Novel regiocontrolled protection of 1,2and 1,3-diols via mild cleavage of methylene acetals

Article abstract of DOI:10.1021/ol902088b

The regiocontrolled protection of unsymmetrical 1,2- and 1,3-diols has been developed. Different types of protected diols are available from the methylene acetal in a one-pot procedure. Highly regioselective protection of diols with a silyl group at the l

Full text of DOI:10.1021/ol902088b

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5138-5141
Novel Regiocontrolled Protection of 1,2-
and 1,3-Diols via Mild Cleavage of
Methylene Acetals
Hiromichi Fujioka,* Kento Senami, Ozora Kubo, Kenzo Yahata,
Yutaka Minamitsuji, and Tomohiro Maegawa
Graduate School of Pharmaceutical Sciences, Osaka UniVersity,
1-6 Yamada-oka Suita, Osaka 565-0871, Japan
fujioka@phs.osaka-u.ac.jp
Received September 9, 2009
ABSTRACT
The regiocontrolled protection of unsymmetrical 1,2- and 1,3-diols has been developed. Different types of protected diols are available from
the methylene acetal in a one-pot procedure. Highly regioselective protection of diols with a silyl group at the less hindered hydroxy group
as well as with a MOM group at the more hindered one were achieved. The reaction conditions are mild without affecting other functional
groups including acid-labile function.
1,2- and 1,3-diols are the basic structures of polyhydroxy
compounds, and the protection of diols is essential for the
construction of such molecules. A variety of protective
groups for diols have been developed, and dioxolanes and
dioxanes are well-known as common protective groups.1
However, the regioselective monoprotection of unsym-
metrical diols is still a challenging theme in organic
syntheses. Such transformations are classified into two types
of protections, i.e., the protection of the less hindered hydroxy
group and protection of the more hindered one. Although a
number of monoprotections of the less hindered hydroxy
group in unsymmetrical diols has been developed,1,2 the
selective protection of the more hindered hydroxy group is
rather difficult. Conversion of cyclic acetals from diols to
monoprotected diols is one of the effective methods for the
regioselective protection at the more hindered hydroxy group.
For example, the reaction of benzylidene acetals of unsym-
metrical diols with a Lewis acid and reducing agent is a
representative method for the mono-Bn protection at the
more hindered hydroxy group.1 Yamamoto and co-workers
reported that the use of trimethyl orthoformate and DIBAL
viatheformationoftheorthoesterproducedmonomethoxym-
ethyl (MOM)-protected diols at the more hindered site.3
A similar protection from trimethyl orthoformate to the
monoester in the absence of a reducing reagent has also
been reported using Yb(OTf)3, but the selectivitiy was not
satisfactory.4 Other selective monoprotections at the more
hindered site, such as cyclic acetals-MeMgI,5 cyclic
silylene-n-BuLi6 or BF3·SMe2-allyltrimethylsilane,7 ben-
(1) (a) Wuts, P. G. W.; Greene, T. W. Greene’s ProtectiVe Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2006.
(b) Kocien˜ski, P. J. Protecting Groups, 3rd ed.; Georg Thieme Verlag:
Stuttgart, 2005.
(2) For selected reports, see: (a) Posner, G. H.; Oda, M. Tetrahedron
Lett. 1981, 22, 5003. (b) Rana, S. S.; Barlow, J. J.; Matta, K. L. Tetrahedron
Lett. 1981, 22, 5007. (c) Takano, S.; Ohkawa, T.; Ogasawara, K.
Tetrahedron Lett. 1988, 29, 1823. (d) Ishihara, K.; Kurihara, H.; Yamamoto,
H. J. Org. Chem. 1993, 58, 3791. (e) Orita, A.; Mitsutome, A.; Otera, J. J.
Org. Chem. 1998, 63, 2420. (f) Martinelli, M. J.; Nayyar, N. K.; Moher,
E. D.; Dhokte, U. P.; Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1,
(3) Takasu, M.; Naruse, Y.; Yamamoto, H. Tetrahedron Lett. 1988, 29,
1947.
(4) Ikejiri, M.; Miyashita, K.; Tsunemi, T.; Imanishi, T. Tetrahedron
Lett. 2004, 45, 1243.
(5) Cheng, W.-L.; Yeh, S.-M.; Luh, T.-Y. J. Org. Chem. 1993, 58, 5576.
(6) Tanino, K.; Shimizu, T.; Kuwahara, M.; Kuwajima, I. J. Org. Chem.
1998, 63, 2422.
447. (g) Srinivas, K. V. N. S.; Mahender, I.; Das, B. Synlett 2003, 2419
.
(7) Yu, M.; Pagenkopf, B. L. J. Org. Chem. 2002, 67, 4553.
10.1021/ol902088b CCC: $40.75
Published on Web 10/12/2009
 2009 American Chemical Society

zoyl peroxide-PPh3,8 silica gel-AcCl,9 etc., have also
been reported. However, the reagents used in these
methods are reactive and may affect other functions within
a molecule, and most of them showed moderate to good
selectivity, but not complete. On the other hand, the further
development of differential protections of both hydroxy
groups of diols with different protective groups have also
been reported. Most of them were applied to sugar
derivatives,1 and there are a few methods for the nonsugar
type diol protection, for example, using acyl chloride and
silyl chloride via a dibutylstannylene acetal intermediate
to give the regioselectively acyl and silyl protected diol.10
Bailey and co-workers developed the selective protection
of diols from methylene acetal using ZnCl2 and AcCl
which regiospecifically afforded the acetyl and MOM-
protected diols.11 However, the use of organotin compound
or acyl chloride is unfavorable in view of its toxicity and
reactivity. Therefore, the development of a mild and regio-
controlled protection method of diols has been strongly
desired. We have developed the chemoselective depro-
tection of acetals in the presence of ketals in combination
with TESOTf (triethylsilyl trifluoromethanesulfonate)-
2,4,6-collidine.12 The reaction proceeded under mild condi-
tions via the formation of pyridinium intermediates. Recently,
we demonstrated the application of this method to the mild and
selective cleavage of acetal type protective groups for hydroxy
groups such as tetrahydropyranyl (THP)13 and methoxymethyl
(MOM)14 ethers. The key to the successful cleavage is the
formation of the pyridinium intermediates followed by hydroly-
sis of the intermediates (Scheme 1).
protection of 1,2-diols from methylene acetals and that the
protection process is controllable. We now describe the mild
and regiocontrolled protection of unsymmetrical diols using
TMSOTf or TESOTf and 2,2′-bipyridyl and the successive
proper treatment leading to the selective synthesis of different
types of protected diols in a one-pot procedure.
As an ongoing study for the mild cleavage of acetal type
protections, we examined the deprotection of methylene
acetals using 4-octyl-1,3-dioxolane 1a as a substrate with
TESOTf and 2,4,6-collidine as the standard conditions.
However, no deprotection of the methylene acetal was
observed, but the pyridinium intermediate from 1a and 2,4,6-
collidine was formed (Table 1, entry 1). In our previous
Table 1. Effect of Pyridine Derivativesa
entry
pyridines
time (x/y) (h) yield (%) ratio (2a:3)
1
2
3
4
5
2,4,6-collidine
1.0/-
-/-
0.5/0.5
1.0/72
0.5/5
b
2,6-dichloropyridine
2-bromopyridine
2-phenylpyridine
2,2′-bipyridyl
N.R.c
73
59:41
17:83
57:43
100:0
69
94
90
6d 2,2′-bipyridyl
0.5/12
a The reaction of 1a was conducted with TESOTf and a base in CH2Cl2
followed by hydrolysis after the formation of the intermediate. b The
hydrolysis of the intermediate did not proceed. c No reaction. d Saturated
aq K2CO3 was used instead of H2O during the hydrolysis.
study, the structure of pyridine was found to be important
not only for the formation of the intermediate but also for
the hydrolysis of the intermediate.14,15 We then investigated
the effect of the pyridine derivatives. Although 2,6-dichlo-
ropyridine did not give the pyridinium intermediate at all
(entry 2), the cleavage of the methylene acetal proceeded
by the use of 2-bromopyridine and unexpectedly afforded a
mixture of the monosilylated diol 2a and free 1,2-diol 3
(entry 3). It is noteworthy that silylation occurred only at
the less hindered hydroxy group, and no protection at the
more hindered hydroxy group was observed. Based on the
results, we examined the highly chemo- and regioselective
silylation of an unsymmetrical diol. Other 2-substituted
pyridines were also examined, and 2,2′-bipyridyl was found
to be the most effective pyridine to give 2a and 3 in high
yield, but the selectivity is moderate (entry 5). We assumed
that the silylated product 2a was first generated in the
reaction, followed by H2O treatment that caused acidic
conditions from the residual TESOTf, and desilylation
occurred to give the 1,2-diol 3a. Alkaline hydrolysis, as
expected, significantly improved the selectivity. To our
surprise, the silylated 2a was obtained as the sole product
in 90% yield by the treatment with a saturated aqueous
K2CO3 solution (entry 6).
Scheme 1. Mild Cleavage of Acetal-Type Protective Groups in
Combination with Silyl Triflate and Pyridine Derivative
During the course of our study on the mild cleavage of
other acetal protective groups, we found the regioselective
(8) Pautard, A. M.; Evans, S. A., Jr. J. Org. Chem. 1988, 53, 2300.
(9) Ogawa, H.; Ide, Y.; Honda, R.; Chihara, T. J. Phys. Org. Chem.
2003, 16, 355.
(10) (a) Ricci, A.; Roelens, S.; Vannucchi, A. J. Chem. Soc., Chem.
Commun. 1985, 1457. (b) Reginato, G.; Ricci, A.; Roelens, S.; Scapecchi,
S. J. Org. Chem. 1990, 55, 5132. (c) Roelens, S. J. Org. Chem. 1996, 61,
5257.
(11) (a) Bailey, W. F.; Rivera, A. D. J. Org. Chem. 1984, 49, 4958. (b)
Bailey, W. F.; Zarcone, L. M. J.; Rivera, A. D. J. Org. Chem. 1995, 60,
2532. (c) Bailey, W. F.; Carson, M. W.; Zarcone, L. M. J. Organic
Syntheses; Wiley: New York, 2004; Collect. Vol. 10, p 492.
(12) (a) Fujioka, H.; Sawama, Y.; Murata, N.; Okitsu, T.; Kubo, O.;
Matsuda, S.; Kita, Y. J. Am. Chem. Soc. 2004, 126, 11800. (b) Fujioka, H.;
Okitsu, T.; Sawama, Y.; Murata, N.; Li, R.; Kita, Y. J. Am. Chem. Soc.
2006, 128, 5930.
(13) (a) Fujioka, H.; Okitsu, T.; Ohnaka, T.; Sawama, Y.; Kubo, O.;
Okamoto, K.; Kita, Y. AdV. Synth. Catal. 2007, 349, 636. (b) Fujioka, H.;
Kubo, O.; Okamoto, K.; Senami, K.; Okitsu, T.; Ohnaka, T.; Sawama, Y.;
Kita, Y. Heterocycles 2009, 77, 1089.
(14) Fujioka, H.; Kubo, O.; Senami, K.; Minamitsuji, Y.; Maegawa, T.
Chem. Commun. 2009, 4429.
(15) The addition of Et2O was necessary to prevent the undesirable side
reaction. See ref 14.
Org. Lett., Vol. 11, No. 22, 2009
5139

The chemo- and regioselective silylation of the 1,2- and
1,3-diols is shown in Table 2. The dioxolanes of the
The chemoselective and regiospecific protection of unsym-
metrical diols from methylene acetals could be explained as
follows (Scheme 2). First, the methylene acetal reacted with
TESOTf which regiospecifically coordinated at the less
hindered oxygen atom.16 The following attack of 2,2′-
bipyridyl on the methylene carbon led to the simultaneous
C-O bond cleavage at bond a to give the TES-protected
pyridinium intermediate A. Subsequent hydrolysis of A
afforded the monosilylated diol. The hydrolysis with H2O
might cause a weak acidic environment by generating TfOH
from the residual TESOTf, which could promote the hy-
drolysis of the silyl group. The use of an alkaline solution
could neutralize TfOH resulting in leaving the silyl group
intact. The accelerating effect of 2,2′-bipyridyl on the
hydrolysis may explain that the nitrogen atom on the adjacent
pyridine ring helps to bring the H2O close to the methylene
carbon and promote the nucleophilic attack by H2O.14
Table 2. Chemoselective and Regioselective Monosilylation of
Unsymmetrical 1,2- and 1,3-Diols from Methylene Acetals
Scheme 2. Plausible Reaction Mechanism
Next, we planned another type of monoprotection of the
1,2-diols. The reaction mechanism suggested that treatment
of the intermediate A with MeOH instead of an aqueous
solution would give MOM ether on the more hindered
hydroxy group. Furthermore, the choice of the Lewis acid
could affect the reaction, and the use of TMSOTf could
undergo a concomitant deprotection of the silyl group
affording the mono-MOM protected diols. As a result, the
treatment of 1a with TMSOTf-2,2′-bipyridyl17 followed by
the methanolysis exclusively led to the mono-MOM-
protected diol 4a at the more hindered hydroxy group (Table
3, entry 1). A variety of methylene acetals of 1,2- and 1,3-
diols can be converted into mono-MOM-protected diols 4
(Table 3). It should be noted that the protection of the MOM
ether onto the tert-alcohol proceeded in high yield (entry
7).
a 4.0 equiv of TESOTf and 6.0 equiv of 2,2′-bipyridyl were used. b The
reaction with TESOTf and 2,2′-bipyridyl was conducted at rt. c The time
indicated in parentheses was required for the formation of the pyridinium
intermediate. d No reaction.
unsymmetrical 1,2-diols were regiospecifically converted to
the monosilylated alcohols in good to high yields, and no
other silylated products were obtained (entries 1-9), whereas
an increase in the reagents was necessary in some cases
(entries 7 and 8). This method is applicable to the substrates
bearing various functional groups including an acid-sensitive
group (entries 3-6). Symmetrical methylene acetals 1h and
1i could also be converted into monosilylated diols (entries
8 and 9). Although the 1,3-dioxane derivative 1j was less
reactive toward the formation of the pyridinium salt, the
treatment of 1j at room temperature with TESOTf-2,2′-
bipyridyl afforded the intermediate followed by the alkaline
hydrolysis to successfully allow the regioselective formation
of the monosilylated alcohol 2j in moderate yield (53%)
(entry 10). The aromatic dioxolane 1k was inactive even at
room temperature, and no pyridinium salt was formed under
the reaction conditions (entry 11).
The regioselective protection of both hydroxy groups with
different protective groups was also possible. The reaction
of 1a with TESOTf followed by the methanolysis with
triethylamine as an additive afforded the hydroxy group
(16) The similar discrimination of two oxygen atoms by the TESOTf
was observed during the selective deprotection of the acetals in the presence
of ketals. We have discussed the reaction mechanism in detail. See refs
12b and 13a.
(17) No other pyridine derivatives afforded a better result than 2,2′-
bipyridyl.
5140
Org. Lett., Vol. 11, No. 22, 2009

Table 3. Selective Mono-MOM Protection of 1,2-Diols from
Methylene Acetals
Scheme 3
.
Simultaneous Regioselective Protection of 1,2-Diol
with TES and MOM Group
ylene acetals in combination with TESOTf or TMSOTf
and 2,2′-bipyridyl. This is a mild, simple, and convenient
method to prepare different types of protected diols in a
one-pot procedure even in the presence of acid-sensitive
functions. The present method is promising for the
construction of polyhydroxy compounds as well as
disclosing the new utilization of methylene acetals. Further
application of this method to more complex molecules is
currently underway.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research (B) and for Scientific Research
for Exploratory Research from the Japan Society for the
Promotion of Science (JSPS) and Special Coordination Funds
for Promoting Science and Technology of the Ministry of
Education, Culture, Science and Technology, the Japanese
Government.
a 1.0 equiv of Et3N was used for the methanolysis. b The time indicated
in parentheses was required for the formation of the pyridinium intermediate.
c The reaction with TMSOTf (4.0 equiv) and 2,2′-bipyridyl (6.0 equiv) was
conducted at rt.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
protected diol 5 with both TES and MOM groups as a single
product in high yield (88%) (Scheme 3).
In summary, we have developed the mild and regio-
controlled protection of unsymmetrical diols from meth-
OL902088B
Org. Lett., Vol. 11, No. 22, 2009
5141