Selective cleavage of acetals with ZnBr2 in dichloromethane

Article abstract of DOI:10.1016/j.tet.2005.10.064

A selective cleavage of acetals of 1,2- and 1,3-diols has been achieved under mild conditions using ZnBr₂ in dichloromethane at room temperature. Acetal types cleavable by this procedure include benzylidene, isopropylidene and cyclohexylidene acetals. This method is compatible with several other types of hydroxyl protecting groups such as Bn, Bz, TBDPS, TIPS and TBDMS.

Full text of DOI:10.1016/j.tet.2005.10.064

Tetrahedron 62 (2006) 1239–1244
Selective cleavage of acetals with ZnBr2 in dichloromethane
*
Celia Ribes, Eva Falomir and Juan Murga
*
´
´
´
´
Departamento de Quımica Inorganica y Organica, Universidad Jaume 1, E-12071 Castellon, Spain
Received 29 July 2005; revised 19 October 2005; accepted 24 October 2005
Available online 15 November 2005
Abstract—A selective cleavage of acetals of 1,2- and 1,3-diols has been achieved under mild conditions using ZnBr2 in dichloromethane at
room temperature. Acetal types cleavable by this procedure include benzylidene, isopropylidene and cyclohexylidene acetals. This method is
compatible with several other types of hydroxyl protecting groups such as Bn, Bz, TBDPS, TIPS and TBDMS.
q 2005 Published by Elsevier Ltd.
1. Introduction
groups. In the event, 4–6 equiv of ZnBr2 in dichloromethane
at room temperature were found necessary to perform a
complete acetal cleavage in a reasonable time (Table 1).
The selective protection and deprotection of hydroxyl
groups has played a crucial role in the synthesis of complex
organic molecules. Among the many reported hydroxyl
protecting groups, acetals are used with high frequency.1
Although protic acids are commonly used to cleave acetal
moieties, a number of Lewis acids have also been shown to
be effective for this purpose. Examples taken from the
literature are FeCl3$6H2O,2 FeCl3/SiO2,3 CuCl2$2H2O,4
Zn(NO3)2$6H2O5 and (NH4)2Ce(NO3)6.6 However, some of
these reagents show a limited compatibility with other
commonly used hydroxyl protecting groups such as silyl
or benzyl fragments.7
Scheme 1.
Table 1. Selective cleavage of acetals of 1,2-diols using ZnBr2
In the course of a research project aimed at the synthesis of
polyfunctionalized, natural compounds, we observed that
ZnBr2 provides extremely mild aprotic conditions for acetal
cleavage. While ZnBr2 has been extensively used for
deprotection of MEM,8 N-Boc,9 t-butyl ester10 and even
silyl groups,11 it has not been systematically used for the
cleavage of acetals.12
Entry
Acetal
P
ZnBr2
(equiv)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
TPS
TIPS
TBS
Bn
4
4
4
4
4
4
4
4
4
6
6
6
6
6
6
6
4
4
5
5
5
5
2
2
3
3
3
6
6
6
5
6
7
5
5
6
6
6
5
3
5
5
5
7
94
95
65
86
78
18a
Bz
THP
MOM
MEM
TPS
TIPS
TBS
Bn
a
—
a
—
9
92
78
61
73
72
43a
2. Results and discussion
10
11
12
13
14
15
16
17
18
19
20
21
22
We here report a very mild and efficient method to cleave
acetals in the presence of several other types of hydroxyl
protecting groups. Scheme 1 shows the case of acetals of
1,2-diols. Thus, the vicinal diol moiety of the commercially
available 1,2,6-hexanetriol was protected as an acetal, and
the distal primary alcohol was protected with other various
Bz
THP
MOM
MEM
TPS
TIPS
TBS
Bn
a
—
a
—
62
75
50
60
68
11a
Keywords: Acetals; Protecting groups; Selective cleavage; Mild conditions;
Lewis acid.
Bz
THP
*
Corresponding authors. Tel.: C34 964 728174; fax: C34 964 728214
e-mail: efalomir@qio.uji.es
a Formation of unprotected 1,2,6-hexanetriol was observed.
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.10.064

1240
C. Ribes et al. / Tetrahedron 62 (2006) 1239–1244
As shown in Table 1, the method is applicable to substrates
containing a range of protecting groups such as t-butyl-
diphenyl silyl (TPS, entries 1, 9 and 17), triisopropyl-silyl
(TIPS, entries 2, 10 and 18), t-butyldimethylsilyl (TBS,
entries 3, 11 and 19), benzyl (Bn, entries 4, 12 and 20) and
benzoyl (Bz, entries 5, 13 and 21). However, ZnBr2 proved
less selective towards other kind of acetals such as
tetrahydropyranyl (THP) ethers, which are extensively
removed under these conditions (entries 6, 14 and 22) and
methoxymethyl (MOM) or methoxyethoxymethyl (MEM)
ethers, which are eliminated simultaneously with the
acetonide function (entries 7, 8, 15 and 16).8
3. Conclusions
We have described a very mild, simple and selective method
for deprotection of acetals using ZnBr2 in dichloromethane
at room temperature. Furthermore, this deprotection
procedure is selective in the presence of some other types
of hydroxyl protecting groups.
4. Experimental
4.1. General
NMR spectra were measured at 300 or 500 MHz in CDCl3
solution at 25 8C. The signals of the deuterated solvent
(CDCl3) were taken as the reference (the singlet at d 7.25 for
1H NMR and the triplet centered at 77.00 ppm for 13C NMR
data). Carbon atom types (C, CH, CH2, CH3) were
determined with the DEPT pulse sequence. THF was
freshly distilled from sodium/benzophenone. Dichloro-
methane was freshly distilled from CaH2. Tertiary amines
were freshly distilled from KOH. Commercially available
reagents were used as received. Unless detailed otherwise,
‘work-up’ means pouring the reaction mixture into brine,
followed by extraction with the solvent indicated in
parenthesis. If the reaction medium was acidic (basic), an
additional washing with 5% aq NaHCO3 (aq NH4Cl) was
performed. Drying over anhydrous Na2SO4 and elimination
of the solvent under reduced pressure were followed by
chromatography of the residue on a silica gel column
(60–200 mm) with the indicated eluent. Where solutions
were filtered through a Celite pad, the pad was additionally
washed with the same solvent used, and the washings
incorporated to the main organic layer.
The procedure also allows the cleavage of acetals of 1,3-
diols under the same conditions. Here, 3-methyl-1,3,5-
pentanetriol was used as the precursor alcohol (see Scheme 2
and Table 2).
Scheme 2.
Table 2. Selective cleavage of acetals of 1,3-diols using ZnBr2
Entry
Acetal
P
ZnBr2
(equiv)
Time (h)
Yield (%)
1
2
3
5
6
6
TPS
TPS
Bn
4
5
5
1
3
3
86
85
81
4.2. Synthesis of the substrates in Tables 1 and 2
ZnBr2 does not dissolve in dichloromethane, where it forms
a cloudy suspension. We thus, explored more polar solvents
such as THF, ethyl acetate or acetonitrile, where a total or
more pronounced solubilization of the reagent might be
achieved. However, no improvements were obtained with
these solvents. Although ZnBr2 is soluble in THF, no
reaction took place in this solvent, probably because
coordination of ZnBr2 with the Lewis-basic THF may
compete with the acetal coordination, thereby preventing
cleavage of the protecting group. Acetonitrile, which
partially solubilizes ZnBr2, was also useless as no reaction
was observed, either. Ethyl acetate solubilizes ZnBr2 but its
use gave rise to very long reaction times (3–5 days) and low
yields. The very weakly Lewis-basic dichlorometane is thus
the solvent of choice.
Compounds 1 (PZH, TPS, TBS, Bn, THP, MOM, MEM),14
2 (PZH),15 3 (PZH),16 4 (PZTPS, TBS, Bn, THP),17 and 7
(PZTPS, Bn)18 have been previously reported. Analytical
data are given hereafter only for new compounds.
4.2.1. General procedure for the preparation of silyl
ethers from the corresponding alcohols. A solution of the
alcohol (1 mmol) in dry CH2Cl2 (5 mL) was treated under
N2 with triethyl amine (1.5 mmol), DMAP (0.03 mmol) and
the corresponding silyl chloride (1.1 mmol). The reaction
mixture was stirred for 12 h at room temperature and
worked up (extraction with CH2Cl2).
4.2.2. General procedure for the preparation of
benzoates from the corresponding alcohols. A solution
of the alcohol (1 mmol) in dry CH2Cl2 (5 mL) was treated
under N2 with triethyl amine (1.5 mmol), DMAP
(0.03 mmol) and benzoyl chloride (1.5 mmol). The reaction
mixture was stirred for 12 h at room temperature and
worked up (extraction with CH2Cl2).
In addition to ZnBr2, we have also investigated the use of
ZnCl2 for acetal cleavage. However, longer reaction times
were needed than with ZnBr2 and yields were lower.
Although we initially ran the reaction under anhydrous
conditions, we later observed that the addition of few drops
of water to the reaction medium did not cause noticeable
changes in either reaction times or yields. In consequence,
simple distilled CH2Cl2 may be used and no special caution
as regards solvent dryness is needed.13
4.2.3. General procedure for the preparation of benzyl
ethers from the corresponding alcohols. A solution of the
alcohol (1 mmol) in dry THF (8 mL) was added dropwise at
0 8C under N2 to a suspension of defatted NaH (1.5 mmol)
in dry THF (5 mL). After stirring the mixture for 1 h at room

C. Ribes et al. / Tetrahedron 62 (2006) 1239–1244
1241
temperature, tetra-n-butylammonium iodide (0.03 mmol)
and benzyl chloride (1.5 mmol) were added. The reaction
mixture was then stirred for 12 h at 60 8C and worked up
(extraction with AcOEt).
12.3, 12.0 (CH), 69.0, 63.1, 36.6, 35.2, 33.5, 32.9, 25.2,
24.0, 23.8, 22.0 (CH2), 18.0, 17.6 (CH3). Anal. Calcd for
C21H42O3Si: C, 68.05; H, 11.42. Found: C, 67.97; H, 11.41.
4.2.5.5.
1,2-O,O-Cyclohexylidene-6-O-t-butyl-
4.2.4. General procedure for the preparation of THP
ethers from the corresponding alcohols. A solution of the
alcohol (1 mmol) in dry CH2Cl2 (5 mL) was treated under
N2 with 3,4-dihydro-2H-pyran (1.5 mmol) and PPTS
(0.03 mmol). The reaction mixture was stirred for 12 h at
room temperature and worked up (extraction with CH2Cl2).
dimethylsilyl-hexane-1,2,6-triol (2, PZTBS). Column
chromatography on silica gel (hexanes/EtOAc 9:1) afforded
2 (PZTBS) (80% yield) as a colourless oil. 1H NMR
(500 MHz) d 4.06 (1H, m), 4.00 (1H, dd, JZ7.51, 6.05 Hz),
3.60 (2H, t, JZ6.41 Hz), 3.48 (1H, t, JZ7.51 Hz), 1.65–
1.30 (16H, m), 0.88 (9H, s), 0.04 (6H, s); 13C NMR
(125 MHz) d 109.1, 18.3 (C), 75.6 (CH), 69.1, 62.9, 36.6,
35.3, 33.5, 32.7, 24.0, 23.8, 22.0 (CH2), 25.9, K5.3 (CH3).
Anal. Calcd for C18H36O3Si: C, 65.80; H, 11.04. Found: C,
65.88; H, 10.99.
4.2.5. General procedure for the preparation of MEM/
MOM ethers from the corresponding alcohols. A solution
of the alcohol (1 mmol) in dry CH2Cl2 (5 mL) was treated
under N2 with diisopropylethyl amine (3 mmol), DMAP
(0.03 mmol) and the corresponding alkoxymethyl chloride
(2 mmol). The reaction mixture was stirred for 3 h at room
temperature and worked up (extraction with CH2Cl2).
4.2.5.6. 1,2-O,O-Cyclohexylidene-6-O-benzoylhexane-
1,2,6-triol (2, PZBz). Column chromatography on silica
gel (hexanes/EtOAc 4:1) afforded 2 (PZBz) (86% yield) as
1
a colourless oil. H NMR (500 MHz) d 8.00 (2H, m), 7.50
(1H, m), 7.38 (2H, m), 4.30 (2H, m), 4.05 (1H, m), 4.00 (1H,
m), 3.46 (1H, m), 1.70 (2H, m), 1.80–1.30 (14H, m); 13C
NMR (125 MHz) d 166.3, 130.2, 109.5 (C), 132.6, 129.3,
128.1, 75.2 (CH), 68.8, 64.5, 36.5, 35.1, 33.1, 28.5, 25.0,
23.8, 23.7, 22.2 (CH2). Anal. Calcd for C19H26O4: C, 71.67;
H, 8.23. Found: C, 71.79; H, 8.22.
4.2.5.1. 1,2-O,O-Isopropylidene-6-O-triisopropylsilyl-
hexane-1,2,6-triol (1, PZTIPS). Column chromatography
on silica gel (hexanes/EtOAc 9:1) afforded 1 (PZTIPS)
(88% yield) as a colourless oil. 1H NMR (500 MHz) d 4.08
(1H, q, JZ6.4 Hz), 4.25 (1H, dd, JZ7.5, 6.0 Hz), 3.69 (2H,
t, JZ3.1 Hz), 3.51 (1H, t, JZ7.5 Hz), 1.68 (2H, m), 1.60–
1.45 (3H, m), 1.41 (3H, s), 1.35 (3H, s), 1.07–1.05 (18H, m);
13C NMR (125 MHz) d 108.7 (C), 76.0, 12.0 (CH), 69.3,
63.4, 33.3, 32.9, 22.0 (CH2), 26.9, 25.7, 18.0 (!4) (CH3).
Anal. Calcd for C18H38O3Si: C, 65.40; H, 11.59. Found: C,
65.58; H, 11.60.
4.2.5.7.
4.2.5.7. 1,2-Di-O,O-cyclohexylidene-6-O-
benzylhexane-1,2,6-triol (2, PZBn). Column chromatog-
raphy on silica gel (hexanes/EtOAc 4:1) afforded 2 (PZBn)
(80% yield) as a colourless oil. 1H NMR (500 MHz) d 7.34–
7.30 (5H, m), 4.50 (2H, s), 4.10–3.98 (2H, m), 3.50–3.46 (3H,
m), 1.65–1.42 (16H, m); 13C NMR (125 MHz) d 138.6, 109.1
(C), 128.3, 127.6, 127.5, 75.6 (CH), 72.9, 70.1, 69.1, 36.6,
35.3, 33.5, 29.7, 25.2, 24.0, 23.8, 22.5 (CH2). Anal. Calcd for
C19H28O3: C, 74.96; H, 9.27. Found: C, 75.08; H, 9.27.
4.2.5.2. 1,2-O,O-Isopropylidene-6-O-benzoylhexane-
1,2,6-triol (1, PZBz). Column chromatography on silica
gel (hexanes/EtOAc 4:1) afforded 1 (PZBz) (80% yield) as
a colourless oil. 1H NMR (500 MHz) d 8.03 (2H, dd, JZ7.9,
1.1 Hz), 7.55 (1H, td, JZ7.9, 1.1 Hz), 7.43 (2H, t, JZ
7.9 Hz), 4.33 (2H, t, JZ6.4 Hz), 4.10 (1H, m), 4.04 (1H, dd,
JZ7.5, 6.4 Hz), 3.52 (1H, t, JZ7.5 Hz), 1.82–1.48 (6H, m),
1.41 (3H, s), 1.35 (3H, s); 13C NMR (125 MHz) d 166.6,
130.4, 108.7 (C), 132.8, 129.5, 128.3, 75.8 (CH), 69.3, 64.7,
33.2, 28.9, 22.3 (CH2), 26.9, 25.6 (CH3). Anal. Calcd for
C16H22O4: C, 69.04; H, 7.97. Found: C, 68.98; H, 7.87.
4.2.5.8.
1,2-O,O-Cyclohexylidene-6-O-(tetra-
hydropyran-2-yl)hexane-1,2,6-triol (2, PZTHP).
Column chromatography on silica gel (hexanes/EtOAc
4:1) afforded 2 (PZTHP) (84% yield) as a colourless oil.
1H NMR (500 MHz) d 4.52 (1H, dd, JZ4.0, 2.7 Hz), 4.01
(1H, dd, JZ6.50, 6.01 Hz), 3.97 (1H, dd, JZ7.69, 5.89 Hz),
3.80 (1H, m), 3.69 (dt, JZ9.7, 6.8 Hz), 3.45 (2H, m), 3.34
(dt, JZ9.7, 6.8 Hz), 1.85–1.31 (22H, m); 13C NMR
(125 MHz) d 109.0 (C), 98.8, 98.7, 75.5 (CH), 69.0, 67.2,
62.2, 36.5, 35.2, 33.5, 30.6, 29.6, 25.4, 25.1, 23.9, 23.8,
22.4, 19.5 (CH2). Anal. Calcd for C17H30O4: C, 68.42; H,
10.13. Found: C, 68.60; H, 10.23.
4.2.5.3. 1,2-O,O-Cyclohexylidene-6-O-t-butyldiphenyl-
silyl-hexane-1,2,6-triol (2, PZTPS). Column chromato-
graphy on silica gel (hexanes/EtOAc 9:1) afforded 2 (PZ
TPS) (85% yield) as a colourless oil. 1H NMR (500 MHz) d
7.71–7.67 (4H, m), 7.43–7.40 (6H, m), 4.05 (2H, m), 3.70
(2H, t, JZ6.00 Hz), 3.51 (1H, t, JZ6.0 Hz), 1.65–1.58 (10H,
m), 1.54–1.39 (6H, m), 1.08 (9H, s); 13C NMR (125 MHz) d
134.1, 109.1, 19.2 (C), 135.6, 129.5, 127.6, 75.6 (CH), 69.1,
63.6, 36.6, 35.3, 33.4, 32.5, 25.2, 24.0, 23.9, 22.0 (CH2), 26.9
(CH3). Anal. Calcd for C28H40O3Si: C, 74.29; H, 8.91.
Found: C, 74.42; H, 8.96.
4.2.5.9. 1,2-O,O-Cyclohexylidene-6-O-(methoxy-
methyl)hexane-1,2,6-triol (2, PZMOM). Column chro-
matography on silica gel (hexanes/EtOAc 9:1) afforded 2
(PZMOM) (86% yield) as a colourless oil. 1H NMR
(500 MHz) d 4.57 (2H, s), 4.04–3.94 (2H, m), 3.50–3.40
(3H, m), 3.31 (3H, s), 1.65–1.30 (16H, m); 13C NMR
(125 MHz) d 109.1 (C), 75.5 (CH), 96.3, 69.0, 67.5, 36.5,
35.2, 33.5, 29.6, 25.1, 23.9, 23.8, 22.4 (CH2), 55.0 (CH3).
Anal. Calcd for C14H26O4: C, 65.09; H, 10.14. Found: C,
65.17; H, 10.12.
4.2.5.4. 1,2-O,O-Cyclohexylidene-6-O-triisopropyl-
silyl-hexane-1,2,6-triol (2, PZTIPS). Column chromato-
graphy on silica gel (hexanes/EtOAc 9:1) afforded 2 (PZ
TIPS) (95% yield) as a colourless oil. 1H NMR (500 MHz) d
4.05 (1H, m), 4.00 (1H, dd, JZ7.51, 5.51 Hz), 3.67 (2H, t,
JZ6.50 Hz), 3.48 (1H, t, JZ7.51 Hz), 1.55–1.30 (9H, m),
1.20–0.80 (18H, m); 13C NMR (125 MHz) d 109.1 (C), 75.6,
4.2.5.10. 1,2-O,O-Cyclohexylidene-6-O-(methoxy-
ethoxymethyl)hexane-1,2,6-triol (2, PZMEM). Column

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C. Ribes et al. / Tetrahedron 62 (2006) 1239–1244
chromatography on silica gel (hexanes/EtOAc 9:1) afforded
2 (PZMEM) (80% yield) as a colourless oil. H NMR
a colourless oil. 1H NMR (500 MHz) d 7.56–7.24 (20H, m),
5.91 (1H, s), 5.79 (1H, s), 4.50 (2H, s), 4.49 (2H, s), 4.24–
4.18 (5H, m), 4.09 (1H, t, JZ7.0 Hz), 3.70 (1H, t, JZ
7.0 Hz), 3.60 (1H, t, JZ7.0 Hz), 3.48 (4H, dt, JZ6.0,
2.5 Hz), 1.77–1.45 (12H, m); 13C NMR (125 MHz) d 138.5,
138.4, 137.9 (C), 129.2, 129.0, 128.3, 127.7, 127.6, 127.5,
126.6, 126.3, 103.9, 103.0, 77.3, 76.4 (CH), 72.9, 70.7, 70.0,
33.2, 33.0, 29.7, 22.5 (CH2). Anal. Calcd for C20H24O3: C,
76.89; H, 7.74. Found: C, 77.00; H, 7.77.
1
(500 MHz) d 4.54 (2H, s), 3.90 (1H, m), 3.86 (1H, dd, JZ
7.53, 6.0 Hz), 3.52 (1H, dd, JZ7.53, 6.0 Hz), 3.40 (4H, m),
3.34 (2H, t, JZ7.50 Hz), 3.23 (3H, s), 1.50–1.20 (16H, m);
13C NMR (125 MHz) d 109.1 (C), 75.5 (CH), 96.4, 69.0,
67.5, 36.6, 35.2, 33.5, 29.7, 25.2, 24.0, 23.8, 22.5 (CH2),
55.0 (CH3). Anal. Calcd for C16H30O5: C, 63.55; H, 10.00.
Found: C, 63.64; H, 9.99.
4.2.5.11. 1,2-O,O-Benzylidene-6-O-t-butyldiphenyl-
silyl-hexane-1,2,6-triol (3, PZTPS). Column chromato-
graphy on silica gel (hexanes/EtOAc 9:1) afforded 3 (PZ
TPS) (87% yield) as a colourless oil. 1H NMR (500 MHz) d
7.91–7.38 (30H, m), 5.94 (1H, s), 5.83 (1H, s), 4.42 (4H, m),
4.21 (2H, m), 3.73–3.61 (4H, m), 2.80–1.20 (12H, m), 1.09
(18H, s); 13C NMR (125 MHz) d 138.2, 137.8, 136.1, 22.0,
19.2 (C), 134.4, 134.0, 129.7, 129.51, 128.9, 128.2, 126.6,
126.3, 103.9, 103.0, 77.3, 76.4 (CH), 70.6, 70.0, 63.6, 33.0,
32.9, 32.3 (CH2), 26.8 (CH3). Anal. Calcd for C29H36O3Si:
C, 75.61; H, 7.88. Found: C, 75.71; H, 7.90.
4.2.5.16. 1,2-O,O-Benzylidene-6-O-(tetrahydropyran-
2-yl)hexane-1,2,6-triol (3, PZTHP). Column chromato-
graphy on silica gel (hexanes/EtOAc 4:1) afforded 3 (PZ
THP) (65% yield) as a colourless oil. 1H NMR (500 MHz) d
7.49–7.35 (10H, m), 5.93 (1H, s), 5.81 (1H, s), 4.58 (2H, s
ancho), 4.49 (2H, s), 4.27–4.19 (3H, m), 4.10 (1H, dd, JZ
7.8, 6.9 Hz), 3.90–3.82 (2H, m), 3.80–3.72 (2H, m), 3.68
(1H, t, JZ7.2 Hz), 3.62 (1H, stma AB), 3.52–3.48 (2H, m),
3.43–3.38 (2H, m), 1.86–1.50 (12H, m); 13C NMR
(125 MHz) d 138.5, 137.8 (C), 129.2, 129.0, 128.3, 126.6,
126.3, 103.9, 103.0, 98.9, 98.8, 77.2, 76.3 (CH), 70.6, 70.0,
67.2, 62.2, 33.1, 33.0, 29.6, 25.4, 22.5, 19.6 (CH2). Anal.
Calcd for C18H26O4: C, 70.56; H, 8.55. Found: C, 70.68; H,
8.61.
4.2.5.12. 1,2-O,O-Benzylidene-6-O-triisopropylsilyl-
hexane-1,2,6-triol (3, PZTIPS). Column chromatography
on silica gel (hexanes/EtOAc 9:1) afforded 3 (PZTIPS)
(92% yield) as a colourless oil. 1H NMR (500 MHz) d 7.52–
7.36 (10H, m), 5.95 (1H, s), 5.82 (1H, s), 4.25 (4H, m), 4.12
(2H, t, JZ7.0 Hz), 3.75–3.68 (4H, m), 3.64 (2H, t, JZ
7.0 Hz), 1.65–1.10 (12H, m), 1.09 (18H, s), 1.08 (6H, s),
1.07 (12H, s); 13C NMR (125 MHz) d 139.0, 138.6, 136.1
(C), 129.1, 128.9, 128.3, 126.6, 126.3, 103.9, 103.1, 77.4,
76.5, 13.0, 12.0 (CH), 70.7, 70.0, 63.1, 33.2, 33.0, 32.8,
22.1, 22.0 (CH2), 18.0, 17.7 (CH3). Anal. Calcd for
C22H38O3Si: C, 69.79; H, 10.12. Found: C, 69.63; H, 10.25.
4.2.5.17. 1,3-O,O-Isopropylidene-3-methylpentane-
1,3,5-triol (5, PZH). A solution of 3-methylpentane-
1,3,5-triol (610 mg, 5 mmol) in dry acetone (25 mL) was
treated under N2 with 2,2-dimethoxypropane (5 mL) and
camphorsulfonic acid (7 mg, 0.03 mmol). The reaction
mixture was stirred for 24 h at room temperature, then
filtered through Celite and evaporated under reduced
pressure. Column chromatography on silica gel (hexanes/
EtOAc 9:1) afforded 5 (PZH) (574 mg, 66% yield) as a
1
colourless oil. H NMR (500 MHz) d 3.92–3.88 (4H, m),
4.2.5.13. 1,2-O,O-Benzylidene-6-O-t-butyldimethyl-
silyl-hexane-1,2,6-triol (3, PZTBS). Column chromato-
graphy on silica gel (hexanes/EtOAc 9:1) afforded 3 (PZ
TBS) (83% yield) as a colourless oil. 1H NMR (500 MHz) d
7.55–7.38 (10H, m), 5.98 (1H, s), 5.82 (1H, s), 4.26 (4H, m),
4.15 (2H, t, JZ7.0 Hz), 3.68 (4H, m), 1.82–1.15 (12H, m),
0.97 (18H, s), 0.12 (6H, s), 0.11 (6H, s); 13C NMR
(125 MHz) d 139.2, 138.8, 22.0 (C), 129.0, 128.8, 128.1,
126.5, 126.2, 103.8, 103.0, 77.2, 76.3 (CH), 70.5, 70.0, 62.7,
33.1, 33.0, 32.6 (CH2), 25.8, K5.4 (CH3). Anal. Calcd for
C19H32O3Si: C, 67.81; H, 9.58. Found: C, 67.92; H, 9.62.
1.91–183 (2H, m), 1.91 (3H, s), 1.38 (3H, s), 1.28–1.20 (2H,
m), 1.21 (3H, s); 13C NMR (125 MHz) d 97.7, 70.7 (C),
60.6, 44.0, 20.8 (CH2), 27.8, 26.7 (CH3). Anal. Calcd for
C9H18O3: C, 62.04; H, 10.41. Found: C, 62.15; H, 10.45.
4.2.5.18. 1,3-O,O-Isopropylidene-5-O-t-butyldiphenyl-
silyl-3-methylpentane-1,3,5-triol (5, PZTPS). Column
chromatography on silica gel (hexanes/EtOAc 9:1) afforded
5 (PZTPS) (85% yield) as a colourless oil. 1H NMR
(500 MHz) d 7.71–7.68 (4H, m), 7.42–7.38 (6H, m), 3.94–
3.80(4H, m), 1.94–1.74 (2H, m), 1.54–1.46 (2H, m), 1.40(3H,
s), 1.32 (3H, s), 1.27 1.40 (3H, s), 1.07 (9H, s); 13C NMR
(125 MHz) d 134.0, 97.8, 71.7, 19.1 (C), 135.6, 129.5, 127.6
(CH), 60.1, 56.6, 45.6, 34.2 (CH2), 28.8, 27.8, 27.4, 26.9
(CH3). Anal. Calcd for C25H36O3Si: C, 72.77; H, 8.79. Found:
C, 72.89; H, 8.80.
4.2.5.14. 1,2-O,O-Benzylidene-6-O-benzoylhexane-
1,2,6-triol (3, PZBz). Column chromatography on silica
gel (hexanes/EtOAc 4:1) afforded 3 (PZBz) (80% yield) as
1
a colourless oil. H NMR (500 MHz) d 8.10–8.00 (4H, m),
7.59–7.36 (16H, m), 5.95 (1H, s), 5.83 (1H, s), 4.36 (4H, dt,
JZ6.41, 3.47 Hz), 4.25 (4H, m), 4.13 (2H, t, JZ7.0 Hz),
4.13 (2H, t, JZ7.0 Hz), 3.72 (2H, t, JZ7.0 Hz), 3.64 (2H,
m), 1.90–1.55 (12H, m); 13C NMR (125 MHz) d 166.5,
138.4, 137.8 (C), 132.8, 129.5, 129.2, 128.3, 126.6, 126.3,
104.0, 103.1, 77.0, 76.2 (CH), 70.6, 70.0, 64.6, 33.0, 32.9,
28.6, 22.4, 22.3 (CH2). Anal. Calcd for C20H22O4: C, 73.60;
H, 6.79. Found: C, 73.50; H, 6.93.
4.2.5.19. 1,3-O,O-Benzylidene-3-methylpentane-1,3,5-
triol (6, PZH). A solution of 3-methyl-1,3,5-pentanetriol
(610 mg, 5 mmol) in dry toluene (25 mL) was treated under
N2 with benzaldehyde (1.5 mL, 15 mmol) and p-toluene-
sulfonic acid monohydrate (6 mg, 0.03 mmol). The reaction
mixture was stirred for 24 h at 60 8C, then filtered through
Celite and evaporated under reduced pressure. Column
chromatography on silica gel (hexanes/EtOAc 9:1) afforded
6 (PZH) (695 mg, 63% yield) as a colourless oil. 1H NMR
(500 MHz) d 7.50–7.35 (10H, m), 5.80 (1H, s), 5.75 (1H, s),
4.16–4.10 (4H, m), 3.91–3.70 (4H, m), 2.65 (2H, m), 2.41
4.2.5.15. 1,2-O,O-Benzylidene-6-O-benzylhexane-
1,2,6-triol (3, PZBn). Column chromatography on silica
gel (hexanes/EtOAc 4:1) afforded 3 (PZBn) (76% yield) as

C. Ribes et al. / Tetrahedron 62 (2006) 1239–1244
1243
(2H, m), 2.05 (2H, dt, JZ6.0, 12 Hz), 1.88 (2H, t, JZ
6.0 Hz), 1.12 (2H, td, JZ5.5, 12 Hz), 1.52 (3H, s), 1.37 (3H,
s); 13C NMR (125 MHz) d 138.8, 138.7, 75.6, 74.1, 70.7 (C),
128.8, 128.7, 128.2, 126.1, 125.9, 95.3, 95.2 (CH), 63.2,
63.1, 45.3, 35.8, 35.1, 33.8 (CH2), 28.5, 20.5 (CH3). Anal.
Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.35; H,
8.19.
1.79 (2H, m), 1.62 (2H, m), 1.51 (2H, m); 13C NMR
(125 MHz) d 166.7, 130.3 (C), 132.9, 129.5, 128.3, 72.0
(CH), 66.7, 64.8, 32.6, 28.7, 22.1 (CH2). Anal. Calcd for
C13H18O4: C, 65.53; H, 7.61. Found: C, 65.62; H, 7.66.
Note added in proof
4.2.5.20. 1,3-O,O-Benzylidene-5-O-t-butyldiphenylsilyl-
3-methylpentane-1,3,5-triol (6, PZTPS). Column chroma-
tography on silica gel (hexanes/EtOAc 9:1) afforded 6 (PZ
TPS) (90% yield) as a colourless oil. 1H NMR (500 MHz) d
7.79–7.72(8H, m), 7.47–7.39(22H, m), 5.77(1H,s), 5.52(1H,
s), 4.35–4.15 (4H, m), 3.90–3.68 (4H, m), 2.40–1.90 (4H, m),
2.0 (4H, t, JZ4.1 Hz), 1.47 (3H, s), 1.30 (3H, s), 1.13 (9H, s),
1.12 (9H, s); 13C NMR (125 MHz) d 139.3, 139.0, 134.2, 73.3,
20.2, 19.1 (C), 135.6, 129.5, 128.1, 127.7, 127.6, 126.1, 126.0,
94.9, 94.7 (CH), 63.2, 59.8, 59.4, 46.7, 35.9, 35.5, 34.4 (CH2),
28.9, 26.9, 26.8 (CH3). Anal. Calcd for C29H36O3Si: C, 75.61;
H, 7.88. Found: C, 75.71; H, 7.89.
For a very recent example of cyclohexilidene acetal
deprotection using ZnBr2 in a multifunctionalized substrate
see: Diaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Peris,
G.; Marco, J. A. J. Org. Chem. 2005, 70, 8130–8139.
Acknowledgements
Wethank ProfessorsJ.A. Marco and M. Carda for their helpful
suggestions during the preparation of this manuscript.
Financial support was provided through the Spanish Ministry
of Science and Technology (project BQU2002-00468) and by
the AVCyT (projects GV05/52 and GRUPOS03/180). J.M.
thanks the Spanish Ministry of Education and Science for a
4.2.5.21. 1,3-O,O-Benzylidene-5-O-benzyl-3-methyl-
pentane-1,3,5-triol (6, PZBn). Column chromatography
on silica gel (hexanes/EtOAc 4:1) afforded 6 (PZBn) (73%
´
contract of the Ramon y Cajal program. C.R. thanks the
Spanish Ministry of Education for a pre-doctoral fellowship.
1
yield) as a colourless oil. H NMR (500 MHz) d 7.60–7.39
(20H, m), 5.83 (1H, s), 5.79 (1H, s), 4.60 (4H, s), 4.19–4.14
(4H, m), 3.81 (3H, m), 3.74 (1H, t, JZ7.0 Hz), 2.6 (2H, m),
2.40–1.98 (6H, m), 1.54 (3H, s), 1.41 (3H, s); 13C NMR
(125 MHz) d 139.2, 139.0, 138.4, 138.2, 73.2, 73.1 (C),
128.4, 128.2, 128.0, 127.5, 127.4, 127.3, 126.0, 94.9, 94.7
(CH), 73.0, 72.8, 65.8, 65.6, 43.6, 35.5, 34.1, 33.1, 28.1
(CH2), 20.2 (CH3). Anal. Calcd for C20H24O3: C, 76.89; H,
7.74. Found: C, 77.01; H, 7.75.
References and notes
1. (a) Greene, G. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999; pp 201–237.
(b) Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme:
Stuttgart, 2004; pp 120–167.
4.3. General procedure for acetal cleavage with ZnBr2
2. Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath, J.
J. Org. Chem. 1997, 62, 6684–6686.
Anhydrous ZnBr2 (4–6 mmol, see Tables 1 and 2) was
added to a solution of the appropriate acetal (1 mmol) in
CH2Cl2 (10 mL). The mixture was stirred at room
temperature for the time indicated in the tables. The
reaction progress was monitored by TLC. After disappear-
ance of the starting material, EDTANa2 (2 mmol/mmol of
ZnBr2) dissolved in 10 mL of water was added to the
reaction mixture. The stirring was then continued for 2 min.
Finally, the reaction mixture was poured into brine and
extracted twice with CH2Cl2. The organic layers were dried
over anhydrous Na2SO4 and filtered. Solvent removal in
vacuo and flash chromatography on silica gel provided the
reaction products.
3. Katoh, T.; Kirihara, M.; Nagata, Y.; Kobayashi, Y.; Arai,
K.; Minami, J.; Terashima, S. Tetrahedron 1994, 50,
6239–6258.
4. Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J. Am.
Chem. Soc. 1995, 117, 8258–8270.
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3223–3226.
6. (a) Marko, I. E.; Ates, A.; Gautier, A.; Leroy, B.;
Plancher, J. M.; Quesnel, Y.; Vanherck, J. C. Angew.
Chem., Int. Ed. 1999, 38, 3207. (b) Manzo, E.; Barone, G.;
Bedini, E.; Iadonisi, A.; Mangoni, L.; Parrilli, M. Tetra-
hedron 2002, 58, 129–133.
7. (a) Debenham, J. S.; Rodebaugh, R.; Fraser-Reid, B. J. Org.
Chem. 1996, 61, 6478–6479. (b) Park, M. H.; Takeda, R.;
Nakanishi, K. Tetrahedron Lett. 1987, 28, 3823–3824. (c)
DattaGuptta, A.; Singh, R.; Singh, V. K. Synlett 1996, 69–71.
(d) Cort, A. D. Synth. Commun. 1990, 20, 757–760.
8. (a) Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett.
1983, 24, 3969–3972. (b) There is one example where ZnBr2
was used to perform a double deprotection in substrates
containing MEM, SEM or MOM groups in a 1,3-relationship
to a dithiane unit: Vakalopoulos, A.; Hoffmann, H. M. R. Org.
Lett. 2001, 3, 2185–2188.
4.3.1. 6-O-(Triisopropylsilyl)hexane-1,2,6-triol (4, PZ
TIPS). Colourless oil; 1H NMR (500 MHz) d 3.74 (1H, m),
3.71 (2H, t, JZ6.0 Hz), 3.67 (1H, dd, JZ11, 3.0 Hz), 3.45
(1H, dd, JZ11, 7.5 Hz), 1.62–1.43 (3H, m), 1.10–1.05
(24H, m); 13C NMR (125 MHz) d 72.3, 12.0 (CH), 66.8,
63.2, 32.9, 32.8, 21.9 (CH2), 18.0 (CH3). Anal. Calcd for
C15H34O3Si: C, 62.01; H, 11.80. Found: C, 62.20; H, 11.71.
4.3.2. 6-O-Benzoylhexane-1,2,6-triol (4, PZBz). Colour-
1
less oil; H NMR (500 MHz) d 8.02 (2H, d, JZ7.32 Hz),
9. Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J.;
Hamilton, G. S. Tetrahedron Lett. 2000, 41, 2847–2849.
10. Kaul, R.; Brouillette, Y.; Sajjadi, Z.; Hansford, K. A.;
Lubell, W. D. J. Org. Chem. 2004, 69, 6131.
7.54 (1H, t, JZ7.50 Hz), 7.43 (2H, t, JZ7.7 Hz), 4.32 (2H,
t, JZ6.6 Hz), 3.71 (1H, m), 3.64 (1H, dd, JZ11.0, 2.74 Hz),
3.44 (1H, dd, JZ11, 7.7 Hz), 2.89 (1H, d ancho, JZ8.4 Hz),

1244
C. Ribes et al. / Tetrahedron 62 (2006) 1239–1244
11. Crouch, R. D.; Polizzi, J. M.; Cleiman, R. A.; Yi, J.;
Romany, C. A. Tetrahedron Lett. 2002, 43, 7151–7153.
12. (a) We have only found one precedent in which acetonide
cleavage was performed with ZnBr2 in a multifunctionalized
substrate: Scarlato, G. R.; DeMattei, J. A.; Chong, L. S.;
Ogawa, A. K.; Lin, M. R.; Armstrong, R. W. J. Org. Chem.
1996, 61, 6139–6152. (b) ZnBr2 has been used in
fact, we did isolate cyclohexanone, but it seems unlikely that it
was formed through hydrolysis of the gem-dibromo derivative
during the work-up. However, the formation of A does seem
likely. Its hydrolysis to diol and ketone should occur easily
during the work-up.
14. (a) (PZTPS, THP, MOM, MEM): Guindon, Y.; Yoakim, C.;
Morton, H. E. J. Org. Chem. 1984, 49, 3912–3920. (b) (PZBn):
Lehmann, J.; Weitzel, U. P. Carbohydr. Res. 1996, 294, 65–94.
(c) (PZH): Bestmann, H. J.; Hadawi, D.; Behl, H.; Bremer, M.;
Hampel, F. Angew. Chem., Int. Ed. Engl. 1993, 105, 1205–1208.
(d) (PZTBS): Wu, Y.; Huang, J-H. ; Shen, X.; Hu, Q.; Tang,
C.-H.; Li, L. Org. Lett. 2002, 4, 2141–2144.
a
transacetalization reaction:
Nakata, M.; Arai, M.;
Tomooka, K.; Ohsawa, N.; Kinoshita, M. Bull. Chem. Soc.
Jpn. 1989, 62, 2618–2635.
13. In relation to the mechanism of the reaction, one referee
suggested one possible pathway in which a gem-dibromo
derivative would be generated via intermediate A under the
anhydrous conditions of the process:
15. Geerlof, A.; Vantol, J. B. A.; Jongejan, J. A.; Duine, J. A.
J. Chromatogr. 1993, 648, 119–129.
16. Edupuganti, O. P.; Singh, Y.; Defrancq, E.; Dumy, P. Chem.
Eur. J. 2004, 10, 5988–5995.
17. (a) (PZTPS, TBS): see Ref. 13a. (b) (PZBn): Ley, S. V.;
Ramarao, C.; Lee, A. L.; Ostergaard, N.; Smith, S. C.; Shirley,
I. M. Org. Lett. 2003, 5, 185–187. (c) (PZTHP): Nishida, A.;
Kawahara, N.; Nishida, M.; Yonemitsu, O. Tetrahedron 1996,
52, 9713–9734.
18. (a) (PZTPS): List, B.; Shabat, D.; Zhong, G.; Turner, J. M.;
Li, A.; Bui, T.; Anderson, J.; Lerner, R. A.; Barbas, C. F., III.
J. Am. Chem. Soc. 1999, 121, 7283–7291. (b) (PZBn):
Nozoe, S.; Takahashi, A.; Ohta, T. Chem. Pharm. Bull. 1993,
41, 1738–1742.
In control experiments with cyclohexanone acetals, we were
not able to detect the formation of 1,1-dibromocyclohexane. In