Highly shape-selective, biomimetic, and efficient deprotection of carbonyl compounds masked as ethylene acetals or dioxolanes produced from 1,2-ethanediol

Article abstract of DOI:10.1002/ejoc.200300279

A simple, mild, efficient, and organic solvent-free biochemical approach for the deprotection of carbonyl compounds protected as 1,3-dioxolanes through the use of cyclodextrins as catalysts has been developed. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300279

FULL PAPER
Highly Shape-Selective, Biomimetic, and Efficient Deprotection of
Carbonyl Compounds Masked as Ethylene Acetals or Dioxolanes Produced
from 1,2-Ethanediol
Hong-Bing Ji[a]
Keywords: Carbonyl compounds / Cyclodextrins / Deprotection / Dioxolanes / Ethylene acetals
A simple, mild, efficient, and organic solvent-free biochem-
ical approach for the deprotection of carbonyl compounds
protected as 1,3-dioxolanes through the use of cyclodextrins
as catalysts has been developed.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
also discovered this biomimetic approach for deprotection
of aromatic acetals by use of β-CD under mild reaction
conditions. Furthermore, the corresponding ethylene acet-
als and dioxolanes produced through protection with 1,2-
ethanediol can be smoothly deprotected to generate the cor-
responding aldehydes and ketones; surprisingly, some of
these deprotections can be accomplished even at room tem-
perature.
Selective protection and deprotection of carbonyl groups
can be of great importance in the course of a total organic
[
1Ϫ4]
synthesis.
Of the various protecting groups for carbonyl
groups, the protection of carbonyl compounds as their acet-
als and ketals has found wide application in the multistep
synthesis of organic molecules.[
5Ϫ18]
The hydrolysis of acet-
als and ketals to regenerate their corresponding carbonyl
compounds is also of interest to synthetic organic chemists.
Recently, considerable interest has been focused on mild,
[
19Ϫ38]
selective methods for acetal and ketal deprotection.
Most of the general methods used for the cleavage of acetals
and ketals involve a variety of catalyst systems, such as bis-
Results and Discussion
[19]
muth triflate/THF/H O,
KMnO supported on alum-
2
4
[
32]
[20]
ina, decaborane/THF/H O, pyridinium poly(hydrogen
2
[
23]
fluoride)/CH CN,
bismuth
nitrate
pentahydrate/
Efficient CD-catalyzed deprotection of ethylene acetals
and dioxolanes was achieved here with the use of water as
Al- the only solvent (Scheme 1). These reactions do not need
3
[
24]
[26]
CH Cl , ceric ammonium nitrate/CH CN/borate/HCl,
2
2
3
[
27]
or (trimethylsilyl)bis(fluorosulfuryl)imide/CH Cl .
2
2
though many mild methods used for deprotection of acetals any other additive, and many deprotection reactions can
and ketals have been developed, some of the reported meth- even be performed at room temperature.
ods for deprotection of the such species still suffered from
one or more disadvantages, such as low product yields, high
cost or toxicity of the reagents, long reaction times, elevated
temperatures, and tedious workups. In view of these limi-
tations of the existing procedures, a totally new, mild, econ-
omical, and safe approach under neutral conditions with
water as solvent was recently developed,[ based on the use
39]
of commercially available, biomimetic, naturally occurring
catalysts: cyclodextrins (CDs). Aromatic acetals were de-
protected to regenerate the corresponding aldehydes by use
of β-CD in water at 50 °C. In our earlier research, we had
Scheme 1
[
a]
School of Chemical Engineering, South China University of
Technology,
Guangzhou 510640, P. R. China
Fax: (internat.) ϩ 86-20/87113735
E-mail: cehbji@scut.edu.cn
The experimental procedure is extremely simple. The re-
actions were performed by dissolving CDs in water, fol-
Eur. J. Org. Chem. 2003, 3659Ϫ3662
DOI: 10.1002/ejoc.200300279
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3659

H.-B. Ji
FULL PAPER
Table 1. Deprotection of 1 with different CDs
Table 2. Hydrolysis of various ethylene acetal and dioxolane pro-
tecting groups to regenerate the corresponding carbonyl com-
pounds[
a]
Entry[a] Catalyst Catalyst mass (mmol) Conv. (%) Yield (%)[b]
1
2
3
4
5
6
β-CD
β-CD
β-CD
α-CD
γ-CD
Ϫ
1
100
87
34
Ͻ 0.5
Ͻ 0.5
0
Ͼ 99
87
34
Ͻ 0.5
Ͻ 0.5
0
0.5
0.1
1
1
Ϫ
[
a]
Reaction conditions: 1 (2 mmol), water (25 mL), 2.5 h, room
temp. (no reflux), Ar. [ Yield of product was determined by GC-
MS with a DB-1 (25m) column by use of an internal standard. In
all cases, product was exclusively obtained.
b]
lowed by the addition of acetals or ketals while stirring.
Firstly, using deprotection of 1 as the typical reaction, three
species of CDs were evaluated as shown in Table 1.
It is strikingly surprising to find out that 1 was efficiently
deprotected into 2 through the use of β-CD as a catalyst,
while little deprotection was achieved in the cases both of
α-CD and of γ-CD (Entries 1, 4 and 5). It might be con-
cluded that the deprotection with CD as a catalyst is highly
shape-selective, owing to the different interior cavity sizes
of these CDs. A similar conclusion could also be arrived at
in the following discussion. With regard to the mass of β-
CD, use of more β-CD accelerated the reaction rate (Entries
1Ϫ3). No deprotection was observed when 1 was stirred in
water in the absence of β-CD, indicating that the presence
of CD is necessary to cause deprotection (Entry 6).
In view of the efficient deprotection of 1, the deprotec-
tion for various ethylene acetals and dioxolanes was investi-
gated and the results are shown as Table 2.
Aromatic ethylene acetals underwent smooth deprotec-
tion (Entries 1 and 3). However, polycyclic aromatic alde-
hyde-derived 5 could not be deprotected to give 6. The lack
of deprotection (Entry 4) might be accounted for, on the
basis of fundamental computation, by the steric volume of
5
being too large to enter into the hydrophobic cavity of β-
[a]
Reaction conditions: β-CD (1 mmol), substrate (2 mmol), water
CD during the reaction. The acetal derived from cyclohex- (25 mL), room temp., no reflux. [ Conversion and yield were de-
b]
termined by GC, GC-MS or LC by use of an internal standard. In
all cases, product was exclusively obtained. Values in parentheses
are isolated yields. Protected by Ar to prevent from further oxi-
dation. Large scale: substrate (20 mmol). Reaction temperature
anecarbaldehydes rather than aromatic aldehydes, (i.e., 7)
suffered from low reactivity towards its deprotection (Entry
[c]
[d]
5). The bulk of the cyclohexyl group, with chair and boat
[e]
[f]
conformations occupying more space than an aromatic
group, might explain the low reactivity towards deprotec-
tion for the small hydrophobic cavity of β-CD as a microre-
[g]
(
60 °C). Substrate (1 mmol).
actor for deprotection. It was also verified that the existence inert gas such as Ar is necessary for the hydrolysis of aro-
of other groups on the aromatic group sharply decreased matic ethylene acetals. Otherwise, the deprotected products
the reactivity, by comparison of the deprotection of 1 with such as 2 could easily be further oxidized to the correspond-
that of 3, in which deprotection of 1 could be performed at ing carboxylic acids, owing to the presence of oxygen.
room temperature while a reaction temperature of 60 °C
was necessary for smooth deprotection of 3 (Entries 1 and of dioxolanes protected by use of 1,2-ethanediol, except the
). When 9 was heated to 60 °C for 12 h, no 10 was formed lower activities owing to the presence of cyclohexyl group
Similar reaction characteristics can be found in the cases
3
and the starting material was recovered unchanged. The (Entries 7Ϫ10). Reaction temperature is a key factor for
lack of deprotection of ethylene acetals derived from ali- the deprotection; the use of elevated reaction temperature
phatic aldehydes might be one reason, as also reported else- sharply increased the level of deprotection (Entries 7 and
[
19,24]
where;
another reason might be the steric structure of 8). From the above discussion, use of CD as a catalyst for
β-CD, as discussed later. It is noteworthy that the use of deprotection of carbonyl compounds masked as ethylene
3660
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3659Ϫ3662

Highly Shape-Selective, Biomimetic and Efficient Deprotection of Carbonyl Compounds
FULL PAPER
acetals and dioxolanes produced from 1,2-ethanediol is
highly dependent on molecular shape and the deprotection
Conclusion
mechanism is different from other reported catalyst systems.
In conclusion, a simple, mild, efficient, and biochemical
The steric factor is the most important, if the hydrophobic procedure for the deprotective hydrolysis of carbonyl com-
cavity of CD is regarded as the microreactor for deprotec- pounds masked as ethylene acetals and dioxolanes pro-
tion. The highly shape-selective and catalytic nature of this duced from 1,2-ethanediol has been developed, through the
system makes some substrates particularly efficient for use of CD as a catalyst to regenerate their corresponding
large-scale synthesis. The effective large-scale utilization of carbonyl compounds. This biomimetic methodology is the
this system is demonstrated by the successful deprotection first of its kind to be applied for the cleavage of ethylene
of 1 (Entry 2).
acetals and dioxolanes under neutral conditions with water
To obtain some mechanistic insights of the CD-catalyzed as solvent in the presence of CDs. These biomimetic reac-
deprotection, special conformations of CDs should be a key tions can be effectively conducted in water as the sole sol-
factor. In general, biotransformations are a useful and vent under neutral conditions without generating any toxic
complementary tool for preparative organic chemistry. In waste products. In addition, the use of water as solvent, the
the course of a biotransformation, the chemo-, regio-, and readily commercial availability of the catalyst, the high
stereoselective transformation of a substrate often takes yields of the products, the easy workup, low costs, and the
place under mild and ecologically compatible conditions. safety of the catalyst are other advantages of this method,
CDs, which are cyclic oligosaccharides with toroidal hydro- making this procedure a useful and attractive addition to
phobic cavities, exert microenvironmental effects giving rise the currently available methods. In addition, this deprotec-
to selective reactions. They catalyze reactions involving tion methodology is highly shape-selective, owing to the
supramolecular catalysis through reversible formation of conformations of CDs.
host-guest complex with substrates by non-covalent bond-
ing, as seen in enzymes. This complexation depends on the
Experimental Section
size, shape, and hydrophobicity of the guest molecule. Thus,
biochemical-like selectivity for shape and substrate with re-
actions performed in water will be superior to chemical sel-
ectivity. The role of CD appears to be to activate the ϪOϪ
group by hydrogen bonding, thus facilitating its cleavage in
the presence of water by acid-base catalysis.
The above discussion might easily explain the greater ease numbers (cm ). GC-MS analyses were performed with a Shim-
of deprotection of carbonyl compounds masked as acetals adzu GCMS-QP5050A GC-mass spectrometer. α-CD, β-CD, γ-
derived from aromatic aldehydes than of those derived from CD, and solvents were purchased from WAKO Co. and solvents
were further purified before use. Other chemicals are commercially
cyclohexanecarbaldehydes. The existence of other groups in
the substrate might retard the host-guest complex inter-
mediate formation by hydrogen bonding, owing to steric
factors. The lack of reaction in the attempted deprotection
of 9 might be attributable to the long aliphatic chain, and
thus the impossibility of formation of an intermediate by Typical Procedure for the Hydrolysis of Ethylene Acetal and Di-
hydrogen bonding, owing to the long distance between the
ϪOϪ group of 1 and the ϪOH group of CD.
In view of the proposed mechanism, we now also specu-
lated that dimethyl acetals or ketals might also be depro-
tected successfully, owing to their similar structures and
ϪOϪ groups. Compound 18 was used to verify this suppo-
sition, and highly efficient conversion was found as shown
in Scheme 2.
General Remarks: 1H and 13C NMR spectra were recorded in
CDCl
trometer. Chemical shifts were reported in parts per million (ppm,
δ) relative to Me Si (δ ϭ 0.00 ppm). IR spectra were recorded with
an FT-IR spectrometer (JASCO FT/IR-410) and reported in wave-
3
at 400 and 100 MHz, respectively, with a JLN AL-400 spec-
4
Ϫ1
available (from Aldrich Co. or WAKO Co.), unless otherwise indi-
cated, and were used as received. Commercially unavailable sub-
1
strates were synthesized by known methods and analyzed by H
1
3
NMR, C NMR, FT-IR and MS.
oxolane Protecting Groups Formed from 1,2-Ethanediol: β-CD
(
1 mmol) was dissolved in water (25 mL) at room temperature, and
the substrate (2 mmol) was added with stirring. When the reaction
was complete, the mixture was extracted with ethyl acetate (2 ϫ
30 mL) and dried with anhydrous sodium sulfate, and the solvent
was removed in vacuo. The crude product was purified by silica gel
column chromatography with ethyl acetate/hexane (3:7) as eluent.
Products were characterized by GC, LC, or GC-MS and compared
with authentic samples.
Large-Scale Hydrolysis of Ethylene Acetal and Dioxolane Protecting
Groups Formed from 1,2-Ethanediol: β-CD (1 mmol) was dissolved
in water (25 mL) at room temperature, and the substrate (20 mmol)
was added with stirring. When the reaction was complete, the mix-
ture was extracted with ethyl acetate (2 ϫ 30 mL) and dried with
anhydrous sodium sulfate, and the solvent was removed in vacuo.
The crude product was purified by silica gel column chromatogra-
phy with ethyl acetate/hexane (3:7) as eluent. Products were charac-
terized by GC, LC, or GC-MS and compared with authentic
samples.
General Procedure for the Preparation of Ethylene Acetals and Di-
oxolanes:[ A mixture of carbonyl compound (10 mmol), ethane-
11]
Scheme 2
Eur. J. Org. Chem. 2003, 3659Ϫ3662
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3661

H.-B. Ji
FULL PAPER
[
[
[
7]
8]
9]
1
(
2
,2-diol (15 mmol), Ti-montmorillonite (0.3 g), and toluene
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[
[
[
[
17]
18]
19]
20]
1
25.28, 124.48, 123.36, 123.06, 102.28, 65.52 ppm. MS (EI, 70 eV):
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[
[
[
23]
24]
25]
(1.02), 73 (100).
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1
9
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207Ϫ3209.
[
[
[
[
27]
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30]
3
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3662
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3659Ϫ3662