Synthesis of enantiopure aliphatic acetylene alcohols and determination of their absolute configurations by 1H NMR anisotropy and/or X-ray crystallography

Article abstract of DOI:10.1002/ejoc.200800012

The MαNP acid method has been applied to racemic aliphatic acetylene alcohols in order to simultaneously prepare enantiopure alcohols and to determine their absolute configurations by ¹H NMR anisotropy. Racemic acetylene alcohols 6-8, 11, and 20 were esterified with MαNP acid (S)-(+)-1 to yield diastereomericMαNP esters which were efficiently separated by HPLC on silica gel with separation factors α in the range 1.60-1.93. The ¹H NMR anisotropy factors Δδ [= δ(2nd fr.) - δ(1st fr.)] were calculated from the data of the first- (22a-27a) and second-eluted MαNP esters (22b-27b). The absolute configurations of the first-eluted esters were determined from the distribution of Δδ values in the MαNP sector rule. In the case of MαNP ester 26b, the assigned absolute configuration was confirmed by X-ray crystallography. The solvolysis of MαNP esters yielded enantiopure acetylene alcohols 5-8 with established absolute configurations. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800012

FULL PAPER
DOI: 10.1002/ejoc.200800012
Synthesis of Enantiopure Aliphatic Acetylene Alcohols and Determination of
1
Their Absolute Configurations by H NMR Anisotropy and/or X-ray
Crystallography
Satoshi Sekiguchi,[a] Megumi Akagi,[a] Junpei Naito,[a] Yoko Yamamoto,[a] Hiromi Taji,[a]
Shunsuke Kuwahara,[a] Masataka Watanabe,[a] Yoshiki Ozawa,[b] Koshiro Toriumi,[b] and
Nobuyuki Harada*[a,c]
Keywords: Acetylene alcohols / Configuration determination / Absolute configuration / MαNP esters / NMR anisotropy /
X-ray diffraction
The MαNP acid method has been applied to racemic ali-
phatic acetylene alcohols in order to simultaneously prepare
enantiopure alcohols and to determine their absolute config-
urations by 1H NMR anisotropy. Racemic acetylene alcohols
6–8, 11, and 20 were esterified with MαNP acid (S)-(+)-1 to
yield diastereomeric MαNP esters which were efficiently sep-
arated by HPLC on silica gel with separation factors α in the
27a) and second-eluted MαNP esters (22b–27b). The absolute
configurations of the first-eluted esters were determined
from the distribution of ∆δ values in the MαNP sector rule. In
the case of MαNP ester 26b, the assigned absolute configura-
tion was confirmed by X-ray crystallography. The solvolysis
of MαNP esters yielded enantiopure acetylene alcohols 5–8
with established absolute configurations.
1
range 1.60–1.93. The H NMR anisotropy factors ∆δ [= δ(2nd
fr.) – δ(1st fr.)] were calculated from the data of the first- (22a–
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ucts. For compounds with known ACs, it is easy to assign
the ACs of products by comparison of their [α]D values.
However, if ACs are unknown, tedious chemical correlation
reactions or pertinent spectroscopic analyses have to be car-
ried out. Therefore, we have developed general and conve-
nient methods that enable one to prepare various enantio-
pure alcohols and determine their ACs simultaneously.
One such method involves the use of chiral CSP (cam-
phorsultam-phthalic) and CSDP (camphorsultam-dichlo-
rophthalic) acids; diastereomeric esters formed from a race-
mic alcohol and an enantiopure acid were easily separated
by HPLC on silica gel, and their ACs were determined by
X-ray crystallography.[8–10] Another method that does not
require crystals, involves the use of MαNP [2-methoxy-2-(1-
naphthyl)propionic] acid (1, Figure 1) which has been
widely applied to various secondary alcohols, especially to
aliphatic alcohols.[9–12] By application of this method, a
variety of chiral synthetic and natural compounds have
been synthesized in enantiopure forms and/or their ACs
have been determined: For example, a thyroid hormone an-
alogue KAT-2003,[11i] (R)-(+)-[VCD(+)945]-4-ethyl-4-meth-
yloctane (the simplest chiral saturated hydrocarbon with a
quaternary chirality center),[11u] synthetic precursors of 5-
lipoxygenase inhibitors[13a] and mispyric acid (an inhibitor
of DNA polymerase β),[13b] pheromones,[13c,13d] hydroxy
metabolites of blonanserin AD-5423 in humans,[13e] in-
herently chiral anti-O,OЈ-dialkylated calix[4]arenes,[13f] and
antibiotic PF1140[13g] are interesting applications of the
MαNP acid method.
Introduction
Chiral acetylene alcohols have been extensively used as
chiral synthons for the total synthesis of natural products,
as in the case of (S)-(–)-1-octyn-3-ol used for the synthesis
of prostaglandin[1] and others.[2] Various approaches have
been developed to prepare chiral acetylene alcohols includ-
ing asymmetric[1d,3] and biochemical reactions,[4] the use of
natural chiral pools,[5] resolution with chiral acids,[6] and
co-crystallization methods with chiral auxiliaries.[7] In such
methods, the greatest problem is how to increase the enan-
tiomeric purity of the products. Recently, it became possible
to obtain chiral acetylene alcohols in more than 99% ee by
selected synthetic[3a,3b,5] or biochemical[4c,4d] reactions un-
der optimized conditions. However, there is still uncertainty
as to whether these methods are generally applicable to a
variety of acetylene alcohols to synthesize enantiopure
alcohols. Furthermore, there is a serious problem of how to
determine the absolute configurations (ACs) of the prod-
[a] Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University,
2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
E-mail: n_harada@ma.mni.ne.jp
[b] Graduate School of Material Science, University of Hyogo,
3-2-1 Kouto, Kamigori-cho, Hyogo 678-1297, Japan
[c] Department of Chemistry, Columbia University,
3000 Broadway, MC3152, New York, NY 10027, USA
E-mail: nh2212@columbia.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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N. Harada et al.
FULL PAPER
Figure 1. General scheme for the preparation of enantiopure acetylene alcohols 2 and simultaneous determination of their absolute
configurations by the use of chiral MαNP acid (S)-(+)-1, a chiral resolving and 1H NMR anisotropy reagent (CAR). In all the cases
reported in this paper, the first-eluted ester 3a takes the absolute configuration as illustrated.
We have previously reported the preparation of some
Results and Discussion
enantiopure acetylene alcohols and the determination of
their ACs by application of the MαNP acid method.[11m,11o]
Synthesis of Racemic Long-Chain Acetylenic Alcohols
By this method, aliphatic acetylene alcohol 4 (Figure 2) was
more efficiently enantioresolved as MαNP ester than aro-
To study the general applicability of the MαNP acid
matic acetylene alcohols. We have now extended this method to aliphatic acetylene alcohols, racemic alcohols
method to aliphatic acetylene alcohols 5–8 with longer alkyl with various chain lengths were synthesized as shown in
chains and obtained excellent results, as will be discussed Scheme 1: C8 chain, 2-octyn-4-ol (11); C12 chain, 1-dode-
below.
cyn-3-ol (5) and 1-trimethylsilyl-1-dodecyn-3-ol (20); C18
Figure 2. Absolute configurations and optical rotation data of enantiopure aliphatic acetylene alcohols, where σ is the standard deviation
of the observed [α]D value; the data for (S)-(–)-4 are taken from ref.[11m]
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Enantiopure Aliphatic Acetylene Alcohols
chain, 10-octadecyn-9-ol (6); C29 chain, 8-nonacosyn-10-ol Preparation of Diastereomeric Esters from Racemic
(7); C38 chain, 17-octatriacontyn-19-ol (8). 2-Butyn-1-ol (9) Acetylene Alcohols with (S)-(+)-MαNP Acid and HPLC
was oxidized with pyridinium chlorochromate (PCC) to Separation
yield 2-butynal (10), which was treated with n-butyllithium
Racemic acetylene alcohols 11, 20, and 6–8 were easily
in hexane. After workup, the organic layer was distilled in
esterified with MαNP acid (S)-(+)-1 to give diastereomeric
a Kugelrohr apparatus to give alcohol 11 (9% for two
esters, which were separated by HPLC on silica gel
steps). The low yield may be due to the volatility of the
(Scheme 2). For example, a mixture of alcohol (Ϯ)-8,
product. 1-Heptadecanol (12) was oxidized with PCC to
MαNP acid (S)-(+)-1, 1,3-dicyclohexylcarbodiimide
afford heptadecanal (14) in good yield. Similarly, 1-icosanol
(DCC), 4-(dimethylamino)pyridine (DMAP), and 10-cam-
(13) was converted into icosanal (15). 1-Nonyne (16) was
phorsulfonic acid (CSA) in CH2Cl2 was stirred at room
treated with n-butyllithium in hexane, and nonanal (18) was
temperature overnight to yield a diastereomeric mixture of
added. After workup, the oily residue was purified by short-
esters 26a and 26b. The mixture was well separated by
column chromatography on silica gel to give acetylene
HPLC on silica gel (hexane/EtOAc = 50:1) with a large elu-
alcohol 6 in good yield. In a similar manner, alcohol 7 was
tion interval, as shown in Figure 3: Separation factor α =
prepared from acetylene compound 16 and aldehyde 15.
1.78; resolution factor Rs = 4.10 (Table 1). The first-eluted
Ethynyltrimethylsilane (17) was treated with n-butyllithium
ester (–)-26a {47%, [α]2D9 = –26.0 (c = 1.36, CHCl3)} and
in hexane, and decanal (19) was added to give alcohol 20.
the second-eluted ester (–)-26b {49%, [α]2D9 = –2.7 (c = 10.9,
CHCl3)} were obtained.
Scheme 2. Preparation of the diastereomeric MαNP esters and sep-
Scheme 1. Preparation of racemic acetylene alcohols. (a) PCC/
aration by HPLC. (a) DCC, DMAP, CSA/CH2Cl2. (b) HPLC on
CH2Cl2. (b) nBuLi/hexane, THF, 9% for 2 steps. (c) PCC/CH2Cl2,
silica gel: first-eluted ester a, 20–49%; second-eluted ester b, 21–
80–81%. (d) nBuLi/hexane, THF, 49–77%. (e) CBr4, PPh3/CH2Cl2,
50%.
85%. (f) nBuLi/hexane, THF, and then 15, 32%.
Triphenylphosphane was added to a solution of CBr4 in
To obtain MαNP esters 27a and 27b, a diastereomeric
CH2Cl2, followed by aldehyde 14 prepared as above. After mixture of esters 23a/23b bearing trimethylsilyl groups was
workup, the oily residue was purified by short-column treated with tetrabutylammonium fluoride (TBAF) in THF,
chromatography on silica gel to yield 1,1-dibromo-1-octa- and the deprotected esters were separated by HPLC on sil-
decene (21). Compound 21 was treated with n-butyllithium ica gel: Separation factor α = 1.93; resolution factor Rs =
in hexane, and icosanal (15), prepared as above, was added. 3.19 (Scheme 3 and Table 1). As shown in Table 1, all the
After workup, the residue was purified by short-column MαNP esters were efficiently separated with a separation
chromatography on silica gel to give the long-chain acetyl- factor α = 1.60–1.93. Such large α values indicate that
ene alcohol 8. The structures of the obtained products were acetylene alcohol MαNP esters are separable on a large
confirmed by spectroscopic and elemental analyses.
scale. This is an advantage of the MαNP acid method for
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N. Harada et al.
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ences in the alkyl chain lengths. This implies that the HPLC
separation is mostly controlled by the shape and polarity of
the acetylene-MαNP ester moiety, the contribution from
the alkyl chains being relatively negligible.
Determination of the Absolute Configurations of MαNP
1
Esters by H NMR Anisotropy
The absolute configurations of the separated MαNP es-
1
ters were determined by H NMR anisotropy as follows. In
the case of 2-octyn-4-ol (C8 chain) esters 22a and 22b, all
1H NMR signals were fully assigned by 1H, 13C, 1H–1H
1
COSY, HMQC, and HMBC methods. The H NMR an-
Figure 3. HPLC separation of the diastereomeric MαNP esters 26a/
26b.
isotropy effect of the MαNP esters is expressed by the ∆δ
value, originally defined as ∆δ = δ(R,X) – δ(S,X), where R,
S, and X denote the absolute configurations of MαNP acids
(R)-1 and (S)-1, and the alcohol moiety, respectively. When
(S)-(+)-MαNP acid 1 is used for the resolution of the race-
mic alcohol, the equation is expressed as ∆δ = δ(R,X) –
δ(S,X) = δ(S,–X) – δ(S,X) = δ(2nd fr.) – δ(1st fr.), where X
and –X denote the absolute configurations of the alcohol
parts of the first- and second-eluted esters, respectively
(Figure 1).[11] Thus, subtraction of the chemical shifts of the
first-eluted fraction δ(1st fr.) from those of the second-
eluted fraction δ(2nd fr.) gives the values of ∆δ. By placing
substituent R1 with a positive ∆δ value on the right-side in
the sector rule shown in Figure 1 and R2 with a negative
∆δ value on the left-hand side, the absolute configuration
X of the first-eluted ester can be determined. As seen in
Figure 4, in the case of MαNP esters 22a/22b, the methyl
group attached to the acetylene moiety shows a positive ∆δ
value, whereas the butyl group shows negative ∆δ values
leading to the (S) absolute configuration of the first-eluted
ester 22a. The second-eluted MαNP ester 22b naturally has
the opposite (R) absolute configuration.
Table 1. HPLC separation of the diastereomeric esters formed from
racemic acetylene alcohol and MαNP acid (S)-(+)-1.
Entry[a] Diastereomers H/EA ratio[b]
α
Rs 1st-eluted fr.
1
2
3
4
5
6
22a/22b
23a/23b
24a/24b
25a/25b
26a/26b
27a/27b
20:1
20:1
20:1
20:1
50:1
20:1
1.76 2.88 (S,4S)-22a
1.60 1.63 (S,3S)-(–)-23a
1.61 1.93 (S,9S)-(–)-24a
1.88 1.65 (S,10S)-(–)-25a
1.78 4.10 (S,19S)-(–)-26a
1.93 3.19 (S,3S)-(–)-27a
[a] Glass column (22 φϫ300 mm) of silica gel (particle size 5–
10 µm). [b] Solvent: H = hexane, EA = ethyl acetate.
the preparation of enantiopure acetylene alcohols because
the (S)-(+)-MαNP acid 1 used is enantiopure[14] and there-
fore the separated esters are also enantiopure. In the HPLC
separation of esters 26a/26b, a less polar mixed solvent
(hexane/EtOAc, 50:1) was used reflecting the less polar na-
ture of these esters, which results from their long-chain
alkyl groups (Table 1). Note also that the α values remain
in a narrow range, that is, 1.60–1.93, despite the large differ-
As listed in the Exp. Sect. and shown in Figure S1 of
the Supporting Information, the proton signals of the butyl
group of ester 22b are widely distributed and high-field-
shifted compared with those of ester 22a. This fact is ex-
plained well by the conformations depicted in Figure 1. In
the second-eluted ester (S,–X)-3b, the substituent R2, that
is, the butyl group in 22b, is located on the same side of the
MαNP plane as the naphthyl group. Namely, the butyl
group is placed above the naphthalene ring, and the dia-
magnetic anisotropy leads to the high-field shift. On the
other hand, in the first-eluted ester (S,X)-3a, the substituent
R2, that is, the butyl group in ester 22a, is located on the
opposite side of the MαNP plane to the naphthyl group.
Therefore, the protons of the butyl group are not affected
1
by the diamagnetic anisotropy. The H NMR behavior of
esters 22a and 22b is thus explained.
In the case of 1-trimethylsilyl-1-dodecyn-3-ol (C12 chain)
esters 23a/23b with a longer alkyl chain, it was difficult to
assign all the proton signals because of the extensive over-
lapping of proton signals of the alkyl chain, especially those
of the central part. Starting from the alcohol methine pro-
ton at the 3-position, we investigated the connectivity of
Scheme 3. Deprotection of the TMS group and HPLC separation
of the diastereomeric MαNP. (a) TBAF/THF. (b) HPLC on silica
gel: first-eluted ester a, 38%; second-eluted ester b, 38%.
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Enantiopure Aliphatic Acetylene Alcohols
Figure 4. Observed ∆δ values and absolute configurations of the acetylene alcohol MαNP esters as determined by the 1H NMR anisotropy
method (∆δ values are given in ppm, 600 MHz in CDCl3).
protons and carbon atoms by analyzing the two-dimen- mined for the first-eluted ester (–)-24a. It is again true that
sional spectra and assigned the protons at the 4-, 5-, and 6- in the second-eluted MαNP esters 24b, the alkyl methylene
positions which allowed the ∆δ values shown in Figure 4 to proton signals are widely distributed and high-field-shifted
be determined. In a similar manner, starting from the ter- compared with those of the first-eluted ester 24a (Fig-
minal methyl group, the protons at the 9-, 10-, and 11-posi- ure S6).
tions were assigned, and the ∆δ values were calculated.
In a similar manner, the ACs of 8-nonacosyn-10-ol (C29
Most of the protons of the C9H19 group show negative ∆δ chain) MαNP esters 25a/25b were determined. The 7-H
values, whereas the protons of the TMS group show a posi- methylene protons show a long-range coupling (J = 2.0–
tive ∆δ value. Therefore, the AC of the first-eluted ester 2.1 Hz) with the 10-H methine proton and could be easily
(–)-23a was unambiguously determined to be (S). In the 1H assigned. The analysis of the two-dimensional spectra led
NMR spectra of 23a/23b, the alkyl chain signals of the sec- to the assignment of protons 6-H, 11-H, and 12-H, and the
ond-eluted ester 23b are widely distributed and high-field- ∆δ values were thus calculated, as shown in Figure 4. Note
shifted compared with those of the first-eluted ester 23a that the ∆δ values assigned to esters 25a/25b are very similar
(see Figures S2 and S3 of the Supporting Information).
to those of esters 24a/24b. The (S) absolute configuration
In the case of 1-dodecyn-3-ol (C12 chain) MαNP esters was thus assigned to the first-eluted ester (–)-25a. The alkyl
27a/27b, a similar distribution of ∆δ values was obtained, methylene proton signals of 25b are also widely distributed
as shown in Figure 4, with the acetylene proton signal and high-field-shifted compared with those of the first-
showing a positive ∆δ value. The (S) absolute configuration eluted ester 25a (Figure S7).
was hence assigned to ester (–)-27a. The alkyl chain signals
of the second-eluted ester 27b are widely distributed and to 17-octatriacontyn-19-ol (C38 chain), an acetylene alcohol
high-field-shifted (Figures S4 and S5). with a much longer chain structure. In MαNP esters 26a/
This MαNP acid method has been successfully applied
1
The assignment of the H NMR signals becomes much 26b, most proton signals overlap with one another. How-
more difficult with increasing alkyl chain length. In the case ever, we could assign the 20-H and 21-H methylene protons
of 10-octadecyn-9-ol (C18 chain) MαNP esters 24a/24b, the in the two-dimensional spectra starting from the alcohol 19-
protons at the 7- and 8-positions were assigned by corre- H methine proton. Furthermore, the long-range coupling
lation with the alcohol methine proton at the 9-position, (J = 1.9–2.0 Hz) through the acetylene bond between the
leading to negative ∆δ values for the left-hand alkyl chain. methylene and methine protons was again useful for the
On the other hand, the protons of the right-hand alkyl assignment of 16-H and 15-H, and the ∆δ values were cal-
chain appear isolated from the alcohol methine proton and culated, as shown in Figure 4, leading to the (S) absolute
others, and therefore it will be difficult to make a clear cor- configuration of the first-eluted ester (–)-26a. Therefore the
relation between these protons. However, we have found (R) absolute configuration was naturally assigned to the
that long-range coupling (J = 2.0–2.1 Hz) through a triple second-eluted ester (–)-26b. Note that the alkyl methylene
bond, that is, coupling between the 9-H methine proton and proton signals of 26b are widely distributed and high-field-
the 12-H methylene protons, is very useful for the assign- shifted compared with those of the first-eluted ester 26a
ment of the right-hand alkyl chain protons. Based on these (Figure S8).
results, the ∆δ values of 24a/24b were obtained, as shown
As shown in Figure 4, the first-eluted MαNP esters 22a–
in Figure 4, and the (S) absolute configuration was deter- 26a have (S) absolute configurations, and hence the second-
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N. Harada et al.
FULL PAPER
eluted esters 22b–26b have (R) absolute configurations. The to the 1ЈЈ-H methine proton, and the methyl group of the
general relationship between the HPLC elution order and propionic acid moiety is synperiplanar to the naphthalene
the AC of the acetylene alcohol moiety is rationalized as proton at the 2Ј-position (see value in Table 3). Table 3 lists
depicted in Figure 1.
the data of the crystalline-state conformation and intramo-
lecular bifurcated hydrogen bond[11s] of ester (–)-26b, which
represents a typical syn,syn,syn conformation of the MαNP
ester.
X-ray Crystallographic Analysis of MαNP Ester (–)-26b
Most MαNP esters 22–26 were obtained as syrups or
amorphous solids except for the ester (–)-26b which was
recrystallized from iPrOH as thin plates. However, because
they were thin crystals with only a 5 µm thickness, conven-
tional X-ray machines could not be used. Therefore, the
strong X-ray of synchrotron radiation was used for the X-
ray diffraction experiment. The X-ray data are compiled in
Table 2. The structure was solved by direct methods and
refined by full-matrix least squares, and all hydrogen atoms
were placed at their idealized positions: R = 0.0814. The
AC of ester (–)-26b was unambiguously determined to be
(S,19R) by using the (S) absolute configuration of the
MαNP acid moiety as an internal reference (Figure 5). The
result was in agreement with the AC determined by 1H
Table 3. Selected data for the crystalline-state conformation and
intramolecular bifurcated hydrogen bond of MαNP ester (–)-26b.[a]
1
NMR anisotropy and thus proved that the H NMR an-
isotropy method using MαNP acid gives the correct AC.
Compound
(–)-26b
Dihedral angle [°]
C2Ј–C1Ј–C2–C3
C1–C2–O7–C4
C1Ј–O5–C1–C2
C1ЈЈ–O5–C1–O6
O6–C1–C2–O7
H1ЈЈ–C1ЈЈ–O5–C1
Interatomic distance [Å]
C8Ј–H8Ј
H8Ј–O6 (= d1)
H8Ј–O7 (= d2)
Interatomic angle [°]
C8Ј–H8Ј–O6 (= θ1)
C8Ј–H8Ј–O7 (= θ2)
O6–H8Ј–O7 (= θ3)
Table 2. X-ray crystallographic data for 17-octatriacontyn-19-ol
MαNP ester (S,19R)-(–)-26b.
–5.1
+175.8
–161.6
+13.6
+17.5
33
Compound
(–)-26b
Empirical formula
Formula mass [amu]
C52H86O3
759.237
Solvent
Crystal size [mm]
Radiation wavelength [Å]
iPrOH
0.2ϫ0.02ϫ0.005
1.45460
0.93
2.83
2.40
Crystal system
Space group
a [Å]
b [Å]
orthorhombic
P212121 (#19)
6.9470(1)
8.4830(2)
84.4530(15)
4976.93(16)
4
140.3
115.8
59.4
c [Å]
V [Å3]
[a] The hydrogen atoms 1ЈЈ-H and 8Ј-H were placed at the calcu-
lated positions, and so the data regarding these atoms are not pu-
rely observed ones.
Z
Dcalcd. [g/cm3]
1.013
No. of independent reflections, Fo Ͼ 2.0σ(Fo)
No. of variables
Goodness of fit, S
3599
500
1.043
The molecular packing in the crystal of ester (–)-26b is
shown in Figure 6, with four molecules contained in the
unit lattice. It is very interesting that the two long alkyl
chains (n-C16H33 and n-C19H39) of the first molecule in the
Absolute configuration
R (Rw)
(S,19R)
0.0814 (0.2368)
As seen in Figure 5, MαNP ester 26b adopts the so-called unit lattice are parallel to each other and that these two
syn,syn,syn conformation[11s] in which the methoxy oxygen alkyl chains form a pair with those of the second molecule
atom O-7 is synperiplanar to the ester carbonyl oxygen in the unit lattice. These alkyl chain pairs are arranged so
atom O-6, the carbonyl oxygen atom O-6 is synperiplanar as to form an aliphatic bilayer in the crystal, and the third
Figure 5. X-ray view of 17-octatriacontyn-19-ol MαNP ester (S,19R)-(–)-26b.
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Enantiopure Aliphatic Acetylene Alcohols
Figure 6. Crystal packing of 17-octatriacontyn-19-ol MαNP ester (S,19R)-(–)-26b. View along the a axis; the rectangle shows a unit
lattice.
and fourth molecules also form an aliphatic bilayer. These
As expected, these acetylene alcohols show small [α]D
aliphatic bilayer structures are similar to those of cell mem- values (Figure 2). In the case of alcohol (S)-(–)-6, the de-
branes. It is interesting that the interaction between ali- pendence of the [α]D value on the sample state and the sol-
phatic chains is operative not only in aqueous solutions but vents used was studied. The observed [α]D values decrease
also in crystals.
in the order of neat, solution in cyclohexane, and solution
in CHCl3: [α]2D4 = –8.0 (σ = 0.30, ρ = 0.858, neat), [α]2D3
=
–6.4 (c = 6.07, cyclohexane), and [α]2D4 = +0.2 (c = 3.05,
CHCl3). Therefore, the neat measurement is better for li-
quid or oil samples. In the case of solid samples, nonpolar
solvents such as cyclohexane are suitable.
Recovery of Enantiopure Acetylene Alcohols with
Established Absolute Configurations and Their Chiroptical
Properties
When comparing the chiroptical properties of com-
pounds, molar rotation [M]D is suitable, but not specific
rotation [α]D. Thus, the [M]D values of acetylene alcohols
were calculated and are listed in Table 4. Note that alcohols
6–8 show similar absolute values of [M]D in cyclohexane,
that is, from 17.1 to 13.7. This implies that the chiroptical
properties of these alcohols are mostly governed by the
acetylene alcohol moiety. On the other hand, the [M]D val-
ues decrease remarkably in CHCl3 solution.
The MαNP esters were hydrolyzed to yield enantiopure
acetylene alcohols (Scheme 4). For example, the first-eluted
MαNP ester (S,S)-(–)-26a was treated with KOH/EtOH to
yield enantiopure (S)-(–)-17-octatriacontyn-19-ol (8, 91%)
as a colorless solid: [α]D28 = –2.4 (σ = 0.07, c = 3.13, cyclo-
hexane). Other acetylene alcohols were similarly obtained:
(R)-(+)-1-dodecyn-3-ol (5), colorless oil, [α]2D1 = +3.0 (c =
1.13, CHCl3); (S)-(–)-10-octadecyn-9-ol (6), colorless oil,
[α]2D4 = –8.0 (σ = 0.30, ρ = 0.858, neat); (S)-(–)-8-nonacosyn-
10-ol (7), colorless solid, [α]2D6 = –3.8 (σ = 0.03, c = 10.1,
cyclohexane).
Table 4. Molar rotation values of the enantiopure acetylene
alcohols.
Entry Alcohol
[M]D(neat) [M]D(cyclohexane) [M]D(CHCl3)
1
2
3
4
5
6
(S)-(–)-4
(R)-(+)-5
(S)-(–)-6
(S)-(–)-7
(R)-(+)-7
(S)-(–)-8
–13.1
–
–21.3
–
–
–
–
–
–8.0
+5.5
+0.5
+0.4
–
–17.1
–16.0
+14.7
–13.7
–
Conclusions
The MαNP acid method has been applied to the prepara-
tion of enantiopure compounds from racemic acetylene
alcohols with long alkyl chains and also to the determi-
1
nation of their absolute configurations by H NMR anisot-
ropy. It was found that diastereomeric MαNP esters were
efficiently separated by HPLC on silica gel with large elu-
tion intervals. The absolute configurations of these MαNP
esters were determined by the MαNP diamagnetic anisot-
ropy method. One of these MαNP esters was obtained as
single crystals, the synchrotron radiation X-ray crystal-
lography of which confirmed the absolute configuration de-
termined by 1H NMR anisotropy. The 1H NMR anisotropy
Scheme 4. Recovery of the enantiopure acetylene alcohols by hy-
drolysis. (a) KOH/EtOH, 83–99%.
Eur. J. Org. Chem. 2008, 2313–2324
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2319

N. Harada et al.
FULL PAPER
b.p. 85 °C/28 Torr. IR (neat): ν
= 3363, 2957, 2932, 2861, 1466,
˜
method using MαNP acid has thus been established. Hy-
drolysis of the MαNP esters yielded enantiopure acetylene
alcohols with established absolute configurations. This
method should be applicable to a variety of acetylene
alcohols, and further applications are being investigated.
max
1379, 1151, 1104, 1038, 891 cm–1. H NMR (400 MHz, CDCl3): δ
= 0.92 (t, J = 7.1 Hz, 3 H), 1.30–1.46 (m, 4 H), 1.62–1.70 (m, 2
H), 1.85 (d, J = 2.2 Hz, 3 H), 4.33 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 3.5, 14.0, 22.3, 27.3, 37.8, 62.7, 80.5,
80.9 ppm.
1
Preparation of Long-Chain Aldehydes 14 and 15: For example, a
mixture of 1-heptadecanol (12) (0.500 g, 1.95 mmol) and pyridi-
nium chlorochromate (PCC, 0.500 g, 2.32 mmol) in CH2Cl2
(10 mL) was stirred at room temperature overnight. After filtration
through Celite, the filtrate was concentrated, and the residue was
subjected to HPLC on silica gel (hexane/EtOAc = 20:1) to yield
aldehyde 14.
Experimental Section
General Methods: Melting points are uncorrected. IR spectra were
obtained neat, as film on KBr, or as KBr disks with a Jasco FT/
IR-410 spectrometer. 1H and 13C NMR spectra were recorded with
a JEOL JNM-LA400 (400 and 100 MHz) and/or a JEOL JNM-
LA600 (600 and 150 MHz) spectrometer. All NMR spectroscopic
data are reported in ppm (δ) downfield from TMS. In the long-
chain aliphatic compounds described below, the 13C NMR peaks
1-Heptadecanal (14): Yield 0.400 g, 80%; colorless solid. IR (film):
1
ν
= 2915, 2849, 1713, 1473 cm–1. H NMR (400 MHz, CDCl3):
˜
max
δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.26 (m, 26 H), 1.63 (tt, J = 7.4,
7.4 Hz, 2 H), 2.42 (td, J = 7.4, 1.9 Hz, 2 H), 9.77 (t, J = 1.9 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 22.0, 22.7, 29.1,
29.3, 29.3, 29.4, 29.5, 29.6–29.7 (m), 31.9, 43.9, 203.0 ppm.
1
heavily overlap each other, like the H NMR signals, and therefore
it was difficult to identify the peaks of all the carbon atoms. The
13C NMR spectroscopic data reported below are those obtained by
peak-picking and therefore the peak numbers do not always agree
with those of the carbon atoms. Optical rotations [α]D were mea-
sured with a Jasco DIP-1000 spectropolarimeter, where σ is the
standard deviation of the observed [α]D value. The starting materi-
als 9, 12, 13, and 16–19 were commercially available. Silica gel 60
1-Icosanal (15): Yield 1.62 g, 81%; colorless solid. IR (film): ν
˜
max
= 2953, 2917, 2848, 2357, 2331, 1770, 1702, 1463, 719 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.19–1.30
(m, 32 H), 1.63 (tt, J = 7.3, 7.3 Hz, 2 H), 2.42 (td, J = 7.3, 1.9 Hz,
2 H), 9.77 (t, J = 1.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 14.1, 22.1, 22.7, 29.2, 29.4, 29.4, 29.6–29.7 (m), 31.9, 43.9,
203.0 ppm.
F
254 precoated plates on glass from Merck Ltd. were used for thin-
layer chromatography (TLC). HPLC separation and purification
were performed using prepacked glass column (Kusano
22 φϫ300 mm, or 25 φϫ400 mm, silica gel particle size 5–10 µm),
a
Preparation of Acetylene Alcohols 6, 7, and 20: For example, a solu-
tion of n-butyllithium in hexane (1.54 , 5.52 mL, 8.5 mmol) was
added dropwise to a solution of 1-nonyne (16, 0.994 g, 8.0 mmol)
in dried THF (35 mL) at 0 °C, followed by the dropwise addition
of nonanal (18, 1.14 g, 8.0 mmol) at 0 °C, and then the mixture
was stirred at room temperature overnight. After addition of an
aqueous NH4Cl solution, the mixture was extracted four times with
EtOAc. The combined organic layers were washed with brine, dried
with anhydrous MgSO4, and the solvents evaporated to dryness.
The oily residue was purified by short-column chromatography on
silica gel (hexane/EtOAc = 10:1) to yield alcohol 6.
a
pump (Jasco PRC-70S, pressure 25–30 kgfcm–2, flow rate
10 mLmin–1) and a UV/RI detector (Shimamura YRU-880). The
purities of the title compounds were shown to be Ն99% by 1H
NMR, TLC, HPLC, and/or elemental analysis.
X-ray Crystallography of MαNP Ester (S,19R)-(–)-26b: As the sin-
gle crystals of MαNP ester (–)-26b obtained by recrystallization
from iPrOH are thin plates, the strong X-ray of synchrotron radia-
tion at SPring-8 in Hyogo, Japan, was employed in the X-ray dif-
fraction experiment: λ = 1.45460 Å; monochromator Si_111; data
collected at 293 K; see Table 2 for other crystallographic data. The
structure was solved by direct methods and refined by full-matrix
least squares, with all hydrogen atoms placed at their idealized posi-
tions: R = 0.0814 for 3599 reflections with IϾ2σ(I) and 500 param-
eters (Figure 4 and Table 2). The absolute configuration of (S,19R)-
(–)-26b was determined by using the (S)-MαNP acid moiety as the
internal reference of absolute configuration. CCDC-671893 con-
tains the supplementary crystallographic data for ester (–)-26b.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_requ-
est/cif.
10-Octadecyn-9-ol (6): Yield 1.64 g, 77%; colorless oil. IR (neat):
ν
= 3346, 2927, 2856, 1466, 1379, 1333, 1142, 1115, 1022 cm–1.
˜
max
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 0.89
(t, J = 6.8 Hz, 3 H), 1.27–1.53 (m, 20 H), 1.61–1.72 (m, 4 H), 2.20
(td, J = 7.0, 2.0 Hz, 2 H), 4.35 (ddt, J = 9.9, 6.3, 2.0 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.1, 14.1, 18.7, 22.6, 22.7, 25.2,
28.7, 28.8, 28.8, 29.2, 29.3, 29.5, 31.7, 31.9, 38.2, 62.8, 81.3,
85.6 ppm.
8-Nonacosyn-10-ol (7): Yield 1.43 g, 68%; colorless solid. IR (film):
ν
max = 3365, 3303, 2954, 2915, 2872, 2848, 1464, 1145, 1080, 1064,
˜
Preparation of Racemic 2-Octyn-4-ol (11): A mixture of 2-butyn-1-
ol (9) (0.561 g, 8.0 mmol) and pyridinium chlorochromate (PCC,
2.59 g, 12.0 mmol) in CH2Cl2 (13 mL) was stirred at room tempera-
ture for 4 h. After filtration through Celite, the filtrate was distilled
to give 2-butynal (10) containing some CH2Cl2. 1H NMR
(400 MHz, CDCl3): δ = 2.08 (d, J = 1.0 Hz, 3 H), 9.16 (q, J =
1.0 Hz, 1 H) ppm. A solution of n-butyllithium in hexane (1.54 ,
5.64 mL, 8.69 mmol) was added dropwise to a solution of the crude
805, 723, 644 cm–1. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J =
6.8 Hz, 3 H), 0.89 (t, J = 6.8 Hz, 3 H), 1.19–1.53 (m, 44 H), 1.66
(m, 2 H), 2.20 (td, J = 7.1, 2.0 Hz, 2 H), 4.35 (tt, J = 6.6, 2.0 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 18.6, 22.6,
22.7, 25.2, 28.6, 28.8, 29.3–29.7 (m), 31.7, 31.9, 38.2, 62.8, 81.3,
85.5 ppm. C29H56O (420.76): calcd. C 82.78, H 13.42; found C
82.55, H 13.46.
1
product 10 in THF (10 mL) at 0 °C, and the mixture was stirred 1-Trimethylsilyl-1-dodecyn-3-ol (20): Yield 1.26 g, 49%; colorless
at room temperature overnight. After addition of aqueous NH4Cl
solution, the mixture was extracted three times with diethyl ether.
The combined organic layers were washed with brine, dried with
anhydrous MgSO4, and distilled with a Kugelrohr apparatus to
yield alcohol 11. Yield 0.092 g, 9% for two steps; colorless liquid;
oil. 1H NMR (400 MHz, CDCl3): δ = 0.17 (s, 9 H), 0.88 (t, J =
7.0 Hz, 3 H), 1.27–1.34 (m, 12 H), 1.43 (m, 2 H), 1.68 (m, 2 H),
1.84 (d, J = 5.6 Hz, 1 H), 4.35 (dd, J = 10.2, 6.6 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 0.0, 14.2, 22.8, 25.2, 29.3, 29.4,
29.6, 29.6, 32.0, 37.8, 63.1, 89.4, 107.1 ppm.
2320
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2313–2324

Enantiopure Aliphatic Acetylene Alcohols
Preparation of 1,1-Dibromo-1-octadecene (21): Triphenylphosphane
(1.7 g, 6.5 mmol) was added portionwise to a solution of CBr4
(1.0 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0 °C, and the mixture was
stirred for 10 min. Heptadecanal (14, 0.390 g, 1.5 mmol) was then
added. After being stirred for 2 h, the mixture was filtered through
Celite, and the filtrate was concentrated to dryness. The oily residue
was purified by short-column chromatography on silica gel (hex-
ane) to yield compound 21. Yield 0.555 g, 85%; colorless oil. IR
(S,4R)-2-Octyn-4-ol MαNP Ester (22b): Yield 0.0230 g, 21%; col-
orless syrup. IR (neat): ν = 3050, 2955, 2934, 2871, 2829, 2359,
˜
max
2341, 2247, 1749, 1509, 1457, 1369, 1237, 1134, 1050, 957, 806,
1
781 cm–1. H NMR (600 MHz, CDCl3): δ = 0.55 (t, J = 7.3 Hz, 3
H), 0.58 (m, 1 H), 0.73 (m, 1 H), 0.86 (m, 2 H), 1.33 (m, 2 H), 1.78
(d, J = 2.0 Hz, 3 H), 2.02 (s, 3 H), 3.10 (s, 3 H), 5.31 (ddq, J = 7.1,
5.7, 2.0 Hz, 1 H), 7.45 (m, 3 H), 7.60 (dd, J = 7.3, 1.1 Hz, 1 H),
7.83 (m, 2 H), 8.42 (m, 1 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 3.6, 13.6, 21.5, 21.8, 26.3, 34.4, 50.9, 65.2, 76.4, 81.5, 81.6,
(neat):
ν
=
2924, 2853, 1466, 800, 721 cm–1. 1H NMR
˜
max
(400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.26 (m, 26 H), 124.6, 125.4, 125.7, 125.9, 126.4, 128.6, 129.4, 131.5, 134.1, 134.9,
1.38–1.43 (m, 2 H), 2.09 (td, J = 7.3, 7.3 Hz, 2 H), 6.39 (t, J =
173.2 ppm. UV (EtOH): λmax (ε) = 291.8 (4700), 281.2 (6800), 271.4
7.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7,
(5500), 224.2 (64700 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) =
27.8, 29.0, 29.3, 29.4, 29.5, 29.6, 29.7–29.8 (m), 31.9, 33.0, 88.4, 292.0 (–1.2), 280.8 (–1.7), 270.6 (–1.4), 231.6 (+2.5), 212.8 (–11.6),
138.9 ppm.
210.8 (–11.8 Lmol–1 cm–1) nm. C22H26O3 (338.44): calcd. C 78.07,
H 7.74; found C 77.91, H 7.93.
Preparation of 17-Octatriacontyn-19-ol (8): A solution of n-butyl-
lithium in hexane (1.54 , 2.0 mL, 3.1 mmol) was added dropwise
to a solution of 1,1-dibromo-1-octadecene (21, 0.550 g, 1.3 mmol)
in dried THF (14 mL) at –78 °C, and the mixture was stirred for
20 min. A solution of icosanal (15, 0.400 g, 1.3 mmol) in THF
(5 mL) was added dropwise, and then the mixture was stirred at
room temperature for 2 h. After addition of an aqueous NH4Cl
solution, the mixture was extracted with EtOAc several times. The
combined organic layers were washed with brine, dried with anhy-
drous MgSO4, and the solvents evaporated to dryness. The residue
was purified by short-column chromatography on silica gel (hex-
ane/EtOAc = 10:1) to yield alcohol 8. Yield 0.234 g, 32%; colorless
(S,3S)-(–)-1-Trimethylsilyl-1-dodecyn-3-ol MαNP Ester (23a): Yield
0.114 g, 49%; colorless syrup. [α]2D0 = –46.7 (c = 1.10, CHCl3). IR
(neat): νmax = 3051, 2926, 2855, 2358, 2179, 1737, 1600, 1510, 1463,
˜
1398, 1372, 1344, 1250, 1180, 1133, 1119, 1053, 954, 845, 805, 778,
1
761 cm–1. H NMR (600 MHz, CDCl3): δ = 0.05 (s, 9 H), 0.88 (t,
J = 7.1 Hz, 3 H), 1.14 (m, 2 H), 1.17 (m, 6 H), 1.22 (m, 2 H), 1.27
(m, 2 H), 1.28 (m, 2 H), 1.62 (m, 2 H), 1.98 (s, 3 H), 3.20 (s, 3 H),
5.35 (dd, J = 7.3, 6.4 Hz, 1 H), 7.45 (m, 3 H), 7.65 (dd, J = 7.3,
0.9 Hz, 1 H), 7.83 (m, 2 H), 8.33 (m, 1 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 0.0, 14.1, 22.2, 22.6, 24.8, 29.2, 29.3, 29.4,
31.6, 31.9, 34.4, 51.3, 65.3, 81.9, 90.2, 102.1, 124.7, 125.1, 125.3,
125.5, 126.3, 128.7, 129.3, 131.0, 134.1, 135.5, 172.9 ppm. UV
(EtOH): λmax (ε) = 291.6 (4000), 281.2 (5800), 271.2 (4800), 223.8
solid. IR (film): ν
= 2917, 2849, 1466, 722 cm–1. 1H NMR
˜
max
(400 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 6 H), 1.23–1.73 (m, 64
H), 2.20 (td, J = 7.1, 2.0 Hz, 2 H), 4.32–4.37 (m, 1 H) ppm. 13C (57000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 281.6 (+0.6),
NMR (100 MHz, CDCl3): δ = 14.1, 14.1, 18.6, 22.7, 22.7, 25.2,
28.6–29.7 (m), 31.9, 38.2, 62.8, 81.3, 85.5 ppm. C38H74O (546.99):
calcd. C 83.44, H 13.64; found C 82.74, H 13.30.
248.0
(–0.6),
244.4
(–0.5),
223.2
(–13.0),
221.0
(–12.6 Lmol–1 cm–1) nm. C29H42O3Si (466.73): calcd. C 74.63, H
9.07; found C 74.51, H 9.05.
Preparation of Diastereomeric Acetylene Alcohol MαNP Esters 22–
26 and HPLC Separation: For example, a solution of racemic
alcohol (Ϯ)-11 (0.0401 g, 0.320 mmol) in CH2Cl2 (0.4 mL) was
added to a solution of (S)-(+)-2-methoxy-2-(1-naphthyl)propionic
acid [MαNP acid (1), 0.081 g, 0.35 mmol], DCC (0.132 g,
0.64 mmol), DMAP (0.020 g, 0.16 mmol), and CSA (0.0149 g,
0.060 mmol) in CH2Cl2 (0.6 mL) at 0 °C, and the mixture was
gently heated at reflux whilst being stirred overnight. After addition
of a small amount of water, stirring for 1 h, and addition of diethyl
ether and anhydrous MgSO4, the mixture was filtered through Ce-
lite which was then washed with EtOAc. The combined organic
layers were concentrated under reduced pressure, and the residue
was subjected to HPLC on silica gel (22 φϫ300 mm column,
Table 1) to give the first- and second-eluted esters 22a and 22b,
respectively.
(S,3R)-(–)-1-Trimethylsilyl-1-dodecyn-3-ol MαNP Ester (23b): Yield
0.118 g, 50%; colorless syrup. [α]2D0 = –3.27 (c = 1.08, CHCl3). IR
(neat): νmax = 3053, 2955, 2926, 2855, 2363, 2341, 2178, 1754, 1600,
˜
1510, 1464, 1368, 1250, 1133, 1120, 1051, 845, 804, 780, 760 cm–1.
1H NMR (600 MHz, CDCl3): δ = 0.13 (s, 9 H), 0.63 (m, 1 H), 0.74
(m, 1 H), 0.84 (m, 2 H), 0.89 (m, 2 H), 0.89 (t, J = 7.2 Hz, 3 H),
1.05 (tt, J = 7.3, 7.3 Hz, 2 H), 1.19 (m, 2 H), 1.22 (m, 2 H), 1.28
(tt, J = 7.2 Hz, 2 H), 1.36 (m, 2 H), 2.01 (s, 3 H), 3.10 (s, 3 H),
5.34 (dd, J = 7.3, 6.5 Hz, 1 H), 7.45 (m, 3 H), 7.60 (dd, J = 7.3,
1.1 Hz, 1 H), 7.83 (m, 2 H), 8.42 (m, 1 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 0.0, 14.1, 21.4, 22.7, 24.2, 28.6, 29.1, 29.2,
29.3, 31.9, 34.3, 51.0, 65.0, 81.5, 90.2, 102.4, 124.6, 125.3, 125.7,
125.9, 126.5, 128.6, 129.5, 131.5, 134.0, 134.7, 173.0 ppm. UV
(EtOH): λmax (ε) = 292.4 (4800), 281.4 (6700), 271.4 (5600), 224.2
(64000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε)
= 291.0
(–1.3), 280.4 (–1.9), 271.0 (–1.5), 229.4 (+2.4), 212.2 (+13.2), 209.0
(–14.2 Lmol–1 cm–1) nm. C29H42O3Si (466.73): calcd. C 74.63, H
9.07; found C 74.60, H 9.00.
(S,4S)-2-Octyn-4-ol MαNP Ester (22a): Yield 0.0219 g, 20%; color-
less syrup. IR (neat): ν
= 3050, 2955, 2935, 2871, 2830, 2361,
˜
max
2341, 2246, 1733, 1510, 1458, 1370, 1237, 1133, 1051, 955, 806,
1
780 cm–1. H NMR (600 MHz, CDCl3): δ = 0.77 (t, J = 7.1 Hz, 3
(S,9S)-(–)-10-Octadecyn-9-ol MαNP Ester (24a): Yield 0.894 g,
47%; colorless syrup. [α]2D2 = –42.6 (c = 1.03, CHCl3). IR (neat):
H), 1.15 (m, 2 H), 1.16 (m, 2 H), 1.59 (m, 2 H), 1.64 (d, J = 2.0 Hz,
3 H), 1.99 (s, 3 H), 3.18 (s, 3 H), 5.31 (tq, J = 6.7, 2.0 Hz, 1 H),
7.45 (m, 3 H), 7.65 (dd, J = 7.4, 1.1 Hz, 1 H), 7.83 (m, 2 H), 8.36
(m, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 3.4, 13.8, 22.0,
22.1, 27.0, 34.3, 51.3, 65.6, 76.1, 81.7, 81.8, 124.7, 125.3, 125.4,
ν
max = 3050, 2927, 2856, 2362, 2342, 1735, 1460, 1245, 1133, 1119,
˜
1053, 805, 778 cm–1. 1H NMR (600 MHz, CDCl3): δ = 0.88 (t, J =
7.1 Hz, 3 H), 0.88 (t, J = 7.1 Hz, 3 H), 1.1–1.35 (m, 16 H), 1.15
(m, 2 H), 1.19 (m, 2 H), 1.32 (m, 2 H), 1.60 (m, 2 H), 1.98 (s, 3
125.5, 126.1, 128.7, 129.3, 131.1, 134.1, 135.5, 173.1 ppm. UV H), 2.00 (td, J = 7.1, 2.1 Hz, 2 H), 3.18 (s, 3 H), 5.34 (tt, J = 6.7,
(EtOH): λmax (ε ) = 291.8 (4100), 281.2 (5900), 271.4 (4900), 224.0
2.1 Hz, 1 H), 7.45 (m, 3 H), 7.64 (dd, J = 7.3, 1.1 Hz, 1 H), 7.82
(57600 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 283.4 (+0.4),
(m, 2 H), 8.36 (m, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ =
248.2 (–0.4), 237.8 (+0.5), 224.2 (–8.4), 222.8 (–9.1), 212.0 14.1, 14.1, 18.5, 22.2, 22.6, 22.6, 24.9, 28.3, 28.7, 28.7, 28.9, 29.1,
(–11.1 Lmol–1 cm–1) nm. C22H26O3 (338.44): calcd. C 78.07, H 7.74;
found C 78.01, H 7.80.
29.3, 31.7, 31.8, 34.7, 51.3, 65.6, 81.8, 86.3, 124.7, 125.3, 125.3,
125.5, 126.1, 128.7, 129.3, 131.1, 134.1, 135.5, 173.0 ppm. UV
Eur. J. Org. Chem. 2008, 2313–2324
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2321

N. Harada et al.
FULL PAPER
1
(EtOH): λmax (ε) = 292.2 (3700), 281.4 (5300), 271.8 (4400), 224.4
804, 777, 721 cm–1. H NMR (600 MHz, CDCl3): δ = 0.88 (t, J =
7.1 Hz, 3 H), 0.88 (t, J = 7.1 Hz, 3 H), 1.10–1.35 (m, 62 H), 1.59
(50000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 285.2 (+0.4),
246.4 (–0.4), 234.4 (+0.3), 223.4 (–8.5), 222.4 (–8.4), 219.6 (m, 2 H), 1.98 (s, 3 H), 1.98 (dtd, J = 16.7, 7.1, 2.0 Hz, 1 H), 2.02
(–7.7 Lmol–1 cm–1) nm. C32H46O3 (478.71): calcd. C 80.29, H 9.69;
found C 80.18, H 9.59.
(dtd, J = 16.7, 7.1, 2.0 Hz, 1 H), 3.19 (s, 3 H), 5.32 (tt, J = 6.7,
2.0 Hz, 1 H), 7.43–7.47 (m, 3 H), 7.64 (dd, J = 7.3, 1.2 Hz, 1 H),
7.80–7.84 (m, 2 H), 8.36 (m, 1 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 14.1, 14.1, 18.5, 22.2, 22.7, 22.7, 24.9, 28.4, 28.7, 28.9,
29.1, 29.4–29.7 (m), 31.9, 34.7, 51.3, 65.6, 81.9, 86.3, 124.7, 125.3,
125.3, 125.5, 126.1, 128.7, 129.3, 131.1, 134.1, 135.6, 173.0 ppm.
UV (EtOH): λmax (ε) = 293.6 (4900), 281.8 (7000), 271.8 (5800),
224.6 (68800 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 281.8
(+0.6), 234.0 (+0.5), 221.6 (–11.6 Lmol–1 cm–1) nm. C52H86O3
(759.24): calcd. C 82.26, H 11.42; found C 82.29, H 11.66.
(S,9R)-(–)-10-Octadecyn-9-ol MαNP Ester (24b): Yield 0.853 g,
45%; colorless syrup. [α]2D2 = –6.1 (c = 1.08, CHCl3). IR (neat):
ν
max = 3051, 2927, 2856, 2359, 2337, 2243, 1752, 1600, 1510, 1465,
˜
1369, 1346, 1237, 1134, 1053, 957, 805, 780, 723, 535 cm–1. 1H
NMR (600 MHz, CDCl3): δ = 0.62 (m, 1 H), 0.75 (m, 1 H), 0.83
(m, 2 H), 0.88 (t, J = 7.3 Hz, 3 H), 0.88 (t, J = 7.1 Hz, 3 H), 1.06
(dddd, J = 7.2, 7.2, 7.2, 7.2 Hz, 2 H), 1.16 (dddd, J = 8.5, 7.2, 7.2,
7.1 Hz, 2 H), 1.34 (m, 2 H), 1.23–1.37 (m, 12 H), 1.44 (br. tt, J =
7.2, 7.2 Hz, 2 H), 2.00 (s, 3 H), 2.13 (td, J = 7.2, 2.0 Hz, 2 H), 3.10
(S,19R)-(–)-17-Octatriacontyn-19-ol MαNP Ester (26b): Yield 49%;
(s, 3 H), 5.33 (ddt, J = 7.0, 5.6, 2.0 Hz, 1 H), 7.45 (m, 3 H), 7.59 colorless needles from iPrOH. [α]2D9 = –2.7 (c = 10.89, CHCl3). IR
(dd, J = 7.3, 1.1 Hz, 1 H), 7.82 (m, 2 H), 8.43 (m, 1 H) ppm. 13C (film): νmax = 3050, 2925, 2853, 1754, 1601, 1510, 1466, 1368, 1237,
˜
NMR (150 MHz, CDCl3): δ = 14.1, 14.1, 18.6, 21.4, 22.6, 22.6,
24.2, 28.4, 28.7, 28.7, 28.7, 29.1, 29.2, 31.7, 31.8, 34.7, 50.9, 65.2,
77.3, 81.4, 86.2, 124.6, 125.4, 125.6, 125.8, 126.4, 128.6, 129.4,
131.5, 134.0, 134.8, 173.1 ppm. UV (EtOH): λmax (ε) = 292.2
(4400), 281.2 (6300), 271.4 (5200), 224.0 (60600 Lmol–1 cm–1) nm.
1181, 1134, 1054, 804, 778, 721 cm–1. 1H NMR (600 MHz, CDCl3):
δ = 0.63 (m, 1 H), 0.75 (m, 1 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.88 (t,
J = 7.1 Hz, 3 H), 0.80–0.94 (m, 4 H), 1.05 (tt, J = 7.2, 7.2 Hz, 2
H), 1.17 (m, 2 H), 1.19–1.39 (m, 52 H), 1.43 (tt, J = 7.2, 7.2 Hz, 2
H), 2.01 (s, 3 H), 2.13 (td, J = 7.2, 1.9 Hz, 2 H), 3.10 (s, 3 H), 5.33
CD (EtOH): λext (∆ε) = 291.6 (–1.3), 280.6 (–1.9), 271.0 (–1.5), (ddt, J = 7.0, 5.6, 1.9 Hz, 1 H), 7.42–7.47 (m, 3 H), 7.59 (dd, J =
232.0 (+1.8), 213.4 (–11.2), 210.2 (–12.4), 208.0 (–12.1), 205.0 7.2, 0.8 Hz, 1 H), 7.80–7.83 (m, 2 H), 8.42–8.44 (m, 1 H) ppm. 13
C
(–11.4 Lmol–1 cm–1) nm. C32H46O3 (478.71): calcd. C 80.29, H 9.69;
NMR (150 MHz, CDCl3): δ = 14.1, 14.1, 18.6, 21.5, 22.6, 22.7,
found C 80.19, H 9.64.
24.2, 28.5, 28.7, 28.7, 29.1, 29.2, 29.4, 29.4, 29.5, 29.6–29.7 (m),
31.6, 31.9, 34.7, 50.9, 65.2, 77.3, 81.5, 86.2, 124.6, 125.4, 125.6,
125.8, 126.4, 128.6, 129.4, 131.5, 134.1, 134.9, 173.1 ppm. UV
(EtOH): λmax (ε) = 291.8 (5000), 281.8 (7300), 271.8 (6000), 224.6
(70400 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 291.6 (–1.5),
281.0 (–2.2), 271.0 (–1.7), 229.0 (+2.9), 208.0 (–14.7 Lmol–1 cm–1)
nm. C52H86O3 (759.24): calcd. C 82.26, H 11.42; found C 82.14, H
11.64.
(S,10S)-(–)-8-Nonacosyn-10-ol MαNP Ester (25a): Yield 0.105 g,
33%; colorless syrup. [α]3D0 = –33.1 (c = 1.03, CHCl3). IR (neat):
ν
max = 3054, 2925, 2854, 2359, 1736, 1509, 1466, 1371, 1246, 1180,
˜
1119, 1053, 804, 777, 423 cm–1. H NMR (600 MHz, CDCl3): δ =
0.88 (t, J = 7.1 Hz, 3 H), 0.88 (t, J = 7.1 Hz, 3 H), 1.10–1.35 (m,
44 H), 1.32 (m, 2 H), 1.60 (m, 2 H), 1.98 (s, 3 H), 2.00 (td, J = 7.1,
2.1 Hz, 2 H), 3.18 (s, 3 H), 5.34 (tt, J = 6.7, 2.1 Hz, 1 H), 7.45 (m,
3 H), 7.64 (dd, J = 7.3, 1.1 Hz, 1 H), 7.82 (m, 2 H), 8.36 (m, 1 H)
ppm. 13C NMR (150 MHz, CDCl3): δ = 14.1, 14.1, 18.5, 22.2, 22.6,
1
Deprotection of the TMS Group of MαNP Esters 23a/23b and
HPLC Separation: A THF solution of tetrabutylammonium fluo-
22.7, 24.9, 28.3–29.7 (m), 31.7, 31.9, 34.7, 51.3, 65.6, 81.9, 86.3, ride (TBAF, 1.0 , 0.439 mL, 0.439 mmol) was added to a solution
124.7, 125.3, 125.3, 125.5, 126.1, 128.7, 129.3, 131.1, 134.1, 135.6, of MαNP esters 23a/23b (diastereomeric mixture, 0.171 g,
173.0 ppm. UV (EtOH): λmax (ε) = 291.8 (2100), 281.6 (3100), 271.8 0.366 mmol) in THF (0.3 mL), and the mixture was stirred at room
(2600), 224.4 (30000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = temperature overnight. The mixture was subjected to short-column
282.6 (+0.2), 247.6 (–0.3), 235.2 (+0.1), 221.8 (–4.5), 218.8 (–4.7), chromatography on silica gel (hexane/EtOAc, 10:1) to give a mix-
216.6 (–4.6 Lmol–1 cm–1) nm. C43H68O3 (633.00): calcd. C 81.59, H
10.83; found C 81.54, H 10.91.
ture of diastereomeric esters which was further separated by HPLC
on silica gel (Table 1) to give the first- and second-eluted esters 27a
and 27b, respectively.
(S,10R)-(–)-8-Nonacosyn-10-ol MαNP Ester (25b): Yield 0.139 g,
44%; colorless syrup. [α]2D2 = –3.2 (c = 1.12, CHCl3). IR (neat):
(S,3S)-(–)-1-Dodecyn-3-ol MαNP Ester (27a): Yield 0.0545 g, 38%;
ν
= 3051, 2925, 2853, 1754, 1509, 1466, 1368, 1247, 1133, 803,
colorless syrup. [α]2D5 = –50.2 (c = 1.02, CHCl ). IR (neat): ν
=
˜
˜
max
3
max
778 cm–1. 1H NMR (600 MHz, CDCl3): δ = 0.61 (m, 1 H), 0.74 3309, 3291, 3051, 2927, 2855, 2359, 2341, 1752, 1510, 1465, 1369,
(m, 1 H), 0.83 (m, 2 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.88 (t, J =
1237, 1181, 1134, 1121, 1052, 991, 805, 780 cm–1. 1H NMR
7.1 Hz, 3 H), 0.89 (m, 2 H), 1.05 (tt, J = 7.3, 7.3 Hz, 2 H), 1.16 (600 MHz, CDCl3): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.15 (m, 8 H),
(m, 2 H), 1.20–1.40 (m, 36 H), 1.44 (tt, J = 7.3, 7.3 Hz, 2 H), 2.01
(s, 3 H), 2.13 (td, J = 7.1, 2.0 Hz, 2 H), 3.10 (s, 3 H), 5.33 (ddt, J
= 7.1, 5.6, 2.0 Hz, 1 H), 7.45 (m, 3 H), 7.59 (dd, J = 7.2, 1.0 Hz, 1
H), 7.82 (m, 2 H), 8.43 (m, 1 H) ppm. 13C NMR (150 MHz,
1.23 (m, 4 H), 1.28 (m, 2 H), 1.65 (m, 2 H), 1.99 (s, 3 H), 2.26 (d,
J = 2.2 Hz, 1 H), 3.20 (s, 3 H), 5.34 (td, J = 6.7, 2.2 Hz, 1 H), 7.45
(m, 3 H), 7.65 (dd, J = 7.1, 1.1 Hz, 1 H), 7.83 (m, 2 H), 8.33 (m,
1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.1, 22.2, 22.7, 24.7,
CDCl3): δ = 14.1, 14.1, 18.6, 21.5, 22.6, 22.7, 24.2, 28.4–29.7 (m), 28.8, 29.2, 29.3, 29.4, 31.8, 34.2, 51.3, 64.8, 73.6, 80.5, 81.8, 124.7,
31.7, 31.9, 34.7, 50.9, 65.2, 77.3, 81.5, 86.2, 124.6, 125.4, 125.6, 125.1, 125.3, 125.5, 126.3, 128.8, 129.4, 131.0, 134.1, 135.4,
125.8, 126.4, 128.6, 129.4, 131.33, 134.0, 134.9, 173.1 ppm. UV 173.0 ppm. UV (EtOH): λmax (ε) = 291.4 (3400), 281.0 (5000), 271.4
(EtOH): λmax (ε) = 292.4 (2200), 281.6 (3200), 272.0 (2700), 224.4
(31300 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) = 291.6 (–0.5),
280.8 (–0.8), 228.2 (+1.3), 210.0 (–4.9), 207.6 (–4.9 Lmol–1 cm–1)
nm. C43H68O3 (633.00): calcd. C 81.59, H 10.83; found C 81.61, H
11.05.
(4100), 223.8 (49000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε) =
243.4 (–0.7), 241.8 (–0.6), 237.2 (–0.5), 222.4 (–4.9), 218.8
(–4.7 Lmol–1 cm–1) nm. C26H34O3 (394.55): calcd. C 79.15, H 8.69;
found C 79.41, H 8.83.
(S,3R)-(+)-1-Dodecyn-3-ol MαNP Ester (27b): Yield 0.0549 g, 38%;
(S,19S)-(–)-17-Octatriacontyn-19-ol MαNP Ester (26a): Yield 47%;
colorless syrup. [α]2D5 = +3.27 (c = 1.03, CHCl ). IR (neat): ν
=
˜
3
max
colorless solid. [α]2D9 = –26.0 (c = 1.36, CHCl ). IR (film): ν
=
3309, 3291, 3051, 2926, 2855, 2358, 2341, 1752, 1600, 1510, 1465,
˜
3
max
1
3053, 2924, 2853, 1736, 1510, 1466, 1371, 1245, 1180, 1120, 1054,
1369, 1237, 1181, 1134, 1121, 1052, 991, 805, 780 cm–1. H NMR
2322
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2313–2324

Enantiopure Aliphatic Acetylene Alcohols
(600 MHz, CDCl3): δ = 0.58 (m, 1 H), 0.73 (m, 1 H), 0.77–0.92 (m, Mazda Foundation (to S. K.), and the Inamori Foundation (to
4 H), 0.89 (t, J = 7.3 Hz, 3 H), 1.05 (tdd, J = 7.5, 7.5, 7.2 Hz, 2
H), 1.17 (m, 2 H), 1.21 (m, 2 H), 1.28 (tt, J = 7.2, 7.2 Hz, 2 H),
1.36 (m, 2 H), 2.02 (s, 3 H), 2.37 (d, J = 2.0 Hz, 1 H), 3.10 (s, 3
H), 5.34 (ddd, J = 7.1, 5.6, 2.0 Hz, 1 H), 7.46 (m, 3 H), 7.60 (dd,
J = 7.3, 0.9 Hz, 1 H), 7.83 (m, 2 H), 8.41 (m, 1 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 14.1, 21.4, 22.7, 24.0, 28.6, 29.1, 29.2, 29.3,
31.8, 34.2, 50.9, 64.3, 73.5, 80.8, 81.4, 124.6, 125.2, 125.7, 125.9,
126.5, 128.6, 129.5, 131.5, 134.0, 134.6, 173.1 ppm. UV (EtOH):
S. K.).
[1] a) J. Fried, C. H. Lin, J. C. Sih, P. Dalven, G. F. Cooper, J. Am.
Chem. Soc. 1972, 94, 4342–4343; b) J. Fried, J. C. Sih, C. H.
Lin, P. Dalven, J. Am. Chem. Soc. 1972, 94, 4343–4345; c) A. F.
Kluge, K. G. Untch, J. H. Fried, J. Am. Chem. Soc. 1972, 94,
9256–9258; d) R. Noyori, I. Tomino, M. Yamada, M. Nishiz-
awa, J. Am. Chem. Soc. 1984, 106, 6717–6725; e) E. J. Corey,
K. Niimura, Y. Konishi, S. Hashimoto, Y. Hamada, Tetrahe-
dron Lett. 1986, 27, 2199–2202; f) R. C. Larrock, F. Kondo, K.
Narayanan, L. K. Sydnes, M.-F. Hsu, Tetrahedron Lett. 1989,
30, 5737–5740.
λmax (ε)
=
292.0 (4200), 281.4 (6000), 271.6 (5000), 224.2
292.0
(58000 Lmol–1 cm–1) nm. CD (EtOH): λext (∆ε)
=
(–1.0), 281.0 (–1.4), 270.4 (–1.1), 230.0 (+3.3), 213.8 (–11.3), 212.0
(–11.1 Lmol–1 cm–1) nm. C26H34O3 (394.55): calcd. C 79.15, H 8.69;
found C 78.85, H 8.61.
[2] K. Mori, T. Ohtaki, H. Ohrui, D. R. Berkebile, D. A. Carlson,
Eur. J. Org. Chem. 2004, 1089–1096.
[3] a) S. Okamoto, T. Shimazaki, Y. Kobayashi, F. Sato, Tetrahe-
dron Lett. 1987, 28, 2033–2036; b) S. Nakamura, S. Kusuda,
K. Kawamura, T. Toru, J. Org. Chem. 2002, 67, 640–647; c)
V. B. Birman, L. Guo, Org. Lett. 2006, 8, 4859–4861.
[4] a) K. Burgess, L. D. Jennings, J. Am. Chem. Soc. 1991, 113,
6129–6139; b) M. Shimizu, H. Kawanami, T. Fujisawa, Chem.
Lett. 1992, 21, 107–110; c) Y. Kita, Y. Takebe, K. Murata, T.
Naka, S. Akai, J. Org. Chem. 2000, 65, 83–88; d) T. Schubert,
W. Hummel, M.-R. Kula, M. Müller, Eur. J. Org. Chem. 2001,
4181–4187.
Recovery of Enantiopure Acetylene Alcohols 5–8: For example,
KOH (0.343 g, 6.11 mmol) was added to a solution of MαNP ester
(S,9S)-(–)-24a (0.450 g, 0.94 mmol) in EtOH (3.1 mL), and the
mixture was stirred at room temperature overnight. After addition
of aqueous saturated NaHCO3, the mixture was extracted several
times with diethyl ether. The combined organic layers were washed
with brine, dried with anhydrous MgSO4, and the solvents evapo-
rated to dryness to yield crude alcohol 6, which was purified by
HPLC on silica gel (hexane/EtOAc, 20:1).
[5] S. Takano, T. Sugihara, K. Ogasawara, Heterocycles 1990, 31,
(S)-(–)-10-Octadecyn-9-ol (6): Yield 0.253 g, 99%; colorless oil.
[α]2D4 = –8.0 (σ = 0.30, ρ = 0.858, neat); [α]2D3 = –6.4 (c = 6.07,
1721–1725.
[6] Th. Kunstler, D. Schollmeyer, H. Singer, M. Steigerwald, Tetra-
hedron: Asymmetry 1993, 4, 1645–1650.
1
cyclohexane). IR and H and 13C NMR spectroscopic data agree
[7] C. Von Dem Bussche-Hünnefeld, A. K. Beck, U. Lengweiler,
D. Seebach, Helv. Chim. Acta 1992, 75, 438–441.
[8] N. Harada, “Chiral auxiliaries powerful for both enantiomer
resolution and determination of absolute configuration by X-
ray crystallography” in Topics in Stereochemistry (Eds.: S. E.
Denmark, J. S. Siegel), Wiley, New Jersey, 2000, vol. 25, chap-
ter 6, pp. 177–203.
with those of racemic alcohol (Ϯ)-6.
(S)-(–)-8-Nonacosyn-10-ol (7): Yield 0.210 g, 99%; colorless solid.
[α]2D6 = –3.8 (σ = 0.03, c = 10.13, cyclohexane). IR and 1H and 13
C
NMR spectroscopic data agree with those of racemic alcohol (Ϯ)-
7. C29H56O (420.76): calcd. C 82.78, H 13.42; found C 82.09, H
13.49.
[9] N. Harada, “Powerful chiral molecular tools for preparation of
enantiopure alcohols and simultaneous determination of their
absolute configurations by X-ray crystallography and/or 1H
NMR anisotropy methods” in Chirality in drug research (Eds.:
E. Francotte, W. Lindner), Wiley-VCH, Weinheim, 2006, chap-
ter 9, pp. 283–321.
(S)-(–)-17-Octatriacontyn-19-ol (8): Yield 0.164 g, 91%; colorless
solid. [α]2D8 = –2.4 (σ = 0.07, c = 3.13, cyclohexane). [α]4D9 = –2.6 (σ
1
= 0.14, c = 7.23, cyclohexane). IR and H and 13C NMR spectro-
scopic data agree with those of racemic alcohol (Ϯ)-6. C38H74O
(546.99): calcd. C 83.44, H 13.64; found C 83.08, H 13.91.
[10] N. Harada, M. Watanabe, S. Kuwahara, “Novel chiral derivat-
izing agents powerful for enantioresolution and determination
(R)-(+)-1-Dodecyn-3-ol (5): Yield 83%; colorless oil. [α]2D1 = +3.0 (c
1
= 1.13, CHCl ). IR (neat): ν
= 3354, 3312, 2927, 2856, 1467,
˜
3
max
of absolute stereochemistry by X-ray crystallographic and H
1017 cm–1. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz,
3 H), 1.20–1.35 (m, 12 H), 1.40–1.50 (m, 2 H), 1.74–1.75 (m, 2 H),
1.82 (d, J = 5.6 Hz, 1 H), 2.46 (d, J = 2.2 Hz, 1 H), 4.37 (td, J =
6.3, 2.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1,
22.6, 25.0, 29.2, 29.3, 29.5, 29.5, 31.8, 37.6, 62.3, 72.8, 85.0 ppm.
HRMS: calcd. for C12H22O 182.1671; found 182.1627.
1
NMR anisotropy methods” in Chiral analysis (Eds.: K. W.
Busch, M. A. Busch), Elsevier, Amsterdam, 2006, chapter 18,
pp. 661–691.
[11] a) S. Kuwahara, K. Fujita, M. Watanabe, N. Harada, T. Ishida,
Enantiomer 1999, 4, 141–145; b) N. Harada, M. Watanabe, S.
Kuwahara, A. Sugio, Y. Kasai, A. Ichikawa, Tetrahedron:
Asymmetry 2000, 11, 1249–1253; c) H. Taji, Y. Kasai, A. Sugio,
S. Kuwahara, M. Watanabe, N. Harada, A. Ichikawa, Chirality
2002, 14, 81–84; d) A. Ichikawa, H. Ono, S. Hiradate, M. Wat-
anabe, N. Harada, Tetrahedron: Asymmetry 2002, 13, 1167–
1172; e) S. Nishimura, S. Matsunaga, M. Shibazaki, K. Suzuki,
N. Harada, H. Naoki, N. Fusetani, J. Nat. Prod. 2002, 65,
1353–1356; f) H. Taji, M. Watanabe, N. Harada, H. Naoki, Y.
Ueda, Org. Lett. 2002, 4, 2699–2702; g) Y. Kasai, M. Watan-
abe, N. Harada, Chirality 2003, 15, 295–299; h) M. Kosaka, T.
Sugio, Y. Kasai, S. Kuwahara, M. Watanabe, N. Harada, G. E.
Job, A. Shvet, W. H. Pirkle, Chirality 2003, 15, 324–328; i) T.
Nishimura, H. Taji, N. Harada, Chirality 2004, 16, 13–21; j) J.
Naito, M. Kosaka, T. Sugio, M. Watanabe, N. Harada, W. H.
Pirkle, Chirality 2004, 16, 22–35; k) A. Ichikawa, H. Ono, N.
Harada, Chirality 2004, 16, 559–567; l) Y. Kasai, H. Taji, T.
Fujita, Y. Yamamoto, M. Akagi, A. Sugio, S. Kuwahara, M.
Watanabe, N. Harada, A. Ichikawa, V. Schurig, Chirality 2004,
16, 569–585; m) K. Gyimesi-Forras, K. Akasaka, M. Lammer-
hofer, T. Fujita, H. Taji, M. Watanabe, N. Harada, W. Lindner,
(R)-(+)-8-Nonacosyn-10-ol (7): Yield 0.188 g, 89%; colorless solid.
[α]2D6 = +3.5 (c = 8.75, cyclohexane). IR and 1H and 13C NMR
spectroscopic data agree with those of racemic alcohol (Ϯ)-7.
C29H56O (420.76): calcd. C 82.78, H 13.42; found C 82.30, H 13.43.
Supporting Information (see also the footnote on the first page of
1
this article): Figure S1. H NMR spectra of MαNP esters.
Acknowledgments
The authors thank Drs. George A. Ellestad and Koji Nakanishi,
Department of Chemistry, Columbia University, for their valuable
suggestions. This work was supported in part by grants from the
Japan Society for the Promotion of Science [Scientific Research
(B), No. 16350069 to N. H., and Young Scientist Research (B), No.
15710073 to S. K.], the Nissan Science Foundation (to S. K.), the
Eur. J. Org. Chem. 2008, 2313–2324
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2323

N. Harada et al.
FULL PAPER
Chirality 2005, 17, S134–S142; n) J. Naito, Y. Yamamoto, M.
Akagi, S. Sekiguchi, M. Watanabe, N. Harada, Monatsh.
Chem. 2005, 136, 411–445; o) M. Kosaka, S. Sekiguchi, J.
Naito, S. Kuwahara, M. Watanabe, N. Harada, K. Hiroi, Chi-
rality 2005, 17, 218–232; p) K. Akasaka, K. Gyimesi-Forras,
T. Fujita, M. Watanabe, N. Harada, W. Lindner, Chirality
2005, 17, 544–555; q) Y. Kasai, K. Shimanuki, S. Kuwahara,
M. Watanabe, N. Harada, Chirality 2006, 18, 177–187; r) Y.
Kasai, A. Sugio, S. Sekiguchi, S. Kuwahara, T. Matsumoto, M.
Watanabe, A. Ichikawa, N. Harada, Eur. J. Org. Chem. 2007,
1811–1826; s) S. Kuwahara, J. Naito, Y. Yamamoto, Y. Kasai,
T. Fujita, K. Noro, K. Shimanuki, M. Akagi, M. Watanabe, T.
Matsumoto, M. Watanabe, A. Ichikawa, N. Harada, Eur. J.
Org. Chem. 2007, 1827–1840; t) J. Naito, H. Taji, S. Sekiguchi,
M. Watanabe, S. Kuwahara, M. Watanabe, N. Harada, Chiral-
ity 2007, 19, 335–343; u) T. Fujita, K. Obata, S. Kuwahara,
N. Miura, A. Nakahashi, K. Monde, J. Decatur, N. Harada,
Tetrahedron Lett. 2007, 48, 4219–4222.
Synth. Org. Chem. 2004, 62, 1114–1127; c) N. Harada, Chirality
2008, 20, DOI: 10.1002/chir.20478.
[13]
a) Y. Okumura, A. Ando, R. William Stevens, M. Shimizu, Tet-
rahedron 2002, 58, 8729–8736; b) Y. Imamura, H. Takikawa,
M. Sasaki, K. Mori, Org. Biomol. Chem. 2004, 2, 2236–2244; c)
A. Ichikawa, H. Ono, Tetrahedron: Asymmetry 2005, 16, 2559–
2568; d) A. Ichikawa, H. Ono, J. Chromatogr. A 2006, 1117,
38–46; e) T. Ochi, M. Sakamoto, A. Minamida, K. Suzuki, T.
Ueda, T. Une, H. Toda, K. Matsumoto, Y. Terauchi, Bioorg.
Med. Chem. Lett. 2005, 15, 1055–1059; f) F. Narumi, T. Hat-
tori, W. Yamabuki, C. Kabuto, H. Kameyama, Tetrahedron:
Asymmetry 2005, 16, 793–800; g) Y. Fujita, H. Oguri, H.
Oikawa, J. Antibiot. 2005, 58, 425–427.
[14] For the preparation of enantiopure MαNP acids, see
refs.[11m,11t]
Received: January 5, 2008
Published Online: March 19, 2008
[12] a) N. Harada, TCI MAIL 2003, 117, 2–27; b) Y. Kasai, J.
Naito, S. Kuwahara, M. Watanabe, A. Ichikawa, N. Harada, J.
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