Mild and facile procedure for clay-catalyzed acetonide protection and deprotection of N(Boc)-amino alcohols and protection of 1,2-diols

Article abstract of DOI:10.1016/j.tetlet.2004.05.079

The application of clay as a catalyst for acetonide protection of N(Boc)-amino alcohols and 1,2-diols to obtain good to excellent yields of the acetonide derivatives is described. Acetonide deprotection to obtain the parent amino alcohol was carried out using a similar catalyst in the presence of methanol as solvent. The reaction takes place at room temperature within 2h to give the parent amino alcohol in quantitative yield keeping the N(Boc) group intact.

Full text of DOI:10.1016/j.tetlet.2004.05.079

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5395–5398
Mild and facile procedure for clay-catalyzed acetonide
protection and deprotection of N(Boc)-amino
alcohols and protection of 1,2-diols
Nadim S. Shaikh, Santosh S. Bhor, Anil S. Gajare, Vishnu H. Deshpande
and Radhika D. Wakharkar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 16 February 2004; revised 10 May 2004; accepted 17 May 2004
Abstract—The application of clay as a catalyst for acetonide protection of N(Boc)-amino alcohols and 1,2-diols to obtain good to
excellent yields of the acetonide derivatives is described. Acetonide deprotection to obtain the parent amino alcohol was carried out
using a similar catalyst in the presence of methanol as solvent. The reaction takes place at room temperature within 2 h to give the
parent amino alcohol in quantitative yield keeping the N(Boc) group intact.
Ó 2004 Elsevier Ltd. All rights reserved.
The acetonide functionality is frequently used as a
protecting group for 1,2-amino alcohols and 1,2-diols in
carbohydrate and peptide chemistry due to its stability
using DMP and PPTS (pyridinium p-toluenesulfonate)
6
at ambient temperature, while dil HCl, TFA (trifluoro-
2
1
acetic acid) and methanolic p-TsOH are the reagents
generally used for the deprotection of acetonides to
obtain the parent diol or amino alcohol.
to mildly acidic as well as basic conditions. During the
course of a synthetic sequence, it usually becomes nec-
essary to protect free hydroxyl or amino groups. Many
syntheses fail because the protecting groups give poor
Several methods are available for the protection of 1,2-
diols as isopropylidenes in sugars and for 1,2-amino
2
results or are difficult to cleave. Hence, in effecting
1
efficient conversion of functional groups present in the
side chain of 1,2-amino alcohols and 1,2-diols, appro-
priate protection of the amine and alcohol functionality
is highly desirable.
alcohols as oxazolidine derivatives. However, the
development of mild and efficient methods is still re-
quired. Recently, in the course of our studies directed
7
towards the synthesis of 4-borono-L-phenylalanine
compound 2 was an important intermediate. The ace-
tonide protection of N(Boc)-protected amino alcohol 1
to give the protected derivative of phenylalanol 2 (as
Classical acetonation of diols in carbohydrates has been
achieved using acetone with various mineral acids, such
as concd sulfuric acid or fuming HCl or phosphoric
acid, in the presence or absence of copper(II) sulfate or
8
shown in Scheme 1) was unsatisfactory with BF
p-TsOH and CuSO
3
2
ÆOEt ,
4
in the presence of acetone and/or
3
zinc chloride. The use of 2,2-dimethoxypropane (DMP)
DMP. A decomposed material was obtained in the first
case whereas a mixture of products or a low yield of 2
was observed in the latter case.
in the presence of CSA (camphorsulfonic acid) or a
catalytic amount of p-TsOH in combination with an
appropriate solvent such as DMF has been employed
for the conversion of 1,2-diequatorial hydroxyl groups
4;5
of carbohydrates into isopropylidene derivatives. 1,2-
Amino(Boc) alcohols can be protected as oxazolidines
I
I
Clay catalyst
DMP, R. T.
O
O
O
N
H
OH
N
O
Keywords: Clay catalyst; Acetonide; Protection; Deprotection; Amino
alcohols; Diols.
O
1
2
*
Corresponding author. Tel./fax: +91-20-25893614; e-mail: rdw@
dalton.ncl.res.in
Scheme 1. Clay-catalyzed protection of amino alcohol 1.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.079

5396
N. S. Shaikh et al. / Tetrahedron Letters 45 (2004) 5395–5398
Table 1. Clay-catalyzed acetonide protection (A) and deprotection (B)
Entry
1
Substrate
Product
Yield (%) A
Yield (%) B
98
9
5
O
O
NH
OH
O
N
O
a
b
c
a
91
93
15
95
97
b
O
3
4
c
20
9
4
95
10
c
c
I
I
0
d
d
9
2
98
2
3
4
O
NH
OH
O
N
O
O
1
O
2
MeOOC
NH
MeOOC
O
N
O
S
85
82
82
81
O
OH
SH
5
O
O
6
MeOOC
NH
MeOOC
O
O
N
7
O
O
8
a
b
c
â
Using EPZG .
Using natural kaolinitic clay.
Without catalyst for 24 h.
With recycled catalyst.
d
Recently, clay minerals have become available for or-
9
ganic syntheses as heterogeneous acid catalysts. Com-
presence of DMP to give 95% of the corresponding
protected compound within 2 h. Natural kaolinitic clay
and envirocat EPZG also showed comparable results
in both acetonide protection and deprotection. In a
blank experiment (without catalyst), after 24 h, only a
poor yield (Table 1, entry 1) of the desired protected
compound (15%) was obtained. The methyl ester of
â
mercially available Montmorillonite K 10 clay has been
used successfully in many important organic transfor-
mations. Experimental procedures using clay are simple
with regard to treatment and removal of the catalyst
because of its non hygroscopic and heterogeneous nat-
ure. As the application of clay in Lewis acid catalyzed
N(Boc) protected L-serine demonstrated excellent yields
10
reactions is of ongoing interest to us, we applied
Montmorillonite K 10 clay in acetone, under reflux to
convert 1 into 2. Only a negligible amount of 2 was
isolated, however, when acetone was replaced with ex-
cess DMP, complete conversion of 1 was observed, and
compound 2 was isolated as the only product in excel-
lent yield (95%).
for both protection and deprotection (Table 1, entry 3).
Such a fully protected serine derivative has many po-
tential synthetic applications including the preparation
11a
of valuable unnatural a-amino acids.
rotation for 6 was in good agreement with the reported
The optical
value indicating no loss in optical purity during the
transformation. Similarly the methyl ester of N(Boc) L-
11b
cysteine gave thiazolidine 8 (entry 4). In all the cases
studied, protection and deprotection occurred smoothly
keeping the N(Boc) group intact. However, acetonide
In a typical experiment derivative 1 was stirred in a
mixture of dry acetone and DMP (3 equiv) in the pres-
ence of Montmorillonite K 10 clay (20% w/w) to afford
protection of free 1,2-amino alcohols such as
alanol and ethanolamine failed.
L-phenyl-
7
5% of the desired product 2 in 3 h.
Selective isopropylidene deprotection using methanolic
p-TsOH at room temperature was incomplete even after
A similar strategy was applied for the acetonide pro-
tection of 1,2-diols to convert them into the corre-
sponding isopropylidene ketals (Scheme 2).
1
4 h. Furthermore, when the reaction mixture was ref-
luxed for 1h in methanolic p-TsOH, partial deprotection
of the N-Boc group was observed. The clay catalyst was
examined for selective cleavage of acetonide 2 in order
to obtain 1. Using methanol as solvent, the reaction
proceeded to completion within 2 h to give compound 1
Various 1,2-diols were studied and the results are sum-
marized in Table 2. The 1,2-diol of styrene, when stirred
with DMP in the presence of the clay catalyst (40%
10f
in quantitative yield without affecting the Boc group.
These results prompted us to develop a simple catalytic
system for different substrates for protection (A) and
deprotection (B) as summarized in Table 1.
R
1
R2
R1
R2
MeO
OMe
O
O
HO
OH
Mont K 10, r.t ., 2 h
As a model, N(Boc) protected ethanolamine underwent
acetonation using Montmorillonite K 10 clay in the
Scheme 2. Montmorillonite K 10 catalyzed protection of 1,2-diols.

N. S. Shaikh et al. / Tetrahedron Letters 45 (2004) 5395–5398
Table 2. Montmorillonite K 10 catalyzed acetonide protection of 1,2-diols
5397
a
b
Entry
Substrate
Product
Yield (%)
OH
O
OH
OH
O
9
1
87
OH
O
2
3
O
80
84
1
0
OH
O
O
OH
O
O
11
OH
OH
O
O
4
5
92
74
12
O
OH
O
13
OH
O
O
OH
OH
OH
HO
H
6
7
8
HO
H
14
90
O
O
HO
O
OH
OH
O
15
O
O
c
O
O
52
HO
OH
HO
OH
OH
OH OH
O
OH
O
d
60
HO
O
OH OH
O
OH
16
a
b
c
All the products were characterized by spectral analysis.
Isolated yields.
Reaction time of 8 h.
d
The triacetonide (25%) was also isolated.
w/w), gave the corresponding isopropylidene derivative
(Table 2, entry 1) in 87% isolated yield. As shown in
Short reaction times, high yields and simple work up
procedures are the main features of this method.
9
Table 2, satisfactory yields were obtained in all the cases
including cyclic, linear aliphatic and sugar diols. In the
case of D-mannitol along with the diacetonide (Table 2,
entry 8) triacetonide formation was observed with 25%
isolated yield.
Acknowledgements
N.S.S. and A.S.G. are grateful to CSIR, New Delhi, for
research fellowships.
Unfortunately the reaction did not work for D-glucose
even after heating for 12 h. Also, the reaction failed in
the case of catechol. Deprotection of the acetonides of
1
,2-diols was also studied and it was found that the
substrates were stable under these conditions (clay in
methanol) even at reflux temperature.
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L-phenylalanine: Unpublished results from our