Mild and efficient chemoselective deprotection of anomeric O-methyl glycosides with trityl tetrafluoroborate

Article abstract of DOI:10.1021/jo800693w

(Chemical Equation Presented) A facile chemoselective deprotection of anomeric O-methyl glycosides has been achieved in good to excellent yields within 10-40 min with use of trityl tetrafluoroborate in dichloromethane at ambient temperatures. The present method is easily implemented and tolerates different functional groups.

Full text of DOI:10.1021/jo800693w

Hence, there remains a need to develop a mild, neutral, and
chemoselective method for deprotecting the anomeric O-methyl
glycosides especially with highly functionalized molecules that
cannot tolerate strong acidic conditions.
Mild and Efficient Chemoselective Deprotection
of Anomeric O-Methyl Glycosides with Trityl
Tetrafluoroborate
In an ongoing project in our laboratory related to the synthesis
of glycosidase inhibitors we faced the difficulty of selectively
hydrolyzing the anomeric -OMe group of molecule 1a (Table
1), which resulted in the decomposition of the starting material
while, using protic acid mediated deprotection. Hence we
explored the possibility of using a rather neutral method for
this purpose. In this context, it was found from literature that
the synthetic use of trityl tetrafluoroborate as a reagent has been
widely investigated8 in various organic transformations par-
ticularly in the deprotection of benzyl ethers. However, it was
anticipated that in preference to a benzyl ether, the anomeric
-OMe group should be easily deprotected due to higher
nucleophilicity of the anomeric oxygen as well as higher stability
of the carbocation at the anomeric center that could result after
the hydride transfer. Based on this, in this Note, we report, for
the first time, a practical and highly chemoselective method
for the deprotection of O-methyl glycosides under extremely
mild conditions by using trityl tetrafluoroborate as a reagent in
good to excellent yields (Table 1). Under these conditions
several functional groups such as benzyl, acyl, amide, and
carbamates remain unaffected. The reactions were carried out
by dissolving anomeric O-methyl glycosides in dichloromethane
followed by the addition of trityl tetrafluoroborate and stirring
the reaction mixture at room temperature. The results are
summarized in Table 1. The yields are good to excellent, ranging
from 72% to 92% in most cases. The functionalized O-methyl
furanosides (entries 1-6) were converted to the corresponding
lactols within 10-45 min, whereas tetrabenzylated O-methyl
pyranosides (entries 7-9) took longer reaction times of up to
8-10 h. These results indicate that in the presence of a benzylic
ether only anomeric O-methyl glycosides are hydrolyzed.
Interestingly, when the same reactions were performed with
2-hydroxy (10a and 11a) as well as NHBoc-substituted (12a)
furanosides (Scheme 1), a dual behavior was observed. Thus,
we found that substrates 10a and 11a afforded the corresponding
epoxides 10a′ and 11a′ whereas compound 12a gave the bicyclic
carbamate 12a′, respectively (Scheme 1). This indicates that an
oxacarbenium ion was formed as an intermediate and the free
hydroxy and amide groups at the C-2 position undergo intramo-
lecular nucleophilic substitution reactions as shown in Scheme
2.
Amit Kumar, Venkata Ramana Doddi, and
Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology
Kanpur 208 016, India
Vankar@iitk.ac.in
ReceiVed March 28, 2008
A facile chemoselective deprotection of anomeric O-methyl
glycosides has been achieved in good to excellent yields
within 10-40 min with use of trityl tetrafluoroborate in
dichloromethane at ambient temperatures. The present method
is easily implemented and tolerates different functional
groups.
One of the crucial steps in organic synthesis, including
carbohydrate chemistry, involves selective interconversion of
functional groups.1 In this context changes at the anomeric center
are particularly important since it usually plays a key role in
the synthesis of oligosaccharides and glycoconjugates2 as well
as in organic synthesis utilizing sugars as chiral synthons.3,4
The anomeric -OMe group in an O-methyl glycoside5 acts as
an effective protecting group in carbohydrate chemistry as it is
relatively stable under basic conditions. Usually the deprotection
of the anomeric O-methyl group is carried out by using protic6
and Lewis acids.7 However, deprotection under these conditions,
sometimes, requires a long reaction time,6a,g high tempera-
ture,6a,d,f and strong acids. Further, selective hydrolysis in the
presence of other functional groups is also not easily observed.
(1) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; Wiley; New York, 1999. (b) Kocienski, P. J. Protecting Groups; George
Thieme: Stuttgart, New York, 1994.
(6) (a) Wong, A.; Munos, J. W.; Devasthali, V.; Johnson, K. A.; Liu, H-W.
Org. Lett. 2004, 6, 3625. (b) Tejima, S.; Fletcher, H. G., Jr J. Org. Chem. 1963,
28, 2999. (c) Ohrui, H.; Misawa, T.; Meguro, H. J. Org. Chem. 1985, 50, 3007.
(d) Smith, A. B.; Yokoyama, Y.; Dunlap, N. K.; Haedener, A.; Tamm, C.
Tetrahedron Lett. 1987, 28, 3663. (e) Bird, P.; Dolphin, D. H.; Withers, S. G.
Can. J. Chem. 1990, 68, 317. (f) Veeneman, G. H.; Gomes, L. J. F.; van Boom,
J. H. Tetrahedron. 1989, 45, 7433. (g) Kuwahara, S.; Moriguchi, M.; Miyagawa,
K.; Konno, M.; Kodama, O. Tetrahedron Lett. 1995, 36, 3201.
(2) (a) Sinay, P. Pure. Appl. Chem. 1987, 59, 445. (b) Sadozai, K. K.; Ito,
Y.; Nukada, T. Ogawa Carbohydr. Res 1986, 150, 91. (c) Paulsen, H.; Lorentzen,
J. P. Carbohydr. Res. 1987, 147, 63. (d) Lemieux, R. U.; Bundle, D. R.; Baker,
D. A. J. Am. Chem. Soc. 1975, 97, 4076. (e) Nashed, M. A.; Anderson, L.
Carbohydr. Res. 1983, 114, 43.
(3) (a) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon Prers; New York, 1983. (b) Inch, T. D. Tetrahedron 1984,
40, 3161.
(7) (a) Paquette, L. A.; Pansegrau, P. D.; Wiedeman, P. E.; Springer, J. P. J.
Org. Chem. 1988, 53, 1461. (b) Schweizer, F.; Otter, A.; Hindsgaul, O. Synlett
2001, 11, 1743.
(4) Fraser-Reid, B.; Anderson, R. C. Prog. Chem. Nat. Prod. 1980, 39, 1.
(5) (a) Zehavi, U.; Sharon, N. J. Org. Chem. 1972, 37, 2141. (b) Ganesh,
N. V.; Jayaraman, N. J. Org. Chem. 2007, 72, 5500. (c) Lee, J.-C.; Pan, G.-R.;
Kulkarni, S. S.; Luo, S.-Y.; Liao, C.-C.; Hung, S.-C. Tetrahedron Lett. 2006,
47, 1621. (d) Anastasia, M.; Allevi, P.; Ciuffreda, P.; Fiecchi, A.; Scala, A.
Carbohydr. Res. 1990, 208, 262. (e) Laventine, D. M.; Jenkins, P. R.; Cullis,
P. M. Tetrahedron Lett. 2005, 46, 2295.
(8) (a) Barton, D. H. R.; Mugnus, P. D.; Smith, G.; Streckert, G. J. Chem.
Soc., Perkin Trans. 1972, 1, 542. (b) Doyle, M. P.; Siegfried, B. J. Am. Chem.
Soc. 1976, 98, 163. (c) Oshima, M.; Murakami, M.; Mukaiyama, T. Chem. Lett.
1986, 1593. (d) Hashimoto, Y.; Sugumi, H.; Okauchi, T.; Mukaiyama, T. Chem.
Lett. 1987, 1691. (e) Uchiro, H.; Mukaiyama, T. Chem. Lett. 1996, 79.
10.1021/jo800693w CCC: $40.75
Published on Web 06/27/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5993–5995 5993

TABLE 1. Deprotection of Anomeric O-Methyl Glycosides with
SCHEME 1. One-Pot Synthesis of Epoxide and Bicyclic
Carbamate from O-Methyl Glycosides
Trityl Tetrafluoroborate at Room Temperaturea, b
SCHEME 2. Plausible Mechanisim for Anomeric O-Methyl
Glycosides Hydrolysis and for Epoxide and Carbamate
Formation
SCHEME 3
irradiation of the H-4 proton of compound 12a′ enhanced the
peaks corresponding to H-3, H-2, and H-1 protons and clearly
these are cis to each other
a Reactions were performed as described in the general procedure.
b Substrates and products displayed satisfactory 1H and 13C NMR and
HRMS.
A plausible mechanism along the lines proposed in the
literature8 with use of trityl tetrafuloroborate is depicted in
Scheme 2. This involves transfer of a hydride ion from the
anomeric -OMe group to the trityl cation followed by loss of
HCHO, generation of an oxonium ion, and finally hydrolysis.
Surprisingly, with substrates bearing C-2 O-tosyl and NH-
tosyl substituents primary O-benzyl groups were debenzylated
as depicted in Scheme 3. The products were characterized by
functional group interconversions as well as NMR and mass
spectral studies.
The stereochemistry at the ring junctions of compounds 11a′
and 12a′ was confirmed by NOE experiments as shown in
Figure-1. For compound 11a′, no NOE interactions were
observed between H-4, H-1, and H-2 indicating that H-1, H-4
and H-2, H-4 are trans to each other. On the other hand,
This peculiar behavior could be attributed to the steric
hindrance provided by O- and N-tosyl groups present adjacent
to the anomeric O-methyl glycosides which prevent the interac-
tion of the -OMe group. Subsequently, the sterically less
hindered primary -OBn group is deprotected.
FIGURE 1. NOE correlations of compounds 11a′ and 12a′.
5994 J. Org. Chem. Vol. 73, No. 15, 2008

) 11.7 Hz), 4.60 (s, 1H), 4.54 (d, 1H, J ) 10.4 Hz), 4.49 (d, 1H,
J ) 10.4 Hz), 4.40 (ddd, 1H, J ) 10.4, 6.3, 4.2 Hz), 4.30 (dd, 1H,
J ) 6.3, 4.6 Hz), 3.73 (dd, 1H, J ) 10.7, 4.2 Hz), 3.64 (dd, 1H, J
) 10.7, 6.6 Hz), 3.41 (s, 3H), 1.29 (s, 9H). 13C NMR (100 MHz)
δ 155.8, 137.7, 137.6, 128.3-127.5 (m), 107.5, 79.1, 77.6, 73.7,
73.0, 68.0, 55.3, 55.0, 40.2, 28.3, 27.7, 21.3. HRMS calcd for
C25H34NO6 [M + H]+ 444.2386, found 444.2310.
In conclusion, trityl tetrafluoroborate chemistry can be
successfully applied to a wide range of functionalized O-methyl
glycosides, affording the corresponding lactols in good to
excellent yields. This method is easy to implement and tolerates
several functional groups and is chemoselective in most of the
cases. Further expolartion of this methodology is currently under
study in our laboratory.
(3aS,5R,6R,6aS)-6-(Benzyloxy)-5-(benzyloxymethyl)tetrahydro-
furo[3,2-d]oxazol-2(1H)-one (12a′). Yield 83% (syrup). Rf 0.50
28
(hexane:ethyl acetate, 6:4), [R]D +18.2 (c 0.85, CH2Cl2). IR
Experimental Section
(CH2Cl2) νmax 3291, 3062, 2923, 1767, 1454 cm-1. 1H NMR (400
MHz, CDCl3) δ 7.37-7.26 (m, 10H, Ar), 5.94 (d, 1H, J ) 2.6 Hz,
H-1), 5.73 (s, 1H, NH), 4.63 (d, 1H, J ) 11.7 Hz, -OCH2Ph),
4.59 (d, 1H, J ) 11.7 Hz, -OCH2Ph), 4.49-4.44 (m, 3H, 2 ×
-OCH2Ph and H-4), 4.16-4.12 (m, 2H, H-3, and H-2), 3.75 (dd,
1H, J ) 11.0, 4.1 Hz, H-5), 3.53 (dd, 1H, J ) 11.0, 7.3 Hz, H-5′).
13C NMR (100 MHz) δ 157.3, 137.9, 136.7, 128.7-127.5 (m),
120.7, 80.1, 77.8, 73.5, 73.4, 69.4, 56.8. HRMS calcd for C20H22NO5
[M + H]+ 356.1498, found 356.1492.
General Experimental Procedure for Deprotection of Ano-
meric O-Methyl Glycosides. To a solution of an anomeric O-methyl
glycoside (1 mmol) in dry dichloromethane (3 mL) was added trityl
tetrafluoroborate (330 mg, 1 mmol) under nitrogen atmosphere. The
reaction mixture was stirred at room temperature for the required
length of time (Table 1). After completion of the reaction (TLC
monitoring), the mixture was quenched with an excess of sodium
hydrogen carbonate. The organic phase was washed with water,
dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The crude product obtained was further purified
by column chromatography on silica gel (100-200 mesh).
Acknowledgment. We thank the Department of Science and
Technology, New Delhi, for financial support in the form of a
Ramanna Fellowship to Y.D.V. (Grant No. SR/S1/RFOC-04/
2006). A.K. and D.V.R. thank the CSIR, New Delhi for senior
research fellowships.
tert-Butyl (2R,3S,4R,5R)-4-(Benzyloxy)-5-(benzyloxymethyl)-2-
methoxytetrahydrofuran-3-ylcarbamate (12a). The amine 2 (200
mg, 1.75 mmol) was dissolved in CH2Cl2 (3 mL) and treated with
Et3N (0.33 mL, 2.37 mmol) and (Boc)2O (518 mg, 2.37) at room
temperature then the mixture was stirred for 3 h. The reaction
mixture was extracted with CH2Cl2 (2 × 10 mL) and the organic
layer was washed with water and brine. The usual workup gave a
crude product that was purified by column chromatography to give
compound 12a. Yield 85%. Rf 0.50 (hexane:ethyl acetate, 4:6),
[R]D28 +88.5 (c 1.45, CH2Cl2). IR (CH2Cl2) νmax 3062, 2823, 1679,
Supporting Information Available: Compounds 5a, 5a′, 7a,
7a′, 8a, 8a′, 9a, 9a′, 10a, 10a′, 13a, and 14a have been
previously characterized and their NMR spectral data were in
good agreement with the literature data; experimental procedures
and full spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
1420 cm-1. H NMR (400 MHz, CDCl3) δ 7.33-7.25 (m, 10H),
5.18 (d, 1H, J ) 4.6 Hz), 4.89 (t, 1H, J ) 4.6 Hz), 4.66 (d, 1H, J
JO800693W
J. Org. Chem. Vol. 73, No. 15, 2008 5995