Epoxidation-alcoholysis of cyclic enol ethers catalyzed by Ti(O iPr)4 or Venturello's peroxophosphotungstate complex

Article abstract of DOI:10.1039/b705244h

Venturello's peroxophosphotungstate compound and Ti(OⁱPr) ₄ were successfully used as catalysts for the epoxidation-alcoholysis of various dihydropyrans and dihydrofuran using H₂O₂ as the oxidant. Different alcohols can be used as solvents and nucleophiles, resulting in hydroxy ether products with varying alkoxy groups. The Venturello compound can also be used as catalyst in a biphasic conversion of dihydropyran, in which long chain alcohols or fatty acids are incorporated in the hydroxy ether products with high yield and (stereo)selectivity. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b705244h

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Epoxidation–alcoholysis of cyclic enol ethers catalyzed by Ti(OiPr)4 or
Venturello’s peroxophosphotungstate complex
Pieter Levecque,a,b David Gammon,b Henok Hadgu Kinfe,†b Pierre Jacobs,a Dirk De Vosa and Bert Sels*a
Received 10th April 2007, Accepted 18th April 2007
First published as an Advance Article on the web 8th May 2007
DOI: 10.1039/b705244h
Venturello’s peroxophosphotungstate compound and Ti(OiPr)4 were successfully used as catalysts for
the epoxidation–alcoholysis of various dihydropyrans and dihydrofuran using H2O2 as the oxidant.
Different alcohols can be used as solvents and nucleophiles, resulting in hydroxy ether products with
varying alkoxy groups. The Venturello compound can also be used as catalyst in a biphasic conversion
of dihydropyran, in which long chain alcohols or fatty acids are incorporated in the hydroxy ether
products with high yield and (stereo)selectivity.
clean and safe oxidant such as aqueous H2O2. The objective is to
Introduction
reach high conversion of the cyclic enol ether model compounds
Natural product chemistry is a rich source of inspiration for
with high (stereo)selectivity within short reaction times. Moreover,
biological investigations and medical discoveries. The develop-
it is desirable to use as large a variety of alcohols or nucleophiles
ment of clean and reliable organic methodologies, including
as possible, since this expands the applicability of the new method.
catalytic procedures, is an essential tool for advancing the synthesis
and modification of natural products. New catalytic reactions
Results and discussion
for the fine chemical industry are often developed using model
substrates. Such molecules contain a motif that is shared by many
relevant potential substrates. This approach is well exemplified by
glycosylation chemistry, in which unsaturated sugars or glycals
are pivotal intermediates for the synthesis of an increasingly
large group of drug molecules or drug precursors.1 The cyclic
enol ether motif of glycals is also found in 3,4-dihydro-2H-pyran
(DHP), which can accordingly be used as a model, for instance in
studying oxidation of the enol ether.2 Enol ethers are frequently
transformed via epoxidation, followed by opening of the epoxide
with an alcohol or an acid. The epoxidation–alcoholysis is not only
relevant for glycal chemistry; DHP and the derived hydroxy ether
products are also used in the study and synthesis of polycyclic ether
frameworks.3 The latter are known as the backbones of several
naturally occurring toxins such as ciguatoxins, maitotoxins and
brevetoxins.
We here present new epoxidation–alcoholysis protocols for
various dihydropyrans and dihydrofuran. While some method-
ologies for oxidative glycal transformation have been reported,4–8
the epoxidation–alcoholysis of DHP has only rarely been
investigated.9,10 Moreover, in several of these reports, organic
oxidants are used, such as 2,6-dichloropyridine N-oxide in combi-
nation with a Ru catalyst,4 iodosylbenzene in combination with a
Mn catalyst,9 the urea adduct of hydrogen peroxide in combination
with CH3ReO3 as a catalyst,5 m-chloroperbenzoic acid,6,10 or the
explosive dimethyldioxirane.7,8 As all these organic oxidants result
in additional waste, the main aim of the present work is to use a
Catalyst screening
Using H2O2 as the oxidant, the epoxidation–alcoholysis of 3,4-
dihydro-2H-pyran (DHP) was attempted using a variety of
catalysts, including the W-based catalysts Na2WO4·2H2O, Q2WO4,
Q2W2O11,11 Q3PW4O24,12,13 and Q4[c-SiW10(H2O)2O34]4−
(Q =
14
quaternary ammonium), Mo catalysts such as Mo(CO)6 and
Q3PMo12O40,15 and a selection of metal alkoxides including
Mo(OiPr)5, Ti(OiPr)4, VO(OiPr)3 and Zr(OEt)4. From this screen-
ing, the Venturello peroxo compound Q3PW4O24 and Ti(OiPr)4
emerged as superior catalysts. Although titanium is commonly
used for epoxidations, e.g. in the Sharpless epoxidation,16 the
results with the Ti-catalyst are quite remarkable, as Ti(OiPr)4 is
generally used with tBuOOH, rather than with aqueous hydrogen
peroxide.17 For both catalysts a short optimization was undertaken
to find the best reaction conditions.
Optimization of reaction conditions for Q3PW4O24 and Ti(OiPr)4
For reactions with the Venturello compound, it was found that
addition of a base, such as an alkaline zeolite is necessary in order
to suppress acid-catalyzed alcohol addition on the double bond.
Therefore 10 mg of NaA zeolite was added per 20 ml of reaction
mixture in all further tests. Other parameters considered were the
nature of the quaternary ammonium salt and the composition of
the solvent–nucleophile mixture (Table 1). Clearly, the Venturello
catalyst can be applied in a range of alcoholic solvents. The highest
activity and selectivity are achieved in ethanol (entries 2 and 3).
As the reaction is rather slow in pure methanol (entry 1), there is
a need for a co-solvent that is miscible with methanol but lacks
nucleophilic properties. Use of acetonitrile (entry 5) led to high
conversion of the starting enol ether, but the desired products were
not formed. Satisfactory conversion and selectivity are obtained in
aCentre for Surface Chemistry and Catalysis, K.U.Leuven, Kasteelpark
Arenberg 23, 3001, Heverlee, Belgium. E-mail: Bert.Sels@biw.kuleuven.be;
Fax: (+32)16 321998
bDepartment of Chemistry, University of Cape Town, Private Bag, 7001,
Rondebosch, South Africa
† Present address: CSIR Biosciences, Ardeer Road, Private Bag X2,
Modderfontein, 1645, Johannesburg, South Africa.
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Table 1 Venturello-compound catalyzed epoxidation–alcoholysis of
Table 2 Ti(OiPr)4 catalyzed epoxidation–alcoholysis of DHPa
DHP: optimization of reaction conditionsa
Base
Solvent
T/K t/h
Yield (%)
trans : cis
Solvent
Nucleophile
t/h
Yield (%)
trans : cis
1
2
3
4
5
6
7
8
9
—
MeOH
MeOH
MeOH
MeOH
EtOH
n-PrOH
Dioxaneb
MeOH
MeOH
MeOH
303
6
3
24
3
2
2
65
2
1
73
88
37
94
33
23
81
87
86
94
10 : 1
11 : 1
115 : 1
20 : 1
2.5 : 1
3 : 1
5.5 : 1
20 : 1
19 : 1
34 : 1
ꢀꢀ
1
2
3b
4
5
6
7
8
9
MeOH
EtOH
EtOH
n-PrOH
—
—
—
—
24
0.5
0.5
0.25 81
1
81
85
88
17 : 1
9 : 1
12 : 1
8 : 1
—
8 : 1
8 : 1
5 : 1
9 : 1
CaCO3
Et3N
NaA
NaA
NaA
NaA
NaA
NaA
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
MeCN
EtOHc
MeOHe
MeOHf
EtOHe
4-Penten-1-olg
0d
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
3
78
70
45
47
0.5
0.5
0.5
313
323
10 NaAc
2
ꢀꢀ
a General conditions: 4 mmol DHP, 0.04 mmol Q3PW4O24 (Q = (Bu)4N),
20 ml solvent, 8 mmol H2O2, 10 mg NaA, 323 K. b Q = (Oct)3MeN.
c Equimolar amounts of nucleophile and substrate (0.2 M). d Conversion
was very high but no desired products were obtained. e Dioxane : alcohol
= 1 : 1. f Dioxane : MeOH = 4 : 1. g Dioxane : 4-penten-1-ol = 7 : 3.
a General conditions: 4 mmol DHP, 0.04 mmol Ti(OiPr)4, 20 ml solvent,
8 mmol H2O2, 10 mg base. b + 4 mmol MeOH. c 30 mg.
product. These experiments led to the proposed optimized reaction
conditions of Scheme 2.
a 1 : 1 mixture of methanol and 1,4-dioxane (entry 6). If a higher
ratio of dioxane : MeOH is used (entry 7) the selectivity drops
because of more diol formation. This is presumably due to the fact
that dioxane enhances the nucleophilicity of both methanol and
water present in the reaction.18
Attempts to incorporate more complex alcohols as nucleophiles
in 1,4-dioxane were less successful. In the case of 4-penten-1-
ol (entry 9) a significant amount of 5-hydroxy-1,2-epoxypentane
was detected, indicating that the reactivity of the enol ether and
terminal olefin were not sufficiently differentiated. Finally, the
influence of the quaternary ammonium species used as counter
ion in the Venturello compound was assessed by comparing the
Scheme 2
Epoxidation–alcoholysis of various cyclic enol ethers
Both catalysts were tested in optimized conditions with a selection
of dihydropyrans and dihydrofuran. The results of the reactions
with the Venturello catalyst in ethanol (method A) and with
Ti(OiPr)4 in methanol (method B) are shown in Table 3. Similar
patterns of reactivity emerge for both catalytic systems, even if
differences are more pronounced with Ti(OiPr)4 than with the
Venturello compound. 2,3-Dihydrofuran (entries 4 and 8) is the
most reactive compound due to the high electron density in the
double bond of its five-membered ring structure. Of the six-
membered ring compounds, unsubstituted 3,4-dihydro-2H-pyran
is more reactive than the related methyl and ethyl acetals. For
these acetals the stereoselectivity of the reactions is somewhat
lower (entries 2, 3, 6 and 7).
R
tetrabutylammonium and trioctylmethylammonium (Aliquatꢀ
336) ions in ethanol (entries 2 and 3). With the latter ion, the yield is
similar but the stereoselectivity in the epoxide opening is improved.
Optimal reaction conditions are summarized in Scheme 1.
Scheme 1
For Ti(OiPr)4 as well, a thorough investigation of catalyst
concentration, base, solvent–nucleophile system and temperature
was performed, and a selection of the data is presented in Table 2.
For optimal catalyst solubility, the Ti(OiPr)4 concentration was
set at 2 mM. Among the different bases tested in methanol
(entries 2–4), zeolite 4A (entry 4) gave the optimum combination
of high reaction rate, selectivity and stereoselectivity. The use of
triethylamine (entry 3) led to almost complete trans selectivity
in the products, but with rather low yield. The solvent choice is
limited due to the poor solubility of Ti(OiPr)4 in alcohols other
than methanol, with consequent poor conversion and selectivity
in ethanol and propanol (entries 4–6). Addition of dioxane as
co-solvent (entry 7) resulted in drastic lowering of the activity
and selectivity. The reaction rate can be increased by performing
the reaction at 323 K; addition of a larger amount of NaA at
this temperature (30 mg per 20 ml, entries 9 vs. 10) resulted in
a high yield with a significantly improved selectivity for the trans
Comparison of both catalytic systems shows that with Ti(OiPr)4
in methanol, slightly higher yields as well as higher stereoselectiv-
ities are obtained. On the other hand, the Venturello compound
is more active on a molar base, as expressed in higher turn-over-
frequency (TOF/h−1, measured at the initial reaction stage) values.
The TOF value measured for 2,3-dihydrofuran with Ti(OiPr)4 is
almost 4 times higher than the TOF value for 3,4-dihydro-2H-
pyran (entries 5 and 8); with the Venturello compound (entries 1
and 4) the TOF for 2,3-dihydrofuran is only slightly higher than
for 3,4-dihydro-2H-pyran. This suggests that Ti(OiPr)4 is more
sensitive to changes in electron density of the double bond.
To confirm this point, relative reactivities of cyclohexene and
dihydropyran were measured for both catalysts in competitive
experiments (Table 4). In both cases cyclohexene, with the less
electron-rich double bond proved to be significantly less reactive
than the enol ether; the difference in reactivity is indeed more
marked in the case of Ti(OiPr)4.
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Table 3 Epoxidation–alcoholyis of dihydropyrans and dihydrofuran with the Venturello catalyst and with Ti(OiPr)4
Substrate
Method
A
t/h
Products
Yield trans + cis (%)
TOF
320
trans : cis
1
2
0.5
88
12 : 1
A
A
A
2
86
75
89
148
168
360
7 : 2
7 : 2
9 : 1
3
4
1
0.5
5
6
7
8
1
2
3
4
B
B
B
B
2.5
6
94
94
84
98
≥80
22
34 : 1
9 : 2
5
35
4 : 1
0.3
300
70 : 1
a Conditions: Method A: 4 mmol olefin, 0.04 mmol Q3PW4O24, 8 mmol 60% aq. H2O2, 10 mg NaA, 20 ml EtOH, 323 K. Method B: 4 mmol olefin,
0.04 mmol Ti(OiPr)4, 8 mmol 60% aq. H2O2, 30 mg NaA, 20 ml MeOH, 323 K. Values for TOF were measured after 10–15 minutes of reactions.
Table 4 Relative reactivities of 3,4-dihydro-2H-pyran and cyclohexene
specified in Scheme 3, with DHP (0.2 M) and the Venturello
catalyst (2 mM, 1%). As nucleophiles, 1-octanol, 1-dodecanol,
1-octadecanol, benzyl alcohol, L-menthol or palmitic acid were
with the Venturello compound and with Ti(OiPr)4
Catalyst
Reactivity ratio 3,4-dihydro-2H-pyran : cyclohexene
Q3PW4O2
Ti(OiPr)4
12 : 1
23 : 1
Conditions:a As in Table 1, entry 3. b As in Table 2, entry 4. As substrates,
an equimolar mixture of cyclohexene and DHP was used. Reactivity ratios
were determined at low conversions.
Biphasic epoxidation–alcoholysis of 3,4-dihydro-2H-pyran with
long alcohols or fatty acids
Apolar, long chain nucleophiles are only poorly soluble in the
water-containing alcoholic reaction mixtures of Schemes 1 and 2.
Therefore reactions were performed in the biphasic conditions
Scheme 3
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Table 5 Incorporation of long chain alcohols and a fatty acid in 3,4-
dihydro-2H-pyran with the Venturello compound in biphasic conditionsa
up to now the only successful example of Ti-catalyzed epoxidation
with H2O2.19
While the electron-rich nature of dihydropyran and related
substrates results in a facile epoxidation, the challenge is to
control the fate of the highly reactive epoxide product. At least
three nucleophiles may attack the epoxide: water, which is the
side product of the reaction, H2O2, especially if used in a large
excess, and the desired alcohol reagent. In the case of W oxidation
catalysis, the in situ opening of the epoxide to the diol, or its further
transformation to carboxylic acids have even been exploited for
their synthetic utility.20,21 In the present work, we have succeeded
in obtaining yields well over 80% of the alcohol-opened products.
This could be realized via adapted concentrations of the alcohol,
and via careful control of reaction temperature and medium
acidity. It is remarkable that even the excess of H2O2, which is
helpful in maintaining a sufficient reaction rate, does not give rise
to an appreciable over oxidation. The scope of the Ti(OiPr)4 based
procedure is rather small, since it is limited to methanol as the
sole alcoholic solvent. However, the Venturello compound proved
to be a very versatile system. As it can be used in monophasic or
biphasic conditions, with a broad range of alcohols and even acids
as nucleophiles, it holds great promise for future applications in
the preparation of fine chemicals.
Nucleophile
t/h
Product
Yield (%)
trans : cis
1
2
3
4
5
6
Octanol
3
4
2
2
2
2
13
14
15
16
17
18
93
>90
>90
>90
>90
85b
14 : 1
12 : 1
13 : 1
>25 : 1
1 : 1
Dodecanol
Octadecanol
Benzyl alcohol
L-Menthol
Palmitic acid
13 : 1
a Conditions: 10 ml ethyl acetate, 2 mmol DHP, 0.02 mmol Q3PW4O24,
4 mmol nucleophile, 4 mmol H2O2, 323 K. b 5–10% of the product mixture
was the protected DHP of the acid-catalyzed side reaction.
added. The results (Table 5) show that the desired hydroxy ether
products are obtained in high yields and within short times.
This confirms that high TOF values can be achieved with the
Venturello compound. For reactions with long aliphatic alcohols
as the nucleophiles, the trans : cis ratios of the hydroxy ether
products are between 12 : 1 and 14 : 1 (entries 1–3). These trans
preferences in biphasic conditions are even slightly higher than
with pure short-chain alcohols in a monophasic system (Table 3).
The reaction with benzyl alcohol gives a surprisingly high
stereoselectivity, with more than 96% selectivity for the trans
isomer (entry 4). In this 2-O-benzylated product, the C-3 13C
signal is strongly shifted in comparison to the C-3 of the products
containing linear alkoxy groups, likely because of the aromatic
nature of the phenyl moiety. With the secondary alcohol menthol
(entry 5), an almost 1 : 1 mixture of cis and trans ring-opened
products is obtained. This suggests that with this sterically
encumbered alcohol, the ring opening may proceed in a non-
concerted fashion. Finally, with palmitic acid as the nucleophile
(entry 6), an 85% yield of the desired hydroxy ester is formed;
direct, Brønsted acid-catalyzed attack of the acid on DHP to form
the protected acid accounts for only 5% of the total products
formed. The same protocol was also applied with some thiols and
amines, but due to the easy oxidation of these nucleophiles no
epoxide-opened products were detected.
Experimental
All chemicals were of the highest grade commercially available.
The peroxophosphotungstate compound Q3PW4O24, with Q =
Bu4N+, was prepared according to a literature procedure.12,13
Epoxidation–alcoholysis of enol ethers using the Venturello
compound
A typical reaction mixture for the epoxidation–alcoholysis of
a dihydropyran or dihydrofuran with the Venturello compound
contains 20 ml of solvent, 4 mmol of enol ether, 0.04 mmol
Q3PW4O24, 8 mmol H2O2 (60 wt% in H2O) and 10 mg of powdered
NaA, which was pre-dried overnight at 350 ◦C. The mixture was
stirred at 323 K. Reaction progress was monitored by GC-analysis.
Conversions, selectivities, yields, turnover numbers (TON, moles
of product per mole of catalyst) and cis : trans ratios were based
on GC and GC-MS data.
Concluding remarks
Lewis acid catalysts for epoxidation such as Ti and W compounds
transfer an electrophilic oxygen atom to a double bond. The
present data show that a cyclic enol ether is highly reactive
towards this electrophilic oxygen atom, even more than a regular
olefin such as cyclohexene. The only side reaction at this stage
is the Brønsted-acid catalyzed ether formation. Therefore, the
use of the isolated peroxophosphotungstate catalyst is to be
preferred over procedures in which the catalyst is formed in situ
from the condensation of tungstic and phosphoric acid.12 In
the latter approach, strong Brønsted acidity would have been
introduced in the reaction, lowering the yields of the epoxide
and products derived from it. By adding bases, the etherification
reaction could be effectively suppressed, without affecting the high
epoxidation activity of the W or Ti Lewis acids. The activity of the
homogeneous Ti(OiPr)4 in combination with H2O2 is remarkable,
since the reactions of the heterogeneous Ti-zeolite TS-1 represent
Titanium-catalyzed epoxidation–alcoholysis of enol ethers
A similar procedure was adopted, using methanol as the solvent,
0.04 mmol Ti(OiPr)4 as the catalyst, and 30 mg dry powdered NaA.
Biphasic epoxidation–alcoholysis
0.02 mmol of Q3PW4O24 is weighed in a small reaction flask and
10 ml of ethyl acetate is added. 2 mmol of DHP is added to
this solution, followed by 5 mg zeolite 4A and 2 equivalents of a
nucleophile. 4 mmol H2O2 (50 wt% solution in H2O) is added to
this mixture which is kept at 323 K in a flask with condenser. The
reaction is monitored by TLC. When the reaction is completed, the
mixture is filtered and the filtrate is taken up in CH2Cl2 and washed
3 times with water. The organic phase is dried with MgSO4, filtered
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and concentrated in vacuo, followed by acetylation. Products and
their stereochemistry ratios are determined by 1H, 13C-NMR,
COSY, HSQC and DEPT analysis. When necessary purification
was done by separation on a silica gel column.
2-Ethyl-3-acetyl-2,3-dihydroxyfuran (trans) (8). Yellowish oil,
Rf: 0.57 (trans), 0.47 (cis) (2 : 8 EtOAc : Petr. Ether), MS (non-
acetylated): 132.9 m/z.
trans. 1H-NMR: (400 MHz, CDCl3) d ppm 5.00 (dd, J = 6.00,
1.57 Hz, 1H, H-2), 4.93 (s, 1H, H-1), 4.02–3.88 (m, 2H, H-4, H-
4ꢀ), 3.68–3.58 (m, 1H, OCH2CH3), 3.46–3.37 (m, 1H, OCH2CH3),
2.34–2.24 (m, 1H, H-3), 1.99 (s, 3H, CH3 acetyl), 1.87–1.79 (m,
1H, H-3ꢀ), 1.12 (t, J = 7.07, 7.07 Hz, 3H, OCH2CH3). 13C-NMR:
Characterization data
The names of compounds 5–18 correspond to the acetylated
derivatives.
=
(100 MHz, CDCl3) d ppm 170.32 (C O), 105.38 (C-1), 77.83 (C-
2-Ethyl-3-acetyl-2,3-dihydroxypyran (5). Yellowish oil, Rf:
0.45 (trans), 0.42 (cis) (2 : 8 EtOAc : Petr. Ether), MS (non-
acetylated): 146 m/z, Anal. calcd for C9H16O4: C, 57.43; H, 8.57.
Found: C, 58.06; H, 8.77%.
trans. 1H-NMR: (300 MHz, CDCl3) d ppm 4.62 (td, J = 4.79,
3.22, 3.22 Hz, 1H, H-2), 4.49 (d, J = 2.96 Hz, 1H, H-1), 3.83–3.63
(m, 2H, H-5 & OCH2CH3), 3.52–3.37 (m, 2H, H-5ꢀ & OCH2CH3),
2.02 (s, 3H, CH3 acetyl), 1.99–1.91 (m, 1H, H-3ꢀ), 1.89–1.73 (m,
1H, H-4), 1.68–1.56 (m, 1H, H-3ꢀ), 1.42–1.31 (m, 1H, H-4ꢀ). 13C-
2), 66.27 (C-4), 62.69 (OCH2CH3), 29.81 (C-3), 21.00 (OCOCH3),
15.06 (OCH2CH3).
2-Methyl-3-acetyl-2,3-dihydroxypyran (trans) (9)22,23
. Yellow-
ish oil, Rf: 0.37 (trans), 0.30 (cis) (2 : 8 EtOAc : Petr. Ether), MS
1
(non-acetylated): 132 m/z H-NMR: (400 MHz, CDCl3) d ppm
4.63 (td, J = 4.69, 3.23, 3.23 Hz, 1H, H-2), 4.39 (d, J = 2.89 Hz,
1H, H-1), 3.76 (dt, J = 10.80, 10.71, 3.06 Hz, 1H, H-5), 3.49 (dtd,
J = 11.23, 4.14, 4.08, 0.96 Hz, 1H, H-5ꢀ), 3.34 (s, 3H, OCH3), 2.03
(s, 3H, CH3 acetyl), 2.00–1.90 (m, 1H, H-3), 1.88–1.76 (m, 1H, H-
4), 1.67–1.58 (m, 1H, H-3ꢀ), 1.42–1.33 (m, 1H, H-4ꢀ). 13C-NMR:
=
NMR: (75 MHz, CDCl3) d ppm 170.17 (C O), 97.43 (C-1),
68.91 (C-2), 63.07 (OCH2CH3), 60.55 (C-5), 23.97 (C-3), 21.07
(OCOCH3), 20.99 (C-4), 14.96 (OCH2CH3).
=
(100 MHz, CDCl3) d ppm 170.30 (C O), 98.88 (C-1), 68.76 (C-2),
60.57 (C-5), 55.09 (OCH3), 24.00 (C-3), 21.19 (OCOCH3), 20.99
cis. 13C-NMR: (75 MHz, CDCl3) d ppm 95.71 (C-1), 70.33 (C-
2), 62.99 (OCH2CH3), 59.16 (C-5), 24.30, 23.16 (C-3, C-4), 14.92
(OCH2CH3).
(C-4).
5-Methyl-2-methyl-3-acetyl-2,3,5-trihydroxypyran (10). Yel-
lowish oil, Rf: 0.28 (2 : 8 EtOAc : Petr. Ether), MS (non-acetylated):
161 m/z.
trans. 1H NMR: (300 MHz, CDCl3) d ppm 4.68 (dd, J = 6.11,
3.16 Hz, 1H, H-5), 4.65–4.59 (m, 1H, H-2), 4.63 (d, J = 2.28 Hz,
1H, H-1), 3.40 (s, 3H, OMe), 3.39 (s, 3H, OMe), 2.60–2.40, 2.01
(s, 3H, CH3 acetyl), 1.95–1.83, 1.80–1.65, 1.60–1.50 (4 × m, 4H,
H-3, H-3ꢀ, H-4, H-4ꢀ). 13C NMR: (75 MHz, CDCl3) d ppm 170.2
5-Methyl-2-ethyl-3-acetyl-2,3,5-trihydroxypyran (6). Yellow-
ish oil, Rf: 0.32 (2 : 8 EtOAc : Petr. Ether), MS (non-acetylated):
174.9 m/z.
trans. 1H NMR: (400 MHz, CDCl3) d ppm 4.66–4.59 (m,
1H, H-2), 4.50 (dd, J = 6.43, 3.15 Hz, 1H, H-5), 4.48 (d, J =
5.17 Hz, 1H, H-1), 3.87–3.75 (m, 2H, OCH2CH3), 3.56–3.46 (m,
2H, OCH2CH3), 3.40 (s, 3H, OMe), 2.60–2.43 (m, 1H, H-3), 1.99
(s, 3H, CH3 acetyl), 1.90–1.81 (m, 1H, H-4), 1.63–1.50 (m, 1H, H-
4ꢀ), 1.49–1.36 (m, 1H, H-3ꢀ), 1.15 (t, 3H, OCH2CH3). 13C-NMR:
=
(C O), 98.87 (C-1), 97.74 (C-5), 68.58 (C-2), 55.58 (OMe), 52.69
(OMe), 26.86 (C-4), 22.86 (C-3), 21.11 (OCOCH3).
cis. 13C NMR: (75 MHz, CDCl3) d ppm 104.45 (C-1), 104.17
(C-5), 55.43 (OMe), 52.66 (OMe).
=
(100 MHz, CDCl3) d ppm 170.3 (C O), 99.86 (C-5), 98.90 (C-1),
70.03 (C-2), 64.35 (OCH2CH3), 55.94 (OMe), 27.33 (C-4), 22.39
(C-3), 21.11 (OCOCH3), 15.10 (OCH2CH3).
5-Ethyl-2-methyl-3-acetyl-2,3,5-trihydroxypyran (trans) (11).
Yellowish oil, Rf: 0.27 (2 : 8 EtOAc : Petr. Ether). MS (non-
acetylated): 175 m/z.
cis. 1H NMR: (400 MHz, CDCl3) d ppm 4.73 (d, J = 4.23 Hz,
1H, H-1), 3.39 (s, 3H, OMe). 13C-NMR: (100 MHz, CDCl3) d ppm
97.88 (C-5), 97.65 (C-1), 68.88 (C-2), 63.83 (OCH2CH3), 55.60
(OMe), 26.81 (C-4), 22.95 (C-3), 20.40 (OCOCH3).
13C NMR: (75 MHz, CDCl3) d ppm 99.09, 98.87 (C-1, C-5),
68.52 (C-2), 63.79 (OCH2CH3), 51.43 (OMe), 26.89 (C-4), 22.87
(C-3), 21.14 (OCOCH3), 15.08 (OCH2CH3).
5-Ethyl-2-ethyl-3-acetyl-2,3,5-trihydroxypyran (7). Yellowish
oil, Rf: 0.37 (2 : 8 EtOAc : Petr. Ether), MS (non-acetylated):
189 m/z, Anal. calcd for C11H20O5: C, 56.88; H, 8.68. Found: C,
57.10; H, 8.32%.
trans. 1H NMR: (400 MHz, CDCl3) d ppm 4.64–4.57 (m, 2H,
H-2, H-5), 4.46 (d, J = 5.72 Hz, 1H, H-1), 3.89–3.73 (m, 2H,
C1-OCH2CH3, C5-OCH2CH3), 3.55–3.40 (m, 2H, C1-OCH2CH3,
C5-OCH2CH3), 2.19–2.08 (m, 1H, H-3), 1.99 (s, 3H, CH3 acetyl),
1.88–1.79 (m, 1H, H-4), 1.67–1.54 (m, 1H, H-4ꢀ), 1.47–1.37 (m,
1H, H-3ꢀ), 1.19–1.12 (m, 6H, OCH2CH3). 13C-NMR: (100 MHz,
2-Methyl-3-acetyl-2,3-dihydroxyfuran (trans) (12)23. Yellowish
oil, Rf: 0.37 (trans), 0.29 (cis) (2 : 8 EtOAc : Petr. Ether), MS (non-
1
acetylated): 118 m/z. H-NMR: (400 MHz, CDCl3) d ppm 5.00
(dd, J = 6.01, 1.46 Hz, 1H, H-2), 4.82 (s, 1H, H-1), 4.00 (dd, J =
15.36, 7.89 Hz, 1H, H-4), 3.91 (dt, J = 8.59, 8.46, 4.93 Hz, 1H, H-
4ꢀ), 3.27 (s, 3H, OCH3), 2.34–2.21 (m, 1H, H-3), 1.99 (s, 3H, CH3
acetyl), 1.88–1.79 (m, 1H, H-3ꢀ). 13C-NMR: (100 MHz, CDCl3)
=
d ppm 170.3 (C O), 106.67 (C-1), 77.63 (C-2), 66.38 (C-4), 54.49
(OCH3), 29.34 (C-3), 20.99 (OCOCH3).
=
CDCl3) d ppm 170.03 (C O), 99.07 (C-1), 98.62 (C-5), 70.20 (C-
2), 64.21 and 64.01 (OCH2CH3), 28.01 (C-4), 23.11 (C-3), 21.08
(OCOCH3), 15.08 (OCH2CH3).
2-Octyl-3-acetyl-2,3-dihydroxypyran (trans) (13). Yellowish
oil, Rf: 0.58 (2 : 8 EtOAc : Petr. Ether), MS (non-acetylated):
230 m/z. 1H NMR: (400 MHz, CDCl3) d ppm 4.70 (td, J = 4.72,
3.27, 3.27 Hz, 1H, H-2), 4.53 (d, J = 2.97 Hz, 1H, H-1), 3.84
(dt, J = 10.81, 10.77, 3.03 Hz, 1H, H-3), 3.72 (td, J = 9.59, 6.73,
6.73 Hz, 1H, H-5), 3.54 (dtd, J = 11.12, 4.12, 4.10, 1.02 Hz, 1H,
H-3ꢀ), 3.41 (td, J = 9.61, 6.53, 6.53 Hz, 1H, H-5ꢀ), 2.09 (s, 3H, CH3
cis. 1H NMR: (400 MHz, CDCl3) d ppm 4.85–4.77 (m, 2H,
H-2, H-5), 4.73 (d, J = 3.88 Hz, 1H, H-1), 2.00 (CH3 acetyl). 13C-
NMR: (100 MHz, CDCl3) d ppm 97.70 (C-1), 96.35 (C-5), 68.78
(C-2), 63.71 and 63.66 (OCH2CH3), 26.90 (C-4), 22.99 (C-3), 21.13
(OCOCH3), 15.05 (OCH2CH3).
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acetyl), 2.06–1.99 and 1.76–1.65 (m, 2H, H-4, H-4ꢀ), 1.94–1.81,
1.63–1.56 and 1.48–1.20 (m, 14H, CH2 octyl), 0.88 (t, 3H, CH3
1), 75.35 (1C, CH, C-2), 69.68 (1C, CH, C-1-menthyl), 60.92 (1C,
CH2, C-5), 48.08, 40.00, 34.37, 31.42, 25.65–21.20, 15.58 (12C, 9C
menthyl, C-3, C-4, OCOCH3).
13
=
octyl). C NMR: (100 MHz, CDCl3) ppm 169.9 (C O), 97.77
(C-1), 69.01 (C-2), 67.89 (C-5), 60.68 (C-3), 31.80 (OCH2), 29.55,
29.35, 29.21, 26.12, 22.61, 21.17 (6C, CH2 octyl), 24.09 (C-4), 14.02
(CH3, octyl).
2-Palmitoyl-3-acetyl-2,3-dihydroxypyran (trans) (18). White
crystals, Rf: 0.49 (2 : 8 EtOAc : Petr. Ether), mp: 54–55 ◦C (from
chloroform), Anal. calcd for C23H42O5: C, 69.31; H, 10.62. Found:
2-Dodecyl-3-acetyl-2,3-dihydroxypyran (trans) (14). Yellowish
oil, Rf: 0.60 (2 : 8 EtOAc : Petr. Ether), MS (non-acetylated): 286
m/z. 1H NMR: (300 MHz, CDCl3) d ppm 4.69 (td, J = 4.63, 3.19,
3.19 Hz, 1H, H-2), 4.53 (d, J = 2.96 Hz, 1H, H-1), 3.84 (dt, J =
10.73, 10.65, 2.99 Hz, 1H, H-3), 3.71 (td, J = 9.55, 6.75, 6.75 Hz,
1H, H-5), 3.54 (dtd, J = 11.18, 4.09, 4.06, 1.08 Hz, 1H, H-3ꢀ), 3.41
(td, J = 9.68, 6.63, 6.63 Hz, 1H, H-5ꢀ), 2.08 (s, 3H, CH3 acetyl),
1.95–1.80 and 1.49–1.37 (m, 2H, H-4, H-4ꢀ), 1.74–1.51, 1.37–1.15
(m, 22H, CH2 dodecyl), 0.88 (t, 3H, CH3 dodecyl). 13C NMR:
1
C, 69.73; H, 10.81%. H NMR: (400 MHz, CDCl3) d ppm 5.83
(d, J = 3.62, 1H, H-1), 4.74 (td, J = 5.23, 3.67, 3.67, 1H, H-2),
3.88 (ddd, J = 3.21, 9.69, 11.63, 1H, H-5), 3.73–3.66 (m, 1H,
H-5ꢀ), 2.35 (t, 2H, OCOCH2), 2.09 (s, 3H, OCOCH3), 2.08–2.01
and 1.84–1.74 (m, 2H, H-3, H-3ꢀ), 1.98–1.87 and 1.55–1.49 (m,
2H, H-4, H-4ꢀ), 1.69–1.59 and 1.38–1.20 (m, 26H, -CH2-), 0.88 (t,
13
=
3H, –CH3). C NMR (100 MHz, CDCl3) d ppm 171.92 (C O),
=
170.00 (C O), 91.33 (1C, CH, C-1), 67.83 (1C, CH, C-2), 62.84
=
(75 MHz, CDCl3) d ppm 170.294 (C O), 97.75 (C-1), 69.01 (C-2),
(1C, CH, C-5), 34.38 (1C, CH2, OCOCH2), 31.96, 29.85–29.05,
24.83 and 22.71 (13C, CH2, palmitic), 24.44 (1C, CH2, C-3), 21.07
(1C, OCOCH3), 20.95 (1C, CH2, C-4), 14.12 (1C, CH3 palmitic).
67.90 (C-5), 60.67 (C-3), 31.90 (OCH2), 29.65, 29.62, 29.60, 29.59,
29.57, 26.14, 25.90, 22.66, 21.20, 21.09 (10C, CH2 dodecyl), 24.09
(C-4), 21.09 (OCOCH3), 14.02 (CH3, dodecyl).
2-Octadecyl-3-acetyl-2,3-dihydroxypyran (trans) (15). Yellow-
ish oil, Rf: 0.63 (2 : 8 EtOAc : Petr. Ether). 1H NMR: (300 MHz,
CDCl3) d ppm 4.70 (td, J = 4.85, 3.20, 3.20 Hz, 1H, H-2), 4.53 (d, J
= 2.92 Hz, 1H, H-1), 3.84 (dt, J = 10.72, 10.61, 3.01 Hz, 1H, H-3),
3.72 (td, J = 9.58, 6.70, 6.70 Hz, 1H, H-5), 3.54 (dtd, J = 11.09,
4.09, 4.05, 1.19 Hz, 1H, H-3ꢀ), 3.41 (td, J = 9.60, 6.54, 6.54 Hz,
1H, H-5ꢀ), 2.09 (s, 3H, OCOCH3), 1.96–1.80 (m, 1H, H-4), 1.50–
1.38 (m, 1H, H-4ꢀ), 1.74–1.50 and 1.38–1.12 (m, 34H, octadecanyl),
0.88 (t, 3H, CH3-octadecanyl). 13C NMR: (75 MHz, CDCl3) d ppm
Acknowledgements
This work was performed in the frame of a Bilateral Agreement
Flanders/South-Africa. We also thank CECAT (K.U.Leuven)
and IAP (Belgian Federal Government) for funding.
Notes and references
=
170.41 (C O), 97.75 (1C, CH, C-1), 69.01 (1C, CH, C-2), 67.90
1 S. J. Danishefsky and M. T. Bilodeau, Angew. Chem., Int. Ed. Engl.,
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(1C, CH2, C-5), 60.67 (1C, CH2, C-3), 31.90 (1C, OCH2), 29.71–
29.29, 26.13, 22.66 and 21.08 (16C, octadecanyl), 24.08 (1C, CH2,
C-4), 21.19 (1C, OCOCH3), 14.07 (1C, CH3 octadecanyl).
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2-Benzyl-3-acetyl-2,3-dihydroxypyran (trans) (16)24. Yellowish
oil, Rf: 0.39 (2 : 8 EtOAc : Petr. Ether), Anal. calcd for C14H18O4: C,
67.18; H, 7.25. Found: C, 66.75; H, 6.86%. 1H NMR: (300 MHz,
CDCl3) d ppm 7.37–7.33 (m, 5H, phenyl), 4.78 (d, J = 11.99, 1H,
CH2-benzyl), 4.78 (m, 1H, H-2), 4.66 (d, J = 2.82 Hz, 1H, H-1),
4.53 (d, J = 11.98, 1H, CH2-benzyl), 3.90 (dt, J = 3.00, 10.92,
10.91 Hz, 1H, H-5), 3.59 (m, 1H, H-5ꢀ), 2.08 (s, 3H, COCH3),
2.14–2.05 (m, 1H, H-3), 1.99–1.83 (m, 1H, H-4), 1.77–1.66 (m,
1H, H-3ꢀ), 1.51–1.39 (m, 1H, H-4ꢀ). 13C NMR: (75 MHz, CDCl3)
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=
d ppm 170.21 (C O), 137.614 (1C, Ph-A), 128.32 and 127.67 (5C,
Ph), 96.87 (1C, CH, C-1), 68.96 (1C, CH2Ph), 68.77 (1C, CH, C-2),
60.71 (1C, CH2, C-5), 23.90 (1C, CH2, C-3), 21.12 (1C, OCOCH3),
20.88 (1C, CH2, C-4).
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2-Menthyl-3-acetyl-2,3-dihydroxypyran (17). Yellowish oil, Rf:
0.59 (2 : 8 EtOAc : Petr. Ether).
trans. 1H NMR: (300 MHz, CDCl3) d ppm 4.69–4.61 (m, 1H,
H-2), 4.57 (d, J = 3.92 Hz, 1H, H-1), 2.09 (s, 3H, OCOCH3). 13
C
=
NMR: (75 MHz, CDCl3) d ppm 170.36 (C O), 100.41 (1C, CH, C-
1), 81.10 (1C, CH, C-2), 69.80 (1C, CH, C-1-menthyl), 61.78 (1C,
CH2, C-5), 48.74, 43.22, 34.51, 31.70, 25.65–21.20, 16.13 (12C, 9C
menthyl, C-3, C-4, OCOCH3).
cis. 1H NMR: (300 MHz, CDCl3) d ppm 4.73 (d, J = 2.78 Hz,
1H, H-1), 4.69–4.61 (m, 1H, H-2), 2.07 (s, 3H, OCOCH3). 13C
=
NMR: (75 MHz, CDCl3) d ppm 170.27 (C O), 94.04 (1C, CH, C-
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1806 | Org. Biomol. Chem., 2007, 5, 1800–1806
This journal is
The Royal Society of Chemistry 2007
©