A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations. Part 2, via catalytic reduction of acetylene alcohol MαNP esters

Article abstract of DOI:10.1016/j.tetasy.2014.10.005

A general method for synthesizing enantiopure (100% ee) aliphatic alcohols with established absolute configurations has been developed and applied to alcohols CH₃(CH₂)_n-CH(OH)-(CH₂)_mCH₃, the enantiomeric discrimination of which is the most difficult, if m = n + 1 and n is large. Racemic saturated alcohols with short chains could be directly enantioresolved as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) esters by HPLC on silica gel, and their absolute configurations were simultaneously determined by ¹H NMR diamagnetic anisotropy. However, the application of this powerful MαNP ester method to alcohols with long chains was difficult, because of smaller values of the separation factor α. In such cases, the use of the corresponding acetylene alcohol MαNP esters was crucial. Acetylene alcohol MαNP esters were largely separated by HPLC on silica gel, and their absolute configurations were unambiguously determined by ¹H NMR as reported in the Part 1 paper. The MαNP esters obtained with established absolute configurations were catalytically hydrogenated to yield saturated alcohol MαNP esters. It was evidenced that no racemization occurred at the stereogenic center of the alcohol moiety during catalytic hydrogenation, by the coinjection of MαNP esters in HPLC. From the MαNP esters obtained, enantiopure (100% ee) aliphatic chain alcohols with established absolute configurations were recovered. Although the [α]_D values of these alcohols were too small for the identification of the enantiomers, it was clarified that the analytical HPLC of MαNP esters is useful for identification in most cases.

Full text of DOI:10.1016/j.tetasy.2014.10.005

Tetrahedron: Asymmetry 25 (2014) 1466–1477
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Tetrahedron: Asymmetry
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A general method for the synthesis of enantiopure aliphatic chain
alcohols with established absolute configurations. Part 2, via
catalytic reduction of acetylene alcohol MaNP esters
Megumi Akagi a, Satoshi Sekiguchi a, Hiromi Taji a, Yusuke Kasai a,b, Shunsuke Kuwahara a,c
,
Masataka Watanabe a, Nobuyuki Harada a,
⇑
a Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
b Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
c Department of Chemistry, Faculty of Science and Research Center for Materials with Integrated Properties, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 September 2014
Accepted 8 October 2014
A general method for synthesizing enantiopure (100% ee) aliphatic alcohols with established absolute
configurations has been developed and applied to alcohols CH3(CH2)n–CH(OH)–(CH2)mCH3, the enantio-
meric discrimination of which is the most difficult, if m = n + 1 and n is large. Racemic saturated alcohols
with short chains could be directly enantioresolved as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid
(M
mined by 1H NMR diamagnetic anisotropy. However, the application of this powerful M
to alcohols with long chains was difficult, because of smaller values of the separation factor
cases, the use of the corresponding acetylene alcohol M NP esters was crucial. Acetylene alcohol M
esters were largely separated by HPLC on silica gel, and their absolute configurations were unambigu-
ously determined by 1H NMR as reported in the Part 1 paper. The M
NP esters obtained with established
absolute configurations were catalytically hydrogenated to yield saturated alcohol M NP esters. It was
evidenced that no racemization occurred at the stereogenic center of the alcohol moiety during catalytic
hydrogenation, by the coinjection of M NP esters in HPLC. From the M NP esters obtained, enantiopure
(100% ee) aliphatic chain alcohols with established absolute configurations were recovered. Although the
D values of these alcohols were too small for the identification of the enantiomers, it was clarified that
the analytical HPLC of M NP esters is useful for identification in most cases.
Ó 2014 Elsevier Ltd. All rights reserved.
a
NP acid) esters by HPLC on silica gel, and their absolute configurations were simultaneously deter-
NP ester method
. In such
NP
a
a
a
a
a
a
a
a
[a]
a
1. Introduction
independent physical methods such as X-ray crystallography
and/or 1H NMR diamagnetic anisotropy.
It is well known that asymmetric synthesis has been success-
fully applied to the synthesis of many chiral organic compounds
such as bioactive natural products and chiral drugs.1–4 However,
enantiopure aliphatic compounds such as chiral aliphatic chain
alcohols are difficult to obtain by asymmetric reactions or by other
enantioresolution methods5–7 including chiral HPLC. For example,
as will be discussed below, it was found that commercially avail-
able chiral 2-butanol, the simplest chiral aliphatic alcohol, was
not enantiomerically pure. Furthermore, it is difficult to determine
the absolute configurations of products based on the asymmetric
reaction mechanism, or by the elution order in chiral HPLC. There-
fore, it is advisable to determine the absolute configurations by
In order to solve the above problems, we have developed a
method8–14 involving (S)-(+)-2-methoxy-2-(1-naphthyl)propionic
acid 1 (M
alcohols. The method is outlined as shown in Figure 1:11 (a) a race-
mic alcohol ( )-2 is esterified with (S)-(+)-M NP acid 1 to give a
mixture of diastereomeric esters, which are easily separable by
HPLC on silica gel. The first-eluted M NP ester is designated as
(S,X)-3a, while the second-eluted ester is (S,ÀX)-3b, where ÀX indi-
a
NP acid),15 which is applicable even to aliphatic chain
a
a
cates the opposite absolute configuration of X; (b) MaNP esters
take preferred conformations as shown. In ester (S,X)-3a, the R1
group is located above the naphthalene ring causing a high field
shift of R1 in the 1H NMR, while in ester (S,ÀX)-3b, the R2 group
exhibits a high field shift. From the observed spectra, 1H NMR
diamagnetic anisotropy
as,
d = d(R,X)-3 À d(S,X)-3 = d(S,ÀX)-3 À d(S,X)-3 = d(2nd fr.) À
d (1st fr.). The R1 group showing positive
d values is placed on
Dd values were calculated and defined
D
⇑
Corresponding author.
E-mail address: n2harada@tagen.tohoku.ac.jp (N. Harada).
D
http://dx.doi.org/10.1016/j.tetasy.2014.10.005
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
1467
O
(a)
R2
MeO
1) Esterification
OH
R1
HO
+
( )-2
1
(S)-(+)-
2) HPLC on Silica gel
R2
H
R2
H
O
O
X
–X
MeO
MeO
O
R1
R1
O
+
(S,X)-3a
(S,–X)-
3b
2nd fraction (S,–X)-
1st fraction
(b)
(S,X)-3a
syn
Me/naphthyl plane
Me/naphthyl plane
3b
syn
H
H
R1
Me
Me
O
R2
(S)
(S)
O
O
Me
R1
Me
R2
O
X
–X
syn
syn
H
O
H
O
syn
syn
MαNP plane
Two planes, perpendicular
MαNP plane
high field shift
high field shift
Two planes, perpendicular
sector rule
Δδ < 0
Δδ > 0
Absolute Configuration
of the First Fraction
R2
R1
X
Δδ = δ(R,X)-3 – δ(S,X)-3
3b
3a
= δ(S,–X)-
– δ(S,X)-
H
O-MαNP
= δ(2nd. fr.) – δ(1st. fr.)
MαNP plane
Δδ
δ
δ
=
(R,X) – (S,X)
R2
(c)
R2
H
O
O
R2 –X R1
X
O
–X
R2
R1
MeO
MeO
X
R1
R1
O
H
H
OH
(–X)-2
H
OH
(X)-2
3b
(S,–X)-
(S,X)-3a
Figure 1. Outline of the Ma
NP acid method for enantioresolution of racemic alcohols and determination of their absolute configurations by 1H NMR anisotropy. Adapted
from Ref. 11.
the right side, while the group R2 showing negative
D
d values is
fact has established the empirical 1H NMR anisotropy method as a
more reliable one.
placed on the left side as shown. From the sector rule, the absolute
configuration X of the first-eluted ester is determined; (c) hydroly-
sis of the first-eluted ester (S,X)-3a gives enantiopure alcohol (X)-2,
while that of the second-eluted ester (S,ÀX)-3b gives alcohol (ÀX)-
We have applied the MaNP acid method to racemic aliphatic
chain alcohols, CH3(CH2)n–CH(OH)–(CH2)mCH3, to synthesize enan-
tiopure (100% ee) alcohols and also to determine their absolute
configurations in an unambiguous way. It should be noted that
the enantiomeric discrimination of these alcohols is the most
difficult, if m = n + 1, and n is large. Therefore, the application of
2. The MaNP acid method is useful for the synthesis of enantiopure
(100% ee) alcohols with established absolute configurations.
Another advantage of the M NP acid method is that MaNP
a
esters have a high probability of giving single crystals suitable
the MaNP acid method to these long chain aliphatic alcohols
for X-ray crystallography, by which an absolute configuration can
remains a challenging problem. Herein we report the synthesis of
enantiopure aliphatic alcohols, 4-octanol (R)-(À)-4, 9-octadecanol
(S)-(+)-5, and 19-octatriacontanol (R)-(À)-7 as shown in Figure 2,
via catalytic reduction of the corresponding acetylene alcohol
be unambiguously determined by using the MaNP ester moiety
as an internal reference of the absolute configuration.12–14,16 We
have not encountered any exceptions where 1H NMR anisotropy
using MaNP esters conflicted with the X-ray crystallography. This
MaNP esters, the absolute configurations of which were unambig-

1468
M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
O
CH3O
OH
CnH(2n+1)
CmH(2m+1)
OH
H
2
1
(S)-(+)-
C9
C3
C8
C4
OH
H
OH
H
4-Octanol
9-Octadecanol
[(S)-MαNP/HPLC(1st fr.)]-(R)-(–)-4
5
[(S)-MαNP/HPLC(2nd fr.)]-(S)-(+)-
C19
C9
OH
H
10-Nonacosanol
[(S)-MaNP/HPLC(1st fr.)]-(R)-6
C18
C19
OH
H
7
19-Octatriacontanol (R)-(–)-
Figure 2. Enantiopure (100% ee) aliphatic secondary alcohols with established absolute configurations, synthesized or identified by the M
a
NP acid method.
uously determined by 1H NMR diamagnetic anisotropy (see Part
that the product was a mixture of diastereomeric esters (S,R)-12a
and (S,S)-12b, the ratio of which was determined to be 1:14 by
the 1H NMR peak ratio, and 4:80 by chemical yield (Table 1).
Therefore, it was concluded that the sample (T) of (S)-(+)-2-buta-
nol was not enantiomerically pure. Since the total yield of the
esters was 84%, it was difficult to determine the enantiomeric
excess (ee) exactly, but it was estimated to be approximately
87–90% ee (for the more exact method for determining % ee by
117 for application of the M
lene alcohols).
aNP acid method to short chain acety-
In general, the [
a
]D values of these alcohols are too small for the
identification of enantiomers, but the analytical HPLC of M
aNP
esters is very useful for identification in most cases, including
10-nonacosanol (R)-6 as will be discussed.
Two recent reports emphasize that Ma
NP ester analysis by 1H
NMR spectroscopy is very powerful for the determination of the
absolute configuration of a long chain alcohol contained in com-
plex natural products,18 and also for the chiral discrimination
1H NMR or MS using M NP acid, see literature,20 where the
a
kinetic resolution effect could be completely removed). The (S)-
absolute configuration of the major component was confirmed
by 1H NMR anisotropy.
and enantiomeric purity determination of d- or e-chiral 1-alkanols
synthesized via the Zr-catalyzed asymmetric carboalumination of
alkenes (ZACA reaction), lipase-catalyzed acetylation, and Cu- or
Pd-catalyzed cross-coupling from terminal alkenes.19 In the latter
Another commercially available sample (A) of (S)-(+)-2-butanol
was similarly treated, where the total yield was 73% and the ratio
was 1:14 or 8:65 (Table 1). The total yield was less than 100%, and
hence the % ee was roughly estimated to be 78–82%. As can be seen
in Table 1, the enantiopurity of the sample (T) was slightly better
than sample (A). It should be emphasized that both samples of
commercially available (S)-(+)-2-butanol were not enantiopure.
This fact exemplifies that the preparation of enantiopure (100%
ee) aliphatic chain alcohols remains difficult.
case, the so-called Mosher acid,
a-methoxy-a-(trifluoro-
methyl)phenylacetic acid (MTPA), was not effective for detecting
the remote chirality.19
2. Results and discussion
2.1. Checking the enantiopurity of commercially available (S)-
2.2. Synthesis of diastereomeric aliphatic chain alcohol M
esters and HPLC separation
aNP
(+)-2-butanol by the MaNP acid method
We have previously reported that the M
a
NP acid method is
Racemic aliphatic alcohols with long chains 5 and 7 were easily
synthesized by catalytic hydrogenation of the corresponding acet-
ylene alcohols 8 and 916 with H2 and PtO2 in diethyl ether
(Scheme 1). It is noteworthy that both alcohols were obtained in
quantitative yield despite having aliphatic long chains, although
( )-19-octatriacontanol 7 was barely soluble even in CHCl3.
Racemic aliphatic alcohols 10, 4, 11, 5, and 7 were esterified
very useful for the enantioresolution of racemic aliphatic chain
alcohols such as 2-alkanols.8–10 For example, racemic 2-butanol
was esterified with (S)-(+)-M
NP esters (S,R)-(À)-12a and (S,S)-(+)-12b, which were easily
separable by HPLC on silica gel as illustrated in Figure 3a. There-
fore, the M NP acid method would be useful for checking the
aNP acid 1 to give diastereomeric
M
a
a
enantiopurity of commercially available chiral 2-butanol, and so
we carried out experiments to obtain the following results.
The commercially available sample (T) of (S)-(+)-2-butanol
with (S)-(+)-M
18 (Scheme 2).
In general, diastereomeric M
HPLC on silica gel. Figure 3 illustrates the analytical HPLC of the
above diastereomeric esters together with 2-butanol M NP esters
12a/12b9 and 10-nonacosanol
NP esters 17a/17b, where
aNP acid 1 to yield esters 13a/13b–16a/16b and
a
NP esters are easily separable by
was subjected to the M
aNP acid method, where an excess
amount of (S)-(+)-M NP acid 1 (2.0 equiv) was used to diminish
a
a
any kinetic resolution effect during the esterification reaction.
The HPLC (Fig. 4) and 1H NMR of the obtained product indicated
Ma

M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
1469
(a) 2-butanol
C1
C2
OMαNP
(S,R)-(–)-12a
12b
(S,S)-(+)-
12a
(S,R)-(–)-
83.9 min
75.6 min
α = 1.12
Rs = 1.87
UV
0
(S,S)-(–)-13b
(b) 3-hexanol
(S,R)-(–)-13a
51.0 min
C2
C3
OMαNP
13a
59.2 min
α = 1.20
Rs = 2.43
(S,R)-(–)-
UV
0
14a
(S,R)-(–)-
14b
(S,S)-(–)-
(c) 4-octanol
37.8 min
45.7 min
C3
C4
OMαNP
α = 1.27
Rs = 3.52
(S,R)-(–)-14a
UV
0
(d) 5-decanol
31.4 min
15a
15b
33.2 min
C5
C4
α = 1.07
OMαNP
15a
Rs = 1.00
UV
0
(e) 9-octadecanol
C8
16a
(S,R)-(–)-
C9
OMαNP
(S,R)-(–)-16a
(S,S)-(–)-16b
77.5 min
= 1.03
α
75.6 min
Rs = 0.27
UV
0
(f) 10-nonacosanol
C9
C19
17b
(S,S)-(–)-
OMαNP
56.3 min
(S,R)-17a
17a
(S,R)-
α = 1.07
53.4 min
Rs = 0.27
UV
0
(g) 19-octatriacontanol
C18
(S,R)-(–)-18 and
(S,S)-(–)-18
C19
OMαNP
79.2 min
α = 1.00
UV
0
Figure 3. Analytical HPLC of diastereomeric (S)-M
by UV; (a)–(d) hexane/EtOAc = 40:1, flow rate 3 mL/min; (e)–(f) hexane/EtOAc = 80:1, flow rate 2 mL/min; (g) hexane/EtOAc = 150:1, flow rate 2 mL/min. To save space, some
solvent peaks were cut off.
aNP esters of aliphatic acyclic alcohols on silica gel (10 / Â 300 mm, n = 34,400): samples (0.1 mg) were injected; detected
samples (0.1 mg) were injected, and eluates were detected by UV.
In HPLC (a)–(d), hexane/EtOAc (40:1) was used as the solvent,
while in (e)–(f), hexane/EtOAc (80:1) and in (g), hexane/EtOAc
(150:1) were used. It should be emphasized that diastereomeric
ical HPLC in Figure 3, while
a = 1.09 for preparative HPLC in
Figure 4. In the HPLC of M NP esters 12a/12b, it was thus possible
a
to discriminate the very small difference between the methyl and
ethyl groups. We had thought that when the alkyl chains became
M
a
NP esters 12a/12b–15a/15b and 17a/17b were baseline sepa-
rated, while esters 16a/16b partially overlapped.
It is noteworthy that the separation factor
too much between analytical and preparative HPLC; for example,
in the case of 2-butanol M NP esters 12a/12b, = 1.12 for analyt-
longer, the a value would decrease, that is, it was expected that
the difference between the ethyl and propyl groups in esters
13a/13b would be smaller than that between the methyl and ethyl
a
does not change
groups, and hence the
the opposite was true;
a
a
value would become smaller. However,
= 1.20 for 3-hexanol M NP esters 13a/
a
a
a

1470
M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
C1
C2
OMαNP
12b
a
= 1.03 thus reflecting the difference between the octyl and nonyl
(S,R)-12a
48.3 min
(S,S)-12b
groups. Finally the
a value became 1.0 for 19-octatriacontanol
51.5 min
(S,S)-
M
a
NP esters 18, where C18H37 and C19H39 groups were compared,
that is, diastereomeric M NP esters 18 appeared as a single peak
and could not be separated as shown in Figure 3g. Overall as the
side chains became longer the value decreased.
However, the situation is not so simple, since 10-nonacosanol
NP esters 17a/17b with long side-chains C9H19 and C19H39 were
surprisingly base-line separated with = 1.07; the result indicates
that the value also depends on the large difference between the
a
sample (T)
α = 1.09
Rs = 1.19
a
RI
0
M
a
Figure 4. HPLC of diastereomeric (S)-MaNP esters prepared from the commercially
a
available sample (T) of (S)-(+)-2-butanol: silica gel column gel (22 / Â 300 mm,
n = 9500–11,600); hexane/ethyl acetate = 20:1. Sample (10 mg) was injected. To
save space, solvent peaks were cut off.
a
two side chains. This HPLC separation is useful for the identifica-
tion of 10-nonacosanol enantiomers, as will be discussed below.
Esters 17a/17b were synthesized by catalytic hydrogenation of
Table 1
the corresponding acetylene MaNP esters 22a/22b.
Check of the enantiopurity of commercially available (S)-(+)-2-butanol by the method
of MaNP acid (S)-(+)-1
2.3. Determination of the absolute configurations by 1H NMR
diamagnetic anisotropy
Entry
(S)-(+)-2-Butanol
aa
Yieldb (%)
Ratioc
Approximate % ee
1
2
Sample (T)
Sample (A)
1.09
1.08
4/80
8/65
1/14
1/10
87–90
78–82
As described above, aliphatic alcohol M
chains such as 13a/13b and 14a/14b were easily separated by
HPLC with values of 1.20–1.27, which made preparative HPLC
separation possible. From the 1H NMR chemical shift data,
aNP esters with short
a
HPLC separation factor: silica gel column (22 / Â 300 mm); hexane/ethyl
acetate = 20:1.
a
b
Yield of (S,R)-12a and (S,S)-12b.
D
d
c
The ratio of 12a/12b was determined by 1H NMR peak intensity.
values {
D
d = d(2nd fr.) À d(1st fr.)} were calculated as shown in
Figure 5; in the assignment of proton chemical shift, 13C NMR,
HMQC, and HH COSY were useful for confirmation. In 3-hexanol
R1
M
a
NP esters 13a/13b, the ethyl group showing positive
was placed on the right side, while the propyl group with negative
d values was placed on the left side. From this placement, the
Dd values
R1
R2
R2
(a)
D
H
OH
OH
H
absolute configuration of the first-eluted ester 13a was determined
to be (R) (Fig. 5). Thus the absolute configurations of the diastereo-
mers were assigned as (S,R)-(À)-13a and (S,S)-(À)-13b.
( )-8, R1 = (CH2)6CH3, R2 = (CH2)7CH3
( )-5, R1 = (CH2)8CH3, R2 = (CH2)7CH3
( )- , R1 = (CH2)15CH3, R2 = (CH2)18CH3
( )- , R1 = (CH2)17CH3, R2 = (CH2)18CH3
9
7
Scheme 1. Preparation of racemic alcohols. Reagents: (a) H2/PtO2 in diethyl ether.
– 0.29
– 0.20
+0.29
+0.19
+0.24
(R)
– 0.43
– 0.25
(R)
–0.41
+0.40
13b. This tendency continued for 4-octanol M
aNP esters 14a/14b
+0.55
– 0.32
+0.73
+0.56
–0.74
–0.56
–0.70
–0.60
(a = 1.27), where the propyl and butyl groups were clearly distin-
H
OMαNP
guished. Currently it is unclear as to why the
a
value increases in
H
0.00
OMαNP
– 0.01
these cases.
In the case of 5-decanol M
denly decreased to = 1.07, which is reasonable in reference to a
very small difference between butyl and pentyl groups. The value
aNP esters 15a/15b, the a value sud-
13a
(S,R)-
14a
(S,R)-
a
Figure 5. Absolute configurations of alcohol M
aNP esters as determined by the
d values in ppm, 600 MHz, CDCl3.
a
1H NMR anisotropy method:
D
decreased further for 9-octadecanol M
aNP esters 16a/16b, with
O
CH3O
OH
R1
R2
(a)
(b)
+
H
OH
( )- , R1 = CH2CH3, R2 = (CH2)2CH3
10
( )-4, R1 = (CH2)2CH3, R2 = (CH2)3CH3
1
(S)-(+)-
( )- , R1 = (CH2)3CH3, R2 = (CH2)4CH3
11
( )-5, R1 = (CH2)7CH3, R2 = (CH2)8CH3
( )- , R1 = (CH2)17CH3, R2 = (CH2)18CH3
7
R1
R1
H
O
O
CH3O
CH3O
R2
R2
O
O
H
+
(S,S)-(–)-13b, R1 = CH2CH3, R2 = (CH2)2CH3
, R1 = CH2CH3, R2 = (CH2)2CH3
13a
(S,R)-(–)-
(S,R)-(–)-14a, R1 = (CH2)2CH3, R2 = (CH2)3CH3
15a
(S,S)-(–)-
, R1 = (CH2)2CH3, R2 = (CH2)3CH3
14b
15b, R1 or R2 = (CH2)3CH3 or (CH2)4CH3
16b
, R1 or R2 = (CH2)3CH3 or (CH2)4CH3
, R1 = (CH2)7CH3, R2 = (CH2)8CH3
(S,R)-(–)-16a, R1 = (CH2)7CH3, R2 = (CH2)8CH3
18
(S,S)-(–)-
(S,S)-(–)-18, R1 = (CH2)17CH3, R2 = (CH2)18CH3
(S,R)-(–)- , R1 = (CH2)17CH3, R2 = (CH2)18CH3
Scheme 2. Preparation of diastereomeric MaNP esters and HPLC separation. Reagents: (a) DCC, DMAP, CSA/CH2Cl2; (b) HPLC on silica gel.

M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
1471
In the case of 4-octanol M
showed positive d values, while the butyl group showed negative
d values. It should be noted that the absolute values of d are
almost symmetrically distributed against the M NP plane (see
Figs. 1 and 5), and b-protons on both sides showed large d values
a
NP esters 14a/14b, the propyl group
21–23 were determined by 1H NMR anisotropy and/or X-ray crys-
tallography.16 Since these acetylene alcohol M
NP esters were
chemically correlated to M NP esters 16–18 as will be discussed
D
a
D
D
a
a
below, their absolute configurations were established.
D
(À0.70, À0.60 and +0.73, +0.56 ppm). From these data, the absolute
configuration of the first-eluted ester 14a was unambiguously
determined to be (R) (Fig. 5). Therefore, absolute configurations
were assigned as (S,R)-(À)-14a and (S,S)-(À)-14b. As will be
discussed below, ester (S,S)-(À)-14b was chemically correlated to
2.4. Synthesis of enantiopure aliphatic alcohols
In order to prepare enantiopure aliphatic alcohols with estab-
lished absolute configurations, M
were directly separated by HPLC on a preparative scale, because
of their larger values. For example, 4-octanol M NP esters 14a/
14b ( = 1.27) were separated by HPLC, and the first-eluted ester
aNP esters with short chains
5-octyn-4-ol M
a
NP ester (S,S)-(À)-20a, the absolute configuration
of which was determined by 1H NMR anisotropy.17 Therefore, the
absolute configurations of esters 14a and 14b were doubly
established.
For longer chain alcohol MaNP esters 16–18, the absolute con-
figurations of the corresponding acetylene alcohol MaNP esters
a
a
a
(S,R)-(À)-14a was treated with KOH in MeOH yielding (R)-(À)-4-
octanol 4, [
{Scheme 3a, (ii)}.
a
]
35 = À0.5 (
q 0.819, neat), in an enantiopure form
D
(a)
(i)
OMαNP
OMαNP
H
H
20a
14b
(S,S)-(–)-
(S,S)-(–)-
(ii)
H
OMαNP
H
OH
(S,R)-(–)-14a
(R)-(–)-4
(b)
C9
(i)
C9
C8
C8
α
OM NP
H
H
OMαNP
(S,S)-(–)-21a
(S,S)-(–)-16b
(ii)
C9
C8
OH
(S)-(+)-5
H
(c)
C9
C19
OMαNP
H
22a
(S,S)-(–)-
(i)
C9
C19
OMαNP
H
(S,R)-17a
(d)
C18
C19
OMαNP
23a
H
(S,S)-(–)-
(i)
C18
C19
H
H
OMαNP
18
(S,R)-(–)-
(iii)
C18
C19
OH
(R)-(–)-7
Scheme 3. Preparation of enantiopure aliphatic alcohols with established absolute configuration and chemical correlation. Reagents and conditions: (i) H2/PtO2 in diethyl
ether, 2-3 h, (ii) KOH/EtOH, reflux, 1–2 days, (iii) NaOMe/iso-PrOH, reflux, 3 days.

1472
M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
Table 2
HPLC separation of diastereomeric esters formed from acetylene alcohols and M
aNP acid (S)-(+)-1. Taken from Refs. 16,17
Entry
Diastereomers
Solventa
a
Rs
1st-eluted Fr.
1
2
3
4
5
19a/19b
20a/20b
21a/21b
22a/22b
23a/23b
H/EA = 20/1
H/EA = 20/1
H/EA = 20/1
H/EA = 20/1
H/EA = 50/1
1.76
1.32
1.61
1.88
1.78
2.88
1.44
1.93
1.65
4.10
(S,S)-19a
(S,S)-(À)-20a
(S,S)-(À)-21a
(S,S)-(À)-22a
(S,S)-(À)-23a
a
H = hexane, EA = ethyl acetate.
C3
C9
C4
C8
OMαNP
OMαNP
OMαNP
H
H
H
5-octyn-4-ol MαNP
20a
10-octadecyn-9-ol MαNP
2-octyn-4-ol MαNP
19a
21a
ester (S,S)-(–)-
ester (S,S)-(–)-
ester (S,S)-
C9
C19
OMαNP
H
8-nonacosyn-10-ol MαNP ester (S,S)-(–)-22a
C18
C19
OMαNP
17-octatriacontyn-19-ol MαNP ester (S,S)-(–)-
H
23a
In the case of long chain alcohol M
and 18, direct HPLC separation was not practical for preparation
because of the smaller values as seen in Figure 3. Hence, we
adopted the indirect method as follows; we have reported that dia-
stereomeric M NP esters of acetylene alcohols with aliphatic
chains can be readily separated by HPLC on silica gel,16,17 and some
data are listed in Table 2. For example, 10-octadecyn-9-ol M NP
esters 21a/21b were separable with = 1.61, and hence prepara-
tive scale separation was possible. From the first-eluted ester
21a, enantiopure (S)-(À)-10-octadecyn-9-ol was synthesized as
reported before.16 Hence, we had thought that the catalytic hydro-
genation of enantiopure (S)-(À)-10-octadecyn-9-ol would yield
enantiopure (S)-9-octadecanol 5. However, Mori et al. reported
that the catalytic hydrogenation of chiral acetylene alcohols
yielded partially racemized saturated alcohols,21 that is, during
the catalytic hydrogenation, racemization occurs at the stereogenic
center of the acetylene alcohols; so we abandoned this route.
We next adopted an alternative strategy, whereby enantiopure
aNP esters 15a/15b–17a/17b
a
(a)
(S,S)-(–)-14b
22.8 min
(S,R)-(–)-14a
20.2 min
a
α = 1.25
a
a
RI
0
(b)
14b
(S,S)-(–)-
C3
C4
24.6 min
OMαNP
H
14b
(S,S)-(–)-
RI
0
acetylene alcohol M
genation, and the saturated alcohol M
hydrolyzed to yield enantiopure saturated aliphatic alcohols. To
check the diastereomeric purity of the saturated alcohol M NP
esters obtained, we carried out the following experiment. Enantio-
pure 5-octyn-4-ol M
NP ester (S,S)-(À)-20a was subjected to
catalytic hydrogenation with H2/PtO2 in diethyl ether (2 h), giving
4-octanol M
a
NP esters were subjected to catalytic hydro-
a
NP esters obtained were
(c)
RI
23.6 min
coinjection
21.2 min
a
a
a
NP ester (S,S)-(À)-14b in 83% yield [Scheme 3a].
0
The diastereomeric purity of product 14b was checked by HPLC
as illustrated in Figure 6, where (a) shows the separation of
Figure 6. Confirmation of the absolute configuration and diastereomeric purity of
(S,S)-(À)-4-octanol M NP ester 14b by coinjection in HPLC on silica gel (22 /
 300 mm, n = 9500–11,600), sample 40 mg, hexane/EtOAc = 20:1, flow rate 10 mL/
min, detected by RI: (a) a mixture of M NP esters 14a and 14b prepared from ( )-4-
octanol; (b) M
NP ester 14b obtained by the catalytic hydrogenation of (S,S)-(À)-5-
octyn-4-ol M NP ester 20a; (c) coinjection of two samples used in (a) and (b). To
save space, some solvent peaks were cut off.
4-octanol MaNP esters 14a and 14b prepared from racemic ( )-
a
4-octanol. Figure 6b shows the HPLC of 4-octanol M
aNP ester
a
(S,S)-(À)-14b prepared from 5-octyn-4-ol M NP ester (S,S)-(À)-
a
a
a
20a, while (c) shows the coinjection HPLC of two samples used
in (a) and (b). From these data, it is obvious that a peak correspond-

M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
1473
C19
C9
OMαNP
H
(S,R)-17a
17b
(S,S)-(–)-
17a
53.4 min
(S,R)-
56.3 min
α = 1.07
(a)
UV
0
17a
(b)
UV
0
0
17a
17b
(c)
UV
Figure 7. Confirmation of the diastereomeric purity of (S,R)-10-nonacosanol M
hexane/EtOAc = 80:1, flow rate 2 mL/min, detected by UV: (a) a mixture of M
by the catalytic hydrogenation of (S,S)-(À)-8-nonacosyn-10-ol M NP ester 22a; (c) coinjection of two samples used in (a) and (b). To save space, solvent peaks were cut off.
a
NP ester 17a by coinjection in HPLC on silica gel (10 / Â 300 mm, n = 34,400), sample 0.1 mg,
aNP esters 17a and 17b prepared from ( )-10-nonacosanol; (b) M NP ester (S,R)-17a obtained
a
a
ing to ester (S,R)-(À)-14a is not detected in (b). Namely, it was
synthesize in an enantiopure form. We have succeeded in synthe-
proved that no partial racemization occurred in the acetylene
sizing enantiopure 19-octatriacontanol (R)-(À)-7 as shown in
alcohol moiety during the catalytic hydrogenation of the M
a
NP
Scheme 3d. 17-Octatriacontyn-19-ol M
was subjected to catalytic hydrogenation to give 19-octatriaconta-
a
NP ester (S,S)-(À)-23a16
ester. The coinjection HPLC shown in Figure 7 also supports the
non-racemization mechanism. The present method is thus useful
nol M
a
NP ester (S,R)-(À)-18 (57% yield), while diastereomer (S,R)-
for the preparation of enantiopure aliphatic alcohol M
aNP esters,
(À)-23b afforded ester (S,S)-(À)-18 (59% yield). In these reactions,
the formation of some hydrocarbon was detected by TLC, implying
that the partial hydrogenolysis mechanism decreased the yield of
which can then be hydrolyzed to yield enantiopure aliphatic
alcohols.
In the above experiment, 5-octyn-4-ol M
20b were used to prepare 4-octanol M NP esters 14a and 14b.
However, 2-octyn-4-ol M
NP esters 19a and 19b16 are more
suitable, because the HPLC -value ( = 1.76) of esters 19a/19b is
much larger than that of esters 20a/20b ( = 1.32) as seen in
Table 2. Namely, it is advised to use acetylene alcohol M NP esters,
a
NP esters 20a and
the M
a
NP esters. The hydrolysis of M
a
NP ester (S,R)-(À)-18
a
needed stronger reagents and conditions; a mixture of ester
(S,R)-(À)-18 and NaOMe in iso-PrOH was heated at reflux for 3 days
to afford enantiopure 19-octatriacontanol (R)-(À)-7 (70%), which
was obtained as colorless crystals from CHCl3: mp 93.5–94.3 °C;
a
a
a
a
a
[a
]
D
53 = À0.038 (
r 0.56, c 1.04, CHCl3). The measurement of [a]
D
in which the acetylene moiety is contained in a shorter aliphatic
chain, but not in a longer one.
was very difficult in this case, because alcohol (R)-(À)-7 was barely
soluble even in CHCl3, and hence the solution sample was heated at
53 °C. Furthermore, the observed value was much smaller than the
The present method was applied to the synthesis of enantiopure
9-octadecanol (S)-(+)-5 as shown in Scheme 3b. Enantiopure 10-
standard deviation
[a] are not scientifically reliable. However, at the moment, we
D
have no proper method to identify the enantiomer of alcohol 7,
r, and so the sign and intensity of the present
octadecyn-9-ol M
was catalytically hydrogenated with H2/PtO2 in diethyl ether to
a
NP ester (S,S)-(À)-21a previously prepared16
afford 9-octadecanol M
was further hydrolyzed with KOH in ethanol to yield enantiopure
9-octadecanol (S)-(+)-5 (91% yield), [
23 = +0.1 (c 6.09, cyclohex-
ane). Another M
a
NP ester (S,S)-(À)-16b (88% yield), which
as will be discussed below. Therefore, the [
as the observed results.
The above assignment of the negative rotation to alcohol (R)-7
is supported by the following results. In a series of chiral alcohols,
CH3(CH2)n–CH(OH)–(CH2)n+1CH3, the alcohols with an (S)-absolute
a] data are described
D
a
]
D
a
NP ester (S,R)-(À)-21b was similarly converted
into ester (S,R)-(À)-16a (83% yield).
10-Nonacosanol 6 can be isolated as a component of plant
wax;22 the absolute configuration of natural product 6 was
determined to be S by the 1H NMR anisotropy method using (R)-
and (S)-2-anthrylmethoxyacetic acids (2ATMA).23 Hence, we next
applied our method to study chiral 10-nonacosanol 6. The syn-
configuration have positive [
a] values, while those with an (R)-
D
absolute configuration have negative [
a
] values, as exemplified
D
as follows: (S)-(+)-2-butanol, (R)-(À)-4-octanol 4, and (S)-(+)-9-
octadecanol 5. Hence, as a member of chiral alcohols, CH3(CH2)n–
CH(OH)–(CH2)n+1CH3, the absolute configuration assignment of
alcohol (R)-(À)-7 is logically supported.
thetic precursor, enantiopure 8-nonacosyn-10-ol
MaNP ester
(S,S)-(À)-22a16 was reduced in a similar way to afford 10-nonacos-
anol MaNP ester (S,R)-17a (36% yield) [Scheme 3c], while diaste-
2.5. Methods for identifying aliphatic chain alcohol enantiomers
reomer (S,R)-(À)-22b was converted into M
aNP ester (S,S)-17b
(49% yield). The low yields of both esters 17a and 17b may imply
partial hydrogenolysis during the reaction. In this case, it was evi-
denced that no racemization occurred during the catalytic hydro-
genation as shown in Figure 7. Although the recovery of
enantiopure 10-nonacosanol 6 was not carried out, we believe that
enantiopure 10-nonacosanol 6 can be synthesized by this route.
Chiral 19-octatriacontanol 7 is a compound with extremely
small chirality or cryptochirality, where the small difference
between two long chains (C18H37- and C19H39-) creates the chiral-
ity of 7. Therefore, it is one of the most difficult compounds to
As discussed above, the [
5, and 7 are so small, and those [
identification of enantiomers. As a result, we looked for a more
appropriate method for identification of the enantiomers, and the
a
]
D values of aliphatic chain alcohols 4,
a]
data are not ideal for the
D
answer was found in Figure 3. The diastereomeric MaNP esters
of alcohols listed in Figure 3 are separable by HPLC on silica gel
except in the case of 19-octatriacontanol 7; hence, based on this
fact, the enantiomers can be identified as follows. For example,
the (R)-enantiomer of 4-octanol is designated as [(S)-M
HPLC(1st fr.)]-(R)-(À)-4, which defines the absolute configuration
aNP/

1474
M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
as follows; chiral 4-octanol 4 is esterified with (S)-MaNP acid to
4. Experimental
4.1. General
yield an ester, which is subjected to HPLC on silica gel. If the ester
appears at the first-eluted peak, the chiral 4-octanol 4 has an (R)-
absolute configuration. If it is the second-eluted peak, it has an
(S)-absolute configuration. This method was applied to alcohols 5
and 6 as indicated in Figure 2. In some cases, the 1H NMR spectra
Silica gel 60 F254 precoated plates on glass from Merck Ltd were
used for thin layer chromatography (TLC). HPLC separation and
purification were performed using prepacked glass columns (22
/ Â 300 mm, theoretical plate number n = 9500–11,600) of silica
of the diastereomeric Ma
NP esters are different from each other,19
and hence it is also possible to identify enantiomers by comparison
of the 1H NMR spectra with those of an authentic sample.
In the case of alcohol 7, these enantiomer identification meth-
gel (particle size 5–10 lm) from Kusano Co., Ltd, or a YMC-pack
SIL-06 column (10 / Â 300 mm, theoretical plate number
n = 34,400) from YMC Co., Ltd, and a UV/RI detector, Shimamura
YRU-880. Melting points were measured on a Mitamura micro
melting point apparatus and are uncorrected. Optical rotations
ods are not useful because diastereomeric M
be separated as shown in Figure 3g, and the 1H NMR spectra of dia-
stereomeric M
aNP esters could not
a
NP esters (S,R)-(À)-18 and (S,S)-(À)-18 looked very
similar to each other. Therefore, at the moment, there is not an
appropriate method for identifying the enantiomer of 19-octatria-
contanol 7, but it should be emphasized that enantiopure long
chain aliphatic alcohol (R)-7 with an established absolute configu-
ration could be synthesized.
[a] were measured on a Jasco DIP-1000 spectropolarimeter. IR
D
spectra were obtained as neat or film on KBr on a Jasco FT/IR-
410 spectrophotometer. 1H NMR spectra were recorded on a Jeol
JNM-LA400 (400 MHz) and/or a Jeol JNM-LA600 (600 MHz) spec-
trometer. 13C NMR spectra were obtained on a Jeol JNM-LA400
(100 MHz) and/or a Jeol JNM-LA600 (150 MHz) spectrometer. All
NMR data are reported in ppm (d) downfield from TMS. In the
13C NMR spectra of some compounds, the number of signal peaks
was less than that of carbon atoms because of the overlap of peaks.
UV and CD spectra were recorded on Jasco UV-570 and J-720WI
spectrophotometers, respectively. The purities of the title com-
pounds were shown to be P99% by 1H NMR, TLC, HPLC, and/or ele-
mental analysis. Compounds used as starting materials without
references were commercially available.
3. Conclusion
We have succeeded in developing a general method for the syn-
thesis of enantiopure (100% ee) aliphatic chain alcohols with estab-
lished absolute configurations as summarized in Scheme 4. In the
case of shorter chain aliphatic alcohols, their diastereomeric MaNP
esters were separated directly by HPLC on silica gel, and the esters
obtained were hydrolyzed to afford enantiopure alcohols, whose
absolute configurations were determined by 1H NMR anisotropy.
In the case of longer chain aliphatic alcohols, the corresponding
4.2. Enantiopurity check of commercially available (S)-(+)-2-
butanol: sample T
acetylene alcohols were esterified with M
aNP acid, and the
diastereomeric esters obtained were largely separated by HPLC
To a mixture of MaNP acid (S)-(+)-1 (62.2 mg, 0.270 mmol), 1,3-
dicyclohexylcarbodiimide (DCC, 61.2 mg, 0.297 mmol), and 4-
dimethylaminopyridine (DMAP, 8.1 mg, 0.067 mmol), in CH2Cl2
(0.27 mL), a sample (T) of (S)-(+)-2-butanol (10.0 lL, 0.135 mmol)
was added at 0 °C, and the mixture was stirred at room tempera-
ture for 24 h. After the addition of a small amount of water, stirring
for 1 h, and the addition of diethyl ether and anhydrous MgSO4, the
mixture was filtered through Celite, which was washed with
EtOAc. The combined organic layers were evaporated under
reduced pressure, and the residue was subjected to short column
chromatography on silica gel (hexane/EtOAc 10:1) to give a crude
on silica gel. The absolute configurations of MaNP esters were
unambiguously determined by 1H NMR anisotropy and/or X-ray
crystallography. The separated acetylene alcohol esters were sub-
jected to catalytic hydrogenation to yield saturated alcohol MaNP
esters. It was confirmed by HPLC that no partial racemization
occurred at the stereogenic center of the alcohol part during cata-
lytic hydrogenation. Hydrolysis of the saturated alcohol MaNP
esters furnished enantiopure long chain aliphatic alcohols. The chi-
ral discrimination of these alcohols is the most difficult, and so we
believe that the present method reported in Parts 1 and 2 is more
easily applicable to the enantiopure synthesis of other ordinary
chiral alcohols and also to the determination of their absolute
configurations.
product. The obtained MaNP esters were subjected to HPLC on sil-
ica gel (22 / Â 300 mm column, hexane/EtOAc 20:1) to give the
first-eluted ester (S,R)-12a (1.4 mg, 4%) and the second-eluted
one (S,S)-12b (30.9 mg, 80%). The ratio of 12a/12b in the mixture
was also determined by 1H NMR (400 MHz, CDCl3): d = 0.25 (t,
J = 7.4 Hz, 4-H, relative intensity 14, 12b), 0.73 (t, J = 7.4 Hz, 4-H,
relative intensity 1, 12a), 0.86 (d, J = 6.4 Hz, 1-H, relative intensity
1, 12a), 1.11 (d, J = 6.4 Hz, 1-H, relative intensity 14, 12b), where
the 1H NMR data of the minor component (S,R)-12a were assigned
by comparison with those of the enantiomeric authentic sample
(R,S)-12a prepared as described below.
R1
R1
R2
R2
(i) esterification
(ii) HPLC
OH
H
H
OMαNP
24
( )-
25
(S,X)-
4.2.1. (S,S)-2-Butanol M
and (S)-M NP acid
Colorless syrup; IR (neat)
1743, 1599, 1509, 1455, 1377, 1255, 1180, 1139, 1109, 1052,
1025, 993, 968, 871, 806, 781 cmÀ1 1H NMR (600 MHz, CDCl3)
aNP ester 12b prepared from sample T
a
R1
R2
R1
R2
mmax = 3050, 2974, 2937, 2879, 2829,
(iv) hydrolysis
(iii) hydrogenation
OH
H
H
OMαNP
;
d = 0.27 (3H, t, J = 7.4 Hz, 4-H), 1.11 (3H, d, J = 6.2 Hz, 1-H), 1.21
(1H, dqd, J = 14.1, 7.4, 5.5 Hz, 3-H), 1.24 (1H, dqd, J = 14.1, 7.4,
7.5 Hz, 3-H), 1.98 (3H, s), 3.10 (3H, s), 4.82 (1H, dqd, J = 7.5, 6.2,
5.5 Hz, 2-H), 7.4–8.5 (7H, m); 13C NMR (150 MHz, CDCl3) d = 8.8,
19.2, 21.7, 28.3, 50.9, 73.3, 81.5, 124.6, 125.4, 125.6, 126.3, 128.5,
(Y)-27
(S,Y)-26
Scheme 4. General procedure for the synthesis of enantiopure aliphatic alcohols
with established absolute configurations. In the synthetic plan, it is advised to place
a triple bond in a shorter chain, because of easier HPLC separation.

M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
1475
129.3, 131.5, 134.0, 135.3, 173.8; UV (EtOH) kmax = 291.6
= 5400), 281.2 (7800), 271.4 (6400), 224.2 (75,500) nm; CD
(EtOH) kext = 292.6 (
= À0.64), 281.2 (À0.88), 271.4 (À0.76),
230.8 (+3.02), 213.8 (À9.05) nm.
4.4.1. (S,R)-(À)-3-Hexanol M
aNP ester 13a
(e
Colorless syrup;
[
a]
24 = À15.6 (c 1.11, CHCl3); IR (neat)
D
D
e
mmax = 2962, 2937, 1743, 1726, 1509, 1457, 1365, 1252, 1140,
1109, 1058, 805, 781 cmÀ1 1H NMR (600 MHz, CDCl3) d = 0.22
;
(3H, dd, J = 7.5, 7.5 Hz, 1-H), 0.82 (3H, dd, J = 7.3, 7.3 Hz, 6-H),
1.20 (2H, m, 5-H), 1.21 (2H, m, 2-H), 1.34 (1H, dddd, J = 13.7, 6.0,
5.0, 5.0 Hz, 4-H), 1.42 (1H, dddd, J = 13.7, 7.7, 5.1, 5.1 Hz, 4-H),
2.00 (3H, s), 3.10 (3H, s), 4.81 (1H, dddd, J = 7.0, 7.0, 5.1, 5.0 Hz,
3-H), 7.43–7.47 (3H, m), 7.60 (1H, br d, J = 7.1 Hz), 7.80–7.83 (2H,
m), 8.45–8.47 (1H, m); 1H NMR assignments were confirmed
by HMQC and HH COSY (600 MHz, CDCl3); 13C NMR (150 MHz,
CDCl3) d = 8.4, 13.9, 18.4, 21.7, 26.3, 35.3, 50.8, 76.3, 81.6, 124.6,
125.4, 125.6, 125.6, 126.3, 128.5, 129.3, 131.5, 134.0, 135.5,
173.9. Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found: C,
76.27; H, 8.34.
4.2.2. (R,S)-2-Butanol MaNP ester 12a prepared from sample A
and (R)-M NP acid
a
Colorless syrup; 1H NMR (600 MHz, CDCl3) d = 0.73 (3H, t,
J = 7.4 Hz, 4-H), 0.87 (3H, d, J = 6.2 Hz, 1-H), 1.39 (1H, dqd,
J = 13.9, 7.4, 5.3 Hz, 3-H), 1.44 (1H, dqd, J = 13.9, 7.4, 6.6 Hz, 3-H),
1.98 (3H, s), 3.11 (3H, s), 4.85 (1H, dqd, J = 7.1, 6.2, 5.5 Hz, 2-H),
7.4–8.5 (7H, m); 13C NMR (150 MHz, CDCl3) d = 9.5, 18.9, 21.8,
28.4, 50.9, 73.4, 81.6, 124.6, 125.2, 125.4, 125.6, 126.2, 128.6,
129.2, 131.3, 134.0, 135.5, 173.8; UV (EtOH) kmax = 291.6
(e
= 4900), 281.2 (7100), 271.2 (5900), 224.0 (71,000) nm; CD
(EtOH) kext = 290.2 = +0.45), 280.8 (+0.68), 270.4 (+0.50),
(De
228.0 (À3.39), 207.6 (+6.00) nm.
4.4.2. (S,S)-(À)-3-Hexanol M
aNP ester 13b
Colorless syrup;
[a
]
D
23 = À4.6 (c 1.08, CHCl3); IR (neat)
4.3. Preparation of racemic alcohols
m
max = 2963, 1744, 1509, 1457, 1369, 1253, 1139, 1111,
781 cmÀ1 1H NMR (600 MHz, CDCl3) d = 0.42 (3H, dd, J = 7.1,
;
4.3.1. ( )-9-Octadecanol 5
6.8 Hz, 6-H), 0.45 (1H, m, 5-H), 0.63 (1H, m, 5-H), 0.77 (3H, dd,
J = 7.5, 7.5 Hz, 1-H), 1.34 (2H, m, 4-H), 1.44 (2H, dqd, J = 7.5, 7.3,
1.1 Hz, 2-H), 2.00 (3H, s), 3.11 (3H, s), 4.79 (1H, dddd, J = 7.5, 7.5,
6.2, 4.8 Hz, 3-H), 7.43–7.48 (3H, m), 7.60 (1H, br d, J = 7.3 Hz),
7.80–7.83 (2H, m), 8.46–8.48 (1H, m); 1H NMR assignments were
confirmed by HMQC and HH COSY (600 MHz, CDCl3); 13C NMR
(150 MHz, CDCl3) d = 9.4, 13.4, 17.3, 21.7, 26.5, 34.9, 50.8, 76.2,
81.5, 124.5, 125.4, 125.6, 125.6, 126.3, 128.5, 129.2, 131.5, 134.0,
135.2, 173.8. Anal. Calcd for C20H26O3: C, 76.40; H, 8.33. Found:
C, 76.35; H, 8.34.
A mixture of ( )-10-octadecyn-9-ol 816 (65.0 mg, 0.150 mmol)
and PtO2 (0.99 mg, 0.0043 mmol) in diethyl ether (0.5 mL) was
stirred under a hydrogen atmosphere for 2 h. After removal of
the catalyst by filtration, the organic layers were evaporated. The
crude product was purified by HPLC on silica gel (hexane/EtOAc
10:1) to give ( )-9-octadecanol 5: yield 65.7 mg, 100%; colorless
needles (EtOH), mp 56–58 °C; IR (film)
mmax = 3322, 3222, 2953,
2918, 2849, 1463, 1352, 1136, 1092, 1018, 901, 871, 849,
721 cmÀ1 1H NMR (400 MHz, CDCl3) d = 0.88 (6H, t, J = 6.8 Hz),
;
1.28–1.43 (30H, m), 3.58 (1H, m); 13C NMR (100 MHz, CDCl3)
d = 14.1, 22.6, 25.6, 29.2, 29.3, 29.5, 29.6, 29.6, 29.7, 31.8, 37.4,
72.0. Anal. Calcd for C18H38O: C, 79.93; H, 14.16. Found: C, 79.72;
H, 14.12.
4.4.3. (S,R)-(À)-4-Octanol M
Yield 35%; colorless syrup; [
(neat)
aNP ester 14a
a]
24 = À11.3 (c 1.28, CHCl3); IR
D
m
max = 3051, 2957, 2934, 2871, 2830, 2359, 1745, 1510,
1465, 1371, 1252, 1181, 1139, 1117, 1054, 954, 899, 806,
4.3.2. ( )-19-Octatriacontanol 7
780 cmÀ1 1H NMR (600 MHz, CDCl3) d = 0.43 (3H, t, J = 7.1 Hz),
;
( )-17-Octatriacontyn-19-ol 916 (22.0 mg) was similarly
reduced and the crude product was purified by HPLC on silica gel
(hexane/EtOAc 20:1) to give ( )-19-octatriaconranol 7: yield
0.49 (1H, m), 0.66 (1H, m), 0.81 (3H, t, J = 7.2 Hz), 1.14 (4H, m),
1.20 (2H, m), 1.39 (2H, m), 1.99 (3H, s), 3.12 (3H, s), 4.85 (1H,
tt, J = 7.3, 5.0 Hz), 7.46 (3H, m), 7.60 (1H, dd, J = 7.3, 1.1 Hz),
7.83 (2H, m), 8.46 (1H, m); 13C NMR (150 MHz, CDCl3) d = 13.5,
13.9, 17.4, 21.7, 22.5, 27.3, 33.3, 35.5, 50.9, 75.1, 81.6, 124.6,
125.4, 125.6, 125.6, 126.3, 128.5, 129.3, 131.5, 134.0, 135.3,
30 mg, 100%; colorless amorphous solid; IR (film)
m
max = 3321,
3256, 2954, 2917, 2848, 1463 cmÀ1
;
1H NMR (400 MHz, CDCl3)
d = 0.88 (6H, t, J = 7.1 Hz), 1.25 (70H, m), 3.58 (1H, m); 13C NMR
(100 MHz, CDCl3) d = 14.1, 22.6, 25.6, 29.3, 29.7, 31.9 in a noisy
spectrum due to the poor solubility.
173.8; UV (EtOH) kmax = 292.2 (
(5200), 224.0 (60,600) nm; CD (EtOH) kext = 292.0 (
281.2 (À0.8), 271.4 (À0.8), 230.8 (+2.1), 217.0 (À9.7) nm.
Anal. Calcd for C22H30O3: C, 77.16; H, 8.83. Found: C, 76.98; H,
8.67.
e
= 4400), 281.2 (6300), 271.4
= À0.6),
D
e
4.4. Preparation of diastereomeric aliphatic alcohol M
and HPLC separation
aNP esters
Racemic alcohols were esterified with (S)-(+)-M
a
NP acid 18,10,15
4.4.4. (S,S)-(À)-4-Octanol M
aNP ester 14b
as follows. To a mixture of M NP acid (99.1 mg, 0.430 mmol), DCC
a
Yield 35%; colorless syrup; [
a]
D
24 = À7.1 (c 1.34, CHCl3); IR (neat)
(114.1 mg, 0.553 mmol), DMAP (27.2 mg, 0.225 mmol), and 10-
camphorsulfonic acid (CSA, 10.3 mg, 0.047 mmol) in CH2Cl2
(1.0 mL), racemic 3-hexanol ( )-10 (0.060 mL, 0.481 mmol) was
added at 0 °C, and the mixture was stirred at room temperature
for 18 h. After the addition of a small amount of water, stirring
for 1 h, and the addition of diethyl ether and anhydrous MgSO4,
the mixture was filtered through Celite, which was washed with
EtOAc. The combined organic layers were evaporated under
reduced pressure, and the residue was subjected to short column
chromatography on silica gel (hexane/EtOAc 10:1) giving a crude
mmax = 3050, 2957, 2935, 2872, 2830, 2362, 1745, 1600, 1510, 1465,
1369, 1251, 1181, 1140, 1118, 1054, 956, 806, 780 cmÀ1 1H NMR
;
(600 MHz, CDCl3) d = 0.40 (1H, m), 0.49 (3H, t, J = 7.4 Hz), 0.50
(1H, m), 0.77 (2H, tq, J = 7.3, 7.3 Hz), 0.83 (3H, t, J = 7.3 Hz), 1.14
(2H, td, J = 7.9, 5.5 Hz), 1.22 (2H, m), 1.33 (1H, m), 1.43 (1H, m),
2.00 (3H, s), 3.10 (3H, s), 4.85 (1H, ddt, J = 7.5, 6.2, 5.4 Hz), 7.46
(3H, m), 7.59 (1H, dd, J = 7.1, 1.1 Hz), 7.82 (2H, m), 8.48 (1H, m);
13C NMR (150 MHz, CDCl3) d = 13.6, 13.9, 18.4, 21.6, 22.2, 26.3,
33.2, 35.8, 50.8, 75.0, 81.5, 124.6, 125.5, 125.7, 125.7, 126.4,
128.5, 129.3, 131.5, 134.0, 135.2, 173.8; UV (EtOH) kmax = 292.2
product. The diastereomeric M
aNP esters were separated by HPLC
(e
= 5000), 281.4 (7300), 271.8 (6000), 224.2 (68,200) nm; CD
on silica gel (22 / Â 300 mm column, hexane/EtOAc 20:1) to afford
the first-eluted ester 13a (55.6 mg, 41%) and the second-eluted one
13b (54.1 mg, 40%).
(EtOH) kext = 292.0 (
D
e
= À0.6), 280.6 (À1.0), 270.2 (À0.8), 228.6
(+3.1), 216.4 (À12.3) nm. Anal. Calcd for C22H30O3: C, 77.16; H,
8.83. Found: C, 76.89; H, 8.67.

1476
M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
4.4.5. A mixture of (S,S)- and (S,R)-5-decanol M
a
NP esters 15
4.5.3. 9-Octadecanol M
10-Octadecyn-9-ol
0.235 mmol) was similarly reduced and the crude product was
a
M
NP ester (S,R)-(À)-16a
Racemic 5-decanol ( )-11 was similarly esterified with M
a
NP
a
NP ester (S,R)-(À)-21b16 (112 mg,
acid (S)-(+)-1 to yield diastereomeric esters 15, which were
base-line separated only in the case of analytical HPLC as shown
in Figure 3d. Since the preparative separation was difficult, further
characterization has not been carried out.
purified by HPLC on silica gel (hexane/EtOAc 40:1) yielding 9-octa-
decanol M
a
NP ester (S,R)-(À)-16a: yield 94.1 mg, 83%; colorless
syrup; [
a
]
D
28 = À5.3 (c 1.22, CHCl3); IR (neat)
mmax = 3051, 2925,
2855, 1748, 1727, 1510, 1465, 1371, 1252, 1181, 1138, 1055,
805, 779 cmÀ1 1H NMR (600 MHz, CDCl3) d = 0.42 (1H, m), 0.51
;
4.4.6. A mixture of 9-octadecanol M
a
NP esters (S,R)-(À)-16a and
(1H, m), 0.71–0.86 (4H, m), 0.88 (6H, t, J = 7.1 Hz), 1.04 (2H, dddd,
J = 7.4, 7.4, 7.4, 7.4 Hz), 1.11–1.31 (20H, m), 1.38 (2H, m), 1.99
(3H, s), 3.10 (3H, s), 4.83 (1H, tt, J = 6.0, 6.0 Hz), 7.45 (3H, m),
7.60 (1H, dd, J = 7.1, 0.9 Hz), 7.82 (2H, m), 8.46 (1H, m); 13C NMR
(150 MHz, CDCl3) d = 14.1, 14.1, 21.6, 22.6, 22.7, 24.2, 25.2, 29.1,
29.2, 29.3, 29.4, 29.5, 29.5, 29.7, 31.8, 31.9, 33.5, 33.7, 50.8, 75.3,
81.5, 124.6, 125.4, 125.7, 126.3, 128.5, 129.3, 131.5, 134.0, 135.3,
173.8; UV (EtOH) kmax = 292.0 (
(5500), 224.4 (63,300) nm; CD (EtOH) kext = 291.8 (
281.0 (À0.8), 271.2 (À0.6), 229.2 (+3.4), 207.0 (À10.0) nm.
(S,S)-(À)-16b
Racemic 9-octadecanol ( )-5 was similarly esterified with
MaNP acid (S)-(+)-1 to yield diastereomeric esters 16a and 16b,
which partially overlapped with each other even in the analytical
HPLC as illustrated in Figure 3e. Therefore, further characterization
was not carried out here. However, esters (S,S)-(À)-16b and
(S,R)-(À)-16a were obtained by catalytic hydrogenation of the
e
= 4600), 281.6 (6600), 271.8
corresponding acetylene alcohol M
a
NP esters (S,S)-(À)-21a and
D
e
= À0.6),
(S,R)-(À)-21b, respectively, and hence were fully characterized as
described below.
4.5.4. 10-Nonacosanol M
aNP ester (S,R)-17a
a
8-Nonacosyn-10-ol
M
NP ester (S,S)-(À)-22a16 (95.0 mg,
4.4.7. A mixture of 19-octatriacontanol M
a
NP esters (S,R)-(À)-
0.150 mmol) was similarly reduced and the crude product was puri-
18 and (S,S)-(À)-18
fied by HPLC on silica gel (hexane/EtOAc 20:1) yielding
Racemic 19-octatriacontanol ( )-7 was similarly esterified with
10-nonacosanol MaNP ester (S,R)-17a: yield 34.8 mg, 36%; colorless
M
a
NP acid (S)-(+)-1 to yield diastereomeric esters (S,R)-(À)-18 and
syrup; 1H NMR (400 MHz, CDCl3) d = 0.47 (2H, m), 0.75 (4H, m), 0.88
(3H, t, J = 7.1 Hz), 0.90 (3H, t, J = 7.1 Hz), 1.03 (2H, m), 1.10–1.41
(44H, m), 1.99 (3H, s), 3.10 (3H, s), 4.83 (1H, tt, J = 6.1, 6.1 Hz),
7.46 (3H, m), 7.59 (1H, dd, J = 7.3, 0.7 Hz), 7.82 (2H, m), 8.47 (1H,
m); 13C NMR (100 MHz, CDCl3) d = 14.1, 14.1, 21.6, 22.7, 24.2,
25.2, 29.2, 29.2, 29.3, 29.4, 29.4, 29.5, 29.5, 29.7, 29.7, 31.9, 31.9,
33.5, 33.7, 50.8, 75.3, 81.5, 124.6, 125.4, 125.6, 126.3, 128.5, 129.3,
(S,S)-(À)-18, which appeared as a single peak even in the analytical
HPLC on silica gel (hexane/EtOAc 150:1). Therefore, both esters
(S,R)-(À)-18 and (S,S)-(À)-18 were obtained by catalytic hydroge-
nation of the corresponding acetylene alcohol
MaNP esters
(S,S)-(À)-23a and (S,R)-(À)-23b, respectively, and hence were fully
characterized as described below.
131.5, 134.0, 135.2, 173.8; UV (EtOH) kmax = 292.2 (
281.6 (5200), 271.8 (4300), 224.6 (50,000) nm; CD (EtOH)
kext = 301.6 (
= +0.3), 228.2 (+4.6), 211.2 (À7.1), 206.6 (À7.6) nm.
e = 3600),
4.5. Synthesis of aliphatic alcohol M
hydrogenation of acetylene alcohol M
a
NP esters by the catalytic
aNP esters
D
e
4.5.5. 10-Nonacosanol M
a
a
NP ester (S,S)-(À)-17b
4.5.1. 4-Octanol M
a
NP ester (S,S)-(À)-14b
NP ester (S,R)-(À)-22b16 (316.5 mg,
A mixture of (S,S)-(À)-5-octyn-4-ol M
a
NP ester 20a17 (33.8 mg,
8-Nonacosyn-10-ol
M
0.50 mmol) was similarly reduced and the crude product was
purified by HPLC on silica gel (hexane/EtOAc 20:1) yielding 10-
0.10 mmol) and PtO2 (0.465 mg) in diethyl ether (0.2 mL) was
stirred under a hydrogen atmosphere for 2 h. After removal of
the catalyst by filtration and short-column chromatography on
silica gel, the organic layers were evaporated. The crude product
was purified by HPLC on silica gel (hexane/EtOAc 20:1) to yield
nonacosanol M
a
NP ester (S,S)-(À)-17b: yield 154.6 mg, 49%; color-
less syrup; [
a]
26 = À2.2 (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d = 0.47 (2H, m), 0.76 (4H, m), 0.88 (3H, t, J = 6.8 Hz), 0.88
(3H, t, J = 6.8 Hz), 1.02 (2H, m), 1.10–1.41 (44H, m), 1.99 (3H, s),
3.10 (3H, s), 4.83 (1H, tt, J = 6.1, 6.1 Hz), 7.46 (3H, m), 7.59 (1H,
dd, J = 7.2, 0.7 Hz), 7.82 (2H, m), 8.47 (1H, m); 13C NMR
(100 MHz, CDCl3) d = 14.1, 21.6, 22.7, 24.2, 25.2, 29.2, 29.2, 29.3,
29.4, 29.4, 29.5, 29.6, 29.7, 29.7, 31.9, 31.9, 33.5, 33.7, 50.8, 75.3,
81.5, 124.6, 125.4, 125.7, 126.3, 128.5, 129.3, 131.5, 134.0, 135.2,
4-octanol M
a
NP ester (S,S)-(À)-14b: yield 28.4 mg, 83%; colorless
syrup. The product was identical to the ester prepared from race-
mic 4-octanol as described above.
4.5.2. 9-Octadecanol M
a
NP ester (S,S)-(À)-16b
10-Octadecyn-9-ol
0.054 mmol) was similarly reduced and the crude product was
purified by HPLC on silica gel (hexane/EtOAc 40:1) yielding 9-octa-
Ma
NP ester (S,S)-(À)-21a16 (26.0 mg,
173.8; UV (EtOH) kmax = 292.4 (
(5900), 224.6 (66,200) nm; CD (EtOH) kext = 281.8 (
228.2 (+5.6), 212.0 (À8.9), 207.4 (À9.2) nm. Anal. Calcd for
43H72O3: C, 81.07; H, 11.39. Found: C, 81.11; H, 11.64.
e
= 4900), 281.8 (7100), 271.8
D
e
= À0.4),
decanol M
a
NP ester (S,S)-(À)-16b: yield 19.1 mg, 88%; colorless
C
syrup; [
a]
23 = À5.0 (c 1.56, CHCl3); IR (neat)
mmax = 3051, 2926,
D
2855, 1747, 1727, 1600, 1510, 1465, 1372, 1250, 1181, 1137,
4.5.6. 19-Octatriacontanol M
17-Octatriacontyn-19-ol M
0.38 mmol) was similarly reduced and the crude product was puri-
a
a
NP ester (S,R)-(À)-18
1121, 1056, 804, 779 cmÀ1 1H NMR (600 MHz, CDCl3) d = 0.42
;
NP ester (S,S)-(À)-23a16 (289 mg,
(1H, m), 0.51 (1H, m), 0.72–0.86 (4H, m), 0.88 (3H, t, J = 7.1 Hz),
0.90 (3H, t, J = 7.3 Hz), 1.03 (2H, dddd, J = 7.3, 7.3, 7.3, 7.3 Hz),
1.09–1.26 (16H, m), 1.28 (4H, dddd, J = 7.1, 7.1, 7.1, 7.1 Hz), 1.38
(2H, m), 1.99 (3H, s), 3.10 (3H, s), 4.83 (1H, tt, J = 6.9, 5.2 Hz),
7.46 (3H, m), 7.60 (1H, dd, J = 7.1, 0.9 Hz), 7.82 (2H, m), 8.46 (1H,
m); 13C NMR (150 MHz, CDCl3) d = 14.1, 14.1, 21.6, 22.6, 22.7,
24.2, 25.2, 29.2, 29.2, 29.3, 29.4, 31.8, 31.9, 33.5, 33.7, 50.8, 75.3,
81.5, 124.6, 125.4, 125.7, 126.3, 128.5, 129.3, 131.5, 134.0, 135.2,
173.8; UV (EtOH) kmax = 291.8 (e = 4400), 281.4 (6300), 271.6
(5200), 224.2 (63,400) nm; CD (EtOH) kext = 281.2 (
229.2 (+2.7), 212.6 (À11.2), 207.4 (À11.1) nm.
fied by HPLC on silica gel (hexane/EtOAc 50:1) yielding 19-octatri-
acontanol M
a
NP ester (S,R)-(À)-18: yield 165 mg, 57%; colorless
amorphous solid; [
a]
28 = À2.6 (c 1.20, CHCl3); IR (film)
mmax = 2924,
D
2853, 1749, 1466, 1251, 1138, 779 cmÀ1
;
1H NMR (400 MHz,
CDCl3) d = 0.36–0.56 (2H, m), 0.69–0.90 (4H, m), 0.88 (6H, t,
J = 6.8 Hz), 1.03 (2H, dddd, J = 7.0, 7.0, 7.0, 7.0 Hz), 1.10–1.47
(62H, m), 1.99 (3H, s), 3.10 (3H, s), 4.83 (1H, dddd, J = 6.1, 6.1,
6.1, 6.1 Hz), 7.42–7.48 (3H, m), 7.60 (1H, dd, J = 7.3, 1.0 Hz),
7.80–7.83 (2H, m), 8.45–8.48 (1H, m); 13C NMR (100 MHz, CDCl3)
d = 14.11, 21.62, 22.69, 24.17, 25.16, 29.18, 29.23, 29.36, 29.43,
D
e
= À1.3),

M. Akagi et al. / Tetrahedron: Asymmetry 25 (2014) 1466–1477
1477
29.47, 29.53, 29.66, 29.70, 31.92, 33.45, 33.68, 50.78, 75.30, 81.46,
124.57, 125.44, 125.65, 126.35, 128.45, 129.28, 131.47, 134.00,
was obtained by filtration. The organic layers were dried over
anhydrous MgSO4 and evaporated under reduced pressure. The
residue was combined with the solid matter, which was subjected
to a short column chromatography on silica gel (CHCl3), and the
product was further purified by recrystallization from CHCl3 giving
(R)-(À)-19-octatriacontanol 7 as colorless crystals: 81 mg, 70%; mp
135.24, 173.28; UV (EtOH) kmax = 292.4 (
272.0 (5800), 224.8 (69,500) nm; CD (EtOH) kext = 283.0
= À0.9), 227.2 (+3.9), 208.4 (À11.8) nm. Anal. Calcd for
52H90O3: C, 81.83; H, 11.89. Found: C, 81.58; H, 11.99.
e = 4900), 282.0 (7000),
(De
C
93.5–94.3 °C; [
a
]
53 = À0.038 (
r
0.56, c 1.04, CHCl3), [/]D = À0.21; IR
D
4.5.7. 19-Octatriacontanol M
17-Octatriacontyn-19-ol M
0.39 mmol) was similarly reduced and the crude product was puri-
a
a
NP ester (S,S)-(À)-18
(film)
m
max = 3321, 3256, 2954, 2917, 2848, 1463 cmÀ1
;
1H NMR
NP ester (S,R)-(À)-23b16 (296 mg,
(400 MHz, CDCl3) d = 0.88 (6H, t, J = 7.1 Hz), 1.25 (70H, m), 3.58
(1H, m); 13C NMR (100 MHz, CDCl3) d = 29.6 in a noisy spectrum
due to the poor solubility in CDCl3. Anal. Calcd for C38H78O: C,
82.83; H, 14.27. Found: C, 82.66; H, 14.52.
fied by HPLC on silica gel (hexane/EtOAc 50:1) yielding 19-octatri-
acontanol M
a
NP ester (S,S)-(À)-18: yield 175 mg, 59%; colorless
amorphous solid; [
a]
24 = À2.4 (c 5.96, CHCl3); IR (film)
mmax = 2924,
D
2853, 1749, 1466, 1251, 1137, 779 cmÀ1
;
1H NMR (400 MHz,
Acknowledgments
CDCl3) d = 0.35–0.56 (2H, m), 0.70–0.90 (4H, m), 0.88 (6H, t,
J = 6.8 Hz), 1.02 (2H, dddd, J = 7.1, 7.1, 7.1, 7.1 Hz), 1.10–1.43
(62H, m), 1.99 (3H, s), 3.10 (3H, s), 4.83 (1H, dddd, J = 6.0, 6.0,
6.0, 6.0 Hz), 7.42–7.48 (3H, m), 7.60 (1H, dd, J = 7.3, 1.0 Hz),
7.80–7.83 (2H, m), 8.45–8.48 (1H, m); 13C NMR (100 MHz, CDCl3)
d = 14.11, 21.62, 22.69, 24.17, 25.16, 29.18, 29.23, 29.36, 29.42,
29.47, 29.53, 29.65, 29.70, 31.92, 33.45, 33.68, 50.78, 75.31,
81.46, 124.57, 125.44, 125.65, 126.35, 128.54, 129.29, 131.47,
The authors thank Dr. George A. Ellestad, Department of Chem-
istry, Columbia University, for his valuable suggestions. This work
was supported in part by grants from the Japan Society for the
Promotion of Science, Scientific Research (B) (to N.H.) and Young
Scientist Research (B) (to S.K.), the Nissan Science Foundation,
Japan (to S.K.), the Mazda Foundation, Japan (to S.K.), and the
Inamori Foundation, Japan (to S.K.).
133.99, 135.23, 173.77; UV (EtOH) kmax = 292.4 (
(7300), 272.0 (6100), 224.6 (72,300) nm; CD (EtOH) kext = 281.4
= À1.0), 227.8 (+4.3), 206.4 (À11.7) nm. Anal. Calcd for
52H90O3: C, 81.83; H, 11.89. Found: C, 81.62; H, 11.99.
e = 5100), 281.8
References
(De
C
1. Christmann, M.; Bräse, S. Asymmetric Synthesis: The Essentials, 2nd ed.;
Wiley-VCH: Weinheim, 2007.
2. Ojima, I. Catalytic Asymmetric Synthesis, 3rd ed.; John Wiley & Sons: Hoboken,
NJ, 2010.
4.6. Preparation of enantiopure aliphatic alcohols
3. Christmann, M.; Bräse, S. Asymmetric Synthesis II: More Methods and
Applications; Wiley-VCH, Weinheim, 2012.
4.6.1. (R)-(À)-4-Octanol 4
4. Andrushko, V.; Andrushko, N. Stereoselective Synthesis of Drugs and Natural
Products, Two Volume Set; John Wiley & Sons: Hoboken: NJ, USA, 2013.
5. The synthesis of chiral alkanols by separating diastereomeric acetal derivatives
of thiophene–alcohols and successive desulfurization was reported, but their
absolute configurations were not determined: Noe, C. R.; Knollmuller, M.;
Dungler, K.; Miculka, C.; Gartner, P. Monatsh. Chem. 1991, 122, 705.
6. The chiral discrimination of methyl-branched alkanols together with
To a solution of (S,R)-(À)-4-octanol M
aNP ester 14a (384 mg,
1.12 mmol) in MeOH (3.7 mL) was added KOH (408 mg,
7.28 mmol) and the mixture was heated at reflux overnight. After
the addition of aqueous saturated NaHCO3, the mixture was
extracted with diethyl ether three times. The combined organic
layers were washed with water and brine successively, dried over
anhydrous MgSO4, and evaporated under reduced pressure. The
crude product was distilled with a Kugelrohr apparatus yielding
(R)-(À)-4-octanol 4 as a colorless liquid: bp 65 °C/25 mmHg; yield
9-octadecanol using
a
chiral acid was reported, but the absolute
configuration of 9-octadecanol was not determined: Ohrui, H.; Terashima, H.;
Imaizumi, K.; Akasaka, K. Proc. Jpn. Acad. Ser. B 2002, 78, 69.
7. (S)-(+)-10-Nonacosanol
was
synthesized
in
six
steps,
where
(R)-O-methylmandelic acid was used for the enantioresolution of an alcohol
intermediate and its absolute configuration determination: Dommisse, A.;
Wirtz, J.; Koch, K.; Barthlott, W.; Kolter, T. Eur. J. Org. Chem. 2007, 3508.
8. Harada, N.; Watanabe, M.; Kuwahara, S.; Sugio, A.; Kasai, Y.; Ichikawa, A.
Tetrahedron: Asymmetry 2000, 11, 1249.
9. Taji, H.; Kasai, Y.; Sugio, A.; Kuwahara, S.; Watanabe, M.; Harada, N.; Ichikawa,
A. Chirality 2002, 14, 81.
10. Kasai, Y.; Taji, H.; Fujita, T.; Yamamoto, Y.; Akagi, M.; Sugio, A.; Kuwahara, S.;
Watanabe, M.; Harada, N.; Ichikawa, A.; Schurig, V. Chirality 2004, 16, 569.
11. Kasai, Y.; Sugio, A.; Sekiguchi, S.; Kuwahara, S.; Matsumoto, T.; Watanabe, M.;
Ichikawa, A.; Harada, N. Eur. J. Org. Chem. 2007, 1811.
12. Kuwahara, S.; Naito, J.; Yamamoto, Y.; Kasai, Y.; Fujita, T.; Noro, K.; Shimanuki,
K.; Akagi, M.; Watanabe, M.; Matsumoto, T.; Watanabe, M.; Ichikawa, A.;
Harada, N. Eur. J. Org. Chem. 2007, 1827.
13. Fujita, T.; Obata, K.; Kuwahara, S.; Miura, N.; Nakahashi, A.; Monde, K.; Decatur,
J.; Harada, N. Tetrahedron Lett. 2007, 48, 4219.
14. Harada, N. Chirality 2008, 20, 691.
15. Naito, J.; Taji, H.; Sekiguchi, S.; Watanabe, M.; Kuwahara, S.; Watanabe, M.;
Harada, N. Chirality 2007, 19, 335.
16. Sekiguchi, S.; Akagi, M.; Naito, J.; Yamamoto, Y.; Taji, H.; Kuwahara, S.;
Watanabe, M.; Ozawa, Y.; Toriumi, K.; Harada, N. Eur. J. Org. Chem. 2008, 2313.
17. Yamamoto, Y.; Akagi, M.; Shimanuki, K.; Kuwahara, S.; Watanabe, M.; Harada,
N. Preceding Part 1 Paper, Tetrahedron: Asymmetry 2014, 25, 1456.
18. Ishidoh, K.; Kinoshita, H.; Igarashi, Y.; Ihara, F.; Nihira, T. J. Antibiot. 2014, 67,
459.
19. Xu, S.; Oda, A.; Kamada, H.; Negishi, E. Proc. Nat. Acad. Sci. U.S.A. 2014, 111,
8368.
20. Taji, H.; Watanabe, M.; Harada, N.; Naoki, H.; Ueda, Y. Org. Lett. 2002, 4,
2699.
103 mg, 70%; [
(S)-enantiomer [
a
]
a
35 = À0.5 (
q
0.819, neat), [/]D = À0.65, Lit.5,24
D
]
20 = +0.8 (neat); 1H NMR (400 MHz, CDCl3)
D
d = 0.91 (3H, t, J = 7.6 Hz), 0.93 (3H, t, J = 7.6 Hz), 1.32–1.46 (10H,
m), 3.61 (1H, m); 13C NMR (100 MHz, CDCl3) d = 14.0, 14.1, 18.8,
22.7, 37.1, 39.6, 71.7.
4.6.2. (S)-(+)-9-Octadecanol 5
To
a
solution of (S,S)-(À)-9-octadecanol
MaNP ester 16b
(270 mg, 0.558 mmol) in EtOH (2.0 mL) was added KOH (204 mg,
3.63 mmol). After stirring at room temperature overnight, the reac-
tion mixture was treated similarly as described above. The crude
product was purified by HPLC on silica gel (hexane/EtOAc 20:1)
giving (S)-(+)-9-octadecanol 5 as solid, which was recrystallized
from hexane/EtOAc (4:1) affording colorless needles: 137 mg,
91%; mp 62–63 °C; [
IR (film) max = 3322, 3222, 2953, 2918, 2849, 1463, 1352, 1136,
1092, 1018, 901, 871, 849, 721 cmÀ1
a]
23 = +0.1 (c 6.09, cyclohexane), [/]D = +0.27;
D
m
;
1H NMR (400 MHz, CDCl3)
d = 0.88 (6H, t, J = 6.8 Hz), 1.28–1.43 (30H, m), 3.58 (1H, m); 13C
NMR (100 MHz, CDCl3) d = 14.1, 22.6, 25.6, 29.2, 29.3, 29.5, 29.6,
29.6, 29.7, 31.8, 37.4, 72.0.
21. Mori, K.; Ohtaki, T.; Ohrui, H.; Berkebile, D. R.; Carlson, D. A. Eur. J. Org. Chem.
2004, 1089.
22. Watanabe, H. Yakugaku Zasshi 1953, 73, 176.
23. Kouda, K.; Kusumi, T.; Ping, X.; Kan, Y.; Hashimoto, T.; Asakawa, Y. Tetrahedron
Lett. 1996, 37, 4541.
24. Levene, P. A.; Rothen, A. J. Org. Chem. 1936, 1, 76.
4.6.3. (R)-(À)-19-Octatriacontanol 7
To a solution of (S,R)-(À)-19-octatriacontanol M
aNP ester 18
(160 mg, 0.21 mmol) in iso-PrOH (1.0 mL) was added NaOMe
(230 mg, 4.20 mmol), and the mixture was heated at reflux for
3 days. After the addition of water and diethyl ether, solid matter