J. Am. Chem. Soc. 1999, 121, 5835-5836
5835
Table 1. Mild Oxidation of p-Hydroxybenzyl Ethersa
temperature yield
Novel Para-Substituted Benzyl Ethers for Hydroxyl
Group Protection
reagent
solvent
time
(°C)
(%)
Laurence Jobron and Ole Hindsgaul*
NaOMe
DDQ (1 equiv)
FeCl3
iodobenzene diacetate
Ag2CO3/Celite + Na2SO4 CH2Cl2 18 h
a The phenolic ethers were reacted with either NaOMe in MeOH or
NaOMe in THF for 5 min at rt prior to the oxidation step.
MeOH 18 h
CH2Cl2 30 min
60
0
20
20
20
>95
>95
>95
90
Department of Chemistry, UniVersity of Alberta
Et2O
5 min
CH2Cl2 2 h
Edmonton, Alberta T6G 2G2 Canada
80
ReceiVed October 14, 1998
The observation that p-hydroxybenzyl ethers readily decompose
under basic conditions to yield the free alcohol has allowed the
development of novel solution-cleavable benzyl ethers as protect-
ing groups in carbohydrate chemistry.
Scheme 2
The O-benzyl group is the most commonly used “persistent”
protecting group in carbohydrate chemistry, where it is almost
always removed at the last step of multistep oligosaccharide
synthesis by hydrogenolysis over insoluble catalysts such as Pd
and PtO2. Those cleavage procedures, besides being sensitive to
catalyst poisoning by impurities, severely limit the use of the
benzyl group in solid-phase oligosaccharide synthesis, where its
removal on the resin would be desirable. We are therefore
investigating the use of modified benzyl groups which are
cleavable by soluble reagents. Here we describe the novel
p-acetoxybenzyl (PAB) and 2-(trimethylsilyl)ethoxymethoxy-
benzyl (p-SEM-benzyl) groups.
The trichloracetimidate 3 and the bromide 4 were prepared as
reagents for the introduction of the PAB group as shown in
Scheme 1. The primary hydroxyl group of 1 was selectively
Scheme 3a
Scheme 1a
a Reagents and conditions: (a) TrCl, pyridine, 20 °C, 2 h, 96%; (b)
Ac2O, pyridine, 20 °C, 2 h, 97%; (c) 5% TFA, 5% TIS in CH2Cl2, 20
°C, 85%; (d) DBU, CCl3CN, CH2Cl2, 20 °C, 5 min, 95%; (e) CBr4, PPh3,
Et2O, 20 °C, 15 min, 95%.
tritylated followed by acetylation of the phenol and cleavage of
the trityl group using a solution of 5% trifluoroacetic acid and
5% triisopropylsilane in CH2Cl2 at room temperature to give 2.
Treatment of 2 with trichloroacetonitrile in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene gave the trichloroacetimidate 3
in 95% yield. The bromide 4 was obtained after treatment of 2
with carbon tetrabromide (2.2 equiv) and triphenylphosphine (4.4
equiv) in diethyl ether to give a 95% yield.
Reaction of the primary hydroxyl group of 5 with the tri-
chloroacetimidate 3 employing trifluoromethanesulfonic acid
(TfOH) or trifluoromethanesulfonic anhydride (Tf2O)1 as a cata-
lyst in CH2Cl2 gave the protected compound 6 in 67% yield
(Scheme 2). The same compound was produced in 78% yield on
reaction of 5 with the bromide 4 by using silver trifluoromethane-
sulfonate (AgOTf) in hexane/CH2Cl2 (1/1). The PAB ether group
can be selectively cleaved in quantitative yield in the presence
of benzyl ethers as shown in Scheme 2. Treatment of 6 with
NaOMe yields the phenoxide 7 which can be isolated by flash
a Reagents and conditions: (a) p-acetoxybenzaldehyde, ZnCl2, CH2Cl2,
20 °C, 18 h, 85%; (b) PMBOCNHCCl3, BF3‚Et2O, CH2Cl2, -78 °C, 5
min, 65%; (c) HCl/Et2O, NaBH3CN, THF, 20 °C, 74%; (d) BF3‚Et2O,
CH2Cl2, 20 °C, 1 h, 80%; (e) DDQ, CH2Cl2, 20 °C, 30 min, 90%; (f)
DMTST, CH2Cl2, MS 4 Å, 20 °C, 52%; (g) NaOMe, MeOH, 0 °C, 5
min (quant) ; (h) FeCl3, Et2O, 20 °C, 15 min, 95% (two steps).
chromatography if desired. Heating of 7 to 65 °C, however, results
in the loss of the PAB group, presumably by formation of a
methylene quinone as shown in 8. Alternatively, the phenoxide
7 can be removed by mild oxidizing agents such as 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ),2 FeCl3,3 iodobenzene di-
acetate,4 and silver carbonate on Celite5 (for conditions and yields,
see Table 1).
(2) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley
& Sons: New York, 1967; Vol. 1, p 215.
(3) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley
& Sons: New York, 1967; Vol. 1, p 390.
(4) Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis; John Wiley
& Sons: New York, 1974; Vol. 4, p 266.
(1) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981, 1240.
10.1021/ja9836085 CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/05/1999