Nickel(II) chloride-mediated regioselective benzylation and benzoylation of diequatorial vicinal diols

Article abstract of DOI:10.1055/s-2004-831318

Ni(II)-chelates of monosaccharide vicinal diols were found to be useful intermediates in regioselective monobenzylation and monobenzoylation. It was observed that the substitution occurs exclusively at the position adjacent to the axially oriented substit

Full text of DOI:10.1055/s-2004-831318

LETTER
2191
Nickel(II) Chloride-Mediated Regioselective Benzylation and Benzoylation of
Diequatorial Vicinal Diols
R
egioselective Ben
m
zylation and Benzo
e
ylation of
D
s
iequatori
h
al
V
icinal Diols B. Gangadharmath, Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University Blvd., St. Louis, MO 63121, USA
Fax +1(314)5165342; E-mail: demchenkoa@umsl.edu
Received 7 June 2004
and esterifications of various carbohydrate derivatives.5,6
Abstract: Ni(II)-chelates of monosaccharide vicinal diols were
Nevertheless, certain drawbacks, such as ‘unexpected’ re-
gioselectivity, harsh reaction conditions, or difficulties re-
lated to the removal of the excess reagent are often
found to be useful intermediates in regioselective monobenzylation
and monobenzoylation. It was observed that the substitution occurs
exclusively at the position adjacent to the axially oriented substitu-
ent of the pyranose ring, for example, at C-2 of a-D-gluco and at C- encountered. One possibility would be to simplify the re-
action conditions,7 alternatively, a search of conceptually
3 of b-D-galacto.
different techniques might be executed. As a result, metal
chelation has come to the fore as one of the alternatives for
regioselective protection of diols. Chelates of such metals
as Cu2+ or Hg2+, have been previously investigated.8 So
far, a fairly strict requirement for complete regioselectiv-
ity, derived from the difficulties of the chromatographic
purification of the regioisomers, hinders this technique.
Key words: carbohydrates, regioselective synthesis, protecting
groups
The explosive growth in the field of glycobiology has
drawn particular attention to complex carbohydrate mole-
cules. The involvement of this class of natural compounds
in many vital biological processes has been determined.1
Along with the achievements in the area of convergent
oligosaccharide assembly,2 the necessity to improve the
synthesis of the monosaccharide building blocks has also
emerged. Carbohydrates, as well as other polyfunctional
organic molecules, require extensive use of temporary
protecting groups. Selective protecting group introduction
and removal are major techniques used in the synthesis of
oligosaccharides, glycoconjugates, antibiotics, steroids,
and heterocycles.3 One of the possible ways to shorten the
building block synthesis would be ‘on demand’ regiose-
lective monoalkylation or monoacylation of diols and
polyols.
As part of a program to develop novel protecting groups
and new strategies for the regioselective protection of car-
bohydrate molecules, we report here our studies on metal
chelates and their effect on regioselective protection of
vicinal 2,3-diols of monosaccharides. We decided to in-
vestigate whether nickel or other transition metals, such as
platinum or zinc, would have an effect on monoacylation
or monoalkylation.9 For this purpose, we selected 2,3-diol
1a10 of the a-D-gluco series (Figure 1) for our initial ex-
periments. As anticipated, benzoylation with BzCl in the
presence of either pyridine or NaH as a base and in the ab-
sence of a metal chelator, proceeded with fair (pyridine)
or no (NaH) regioselectivity. These experiments are listed
in Table 1 (entries 1 and 2).
Some diols in carbohydrate molecules can be fairly easily
distinguished from one another based on the difference in
their reactivity, for example, axial/equatorial or primary/
secondary alcohol pairs. Others, for example vicinal
diequatorial diols, are more similar in their relative reac-
tivity. This raises the challenge of their regioselective
monosubstitution. Some relevant examples of compounds
in this category include, but are not limited to, 2,3-diols of
glucose or galactose. Typically, poor regioselectivity is
achieved when monoacylation or monoalkylation of these
compounds is attempted. Also, substantial amounts of the
disubstituted product are formed.
Ph
O
Ph
O
O
O
a: R2=R3=H
O
O
R3O
R3O
b: R2=Bz, R3=H
c: R2=H, R3=Bz
d: R2=R3=Bz
OMe
R2O
R2O
OMe
1a–g
2a–d
e: R2=Bn, R3=H
f: R2=H, R3=Bn
g: R2=R3=Bn
Ph
Ph
Ph
O
O
O
O
O
O
O
O
O
R3O
R3O
R3O
OMe
SPh
R2O
3a–d
R2O
R2O
OMe
4a–g
5a–g
To address this challenge, specifically designed methods
have been developed. These include, but are not limited
to, substitution under phase-transfer catalysis conditions4
and, especially, via stannylene acetals. The latter strategy
has been widely employed in regioselective alkylations
Figure 1 Derivatives of D-glucose (1 and 2) and D-galactose (3–5)
Since hydroxyl-containing molecules are typically en-
gaged in hydrogen bonding, in some cases it might be
beneficial to deprotonate the hydroxyls with a strong base
(NaH) prior to chelation with the metal salt. To our de-
light, metal chelation-assisted benzoylation proceeded en-
tirely regioselectively, affording the 2-O-substituted
SYNLETT 2004, No. 12, pp 2191–2193
0
1
.1
0
.2
0
0
4
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831318; Art ID: S05304ST
© Georg Thieme Verlag Stuttgart · New York

2192
U. B. Gangadharmath, A. V. Demchenko
LETTER
Table 1 Metal Salt-Mediated Benzoylation of Diols 1a–5a
Entry
1
Sugar
1a
1a
1a
1a
1a
1a
2a
2a
3a
3a
3a
3a
3a
3a
4a
5a
5a
Base
Salt
Solventa
DCE
THF
DCE
THF
THF
THF
THF
THF
DCE
THF
DCE
THF
THF
THF
THF
THF
THF
Yield of b, c, d (%)
Ratio b:c:d
11:3:1
1:1:1
Pyridine
NaH
None
None
NiCl2
NiCl2
PtCl2
ZnCl2
None
NiCl2
None
None
NiCl2
NiCl2
PtCl2
ZnCl2
NiCl2
None
NiCl2
67, 16, 6
b
2
3
Pyridine
NaH
85, 0, 0
85, 0, 0
58, 0, 0
1:0:0
4
1:0:0
5
NaH
1:0:0
6
NaH
62, 0, 0
1:0:0
b
7
NaH
0:0:1
b
8
NaH
1:2:2
9
Pyridine
NaH
4, 51, 0
1:13:0
1:1:1
b
10
11
12
13
14
15
16
17
Pyridine
NaH
0, 70, 0
3, 72, 0
12, 48, 0
0:1:0
1:24:0
1:4:0
NaH
NaH
6, 62, 0
1:10:0
1:1:3
b
NaH
b
NaH
1:1:1
NaH
0, 67, 0
0:1:0
a DCE: 1,2-dichloroethane, THF: tetrahydrofuran.
b The product ratio was estimated from TLC and/or 1H NMR analysis of the crude reaction mixture.
product 1b (entries 3–6). While all investigated transition ing to preferential (de)activation of one of the groups
metals Zn2+, Pt2+, and Ni2+ allowed complete regioselec- involved in the chelate over another is a less studied phe-
tivity, NiCl2 performed marginally better in terms of reac- nomenon. As aforementioned, stannylene acetals and
tion rate and yield. Thus, 2-O-benzoylated 1b was isolated copper chelates are the most extensively investigated ex-
in 85% yield in the presence of either pyridine or NaH (en- amples in this respect. As a result of the chelation, regio-
tries 3 and 4). Remarkably, no traces of 3-O-benzoylated selective substitution takes place at the less deactivated
(1c) or 2,3-di-O-benzoylated products (1d) were detected hydroxyl group. The stability of the obtained complex de-
in any of the metal salt-assisted experiments.
pends on many factors, such as: ionic radius of the metal
ion, reaction conditions, metal salt used, donor atom
present and geometry around the metal center.11
Encouraged by these results, we decided to employ the
new technique for regioselective benzoylations of other
monosaccharide substrates. To our disappointment, this With these considerations in mind, and in order to test this
concept did not seem to work well for the 2,3-diol of the concept, we decided to investigate the monosubstitution
b-D-gluco series (2a).10 Despite a notable shift toward of 3a,12 a derivative of the b-D-galactose series. We were
monosubstituted product formation in comparison to the pleased to find out that the metal salt-assisted benzoyla-
benzoylation in the absence of the metal salt, the regiose- tion of 3a proceeded with high regioselectivity (entries
lectivity remained low (entries 7, 8).
11–14). As anticipated, the acylation took place at C-3,
the neighboring hydroxyl group in respect to the axial C-
4. High regioselectivity was also noted with ZnCl2 and
PtCl2, but as in the case of benzoylation of 1a, the best re-
sults were achieved with NiCl2.
We assumed that in order to achieve high regioselectivity,
it is essential to have at least one axially oriented pyranose
ring substituent.6 In that case, the substitution will have
occurred at the neighboring equatorial hydroxyl. In the
case of 2a, all substituents, including that at the anomeric In addition, it seemed interesting to investigate whether a
position, are equatorially oriented. It is well documented compound with two axial substituents would allow regio-
that carbohydrates containing two (or more) free hydroxyl selective benzoylation. For this purpose we chose a deriv-
(or amino) groups with either axial or equatorial orienta- ative of the a-D-galacto series, 4a.12 In this case, no
tion can bind to the metal ion.11 The chelation effect lead- regioselective substitution took place. Instead, the disub-
Synlett 2004, No. 12, 2191–2193 © Thieme Stuttgart · New York

LETTER
Regioselective Benzylation and Benzoylation of Diequatorial Vicinal Diols
2193
General Procedure for the Metal Salt-Assisted Benzoylation
and Benzylation in the Presence of NaH.
stituted product 4d was the predominant species in the
reaction mixture (entry 15). We have also engaged a phe-
nylthio galactoside 5a13 in our studies. As expected, its
benzoylation proceeded with high regioselectivity favor-
ing the 3-O-substitited 5c (entry 17).
The partially protected monosaccharide diol (1a–5a, 0.2 mmol) was
dissolved in anhyd THF (2–3 mL). In the case of benzylation, DMF
(0.2–0.6 mL) was also added. To this mixture NaH was added (0.42
mmol) and the reaction mixture was stirred under argon for 1 h at
r.t. to give a white slurry of the corresponding dialkoxide ion. An-
hyd metal salt (0.2 mmol) was added and the reaction mixture was
stirred for 1 h at r.t. BnBr or BzCl (0.22–0.24 mmol) was added
dropwise and the reaction mixture was stirred for additional 4–16 h
at r.t. Upon completion, H2O (0.1 mL) and HOAc (1–2 drops) were
added to the reaction mixture. Volatile solvents were then removed
in vacuo, and the residue was diluted with CH2Cl2 (20 mL), washed
with H2O (10 mL), sat. aq NaHCO3 (10 mL), and H2O (or brine,
3 × 10 mL). The organic layer was separated, dried and concentrat-
ed in vacuo. The residue was purified by column chromatography
on silica gel (gradient acetone–toluene). All synthesized com-
pounds have unambiguous 1H NMR data.
Similarly, regioselective benzylation of diols 1a, 3a, and
5a was performed with BnBr. While benzylations in the
absence of NiCl2 were non-regioselective typically allow-
ing a number of products (entries 1,3, or 5, Table 2), reac-
tions in the presence of NiCl2 were completely
regioselective. Products with the expected regioselectivi-
ty, the same as in the case of benzoylation with BzCl, were
obtained (entries 2, 4, or 6).
Table 2 NiCl2-Mediated Benzylation of Diols 1a, 3a, and 5a in the
Presence of NaH in THF–DMF,a 4–9/1, v/v.
Entry
Sugar
1a
Salt
Yield of e, f, g (%)
Ratio e:f:g
3:1:1
Acknowledgment
b
1
2
3
4
5
6
None
NiCl2
None
NiCl2
None
NiCl2
This work was supported by the University of Missouri – St. Louis.
1a
63, 0, 0
1:0:0
b
References
3a
0:1:3
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Synlett 2004, No. 12, 2191–2193 © Thieme Stuttgart · New York