4-Acetoxy-2,2-dimethylbutanoate: A useful carbohydrate protecting group for the selective formation of β-(1→3)-D-glucans

Article abstract of DOI:10.1016/j.tetlet.2005.03.099

The use of 4-acetoxy-2,2-dimethylbutanoyl protecting group for the C2-hydroxyl allows the selective formation of β-glycosides without producing α-glycosides. This very bulky protecting group can be removed under mild conditions.

Full text of DOI:10.1016/j.tetlet.2005.03.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3417–3421
4
-Acetoxy-2,2-dimethylbutanoate: a useful carbohydrate
protecting group for the selective formation of b-(1!3)-D-glucans
a
Hai Yu, David L. Williams and Harry E. Ensley
b
a,
*
a
Department of Chemistry, Tulane University, New Orleans, LA 70118, USA
Department of Surgery, East Tennessee State University, Johnson City, TN 37614, USA
b
Received 20 January 2005; revised 1 March2005; accepted 4 March2005
Available online 2 April 2005
Abstract—The use of 4-acetoxy-2,2-dimethylbutanoyl protecting group for the C2-hydroxyl allows the selective formation of
b-glycosides without producing a-glycosides. This very bulky protecting group can be removed under mild conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Methodology for the synthesis of complex oligosaccha-
rides has progressed remarkably during the past decade
primarily due to the discovery of new anomeric activa-
anism of a-glycoside formation is unknown, Kong and
co-workers proposed that the orthoesters is an interme-
diate in the formation of the a-glycoside. While Kong
and co-workers showed the utility of this process for
the preparation of 1,3-glucans with mixed a- and b-link-
1
tion procedures and coupling protocols. In spite of
this progress, the successful linking of two saccharide
units can still be thwarted by unexpected difficulties.
An example of this is the recent disclosure by Kong
and co-workers that, in certain cases, a-linked products
are unexpectedly obtained in glycosylations using
trichloroacetimidate activated donors with a C2 ester
2
ages, the unexpected formation of the a–linkage is a
major impediment to the preparation of b-1,3-glucans,
an important class of immune stimulators.
7
Recently, during the preparation of a small library of
b-1,3-polyglycosides (b-1,3-glucans), we encountered a
similar problem witha lack of stereoselectivity in gly-
cosylations under conditions where b-selectivity was
expected. As shown in Table 1, the reaction of various
donors (1a–f) with1,2,4,6-tetra- O-acetyl-a-D-glycopyr-
anose 2 or the b-linked disaccharide 3 afforded disaccha-
ride or trisaccharide products whose newly formed
glycosidic linkage ranged from b-only to a-only.
2
capable of neighboring group participation.
The stereoselective preparation of b-glycosidic linkages
are most reliably formed using a 2-carboxyprotected
3
4
(
aka ÔdisarmedÕ ) glycosyl donor (A). Neighboring
group participation of the 2-carboxy group assists the
departure of the leaving group (to give B) and nucleo-
philic attack of the glycosyl acceptor affords the disac-
charide (C). A problem sometimes encountered during
the preparation of b-glycosides using this approach is
the production of orthoesters (D) instead of the desired
As shown in Table 1, formation of the unexpected a-
linkage occurs bothfor tric hl oroacetimidate activation
and for thioglycoside mediated couplings. The use of
pivaloate esters at C2 is clearly beneficial to the form-
ation of the b-glycoside but does not completely inhibit
formation of the a-glycoside. In spite of the stereochem-
ical benefits of the C2-Piv group we were concerned that
the harsher conditions required for the deprotection of
multiple pivaloate esters (at sterically hindered second-
ary centers) would be a limitation in the production of
5
glycoside (Scheme 1). The orthoesters complication has
not been a major concern since there are numerous
reports that the orthoesters can easily be converted into
6
the b-glycoside. The reliability of the stereochemical
outcome from coupling a disarmed glycosyl donor with
a glycosyl acceptor has been called into question by
2
Kong and co-workers work. Although the exact mech-
1
,3-b-glucans. Therefore we set out to prepare a protect-
Keywords: b-Glycoside formation; Carbohydrate protecting groups;
b-Glucan.
Corresponding author. Tel.: +1 504 865 5573; fax: +1 504 862
8949; e-mail: hensley@tulane.edu
ing group with the steric advantages of the bulky piva-
loyl group but which could be removed under mild
conditions.
*
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.099

3418
H. Yu et al. / Tetrahedron Letters 46 (2005) 3417–3421
RO
RO
RO
RO
RO
HO
O
O
O
RO
O
OR
RO
O
RO
RO
RO
OR
O
RO
RO
RO
OR
O
O
O
OR
C
R1
RO
X
-
X
O
O
O
R
1
B
RO
O
RO
R
1
A
O
RO
RO
OR
O
O
O
OR
D
R
1
Scheme 1.
Table 1. Glycosylation using glycosyl donors withvarious ester-protecting groups at C2
Donor
Acceptors
OAc
OAc
OR1
OAc
O
O
AcO
HO
AcO
O
R2O
BnO
AcO
HO
O
O
X
AcO OAc
1a
PO
AcO
OAc
AcO
3
2
b
1
1
1
1
1
1
a P = Ac X = O-trichloroacetimidate
84% (a:b 1:1)
NA
NA
NA
b
b P = Bz X = O-trichloroacetimidate
c P = ClCH CO X = O-trichloroacetimidate
d P = CH OCO X = O-trichloroacetimidate
e P = (CH CCO X = O-trichloroacetimidate
f P = (CH
86% (a only)
85% (a only)
83% (a only)
81% (a:b 2:3)
82% (a:b 1:3)
b
2
b
3
85% (a:b 1:1)
80% (b only)
NA
b
3 3
)
c
3
)
3
CCO X = SPh
a
b
c
Compound 1a–e, R
1
= Ac, R
2
1 2
= Ac; compound 1f, R :R = CHPh.
Activation withTMSOTf.
Activation withNIS/AgOTf.
There were two reports in the literature where a similar
8
group appeared to be a likely candidate. It was antici-
pated that base catalyzed hydrolysis of the 4-acetoxy
group would initiate an intramolecular lactonization
and loss of dimethylbutyrolactone. The preparation
of 4-acetoxy-2,2-dimethylbutanoic acid and the corre-
sponding acid chloride has been described but its
potential utility as a protecting group has not been
explored.
problem has been faced and overcome. Crimmins et al.
had utilized the 2,2-dimethyl-4-pentenoyl protecting
group which could be removed by hydroboration, oxid-
9
ation, and mild base treatment and Trost and Hembre
10
had used the 4-tert-butyldimethylsilyloxy-2,2-dimeth-
ylbutanoyl protecting group which could be removed
on treatment withfluoride anion. T he additional steps
required in the Crimmins approach made it less attrac-
tive and since we wanted to reserve the use of TBDMS
for the C-3 hydroxyl group protection, TrostÕs approach
could not be used. The 4-acetoxy-2,2-dimethylbutanoyl
The 4-acetoxy-2,2-dimethylbutanoyl (ADMB) esters are
easily prepared under the same conditions used for
pivaloate esters and shows similar selectivity in
Table 2. Comparison of hydrolysis of pivaloyl and 4-acetoxy-2,2-dimethylbutanoyl esters (ADMB)
Substrate
Equiv of DBU
Time (h)
ROH yield (%)
4
a P = Piv
4b P = ADMB
b P = ADMB
0.5
0.5
0.1
24
0.5
2
0
100
100
OP
4
4
OP
O
O
5
O
5a P = Piv
5b P = ADMB
0.5
0.5
0.1
10
1
12
100
100
O
O
5
b P = ADMB
3
Ph
O
O
O
6
7
SPh
6a P = Piv
6b P = ADMB
0.5
0.1
24
3
0
98
BnO
PO
Ph
O
O
O
7a P = Piv
7a P = Piv
0.5
0.5
0.5
2
12
1
30
97
99
HO
PO
OMe
7
b P = ADMB

Table 3. Glycosylation using glycosyl donors withC2 4-acetoxy-2,2-dimet hy lbutanoate protecting group
Entry
Donor
Acceptor
Product
OAc
O
OAc
O AcO
Ph
O
O
OAc
O
O
O
O
Ph
OAc
O AcO
O
O
AcO
SPh
O
O
BnO
AcO
BnO
AcO
O
1
AcO
HO
O
AcO
OAc
OAc
AcO
OAc
OAc
O
O
9
83% β only
8
3
OBz
O
OBz
BzO
BzO
O
O
BzO
BzO
Ph
O
O
O
OBz
AcO
O
OBz
O
O
O
CAO
AcO
Ph
2
O
O
O
OO CCl3
NH
AcO
O
O
CAO
AcO
HO
O
O
AcO
SEt
AcO
SEt
O
O
1
0
O
1
2
88% β only
1
1
O
Ph
O
O
O
Ph
O
O
Ph
O
O
Ph
O
Ph
O
Ph
O
O
O
Ph
O
O
O
O
O
O
O
O
O
Ph
O
O
O
O
O
O
TBSO
O
BzO OBz
3
TBSO
O
O
BzO
HO
BzO
AcO
SEt
BzO
AcO
BzO
OBz
O
BzO
O
1
5
92% β only
1
3
14
Ph
O
Ph
O
O
Ph
O
Ph
O
Ph
O
O
O
Ph
O
O
O
Ph
O
O
O
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
TBSO
OSEt
O
4
TBSO
HO
BzO
AcO
O
CCl
NH
SEt
BzO
AcO
BzO
AcO
3
BzO
AcO
O
O
O
1
8
91% β only
1
6
17

3420
H. Yu et al. / Tetrahedron Letters 46 (2005) 3417–3421
2. (a) Zeng, Y.; Ning, J.; Kong, F. Tetrahedron Lett. 2000,
OR
O
O
43, 3729; (b) Zeng, Y.; Ning, J.; Kong, F. Carbohydr. Res.
2003, 338, 307.
3. Paulsen, H.; Richter, A.; Sinnwell, V.; Stenzell, W.
Carbohydr. Res. 1978, 64, 339–362; (b) Fraser Reid, B.;
Udodong, U. E.; Wu, Z.; Ottesson, H.; Merritt, J. R.;
Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927–
RO
RO
O
O
O
9
42.
Scheme 2.
4
5
. Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21–123.
. (a) Seeberger, P. H.; Eckhardt, M.; Gutteridge, C. E.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10064–
carbohydrate acylations. Jiang and Chan has reported
the selective pivaloylation of a number of mono- and
1
1
disaccharides using pivaloyl chloride. Similarly, under
the same conditions, we have found that treatment of
methyl 4,6-benzylidene-a-D-glucoside and ethyl 4,6-benz-
ylidene-1-thio-a-D-glucoside with4-acetoxy-2,2-dimeth-
ylbutanoyl chloride permits selective acylation of the
C2 hydroxyl group in 95% and 94% yield, respectively.
The ease of removal of the ADMB ester group on treat-
ment withcatalytic quantity of diazabicycloundecane
1
0072; (b) Modern Methods in Carbohydrate Synthesis;
Khan, S. H., OÕNeil, R. A., Eds.; Harwood Academic:
United States, 1996, p 125.
6. (a) Wang, W.; Kong, F. J. Org. Chem. 1998, 63, 5744; (b)
Sznaidman, M. L.; Johnson, S. C.; Crasto, C.; Hecht, S.
M. J. Org. Chem. 1995, 60, 3942; (c) Gass, J.; Strobl, M.;
Kosma, P. Carbohydr. Res. 1993, 244, 69.
. Brown, G. D.; Gordon, S. Nature 2001, 413, 36.
. Crimmins, M. T.; Carroll, C. A.; Wells, A. J. Tetrahedron
Lett. 1998, 39, 7005–7008.
7
8
(DBU) in methanol at room temperature is demon-
strated in Table 2.
1
2
9
. Trost, B. M.; Hembre, E. J. Tetrahedron Lett. 1999, 40,
2
19–222.
We had anticipated that the facile removal of the C2-
ADMB group would be the only difference between it
and the pivaloyl group. However, we were gratified to
find that the problem of a-glycoside formation was elimi-
nated when using the C2-ADMB group in carbohydrate
coupling reactions. The couplings afford good yields
1
0. Hoffman, W. F.; Monocyclic lactone derivatives of
mevinolin and compactin as hydroxymethylglutaryl co-
enzyme A reductase inhibitors. U.S. Patent 4665091, May
12, 1987; CA 107: 96514. Briefly, 2-methylbutyrolactone is
treated withLDA and tehn CH
3I to afford 2,2-di-
methylbutyrolactone. After distillation, the lactone is
treated with1 equiv of 1 N NaOH in met ah nol and
stirred overnight at rt. The solution is concentrated on a
rotary evaporator and dried azeotropically using toluene
(
80–92%) of b-glycosides. For example, the coupling of
glycoside 8, withdisacc ha ride 3 gave an 83% yield of
the all b-linked trisaccharide 9 as the only product (Ta-
ble 3, entry 1) (comparing withthe last entry in Table 1).
(
temp <50 °C). The dried sodium salt is added to pyridine
containing a catalytic amount of DMAP, cooled to 0 °C
and 2 equiv of acetic anhydride was added dropwise. After
stirring overnight and extraction a mixture of recyclized
2,2-dimethylbutyrolactone and 4-acetoxy-2,2-dimethyl-
butyric acid is obtained. The acid is separated by base
extraction followed by careful acidification. Treatment
withoxalyl c lho ride in benzene affords 4-acetoxy-2,2-
dimethylbutanoyl chloride.
Other examples showing the glycosyl trichloroacetimi-
date and thioglycoside mediated couplings are given in
Table 3. Highyields of b-glycosides are obtained in all
of the cases we have examined. The structures of the oli-
gosaccharides are evident from their NMR spectra. The
anomeric protons of oligosaccharide differ significantly
witht he a- and b-anomers showing proton coupling
1
1. Jiang, L.; Chan, T. H. J. Org. Chem. 1998, 63, 6035–6038.
1
3
12. Typical procedure for the deprotection of 4-acetoxy-2,2-
dimethylbutanoyl protecting rg oup . To a solution of 6b
constants of ꢀ3 and ꢀ8 Hz, respectively. C NMR spec-
tra were recorded giving the C-1 a in the d 90–93 ppm
(
room temperature was
250 mg, 0.41 mmol) in CH
2
Cl
2
–MeOH (6 mL, 1:1) at
added 1,8-diazabicy-
13
range and the C-1 b in the d 96–104 ppm range.
clo[5.4.0]undec-7-ene (DBU) (7 lL, 0.04 mmol). After
being stirred for 3 h, the solution was concentrated to a
residue, which was purified by a silica gel column
chromatography to give the alcohol (183 mg, 98%).
Although it is unclear why the ADMB ester is beneficial
to b-glycoside formation, if, as Kong and co-workers
proposed, the orthoesters is an intermediate in the for-
mation of the a-glycoside, the presence of the ADMB
group could stabilize the dioxolenium ion and sterically
prevent orthoesters formation (Scheme 2). Irrespective
of the mechanism-of-action, the use of the ADMB
group makes possible the selective formation of pure
2
1
13
1
3. H NMR (400 MHz, CDCl
CDCl ) data for compounds 12, 15, and 18. Compound
2: H NMR d 7.94–7.19 (m, 25H), 5.80 (t, J = 9.6 Hz, 1H,
3
) and C NMR (100 MHz,
3
1
1
0
0
00
H-3 ), 5.60 (t, J = 9.6 Hz, 1H, H-4 ), 5.44 (dd, J = 9.6 Hz
0
and 8.0 Hz, 1H, H-2 ), 5.42 (s, 1H), 5.36 (d, J = 5.6 Hz,
00
1
H, H-1), 5.20 (t, J = 9.2 Hz, 1H, H-2 ), 4.82–4.74 (m, 4H,
(
1!3)-b glucan polymers. This may lead to the develop-
0
0
H-1, H-1 , H-2, H-3 ), 4.65 (t, J = 10.0 Hz, 1H), 4.57 (dd,
J = 12.4 Hz and 3.2 Hz, 1H), 4.42–4.29 (m, 3H), 4.11–3.90
(m, 9H), 3.68–3.44 (m, 4H), 2.20–2.09 (m, 2H), 1.92–1.83
ment of synthetic glucan ligands for biomedical
applications.
(
1
(
m, 2H), 1.96 (s, 3H), 1.93 (s, 3H), 1.89 (s, 3H), 1.75–
.69 (m, 2H), 1.21 (s, 3H), 1.18 (s, 3H), 1.05 (s, 6H), 0.89
t, J = 7.6 Hz, 3H); C NMR d 175.9, 175.7, 171.2, 171.1,
1
3
References and notes
1
1
1
7
6
3
69.6, 166.8, 166.3, 160.0, 165.4, 165.3, 136.6, 133.7, 133.6,
33.5, 133.4, 130.1, 130.0, 129.7, 129.6, 129.4, 128.9, 128.8,
28.7, 128.6, 128.6, 128.5, 128.5, 126.3, 101.9, 101.3, 100.1,
9.7, 78.5, 75.1, 74.1, 73.5, 73.1, 72.5, 72.3, 71.9, 69.7, 69.1,
8.7, 68.5, 66.6, 63.2, 61.5, 61.1, 41.4, 41.0, 40.8, 38.3,
8.1, 25.7, 25.6, 25.3, 24.9, 23.2, 21.2, 21.1, 21.0, 14.3.
1
. (a) Carbohydrates in Chemistry and Biology; Ernst, B.,
Hart, G. W., Sinay, P., Eds.; Wiley-VCH: Weinheim,
Germany, 2000; Vol. 1; (b) Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,
1997.

H. Yu et al. / Tetrahedron Letters 46 (2005) 3417–3421
3421
1
Compound 15: H NMR d 8.28–7.29 (m, 40H), 6.72 (d,
J = 4.0 Hz, 1H, H-1), 5.92 (s, 1H), 5.64 (s, 1H), 5.50 (dd,
J = 9.6 Hz and 4.0 Hz, 1H, H-2), 5.46 (t, J = 8.8 Hz, 1H),
5
1
1H), 5.78 (d, J = 5.6 Hz, 1H, H-1), 5.64 (s, 1H), 5.46 (t,
J = 8.0 Hz, 1H), 5.25 (d, J = 8.0 Hz, 1H, H-1), 5.16 (s,
1H), 5.04 (dd, J = 9.6 Hz and 6.0 Hz, 1H, H-2), 4.99–4.97
(m, 2H), 4.85–4.80 (m, 2H), 4.50–3.88 (m, 18H), 3.88–3.45
(m, 6H), 3.02 (t, J = 9.6 Hz, 1H), 2.73–2.62 (m, 2H), 2.14
(s, 3H), 2.06 (s, 3H), 1.99–1.96 (m, 2H), 1.87–1.82 (m, 2H),
1.38 (t, J = 7.2 Hz, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.15 (s,
3H), 1.12 (s, 3H), 0.84 (s, 9H), 0.09 (s, 3H), 0.00 (s, 3H);
.39 (s, 1H), 5.27 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 7.6 Hz,
H), 4.84–4.73 (m, 3H), 4.58 (t, J = 9.6 Hz, 1H), 4.53–4.36
m, 3H), 4.32–3.49 (m, 18H), 3.44 (t, J = 10.0 Hz, 1H),
.74 (t, J = 9.6 Hz, 1H), 2.06 (s, 3H), 1.75–1.73 (m, 2H),
.03 (s, 3H), 0.99 (s, 3H), 0.84 (s, 3H), 0.09 (s, 3H), 0.00 (s,
H); C NMR d 176.2, 175.8, 171.2, 165.6, 165.1, 164.0,
37.3, 134.0, 130.2, 130.0, 129.9, 129.4, 129.2, 129.1, 128.8,
28.6, 128.5, 128.3, 128.0, 126.8, 126.7, 126.5, 126.2, 102.3,
02.1, 102.0, 100.3, 99.3, 98.1, 96.3, 92.1, 82.2, 81.9, 79.5,
7.9, 76.1, 74.9, 74.8, 74.3, 73.7, 73.1, 72.9, 72.4, 68.9, 68.8,
8.6, 66.6, 66.2, 65.0, 63.1, 61.5, 61.2, 40.9, 40.7, 38.1, 29.9,
(
2
1
3
1
1
1
7
6
2
1
3
13
C NMR d 180.9, 180.6, 175.9, 175.9, 170.2, 169.8, 142.3,
142.1, 142.0, 138.8, 138.5, 135.0, 134.8, 134.7, 134.5, 134.4,
134.2,134.0, 133.8, 133.6, 133.4, 133.2, 133.1, 132.8, 131.6,
131.5, 131.2, 131.0, 107.0, 106.9, 106.7, 105.0, 104.0, 102.8,
101.0, 86.9, 86.5, 84.3, 82.6, 82.2, 80.8, 79.7, 79.6, 79.1,
78.4, 77.9, 77.5, 77.2, 73.7, 73.6, 73.5, 71.3, 70.9, 69.7, 67.8,
66.3, 65.9, 45.7, 45.5, 42.8, 42.7, 30.5, 30.1, 29.8, 29.0, 25.9,
25.8, 22.9, 19.7, 0.68, 0.00.
5.7, 25.3, 25.0, 21.2, 21.1, 18.1, 15.0, ꢁ4.1, ꢁ4.8.
1
Compound 18: H NMR d 8.26–7.38 (m, 30H), 5.87 (s,