Selective hydrogenolysis of benzyl ethers in the presence of benzylidene acetals with Raney nickel

Article abstract of DOI:10.1016/j.tetlet.2006.03.189

A simple method to remove selectively a benzyl group protecting a hydroxyl function in the presence of a benzylidene acetal by catalytic hydrogenolysis with Raney nickel is reported. This method was successfully applied to the synthesis of the C1-C14 fragment of dolabelides.

Full text of DOI:10.1016/j.tetlet.2006.03.189

Tetrahedron Letters 47 (2006) 4075–4077
Selective hydrogenolysis of benzyl ethers in the presence
of benzylidene acetals with Raney nickel
*
´
Aurelie Vincent and Joe¨lle Prunet
`
Laboratoire de Synthese Organique, UMR CNRS 7652, Ecole Polytechnique, DCSO, F-91128 Palaiseau, France
Received 23 November 2005; revised 17 January 2006; accepted 29 March 2006
Abstract—A simple method to remove selectively a benzyl group protecting a hydroxyl function in the presence of a benzylidene
acetal by catalytic hydrogenolysis with Raney nickel is reported. This method was successfully applied to the synthesis of the
C1–C14 fragment of dolabelides.
Ó 2006 Elsevier Ltd. All rights reserved.
Benzylidene acetals are frequently used as 1,2- and 1,3-
diol protecting groups. They can be conveniently
removed under neutral conditions by hydrogenolysis,
or by acid hydrolysis. However, discrimination among
reactive sites of the same class of benzyl-type protecting
group is required for the synthesis of complex natural
products. Indeed, in the course of our studies toward
the synthesis of dolabelides, we needed to deprotect
selectively the benzyl group at C14 in the presence of a
para-methoxybenzyl (PMB) ether at C3 and the benzyl-
idene acetal protecting the diol at C9 and C11 (Fig. 1).
example, selective hydrogenolysis of a secondary benzyl
ether in the presence of a primary para-methoxybenzyl
(PMB) ether is feasible using Raney nickel in
ethanol.1–3 However, when Tatsuta et al. used this meth-
od during their synthesis of herbimycin A, they observed
the concomitant deprotection of a 4,5-disubstituted
1,3-benzylidene acetal.4 Indeed, only a few cases of
selective removal of benzyl groups in the presence of
1,3-benzylidene acetals have been reported, and only
for carbohydrate derivatives. Three of these methods
involve transfer hydrogenation catalyzed by palladium
or palladium hydroxide on carbon with cyclohexene,5
ammonium formate6 or hydrazine hydrate.7 The last
one involves the oxidation of the benzyl ether with
tetrabutylammonium peroxydisulfate, followed by
debenzoylation with sodium methoxide.8
Catalytic hydrogenolysis offers the mildest method for
deprotecting benzyl ethers. Moreover, the electronic
properties of the aromatic ring introduce sufficient
latitude in the rate of hydrogenolysis of benzyl ether
protecting groups to allow selective deprotection. For
In this letter, we describe the selective deprotection of
benzyl ethers in some representative compounds in the
presence of other benzyl-type protecting groups by
hydrogenolysis with Raney nickel.9
Ph
O
O
OSiR3
OPMB
BnO
HO
OTBS
OTBS
11
9
3
14
We first examined the case of a simple monosubstituted
1,3-benzylidene acetal. Selective deprotection of even a
primary benzyl group was not possible (Table 1, entry
1). Fortunately, primary and even secondary benzyl
ethers can be selectively deprotected in the presence of
4,6-disubstituted 1,3-benzylidene acetals (entries 2 and
3). As expected, a PMB ether was stable under these
conditions (entry 4). Application of this method to the
C1–C14 fragment of dolabelides was successful, as we
managed to deprotect the benzyl group at C14 without
hydrogenolysis of the PMB group or the benzylidene
?
Ph
O
O
OSiR3
OPMB
3
14
Figure 1. Selective deprotection of the Cl–Cl4 fragment of dolabelides.
*
Corresponding author. Tel.: +33 1 69 33 48 73; fax: +33 1 69 33 38
51; e-mail: joelle.prunet@polytechnique.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.189

4076
A. Vincent, J. Prunet / Tetrahedron Letters 47 (2006) 4075–4077
Table 1. Cleavage of benzyl ethers by catalytic hydrogenation using Raney nickel in ethanol
Entry
1
Starting materials
Products
Yield (%)
—
OH OBn
Ph
O
O
OH OH
Ph
+
Ph
+
BnO
Ph
HO
Ph
2
3
70–80
72–85
O
O
O
O
O
O
O
BnO
HO
OH
OMe
OMe
OMe
OMe
Ph
Ph
OBn
O
O
O
O
O
Ph
Ph
OH OPMB
O
O
OTBSOH OPMB
O
O
O
OTBS
4
81
BnO
HO
OTBS
OTBS
OTBS
OTBS
Ph
Ph
OPMB
OPMB
O
O
OTBS
O
OTBS
5
6
7
87
1
1
BnO
BnO
HO
7
7
14
14
Ph
OH
82
O
HO
OH
O
Ph
OBn
86a,b
O
O
BnO
HO
OH
O
BnO
BnO
S
Ph
OH
OH
8
79
O
COOMe
COOMe
S
Ph
c
9
—
+
Ph
BnO
+
BnO
O
O
10
78
BnO
BnO
OMe
OMe
a Reaction carried out at 0 °C.
b Yield based on 25% recovered starting material.
c Quantitative recovery of the benzyl ether.
acetal (entry 5). However, the selectivity was not total
for this substrate when a less bulky protecting group
was present on the alcohol at C7: a 6:3:1 mixture of de-
benzylated product/starting material/triol was obtained
with the TES derivative.
Raney nickel in the presence of a primary benzyl ether
(entries 9 and 10).
In conclusion, we have investigated the hydrogenation
of O-benzyl ether protecting groups in the presence of
diverse functional groups by catalytic hydrogenolysis
with Raney nickel in ethanol.
With 1,2-benzylidene acetals, selective deprotection of
benzyl groups was not possible, even with a disubsti-
tuted acetal (entries 6 and 8). Interestingly, monoreduc-
tion of 1,2-benzylidene acetal occurred very cleanly
without deprotection of the benzyl group when carrying
out the experiment at 0 °C (entry 7).
Acknowledgments
Financial support was provided by the CNRS and
the Ecole Polytechnique. A.V. acknowledges the
´ ´
´ ´
On the other hand, we also showed that a 1,3-dithiane or
a conjugated ester can be selectively hydrogenated with
Delegation Generale pour l’Armement (DGA) for a
fellowship.

A. Vincent, J. Prunet / Tetrahedron Letters 47 (2006) 4075–4077
4077
6. Bieg, T.; Szeja, W. Synthesis 1985, 76–77.
7. Bieg, T.; Szeja, W. Synthesis 1986, 317–318.
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9. General procedure for the hydrogenolysis of Bn groups
over Raney Ni catalyst: a solution of a Bn ether in absolute
EtOH (0.1 M) was stirred under a hydrogen atmosphere
(1 bar) over excess Raney Ni (Fluka, used as received) at
20 °C. After the reaction was complete, the catalyst was
removed by filtration and the filtrate concentrated in vacuo.
The residue was purified by chromatography on silica gel to
give the corresponding product.
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mitsu, O. Tetrahedron 1986, 42, 3021–3028.
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