DOI: 10.1002/chem.201501799
Communication
&
Protecting Groups
MgI2-Mediated Chemoselective Cleavage of Protecting Groups:
An Alternative to Conventional Deprotection Methodologies
MathØo Berthet,[a] Florian Davanier,[a] Gilles Dujardin,[b] Jean Martinez,[a] and
Isabelle Parrot*[a]
A literature survey reveals that, due to their difficult selective
Abstract: The scope of MgI2 as a valuable tool for quanti-
removal, Fmoc/methyl or ethyl ester duos have only been mar-
tative and mild chemoselective cleavage of protecting
ginally investigated in orthogonal protection strategies.[4–7] Be-
groups is described here. This novel synthetic approach
sides tediously efficient or racemizing procedures using CaCl2,
expands the use of protecting groups, widens the concept
or AlCl3/DMA,[8] organotins seem to be the most reliable re-
of orthogonality in synthetic processes, and offers a facile
agents.[4] So, trimethyltin hydroxide (TMTOH), initially explored
opportunity to release compounds from solid supports.
by O. Mascaretti et al.,[9] and further applied at a specific point
in a total synthesis reaction,[10] was described to cleave ethyl/
methyl esters without affecting the Fmoc PG in good yields
Protecting groups (PGs) have had a tremendous positive
impact on the art of biomolecule synthesis. In particular, the
exploitation of the orthogonal stability principle allows condi-
tion-dependent elimination of defined PGs, Fmoc/tBu, or Boc/
Bzl, which are probably the most popular couples to illustrate
this concept. Several orthogonal deprotection processes have
been described,[1–3] though an examination of the literature
still highlights some gaps in chemoselective flexibility or limita-
tions due to harsh cleavage conditions. Indeed, the develop-
ment of a mild, clean, and selective method for deprotection
would be a welcome synthetic strategy.
with occasional slight epimerization. In Fmoc-free syntheses,
ethyl, isopropyl, or allyl esters were partially susceptible to de-
protection in the presence of TMTOH, whereas Boc and Alloc
remained stable. In a more general way, a wide range of mild
methods using Lewis acids to remove PGs were advanced to
overcome basic racemizing conditions, side reactions inherent
to strong acidolytic deprotections, catalytic hydrogenolysis, or
even palladium-catalyzed PG cleavages.
Then, mild non-transition-metal-assisted deprotection sys-
tems of the most usual PGs of amines (trityl,[11,12] Z,[13–15]
Boc[14,16–18]) or carboxylic acids[19] (tert-butyl,[18,20–23] benzyl[24–28]
esters) were reported, besides a low effective method for allyl
ester,[27] and none for the alloc PGs.[29] Here, we reasoned that
Lewis acids in aprotic medium needed to be explored in
a more systematic way for their chemoselective potential,
amino-acids being indeed an ideal model of functional group
diversity and for racemization studies. During our campaign to
find selective conditions to cleave ethyl esters while preserving
the Fmoc group, we discovered the impressive potential of
MgI2, enlarging afterwards the scope to facile chemoselective
cleavages of various standards PGs or PS-resins (Figure 1).
In this context, we offer an exceptionally simple, quantita-
tive, and chemoselective process. By demonstrating how to ef-
ficiently preserve a Fmoc moiety (one of the most popular
base-labile N-terminal PGs) while performing an ester cleavage,
simple but mostly unreturned questions in PGs strategies were
then solvable, that is, how to cleave a benzyloxycarbonyl (Z)
while keeping benzyl ethers, an allyl, or an alloc in a palladi-
um-free process, or even how to remove a peptide from a Mer-
rifield resin under mild conditions. Though experimental proce-
dures to remove a Fmoc usually do not affect esters, the oppo-
site chemoselectivity is not obvious. Although the Z group is
a N-PG of choice (ease of introduction, stability), its cleavage
(strong acidic conditions or hydrogenolysis) limits its applica-
tions. Similarly, the final release of a compound from the at-
tractive Merrifield’s resin requires harsh acidic conditions (neat
HF, TFMSA), which restrains its use.
[a] M. Berthet, F. Davanier, Prof. J. Martinez, Dr. I. Parrot
Institut des BiomolØcules Max Mousseron, IBMM
UMR-5247, CNRS, UniversitØ Montpellier, ENSCM,
CC17-03, Pl. E. Bataillon, 34095 Montpellier Cedex 5 (France)
[b] Dr. G. Dujardin
IMMM UMR 6283 CNRS
UniversitØ du Maine, Le Mans (France)
Supporting information for this article is available on the WWW under
Figure 1. Sensitivity of PGs and resins to MgI2 in THF under microwave (MW)
irradiation.
Chem. Eur. J. 2015, 21, 11014 – 11016
11014
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