Tandem epoxidation-alcoholysis or epoxidation-hydrolysis of glycals catalyzed by titanium(IV) isopropoxide or Venturello's phosphotungstate complex

Article abstract of DOI:10.1002/adsc.200800079

Venturello's phosphotungstate complex and titanium(IV) isopropoxide [Ti(O-i-Pr)₄] were successfully used as catalysts for the epoxidation-alcoholysis of glycals using hydrogen peroxide [H₂O ₂]. Reaction substrates included a range of variously protected glycals and different alcohols were used as solvents. Ti(O-i-Pr)₄ was only effective in methanol as solvent, but gave methyl glycosides in high yields and high selectivities. The Venturello complex proved to be a very versatile and efficient catalyst. Apart from epoxidation-alcoholysis in alcoholic solvents it also showed activity in biphasic conditions to allow for glycosylation of long-chain alcohols and was very effective in the stereoselective dihydroxylation of benzylated glucal.

Full text of DOI:10.1002/adsc.200800079

FULL PAPERS
DOI: 10.1002/adsc.200800079
Tandem Epoxidation-Alcoholysis orEpoxidation-Hydrolysis of
Glycals Catalyzed by Titanium(IV) Isopropoxide or Venturelloꢀs
Phosphotungstate Complex
Pieter Levecque,a,b David W. Gammon,b,* Henok Hadgu Kinfe,b,c Pierre Jacobs,a
Dirk De Vos,a and Bert Selsa,*
a
Centre for Surface Chemistry and Catalysis, K.U. Leuven, Kasteelpark Arenberg 23, 3001 Heverlee, Belgium
Fax : (+32)-16-32-1998; e-mail: bert.sels@biw.kuleuven.be
Department of Chemistry, University of Cape Town, Private Bag, 7001 Rondebosch, South Africa
b
Fax : (+27)-21-689-7499; e-mail: david.gammon@uct.ac.za
Present address: CSIR Biosciences, Ardeer Road, Private Bag X2, Modderfontein, Johannesburg, South Africa
c
Received: February 6, 2008; Revised: April 15, 2008; Published online: June 3, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Venturelloꢀs phosphotungstate complex Apart from epoxidation-alcoholysis in alcoholic sol-
and titanium(IV) isopropoxide [Ti(O-i-Pr)4] were vents it also showed activity in biphasic conditions to
G
successfully used as catalysts for the epoxidation-al- allow for glycosylation of long-chain alcohols and
coholysis of glycals using hydrogen peroxide [H2O2]. was very effective in the stereoselective dihydroxyla-
Reaction substrates included a range of variously tion of benzylated glucal.
protected glycals and different alcohols were used as
solvents. Ti(O-i-Pr)4 was only effective in methanol
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as solvent, but gave methyl glycosides in high yields Keywords: dihydroxylation; epoxidation-alcoholysis;
and high selectivities. The Venturello complex glycals; hydrogen peroxide; titanium isopropoxide;
proved to be a very versatile and efficient catalyst. Venturelloꢀs complex
Introduction
tion to obvious applications in the synthesis of oligo-
saccharides, the use of long-chain alcohols as nucleo-
Oligosaccharides and glycoconjugates are now known philes can provide an ꢁanchoringꢀ chain on C-1 and
to play essential roles in biological systems, in diverse allows synthesis of artificial cell membrane compo-
areas such as protein folding, tissue structure, blood nents. A further application is the stereoselective pro-
coagulation, immune response, cell-cell recognition, duction of sugar 1,2-diols. These are useful synthetic
pathogen-cell recognition, and inflammation.[1] These intermediates in several organic transformations, such
advances in glycobiology were the basis for the dis- as the synthesis of chiral polyols, O-glycosides, C-gly-
covery of a number of sugar-based drugs and vaccine- cosides and in intermolecular O-glycosylations.[6]
s[1a] and are fuelling interest in the development of
The most common epoxidation method uses dime-
chemical tools to manipulate the sugar entities in thyldioxirane[5] (DMDO). However, the instability
order to acquire a better understanding of their func- and explosivity of DMDO are serious drawbacks.
tions. Because of their versatility, glycals have often Other proposed methods include m-chloroperbenzoic
been used as building blocks in the synthesis of these acid/KF[7] and Tf2O with diphenyl sulfoxide.[8] These
oligosaccharides and glycoconjugates. Different strat- methods all use stoichiometric amounts of reagents,
egies for activation of the double bond in glycals are resulting in large amounts of waste. However, the
known,[1e,f,2,3,4,5] of which epoxidation[5a] is probably the economic and environmental realities calling for sus-
most common. Epoxidation of glycals yields 1,2-anhy- tainable processes are fuelling the current interest in
dro sugars which are good glycosyl donors. Regiospe- incorporating catalysts in synthetic pathways. Cata-
cific opening of the epoxide with a suitable nucleo- lysts for epoxidation of glycals have only recently
phile leaves O-2 unprotected and hence available for been identified, including Ru-porphyrin[9] and
further manipulation, while the C-1 can carry a glyco- CH3ReO3 (MTO).[10,11]. The latter has also been ap-
sidic substituent or can further be activated. In addi- plied in a heterogeneous version.[10c] Apart from epox-
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Pieter Levecque et al.
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idation with DMDO, followed by hydrolysis, a differ- dard literature procedures and used as substrates in
ent set of methodologies exists to perform the dihy- reactions with a variety of alcohols. It is known that
droxylation of unsaturated sugars. In one of the earli- the reactivity of glycals is influenced by the nature of
est reports on the matter, Bilik et al.[12] used a range the protecting groups,[17] with esters providing an elec-
of metal oxides among which MoO3 gave the best re- tron-withdrawing effect on the double bond which is
sults. Other methods include the use of oxone-ace- deactivating in view of the electrophilic mechanism of
tone,[13] OsO4-NMO[14] and the bimetallic system epoxidation using peroxometal catalysts,[18] but also
RuCl3/CeCl3/NaIO4.[15]
potentially a “participating” effect on reactions at the
Against this background we here present a method- anomeric centre, while ether protecting groups are
ology for the selective formation of a-epoxides from electron donating and thus activating.
protected glycals, followed by in situ opening of the
epoxides to give either 2-hydroxyglycosides or sugar
1,2-diols. The method uses either Ti
A
turelloꢀs peroxotungstate PW4O24 as catalysts, and
hydrogen peroxide as benign and cheap oxidant in al-
coholic solvents. Biphasic conditions are applied to
the Venturello complex to allow for incorporation of
long-chain alcohols or to selectively obtain sugar 1,2-
diols. The Venturello complex, in particular, has been
shown to be a highly efficient and versatile catalyst,
with potential use in the production of a wide range
of high-value products.
Results and Discussion
We recently described the use of Venturelloꢀs peroxo-
phosphotungstate compound, Q3PW4O24, as well as
Ti(O-i-Pr)4 as efficient catalysts for H2O2-mediated
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epoxidations of simple cyclic enol ethers (Q=quater-
nary ammonium ion)[16]. Small quantities of dry NaA
zeolite were used to suppress the undesired acid-cata-
lyzed alcohol addition to the double bond. We here
report on an investigation of the applicability of these
methods to selective tandem epoxidation-alcoholysis
or epoxidation-hydrolysis of glycals (1,2-anhydro
sugars) to give the corresponding glycosides or glyco-
ses (I!II!III, Scheme 1).
Epoxidation-Alcoholysis of Glycals
The results of reactions of glycals with H2O2 and cata-
lysts in either methanol, ethanol or propanol as nucle-
Selection and Preparation of Glycals
ophilic solvents are summarized in Table 1, for Ti(O-
A
In order to assess the factors influencing activity of i-Pr)4 as the catalyst, and in Table 2, for the Venturel-
the catalyst, reactivity of the starting glycals and se- lo compound as the catalyst. In all cases 2-hydroxy-
lectivity in product formation, a range of variously glycosides were formed; the initially formed epoxide
protected or selectively unprotected glucals (1–7), is unstable under these reaction conditions, and the
xylal (8) and galactals (9, 10) was prepared using stan- stereochemistry of the products reflects the stereose-
Scheme 1. Generalized reaction scheme for tandem epoxidation-alcoholysis or epoxidation-hydrolysis of variously protected
glycals.
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Tandem Epoxidation-Alcoholysis or Epoxidation-Hydrolysis of Glycals
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lectivity in initial epoxide formation. In some instan- were carefully monitored by TLC and where the reac-
ces product identification was facilitated by acetyla- tion went to completion, the reported reaction times
tion of the 2-hydroxyglycosides to give 2-O-acetyl correspond to the disappearance of starting material.
products, with resultant downfield shift of the H-2 In cases of incomplete conversion the reaction times
1
signal in the H NMR spectrum. In all cases reactions reflect the time of reaction quenching and the conver-
Table 1. Results of epoxidation-methanolysis of various glycals with Ti
Entry Substrate Time [h] Conv. [%] Products
A
Ratio
Ratio opening epoxide
a:b epoxide[b] (trans:cis)
1
170
ꢁ50
80
70
16:1[c]
a only
a only
6:1
trans mainly
trans only
trans only
trans only
trans only
trans only
10:1
2
3
4
5
6
7
100
55
120
70
100
95
3:1
100
140
20
16:1
100
a only
8
9
ꢁ50
100
60
a only
6:1
135
3:4
trans only
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Pieter Levecque et al.
Ratio opening epoxide
FULL PAPERS
Table 1. (Continued)
Entry Substrate
Time [h] Conv. [%] Products
Ratio
a:b epoxide[b] (trans:cis)
10
170
90
1:1.5[d]
trans only
[a]
Conditions: glycal: 0.1M in MeOH, Ti(O-i-Pr)4: 2 mM (0.02 equiv., based on substrate), NaA (dry): 15 mg/10 mL, H2O2:
A
4M (4 equiv.), 323 K. The alkaline nature of the zeolite is needed to suppress the acid-catalyzed addition of alcohols to
the double bond.
All ratios were determined by integration of selected signals in the H NMR spectra of the crude reaction mixture.
Another isomer, presumably cis opened a epoxide, was also detected. However yield was very low (under 5%).
Products were obtained by immediate acetylation on completion of reaction.
[b]
[c]
[d]
1
Table 2. Comparison of results with Ti
Substrate Products
ACHTREUNG
Ratio
Time
Ref
A
1:0:0
11:1:21
5.3:1:0
50 h
?
15 h
This paper
[11]
MTO-H2O2
MTO-UHP
[10c]
Ti
A
16:1
2:1
2:1
170 h
2 h
?
This paper
[11]
[11]
MTO-H2O2
MTO-UHP
MTO-UHP
1.9:1
20 h
A
Ti
A
6:0:1
-
1.7:1:0
50 h
-
3.5 h
This paper
[11]
MTO-H2O2
MTO-UHP
[10c]
Ti
A
10:0:1
3:1:0
7.5:1:0
140 h
?
19 h
This paper
[11]
MTO-H2O2
MTO-UHP
[10c]
Ti
A
1:1.5
2:1
170 h
?
This paper
[11]
MTO-H2O2
1
sion percentages were calculated from H NMR spec- pound was not completely soluble in methanol. How-
tra of crude product mixtures. ever, it is immediately apparent from the results in
A full comparison of the activity of the two cata- Table 1 and Table 2 that the Venturello compound is
lysts is limited by their complementary solubilities in more active and versatile as a catalyst than Ti(O-i-
the solvents investigated. Ti(O-i-Pr)4 could only be Pr)4, with the former tolerating a wider range of alco-
ACHTREUNG
AHCTREUNG
used in methanol due to the formation of precipitates hols in generally shorter reaction times.
in ethanol or propanol, whereas the Venturello com-
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Tandem Epoxidation-Alcoholysis or Epoxidation-Hydrolysis of Glycals
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Reactions using Ti
A
rior in most cases. However, in the case of galactal
the opening of the epoxide seems less selective. Re-
Ti(O-i-Pr)4 proved to only be effective as a catalyst markably, the reaction of the unprotected glucal pro-
U
when reactions were conducted in methanol, and re- ceeded with reversed selectivity compared to the one
quired long reaction times. However, these drawbacks achieved with MTO-H2O2.
were offset by the excellent selectivity in reactions of
protected glucals, which yielded predominantly or
sometimes exclusively the b-glucosides (entries 1, 2 Reactions using Venturelloꢀs Complex
and 3, Table 1). The implication is that with this cata-
lyst epoxidation from the a-face is favoured, with sub- The Venturello complex is significantly more active
sequent concerted b-face nucleophilic attack at the than Ti
anomeric carbon and opening of the C-1 O bond. Ex- sis reactions, giving high conversions in a range of sol-
A
ꢀ
clusive a-selectivity in epoxide formation is retained vents, in reaction times generally shorter than 24 h
when the 6-OH is free (entry 3) and drops only mar- (Table 3). While epoxidation from the a-face was
ginally with the TBDMS-protected glucal (entry 6). again favoured for the fully protected glycals, exclu-
However, the selectivity dropped more markedly with sive a-epoxidation was only achieved in selected reac-
Me-protected glucal (entry 4), deteriorated further tions of galactal derivatives (Table 3, entries 19 and
with the 2,3-unprotected glucal (entry 5), and was re- 20), and all glucal derivatives gave mixtures which in-
versed to favour b-epoxide formation with unprotect- cluded small proportions of products derived from b-
ed d-glucal (entry 10). In addition, the protected xylal epoxide intermediates.
derivative (entry 9), which can be thought of as a
As before, reactivity was lower for acetylated glu-
glucal derivative from which C-6 has been removed, cals (entries 11 and 19) than for their ether-protected
gave a mixture of a- and b-epoxides. Overall, these counterparts (entries 14 and 21). The influence of the
results suggest that facial selectivity in epoxide forma- nature of the protecting groups and pattern of protec-
tion is influenced by a subtle interplay between the tion can be evaluated by comparing results for reac-
nature and steric bulk of the substituent at C-5, the tions in ethanol. For fully protected glucals, reactivity
nature of the protecting groups in general, and wheth- decreases in the order Bn>Me>TBDMS(entries 13,
er the allylic hydroxy group at C-3 is protected or 16, 18). The low reactivity of the TBDMS-protected
not, with the latter having a syn-directing effect on glucal can be attributed to the significant steric
the epoxidation. In addition, a free 6-OH in an other- demand of the bulky TBDMSgroups which forces
5
wise protected glucal appears to result in a-epoxide the glucal into the H4 conformation, where the sub-
formation. The stereochemistry at C-4 appears to stituents at C-3, C-4 and C-5 are in a pseudo-axial ori-
have a limited effect on the stereoselectivity of epox- entation. These inhibit access of the electrophilic
ide formation in acetylated glycals: acetylated glucal oxygen species to the double bond between carbons 1
(entry 1) yields a- and b-epoxide in a ratio 16:1, while and 2. Selectivities towards a-epoxidation are compa-
only a-epoxide is formed from acetylated galactal rable for these three protecting groups, although in
(entry 7). In the case of benzylated glycals, the prod- the opening of the epoxide some 1,2-cis glycoside for-
uct distributions indicate exclusive a-epoxide forma- mation is observed with methyl- or TBMDS-protect-
tion from both glucal and galactal. However, a signifi- ed glucals. Removal of the benzyl group at O-6
cant difference is seen in the stereoselectivity of the (entry 15) results in significantly enhanced selectivity
subsequent opening of the epoxides. Whereas the in epoxide formation (a:b = 25:1, compared to 7:1 in
glucal derivatives all exhibit almost exclusive selectiv- benzylated glucal, entry 13). The benzylated xylal de-
ity towards formation of 1,2-trans glycosides, the gal- rivative (entry 22, Table 2) gives selectivities compara-
actal derivatives give significant proportions of 1,2-cis ble to those of the benzylated glucal (entry 13), a
glycosides, suggesting that the substituent at C-4 may result in marked contrast to the b-selectivity in epoxi-
assist in stabilizing a carbenium ion at C-1 formed by dation of benzylated xylal with Ti
ACHTREUNG
opening of the epoxide.
The results of reactions with Ti
ACHTREUNG
nol can be compared with similar tandem catalytic ox- b-epoxidation in the 3,4-unprotected glucal (entry 17),
idations in methanol using methyltrioxorhenium while in a remarkable result, the fully unprotected d-
(MTO) as catalyst and either H2O2 or urea-hydrogen glucal (entry 23) gives exclusively the product result-
peroxide (UHP) as oxidant, as reported independent- ing from b-epoxide formation. As in the case of the
ly by Quayle and co-workers[11] and Goti and co- Ti
ACHTREUNG
AHCTREUNG
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Table 3. Results of epoxidation-alcoholysis of various glycals with Venturelloꢀs compound.[a]
Entry Substrate
Solvent Time Conv. Product(s)
Ratio
Ratio
[h]
[%]
a:b
opening
epoxide[b] epoxide
(trans:cis)
11
12
13
14
15
16
17
18
19
n-PrOH 22
100
ꢂ99
100
8:1[c]
trans only
trans only
trans only
3:1
MeOH/
1,4-di-
oxane
170
8:1
EtOH
2
7:1
n-PrOH ꢁ1 100
4:1
EtOH
EtOH
EtOH
EtOH
8
ꢂ99
>25:1
12:1
1:2.7
8.5:1
a only
trans only
ꢁ14 100
9:1
1.5
24
100
100
100
10:1
27:1
n-PrOH 22
2.5:1
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Table 3. (Continued)
Entry Substrate
Solvent Time Conv. Product(s)
Ratio
Ratio
[h]
[%]
a:b
opening
epoxide[b] epoxide
(trans:cis)
20
EtOH
2
100
a only
2.5:1
21
22
n-PrOH 4.5
100
ꢂ95
100
6:1
2:1
EtOH
EtOH
20
10:1
trans only
23
3.5
b only[d] trans only
[a]
Conditions: glycal: 0.1M in selected solvent, Q3PW4O24: 2 mM (0.02 equiv., based on substrate), NaA (dry): 5 mg/10 mL,
H2O2: 4M (4 equiv.), 323 K. The alkaline nature of the zeolite is needed to suppress the acid catalyzed addition of alcohols
to the double bond.
All ratios were determined by integration of the NMR signals of the crude reaction mixture.
Another isomer, presumably cis opened a epoxide, was also detected. However yield was very low (under 5%).
Products were obtained by immediate acetylation on completion of reaction.
[b]
[c]
[d]
reactions of the benzylated glucal and galactal in eth- erogeneous Ru-porphyrin catalyst,[9] but this was only
anol and propanol. In the case of the glucals (en- achieved with acetylated glucal and the heterogene-
tries 13 and 14) a change from ethanol to propanol re- ous reaction gave no result with benzylated glucal.
sults in a slight lowering of the selectivity towards a- Another general feature of these methods is the high
epoxide formation, and appearance of an additional yield obtained, in the range of 85 to 90%. Similar
a-glucoside product resulting from non-stereospecific yields have been achieved with MTO for a few sub-
opening of the a-epoxide. With galactals (entries 20 strates,[10–11] and in the work of Danishefsky and
and 21) exclusive a-epoxidation is achieved in etha- others using DMDO[5] but most other methods are as-
nol, while in propanol some b-epoxide formation is sociated with yields under 80%.
observed.
While the Ti(O-i-Pr)4 protocol is limited to metha-
A
nol, the Venturello compound appears to be effective
in a broader range of alcoholic solvents. For protected
glucals the reaction is faster with n-propanol than
with ethanol and methanol. As epoxides are not de-
General Comments on the Epoxidation-Alcoholysis
It is clear from these results that starting from the tected in the product mixtures, it is safe to assume
fully protected glycals, the a-epoxide is formed pre- that the epoxidation is the rate-limiting step, rather
dominantly and in some cases exclusively with both than the epoxide opening. Thus, it appears that the
catalytic systems, a result which has general synthetic epoxidation is faster in n-propanol. Tests with the
significance. Selective formation of one epoxide has Venturello compound in different solvents with 3,4-di-
been reported for some stoichiometric methods, but is hydro-2H-pyran showed the same phenomenon,[16]
highly dependent on the substrate[5] or the type of re- suggesting that the rate differences are due to differ-
agent.[8] Liu et al. and Yu et al. managed to selectively ent solvation of the transition states in the various sol-
obtain the a-epoxide with a homogeneous and a het- vents, or to a different solubility of the catalyst itself.
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With the protected galactals (entries 20 and 21) the ucts were acetylated and their NMR spectrum com-
order n-propanol/ethanol is surprisingly reversed. pared with that of the acetylated Venturello product
The stereochemical outcome of the epoxidations is mixture, with no change in the trans/cis ratio ob-
directed by a number of different factors. Firstly there served. This confirms that the ratios obtained are not
are the steric and stereoelectronic considerations caused by acid-catalyzed rearrangement. As cis open-
taking into account the orientation of the ring sub- ing of the epoxide is hardly discussed in the literature
5
stituents and the preferred conformation (4H5 vs. H4) it is difficult to make a thorough comparison with lit-
of the glycals, as noted above for both the Ti and erature.
Venturello catalytic systems. Secondly, a free OH
For reactions with the Venturello catalyst, 1,2-cis-
group on C-3 may direct the epoxidation, either by disubstituted compounds are particularly formed
coordination of the alcohol group to a metal catalyst, when the substituents or the nucleophile are bulky.
or by hydrogen bonding. In the case of hydrogen Thus, more cis opening is obtained from a glucal with
bonding, the oxirane transition state is stabilized by bulky TBDMSsubstituents than from the benzylated
intramolecular hydrogen bonding with an adjacent glucal (entries 18 vs. 13). cis-Opened products are
OH group, causing a syn-directing effect for the epox- also abundant in the reactions of the galactals, in
idation reaction. The use of polar, alcoholic solvents, which the crowding at the b-side favours nucleophile
however, partly cancels this syn-directing effect by attack via the a-side, even on an a-epoxide (en-
disturbing the hydrogen bonding.[5b,11] Coordination of tries 19–21). On closer examination it appears that
a substrate allylic alcohol on the metal centre has a the group on the C-5 position exerts a significant in-
similar syn-directing effect. As the a-epoxide was ob- fluence. When a C-5 substituent is absent (xylal deriv-
tained predominantly from all substrates with a pro- ative, entry 22) or is an unprotected hydroxymethyl
tected O-3, it seems that the epoxide is formed prefer- group (entry 15), only trans-opening of the epoxide is
entially on the opposite face of the C-3 substituent. observed, presumably due to the easy access to the b-
Since all our compounds have the C-3 in an upper face of the a-epoxide. With an acetyl protecting
face b-orientation, this outcome was expected.
group on O-6, only a small degree of cis opening is
For 6-O-TBDPS-d-glucal both hydrogen bonding detected, even with propanol (entry 11). Obviously,
or coordination, and steric effects come into play. The the size of the alcohol also determines the stereo-
OH group on C-3 can direct the epoxide to the b- chemical outcome of the epoxide opening. cis-Product
face, although this effect may be cancelled out by the formation from glucal and galactal derivatives are
use of alcoholic solvents and the steric factors which more pronounced with n-propanol. cis-Opening of the
favour a-epoxide formation. The directing effect of epoxide was observed less frequently in the Ti-cata-
the OH group is, however, particularly clear in the re- lyzed reactions; only in reactions of galactals, are 1,2-
action catalyzed by Venturello complex, where b-face cis-disubstituted compounds observed, with selectivi-
attack predominates (entries 17 and 23). Steric effects ties between 10 and 15% (entries 7 and 8).
are dominant for the Ti(O-i-Pr)4 reaction, with a 3:1
G
a:b ratio (entry 5).
Regarding the stereochemistry of epoxide opening, Incorporation of Long-Chain Alcohols using Biphasic
the high proportion of the 1,2-trans-products and Conditions
hence the b-configuration at C-1 after opening of the
epoxides suggests that a concerted or SN2-type mecha- To broaden the scope of possible nucleophiles beyond
nism predominates in many cases. To rule out the pos- alcohol solvents, we decided to test the Venturello
sibility that the trans/cis ratios detected here are compound in biphasic conditions on a range of glycals
caused by Lewis acid-catalyzed isomerization of the (Scheme 2). CHCl3 was used as solvent and aqueous
trans-product, the crude product mixture of a reaction H2O2 as oxidant. Octanol or octadecanol were added
of benzylated glucal and the Venturello compound in as a nucleophile. This protocol is similar to the one
ethanol was concentrated under vacuum and then re- that we previously successfully used for the oxidative
acted for 36 h in the Ti(O-i-Pr)4 conditions. The prod- incorporation of long alcohols in a more simple cyclic
G
Scheme 2. General scheme for incorporation of long-chain alcohols with Venturelloꢀs compound.
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Tandem Epoxidation-Alcoholysis or Epoxidation-Hydrolysis of Glycals
FULL PAPERS
Table 4. Incorporation of long alcohols by applying Venturelloꢀs compound in biphasic conditions.[a]
Entry
Substrate
Nucleophile
Time
Conv. [%]
Products
Diol:Ether
2:1
24
Octanol
8 h
100
25
26
Octadecanol
5 h
100
3.5:1
Octadecanol
Octadecanol
2 h
3 h
100
100
4:1
27
1.7:1
[a]
Conditions: glycal: 25 mM in CHCl3, Q3PW4O24: 1 mM (0.04 equiv., based on substrate), NaA (dry): 2.5 mg/10 mL, nucle-
ophile: 50 mM (2 equiv.), H2O2: 37.5 mM (1.5 equiv.), 323 K.
enol ether such as 3,4-dihydro-2H-pyran.[16] From the Selective Dihydroxylation of 1,2-Glycals
results obtained (Table 4) it is immediately clear that
protocols based on the use of aqueous hydrogen per- As incorporation of long alcohols was unsuccessful
oxide are not applicable to the glycals, as the latter because of the competing formation of glycal diols, at-
are much more sterically encumbered than 3,4-dihy- tention was turned to adaptation of the reaction pro-
dro-2H-pyran. Due to the lower reactivity of the long tocol in order to selectively obtain 1,2-diols from gly-
aliphatic alcohols, water is a competitive nucleophile cals (Scheme 3). Although these diols are synthetical-
in opening the epoxide, leading to the formation of ly very useful compounds (vide supra, Introduction),
1,2-diol as the major product. Only with the benzylat- only a few methods for their selective preparation
ed xylal (entry 27) was it possible to achieve an have been reported[6b,d,12–14]. The existing methods for
almost 1:1 ratio of desired product and diol. In order direct dihydroxylation of glycals all have drawbacks
to exclude water as much as possible the same reac- such as the removal of Os salts[12–14] problems in scale-
tion was performed with the urea-hydrogen peroxide up in the case of DMDO,[13] formation of C-2 epimers
adduct (UHP) as the oxidant instead of hydrogen per- or use of high mol% of metal.[14]
oxide. The reaction only went to completion with ad-
In a first approach, the same reaction conditions as
dition of 3 equivalents of UHP, but no significant en- for the incorporation of long-chain alcohols were
hancement of the selectivity towards the desired used, but the nucleophile was replaced by an excess
products was observed. Apparently, the molar equiva- of water. Diol was formed only as minor product.
lent of water formed during the epoxidation competes This is presumably due to the low polarity of the
efficiently with long aliphatic alcohols in the nucleo- chloroform. To overcome this problem, 1,4-dioxane
philic opening of the epoxide. In a second set of ex- was employed as solvent, and water added in excess.
periments the use of selectively unprotected pyrano- The desired gluco-diol was obtained within 24 h in
sides as nucleophiles was attempted in order to ex- 86% selectivity and in a 1:1 a:b ratio. A subsequent
plore the potential for disaccharide synthesis under attempt in a mixture of acetonitrile-ethyl acetate-
these conditions. In all cases complete conversion of water (based on Tiwari et al.[14]) led to gluco-diol
the starting material was observed but a complex mix- being obtained with improved selectivity (95%) and
ture of products was obtained and even after chroma- a:b ratio (1.35:1), while the reaction time was similar.
tographic separation on silica gel it was not possible The formation of only gluco-products in all reactions
to unambiguously identify disaccharide products.
confirms that the Venturello catalyst selectively forms
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Pieter Levecque et al.
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Scheme 3. Selective dihydroxylation of benzylated glucal.
Catalysts
the a-epoxide and that it is an effective catalyst for
selective synthesis of 1,2-diols from benzylated glucal.
Ti(O-i-Pr)4 was commercially obtained. Venturelloꢀs phos-
G
photungstate complex was prepared as described in a litera-
ture report.[26]
Conclusions
Venturello Complex
New catalytic protocols have been developed for the
epoxidation-alcoholysis and dihydroxylation of unsa-
turated sugars using H2O2 as environmentally benign
oxidant. Both Ti isopropoxide and a Venturello com-
pound have been shown to be effective catalysts in re-
actions on a range of glycals differing in configuration
and protecting group patterns. Both catalysts gave ex-
ceptionally high selectivity for a-epoxide formation,
as inferred from the stereochemistry of products de-
rived from in situ opening of the epoxides. The Ven-
turello compound in particular proved to be a very
versatile catalyst. It tolerates a wide range of solvents
and protecting groups in the substrates, and can also
work in biphasic conditions for the dihydroxylation of
glycals.
H2WO4 (10 g) was added to 35 wt% aqueous H2O2 (28 mL).
The yellow mixture was stirred for 1.5 h at 333 K and then
filtered to remove insoluble WO3 particles. The filtrate was
allowed to cool to room temperature and H3PO4 (1.2 mL)
added. Doubly distilled H2O was added to the mixture to a
combined weight of 120 g. After stirring for 30 min at room
temperature a solution of Aliquat 336 (8.56 g) in CH2Cl2
(180 mL) was added dropwise over 15 min. The resulting
mixture was stirred vigorously for 1 h after which the organ-
ic phase was separated, washed once with H2O then dried
with MgSO4 and concentrated under vacuum to give the
complex as a sticky transparent yellow syrup; yield: 11 g
ꢀ
(70%). IR (KBr): n=1050 (P O), 975 (W=O), 856 and
846 cmꢀ1 (W-O-O). The data agree with reported values.[26b]
Reaction Protocols
Epoxidation-alcoholysis using the Venturello compound: A
typical procedure for the epoxidation-alcoholysis of the
glycal compounds with the Venturello complex is as follows:
glycal (1.0 mmol), Q3PW4O24 (0.02 mmol), H2O2 (50 wt%
solution in H2O, 4.0 mmol) and dry powdered NaA (5.0 mg)
were combined and stirred in a selected solvent (10 mL) at
323 K. Reaction progress was monitored by TLC. On com-
pletion of the reaction, the mixture was filtered and the fil-
trate is taken up in CH2Cl2 and washed 3 times with water.
The organic phase was dried with MgSO4, filtered and con-
centrated under vacuum. The identity of products and ratios
of diastereomers in product mixtures were determined by
1H- and 13C NMR, including COSY, HSQC and DEPT anal-
ysis. In some instances products were acetylated using acetic
anhydride and pyridine.
Experimental Section
General Remarks
Commercially obtained compounds were used as received.
Solvents used were AR grade or dried according to
common procedures. Reaction progress was followed by
TLC. NMR spectra were recorded on a Bruker AMX 300
or a Varian Mercury 300 (300 MHz) and a Varian Unity 400
(400 MHz).
Substrates
d-Glucal and tri-O-acetyl-d-glucal were commercially ob-
tained. All other glycals and the glycosides used as nucleo-
philes were synthesized according to known literature proce-
dures: tri-O-benzyl-d-glucal,[17] 3,4-di-O-benzyl-d-glucal,[18,19]
tri-O-methyl-d-glucal,[20] 6-O-TBDPS-d-glucal,[18] tri-O-
TBDMS-d-glucal,[19] tri-O-acetyl-d-galactal,[22] tri-O-benzyl-
d-galactal,[18] di-O-benzyl-d-xylal,[21,23] 2,3,4-tri-O-benzyl-d-
methylglucoside,[24] 2,3,4,6-tetra-O-benzyl-d-glucoside.[20a,25]
Epoxidation-alcoholysis using the Ti catalysts: A typical
procedure for the epoxidation-alcoholysis of the glycal com-
pounds with Ti isopropoxide is as follows: glycal (1 mmol),
Ti(O-i-Pr)4 (0.02 mmol), H2O2 (50 wt% solution in H2O,
A
4 mmol), and dry powdered NaA (15 mg) were combined in
methanol (10 mL), with stirring at 323 K. Progress of reac-
tions was monitored by TLC. On completion of the reaction,
the mixture was filtered and the filtrate taken up in CH2Cl2
and washed 3 times with water. The organic phase was dried
with MgSO4, filtered and concentrated under vacuum. Prod-
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Tandem Epoxidation-Alcoholysis or Epoxidation-Hydrolysis of Glycals
FULL PAPERS
ucts and their stereochemistry were determined by 1H,
13C NMR, COSY, HSQC and DEPT analysis. With complex
Kinfe, D.E De Vos, P. A. Jacobs, B. F. Sels, J. Carbo-
hydr. Chem. 2007, 26, 3, 141.
mixtures, the products were acetylated (Ac2O, pyridine) and
analyzed by NMR.
[3] T. Linker, T. Sommermann, F. Kahlenberg, J. Am.
Chem. Soc. 1997, 119, 9377.
Biphasic reaction using the Venturello compound: To a
solution of 0.01 mmol of Q3PW4O24 in CHCl3 (10 mL) was
added glycal (0.25 mmol), dry NaA (2.5 mg), nucleophile (2
equiv.) and H2O2 (0.375 mmol of 50 wt% solution in H2O;
1.5 equiv. against glycal). The reaction was stirred at 323 K
and monitored by TLC. On completion of the reaction, the
mixture was filtered and the filtrate taken up in CH2Cl2 and
washed 3 times with water. The organic phase was dried
with MgSO4, filtered and concentrated under vacuum, and
then acetylated (Ac2O, pyridine). The identity of products
and the ratio of stereoisomers was determined by analysis of
[4] J.-P. G Seerden, M. M. M. Boeren, H. W. Scheeren, Tet-
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[5] a) R. L. Halcomb, S. J. Danishefsky, J. Am. Chem. Soc.
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3072; b) W. J. Sanders, L. L. Kiessling, Tetrahedron
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Marcoux, B. Cote, Tetrahedron Lett. 1991, 32, 7215;
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1
the mixtures by H and 13C NMR, and COSY, HSQC and
DEPT analysis. Where necessary, separation and purification
of products was achieved by chromatography on a column
of silica gel using mixtures of ethyl acetate and hexane as
eluent.
Dihydroxylation using the Venturello compound: To a so-
lution of Q3PW4O24 (0.005 mmol) in 1,4-dioxane (2.5 mL)
(A) or CH3CN (1.5 mL) and EtOAc (1 mL) (B) was added
H2O (0.5 mL), H2O2 (0.190 mmol, 1.5 equiv. against glycal)
and glycal [0.125 mmol dissolved in 0.5 mL 1,4-dioxane (A)
G
[7] G. Bellucci, G. Catelani, C. Chiappe, F. D’Andrea, Tet-
or EtOAc (B)]. The reaction was stirred at 323 K and moni-
tored by TLC. When the reaction was complete, the mixture
was diluted with EtOAc, dried with MgSO4, filtered and
concentrated under reduced pressure. The crude mixture
was acetylated (Ac2O, pyridine) and the mixture of products
analyzed by 1H NMR and 13C NMR spectroscopy, using
COSY, HSQC and DEPT analysis.
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Acknowledgements
[11] E. C. Boyd, R. V. H. Jones, P. Quayle, A. J. Waring,
This research is supported by the National Research Founda-
tion (South Africa) and the Flemish Government (Bilateral
Scientific Cooperation). The authors wish to further thank
CECATand the GOA program (KU Leuven) and IAP (Bel-
gian Federal Government) for funding.
Green Chem. 2003, 5, 679.
[12] V. Bilik, S. Kucar, Carbohydr. Res. 1970, 13, 311.
[13] S. Rani, Y. D. Vankar, Tetrahedron Lett. 2003, 44, 907.
[14] P. Tiwari, A. K. Misra, J. Org. Chem. 2006, 71, 2911.
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Adv. Synth. Catal. 2008, 350, 1557 – 1568