Regioselective control in the oxidative cleavage of 4,6-o-benzylidene acetals of glycopyranosides by dimethyldioxirane

Article abstract of DOI:10.1021/jo9026098

"Chemical Equation Presentation" The oxidative cleavage of 4,6-O-benzylidene acetals of glycopyranosides using dimethyldioxirane (DMDO) leads to the corresponding hydroxy-benzoates in excellent yields. With a proper choice of the neighboring protecting groups, this oxidative fragmentation provides the 6- or 4-hydroxyl derivatives in a highly regioselective manner.

Full text of DOI:10.1021/jo9026098

pubs.acs.org/joc
SCHEME 1. Reported Methods for Oxidative Opening
Regioselective Control in the Oxidative Cleavage
of 4,6-O-Benzylidene Acetals of Glycopyranosides
by Dimethyldioxirane
†
Arnaud Stevenin, Franc-ois-Didier Boyer,*,‡ and
ꢀ
Jean-Marie Beau*,†,§
Centre de Recherche de Gif, Institut de Chimie des
Substances Naturelles, †CNRS, and ‡INRA, 1 avenue de la
Terrasse, F-91198 Gif-sur-Yvette Cedex, France, and
§
group, is less frequently employed because most known
procedures suffer from rather harsh or environmentally
unfriendly conditions. Oxidative cleavage of benzylidene
acetals of nonsaccharidic acetals using tritylfluoroborate
(Ph3CþBF4-),3 pyridinium dichromate/tert-butyl hydroper-
oxide,4 NaBO3,5 Co(OAc)2/N-hydroxyphthalimide,6 2,20-
ꢀ
ꢀ
Universite Paris-Sud, Institut de Chimie Moleculaire
ꢀ
ꢀ
et des Materiaux associe au CNRS, F-91405
Orsay Cedex, France
boyer@versailles.inra.fr; jean-marie.beau@u-psud.fr
Received December 9, 2009
8
bipyridinium chlorochromate/m-CPBA,7 NaBrO3/Na2S2O4
10
and KBrO3/Na2S2O4,9 and more recently RuCl3/NaIO4
has been evaluated and gave varying degrees of regio-
selectivity. Similarly, many methods have been developed
for the selective oxidative cleavage of 4,6-O-benzylidene
acetals of pyranosides. Ozone,3 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ),11,12 NBS/H2O,13 Pd(OAc)2 or CuCl2/
t-BuOOH,14 NaBrO3/Na2S2O4,8 Co(OAc)2/N-hydroxy-
9
phthalimide,6 and KBrO3/Na2S2O4 gave, in most cases,
the benzoyl esters in high yield but with moderate regio-
selectivity (Scheme 1).
As part of our ongoing interest to develop easy new
methods for the regioselective protection of carbohydrates,15
we now report conditions for the regioselective oxidative
opening of 4,6-O-benzylidene acetals of glycopyranosides
A using dimethyldioxirane (DMDO), leading to the corre-
sponding 4-alcohols B or 6-alcohols C (Scheme 2),
valuable intermediates as glycosyl acceptors in glycoside
synthesis.16
The oxidative cleavage of 4,6-O-benzylidene acetals of
glycopyranosides using dimethyldioxirane (DMDO)
leads to the corresponding hydroxy-benzoates in excel-
lent yields. With a proper choice of the neighboring
protecting groups, this oxidative fragmentation provides
the 6- or 4-hydroxyl derivatives in a highly regioselective
manner.
(3) Deslongchamps, P.; Moreau, C.; Frehel, D.; Chenevert, R. Can. J.
Chem. 1975, 73, 1204–1211.
(4) (a) Chidambaram, N.; Bhat, S.; Chandrasekaran, S. J. Org. Chem.
1992, 57, 5013–5015. (b) Sato, K.; Igarashi, T.; Yanagisawa, Y.; Kawauchi,
N.; Hashimoto, H.; Yoshimura J. Chem. Lett. 1988, 1699–1702. (c) Ziegler,
F. E.; Tung, J. S. J. Org. Chem. 1991, 56, 6530. (d) Wiegerinck, P. H. G.;
Fluks, L.; Hammink, J. B.; Mulders, S. J. E.; de Groot, F. M. H.; van
Rozendaal, H. L. M.; Scheeren, H. W. J. Org. Chem. 1996, 61, 7092. (e)
Hosokawa, T.; Imada, Y.; Murahashi, S. I. J. Chem. Soc., Chem. Commun.
1983, 1245–1246.
(5) Bhat, S.; Ramesh, A. R.; Chandrasekaran, S. Synlett 1995, 329.
(6) (a) Chen, Y.; Wang, P. G. Tetrahedron Lett. 2001, 42, 4955–4958. (b)
Karimi, B.; Rajabi, J. Synthesis 2003, 2373–2377.
(7) Luzzio, F. A.; Bobb, R. A. Tetrahedron Lett. 1997, 38, 1733–1736.
(8) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A. Tetrahedron
Lett. 1999, 40, 8439–8441.
(9) Senthilkumar, P. M.; Aravind, A.; Baskaran, S. Tetrahedron Lett.
2007, 48, 1175–1178.
(10) Ponminor Senthil, K.; Amit, B.; Sundarababu, B. Angew. Chem., Int.
Ed. 2010, 49, 804–807.
(11) Oikaw, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23,
889–892.
(12) Zhang, Z. Y.; Magnusson, G. J. Org. Chem. 1996, 61, 2394–2400.
(13) Binkley, R. W.; Goewey, G. S.; Johnson, J. C. J. Org. Chem. 1984, 49,
992–996.
Carbohydrates contain many hydroxyl groups with simi-
lar chemical reactivities. It is often a difficult task to perform
useful differential manipulations on such molecules, parti-
cularly the discrimination between secondary hydroxyl
groups.1 The regioselective opening of cyclic derivatives is
an attractive approach for this purpose. Benzylidene acetal
groups are widely used as protecting groups of diols because
of their easy introduction and their tolerance to a variety of
chemical conditions. These acetals provide a selective 4,6-O-
protection of pyranoses such as glucose, 2-acetamido-2-
deoxy-glucose, galactose, mannose, or altrose. Reductive
opening of carbohydrate benzylidene acetals, furnishing
benzyl ether at either the C4 or C6 hydroxyl group, was
extensively investigated in the literature.2 Selective cleavage
of benzylidene acetals under oxidative conditions, allowing
formation of a benzoate ester at either the C4 or C6 hydroxyl
(14) Sato, K.; Igarashi, T.; Yanagisawa, Y.; Kawauchi, N.; Hashimoto,
H.; Yoshimura, J. Chem. Lett. 1988, 1699–1702.
(15) Franc-ais, A.; Urban, D.; Beau, J.-M. Angew. Chem., Int. Ed. 2007,
46, 8662–8665.
(16) Zhu, X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 2–37.
(1) Protecting Groups, 3rd ed.; Kocienski, P. J., Ed.; Georg Thieme
Verlag: Stuttgart, 2005.
(2) Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker, Inc.: New York, 1997; pp 53-65.
DOI: 10.1021/jo9026098
r
Published on Web 02/08/2010
J. Org. Chem. 2010, 75, 1783–1786 1783
2010 American Chemical Society

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Stevenin et al.
JOCNote
SCHEME 2. Oxidative Cleavage with DMDO
carbohydrate series, with excellent discrimination of the
glycosidic acetal.23 In all cases the moderate to high regios-
electivity was mostly determined by the nature of the pro-
tecting group at the C3 position. Also, the results are
similar for the 2-deoxy-2-phthalimido-glucopyranoside ser-
ies (Table 1, entries 1-9) and the glucopyranoside series
(Table 1, entries 11-19).
O the basis of the experimental results, the following
conclusions can be drawn. An increase of the electron-with-
drawing character of the protecting group at C3 (Ac,
ClCH2CO, Cl2CHCO) increases selectivity in favor of the
formation of the primary benzoate at C6 (selectivities from
80:20 to 98:2, Table 1, entries 7-9 and 11, 14, 17). A bulky
electron-withdrawing protecting group at C3 will however
decrease the formation of the benzoate at C6 position
(selectivities of 80:20, 62:38, and 56:44, respectively, with
the Ac, Bz and Piv protecting groups at C3). Further, a
bulkier electron-donating group at C3 (OTBS, OTBDPS,
entries 5, 6, and 18) induces a reversal of selectivity with a
high preference for the formation of the secondary benzoate
at C4 (selectivities from 3:97 to 1:99 and higher).
DMDO is a powerful oxidant prepared from Oxone and
acetone and used as a dilute solution (∼0.1 M) in acetone
according to the literature.17 The reaction is easy to per-
form and produces no waste other than acetone. DMDO
can be employed under neutral, non-nucleophilic condi-
tions that facilitate the isolation of products especially in
cases of unstable intermediates.18 Hayes et al.19 have
recently reported a selective benzylidene acetal cleavage
with DMDO in order to access the primary alcohol during
the total synthesis of (þ)-lactacystin. They also extended
this oxidative deprotection method to various benzyli-
dene acetals derived from noncarbohydrate 1,2- and
1,3-diols.20
The preparation of a range of 4,6-O-benzylidene acetals of
glucose, 2-amino-2-deoxy-glucose, galactose, mannose, and
altrose derivatives was easily achieved from the correspond-
ing glycopyranosides by standard acid-catalyzed condensa-
tion with benzaldehyde dimethyl acetal, furnishing the
corresponding 4,6-O-benzylidene acetals (see Supporting
Information).
A mesylate group14 (Table 1, entry 16) at C3 gave poor
regioselectivity in favor of the secondary benzoate at C6
similar to the benzoate group (Table 1, entry 12). Surpris-
ingly, a tosylate group (Table 1, entry 15), a bulky electron-
withdrawing group, at C3 led to good selectivity in favor of
the secondary benzoate at C4. This result is in accordance
with the regioselectivity observed with ozone by Deslong-
champs et al.3 and better than that obtained with t-BuOOH
and CuCl2 by Sato et al.14
In all cases, oxidation of the 4,6-O-benzylidene acetal
derivatives was performed using an excess of DMDO21
(0.1 M in acetone), and the resulting solution was stirred at
5 °C for 96 h. The slow rate of the cleavage explains the
possibility of using DMDO for other oxidizing purposes in
the presence of the benzylidene acetal group in the same
molecule.22 Removal of the volatiles in vacuo furnished the
crude product that was purified by chromatography. The
isolated yields of the 6-OH or 4-OH derivatives are provided
in Table 1. H-1H COSY, H-13C HMQC, and H-13C
HMBC spectra established unambiguously the structure of
each regioisomer. In almost all cases no byproduct could be
detected. The examples given show the chemoselectivity and
functional group tolerance (except when the trichloroacetate
group was used, Table 1, entry 10) of this oxidation in the
The oxidation of epoxide 19 furnished with high selectivity
(>98:2) the benzoate at C6 contrary to the results of Sato
et al.14 with t-BuOOH and CuCl2, who observed a poor
selectivity in favor of the secondary benzoate at C4 (54:46).
The half-chair conformation of 19 could explain this surpris-
ing regioselectivity.
Similar yields were obtained with the 2-acetamido-2-
deoxy-D-glucopyranoside series, with however a decrease in
the regioselectivity of the reaction by comparison with the
2-deoxy-2-phthalimido series [for R = ClCH2CO, ratio of
8:2 (Table 1, entry 22) vs 94:6 (Table 1, entry 8) and for R =
TBS, a ratio of 10:90 (Table 1, entry 23) vs 1:99 (Table 1,
entry 5)]. In the altro series, with an axial orientation of the
protecting group at C3, the regioselectivity of the reaction
was lost (Table 1, entries 24, 25). Finally, the regioselectivity
was not sensitive to the configuration at C4 (compound 26 of
the galacto series) or C2 (compound 27 of the manno series)
(Table 1, entries 26, 27).
1
1
1
(17) (a) Adam, W.; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377.
(b) Murray, R. W.; Singh, M. Org. Synth. 1997, 74, 91-97. CAUTION:
DMDO is a very volatile peroxide that should be handled in a hood and behind a
shield.
The putative first step24 of this oxidative fragmentation is
the formation of the O-insertion transition state D via a
direct concerted electrophilic oxygen insertion process
(Scheme 3) or the formation of intermediate E via a radical
(18) (a) Boyer, F. D.; Descoins, C. L.; Thanh, G. V.; Descoins, C.; Prange,
T.; Ducrot, P. H. Eur. J. Org. Chem. 2003, 1172–1183. (b) Boyer, F. D.;
Beauhaire, J.; Martin, M. T.; Ducrot, P. H. Synthesis 2006, 3250–3260.
(19) Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson, C.; Blake, A. J.;
Selby, M. D.; Prodger, J. C. J. Org. Chem. 2008, 73, 2041–2051.
(20) Mycock, D. K.; Sherlock, A. E.; Glossop, P. A.; Hayes, C. J.
Tetrahedron Lett. 2008, 49, 6390-6392 and references therein.
(21) The reaction of compound 1 was also performed directly with Oxone
and wet Al2O3 in refluxing CH2Cl2. After 48 h, this provided only 8% yield of
the primary benzoate 1a with the starting material 1. See: Curini, M.;
Epifano, F.; Marcotullio, M. C.; Rosati, O. Synlett 1999, 777–779.
(22) Despite its high reactivity, DMDO displays good selectivity for
olefins as seen in the selective epoxidation of glycals equipped with a
benzylidene acetal protecting group; see: (a) Halcomb, R. L.; Danishefsky,
S. J. J. Am. Chem. Soc. 1989, 111, 6661–6666. (b) For a review, see: Handbook
of Chemical Glycosylation; Demchenko, A. V., Ed., Wiley-VCH: Wein-
heim,2008; pp 436-437.
(23) However, under these oxidation conditions, the 4,6-O-benzylidene
acetal cleavage in C-glucoside 28 gave a mixture of the 4-OH and 6-OH
derivatives (28a/28b 1:1 ratio) accompanied by oxidation products at the C1
position.
(24) Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006, 39, 1-9
and references therein.
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Stevenin et al.
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TABLE 1. Oxidative Cleavage of 4,6-O-Benzylidene Acetals of Carbohydrate Derivatives
aRatio determined by 1H NMR in the crude product. bInseparable mixture, ratio determined by 1H NMR.
mechanism involving hydrogen-atom abstraction of the
benzylidene acetal hydrogen (caged radical pair). Intermedi-
ate D or E would give the corresponding hemiortho ester F .
Both E or F could lead, by cleavage of bond a or b, to the
6-OH and/or 4-OH derivatives. An alternative route could
directly provide products B or C from D.25
As previously reported,20 the regiocontrol of the fragmen-
tation may be determined by the relative stability of the
partially charged intermediates I and J (or the analogous
polarized intermediates directly from D) or the correspond-
ing alkoxides (Scheme 3). With an electron-withdrawing
(25) This would explain why the trapping of the putative hemiortho ester
F by running the reaction of 1 with DMDO in the presence of an excess of
MeOH failed and only led to its slowing down.
J. Org. Chem. Vol. 75, No. 5, 2010 1785

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Stevenin et al.
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SCHEME 3. Putative Intermediates for Regioselective Control
in the Oxidative Ring Cleavage by DMDO
Experimental Section
Oxidative Opening of Benzylidene Acetal 10. Methyl 6-O-
Benzoyl-2-deoxy-3-O-(2,2-dichloroacetyl)-2-phtalimido-β-D-glu-
copyranoside, 10a. Freshly distilled solution of DMDO16 in
acetone (30 mL, ∼0.1 M) was added to benzylidene acetal 10
(317 mg, 0.607 mmol). The reaction mixture was stirred for 96 h
at 5 °C, the volatiles were evaporated under reduced pressure,
and the crude material was purified by chromatography on silica
gel (heptane/EtOAc 9:1 to 7:3) to give the benzoate 10a (310 mg,
95%) as a white solid. Mp 79.6-82.8 °C (heptane/EtOAc).
[R]23 -13.6 (c 1, CHCl3). 1H NMR (500 MHz, CDCl3) δ
D
8.10 (d, J = 7.3 Hz, 2H, Bz), 7.87-7.79 (m, 2H, NPhth),
7.75-7.68 (m, 2H, NPhth), 7.61 (t, J = 7.3 Hz, 1H, Bz), 7.48
(t, J = 7.3 Hz, 2H, Bz), 5.83-5.76 (m, 2H, H3 þ CHCl2), 5.28 (d,
protecting group at C3, the secondary intermediate I at C4 is
more stable, favoring cleavage of the C-O bond a and hence
the primary benzoate B (path a or path a0). If the group at C3 is
electron-donating, the primary intermediate J at C6 is favored
with cleavage of the C-O bond b and formation of the
secondary benzoate C as the major product (path b or path b0).
If so, with a developing negative charge at O4, path a may
be counterbalanced by the presence of acids. We performed
the reaction on compound 1 with DMDO in acidic medium,26
namely, with TsOH (1 equiv). The reaction was slowed down
and the regioselectivity was lost and reversed (ratio 4-OH/6-OH
of 4:6 compared with a ratio of 8:2, entry 11, Table 1).27 This is in
good agreement with the above rationale. This reasoning would
only be valid for an equatorial orientation of the protecting
group at C3 (e.g., in the gluco, galacto, and manno series), as in
the altro series, with an axial orientation at C3, the regiocontrol is
lost (see Table 1, entries 24, 25). In all cases, steric effects should
also be accounted for in the regiocontrol.
0 0
1,2 = 8.2 Hz, 1H, H1), 4.90 (dd, J6,6 = 12.2 Hz, J6 ,5 = 3.4 Hz,
J
1H, H6), 4.56 (dd, J6 ,6 = 12.2 Hz, J6 ,5 = 2.1 Hz, 1H, H60), 4.30
(dd, J2,3 = 11.0 Hz, J2,1 = 8.2 Hz, 1H, H2), 3.83 (ddd, J5,4 = 9.8
0
0
0
Hz, J5,6 = 3.4 Hz, J5,6 = 2.1 Hz, 1H, H5), 3.78 (ddd, J4,5
=
J4,3 = 9.8 Hz, J4,OH = 4.6 Hz, 1H, H4), 3.45 (s, 3H, OMe), 3.10
(d, JOH,4 = 4.6 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3) δ
167.7 (C, PhCO), 164.9 (2C, N(CO)2), 164.6 (C, Cl2CHCO),
134.6 (2CH, NPhth), 133.8 (CH, Bz), 131.7 (2C, NPhth), 130.2
(2CH, Bz), 129.5 (C, Bz), 128.8 (2CH, Bz), 123.8 (2CH, NPhth),
99.3 (CH, C1), 75.9 (CH, C3), 74.5 (CH, C5), 69.6 (CH, C4), 64.0
(CH, CHCl2), 63.5 (CH2, C6), 57.3 (CH3, OMe), 54.3 (CH, C2).
IR ν (film, cm-1) 3473, 3064, 2945, 2852, 1770, 1712, 1602. MS
m/z 560 (MNaþ, 100%). HRMS (ESI) calcd for
C24H21Cl2NNaO9 [M þ Na]þ 560.0491, found 560.0494. Anal.
Calcd for C24H21Cl2NO9: C, 53.55; H, 3.93; N, 2.60. Found: C,
53.21; H, 4.05; N, 2.56.
In conclusion, we have shown that DMDO is a valuable
reagent for the regioselective oxidative opening of 4,6-O-
benzylidene acetals of glycopyranosides controlled by the
nature of the hydroxyl protecting group at position 3. It gave
6-benzoate-4-hydroxy or 4-hydroxy-6-benzoate derivatives
of glycopyranosides in good to high yields.
Acknowledgment. This study was financially supported
by the ICSN-CNRS and INRA.
Supporting Information Available: Experimental proce-
dures, characterization data, 1H and 13C NMR spectra for
compounds 3a, 3b, 4, 4a, 4b, 5, 5a, 5b, 6, 6b, 7, 7b, 8a, 9, 9a,
10, 10a, 12a, 12b, 14a, 17a, 18, 18b, 22a, 23, 23b, 24a, 25, 25a,
25b, 26a, 26b, 27a, and 27b. This material is available free of
charge via the Internet at http://pubs.acs.org.
(26) Adam, W.; Shimizu, M. Synthesis 1994, 560–562.
(27) The addition of a Lewis acid (FeCl3 6H2O or CeCl3 7H2O) had no
3
3
effect on the course of the reaction, as was the case in a basic medium
(NaHCO3).
1786 J. Org. Chem. Vol. 75, No. 5, 2010