Optical resolution of C2-symmetric racemic 1,4-diols with o-xylylene structure by chiral resolving agent (S)-ALBO-V

Article abstract of DOI:10.1246/bcsj.20150066

Optical resolution of C₂-symmetric racemic 1,4-diols, 1,2-bis(1-hydroxyalkyl)benzene, was examined using (S)-5-allyl-2-oxabicyclo[3.3.0]octene ((S)-ALBO-V) as chiral resolving agent. Diastereomeric acetals obtained from the 1,4-diols with (S)-A

Full text of DOI:10.1246/bcsj.20150066

Short Articles
On the other hand, optical resolution is another method to
obtain optically active compounds. As for the optical resolution
of chiral secondary alcohols, (S)-5-allyl-2-oxabicyclo[3.3.0]-
octene ((S)-ALBO-V) was reported as a useful chiral resolving
agent.9 Various diastereomeric acetals prepared from racemic
secondary alcohols with (S)-ALBO-V were easily separated by
silica-gel column chromatography, and both enantiomers of the
alcohols with high enantiomeric excesses were easily obtained
after removal of (S)-ALBO-V by deacetalization. Herein, we
established a facile procedure for the preparation of both enan-
tiomers of chiral 1,4-diols 1 bearing various alkyl groups by
optical resolution using (S)-ALBO-V.
Optical Resolution of C2-Symmetric
Racemic 1,4-Diols with o-Xylylene
Structure by Chiral Resolving
Agent (S)-ALBO-V
Masatoshi Asami,* Lvling Zhong, Naoki Sekiguchi,
Kumiko Yamada, Yuya Hiwatashi,
Toshiro Taniguchi, Naoya Hosoda, and Suguru Ito
In the first place, various racemic 1,4-diols 1a-1g were syn-
thesized from o-phthalaldehyde (2) and the corresponding
Grignard reagents according to a known procedure with slight
modification (Table 1).10 Namely, to dialdehyde 2 in cyclo-
pentyl methyl ether (CPME) was added an ethereal solution of
ethylmagnesium bromide, prepared from 2.5 molar amounts of
bromoethane, at 0 °C and the reaction mixture was refluxed
for 3 h. After acidic work-up, a mixture of desired 1,4-diol
rac-1a, its diastereomer meso-3a, and reduced product 4a,
which resulted from a single nucleophilic addition followed
by a reduction by β-hydrogen of the Grignard reagent, were
obtained in 55%, 13%, and 16% yields, respectively (Entry 1).
Similarly, the reaction with methylmagnesium iodide gave
rac-1b and meso-3b in 46% and 47% yields, respectively
(Entry 2). As for the synthesis of rac-1c, the amount of
isopropylmagnesium bromide was increased to that prepared
from 5.0 molar amounts of 2-bromopropane until 2 was not
detected by TLC, and rac-1c was obtained in 29% yield along
with meso-3c and 4c with 6% and 31% yields, respectively
(Entry 3). 1,4-Diols 1d-1f were also obtained in 37-57%
yields by the reaction of 2 with Grignard reagents prepared
from 4-5 molar amounts of the corresponding alkyl halides
(Entries 4-6).
Department of Advanced Materials Chemistry, Graduate
School of Engineering, Yokohama National University, 79-5
Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa 240-8501
E-mail: m-asami@ynu.ac.jp
Received: February 28, 2015; Accepted: March 26, 2015;
Web Released: April 3, 2015
Optical resolution of C2-symmetric racemic 1,4-diols,
1,2-bis(1-hydroxyalkyl)benzene, was examined using (S)-
5-allyl-2-oxabicyclo[3.3.0]octene ((S)-ALBO-V) as chiral
resolving agent. Diastereomeric acetals obtained from the
1,4-diols with (S)-ALBO-V were easily separated by silica-
gel column chromatography. After removal of the resolving
agent, both enantiomers of the 1,4-diols were obtained with
high enantiomeric excesses.
C2-Symmetric 1,2-, 1,3-, and 1,4-diols have been recognized
as useful chiral scaffolds in various asymmetric transformations
as chiral ligands and chiral auxiliaries,1-5 since the existence of
a C2-symmetric element is often important in asymmetric syn-
thesis to induce high levels of stereoselectivity.6 Among them,
the structural variety of chiral C2-symmetric 1,4-diols is rather
limited, and the precise control of the stereochemical outcome
of asymmetric reactions is generally difficult due to their
structural flexibility except for 1,1¤-bi-2-naphthol (BINOL)
derivatives3 and α,α,α¤,α¤-tetraaryl-1,3-dioxolane-4,5-dimetha-
nol (TADDOL) derivatives4 with relatively rigid structures.
We have reported the asymmetric synthesis of chiral C2-
symmetric 1,4-diols with o-xylylene structure, (S,S)-1,2-bis-
(1-hydroxyalkyl)benzene (1), and the use of (S,S)-1,2-bis-
(1-hydroxypropyl)benzene (1a) (R = Et) as chiral auxiliary
or starting material of chiral ligands.7 The superiority of chiral
1,4-diol 1a as chiral auxiliary was shown in the 1,4-addition
of phenyllithium to a β-nitrostyrene derivative by comparing
the results using other C2-symmetric chiral 1,2-, 1,3-, and 1,4-
diols.7c In the previous report,7a however, the stepwise enan-
tioselective addition of dialkylzinc reagent to aromatic aldehyde
was utilized for the construction of two benzylic stereogenic
centers of 1,4-diol 1. Therefore, the examples of chiral 1,4-diols
1 with high enantiomeric excesses have been limited to 1a
and 1b (R = Me). Although van Koten et al. also reported the
enantioselective synthesis of several examples of 1,4-diol 1, the
enantioselectivities of the reactions were less than 90%.8
Table 1. Synthesis of Racemic 1,4-Diols 1a-1f
rac-1
/%b)
meso-3
/%b)
4
/%b)
Entry
RMgXa)
1
2
3
4c)
5
EtMgBr (2.5)
MeMgI (2.5)
i-PrMgBr (5.0)
i-BuMgBr (4.0)
n-C5H11MgBr (5.0)
c-C6H11MgCl (5.0)
55
46
29
37
41
57
13
47
6
15
23
14
16
0
31
39
34
14
6
a) Molar amounts of the corresponding alkyl halides used were
in parentheses. b) Isolated yield. c) The reaction was carried
out at room temperature.
966 | Bull. Chem. Soc. Jpn. 2015, 88, 966–968 | doi:10.1246/bcsj.20150066
© 2015 The Chemical Society of Japan

Table 3. Acetalization of Various 1,4-Diols with (S)-
ALBO-V
7/%a)
8/%a)
Entry
1
R
(R)
(S)
(R)
(S)
1
2
3
1b
1c
1d
1e
1f
Me
i-Pr
i-Bu
n-C5H11
c-C6H11
(C2H5)2CH
Trace
15
5
7
14
14
Trace
5
Trace
Trace
5
40
28
45
37
30
28
43
42
46
42
37
39
Scheme 1. Synthesis of 1,2-bis(2-ethyl-1-hydroxybutyl)-
benzene (1g).
4b)
5
Table 2. Acetalization of rac-1a with (S)-ALBO-V
6c)
1g
6
a) Isolated yield. b) Reaction time was 3 h. c) Reaction was
carried out using 20 mol % of p-TsOH.
and (R)-8a and (S)-8a were obtained in high isolated yields
(Entry 3). The amount of (S)-ALBO-V was reduced to 2.2
molar amounts to give (R)-8a and (S)-8a in 40% and 45%
yields, respectively (Entry 4).
As a good result was obtained for rac-1a, the optical resolu-
tion of various 1,4-diols 1b-1g was then examined (Table 3).
When 1b (R = Me), 1d (R = i-Bu), and 1e (R = n-C5H11) were
reacted with (S)-ALBO-V, diacetals 8b, 8d, and 8e were
obtained in high isolated yields (Entries 1, 3, and 4). In the
cases of 1c (R = i-Pr) and 1f (R = c-C6H11), diacetals (S)-8c
and (S)-8f were obtained in high yields although ca. 15% of
monoacetals (R)-7c and (R)-7f were isolated and the yields of
(R)-8c and (R)-8f were moderate probably due to the steric
hindrance of the substituents (Entries 2 and 5). The yields of
(R)-8c and (R)-8f were not improved by elongation of the reac-
tion time or increasing the amount of p-toluenesulfonic acid.
As for 1,4-diol 1g (R = (C2H5)2CH), a higher catalyst loading
(20 mol %) was required for the formation of diacetals (R)-8g
and (S)-8g (28% and 39% yields, Entry 6). All diastereomeric
diacetals (R)-8b-8g and (S)-8b-8g were also separated by
silica-gel column chromatography.
As both enantiomers of various 1,4-diols 1a-1g were ob-
tained in diacetal form with (S)-ALBO-V, deacetalization of
diacetals 8a-8g was carried out to obtain (R)-1a-1g and (S)-
1a-1g (Table 4). In the presence of 1 mol % of p-toluene-
sulfonic acid, a methanol solution of diacetal (R)-8a was heated
under reflux for 1 h to give (R)-1a in 98% yield with 98% ee
(Entry 1). The chiral resolving agent was recovered as meth-
anol adduct, which is the precursor of (S)-ALBO-V and there-
fore reusable.9 Similarly, deacetalization of (S)-8a afforded (S)-
1a in 96% yield with 97% ee (Entry 2). Deacetalization of
other diacetals, (R)-8b-8g and (S)-8a-8g, also proceeded to
give the corresponding 1,4-diols (R)-1b-1g and (S)-1a-1g in
high yields and enantiomeric excesses (Entries 3-14). Although
the ee values of 1,4-diols 1a-1g should be >99% in principle
since enantiomerically pure (S)-ALBO-V was used as chiral
resolving agent, the ee values were 92-98% in some cases. This
is probably due to the technical problem in the separation of
diastereomeric diacetals (R)-8 and (S)-8 by silica-gel column
7a/%a)
8a/%a)
(S)-ALBO-V Time
Entry
/mol. amt.
/h
(R)
(S)
(R) (S)
1b)
2
3
1.0
2.0
3.0
2.2
3
10
7
22
15
26
8
6
29
42
40
9
41
45
45
Trace Trace
9
4
17
4
a) Isolated yield. b) Recovery of rac-1a was 13%.
1,2-Bis(2-ethyl-1-hydroxybutyl)benzene 1g was prepared
from 1,2-dibromobenzene (5), since the reaction of 1-ethyl-
propylmagnesium halide with 2 afforded rac-1h in ca. 10%
yield due to the predominant formation of 4g and 1,2-bis-
(hydroxymethyl)benzene. Dibromide 5 was mono-lithiated by
butyllithium in Et2O/THF at between ¹115 and ¹110 °C, and
the resulting aryl lithium was reacted with 2-ethylbutanal to
give bromoalcohol 6 in 81% yield. Treatment of 6 with butyl-
lithium in Et2O at room temperature, and the subsequent reac-
tion with 2-ethylbutanal afforded rac-1g and meso-3g in 32%
and 36% yields, respectively (Scheme 1).
Next, the optical resolution of rac-1a was examined using
(S)-ALBO-V (Table 2). When rac-1a was mixed with 1.0
molar amount of (S)-ALBO-V in the presence of a catalytic
amount (1 mol %) of p-toluenesulfonic acid in toluene at room
temperature for 3 h, diastereomers of monoacetals (R)-7a and
(S)-7a were obtained in moderate yields along with diastereo-
meric diacetals (R)-8a and (S)-8a. The resulting four products
((R)-7a, (S)-7a, (R)-8a, and (S)-8a) were separated by a single
silica-gel column chromatography (Entry 1). The reaction was
then examined using 2.0 molar amounts of (S)-ALBO-V, and
diacetals (R)-8a and (S)-8a were obtained in 29% and 41%
yields, respectively (Entry 2). Monoacetals were fully con-
verted to diacetals by using 3.0 molar amounts of (S)-ALBO-V,
Bull. Chem. Soc. Jpn. 2015, 88, 966–968 | doi:10.1246/bcsj.20150066
© 2015 The Chemical Society of Japan | 967

Table 4. Deacetalization of Various Acetals 8
mental Analysis Center, Yokohama National University) for
their technical assistance in the elemental analyses and the
high-resolution mass spectrometric analyses.
Supporting Information
Details of experimental procedures and characterization data
of synthesized compounds. This material is available electroni-
cally on J-STAGE.
Entry
R
Acetal
Yield/%a)
ee/%b)
98
97
98
98
97
99
92 (>99)c)
98 (>99)c)
96
>99
>99
98
97
96
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Et
(R)-8a
(S)-8a
(R)-8b
(S)-8b
(R)-8c
(S)-8c
(R)-8d
(S)-8d
(R)-8e
(S)-8e
(R)-8f
(S)-8f
(R)-8g
(S)-8g
98
96
95
96
86
87
72
79
85
88
92
81
84
85
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This work was supported by JSPS KAKENHI Grant Number
24550113. The authors are grateful to ZEON CORPORATION
for providing (S)-ALBO-V and CPME. The authors also wish
to thank Mr. Shinji Ishihara and Dr. Hironari Kurihara (Instru-
968 | Bull. Chem. Soc. Jpn. 2015, 88, 966–968 | doi:10.1246/bcsj.20150066
© 2015 The Chemical Society of Japan