The 2-(allyloxy) phenyl acetyl ester as a new relay protecting group for oligosaccharide synthesis

Article abstract of DOI:10.1016/S0040-4039(01)01303-X

The 2-(allyloxy) phenyl acetyl group can be removed by a relay approach using Pd(PPh₃)₄ in combination with proton sponge, conditions that do not affect acetyl, benzoyl and levulinoyl esters. On the other hand, the acetyl and levulin

Full text of DOI:10.1016/S0040-4039(01)01303-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6469–6471
The 2-(allyloxy) phenyl acetyl ester as a new relay protecting
group for oligosaccharide synthesis
Esther Arranz and Geert-Jan Boons*
Complex Carbohydrate Research Center, University of Georgia, 220 Riverbend Road, Athens, GA 30602-4712, USA
Received 15 June 2001; revised 17 July 2001; accepted 19 July 2001
Abstract—The 2-(allyloxy) phenyl acetyl group can be removed by a relay approach using Pd(PPh3)4 in combination with proton
sponge, conditions that do not affect acetyl, benzoyl and levulinoyl esters. On the other hand, the acetyl and levulinoyl ester could
be cleaved without removal of the 2-(allyloxy) phenyl acetyl group. The new protecting group is compatible with glycosylations
and can perform efficiently neighboring group participation leading to the exclusive formation of 1,2-trans glycosides. © 2001
Elsevier Science Ltd. All rights reserved.
Recent developments in oligosaccharide chemistry
focus on the preparation of compound libraries either
by parallel synthesis or by a mix and split approach.1 In
particular, the use of monosaccharide building blocks
that are substituted with orthogonal protecting groups
proved to be attractive for parallel synthesis of collec-
tions of oligosaccharides. For example, Wong and co-
intramolecular ester cleavage by nucleophilic attack of
the revealed hydroxyl.
2-(Allyloxy) phenyl acetic acid (3) was prepared by
treatment of methyl 2-hydroxyl phenylacetic acid (1)5
with allyl bromide in the presence of sodium hydride
and tetra-n-butyl ammonium iodide, followed by
workers
reported2
that
chloroacetyl
(ClAc),
AllO
CO2H
RO
CO2Me
p-methoxybenzyl (PMB), levulinoyl (Lev), and tert-
butyldiphenylsilyl (TBDPS) are a set of orthogonal
protecting groups. Recently, we reported3 that the
Fmoc, Lev and diethylisopropylsilyl (DEIPS) are an
attractive set of orthogonal hydroxyl protecting groups
for amino sugars. The cleavage conditions of these
protecting groups did not affect the base sensitive
amino protecting group trichloroethoxycarbonyl
(Troc).
LiOH, MeOH
3
1. R = H
2. R = All
NaH, AllBr,
TBAI
O
O
OBn
O
HO
BnO
OBn
O
OAll
BnO
BnO
3, DCC, DMAP
3, DCC, DMAP
BnO
OMe
OMe
7
4
Although these sets of protecting groups allow the
synthesis of a wide range of oligosaccharides, the sensi-
tivity of esters such as ClAc and Fmoc imposes
limitations.
Ph
O
Ph
O
O
O
O
O
O
SEt
SEt
BnO
BnO
HO
O
8
Here we present the 2-(allyloxy) phenyl acetyl (APAC)
as a new protecting group for oligosaccharide synthesis,
which is orthogonal with the levulinoyl and acetyl ester
and is capable of controlling the anomeric selectivity of
glycosylations by neighboring group participation. The
new protecting group can be removed by relay
deprotection4 whereby the phenolic allyl ether is cleaved
by treatment with a transition metal followed by
5
6
OAll
OBn
O
OBn
O
3, DCC, DMAP
BnO
SEt
BnO
BnO
SEt
BnO
O
HO
O
9
OAll
* Corresponding author. Tel.: +1-706-542-9161; fax: +1-706-542-4412;
e-mail: gjboons@ccrc.uga.edu
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01303-X

6470
E. Arranz, G.-J. Boons / Tetrahedron Letters 42 (2001) 6469–6471
Ph
O
saponification of the ester moiety of the resulting 2 with
lithium hydroxide in methanol/water (Scheme 1). The
hydroxyls of 4,6 5,7 and 6 could be protected as an
APAC ester to give 7, 8 and 9 by reaction with 3 in the
presence of DCC and DMAP in DCM. In each case,
the ester was isolated in an almost quantitative yield.
Several conditions were examined for removal of the
APAC ester (Table 1). Thus, treatment of 7 with PdCl2
in MeOH at 60°C gave, after a reaction time of 1 h, the
required alcohol 4 together with a small amount of
deallylated derivative 10. Intermediate 10 could be con-
verted into the alcohol 4 by treatment with triethyl
amine or imidazole but this approach was deemed less
attractive than a one-pot cleavage reaction. The use of
Pd(PPh3)4 and Et3N in ethanol/H2O gave a higher yield
of alcohol 4, but also in this case the product was
contaminated with 10. Fortunately, the application of
Pd(PPh3)4 in combination with proton sponge in reflux-
ing ethanol/water gave, after a reaction time of 2 h, 4 in
almost quantitative yield.
O
OH
O
+
+
O
i
i
8
8
BnO
BzO
O
BnO
O
BnO
RO
BnO
BzO
OMe
OMe
12. R = APAC
13. R = H
BnO
ii
OMe
11
Ph
OH
O
O
O
BnO
AcO
O
O
BnO
BnO
BnO
14
O
RO
AcO
15. R = APAC
BnO
OMe
ii
16. R = H
Ph
O
O
OH
+
O
i
O
8
LevO
AcO
O
BnO
R2O
1
O
BnO
R O
OMe
R3O
17
BnO
OMe
18. R1 = APAC, R2 = Lev, R3 = Ac
19. R1 = H, R2 = Lev, R3 = Ac
20. R1 = APAC, R2 = H, R3 = Ac
21. R1 = APAC, R2 = R3 = H
ii
Having established mild conditions for the introduction
and removal of the APAC protecting group, attention
was focussed on the employment of APAC protected
glycosyl donors. Furthermore, its ability to perform
neighboring group participation was explored. NIS/
TMSOTf-mediated glycosylations of glycosyl donor 8
with acceptors 11, 14,8 and 17 gave disaccharides 12, 15
and 189 in yields of 76, 67 and 81%, respectively
(Scheme 2). As expected, in each case only the b-
anomer was formed. Glycosylation of 9 with the less
reactive acceptor 2110 was also successful and in this
case 22 was isolated in a yield of 71% as exclusively the
b-anomer. In each case, the APAC protecting group of
disaccharides 12, 15, 18 and 22 could be removed using
standard conditions to give 13, 16, 19 and 23 in good
yields. It is important to note that the acetyl, benzoyl,
and levulinoyl esters of 12, 15, 18 and 22 were not
affected when the APAC protecting group was
removed.
iii
iv
i
Ph
O
Ph
O
BnO
BnO
O
O
O
O
O
+
9
HO
O
BnO
BzO
BzO
OMe
RO
OMe
21
22. R = APAC
23. R = H
ii
Scheme 2. Reagents and conditions: (i) NIS, TMSOTf, DCM;
(ii) Pd(PPh3)4, proton sponge, EtOH/H2O; (iii) NH2NH2·
AcOH, DCM, guanidine, 0.1 M in MeOH, DCM.
quantitative yield. Furthermore, the acetyl ester of 20
could be selectively removed by guanidine in
methanol11 to furnish diol 21. The latter two deprotec-
tions demonstrate that the APAC is a robust ester
functionality that is more stable towards base treatment
than the Lev and acetyl ester.
Finally, the orthogonality of the APAC protecting
group with the Lev and acetyl ester was explored.
Treatment of 18 with hydrazine acetate in DCM
resulted in clean removal of the Lev ester without
affecting the APAC or acetyl ester to give 20 in a
In conclusion, the APAC ester is a robust protecting
group that can be cleaved under mild conditions using
a relay approach involving cleavage of a phenolic allyl
ether followed by cyclization. The new protecting group
performs neighboring group participation in glycosyla-
tions and is orthogonal with acetyl and Lev esters. We
anticipate that the APAC protecting group will be a
valuable tool for combinatorial synthesis of oligosac-
charide libraries.
Table 1. Cleavage of APAC protecting group
Experimental procedure for removal APAC ester:
Pd(PPh3)4 (5 mg) and proton Sponge (0.2 mmol) were
added to a solution of the protected sugar (0.2 mmol, 7,
12, 15, 18 or 22) in ethanol/water (2/1, v/v). The
reaction mixture was heated under reflux (2–7 h) until
TLC analysis indicated completion of the reaction. The
solvents were evaporated under reduced pressure and
the crude product purified by silica gel column chro-
matography.
Cleavage conditions
Yield 4 (%)
Yield 10 (%)
PdCl2, MeOH, 60°C
59
70
89
11
25
–
Pd(PPh3)4, Et3N, EtOH/H2O, D
Pd(PPh3)4, proton sponge,
EtOH/H2O, D

E. Arranz, G.-J. Boons / Tetrahedron Letters 42 (2001) 6469–6471
6471
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