Metal-free deprotection of terminal acetonides by using tert -butyl hydroperoxide in aqueous medium

Article abstract of DOI:10.1055/s-0030-1259917

Employing aqueous tert-butyl hydroperoxide (70%) as an inexpensive reagent a useful methodology for the regioselective and chemoselective deprotection of terminal acetonide groups in aqueous medium is developed. A variety of acetonide derivatives on reaction with aqueous tert-butyl hydroperoxide in water:tert-butanol (1:1) furnish the corresponding acetonide deprotected diols in good yields. A large number of acid labile protecting functional groups and other functional moieties were found to be unaffected under the conditions employed for the present deprotection. This method has been successfully applied to sugar derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259917

LETTER
821
Metal-Free Deprotection of Terminal Acetonides by Using tert-Butyl
Hydroperoxide in Aqueous Medium
D
eprotectionof Termi
a
A
cetoni
h
des agundappa R. Maddani, Kandikere R. Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
Fax +91(80)23600529; E-mail: prabhu@orgchem.iisc.ernet.in
Received 3 January 2011
tert-Butyl hydroperoxide (TBHP) is a good oxygen
source which finds application in a variety of oxidation re-
actions.21 One of the major advantages of using TBHP
over other oxidants such as hydrogen peroxide and perac-
Abstract: Employing aqueous tert-butyl hydroperoxide (70%) as
an inexpensive reagent a useful methodology for the regioselective
and chemoselective deprotection of terminal acetonide groups in
aqueous medium is developed. A variety of acetonide derivatives
on reaction with aqueous tert-butyl hydroperoxide in water:tert- ids is its selectivity in several reactions. TBHP is inactive
butanol (1:1) furnish the corresponding acetonide deprotected diols
towards most organic compounds in the absence of metal
in good yields. A large number of acid labile protecting functional
catalysts; whereas hydrogen peroxide and peracids are ac-
groups and other functional moieties were found to be unaffected
tive even in the absence of metal catalysts. Thus, TBHP
under the conditions employed for the present deprotection. This
has been extensively used for selective oxidation in the
method has been successfully applied to sugar derivatives.
presence of various metal catalysts and, from an environ-
Key words: deprotection, acetonide, tert-butyl hydroperoxide,
mental and economical point of view, the protocols ap-
chemoselectivity, protecting group, diols
pear to be very attractive.22 Among them, molybdenum
catalysts are widely studied oxo-transfer reagents in aque-
ous medium and have aroused interest as models for mo-
Protection of multifunctional groups and their regenera-
lybdoenzymes.23 A literature survey on the utility of
tion is an important research area in organic synthesis.1 In
TBHP indicates that reactions employing TBHP as the
this context, selective protection and deprotection plays a
sole reactant are rare in synthetic organic chemistry.24,25
major role in the synthesis of several complex natural
However, there are reports by Wakharkar and co-workers
products.1,2 The acetonide functionality (isopropylidene
on the utility of TBHP in deprotection of oximes and
ketal) is one of the most exploited protecting groups for
tosylhydrazones24 to furnish the corresponding carbonyl
1,2-amino alcohols and 1,2-diols in carbohydrate and pep-
compounds. Similarly, deprotection of 1,3-dithiolanes
tide chemistry.1 As a result, selective deprotection of ace-
and dithianes25 to provide carbonyl compounds has been
tonides continues to be an active research field.1,2 The
carried out by using TBHP.
conventional methods for the deprotection of acetonides
use acidic reagents3–10 such as HCl, HBr, and H2SO4.11 A
number of Lewis acids have been employed to achieve the
deprotection of acetonides; these include FeCl3·6H2O/
In continuation of our investigations into the utility of mo-
lybdenum xanthate [MoO2(Et2NCS2)2, 1] as catalyst for
oxidations and reductions,26 we designed a reaction of 1 to
oxidize anomeric alcohols to the corresponding lactones.
Therefore, reaction of catalyst 1 with 2,3:5,6-di-O-isopro-
pylidine-D-manno-furanose27 (2) in the presence of aque-
ous TBHP was planned. Accordingly, in an initial
experiment, diisopropylidine derivative 2 (1 mmol) was
reacted with catalyst 1 (10 mol%) in the presence of aque-
ous TBHP (70%, 2 equiv) in aqueous medium. Interest-
ingly, the starting material 2 disappeared in 10 hours
under reflux conditions (Scheme 1).28 However, spectro-
scopic analysis of the product revealed that the lactol
group was unaffected during the reaction, while the termi-
nal acetonide group underwent a deprotection to furnish
the corresponding diol 2a. A literature survey indicated
that metal catalysts, such as CuCl2·2H2O13 or VCl3,19
which are Lewis acidic, are known to catalyze the depro-
tection of acetonides. In this context, we decided to test
whether molybdenum reagent 1, in the absence of TBHP,
could catalyze the deprotection of acetonides. Thus, bis-
actonide 2 with stoichiometric amount of reagent 1 was
refluxed in water, only to find that there was no reaction
with starting material 2 being recovered unchanged (20 h,
Scheme 1). As the reaction of bisacetonide 2 with catalyst
12
SiO2 and CuCl2·2H2O.13–19 More recently, alternative
methods for deprotection of acetonides using DDQ, aque-
ous DMSO, lithium halides, silanes, and insoluble acidic
matrices have been reported.20 However, many of these
procedures suffer from disadvantages of using harsh reac-
tion conditions such as high acidity, poor yields, and non-
selectivity, which results in lowering the yield of the
desired product. Particularly, many of the methods are not
suitable for the selective and mild deprotection of ace-
tonide groups in the presence of acid-sensitive functional
groups. Selective cleavage of acetonides in the presence
of acid-sensitive functional groups is a useful protocol and
often plays a crucial role in total synthesis.1 Hence, there
is a need to develop new and selective methods with a
good compatibility and selectivity with other protecting
groups under environmentally benign conditions.
SYNLETT 2011, No. 6, pp 0821–0825
x
x.
x
x.
2
0
1
1
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259917; Art ID: D00211ST
© Georg Thieme Verlag Stuttgart · New York

822
M. R. Maddani, K. R. Prabhu
LETTER
1 failed to produce the corresponding lactone, we thought
it reasonable to perform a reaction of acetonide 2 with
TBHP. Thus, a reaction of diacetonide 2 with aqueous
TBHP (2 equiv) in water in the absence of catalyst 1 at re-
flux resulted in deprotection of terminal acetonide to pro-
duce the corresponding diol 2a in good yield (70%, 10 h,
Scheme 1). Interestingly, in the above reaction the inter-
nal acetonide group remained intact and only the terminal
acetonide group was deprotected.
HO
HO
O
OH
MoO2(Et2NCS2)2 (1, 10 mol%)
TBHP, H2O, reflux ,10 h
O
O
O
O
2a, 60%
MoO2(Et2NCS2)2 (1)
H2O, reflux, 20 h
O
O
no reaction;
starting material
recovered
OH
O
These experiments (Scheme 1) indicated that TBHP is re-
sponsible for the deprotection of the terminal acetonide
group, presenting the opportunity to carry out deprotec-
tion of terminal acetonides without using any metal cata-
lysts. Herein, we describe a useful method for the
deprotection of terminal acetonide groups by using aque-
ous TBHP in an aqueous medium.
2
TBHP, H2O, reflux, 10 h
2a, 70%
Scheme 1 Reaction of bisacetonode 2 with reagent 1 and TBHP
added to a to a well-stirred mixture of acetonide derivative
(1 mmol) in t-BuOH–H2O (1:1, 4 mL) and the reaction
mixture was refluxed until completion of reaction (moni-
tored by TLC). Upon work up the corresponding diol was
isolated.
As can be seen in the following section, a wide range of
terminal acetonide derivatives was deprotected regiose-
lectively and chemoselectively, using aqueous TBHP
(70%), to generate the corresponding diols in good to
moderate yields. This deprotection is performed by using
aqueous t-BuOH as the solvent at reflux conditions. In a
typical experiment, aqueous TBHP (70%, 2 mmol) was
Table 1 Deprotection of Terminal Acetonide Using TBHP
Entry
Substrate
Time (h)a
Product
HO
Yield (%)b
O
O
O
O
O
O
HO
OH
OH
1
10
70
O
O
2
2a
O
HO
O
O
O
O
O
HO
OTBDMS
OTBDMS
2
10
71
O
O
3
3a
HO
O
O
O
O
O
HO
O
O
Ph
Ph
O
Ph
Ph
3
4
20
53c,d
O
O
Ph
Ph
4
4a
HO
O
O
O
O
HO
HO
8
83
O
O
HO
O
O
5
5a
Synlett 2011, No. 6, 821–825 © Thieme Stuttgart · New York

LETTER
Deprotection of Terminal Acetonides
823
Table 1 Deprotection of Terminal Acetonide Using TBHP (continued)
Entry
5
Substrate
Time (h)a
Product
Yield (%)b
O
O
HO
HO
O
O
12
63e
O
O
MOMO
MOMO
O
O
O
6
6a
O
HO
O
O
HO
6
12
65e
O
O
O
O
O
O
7
7a
HO
O
O
O
O
HO
7
8
12
56c
O
O
O
O
O
O
8a
8
9
O
O
O
HO
O
O
9
64
O
HO
O
O
9a
O
HO
O
O
O
O
O
HO
O
O
9
10
56
O
O
10
11
10a
HO
O
O
O
O
HO
10
11
12
74d,e
BnO
O
BnO
O
O
O
O
11a
O
O
HO
O
O
O
HO
OH
OH
9
72
O
O
O
O
12
12a
a Heated at reflux.
b Isolated yields.
c TBHP (excess).
d Yield based on the recovery of the starting material (10%).
e TBHP (3 equiv).
The results summarized in Tables 1 and 2 reveal the scope the corresponding diol 2a in 70% yield (entry 1, Table 1).
and selectivity of the present methodology. The bisace- The acetonide derivative of D-mannose 3 possessing the
tonide derivative of D-mannose 2 was reacted with aque- acid-labile TBDMS group underwent a clean deprotection
ous TBHP (70%) at reflux in t-BuOH–H2O (1:1) to afford to produce the corresponding diol 3a in good yield (70%,
Synlett 2011, No. 6, 821–825 © Thieme Stuttgart · New York

824
M. R. Maddani, K. R. Prabhu
LETTER
10 h, entry 2, Table 1). Similarly, D-mannose derivative 4 groups in aqueous medium. A number of acid-labile pro-
containing a terminal acetonide and O-trityl ether reacted tecting functional groups and common functional moi-
with TBHP to produce the diol 4a, in which the O-trityl eties were found to be unaffected under the conditions
group was unaffected (entry 3, 53%,29 Table 1). The employed for the present deprotection. Additionally, the
bisacetonide derivative of D-glucose 5 furnished the cor- present method is selective for terminal acetonides and in-
responding triol 5a in 83% yield (entry 4, Table 1). Simi- ternal acetonides are unaffected during the reaction.
larly, D-glucose derivatives containing acid-sensitive
Table 2 Deprotection of Terminal Acetonide in Acyclic Systems
Using TBHP
groups such as methoxymethyl (6) and propargyl ether (7)
furnished the corresponding diols 6a and 7a in good
yields (63% and 65%, respectively, entries 5 and 6,
Table 1) with the methoxymethyl ether and propargyl
ether being inert under the reaction conditions.
Entry Substrate
Time Product
(h)a
Yield
(%)b
OMe
O
OMe
O
Bisacetonide derivatives containing an allyl ether 8 pro-
duced the corresponding diol 8a under the reaction condi-
tions without affecting the allyl ether group (entry 7,
Table 2). 1,2:3,5-Di-O-isopropylidene-a-D-xylofuranose
(9) produced the corresponding diol 9a in good yield
(64%, entry 8, Table 1). Similarly, the lactone group in
HO
O
HO
O
O
HO
1
10
61
64
66c
O
HO
O
O
13
13a
2,3:5,6-di-O-isopropylidene-D-gulonic-g-lactone
(10)
OMe
OMe
O
O
O
O
HO
HO
was stable under the reaction conditions, furnishing the
corresponding diol 10a in moderate yield (entry 9, 56%,
Table 1). The cyclopropane ester group in 1130 survived
the reaction conditions to furnish the corresponding diol
11a in moderate yield (entry 10, 74% Table 1).31 The
bisacetonide derivative containing a five-membered lac-
tone (12, entry 11, Table 1), produced the corresponding
diol 12a in good yield (72%).
O
O
O
O
2
3
11
10
HO
HO
14
14a
OH
OH
HO
O
HO
O
O
HO
HO
O
O
O
The deprotection of terminal acetonides seems to be gen-
eral as can be seen from Table 2. A variety of acyclic sys-
tems containing terminal acetonide groups was subjected
to the present deprotection strategy. D-Glucose deriva-
tives containing bisacetonide protective groups (13 and
14) were prepared from D-glucono-1,5-lactone as de-
scribed by Chittenden32 and the ester functionality of 13
was reduced using lithium aluminium hydride to afford
the diol 15. Similarly, acetonides containing acid-labile
groups such as TBDPS (16) and N-Boc (17) groups were
prepared by known methods.33
15
16
17
15a
Ph
Si
Ph
Ph
Si
Ph
O
HO
4
5
12
12
72d
76d
O
O
O
HO
16a
HO
O
HO
O
NHBoc
NHBoc
17a
Bisacetonide 13, when subjected to the deprotection pro-
tocol, furnished the corresponding triol 13a in good yield
a Heated at reflux.
b Isolated yields.
(61%, entry 1, Table 2). In this reaction, as expected the c TBHP (3 equiv).
d TBHP (excess).
terminal acetonide was deprotected to furnish the corre-
sponding triol 13a, whereas the internal acetonide and es-
ter groups were inert. Similarly, substrate 14 furnished the
corresponding triol 14a in good yield (64%, entry 2,
Table 2). The acetonide derivative containing free diols
such as 15 underwent a clean deprotection to furnish the
product 15a in 66% yield (entry 3, Table 2). In the same
way, acetonide derivatives 16 and 17 containing TBDPS
and N-Boc protecting groups produced the corresponding
diols 16a (72%) and 17a (76%) in good yields (entry 4 and
General Experimental Procedure for the Deprotection of Ace-
tonides
To a suspension of acetonide substrate (1 mmol) in t-BuOH–H2O
(1:1; 4 mL) was added TBHP (70% solution in H2O, 2 mmol). The
mixture was refluxed until the completion of reaction (monitored by
TLC). The solvent was evaporated completely. The residue was pu-
rified by column chromatography on silica gel to furnish the corre-
5, Table 2). Further work is under way to elucidate the re- sponding product in good yield.
action mechanism for the above reaction.
In conclusion, employing aqueous TBHP (70%) we have
developed a useful methodology for the regioselective
and chemoselective deprotection of terminal acetonide
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 6, 821–825 © Thieme Stuttgart · New York

LETTER
Deprotection of Terminal Acetonides
825
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