Facile oxidative cleavage of 4-O-benzyl ethers with dichlorodicyanoquinone in rhamno- and mannopyranosides

Article abstract of DOI:10.1021/jo062411p

On exposure to dichlorodicyanoquinone in wet dichloromethane at room temperature, equatorial 4-O-benzyl ethers are removed with moderate selectivity in the presence of other benzyl ethers in glycopyranosides and glycothiopyranosides.

Full text of DOI:10.1021/jo062411p

cleavage of the PMB or Nap ethers in their presence.1,2 By way
of illustration, we have collated some recent examples of this
type from our own laboratory,17-23 along with an oxidative
cyclization17 and a pertinent literature example1 in Table 1.
Facile Oxidative Cleavage of 4-O-Benzyl Ethers
with Dichlorodicyanoquinone in Rhamno-
and Mannopyranosides
David Crich* and Olga Vinogradova
TABLE 1. Examples of Selective Cleavage
Department of Chemistry, UniVersity of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607-7061
dcrich@uic.edu
ReceiVed NoVember 22, 2006
On exposure to dichlorodicyanoquinone in wet dichlo-
romethane at room temperature, equatorial 4-O-benzyl ethers
are removed with moderate selectivity in the presence of
other benzyl ethers in glycopyranosides and glycothiopyra-
nosides.
The p-methoxybenzyl (PMB) ethers and their somewhat less
acid sensitive congeners, the 2-naphthylmethyl (Nap) ethers,
are staple protecting groups in organic synthesis, in general,
and especially in oligosaccharide synthesis, owing to their facile
oxidative cleavage with either dichlorodicyanoquinone (DDQ)
or ceric ammonium nitrate (CAN).1-6 Simple benzyl ethers are
not inert to these oxidative cleavage conditions but typically
react significantly more slowly,5-16 enabling the highly selective
(1) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.; Alderfer, J. L.;
Matta, K. L. Tetrahedron Lett. 2000, 41, 169-173.
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370.
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Reagents for Glycoside, Nucleotide, and Peptide Synthesis; Crich, D., Ed.;
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Peptide Synthesis; Crich, D., Ed.; Wiley: Chichester, 2005; pp 459-460.
(5) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
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a PMPCH ) p-methoxybenzylidene.
Accordingly, we were surprised when, in the course of an
ongoing synthesis, we encountered significant cleavage of a
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10.1021/jo062411p CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/22/2007
J. Org. Chem. 2007, 72, 3581-3584
3581

benzyl ether when removing a vicinal Nap ether with DDQ
(Table 2, entry 1). Intrigued by this unusual observation, we
carried out a more detailed investigation, the results of which
are presented here.
romethane at 0 °C for 30 min, followed by stirring at room
temperature for 3 h, gave 63% of the anticipated mono-ol 16,
along with 13% of diol 1728 (Table 2, entry 1). Comparable
results were obtained with the corresponding 2,4-di-O-benzyl-
3-O-p-methoxybenzyl ether 9 (Table 2, entry 2). When the
alcohol 16 was subjected to the standard reaction conditions,
the diol 17 was again formed in amounts depending on the
reaction conditions and stoichiometry employed (Table 2, entry
3). When the 2,3,4-tri-O-benzyl ether 1829 was similarly treated,
a complex reaction mixture was obtained in which the product
arising from selective removal of the 4-O-benzyl ether 19
predominated significantly (Table 2, entry 4). With the 2-O-
pivalate ester 10 and the 2-O-acetate 11, the pattern was
continued with cleavage of the 3-O-p-methoxybenzyl ether,
accompanied by partial loss of the benzyl ether at the 4-O-
position (Table 2, entries 5 and 6). Analysis of the initial reaction
mixture from the reaction of 11 with DDQ was complicated by
migration of the acetate group but was facilitated by saponifica-
tion.
Substrate Preparation. Treatment of triol 124 with dibutyltin
oxide in toluene under Dean-Stark conditions gave an interme-
diate stannylene acetal, which, on quenching with either
2-bromomethylnaphthalene or benzyl bromide in the presence
of cesium fluoride, gave the 3-O-naphthylmethyl and 3-O-benzyl
ethers 2 and 3, respectively. Exhaustive benzylation of 2 then
gave the differentially protected substrate 4 (Scheme 1).
SCHEME 1
Reaction of the dibutylstannylene acetal derived from the
known 4-O-benzyl ether 525 with p-methoxybenzyl chloride in
the presence of cesium fluoride and tetrabutylammonium
bromide afforded the 4-O-benzyl-3-O-p-methoxybenzyl ether
6, while reaction with naphthylmethyl bromide or benzyl
bromide gave products 7 and 8,26 respectively (Scheme 2). The
alcohol 6 was then converted to the fully protected systems 9,
10, and 11, under standard conditions, whereas reaction of the
3,4-di-O-benzyl ether 8 with naphthylmethyl bromide and
sodium hydride provided 12 (Scheme 2).
With the 3,4-di-O-benzyl-2-O-naphthylmethyl system 12,
regioisomeric with the initial substrate 4, partial cleavage of
the 4-O-benzyl ether was again observed (Table 2, entry 7).
However, the trend did not extend to the third regioisomer in
the series, the 2,3-di-O-benzyl-4-O-naphthylmethyl system 15,
where the oxidative cleavage reaction was much cleaner and
only minor amounts of debenzylated products were observed
under the standard conditions (Table 2, entry 8).
The methyl 2,4-di-O-benzyl rhamnopyranoside 2430 (Table
2, entry 9) performed much as the corresponding S-phenyl
thioglycoside 16 (Table 2, entry 3) with considerable cleavage
of the 4-O-benzyl ether depending on the stoichiometry
employed. Finally, methyl 2,3,4,6-tetra-O-benzyl-R-D-mannopy-
ranoside 2631 was explored as a substrate for the oxidative
cleavage reaction. All four possible mono-ols were obtained
from this reaction, but it is noteworthy that the 4-ol 2732 is by
far the most significant product with a yield surpassing that of
2-, 3-, and 6-ols combined (Table 2, entry 10).
SCHEME 2
It is apparent from the entirety of results presented in Table
2 that benzyl ethers located on the 4-position of rhamno- and
mannopyranosides are cleaved oxidatively with DDQ signifi-
cantly more easily than benzyl ethers located at other posi-
tions around the ring. In hindsight, the moderate yield
recorded for the example of entry 4 of Table 1 can most likely
be ascribed to the same phenomenon. From entry 3 of Table 2,
it is clear that the oxidative cleavage of the 4-O-benzyl ether is
an inherent characteristic of that group and does not require
Naphthylmethylation of acetonide 1327 gave 14, which was
heated to reflux in a mixture of acetic acid and aqueous dioxane
followed, without isolation of the intermediate 2,3-diol, by
exposure to sodium hydride and benzyl bromide to give the
2,3-di-O-benzyl-4-O-naphthylmethyl system 15 (Scheme 3).
SCHEME 3
(21) Crich, D.; Banerjee, A.; Yao, Q. J. Am. Chem. Soc. 2004, 126,
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Oxidative Cleavage Reactions. Exposure of the 2,4-di-O-
benzyl-3-O-naphthylmethyl system 4 to DDQ in wet dichlo-
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15086.
3582 J. Org. Chem., Vol. 72, No. 9, 2007

TABLE 2. Oxidative Cleavage Reactions with DDQ
J. Org. Chem, Vol. 72, No. 9, 2007 3583

the presence of the Nap or PMB ethers; that is, the mechanism
must involve direct oxidation of the benzyl ether rather than
hole transfer from a more readily oxidized neighboring group.33,34
Likewise, entries 9 and 10 of Table 2 reveal that the thiogly-
coside is not the site of the initial oxidation step. Comparison
of entries 9 and 10 of Table 2 indicates that the absence of a
C6-O bond is not a requirement for the selective removal of
the 4-O-benzyl ether.
While we have restricted our study to the rhamno- and
mannopyranosyl systems of greatest interest to our laboratory,
useful indications may also be gleaned from the literature. Thus,
as set out in Table 1, entry 10, Matta and co-workers reported
the selective cleavage of a 3-O-Nap ether in the presence of a
4-O-benzyl ether in the galactopyranose series,1 leading to the
implication that an axial benzyloxy group at the 4-position of
a pyranose is less readily oxidized than the equatorial counter-
part. This postulate is reinforced by the apparent need for more
forcing conditions: 30 equiv of DDQ and 10 h at room
temperature, to obtain a 70% yield in the cleavage of a 4-O-
benzyl ether from an R-fucopyranoside noted in the course of
a total synthesis of polycavernoside A.13 While we have not
studied the glucopyranose series here, we do expect that
selective cleavage of 4-O-benzyl ethers will be a feature of that
system based on our results so far.
Overall, we are led to the conclusion that the selective
cleavage of the 4-O-benzyl ether derives from the fixed
antiperiplanar nature of the C4-O4 and C5-O1 bonds, which
maximizes the electron-withdrawing properties of the latter, and
accelerates decomposition of the radical cation, just as the
disarming effect of a 4,6-O-alkylidene acetal in glycosylation
reactions is attributed to the enforcement of the more electron-
withdrawing tg conformation.35,36 Selective protection strategies
are key features of the enormous majority of work in the
carbohydrate and oligosaccharide fields,37-43 and it is possible
that, with optimization, perbenzylation and selective debenzy-
lation at O4 might provide a short, cost-effective entry into the
4-OH systems.
Experimental Section
General Procedure for the Deprotection with DDQ. To a
solution of the substrate (0.03 M) in a mixture of CH2Cl2/H2O (17/
1) was added DDQ (2.3 or 0.3 equiv) at 0 °C. After 30 min, the
reaction mixture was warmed to room temperature and further
stirred for the specified time (Table 2) before it was diluted with
CH2Cl2 and quenched with saturated aqueous Na2CO3. The organic
phase was separated, washed (saturated aqueous Na2CO3), dried
(Na2SO4), and concentrated. The crude reaction mixture was filtered
through a pad of silica gel (with ethyl acetate as an eluent) and
then purified by chromatography on SiO2.
Reaction of S-Phenyl 2,4-Di-O-benzyl-3-O-(2-naphthyl-
methyl)-R-L-thiorhamnopyranoside (4) with DDQ. Compound
4 (737 mg, 1.28 mmol) was deprotected with 2.3 equiv of DDQ
(667 mg, 2.9 mmol) for 3 h. Purification by radial chromatography
(SiO2, hexanes to 2:3 ethyl acetate/hexanes) gave 16 (351 mg, 63%)
and 17 (59 mg, 13%).
Reaction of S-Phenyl 2,4-Di-O-benzyl-3-O-(4-methoxybenzyl)-
R-L-thiorhamnopyranoside (9) with DDQ. Compound 9 (88 mg,
0.16 mmol) was deprotected with 2.3 equiv of DDQ (83 mg, 0.37
mmol) for 1.5 h. Purification by radial chromatography (SiO2,
hexanes to 2:3 ethyl acetate/hexanes) gave 16 (54 mg, 78%) and
17 (8 mg, 14%).
Reaction of S-Phenyl 4-O-Benzyl-3-O-(4-methoxybenzyl)-2-
O-pivaloyl-R-L-thiorhamnopyranoside (10) with DDQ. Com-
pound 10 (96 mg, 0.17 mmol) was deprotected with 2.3 equiv of
DDQ (91 mg, 0.40 mmol) for 4 h. Radial chromatography (SiO2,
hexanes to 3:7 ethyl acetate/hexanes) gave 20 (55 mg, 74%) and
21 (8 mg, 13%).
Reaction of S-Phenyl 3,4-Di-O-benzyl-2-O-(2-naphthyl-
methyl)-R-L-thiorhamnopyranoside (12) with DDQ. Compound
12 (69 mg, 0.12 mmol) was deprotected with 2.3 equiv of DDQ
(62 mg, 0.27 mmol) for 2.5 h. Radial chromatography (SiO2,
hexanes to 3:7 ethyl acetate/hexanes) gave 8 (41 mg, 60%) and 3
(5 mg, 11%).
Reaction of S-Phenyl 2,3-Di-O-benzyl-4-O-(2-naphthyl-
methyl)-R-L-thiorhamnopyranoside (15) with DDQ. Compound
15 (104 mg, 0.18 mmol) was deprotected with 2.3 equiv of DDQ
(94 mg, 0.42 mmol) for 2 h. Radial chromatography (SiO2, hexanes
to 2:3 ethyl acetate/hexanes) gave 19 (67 mg, 85%), 3 (4 mg, 6%),
and 17 (2 mg, 3%).
(33) For examples of hole (radical cation) transfer and delocalization
and its consequences, see the extensive work on the oxidative cleavage of
DNA: Charge Transfer in DNA: From Mechanism to Application;
Wagenknecht, H.-A., Ed.; Wiley-VCH: Weinheim, Germany 2005; and
ref 34.
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Acknowledgment. We thank the NIH (GM62160) for
support of this work, and an anonymous reviewer for insight
into the origin of the phenomenon.
(38) Green, L. G.; Ley, S. V. In Carbohydrates in Chemistry and Biology;
Ernst, B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, Germany,
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Supporting Information Available: Full experimental details
for substrate preparation and copies of spectra of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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