Tetrahedron Letters 49 (2008) 6962–6964
Tetrahedron Letters
A mild Boc deprotection and the importance of a free carboxylate
a
Ali Thaqi a, Adam McCluskey b, , Janet L. Scott
*
a Centre for Green Chemistry, Monash University, Wellington Road, Clayton, Victoria 3800, Australia
b Chemistry, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a facile and rapid removal of Boc protecting groups using microwave heating in H2O, with
deprotection only requiring a free carboxylic acid group in the starting material. Unlike previous
approaches, no additional reagents are required.
Received 8 August 2008
Revised 26 August 2008
Accepted 8 September 2008
Available online 11 September 2008
Ó 2008 Published by Elsevier Ltd.
The protection–deprotection cycle associated with the synthe-
sis of modified amino acids and peptides has been crucial to yield
improvement and ease of synthesis. With Boc-protection, of amino
acids and amines in general, the installation of the protecting
group is typically by addition of Boc-anhydride; and deprotection
via acidic means such as TFA and HCl.1–3 Whilst from a green
chemistry perspective, the addition of two additional steps is con-
trary to the ‘12 principles of green chemistry’, it does facilitate
rapid access to materials that would otherwise be generated in a
significantly less efficient, and hence in a less green manner.4 How-
ever, the use of acidic deprotection strategies means that such
approaches are not suited to acid-sensitive substrates and alter-
native protecting groups are required. Notwithstanding this, our
group has had a long held interest in rapid access to focused
libraries of biologically active molecules, in particular, protein
phosphatase 1 and 2A5–10 and dynamin GTPase inhibitors,11–13
and it is this access rather than the synthetic elegance that has typ-
ically been our focus. In our most recent effort, we wished to exam-
ine the effect of the 5,6-ethyl bridge and oxygen atom of the THF
ring associated with cantharidin (1) and norcantharidin (2) to
determine their roles, if any, in the inhibition of protein phospha-
tases 1 and 2A and their potential role in the associated anticancer
Microwave quick heating is significantly beneficial in accelerating
a number of conventional heated chemistries with enhanced selec-
tivity, improved reaction rates, milder and solvent-free reaction
conditions and formation of cleaner products with associated ease
of manipulation. These are facets of green chemistry.
In this work, we report our observations of an extremely mild,
TFA- and HCl-free method for the rapid and highly efficient Boc-
deprotection of amino acids, dipeptides and of related compounds.
The syntheses of 4 with various amino acids were conducted
under standard thermal conditions, however as analogues of 3
had been prepared in good to high yield under microwave condi-
tions (data not shown, using a Smith Synthesiser from Personal
Chemistry), we attempted to apply microwave heating to the syn-
thesis of 4 via a Boc-protected pyrrole diacid. Interestingly, we
observed, in those examples where a Boc protecting group was
required, that in H2O and under microwave conditions, recovery
of only the free amino substituted analogue, with quantitative
Boc group removal in as little as 2–3 min. Intrigued by this obser-
vation, and given the typical use of harsher conditions with TFA
and HCl, we sought to explore the utility of microwave heating
in H2O as a mild and green approach to removing a Boc group.
The outcome of a systematic evaluation of several Boc-protected
amino acids is shown in Table 1.
effects for this class of compounds. In the synthesis of these
D-5,6-
ethyl analogues, such as (3R,6S)-tetrahydrofuro[3,4-c]furan-1,3-
dione (3), we investigated the possibility of conducting key steps
using rapid microwave heating, especially for the preparation of
a focused library of amino acid substituted imides (4).
The data in the Table clearly show that the Boc-deprotection in
H2O is a remarkably facile process, but only in those instances in
which the starting protected amino acids possessed a free carbox-
ylate moiety (entries 1–7). Disappointingly, the deprotection of
Microwave heating has added to the organic and medicinal
chemists repertoire of techniques to impart the energy necessary
to effect a synthetic transformation.14–17 Microwaves heat reac-
tants much more quickly than conventional means and many syn-
theses that usually take hours are now conducted in minutes.
Boc-L-Glu (entry 8) proceeded predominately with cyclisation to
the corresponding b-lactam. This is likely due to the favourable
length of the amino side chain, and whilst an unwanted outcome,
knowing the limitation of this technology is also crucial for deter-
mining its widespread utility. Also of note is that esterification of
the free carboxylate (entry 9) followed by microwave irradiation
in H2O, under the same conditions as those used in entries 1-7, re-
sulted in recovery of starting material only, suggesting that the free
carboxylic acid is important in the removal of the Boc group (this
* Corresponding author. Tel.: +61 2 4921 6486; fax: +61 2 4921 5472.
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.09.027