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SHORT PAPER
Lewis Acid-Mediated Selective Removal of N-tert-Butoxycarbonyl Protective
#
Group (t-Boc)
D. Subhas Bose,* V. Lakshminarayana
Organic Chemistry Division III
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax: +91-40-7173387/7173757; E-mail: root@csiict.ren.nic.in
Received 29 April 1998; revised 10 July 1998
(
AlCl ) in CH Cl at room temperature (Scheme). During
3 2 2
Abstract: A simple and efficient method for the selective cleavage
of N-Boc protective groups from amines employing Lewis acid alu-
minum chloride, is described. The scope of this procedure is ex-
plored for the deprotection of a variety of amines including amino
acid derivatives.
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the studies on â-lactam antibiotics, Tsuji and coworkers
reported that concurrent deprotection of the carboxyl ester
benzyl) and amino protecting group (t-Boc) was ob-
served by using aluminum chloride (3.0 equiv) and ani-
sole (3.0 equiv) in CH Cl /MeNO at room temperature.
(
Key words: aluminum chloride, t-Boc carbamates, selective cleav-
2
2
2
age
However, to our surprise, there is no report on the gener-
ality of this procedure. Moreover, this method overcomes
many of the disadvantages associated with Lewis acids re-
ported so far, e.g. some of them are restricted to sec-N-
Boc amines or requires longer reaction times etc.
Developing mild and selective methods for the protection
of functional groups and the deprotection of the protected
derivatives continues to be a significant aspect in the syn-
thetic chemistry of polyfunctional molecules including
the total synthesis of natural products. Thus a large variety
of protective groups have been developed along with nu-
merous methods for their removal.
Scheme
Carbamates are widely used as a protective group during
the synthesis of amino acids, peptides and other natural The results illustrated in the Table indicate that the reac-
1
products. Among the various amine protecting groups, tion is successful for a variety of t-Boc protected primary
the tert-butoxycarbonyl (t-Boc) group is one of the most and secondary amines. Notably, ester, ether linkages, acid
frequently used in organic synthesis due to its stability to and base-sensitive protecting groups present in the mole-
mild acidic and basic conditions and its ease of removal cule, were found to be resistant under the conditions em-
under specific conditions.
ployed. It should be emphasized that excellent
chemoselectivity was also observed in the presence of
tert-butyldimethylsilyl (TBS) and acetate groups (entry
1g). N-Boc derivatives bearing ÔαÕ stereogenic centers af-
ford the corresponding amines with complete retention of
the original configuration. Finally, removal of t-Boc in
the presence of benzyl carbamate (entry 1i), was achieved
with high selectivity.
Removal of the t-Boc group is conveniently carried out
with the strong acid trifluoroacetic acid (TFA) either neat
or in combination with CH Cl , although deprotection
with other mineral acids has been reported. In some in-
stances Lewis acids have also been used, e.g. BF ¥OEt .
Stafford et al. recently reported a method for the selective
removal of one Boc group from tert-butylimidodicarbon-
2
2
2
3
1
1
4
3
2
ates, and N-Boc substituted amides, employing magne- In summary, a mild and efficient protocol for the cleavage
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sium perchlorate. Less frequently, non-acidic conditions of t-Boc group has been developed. We believe that the
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have been developed. In some cases, such as with elec- present procedure has potential application in solid-phase
tron rich substrates, thermolytic conditions have also been peptide synthesis due to its high chemoselectivity, effi-
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used. Recently Wensbo has described that N-Boc protect- ciency and simplicity.
ed indoles and hetero-condensed pyrroles could be depro-
tected simply by adsorbing the substrate onto silica gel, Deprotection of tert-Butylcarbamates 1aÐj; General Procedure
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2
To a solution of t-Boc derivative (1.0 mmol) in anhyd CH Cl2
followed by gentle heating under reduced pressure.
(5 mL) in a 25 ml round-bottomed flask equipped with a magnetic
In the course of our studies on the synthesis of biological-
ly interesting natural products, we required a mild and ef- in portions at 0¡C. The suspension was vigorously stirred at r.t. for
ficient method for the removal of a t-Boc group from DC-
1 precursor of type 1a. Herein we report our new find-
ings that N-Boc derivatives can be selectively deprotected
stirrer under N atmosphere, was added AlCl (133 mg, 1.0 mmol)
2
3
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the specified time (Table). After completion of the reaction (moni-
tored by TLC; eluent: hexane/EtOAc, 1:9), it was neutralized with
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aq NaHCO solution and the product was extracted with EtOAc
3
(
30 mL). The organic phase was separated, dried (Na SO ), filtered
2 4
by treatment with the Lewis acid, aluminum chloride
and the solvent was removed in vacuo to afford the crude product
Synthesis 1999, No. 1, 66Ð68 ISSN 0039-7881 © Thieme Stuttgart · New York