Selective light supported oxidation of hexoses using air as oxidant - synthesis of tetrahydroxyazepanes

Article abstract of DOI:10.1002/adsc.200700282

Unprotected alkyl glycosides have been oxidized using air as oxidant and copper(I) chloride/TEMPO as the catalytic system. The primary hydroxy group in the 6 position is selectively transformed into an aldehyde equivalent. The process was optimized by irr

Full text of DOI:10.1002/adsc.200700282

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DOI: 10.1002/adsc.200700282
Selective Light Supported Oxidation of Hexoses Using Air as
Oxidant – Synthesis of Tetrahydroxyazepanes
Abdoulaye Gassamaa and Norbert Hoffmanna,*
a
Laboratoire des RØactions SØlectives et Applications, UMR 6519 CNRS et UniversitØ de Reims Champagne-Ardenne,
UFR Sciences, B.P. 1039, 51687 Reims, Cedex 02, France
Fax : (+33)-(0)3-2691-3166; e-mail: norbert.hoffmann@univ-reims.fr
Received: June 7, 2007; Revised: September 28, 2007; Published online: November 23, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Unprotected alkyl glycosides have been
oxidized using air as oxidant and copper(I) chlo-
ride/TEMPO as the catalytic system. The primary
hydroxy group in the 6 position is selectively trans-
formed into an aldehyde equivalent. The process
was optimized by irradiation with visible light.
Without further purification and with high yields,
the resulting lactols have been transformed into tet-
rahydroxyazepane.
hances its scope of application to organic synthesis. In
combination with catalase, this oxidation has been ap-
plied to the synthesis of polyhydroxyazepanes.[5] The
galactose oxidase activity is. however. strictly related
to the presence of a hydroxy function in position 4
possessing the configuration of hexoses belonging to
the d-threose series.[5,6] For this reason, for instance,
talose or galactose derivatives can be transformed
while mannose or glucose derivatives cannot be oxi-
dized.
Keywords: aerobic oxidation; biomimetic synthesis;
azasugars; carbohydrates; photochemistry; TEMPO
In order to develop a more generally applicable
method for this oxidation of carbohydrates, we
became interested in the oxidation system of Semmel-
hack.[7] Hydroxy functions are oxidized by Cu(II) and
TEMPO (Scheme 1).[4,8] TEMPO also reoxidizes
Cu(I) to Cu(II). In both cases, TEMPOH is generat-
Carbohydrates are valuable synthons for organic ed. The latter compound is reoxidized to TEMPO by
chemistry. As they possess numerous hydroxy groups, air. The method is particularly attractive because air
selective transformations often need a sophisticated as a mild and environmentally friendly oxidant[9] is
strategy of using suitable protecting groups.[1] On the
other hand, in living organisms, reactions of carbohy-
drates do not need protecting groups since they are
catalyzed by enzymes. The enzymatic activity, howev-
er, is generally linked to a very restricted scope of
substrates. As far as carbohydrates are concerned,
their stereochemistry is often a key element of reac-
tivity discrimination.
An artificial catalytic system possessing the same
reactivity as an enzyme but applicable to a larger va-
riety of substrates (biomimetic reactions[2]) may sim-
plify or even make redundant a strategy of using pro-
tecting groups. In this way, syntheses involving carbo-
hydrates as substrates would considerably be short-
ened and facilitated.
In this context, we became interested in the enzy-
matic activity of galactose oxidase. This enzyme cata-
lyzes the oxidation of the primary alcohol function in
the 6 position of galactose into an aldehyde func-
tion.[3,4] The presence of two aldehyde functions in the
Scheme 1. Mechanism of oxidation using the Cu(I)/TEMPO
carbohydrate molecule increases its reactivity and en- system.[4,8]
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35

Abdoulaye Gassama and Norbert Hoffmann
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Table 1. Selective oxidation of primary alcohols with air and the Cu(I)/TEMPO catalytic system and effect of irradiation
with visible light.
Entry
Substrate
Product
Condtions
Reaction time [h]
Yield [%]
1
2
Irradiation
Without irradiation
14
29
72
70
3
4
Irradiation
Without irradiation
20
30
69
60
5
6
Irradiation
Without irradiation
140
200
51
30–40
7
8
Irradiation
Irradiation
140
140
52
50
used. Primary alcohols are selectively oxidized to al-
dehydes. The reactivity of secondary hydroxy func-
tions is significantly lower. It has been reported that
the reactivity of simple primary aliphatic alcohols is
also reduced[4,8] although later, some aerobic oxida-
tions of these alcohols have been described which
have been performed with Cu/TEMPO systems.[10]
When applied to the oxidation of carbohydrate de-
rivatives, we observed that this oxidation system was
Figure 1. Secondary hydroxy functions were not oxidized
under the discussed reaction conditions.
not efficient. Using stronger oxidation reagents, the proved and the reaction time was reduced (Table 1,
primary hydroxy group was oxidized most frequently entries 3 and 4).
to a carboxylic function leading to uronates.[11] Only
The reaction was then performed with the methyl
recently have the corresponding aldehydes been ob- glucoside 4 (entries 5and 6). Once again, an improve-
tained by oxidation with the TEMPO/TCC system ment was observed when the transformation was per-
(TCC: trichloroisocyanuric acid).[12] We wondered formed under irradiation with visible light. No prod-
whether simultaneous irradiation with visible light ucts resulting from the oxidation of secondary hy-
could improve the results obtained with air as oxi- droxy functions have been detected. In this case, how-
dant. Recently, similar effects of irradiation have ever, the lactol form 5 was isolated. For the case of
been reported for other catalytic oxidations.[13]
corresponding galactose derivatives, the formation of
In order to test this hypothesis, we started with the lactol, hydrates and acetals has been previously de-
oxidation of 3-phenylpropanol 1 (Table 1, entry 1). scribed.[14] These structures proved to be more stable
When irradiated with visible light, the reaction time than the corresponding free aldehyde forms. This ob-
was significantly reduced. With several examples, we servation is in agreement with the fact that simple al-
then checked whether under these modified reaction dohexoses also prefer the lactol forms. Both constitu-
conditions, the oxidation is selective for primary alco- ents of the catalyst system are necessary. In the ab-
hols (Figure 1). Indeed, none of the secondary alco- sence of TEMPO or CuCl, no reaction was observed.
hols in Figure 1 were oxidized. When the oxidation of Under the same optimized reaction conditions, the
the protected galactose derivative 2 to the aldehyde 3 benzyl glucoside 6 and the benzyl mannoside 8 were
was performed with irradiation, the yield was im- transformed into the corresponding lactols 7 and 9
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 35 – 39

Selective Light Supported Oxidation of Hexoses Using Air as Oxidant
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Figure 2. UV spectra obtained from solutions of TEMPO
and Cu(I) acetate in acetonitrile. A: solution of TEMPO
and Cu(I) acetate kept in the dark; B: solution of TEMPO
and Cu(I) acetate irradiated with visible light; C: solution of
TEMPO.
(entries 7 and 8). The products have been isolated
and purified by flash chromatography using mixtures
of CH2Cl2/MeOH containing 5% of triethylamine.
When the purification was performed without the
amine base, methyl half acetals have been isolated in
low yields instead of the lactols.
Scheme 2. Efficient transformation of benzyl glycosides into
tetrahydroxyazepanes.
In order to gain a first insight in the mechanism of
the photo-promoted oxidation, and in analogy to pre- center and intramolecular reductive amination oc-
vious experiments.[4] we prepared two solutions of curred. The resulting tetrahydroxyazepanes 12 and 13
Cu(I) acetate and TEMPO in acetonitrile possessing have been obtained in high yields.
the same concentrations as the corresponding DMF
Attempts were made to perform debenzylation of
solutions used for the transformations described in the anomeric center, the first intermolecular and the
Table 1. One of them was kept in the dark, while the second intramolecular reductive amination in one
other was irradiated with visible light using the same step using hydrogenation conditions. However, under
conditions as for the transformation of the substrates. these conditions, considerable amounts of products
In the case of the irradiated sample, the intensity of resulting from the addition of two butylamine mole-
the UV absorption at l=362 nm (Figure 2) ascribed cules were observed. Tetrahydroxyazepanes belong to
to the Cu(II)-TEMPO intermediate[4] (Scheme 1) was the family of azasugars possessing various biological
significantly reduced with respect to the reference activities such as the inhibition of glycosidases or gly-
sample. This observation indicates that the transfor- cosyltranferases.[15]
mation of this intermediate is photochemically accel-
In conclusion, we have developed an efficient bio-
erated, which may contribute to the higher efficiency mimetic oxidation method using the CuCl/TEMPO
under irradiation conditions. During this process, the catalytic system and air as oxidant. The reactivity is
concentration of Cu(II) (l=666 nm) does not signifi- enhanced when the reaction mixture was irradiated
cantly change with respect to the reference sample.
with visible light. Thus the activity of galactose ox-
In view to further optimize the procedure and to idase was imitated. In contrast to the enzymatically
prove its usefulness for organic synthesis, we decided catalyzed reaction, the presented method also enables
to perform further ground state transformations with the oxidation of hexoses of the d- or l-erythro series
the crude product. It was previously reported that pu- such as glucose or mannose derivatives. Only two ad-
rification of such oxidation products of carbohydrates ditional steps led to tetrahydroxyazepane derivatives
is difficult.[12] After concentration, the raw reaction in high yields. At this stage, the oxidation should be
mixture was subjected to reductive amination considered as semi-catalytic since larger amounts (0.5
(Scheme 2). The overall yields of these two steps equivalents) of the catalytic system are necessary. Fur-
were increased to 76%. The resulting 6-aminopyrano- ther investigations concerning the improvement of
sides 10 and 11 were treated under hydrogenation the catalytic process, the scope of the oxidation and
conditions. In this way deprotection at the anomeric mechanistic aspects in order to explain the enhanced
Adv. Synth. Catal. 2008, 350, 35– 39
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37

Abdoulaye Gassama and Norbert Hoffmann
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reactivity under light irradiation are currently under- Acknowledgements
way.
We are grateful to the RØgion Champagne-Ardenne, Prof.
Arnaud Haudrechy and the CNRS for financial support.
Experimental Section
General Procedure for the Oxidation of Primary
Alcohols
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