LETTER
1293
FeCl3-Catalysed Cleavage of 1,2-Butanediacetal Protected Diols
F
eCl -Catalyse
d
.
A
-Depro
C
3
Ngampong Kongkathip,b Steven V. Ley*a
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Department of Chemistry, Kasetsart University, Bangkok, Thailand
b
Received 17 March 2008
MeO
R1
R2
OH
O
O
5 mol% FeCl3, 2 equiv H2O
AcOH, r.t.
Abstract: Catalytic FeCl3 in acetic acid has been employed as a
cost-effective, low-toxicity reagent for the removal of butane 1,2-
diacetal protecting groups under mild conditions.
R2
R1
MeO
OH
Key words: protecting groups, diols, hydrolysis, acetals, iron
Equation 1
The presence of stoichiometric quantities of water is nec-
essary, otherwise incomplete conversion of the starting
material is observed. Lewis acids other than FeCl3, such
as AuCl3 or PtCl4, were also effective as catalysts but were
not considered any further due to their high cost and their
ability to promote other reactions. Acetyl chloride in ace-
tic acid, as a source of HCl, did not give any reaction. Ace-
tic acid alone also did not give any conversion of the
starting material, demonstrating that the FeCl3 is neces-
sary for the cleavage of the BDA group. Similarly, FeCl3
in MeOH or THF did not lead to the desired deprotection,
even in the presence of acetic acid as co-solvent, while the
use of CH2Cl2 as solvent led to irreproducible results.
Butane 1,2-diacetal (BDA) protecting groups have been
used in a number of synthetic applications ranging from
selective 1,2-diequatorial diol protection to rigidifying
templates and their use in chiral memory protocols.1 By
taking advantage of these properties, several applications
to natural product synthesis have been reported by our
group and others.1a,2 Most frequently, however, the BDA
group has been used in the field of carbohydrate synthesis.
For the removal of BDA protecting groups a number of
methods has been described. These include TFA–water
mixtures,1a stoichiometric TiCl4 in CH2Cl2,3 excess
BF3·OEt2 and 1,2-ethanedithiol,4 and excess TMSBr in
CH2Cl2.5 Although the combination of TFA–water, com-
monly 9:1, has been the most popular deprotection meth-
od, some minor drawbacks arise from the strong acidic
character and the general toxicity of this mixture.
The general method proved compatible with a range of
functional groups (Table 1). As expected benzyl and pro-
pargyl ethers were not cleaved under the reaction condi-
tions. Different esters, such as acetate protecting groups,
were found to be equally stable. Of particular interest is
the behaviour of potentially acid-sensitive functionalities.
Thus, the BDA group could be removed in the presence of
an epoxide without epoxide opening (Table 1, entry 5), al-
lylic and tertiary alcohols could be deprotected without
elimination (Table 1, entries 2, 3, 11). A tert-butyldimeth-
ylsilyl ether, however, was cleaved under the standard re-
action conditions (not shown). Modified mannose-
derived carbohydrates underwent clean deprotection,
without compromising the a-glycosidic methoxy group
(Table 1, entries 18–21).
Recently, we employed BDA-protected alkyne diols de-
rived from mannitol or tartaric acid as enantiopure starting
materials for a PtCl4-catalysed domino deprotection–cy-
cloisomerisation sequence to rapidly access bicyclic ace-
tals.6 During the optimisation of these reactions we found
that a solution of FeCl3 in acetic acid cleanly removed the
BDA protecting group to reveal the free diol. Previously,
FeCl3·6H2O adsorbed on silica gel has been used for the
cleavage of acetonides in CHCl3.7 Excess FeCl3 in CH2Cl2
has been employed for the removal of benzylic dispiroket-
al protection groups.8 We felt that the use of catalytic
amounts of FeCl3 in acetic acid might offer an attractive
alternative to the known BDA deprotection methods
(Equation 1). The possible advantages could be the lower
toxicity and cost of the reagents involved (particularly on
a large scale).
While reactions were generally conducted at room tem-
perature, we found that carbonyl groups in proximity of
the BDA group can slow down or even suppress the reac-
tion and therefore necessitate the use of elevated temper-
atures in order to achieve full conversion. This inhibitory
effect might be the result of complexation of the Lewis
acid and formation of chelate complexes which are not
catalytically active. Likewise we found that the presence
of a secondary amine in the substrate entirely prevented
any deprotection (Table 1, entry 12).
After brief optimisation of the reaction conditions we
found that most of the substrates could be deprotected
within 2–4 hours at room temperature, employing two
equivalents of water and 5 mol% of FeCl3 in acetic acid.
SYNLETT 2008, No. 9, pp 1293–1296
x
x.
x
x.
2
0
0
8
In conclusion catalytic FeCl3 in acetic acid is a convenient
reagent for the removal of BDA protecting groups under
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072752; Art ID: D08108ST
© Georg Thieme Verlag Stuttgart · New York