Nafion-H mediated selective deprotection of terminal isopropylidene acetals and trityl ethers. Application in the synthesis of a substituted piperidone

Article abstract of DOI:10.1016/j.tetlet.2006.10.067

A facile chemoselective hydrolysis of terminal isopropylidene acetals has been achieved in good to excellent yields within 2-4 h using Nafion-H in methanol at ambient temperature. This procedure has been employed to synthesize a substituted piperidone der

Full text of DOI:10.1016/j.tetlet.2006.10.067

Tetrahedron Letters 47 (2006) 9117–9120
Nafion-H mediated selective deprotection of terminal
isopropylidene acetals and trityl ethers. Application in the
synthesis of a substituted piperidone
Girish K. Rawal, Shikha Rani, Amit Kumar and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 20 August 2006; revised 3 October 2006; accepted 13 October 2006
Available online 7 November 2006
Abstract—A facile chemoselective hydrolysis of terminal isopropylidene acetals has been achieved in good to excellent yields within
2–4 h using Nafion-H in methanol at ambient temperature. This procedure has been employed to synthesize a substituted piperidone
derivative. Similarly, trityl ethers are also deprotected to the corresponding alcohols in excellent yields using Nafion-H at room
temperature.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Similarly, the benefits of trityl ethers as protecting
groups in organic synthesis, especially in carbohydrate
chemistry1 are also well known and the reagents
employed for their deprotection include formic acid,6a
acetic acid,6b trifluoroacetic acid,6c 1% methanolic solu-
tion of iodine,6d BCl3,6e Yb(OTf)3,6f AlClEt3,6g ZnBr2,6h
ceric ammonium nitrate6i and CBr4–MeOH.6j Recently,
The usefulness of isopropylidene acetals (or acetonides)
as protecting groups for 1,2- and 1,3-diols in organic
synthesis, in general, and in carbohydrate and nucleo-
side chemistry, in particular, has been well documented.1
Various reagents used for the regioselective hydrolysis of
terminal isopropylidene acetals in the presence of
internal ones include both protic and Lewis acids. The
protic acids employed include aq HCl,2a aq HBr,2b
60% aq CH3CO2H,2c 8% H2SO4 in MeOH,2d Dowex
H+ in MeOH:H2O (9:1),2e trifluoroacetic acid,2f cam-
phorsulfonic acid,2g and p-TsOH,2h whereas the Lewis
acids include CuCl2 Æ2H2O in EtOH,3a Zn(NO3)2 Æ
6H2O,3b Yb(OTf)3 ÆH2O,3c CeCl3 Æ7H2O/(COOH)2,3d
La(NO3)3 Æ6H2O3e and VCl3.3f Clearly, some of these
acids are strong enough to allow non-selective hydroly-
sis leading to lower yields of the desired products, partic-
ularly in the presence of water. In addition to this, a
neutral method employing thiourea4 has been reported
for this purpose. A few supported reagents such as
FeCl3 Æ6H2O/SiO2,5a NaHSO4 ÆSiO2,5b PMA/SiO2,5c
5% trifluoroacetic acid7a and NaHSO4 adsorbed on
7b
column silica gel have also been reported for the depro-
tection of trityl ethers. More recently, we reported
HClO4 supported on silica gel8 for the selective depro-
tection of terminal isopropylidenes and trityl ethers.
Nafion-H (a perfluorinated resin sulfonic acid) has
attracted significant attention9 and has been useful in
various organic transformations as a solid catalyst. We
have also reported a few organic transformations cata-
lyzed by Nafion-H10 such as acetylation of alcohols,10a
Mukaiyama aldol condensations10b and deprotection
of tert-butyldimethylsilyl ethers.10c Due to the ease of
handling and reusability of Nafion-H and our continued
interest in developing new methods in carbohydrate
chemistry,11 we now report that Nafion-H in methanol
effectively deprotects terminal isopropylidene groups
and trityl ethers at room temperature in good to excel-
lent yields. Under these conditions several functional
groups such as benzoyl, p-nitrobenzoyl (PNB), tosyl
and TBDMS ethers remained unaffected. Our results
are summarized in Tables 1 and 2. Interestingly, methyl
4-acetoxy-2,3-di-O-benzyl-6-O-trityl glucopyranose 44
5d
5e
polymer supported FeCl3 and H2SO4 ÆSiO2 have
also been reported to address the issues of ease of
work-up and environmental factors.
*
Corresponding author. Tel.: +91 512 2597169; fax: +91 512
2597436; e-mail: vankar@iitk.ac.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.067

9118
G. K. Rawal et al. / Tetrahedron Letters 47 (2006) 9117–9120
Table 2. Deprotection of trityl ethers
Table 1. Deprotection of isopropylidene acetals
Diisopropylidene
Product 1,2-diol
Time
(h)
Yield
(%)
Trityl ether
Product
Time Yield
(h)
(%)
OTr
OH
O
HO
O
O
HO
O
O
O
BnO
BnO
BnO
BnO
O
O
7
90
BnO
3918a
BnO
OMe
OMe
O
O
RO
RO
2015b
4918b
1: R = OH15a
2: R = Bn15c
3: R = Allyl15d
4: R = Ms15e
5: R = Ts15e
3
3
3
2.5
3
3
4
2
4
96
94
91
87
88
96
89
68
80
2115c
2215d
2315f
245b
255b
268
OTr
OH
O
O
HO
BnO
HO
BnO
9
12
10
92
86
75
6: R = Bz8
BnO
5018d
BnO
4018c
OMe
OMe
7: R = PNB8
8: R = TBDMS5a
9: R = OAc15h
2715g
2815i
OH
OTr
O
O
HO
HO
O
O
AllO
BnO
AllO
BnO
O
O
OR
OR
BnO
BnO
OMe
O
OMe
4118c
518
O
O
O
O
OTr
OH
10: R = Ac16a
11: R = Allyl16b
2916a
3016b
3
3
92
83
O
PNBO
BnO
PNBO
BnO
BnO
BnO
OMe
52
OMe
O
O
O
O
42
O
O
O
OMe
OMe
OR
OR
OH
OH
OTr
HO
O
O
O
MsO
BnO
MsO
BnO
14
82
12: R = H17a
13: R = Ts8
14: R = Bz8
3117a
328
338
34
3
3
2
2.5
4
5
2
3.5
82
84
88
86
90
92
74
92
BnO
538
BnO
438
OMe
OMe
15: R = Ms17a
16: R = Ac
35
OTr
OAc
17: R = Bn17b
18: R = TBS17c
19: R = PNB
36
3717c
38
O
O
AcO
BnO
HO
BnO
9
85
BnO
4418e
BnO
OMe
OMe
54
underwent migration12 of the acetyl group from C-4- to
C-6.
OTr
OH
Our current interest11d,13 in the synthesis of glycosidase
inhibitors and other biologically important compounds
led us to explore the utility of this method in the synthe-
sis of piperidinone derivative 61 which is a potential
glycosidase inhibitor.14 Treatment of gluconolactone
derived compound 17 with Nafion-H gave the corre-
sponding diol 36 (see the Supplementary data for exper-
imental details and data), which on subsequent
treatment with sodium periodate followed by reductive
amination with benzylamine led to the open chain
amino ester 58. The internal acetonide moiety was then
cleaved with 0.5% HCl in methanol and subsequent
treatment with Hunig’s base in CH2Cl2 readily gave
the cyclized piperidinone derivative 59, which was
acetylated to give diacetyl derivative 60 in good yield.
Debenzylation followed by acetylation gave triacetoxy-
piperidinone 61 (Scheme 1).
4
4
4
4
16
15
88
89
OAc
45
OAc
55
OTr
OH
OBz
OBz
46
56
OTr
OTr
OH
OH
18
16
91
90
47
57
OTr
OH
OH
OH
48
57
See Refs. 8 and 18.

G. K. Rawal et al. / Tetrahedron Letters 47 (2006) 9117–9120
9119
O
O
O
O
O
O
O
O
O
OMe
(b), (c)
(a)
O
OMe
OMe
OBn
OBn
OH
OBn
HO
BnHN
O
58
17
36
OAc
OAc
OH
AcO
OBn
AcO
OAc
O
HO
OBn
O
(g), (h)
(f)
(d), (e)
N
O
N
N
Bn
Bn
Bn
60
61
59
Scheme 1. Reagents and conditions: (a) Nafion-H, methanol, rt, 5 h, 92%; (b) NaIO4, CH3CN:H2O (3:1), rt; (c) BnNH2, NaCNBH3, AcOH, MeOH,
two steps 61%; (d) 0.5% HCl in methanol; (e) Hunig’s base, DCM, two steps 62%; (f) Ac2O, Et3N, DCM 94%; (g) 10% Pd/C, ammonium formate,
MeOH and (h) Ac2O, Et2N, DCM two steps 72%.
Since Nafion-H is cheap, easy to handle and reusable
and the work-up merely involves decantation followed
by purification, it would be expected that this method
would find application in organic synthesis.
and the combined organic extract was concentrated
and the residue purified by column chromatography to
give pure detritylated products.
Acknowledgement
2. General experimental procedures
We thank the Department of Science and Technology,
New Delhi for financial support (Grant no. SP/S1/G-
21/2001). Three of us (GKR, SR, AK) thank the Coun-
cil of Scientific and Industrial Research, New Delhi for
Senior Research Fellowships.
Nafion-H was prepared from Nafion-K by the following
procedure:9h Nafion-K (10 g) was treated with boiling
deionized water (30 mL) for 2 h and filtered. The resin
was then stirred in 20–25% nitric acid (40 mL) for
4–5 h at room temperature and filtered. This acid
treatment was repeated three to four times to obtain
maximum exchange of potassium ions in the resin with
protons. The resin was finally washed several times with
deionized water until the filtrate was neutral to litmus. It
was then dried under vacuum at 105 °C for 24 h. This
Nafion-H was stored in an air-tight vial and used as
such throughout.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.10.067.
2.1. Deprotection of isopropylidene acetals
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