. 1989, 54, 1346–1353; (c)
Kartha, K. P. R.; Kiso, M.; Hasegawa, A.; Jennings, H.
J. J. Carbohydr. Chem. 1998, 17, 811–817; (d) Klemer, A.;
Beiber, M.; Wilbers, H. Justus Leibigs Ann. Chem. 1983,
1416–1421; (e) BeMiller, J. N.; Muenchow, H. L. Carbo-
hydr. Res. 1973, 28, 253–262; (f) Angibeaud, P.; Defaye,
J.; Gadelle, A.; Utille, J. P. Synthesis 1985, 1123–1125; (g)
Bieg, T.; Szeja, W. Carbohydr. Res. 1990, 205, C10–C11.
4. Recent examples include methoxy-substituted benzyl
ethers: Yu, W.; Su, M.; Gao, X.; Yang, Z.; Jin, Z.
Tetrahedron Lett. 2000, 41, 4015–4017. Halobenzyl
ethers: Plante, O. J.; Buchwald, S. L.; Seeberger, P. H. J.
Am. Chem. Soc. 2000, 122, 7148–7149. a,a-Dimethylfluo-
robenzyl ethers: Cho, H.-S.; Yu, J.; Falck, J. R. J. Am.
Chem. Soc. 1994, 116, 8354–8355.
Figure 1. Chromium complex with 1.
Application of the standard deprotection conditions to
methyl 2,3,4,5-tetra-O-benzyl-a-D
-mannopyranoside13
(16) afforded 1714 exclusively (entry 8). On the other
hand, methyl glucopyranosides are not able to adopt a
stable three-point complex without energetically unfa-
vorable conformational changes and, consequently,
showed only modest regioselectivity: a-anomer 1815 fur-
nished alcohols 1916/2017 in a 60:40 ratio (entry 9) and
b-anomer 2115 yielded 22/2318 as a 70:30 mixture (entry
10).
5. Falck, J. R.; Barma, D. K.; Baati, R.; Mioskowski, C.
Angew. Chem., Int. Ed. Engl. 2001, 40, 1281–1283.
6. Ding, X.; Kong, F. Carbohydr. Res. 1996, 286, 161–166.
Acyclic monosaccharides, with their greater conforma-
tional mobility, were generally quite reactive and
undergo multiple rounds of ether cleavage. The evolu-
1
7. Spectral data for 3: H NMR (CDCl3, 300 MHz) l 1.29
tion of 1,2,6-tri-O-benzyl-
-mannitol (25),3b a HIV
D
(s, 3H), 1.49 (s, 3H), 1.91 (s, 3H), 3.68 (dd, 1H, J=5.4,
10.2 Hz), 3.84–3.96 (m, 2H), 4.36 (dd, 1H, J=3.0, 9.0
Hz), 4.47 (dd, 2H, J=3.9, 7.8 Hz), 4.60 (s, 2H), 4.78 (d,
1H, J=11.4 Hz), 5.31 (d, 1H, J=2.7 Hz), 5.86 (d, 1H,
J=3.6 Hz), 7.20–7.40 (m, 10H). 13C NMR (CDCl3, 75
MHz) l 20.91, 26.40, 26.74, 71.04, 72.62, 73.61, 74.98,
76.22, 77.62, 83.17, 104.91, 112.33, 127.69, 127.76, 127.86,
128.04, 128.48, 128.54, 138.21, 138.45, 169.73. 4: 1H
NMR (CDCl3, 400 MHz) l 1.31 (s, 3H), 1.51 (s, 3H),
2.10 (s, 3H), 2.69 (d, 1H, J=5.2 Hz), 3.61 (dd, 1H,
J=6.4, 9.6 Hz), 3.77 (dd, 1H, J=2.4, 9.6 Hz), 3.82–3.94
(m, 1H), 4.23 (dd, 1H, J=2.4, 8.8 Hz), 4.53 (d, 1H,
J=3.6 Hz), 4.55–4.63 (m, 2H), 5.32 (d, 1H, J=2.8 Hz),
aspartyl protease inhibitor,19 directly from 24 (entry 11)
is typical.
General procedure: A mixture of CrCl2 (0.8 mmol;
Strem Chem.) or CrCl3 (1.6 mmol) and LiI (2 mmol;
Aldrich Chem.) in ethyl acetate (8 mL) was heated
under argon at 70°C until a brown, homogeneous
solution was obtained (ꢀ0.5 h). The carbohydrate (0.2
mmol) in moist ethyl acetate (EtOAc:H2O=1:0.005, 1
mL) was added to the mixture at room temperature,
then heated at 55–75°C for 8–14 h. The reaction was
cooled to rt, quenched with water, and extracted with
EtOAc. The combined organic extracts were washed
with saturated aq. sodium sulfite, water, brine, dried
(Na2SO4) and concentrated in vacuo. Purification of the
residue by silica gel chromatography afforded the
respective products.
1
5.89 (d, 1H, J=4.0 Hz), 7.20–7.40 (m, 5H). 7: H NMR
(CDCl3, 400 MHz) l 1.36 (s, 3H), 1.52 (s, 3H), 3.78 (s,
6H), 3.62–3.71 (m, 1H), 4.03–4.07 (m, 1H), 4.18 (d, 1H,
J=2.8 Hz), 4.24 (dd, 1H, J=2.8, 9.2 Hz), 4.57–4.62 (m,
3H), 4.72–4.80 (m, 4H), 5.89 (d, 1H, J=3.6 Hz), 6.52 (d,
2H, J=8.0 Hz), 7.22–7.35 (m, 11H). 9: 1H NMR (CDCl3,
300 MHz) l 1.30 (s, 3H), 1.46 (s, 3H), 3.68–3.73 (m, 2H),
3.77 (s, 6H), 3.80 (s, 6H), 4.04 (dd, 1H, J=3.3 Hz),
4.34–4.39 (m, 1H), 4.59–4.61 (m, 1H), 4.65–4.71 (m, 4H),
5.87 (d, 1H, J=3.9 Hz), 6.53 (dd, 4H, J=1.8, 8.1 Hz),
7.19–7.26 (m, 2H). 10: 1H NMR (CDCl3, 400 MHz) l
1.35 (s, 3H), 1.49 (s, 3H), 2.90 (t, 1H, J=6.8 Hz),
3.78–3.81 (m, 2H), 3.84 (s, 6H), 4.05 (d, 1H, J=3.6 Hz),
4.27–4.29 (m, 1H), 4.59 (d, 1H, J=10 Hz), 4.71 (d, 1H,
J=4.0 Hz), 4.84 (d, 1H, J=10.4 Hz), 5.97 (d, 1H, J=4.0
Hz), 6.57 (d, 2H, J=8.4 Hz), 7.25–7.29 (m, 1H).
8. Koell, P.; Lendering, U. J. Carbohydr. Chem. 1987, 6,
281–293.
In summary, we describe an efficient, operationally
simple protocol for the regioselective cleavage of benzyl
ethers using CrCl2/LiI under conditions suitable for
polyfunctional or labile molecules. Optimal regioselec-
tivity required three-point coordination between the
carbohydrate and Cr.
Acknowledgements
9. Stepowska, H.; Zamojski, A. Tetrahedron 1999, 55, 5519–
5538.
10. Billington, D. C.; Baker, R.; Kulagowski, J. J.; Mawer, I.
M.; Vacca, J. P.; Jane deSolms, S.; Huff, J. R. J. Chem.
Soc., Perkin Trans. 1 1989, 1423–1429.
Financial support provided by the Robert A. Welch
Foundation, NIH (GM 31278, DK 38226) and an
unrestricted grant from Taisho Pharmaceutical Co.,
Ltd. Dr. E. R. Fogel is thanked for helpful discussions.

966
J. R. Falck et al. / Tetrahedron Letters 43 (2002) 963–966
11. Micheel, F.; Brodde, O. E.; Reinking, K. Justus Leibigs
Ann. Chem. 1974, 124–136.
16. Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990–
2016.
17. Chiu-Machado, I.; Castro-Palomino, J. C.; Madrazo-
Alonzo, O.; Lopetegui-Palacios, C.; Verez-Bencomo, V. J.
Carbohydr. Chem. 1995, 14, 551–562.
12. Carmen, C. M.; Martin-Lomas, M. Carbohydr. Res. 1988,
175, 193–199.
13. Fuegedi, P.; Liptak, A.; Nanasi, P.; Neszmelyi, A. Carbo-
hydr. Res. 1982, 107, C5–C9.
18. Kanaoka, M.; Yano, S.; Kato, H.; Nakada, T. Chem.
Pharm. Bull. 1986, 34, 4978–4983.
19. Sauve, G.; Bouzide, A. PCT Int. Appl. 2000, 152 pp, WO
0066524.
14. Chervenak, M. C.; Toone, E. J. Bioorg. Med. Chem. 1996,
4, 1963–1978.
15. Briner, K.; Vasella, A. Helv. Chim. Acta 1992, 75, 621–637.