Studies of the stereoselective reduction of ketosugar (hexosulose)

Article abstract of DOI:10.1016/S0040-4039(01)01472-1

The results from the studies of the stereoselective reduction of ketosugar (hexosulose) were reported. Combining our results and those reported in the literature, we summarize the factors in controlling the stereoselective reduction of ketosugars. These findings are valuable in the synthesis of various carbohydrate derivatives.

Full text of DOI:10.1016/S0040-4039(01)01472-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7019–7023
Studies of the stereoselective reduction of ketosugar (hexosulose)
Cheng-Wei Tom Chang,* Yu Hui and Bryan Elchert
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300, USA
Received 16 July 2001; revised 8 August 2001; accepted 9 August 2001
Abstract—The results from the studies of the stereoselective reduction of ketosugar (hexosulose) were reported. Combining our
results and those reported in the literature, we summarize the factors in controlling the stereoselective reduction of ketosugars.
These findings are valuable in the synthesis of various carbohydrate derivatives. © 2001 Published by Elsevier Science Ltd.
1. Introduction
oxidize the hydroxyl group to a ketone that can then be
reduced by NaBH4 to a hydroxyl group of the opposite
configuration. It has been our experience, which is
fortified by other literature examples,7–16 that the pro-
tecting groups on the a-hydroxyl groups of the ketone
have an effect on whether the configuration of the
resulting alcohol can be inverted or not. According to
the literature results, the reduction of the 4-tert-butyl-
cyclohexanone with LiAlH4 or NaBH4 favors the for-
mation of a hydroxyl group with an equatorial
configuration (Scheme 1.1).17,18 Large nucleophile or
hydride reducing agents, such as L-Selectride, favor the
formation of an axial hydroxyl group. However, our
results as well as some examples in the literature
showed that NaBH4 could reduce the ketohexoses and
provide an axial hydroxyl group as the dominant
product (Scheme 1.2). This paper summarizes our
findings and discusses the conditions that allow for this
transformation, the inversion from equatorial to axial
hydroxyl group on a hexose, to occur.
Natural or non-natural carbohydrate mimetics,1,2 such
as fluorosugars, aminosugars, and deoxysugars, have
attracted a growing interest due to their broad spec-
trum of application in chemistry, biochemistry, medici-
nal, and pharmaceutical fields. Our group is interested
in studying the structure–activity relationship of
aminosugars through a synthetic approach. Aminosug-
ars are a group of structurally diverse unusual sugars
bearing amino substitution from a normal sugar scaf-
fold, and have been shown to closely relate to the
activity of the aminosugar-containing antibiotics.3–6 As
part of our research, which involves the introduction of
an amino (azido) group on the equatorial position of a
hexose, it is necessary to epimerize the equatorial
hydroxyl group into an axial configuration on the
hexose scaffold, followed by a SN2 azide substitution.
Typically our method of inverting the configuration of
the hydroxyl group consists of a Swern oxidation to
1) Literature result
LiAlH4
OH
or
NaBH4
+
9 : 1
O
HO
OR
axial OH
minor product
equatorial OH
major product
2) Our and several literature results
OR
OR
HO
RO
Swern
O
O
O
axial OH
O
NaBH4
oxid.
HO
RO
major product
OR
OR
OMe
RO
OR
OMe
OMe
R = alkyl
Scheme 1. Stereoselective reduction of cyclohexanone moieties.
Keywords: ketosugar; hexosulose; stereoselective reduction; aminosugar.
* Corresponding author. Tel.: 435-797-3545; fax: 435-797-3390; e-mail: chang@cc.usu.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01472-1

7020
C.-W. T. Chang et al. / Tetrahedron Letters 42 (2001) 7019–7023
2. Results and discussion
sugars were subjected to the NaBH4 reduction without
purification. The products were purified by column
Various hexose moieties19 were converted into their
corresponding ketosugars via Swern oxidation. The keto-
chromatography and the configuration of each sugar was
1
assigned by the coupling constant from H NMR.
Table 1. Stereoselective reduction of 4-ketosugars from the work of this paper
products (% yield)
entry ketosugars
axial OH
equatorial OH
OBn
OBn
HO
O
O
O
1
not isolated
80%
BnO
BnO
BnO
HO
BnO
OMe
OMe
OTr
OTr
O
O
O
not isolated
not isolated
2
3
4
51%
94%
BnO
BnO
BnO
HO
BnO
OMe
OMe
OMe
OMe
O
O
O
BnO
BnO
N3
BnO
BnO
N3
HO
BnO
HO
O
O
O
not isolated
80%
BnO
BnO
BnO
OMe
OMe
OMe
N3
O
N3
O
O
65%
49%
not isolated
not isolated
5
6
BnO
BnO
HO
OMe
OMe
N3
O
N3
O
O
PMBO
PMBO
OMe
OTr
O
OTr
O
O
not isolated
80%
7
8
HO
BnO
OBn
BnO
OBn
OMe
OMe
OMe
HO
O
O
O
O
O
HO
BnO
62%
26%
BnO
BnO
HO
N3
OMe
OMe
OMe
N3
O
N3
N3
O
O
14%
9
10
11
12%
99%
N3
HO
N3
OMe
OMe
OMe
OMe
O
BnO
OTr
O
O
HO
not isolated
not isolated
BnO
OTr
O
O
O
BnO
79%
HO
HO
OMe
BnO
N3
OMe
N3
O
O
12
13
O
MOMO
BnO
not isolated
not isolated
OMe
BnO
MOMO
OMe
N3
N3
O
O
O
BzO
BnO
HO
OMe
BnO
BzO
OMe

C.-W. T. Chang et al. / Tetrahedron Letters 42 (2001) 7019–7023
7021
We did not find any explanation in the literature
regarding this reverse stereoselectivity. The only orga-
nized data comes from the reduction of 2-ketosugars.11
Therefore, we decided to examine the results from our
synthetic work, and those results reported in the litera-
ture. We discovered that the presence of a vicinal
equatorial alkoxyl group is the pivotal criterion for the
formation of an axial hydroxyl group during the
NaBH4 reduction, which is consistent with the observa-
tion for the stereoselective reduction of 2-ketosugars
(Table 1, entries 1–6 and Table 2, entries 1 and 2).
When no vicinal equatorial alkoxyl group is present as
in the cases of deoxysugars, the sodium borohydride
reduction will favor the formation of an equatorial
hydroxyl group, which is consistent with the literature
result for the reduction of the 4-tert-butylcyclohex-
anone (Table 1, entries 10 and 11). We also noticed that
the azido group has little effect on the stereoselectivity
of reduction (Table 1, entry 9). The substituents (BnO,
TrO, H, or N3) on the C-6 carbon have no effect on the
stereoselectivity of the reduction of 4-ketosugars (Table
1, entries 1–4). However, one interesting example shows
that when there is a free hydroxyl group on the C-6, the
reduction favors the formation of the equatorial
hydroxyl group, despite the presence of a benzyl group
on C-3 (Table 3, entry 9). It was proposed that the C-6
hydroxyl group complexes with the reducing agent,
NaBD(OAc)3, and proceeds through a geometrically
favored axial attack, which generated the observed
equatorial hydroxyl group.
benzoyl group offered an axial hydroxyl group from a
3-ketogalactose (Table 3, entry 7). Galactose is known
to adopt a twisted chair conformation, which may
explain this exceptional result. In addition, this result
implies that in order to predict the stereoselectivity via
the use of the vicinal equatorial alkoxyl group as the
controlling factor for the formation of an axial
hydroxyl group, a chair-like conformation of the hexo-
sulose (ketosugar) is essential. When the conformation
of a hexosulose is distorted from a chair-like one, the
prediction regarding the presence of the vicinal equato-
rial alkoxyl group on the stereoselectivity starts to
deviate. We also obtained similar results in Table 2,
entry 3, where a significant amount of equatorial
hydroxyl group was observed from a ketosugar with
galactose-like configuration, despite the presence of a
vicinal equatorial alkoxyl group on C-2. The impor-
tance of the chair conformation can also be noticed in
the example of Table 1, entry 8. A conformationally
more flexible 2,6-dideoxysugar gave only about a 2/1
ratio of axial OH/equatorial OH when subjected to the
hydroxyl group inverting reactions.
To our surprise, the methoxylmethyl (MOM) group
provides equatorial hydroxyl group as the dominant
product (Table 1, entry 12). To our knowledge, this is
the first example concerning the stereoselective reduc-
tion of a ketosugar with a MOM group participation.
When the steric factor governs the selectivity as in the
case of the reduction of 2-ketosugars on methyl a-D-
glycoside (Table 2, entries 4 and 5), an equatorial
hydroxyl group was obtained as expected. We also
obtained the same result where a vicinal axial alkoxyl
group on C-3 directed the formation of an equatorial
hydroxyl group on C-4 by, presumably, steric effect
(Table 1, entry 7). In general, the steric factor has a
The presence of a vicinal benzoyl group favors the
formation of the equatorial hydroxyl group, which is
consistent with studies of the reduction of 2-ketosugars
(Table 1, entry 13). However, we found a reported
example in the literature where the presence of a vicinal
Table 2. Stereoselective reduction of 2- and 3-ketosugars from the work of this paper
products (% yield)
entry
ketosugars
axial OH
O
equatorial OH
O
O
O
96%
OMe
not isolated
O
O
Ph
Ph
1
2
Ph
Ph
BnO
O
BnO
OMe
O
O
HO
O
O
O
O
O
61%
OMe
not isolated
OMe
OH
N3
N3
N3
N3
O
N3
HO
N3
O
O
O
3
62%
OMe
14%
BnO
BnO
O
BnO
OMe
OMe
HO
O
O
O
4
5
not isolated
not isolated
O
Ph
O
Ph
69%
BnO
BnO
O
HO
OMe
OMe
OMe
O
O
O
O
O
O
O
Ph
Ph
HO
OMe

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C.-W. T. Chang et al. / Tetrahedron Letters 42 (2001) 7019–7023
Table 3. Stereoselective reduction of ketosugars from the reported work
products (% yield)
ratio of OH(ax)/OH(eq)
note
entry
1
ketosugars
O
axial OH
equatorial OH
O
not isolated
ref. 7,8
77%
BnO
OH
BnO
OMe
HO
OMe
O
O
O
OMe
O
O
OMe
O
O
O
O
ref. 9
OMe
OMe
O
10 : 1
O
Ph
BnO
O
Ph
Ph
HO
O
2
O
Ph
BnO
BnO
HO
OMe
O
O
TsO
O
OMe
ref. 10
ref. 11
O
O
2 : 1
Ph
O
O
HO
3
Ph
TsO
TsO
HO
O
O-iPr
BnO
BnO
O
O-iPr
O
O-iPr
BnO
BnO
BnO
50 : 1
BnO
BnO
BnO
BnO
HO
O
4
5
6
O
HO
O-iPr
O-iPr
BzO
BzO
O
O-iPr
O-iPr
O
O-iPr
O-iPr
BzO
BzO
ref. 12
ref. 13
5 : 2
3 : 1
BzO
BzO
BzO
BzO
HO
O
BzO
O
HO
PivO
PivO
O
O
PivO
PivO
PivO
PivO
PivO
PivO
PivO
HO
O
OBz
OBz
O
BzO
BzO
OBz
O
BzO
O
ref. 14
ref. 15
9 : 1
HO
HO
7
BzO
BzO
OH
BzO
OMe
OMe
O
OMe
O
O
O
O
98%
O
not reported
8
9
O
OMe
CMe2
O
OMe
OMe
CMe2
OH
O
OH
O
D
O
ref. 16
not reported
93%
HO
BnO
BnO
BnO
OMe
BnO
greater influence on the stereoselectivity of a ketosugar
reduction than the presence of vicinal equatorial alkoxyl
group, which has a more dominant effect than the vicinal
deoxygenation.
group, or CH2 funcitionality from deoxygenation reduces
or inverses the preference for the formation of the axial
hydroxyl group. (5) Vicinal azido group has no effect in
controlling the stereoselectivity of the reduction of keto-
sugars. (6) The protecting groups on the C-6 of a
4-ketosugar have no effect on the stereoselectivity of the
reduction of ketosugar except when a free hydroxyl group
is present. In which case, the C-6 hydroxyl group has a
greater effect in controlling the stereoselectivity of the
reduction of a 4-ketosugar than a vicinal equatorial
alkoxyl group does.
Based on our and the literature reported results, we
summarize the factors in controlling the stereoselective
reduction of ketosugars as the following: (1) A chair-like
conformation is essential, although not critical, for the
prediction of favored stereoselectivity. (2) The presence
of a protected vicinal axial hydroxyl group favors the
formation of an equatorial hydroxyl group due to the
steric effect. (3) In the absence of steric factors, the
presence of a vicinal equatorial alkoxyl group, such as
BnO, PMBO, benzylidene, or isopropylidene, favors the
formation of an axial hydroxyl group. (4) The presence
of vicinal acyl groups (Bz, Piv, or Ts groups), MOM
Ingeneral, thesummarizedresultsfromthispaperprovide
a practical method for synthesizing various carbohydrate
derivatives. We are currently employing these findings for
the preparation of biologically interesting azide-substi-
tuted hexoses in regiospecific and stereospecific fashions.

C.-W. T. Chang et al. / Tetrahedron Letters 42 (2001) 7019–7023
7023
General procedure for Swern oxidation and NaBH4
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removal of solvent and purification with gradient
column chromatography the product was obtained usu-
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