Selective deprotection of methylene acetal and mom ether in the presence of ketal-type protective groups: Remarkable effect of tbsot

Article abstract of DOI:10.3987/COM-12-S(N)43

A novel procedure for highly selective deprotection of methylene acetals and MOM (methoxymethyl) groups in the presence of ketal-type protective groups has been developed. The method, which utilizes a combination of TBSOTf and 2,2'-bipyridyl, displays a c

Full text of DOI:10.3987/COM-12-S(N)43

HETEROCYCLES, Vol. 86, No. 1, 2012
455
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 455 - 467. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 19th June, 2012, Accepted, 20th July, 2012, Published online, 24th July, 2012
DOI: 10.3987/COM-12-S(N)43
SELECTIVE DEPROTECTION OF METHYLENE ACETAL AND MOM
ETHER IN THE PRESENCE OF KETAL-TYPE PROTECTIVE GROUPS:
REMARKABLE EFFECT OF TBSOTf†
Tomohiro Maegawa, Yasuyuki Koutani, Kento Senami, Kenzo Yahata, and
Hiromichi Fujioka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka,
Suita, Osaka 565-0871, Japan; E-mail: fujioka@phs.osaka-u.ac.jp
Abstract – A novel procedure for highly selective deprotection of methylene
acetals and MOM (methoxymethyl) groups in the presence of ketal-type
protective groups has been developed. The method, which utilizes a combination
of TBSOTf and 2,2’-bipyridyl, displays a completely opposite selectivity
compared with those of acid-mediated deprotection protocols.
INTRODUCTION
In the area of organic synthesis, acetals and ketals are among the most widely employed protective groups
for aldehydes and ketones.1 In addition, various acetal and ketal containing groups, such as MOM, BOM,
acetonides and benzylidene acetals, have also been developed for protection of alcohols and diols. These
protective groups are easily removed utilizing acidic conditions to produce the parent carbonyl and
alcohol compounds. It is well-known that under these conditions ketals are deprotected more rapidly than
acetals owing to the relative stabilities of the respective oxonium ion intermediates.2 The reactivities of
acetal and ketal protective groups display the same trend, and methylene acetals are more robust diol
protecting groups under acidic conditions than their counterparts. In fact, acetonides are preferentially
cleaved under acidic conditions in the presence of methylene acetals3 (Scheme 1). In contrast, it is often
difficult to cleave methylene acetals using mildly acidic conditions and, as a result, they are rarely used in
organic synthesis because strong Lewis acids often need to be employed for their removal.1
Me
Me
HO
O
CF3CO2H–H2O
rt
O
O
HO
O
O
O
7
7
1a
2 (87%)
Scheme 1. Deprotection of 1a, containing an acetonide and methylene acetal, under acidic conditions
† This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
In recent studies, we investigated the reactivity of stable cationic species, including pyridinium-type salts
generated by the reaction of acetals with TESOTf and 2,4,6-collidine. These salts were found to readily
react with various nucleophiles including water (Scheme 2, eq. 1).4
OMe
N
TESOTf
2,4,6-collidine
-OTf
OMe
OMe
OMe
OH
H2O
rt
O
(eq.1)
(eq.2)
R
R
R
CH2Cl2, 0 ºC
R
H
-OTf
TMSOTf
2,2'-bipyridyl
H2O-Et2O
or
N
R O
R OH
R OMOM
N
CH2Cl2, 0 ºC
1N HCl-Et2O
TMSOTf
2,2'-bipyridyl
H2O-Et2O
or
N
O
OH
N
O
(eq.3)
OH
O
R
CH2Cl2, 0 ºC
R
1N HCl-Et2O
OTMS
-OTf
R
Scheme 2. Mild deprotection of acetals via the corresponding pyridinium salts
The results of this effort showed that the process, involving formation and hydrolysis of pyridinium salts,
serves as a mild method for deprotection of acetal groups, THP and MOM ethers, as well as methylene
acetals.5-7 In the cases of MOM and related ethers, the combination of TMSOTf (or TESOTf) and
2,2’-bipyridyl can be used for effective deprotection.6 In this process, 2,2’-bipyridylium salts are formed
in situ and readily undergo hydrolysis to generate hemiacetals in routes to formation of parent alcohols
(Scheme 2, eq. 2). The conditions employed are sufficiently mild to enable acid-labile groups, such as
TBS and trityl (triphenylmethyl), to survive the reaction. It is noteworthy that, depending on the work-up
conditions utilized to treat the intermediates, methylene acetals are also cleaved to afford the
corresponding diols and their derivatives.7 For example, employment of acidic work-up (eg., 1N HCl)
leads to formation of fully deprotected diols (Scheme 2, eq. 3), whereas basic work-up (satd. K2CO3 aq)
can be employed to regioselectively generate monosilylated diols. Finally, methanolysis of cationic
intermediates produces MOM protected diols in a regioselective manner.
The results of the studies described above indicate that TMSOTf (or TESOTf) would be capable of
distinguishing between the different steric environments present in bis-acetals that contain the less
crowded oxygen of methylene acetals. Initial work aimed at probing the selective deprotection process
focused on the mixed ketal/acetal 1b, possessing a bulky benzophenone ketal and unhindered methylene
acetal. Benzophenone ketals are known to be cleaved using weakly acidic conditions, such as AcOH or

HETEROCYCLES, Vol. 86, No. 1, 2012
457
dilute HCl.1 In contrast, the results of this study showed that the methylene acetal moiety in 1b is
selectively removed employing the TMSOTf based deprotection method (Scheme 3).7b
Ph
O
Ph
O
TMSOTf
2,2'-bipyridyl 1N HCl–Et2O
Ph
Ph
O
OH
O
O
O
OH
rt, 3h
CH2Cl2, 0 ºC
0.5 h
8
8
1b
3
(78%)
Scheme 3. Selective deprotection of a methylene acetal in the presence of a benzophenone ketal
RESULTS AND DISCUSSION
In a more thorough investigation, summarized below, we explored the scope and limitations of the novel
method for highly selective deprotection of acetals in the presence of ketals that takes advantage of the
remarkable properties of TBSOTf. In the initial phase of this effort, we investigated reactions of 1c,
which contains a methylene acetal and a cyclohexylidene ketal. An attempt to promote selective
deprotection of 1c using TESOTf and 2,2’-bipyridyl followed by base treatment led to formation of 4a in
a 28% yield. Moreover, enol ether 4a’ was produced as the major product (55%) in this process through
-elimination of the TESOTf activated cyclohexylidene acetal (Scheme 4).
TESOTf (2 equiv)
2,2'-bipyridyl (3 equiv)
K2CO3 aq
Et2O, rt
O
OH
O
OH
O
O
+
OTES
TESO
OTES
O
O
O
CH2Cl2, 0 ºC
7
7
7
1c
4a (28%)
4a' (55%)
Base
H
O
O
TESO
O
TESOTf
4a'
the mechanism of enol ether formation
Scheme 4. Initial attempt to promote selective deprotection of methylene acetal in the presence of
cyclohexylidene acetal by using the TESOTf−2,2’-bipyridyl combination
This observation indicated that the steric bulkiness of TESOTf was insufficient to discriminate between
the oxygens in the methylene acetal and the cyclohexylidene ketal moieties. Consequently, we next

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HETEROCYCLES, Vol. 86, No. 2, 2012
investigated the use of more bulky TBSOTf in this process and found that the selectively
acetal-deprotected product 4b is generated exclusively in a 92% (Table 1, entry 1). In addition, the results
showed that the methylene acetal group can be preferentially cleaved when other ketal protective groups
are present. This selectivity is observed even in bis-ketal/acetals containing cyclopentylidene ketals,
which are typically more highly susceptible to acid-catalyzed hydrolysis than cyclohexylidene ketals and
acetonides8 (Table 1, entries 2 and 3). As expected, a contrastingly different reaction profile is observed
when 1a is subjected to an acid-catalyzed deprotection reaction, which leads to formation of ketal
deprotected product 2 (Scheme 1, Table 1, entry 4).
Table 1. Selective deprotection of a methylene acetal in the presence of ketal protective groups by using
TBSOTf
R2
O
R2
O
TBSOTf (2 equiv)
2,2'-bipyridyl (3 equiv)
R1
R1
K2CO3 aq
rt, time B
HO
O
O
OH
+
OTBS
HO
O
O
O
O
CH2Cl2, rt, time A
7
7
7
1
4
2
entry R1
R2
time A (h)
time B (h)
yield (%)
92 (4b)
96 (4c)
95 (4d)
1
2
−(CH2)5− (1c)
−(CH2)4− (1d)
Me (1a)
1.5
0.5
1.5
−
8
7
3
Me
Me
12
4a
Me (1a)
1.5
0 (87 (2))b
a The reaction was conducted under acidic conditions (CF3CO2H-H2O). b The yield of 2 is indicated in the
parenthesis.
Additional studies showed that the TBSOTf based method can be employed in a diverse array of selective
deprotection reactions of methylene acetals (Scheme 5). For example, basic work-up of the intermediate,
2,2’-bipyridilium salt, formed by treatment of 1a with the TBSOTf−2,2’-bipyridyl combination, affords
the mono-TBS protected diol 4d in 95% yield. In addition, treatment of the salt with methanol and
triethylamine results in regioselective generation of the MOM and TBS protected diol 5 in high yield
(93%). Finally, conversions of the salt derived from 1a to diol 6 and mono-MOM protected diol 7 are
achieved by using a one-pot protocol involving initial work-up with saturated K2CO3 aqueous solution
and methanol, respectively, followed by treatment with TBAF/THF solution in one-pot.

HETEROCYCLES, Vol. 86, No. 1, 2012
459
Me
O
Me
K2CO3 aq
Et2O, rt
OH
O
OTBS
7
4d (95%)
Me
Me
OMOM
OTBS
MeOH
O
-OTf
Me
O
O
TBSOTf
2,2'-bipyridyl
Et3N, rt
N
Me
Me
O
7
N
Me
O
O
5 (93%)
O
O
CH2Cl2, rt
O
OTBS
7
7
1a
Me
Me
K2CO3 aq
O
OH
O
OH
Et2O, rt
7
then TBAF
6 (93%)
Me
Me
OMOM
MeOH
O
O
OH
Et3N, rt
7
then TBAF
7 (71%)
Scheme 5. Diverse deprotection reactions of the methylene acetal in the presence of acetonide function
Owing to the fact that MOM ethers also contain sterically unhindered acetal moieties, we presumed that
they would be cleaved in preference to ketal protective groups. A method for selective deprotection of
MOM ethers in the presence of acetonides and THP ethers, employing dimethylboron bromide and
diphenylboron bromide at −78 ºC, has been described by Guindon and co-workers.9 However, these
reagents are also capable of cleaving a variety of ethers and potentially can have effects on acid-sensitive
functionality.
In studies probing the selective deprotection of MOM ethers 8a-c, which also contain ketals, we observed
that the use of increased quantities of TBSOTf and 2,2’-bipyridyl are required (Table 2). Under these
conditions, selective deprotection of the MOM ether moieties was found to take place in high yields
without adverse effects on cyclohexylidene, cyclopentylidene and acetonide ketal groups (entries 1-3). In
addition, more bulky sec- and tert-MOM ethers 8d and 8e undergo the selective deprotection process
under the optimized conditions to give the corresponding alcohols 9d and 9e in 93% and 91% yields,
respectively (entries 4 and 5). In these cases, acid-promoted hydrolysis results in preferential deprotection
of the ketal protective groups, leaving the MOM ethers intact (Scheme 6).

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HETEROCYCLES, Vol. 86, No. 2, 2012
Table 2. Selective deprotection of MOM ethers in the presence of other ketal protective groups
R2
R2
R1
TBSOTf (4 equiv)
2,2'-bipyridyl (6 equiv)
R1
R3 R4
OMOM
O
R3 R4
OH
K2CO3 aq
O
O
O
CH2Cl2, rt, time A
Et2O, rt
time B
8
8
8
9
entry
R1
R2
R3
R4
time A (h) time B (h) yield (%)
1
2
3
4
5
−(CH2)5−
−(CH2)4−
Me
H
H (8a)
H (8b)
H (8c)
H (8d)
Me (8e)
7
7
6
6
6
12
15
9
98 (9a)
92 (9b)
96 (9c)
93 (9d)
91 (9e)
H
Me
Me
Me
H
Me
Me
Me
14
2
Me
HO
O
AcOH / H2O
HO
O
OMOM
OMOM
50 ºC, 3 h
8
8
8a
10
(73%)
Scheme 6. Acid promoted hydrolysis of the mixed MOM and cyclohexylidene protected substance 8a
A plausible mechanism for the selective deprotection process is depicted in Scheme 7. The initial and the
most significant step in the pathway is Lewis acid coordination of TBSOTf to the acetal, which takes
place in a highly discriminatory manner at the least sterically encumbered acetal. This conclusion is
consistent with the observation that no selectivity is displayed in reactions promoted using the less
sterically demanding TESOTf rather than TBSOTf. It is interesting to note that strict discrimination
among four oxygen atoms is observed in these processes. Successive attack of 2,2’-bipyridyl on the
complex then leads to formation of the salt intermediate in a chemo- and regioselective fashion. Finally,
work-up with H2O affords the corresponding deprotected substances via hemi-acetal intermediate.

HETEROCYCLES, Vol. 86, No. 1, 2012
461
N
R2
R2
R2
R1
R1
N
R1
O
O
O
O
O
O
-OTf
O
O
O
O
O
OTBS
TBSOTf
2,2'-bipyridyl
n
TBSOTf
CH2Cl2
n
n
1
R2
R2
R2
O
R1
R3 R4
R1
R1
O
R3 R4
O
R3 R4
N
N
TBSOTf
O
O
O
O
O
n
OMOM
O
n
n
-OTf
8
selective coordination
R2
OH
O
R2
O
R1
O
OH
R1
O
OTBS
O
OTBS
n
K2CO3 aq
Et2O, rt
n
4
R2
O
R2
R1
R1
R3 R4
R3 R4
OH
O
O
O
O
OH
n
n
9
Scheme 7. A plausible mechanism for the TBSOTf promoted selective deprotection reaction
In conclusion, in the effort described above, we developed a novel, selective procedure for methylene
acetal deprotection in substances that also contain ketal protective groups. This method displays a
selectivity that is opposite to that of acid-mediated hydrolysis reactions because the reactivity differences
arise from steric and not electronic effects. The new method is also applicable to MOM ether selective
deprotection of substances in the presence of ketal-type protective groups. We believe that the current
study has provided useful information about acetal deprotection reactions that will benefit those involved
in the area of synthetic organic chemistry.
EXPERIMENTAL
General Information
Melting point (mp) was measured by Büchi B-545. Infrared spectra (IR) were recorded by Shimadzu
1
FTIR 8400 using a diffuse reflectance measurement of samples dispersed in KBr powder. H NMR and
13C NMR spectra were recorded on a JEOL JNM-LA 500, JNM-ECS 400, JNM-AL 300 spectrometer in
CDCl3 with tetramethylsilane as an internal standard. Data are reported as follows: chemical shift in ppm
(), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet),
coupling constant (Hz) and integration. Mass spectra were obtained on a Shimadzu GCMS-QP 5000

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HETEROCYCLES, Vol. 86, No. 2, 2012
instrument with ionization voltages of 70 eV. Column chromatography and TLC were carried out on
Merck Silica gel 60 (230-400 mesh), Kanto Kagaku Silica gel 60N (40-50 m, spherical, neutral), and
Merck silica gel F254 plates (0.25 mm), respectively. The commercially available reagents were used
without further purification. Compounds 9c9 is known compound.
Acidic hydrolysis of 1a (Scheme 1)
1a (39.5 mg, 0.145 mmol) was treated with CF3COOH (0.7 mL) and H2O (0.6 mL) for 1.5 h at room
temperature. Then the mixture was extracted with CH2Cl2 (30 mL × 3) and the combined organic layers
was dried over Na2SO4 and concentrated in vacuo. The residue was subjected to flash column
chromatography (SiO2, hexanes/AcOEt = 10/1) affording 2 as colorless oil (29.1 mg, 87%).
9-(1,3-Dioxolan-4-yl)nonane-1,2-diol (2)
1
White solid (mp 39-42 °C); IR (KBr): 3395, 2932, 2361, 1466 cm-1; H NMR (400 MHz, CDCl3) δ:
1.21-1.41 (m, 13H), 1.53-1.68 (m, 1H), 2.01 (brs, 1H), 2.12 (brs, 1H), 3.35-3.45 (m, 2H), 3.59-3.74 (m,
13
2H), 3.89-4.02 (m, 2H), 4.84 (s, 1H), 4.99 (s, 1H); C NMR (100 MHz, CDCl3) δ: 25.5, 25.8, 29.43,
29.47, 29.5, 32.9, 33.1, 66.8, 69.6, 72.2, 76.2, 94.8; HRMS (FAB) calcd for C12H25O4 (M+H+) 233.1753,
found 233.1743.
The Selective Deprotection of 1b (Scheme 3)
TMSOTf (73.1 L, 0.404 mmol) was added to a solution of 1b (82.9 mg, 0.202 mmol) and 2,2’-bipyridyl
(94.6 mg, 0.606 mmol) in CH2Cl2 (0.4 ml) at 0 °C under N2. The reaction mixture was stirred for 30 min
at 0 °C. After disappearance of 1b on TLC, Et2O (2 ml) and 1N HCl (2 ml) was added to the reaction
mixture. The resulting solution was stirred until disappearance of the pyridinium salt (highly polar
compound). The mixture was extracted with CH2Cl2. The combined organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography (SiO2,
hexanes/AcOEt = 1/1) to give a diol 3 (63.1 mg, 78%).
10-(2,2-Diphenyl-1,3-dioxolan-4-yl)decane-1,2-diol (3)
Colorless oil; IR (KBr): 3582, 2934, 2305 cm-1; 1H NMR (500 MHz, CDCl3) δ: 1.24-1.74 (m, 16H), 2.38
(brs, 2H), 3.39-3.42 (m, 1H), 3.61-3.69 (m, 3H), 4.08-4.16 (m, 2H), 7.24-7.34 (m, 6H), 7.48-7.52 (m,
13
4H); C NMR (125 MHz, CDCl3) δ:25.5, 25.7, 29.4, 29.47, 29.51, 33.1, 33.4, 66.8, 70.0, 72.3, 76.8,
109.3, 126.2, 127.8, 127.9, 128.1, 142.8; HRMS (EI) calcd for C25H34O4 (M+) 398.2457, found 398.2452.
The reaction of 1c with TESOTf and 2,2’-bipyridyl (Scheme 4)
TESOTf (94.5 μL, 0.42 mmol) was added dropwise to a solution of methylene acetal 1c (65.4 mg, 0.21
mmol) and 2,2′-bipyridyl (98.0 mg, 0.63 mmol) in CH2Cl2 (0.42 mL) at 0 ºC under N2. The reaction

HETEROCYCLES, Vol. 86, No. 1, 2012
463
mixture was stirred at the same temperature. After checking the disappearance of 1c on TLC (1.5 h), satd.
aq. K2CO3 (2 mL) and Et2O (2 mL) were added to the reaction mixture, which was then stirred vigorously.
After disappearance of the high polar component, monitored by TLC, the mixture was extracted with
CH2Cl (30 mL × 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was subjected to flash column chromatography (SiO2, hexane/AcOEt = 8/1) to give 4a
as yellow oil; 24.4 mg (28%) and 4a’ as colorless oil; 60.8 mg (55%).
9-(1,4-Dioxaspiro[4.5]decan-2-yl)-1-(triethylsilyloxy)nonan-2-ol (4a)
Colorless oil; IR (KBr): 2936, 2251, 1462 cm-1; 1H NMR (300 MHz, CDCl3) δ: 0.60 (q, J = 7.8 Hz, 6H),
0.94 (t, J = 7.8 Hz, 9H), 1.21-1.65 (m, 24H), 2.48 (brs, 1H), 3.30-3.37 (m, 1H), 3.44-3.49 (m, 1H),
13
3.57-3.66 (m, 2H), 3.97-4.06 (m, 2H); C NMR (100 MHz, CDCl3) δ: 4.3, 6.7, 23.9, 24.0, 25.2, 25.6,
25.7, 29.4, 29.58, 29.59, 32.7, 33.8, 35.3, 36.6, 66.9, 69.1, 71.8, 75.7, 109.1; HRMS (EI) calcd for
C23H46O4Si (M+) 414.3165, found 414.3156.
11, 14-Bis(triethylsilyloxy)-13-(cyclohex-1’-enyloxy)-dodecan-2-ol (4a’)
Colorless oil, IR (KBr): 2936, 2251, 1664, 1456 cm-1; 1H NMR (500 MHz, CDCl3) δ: 0.53-0.63 (m, 12H),
0.89-0.97 (m, 18H), 1.23-1.65 (m, 18H), 1.97-2.04 (m, 4H), 2.44 (brs, 1H), 3.33-3.36 (m, 1H), 3.50-3.66
13
(m, 4H), 3.90-3.95 (m, 1H), 4.62-4.65 (m, 1H); C NMR (100 MHz, CDCl3) δ: 4.1, 4.3, 6.6, 6.7, 22.7,
23.0, 23.6, 25.4, 25.6, 28.1, 29.5, 29.7, 31.2, 32.7, 64.1, 66.9, 71.9, 75.8, 95.1, 153.3; HRMS (EI) calcd
for C29H60O4Si2 (M+) 528.4030, found 528.4027.
Typical procedure for selective conversion of methylene acetals to mono-TBS protected diols 4
(Table 1). TBSOTf (91.9 L, 0.40 mmol) was added dropwise to a solution of methylene acetal 1c (62.3
mg, 0.20 mmol) and 2,2′-bipyridyl (93.7 mg, 0.60 mmol) in CH2Cl2 (0.4 mL) at room temperature under
N2. After observing the disappearance of 1c by using TLC (1.5 h), satd. aq. K2CO3 (2 mL) and Et2O (2
mL) were added to the mixture, which was then stirred vigorously. After disappearance of the high polar
component, monitored by using TLC (8 h), the mixture was extracted with CH2Cl2 (20 mL × 3). The
combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was
subjected to flash column chromatography (SiO2, hexanes/AcOEt = 5/1) to give the mono-TBS protected
alcohol 4b (76.1 mg, 92%).
1-(tert-Butyldimethylsilyloxy)-9-(1,4-dioxaspiro[4.5]decan-2-yl)nonan-2-ol (4b): Colorless oil; IR
1
(KBr): 2932, 1464 cm-1; H NMR (300 MHz, CDCl3) δ: 0.05 (s, 6H), 0.89 (s, 9H), 1.17-1.69 (m, 24H),
13
2.41 (brs, 1H), 3.32-3.39 (m, 1H), 3.44-3.49 (m, 1H), 3.57-3.61 (m, 2H), 3.99-4.06 (m, 2H); C NMR
(100 MHz, CDCl3) δ: -5.39, -5.44, 18.2, 23.8, 24.0, 25.2, 25.5, 25.7, 25.8, 29.4, 29.5, 29.6, 32.7, 33.7,
35.3, 36.6, 67.2, 69.1, 71.8, 76.7, 109.0; HRMS (FAB) calcd for C23H47O4Si (M++H) 415.3244, found
415.3250.

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HETEROCYCLES, Vol. 86, No. 2, 2012
1-(tert-Butyldimethylsilyloxy)-9-(1,4-dioxaspiro[4.4]nonan-2-yl)nonan-2-ol (4c): Colorless oil; IR
(KBr): 3574, 2929, 2247, 1462 cm-1; 1H NMR (400 MHz, CDCl3) δ: 0.03 (s, 6H), 0.86 (s, 9H), 1.20-1.47
(m, 13H), 1.58-1.79 (m, 9H), 2.43 (brs, 1H), 3.32-3.37 (m, 1H), 3.42 (t, J = 6.8 Hz,1H), 3.56-3.62 (m,
13
2H), 3.92-3.99 (m, 2H); C NMR (100 MHz, CDCl3) δ: -5.45, -5.38, 18.2, 23.3, 23.6, 25.5, 25.7, 25.8,
29.4, 29.53, 29.56, 32.7, 33.6, 36.3, 36.7, 67.2, 69.2, 71.7, 75.9, 118.5; HRMS (EI) calcd for C22H44O4Si
(M+) 400.3009, found 400.3011.
1-(tert-Butyldimethylsilyloxy)-9-(2,2-dimethyl-1,3-dioxolan-4-yl)nonan-2-ol (4d): Colorless oil; IR
(KBr): 3572, 2930, 2249, 1464 cm-1; 1H NMR (500 MHz, CDCl3) δ: 0.05 (s, 6H), 0.88 (s, 9H), 1.23-1.66
13
(m, 20H), 2.40 (brs, 1H), 3.36 (m, 1H), 3.46-3.49 (m, 1H), 3.58-3.61 (m, 2H), 4.00-4.06 (m, 2H); C
NMR (75 MHz, CDCl3) δ: -5.44, -5.37, 18.3, 25.5, 25.72, 25.83, 26.9, 29.38, 29.54, 29.56, 32.7, 33.5,
67.2, 69.5, 71.7, 76.1, 108.5; HRMS (FAB) calcd for C20H43O4Si (M+ +H) 375.2931, found 375.2948.
Typical procedure for the selective deprotection of methylene acetal 1a (Scheme 5)
Conversion of 1a to mono-TBS protected diol 4d. See the procedure for Table 1.
Conversion of 1a to MOM and TBS-protected diol 5. TBSOTf (114.0 μL, 0.49 mmol) was added
dropwise to a solution of methylene acetal 1a (64.4 mg, 0.24 mmol) and 2,2′-bipyridyl (116.0 mg, 0.74
mmol) in CH2Cl2 (0.5 mL) at room temperature under N2. After observing the disappearance of 1a by
using TLC (1.5 h), Et3N (98.0 μL, 0.71 mmol) and MeOH (2 mL) were added to the mixture, which was
then stirred vigorously. After disappearance of the high polar component, monitored by using TLC (12 h),
the mixture was extracted with AcOEt (20 mL × 3). The combined organic layers was washed with 3.5%
aq. HCl (20 mL), H2O (20 mL) and satd. aq. NaHCO3 (20 mL). The organic layer was dried over Na2SO4,
filtered and concentrated in vacuo. The residue was subjected to flash column chromatography (SiO2,
hexanes/AcOEt = 10/1) affording product 5 (91.5 mg, 93%).
5-[7-(2,2-Dimethyl-1,3-dioxolan-4-yl)heptyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane
(5):
1
Yellow oil; IR (KBr): 2929, 2249, 1464 cm-1; H NMR (400 MHz, CDCl3) δ: 0.02 (s, 6H), 0.85 (s, 9H),
1.19-1.64 (m, 20H), 3.34 (s, 3H), 3.45 (t, J = 6.8 Hz, 1H), 3.52-3.58 (m, 3H), 3.97-4.03 (m, 2H), 4.61 (d,
J = 6.8 Hz, 1H), 4.74 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: -5.46, -5.42, 18.2, 25.3, 25.7,
25.9, 26.9, 29.4, 29.57, 29.59, 31.6, 33.5, 55.4, 65.8, 69.5, 76.1, 78.1, 96.2, 108.5; HRMS (FAB) calcd for
C22H46O5SiNa (M++Na) 441.3012, found 441.3029.
Conversion of 1a to diol 6. TBSOTf (107.0 μL, 0.47 mmol) was added dropwise to a solution of
methylene acetal 1a (63.5 mg, 0.23 mmol) and 2,2′-bipyridyl (109.0 mg, 0.70 mmol) in CH2Cl2 (1.2 mL)
at room temperature under N2. After observing the disappearance of 1a on TLC (1 h), satd. aq. K2CO3
(0.5 mL) and Et2O (0.5 mL) were added to the mixture, which was then stirred vigorously. After

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disappearance of the high polar component, monitored by using TLC (17 h), TBAF (1.0 M THF solution,
1.16 mL, 1.16 mmol) was added to the mixture, which was then stirred for 9 h. The mixture was extracted
with CH2Cl2 (20 mL × 3) and the combined organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was subjected to flash column chromatography (SiO2, AcOEt only)
affording product 6 (56.2 mg, 93%).
9-(2,2-Dimethyl-1,3-dioxolan-4-yl)nonane-1,2-diol (6): Colorless oil; IR (KBr): 3402, 2931, 2250, 1464
cm-1; 1H NMR (400 MHz, CDCl3) δ: 1.23-1.50 (m, 19H), 1.56-1.66 (m, 1H), 1.99 (brs, 2H), 3.39-3.49 (m,
2H), 3.62-3.70 (m, 2H), 3.99-4.07 (m, 2H); 13C NMR (75 MHz, CDCl3) δ: 25.5, 25.68, 25.71, 26.9, 29.3,
29.47, 29.51, 33.1, 33.5, 66.8, 69.5, 72.2, 76.1, 108.6; HRMS (FAB) calcd for C14H29O4 (M++H)
261.2066, found 261.2090.
Conversion of 1a to mono-MOM protected diol 7. TBSOTf (127.0 μL, 0.55 mmol) was added
dropwise to a solution of methylene acetal 1a (73.9 mg, 0.27 mmol) and 2,2′-bipyridyl (130.0 mg, 0.83
mmol) in CH2Cl2 (0.55 mL) at room temperature under N2. After observing the disappearance of 1a by
using TLC (1.5 h), MeOH (0.5 mL) and Et3N (112 μL, 0.81 mmol) were added to the mixture, which was
then stirred vigorously. After disappearance of high polar component, monitored by using TLC (4 h),
TBAF (1.0 M THF solution, 1.35 mL, 1.35 mmol) was added to the mixture, which was stirred for 24 h.
The mixture was extracted with AcOEt (20 mL × 3) and the combined organic layers was washed with
3.5% aq. HCl (20 mL), H2O (20 mL) and satd. aq. NaHCO3 (20 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography
(SiO2, hexanes/AcOEt = 2/1) affording product 7 (58.5 mg, 71%).
9-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-(methoxymethoxy)nonan-1-ol (7): Colorless oil; IR (KBr): 3450,
2931, 2249, 1456 cm-1; 1H NMR (400 MHz, CDCl3) δ: 1.21-1.57 (m, 20H), 3.10 (brs, 1H), 3.39 (s, 3H),
3.42-3.54 (m, 4H), 3.97-4.04 (m, 2H), 4.64 (d, J = 6.8 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 25.4, 25.68, 25.69, 26.9, 29.3, 29.46, 29.51, 31.6, 33.5, 55.6, 65.6, 69.4, 76.1, 82.2, 96.9,
108.5; HRMS (FAB) calcd for C16H33O5 (M++H) 305.2328, found 305.2326.
Typical procedure for selective deprotection of MOM ether 8 (Table 2). TBSOTf (170.9 μL, 0.74
mmol) was added dropwise to a solution of MOM ether 8a (61.2 mg, 0.19 mmol) and 2,2′-bipyridyl
(174.3 mg, 1.12 mmol) in CH2Cl2 (0.93 mL) at room temperature under N2. After observing the
disappearance of 8a by using TLC (7 h), satd. aq. K2CO3 (2 mL) and Et2O (2 mL) were added to the
mixture, which was then stirred vigorously. After disappearance of high polar component, monitored by
using TLC (12 h), the mixture was extracted with AcOEt (20 mL × 3). The combined organic layer was
washed with 3.5% aq. HCl (20 mL), H2O (20 mL) and satd. aq. NaHCO3 (20 mL). The organic layer was

466
HETEROCYCLES, Vol. 86, No. 2, 2012
dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to flash column
chromatography (SiO2, hexanes/AcOEt = 8/1) affording product 9a (52.1 mg, 98%).
1
9-(1,4-Dioxaspiro[4.5]decan-2-yl)nonan-1-ol (9a): Colorless oil; IR (KBr): 2934, 2253, 1464 cm-1; H
NMR (400 MHz, CDCl3) δ: 1.23-1.65 (m, 26H), 3.45-3.49 (m, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.98-4.07 (m,
2H); 13C NMR (100 MHz, CDCl3) δ: 23.8, 23.9, 25.1, 25.7, 29.31, 29.35, 29.4, 29.5, 32.7, 33.7, 35.2, 36.5,
62.8, 69.0, 75.7, 109.0; HRMS (FAB) calcd for C17H33O3 (M++H) 285.2430, found 285.2430.
9-(1,4-Dioxaspiro[4.4]nonan-2-yl)nonan-1-ol (9b): Yellow oil; IR (KBr): 3404, 2929, 2250, 1466 cm-1;
1H NMR (400 MHz, CDCl3) δ: 1.27-1.80 (m, 24H), 3.43-3.46 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.94-3.99
(m, 2H); 13C NMR (100 MHz, CDCl3) δ: 23.3, 23.5, 25.6, 29.3, 29.36, 29.41, 29.5, 32.7, 33.5, 36.3, 36.7,
62.9, 69.2, 75.9, 118.5; HRMS (EI) calcd for C16H30O3 (M+) 270.2195, found 270.2208.
1
9-(2,2-Dimethyl-1,3-dioxolan-4-yl)nonan-1-ol (9c)9: Colorless oil; H NMR (300 MHz, CDCl3) δ:
1.17-1.65 (m, 22H), 3.40-3.47 (m, 1H), 3.57 (t, J = 6.5 Hz, 2H), 3.94-4.05 (m, 2H)
10-(2,2-Dimethyl-1,3-dioxolan-4-yl)decan-2-ol (9d): Colorless oil; IR (KBr): 3616, 3465, 3155, 2931,
1
2250, 1456 cm-1; H NMR (500 MHz, CDCl3) δ: 1.15-1.49 (m, 23H), 1.59-1.65 (m, 2H), 3.46-3.49 (m,
13
1H), 3.74-3.77 (m, 1H), 3.99-4.07 (m, 2H); C NMR (125 MHz, CDCl3) δ: 23.4, 25.73, 29.75, 26.9,
29.41, 29.47, 29.58, 29.61, 33.5, 39.3, 68.1, 69.5, 76.2, 108.6; HRMS (FAB) calcd for C15H31O3 (M++H)
259.2273, found 259.2258.
10-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-methyldecan-2-ol (9e): Colorless oil; IR (KBr): 3417, 2931,
2249, 1714, 1456 cm-1; 1H NMR (400 MHz, CDCl3) δ: 1.11-1.68 (m, 28H), 3.43-3.48 (m, 1H), 3.97-4.06
13
(m, 2H); C NMR (75 MHz, CDCl3) δ: 24.3, 26.0, 26.9, 29.1, 29.41, 29.45, 29.47, 29.55, 29.60, 30.1,
33.5, 43.9, 69.5, 71.0, 76.1, 108.5; HRMS (FAB) calcd for C16H32O3Na (M++Na) 295.2249, found
295.2250.
Acidic hydrolysis of 8a (Scheme 6)
8a (39.7 mg, 0.121 mmol) was treated with AcOH (1.2 mL) and H2O (0.3 mL) at 50 °C and stirred for 3 h.
Satd. aq. NaHCO3 was added to the reaction mixture and the mixture was extracted with AcOEt (30 mL ×
3). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue
was subjected to flash column chromatography (SiO2, hexanes/AcOEt = 10/1) affording 10 (21.9 mg,
73%).
11-(Methoxymethoxy)undecane-1,2-diol (10): white solid (mp 40-41 °C); IR (KBr): 3366, 2929, 2251,
1
1465 cm-1; H NMR (400 MHz, CDCl3) δ: 1.26-1.40 (m, 14H), 1.52-1.59 (m, 2H), 2.20 (t, J = 5.6 Hz,
1H), 2.28 (t, J = 4.0 Hz, 1H), 3.33 (s, 3H), 3.37-3.42 (m, 1H), 3.49 (t, J = 6.8 Hz, 2H), 3.60-3.68 (m, 2H),
13
4.59 (s, 2H); C NMR (100 MHz, CDCl3) δ: 25.5, 26.1, 29.42, 29.45, 29.5, 29.6, 29.7, 33.1, 55.1, 66.8,
67.8, 72.3, 96.3; HRMS (FAB) calcd for C13H29O4 (M+H+) 249.2066, found 249.2061.

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ACKNOWLEDGEMENTS
This work was financially supported by the Hoansha Foundation, the Uehara Memorial Foundation, and
Granted-in-aid for scientific research from the Ministry of Education, Culture, Sports, Sciences, and
Technology of Japan.
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