Mild oxidative one-pot allyl group cleavage

Article abstract of DOI:10.1021/ol016278t

(equation presented) A new one-pot method is described for the removal of O-and N-allyl protecting groups under oxidative conditions at near neutral pH. The allyl group undergoes hydroxylation and subsequent periodate scission of the vicinal diol, followed by repetition of this reaction sequence on the enolic form of the aldehyde intermediate.

Full text of DOI:10.1021/ol016278t

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2835-2838
Mild Oxidative One-Pot Allyl Group
Cleavage
Pavel I. Kitov and David R. Bundle*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
daVe.bundle@ualberta.ca
Received June 14, 2001 (Revised Manuscript Received July 26, 2001)
ABSTRACT
A new one-pot method is described for the removal of O- and N-allyl protecting groups under oxidative conditions at near neutral pH. The allyl
group undergoes hydroxylation and subsequent periodate scission of the vicinal diol, followed by repetition of this reaction sequence on the
enolic form of the aldehyde intermediate.
The allyl ether is a common protecting group that permits
orthogonal protection strategies with a wide range of
protecting groups and is widely employed in multistep
synthetic schemes. Common allyl deprotection methods are
two-step procedures that include isomerization to the more
labile 1-propenyl group with a variety of agents. The most
frequently employed conditions are treatment of allyl ether
with t-BuOK,1 Wilkinson catalyst,2 Pd/C,3 PdCl2,4 ruthenium-
(II),5 and iridium(I)6 complexes followed usually by acid
hydrolysis or oxidation of the resulting enol ether. Also
reported are methods including oxidative conditions such as
DDQ,7 SeO2,8 and NBS-hν.9 On the other hand, transforma-
tion of the allylic double bond may be used to provide a
convenient attachment point in various conjugation strate-
gies.10
In the course of our investigation into the synthesis of
glycoconjugate inhibitors of bacterial AB5 toxin binding to
target cell membranes,11 we performed a sequence of
reactions intended to convert a hexopyranoside 2-O-allyl
ether into a 2-hydroxyethyl linker (Scheme 1). When all
Scheme 1. Side Product Formed during Attempts To Convert
an Allyl Group to a 2-Hydroxyethyl Substituent11
steps, including oxidation of the double bond by OsO4 and
4-methylmorpholine N-oxide followed by periodate oxidation
of the resulting diol and final reduction of the aldehyde with
NaBH4, were conducted in one pot, a significant quantity of
side product was observed.
The identification of this unknown as the product of allyl
ether cleavage provided an opportunity to develop a new
method for allyl group deprotection.
(1) Gent, P. A.; Gigg, R. Carbohydr. Res. 1976, 49, 325-333. Rollin,
P.; Sinay, P. J. Chem. Soc., Perkin Trans. 1 1977, 2513-2517.
(2) Warren, C. D.; Jeanloz, R. W. Carbohydr. Res. 1977, 53, 67-84.
(3) Boss, R.; Scheffold, R. Angew. Chem., Int. Ed. Engl. 1976, 15, 558-
559.
(4) Ogawa, T.; Nakabayashi, S.; Kitajima, T. Carbohydr. Res. 1983, 114,
225-236. Smith, A. B.; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am.
Chem. Soc. 1991, 113, 2092-2112.
(5) Nicolaou, K. C.; Hummel, C. W.; Bockovich, N. J.; Wong, C.-H. J.
Chem. Soc., Chem. Commun. 1991, 870-872.
(6) Oltvoort, J. J.; van Boeckel, C. A. A.; de Koning, J. H.; van Boom,
J. H. Synthesis 1981, 305-308. Hecker, S. J.; Minich, M. L.; Lackey, K.
J. Org. Chem. 1990, 55, 4904-4911.
(10) Roy, R.; Tropper, F. D. J. Chem. Soc., Chem. Commun. 1988, 15,
1058-1060. Ramos, D.; Rollin, P.; Klaffke, W. Angew. Chem., Int. Ed.
2000, 39 (2), 396-398. Yudina, O. N.; Sherman, A. A.; Nifantiev, N. E.
Carbohydr. Res. 2001, 332, 363-371.
(11) Kitov, P. I.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 2001, 8,
838-853.
(7) Yadav, J. S.; Chandrasekhar, S.; Sumithra, G.; Kache, R. Tetrahedron
Lett. 1996, 37, 6603-6606.
(8) Kariyone, K.; Yazawa, H. Tetrahedron Lett. 1970, 2885-2888.
(9) Diaz, R. R.; Melgarejo, C. R.; Lopez-Espinosa, M. T. P.; Cubero, I.
I. J. Org. Chem. 1994, 59, 7928-7929.
10.1021/ol016278t CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/11/2001

Two specific oxidizing reagents were employed for the
reaction: osmium tetroxide with 4-methylmorpholine N-
oxide as a co-oxidant that specifically oxidizes double bonds
and a periodate salt that cleaves vicinal diols.
The reaction conditions for deprotection were optimized
on the allyl galactoside 112 as an example (Scheme 2).
reaction mixture consisted mainly of diol 2 and, surprisingly,
some product of overoxidation, galactonolactone 6 (Scheme
2).
Under the heterogeneous conditions, the intermediate
aldehyde 3 accumulates in the reaction mixture immediately
after NaIO4 is added and can be isolated. Evidently, the
presence of both oxidizing agents, 4-methylmorpholine
N-oxide with catalytic OsO4 and NaIO4, is necessary for the
conversion of the aldehyde 3 into the free hydroxyl derivative
5: stirring of a solution of 2 at 60 °C and in the presence of
any one of the oxidizing agents separately led only to
unidentified decomposition products, whereas the reaction
with a mixture of both agents gave the target alcohol in 67%
yield.
Scheme 2. One-Pot, Allyl Group Cleavage of Allyl
Galactoside 1 and the Sequential Products Observed during
Conversion of 1 to 5a
Some decomposition of periodate under the reaction
conditions is possible. Therefore, addition of extra amounts
of an NaIO4 solution during the advanced stages of the
process (if TLC indicates accumulation of the diol intermedi-
ate) may improve yields by 10-20%.
On the basis of these observations, a mechanism for the
oxidative removal of the allyl functionality is proposed in
Scheme 3. It includes an initial osmium tetroxide-catalyzed
a Asterisk indicates side product observed under homogeneous
conditions.
Scheme 3. Proposed Mechanism of Allyl Group Oxidative
Cleavage
Heterogeneous conditions in which an aqueous solution of
3 equiv of sodium or potassium periodate was added to a
dioxane solution of 1, containing 3 equiv of 4-methylmor-
pholine N-oxide and a catalytic amount of OsO4, were found
to give the best yield. At room temperature, the reaction gives
a good yield (73%) of pure product in 4-5 days. Increasing
the temperature to 50-60 °C reduces the reaction time to
5-16 h but the yield of 5 is lower (60%).
Over the course of the reaction, the allyl group gradually
oxidizes to an O-formate derivative which undergoes slow
hydrolysis. Intermediates accumulate in the reaction mixture
and can be isolated at certain stages of the reaction. Thus,
diol 2 (as an epimeric mixture), aldehyde 3, and formate 4
were each isolated and characterized.
Homogeneous conditions that employed tetrabutylammo-
nium periodate were also explored, but no noticeable
acceleration of the reaction was observed. Presumably, the
rate-limiting step is the double bond dihydroxylation, whereas
diol cleavage occurs rapidly.
Water is an important constituent of the reaction mixture
even in the homogeneous reaction format. Water is required
to complete the catalytic cycle and regenerate OsO4,13 and
its quantity may change the course of the reaction. When
water was used as co-solvent (dioxane-water ) 3:2), the
composition of the reaction mixture resembled that under
heterogeneous conditions. However, when just ∼10 equiv
of water was used, only trace amounts of the target hydroxyl
derivative 514 were observed after 24 h at 60 °C and the
dihydroxylation of the double bond in 7, followed by
periodate oxidation of the resulting glycerol derivative 8 to
provide the glycolaldehyde ether 9. The enol tautomeric form
of the aldehyde 9 undergoes further OsO4-promoted oxidation
to give hemiacetal 10, which may either undergo hydrolysis
directly to free hydroxy compound 12 or be subjected to
one more oxidative cleavage by peroxide to generate the
hydrolysis prone formate derivative 11.
During the review of this manuscript, one referee sug-
gested that formation of an enamine intermediate should
promote allyl group cleavage by shifting the aldehyde-enol
tautomeric equilibrium. Indeed, when reaction with 1 was
conducted in the presence of 1 equiv of a secondary amine,
piperidine, complete conversion into 5 was achieved in 3 h
(see Table 1, entry 3).
(12) Gigg, J.; Gigg, R.; Payne, S.; Conant, R. J. Chem. Soc., Perkin
Trans. 1 1987, 1165-1170.
(13) Do1bler, C.; Mehltretter, G. M.; Sundermeier, U.; Beller, M. J. Am.
Chem. Soc. 2000, 122, 10289-10297.
Further examples of oxidative cleavage of allyl groups in
different chemical environments are presented in Scheme 4.
(14) Koike, K.; Sugimoto, M.; Sato, S.; Ito, Y.; Nakahara, Y.; Ogawa,
T. Carbohydr. Res. 1987, 163, 189-208.
2836
Org. Lett., Vol. 3, No. 18, 2001

Table 1. Optimization of Reaction Conditions and Test Reactions
entry
1
substrate
reaction conditions
products
1
NMO (3 equiv), OsO4, dioxane-water (10:1),
aqueous NaIO4 (2 equiv), 60 °C, 18 h
5 (60%), 4 (8%)
2
3
4
1
1
1
NMO (3 equiv), OsO4, dioxane-water (10:1),
aqueous NaIO4 (2 equiv), 20 °C, 5 days
1. NMO (3 equiv), OsO4, dioxane-water (10:1), 60 °C 1 h
2. piperidine (1 equiv), aqueous NaIO4 (2 equiv), 60 °C, 3 h
1. NMO (3 equiv), OsO4, dioxane-water (10:1), 20 °C, 5 h
2. aqueous NaIO4 (2 equiv), 20 °C, 30 min
5 (73%), 4 (10%)
5 (75%), 4 (4%)
3 (77%)
5
6
7
3
3
1
NMO (3 equiv), OsO4, dioxane-water (10:1), 60 °C, 16 h
aqueous NaIO4 (2 equiv), dioxane-water (10:1), 60 °C, 16 h
NMO (3 equiv), OsO4, dioxane, water (10 equiv),
Bu4NIO4 (2 equiv), 50 °C, 5 days
partial decompositiona
partial decompositiona
2 (40%), 5 (16%), 6 (22%)
8
1
NMO (3 equiv), OsO4, dioxane-water (3:1),
Bu4NIO4 (2 equiv), 20 °C, 5 days
2 (13%), 5 (55%)
a TLC detection.
They include selective removal of O-allyl ethers from
secondary alcohol and anomeric positions, in the presence
of base-labile ester protecting groups as well as acid-labile
cyclic ketal and acetals of diol. The last entry demonstrates
the possibility of N-allyl deprotection. Typical deprotection
procedures with and without the inclusion of a secondary
amine to accelerate the reaction are described.26
Allyl derivatives 11,15 13,16 15,17 17,18 19,19 and 2120 were
prepared according to known procedures. The products of
deallylation 12,21 14,22 16,23 2024 and 2225 were previously
described. The new compound 18 was characterized by
proton NMR and mass spectra (see Supporting Information).
The oxidative cleavage of allyl groups is compatible with
a wide range of common O- and N-protective groups and
generally proceeds without oxidation of the liberated hy-
droxyl group. The stable intermediates may be observed by
TLC as the reaction proceeds to completion. Benzyl ethers
Scheme 4. Representative Examples of Allyl Group Cleavagea
(15) Nilsson, U.; Ray, A. K.; Magnusson, G. Carbohydr. Res. 1994, 252,
117-136.
(16) Suhr, R.; Scheel, O.; Thiem, J. J. Carbohydr. Chem. 1998, 17 (6),
937-968.
(17) Sabesan, S.; Lemieux, R. U. Can. J. Chem. 1984, 62, 644-654.
(18) Ziegler, T.; Eckhardt, E.; Strayle, J.; Herzog, H. Carbohydr. Res.
1994, 253 (1), 167-184.
(19) Mereyala, H. B.; Gurrala, S. R.; Mohan, S K. Tetrahedron 1999,
55 (37), 11331-11342.
(20) Spevak, W.; Dasgupta, F.; Hobbs, C. J.; Nagy, J. O. J. Org. Chem.
1996, 61 (10), 3417-3422.
(21) Takeo, K.; Maki, K.; Wada, Y.; Kitamura, S. Carbohydr. Res. 1993,
245 (1), 81-96.
(22) Knerr, L.; Pannecoucke, X.; Luu, B. Tetrahedron Lett. 1998, 39
(3-4), 273-274.
(23) Jansson, K.; Frejd, T.; Kihlberg, J.; Magnusson, G. Tetrahedron
Lett. 1988, 29 (3), 361-362.
(24) Stevens, J. D. In Methods in Carbohydrate Chemistry; Whistler, R.
L., BeMiller, J. N., Eds.; Academic Press: New York and London, 1972;
Vol. VI, Chapter 16, pp 124-125.
(25) Priya, K.; Loganathan, D. Tetrahedron 1999, 55 (4), 1119-1128.
(26) Typical Procedures for Allyl Deprotection. i. To a solution of
allyl 2,3,4,6-tetra-O-benzyl-R-D-galactopyranoside 1 (585 mg, 1.007 mmol)
in dioxane (5 mL) and water (0.5 mL) was added a mixture of 4-methyl-
morpholine N-oxide (3 equiv, 354 mg) and OsO4 (0.2 mL, 100 mg/mL
solution in t-BuOH) followed by addition of a suspension of NaIO4 (3 equiv,
646 mg) in water (2 mL). The mixture was stirred at 60 °C for 18 h and
then diluted with brine and extracted with DCM. Chromatography on silica
gel with hexanes-ethyl acetate (8:2-6:4) gave formate 4 (46 mg, 8%) and
the target 2,3,4,6-tetra-O-benzyl-D-galactopyranose 5 (335 mg, 60%). ii.
To a solution of allyl 2,3,4,6-tetra-O-benzyl-R-D-galactopyranoside 1 (390
mg, 0.671 mmol) in dioxane (10 mL) and water (1 mL) were added
4-methylmorpholine N-oxide (3 equiv, 236 mg) and OsO4 (0.3 mL, 100
mg/mL solution in t-BuOH). The mixture was stirred at 60 °C for 2 h
followed by addition of piperidine (1 equiv, 57 mg) and suspension of NaIO4
(3 equiv, 431 mg) in water (5 mL). The mixture was stirred at 60 °C for 3
h and then diluted with brine and extracted with DCM. Chromatography
on silica gel with hexanes-ethyl acetate (8:2-6:4) gave formate 4 (18 mg,
4.6%) and 2,3,4,6-tetra-O-benzyl-D-galactopyranose 5 (275 mg, 75%).
a (i) 4-Methylmorpholine N-oxide, OsO4, NaIO4, dioxane-water
(2:1), 60 °C 18 h.
Org. Lett., Vol. 3, No. 18, 2001
2837

are unaffected by the reaction conditions. The reaction is
relatively independent of pH. Reaction conditions are slightly
basic due to the presence of morpholine, but slight acidifica-
tion with acetic acid does not affect the reaction course and
enables the reaction to proceed without migration of ester
groups.
The new method is well suited to selective deprotection
of a wide variety of orthogonally protected polyhydroxy
derivatives, and its application permits novel manipulation
of more complex allyl protecting groups either in solution
or on solid-phase supports. The later will be the topic of
future communications.
Functional groups susceptible to oxidation are obviously
incompatible with this method of allyl deprotection and
include thioethers, thioglycosides, vicinal diols, and alkenes.
Deprotection may be achieved with a relatively extended
reaction time of 10-20 h at 60 °C. However, addition of
secondary amine, which presumably accelerates the rate-
limiting step by formation of an enamine intermediate,
dramatically shortens reaction time to 5 h at 60 °C.
Acknowledgment. Financial support was provided by the
Canadian Bacterial Disease Network (CBDN).
Supporting Information Available: Spectral data for
previously unreported compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL016278T
2838
Org. Lett., Vol. 3, No. 18, 2001