Unambiguous determination of the absolute configurations of acetylene alcohols by combination of the Sonogashira reaction and the CD exciton chirality method - Exciton coupling between phenylacetylene and benzoate chromophores

Article abstract of DOI:10.1007/s00706-005-0281-3

The CD exciton chirality method was applied to various phenylacetylene alcohols to determine their absolute configurations; the long axis polarized π-π* transition (λ_max = 252 nm) of the 4-methoxyphenylacetylene chromophore couples with the tra

Full text of DOI:10.1007/s00706-005-0281-3

Monatshefte f€ur Chemie 136, 411–445 (2005)
DOI 10.1007/s00706-005-0281-3
Unambiguous Determination of the Absolute
Configurations of Acetylene Alcohols
by Combination of the Sonogashira Reaction
and the CD Exciton Chirality Method –
Exciton Coupling between Phenylacetylene
and Benzoate Chromophores
Junpei Naito, Yoko Yamamoto, Megumi Akagi,
Satoshi Sekiguchi, Masataka Watanabe, and Nobuyuki Harada
ꢀ
Institute of Multidisciplinary Research for Advanced Materials, Tohoku University,
Sendai 980-8577, Japan
Received November 5, 2004; accepted November 29, 2004
Published online March 8, 2005 # Springer-Verlag 2005
Summary. The CD exciton chirality method was applied to various phenylacetylene alcohols to
ꢀ
determine their absolute configurations; the long axis polarized ꢀ–ꢀ transition (ꢁmax ¼ 252 nm) of
the 4-methoxyphenylacetylene chromophore couples with the transition (ꢁmax ¼ 257 nm) of the 4-
methoxybenzoate group to generate intense exciton split CD Cotton effects, from the signs of which
the absolute configurations of phenylacetylene alcohols were unambiguously determined. As an exten-
sion of the results, a new methodology for determining the absolute configurations of acetylene
alcohols having the HCꢁCCH(OH)-moiety by combination of the Sonogashira reaction and the CD
ꢀ
exciton chirality method has been developed and applied. Since the ꢀ–ꢀ transition of acetylene triple
bond is located below 180 nm, it is difficult to observe ideal bisignate CD Cotton effects due to the
exciton coupling between acetylene and benzoate chromophores. To observe the ideal exciton split
Cotton effects necessary for the unambiguous determination of absolute configuration, the terminal
acetylene group was converted, by the Sonogashira reaction, to the 4-methoxyphenylacetylene moiety,
ꢀ
which exhibits an intense ꢀ–ꢀ absorption band polarized along the long axis of the chromophore at
ꢀ
252 nm. As a partner of exciton coupling, 4-methoxybenzoate showing a ꢀ–ꢀ band at 257 nm was
introduced into the alcohol moiety, and the benzoates formed showed intense bisignate CD Cotton
effects, from the signs of which the absolute configurations of original acetylene alcohols could be
determined in an unambiguous manner.
Keywords. Exciton CD; Absolute configuration; CD exciton chirality method; Chiral phenylacetylene
alcohol; Sonogashira reaction.
ꢀ
Corresponding author. E-mail: n-harada@tagen.tohoku.ac.jp

412
J. Naito et al.
Introduction
It is well known that the molecular chirality is essential to life processes, and most
biologically active compounds controlling physiological functions of living organ-
isms are chiral. Hence in the structural study of biologically active compounds,
including natural products, the determination of absolute configuration becomes
the first major issue. The methodologies for determining the absolute configura-
tions of chiral compounds are classified into the following two categories: a) non-
empirical methods; there are the Bijvoet method of X-ray crystallography [1] and
the circular dichroism (CD) exciton chirality method [2]. These methods provide
nonempirical determination of a target molecule’s configuration without knowl-
edge of the absolute configuration of reference compounds. In X-ray crystallogra-
phy, since the anomalous dispersion effect of heavy atoms can be measured very
accurately under proper conditions, the absolute stereostructure obtained is unam-
biguous and reliable. However, the X-ray method needs single crystals of suitable
size for X-ray diffraction, and so the critical problem is how to obtain such single
crystals. The CD exciton chirality method [2–4] is also useful because the absolute
configuration can be determined in a nonempirical manner, and it does not require
crystallization. Furthermore, even the absolute configurations of unstable com-
pounds can be obtained by this method.
Another category is: b) relative and=or empirical methods for determining abso-
lute configuration using an internal reference with known absolute configuration.
Absolute configuration can be obtained by determining the relative configuration
at the position of interest against a reference compound or substituent with known
absolute configuration. A typical example is the X-ray crystallography taken after
the introduction of a chiral auxiliary with known absolute configuration [5–7]. In
this case, the absolute configuration of the point in question can be automatically
determined using the chirality of the auxiliary introduced as an internal reference.
The relative X-ray methods are expected to find widespread application.
Recently, the proton nuclear magnetic resonance (1H NMR) anisotropy method
has often been employed as a relative and empirical method [8–14]. In particular, the
absolute configurations of secondary alcohols are frequently determined using the
advanced Mosher method developed by Kusumi et al. In this case, the absolute
configurations of chiral auxiliaries, such as Mosher’s reagent [ꢂ-methoxy-ꢂ-(tri-
fluoromethyl)phenylacetic acid (MTPA)] [8–10], Trost’s reagent [ꢂ-methoxyphenyl-
acetic acid (MPA)] [11], and Harada’s reagent [2-methoxy-2-(1-naphthyl)propionic
acid (MꢂNP acid)] [13, 14], are known, and the preferred conformation of the esters
formed with chiral secondary alcohols and these chiral acids is rationalized. In
addition, the aromatic substituent (phenyl or naphthyl group) generates a magnetic
anisotropy effect due to the ring current induced under the external magnetic field,
and so the proton NMR signals of the alcohol moiety facing the phenyl or naphthyl
group in the preferred conformation are moved to a higher magnetic field (high field
shift). By observing the 1H NMR anisotropy effect, the absolute configuration of the
alcohol part can be determined in an empirical manner.
These nonempirical and empirical methods are based on totally different phys-
ical phenomena, but when those methods are applied to a specific compound, they
should give the same conclusion of absolute configuration, of course. In this paper,

Exciton CD of Phenylacetylene Alcohol Benzoates
413
we report the application results of these methods to chiral acetylene alcohols,
together with the brief explanation of the CD exciton chirality method. As an ex-
tension of the results, we have developed a general methodology for determining the
absolute configurations of acetylene alcohols having the HCꢁCCH(OH)-moiety by
combination of the Sonogashira reaction and the CD exciton chirality method.
The CD Exciton Chirality Method [2–4]
The exciton CD Cotton effects are observable, when two identical chromophores
exhibiting intense ꢀ–ꢀ UV absorption are located in chiral positions with respect
ꢀ
to each other, as exemplified by 1,2-diol bis(4-substituted benzoate) shown in
Fig. 1(a). By the exciton coupling between two chromophores i and j, the excited
state a splits into two energy levels, while the ground state 0 remains as a single
level as shown in Fig. 1(b). The energy gap 2Vij in the excited state is called the
Davydov splitting. In consequence, there are two electronic transitions leading to
two UV absorption bands.
The excitations to the two split energy levels give rise to CD Cotton effects of
mutually opposite signs. As illustrated in Fig. 2, this leads to a CD spectrum with
two component Cotton effects of opposite signs which are separated by the energy
gap Dꢁ (¼2Vij, Davydov splitting). Summation of the component Cotton effects
results in the solid curve having two extrema. The extremum at longer wavelength
is called the first Cotton effect, and the one at shorter wavelength is called the
second Cotton effect. The amplitude A of split CD Cotton effects is defined as:
A ¼ D"1 ꢂ D"2, where D"1 and D"2 are intensities of the first and second Cotton
effects. In the case of UV spectra, summation of two component spectra leads to a
Fig. 1. (a) Exciton coupling between two identical chromophores (degenerate system), as exemplified
by the system of 1,2-diol bis(4-substituted benzoate); (b) by the exciton coupling, the excited state
splits into two energy levels; the energy gap 2Vij is called Davydov splitting (adapted from Ref. [2])

414
J. Naito et al.
Fig. 2. Typical pattern of CD and UV spectra of exciton coupling system; summation of two
component Cotton effects (dotted line) of opposite signs separated by Davydov splitting Dꢁ yields
CD and UV curves of solid line; positive chirality gives positive first and negative second CD Cotton
effects, whereas negative chirality gives negative first and positive second Cotton effects; the am-
plitude (A) of split CD Cotton effects is defined as: A ¼ D"1 ꢂ D"2 where D"1 and D"2 are intensities
of first and second Cotton effects; in the case of UV spectra, summation of two component spectra
leads to a single maximum (adapted from Ref. [2])
single maximum, because the energy gap Dꢁ is relatively small compared to the
bandwidth in most cases (Fig. 2).
Provided the electric transition dipole moments of the two chromophores con-
stitute a clockwise screw sense (positive exciton chirality), as exemplified by the
dibenzoate in the right side of Fig. 1, the sign of the first CD Cotton effect is positive
and that of the second Cotton effect is negative (Fig. 2). When the two dipole mo-
ments make a counter-clockwise screw sense (negative exciton chirality: the dibenzo-
ate in the left side of Fig. 1), the signs of the first and second Cotton effects are
negative and positive. The exciton chirality governing the sign and amplitude of split
Cotton effects is theoretically defined as: Rij ꢃ (li0aꢄlj0a)V , where Rij is the inter-
ij
chromophoric distance vector from i to j, the symbol ꢃ denotes the scalar product of
two vectors, li0a and lj0a are electric transition dipole moment vectors of excitation
0!a of groups i and j, the symbolꢄdenotes the vector product of two vectors, and Vij
is the interaction energy between two electric transition dipole moments, li0a and lj0a.
If the direction of the electric transition moment in the chromophore, i.e.,
the polarization of the transition, is established, the signs of the observed two
Cotton effects enable one to determine the absolute stereochemistry of the two
chromophores in space. Namely, the absolute configuration of a target compound

Exciton CD of Phenylacetylene Alcohol Benzoates
415
Fig. 3. CD and UV spectra of cholest-5-ene-3ꢃ,4ꢃ-diol bis(4-dimethylaminobenzoate) in EtOH
(adapted from Ref. [2])
can be determined from the signs of CD Cotton effects on the basis of the chiral
exciton coupling mechanism. Figure 3 shows a typical example of exciton coupling
CD spectra observed in cholest-5-ene-3ꢃ,4ꢃ-diol bis(4-dimethylaminobenzoate).
ꢀ
The 4-dimethylaminobenzoate chromophore exhibits an intense ꢀ–ꢀ UV band
around 310 nm, which is polarized along the long axis of the chromophore. In the
corresponding region, the CD spectrum shows negative first and positive second
Cotton effects: ꢁext(D") ¼ 320.5 nm (D" ¼ ꢂ63.1 molꢂ1dm3 cmꢂ1), 295.5 (þ39.7),
A ¼ ꢂ102.8. The observed negative exciton chirality indicates the counterclock-
wise screw sense between the two long axes of the benzoate chromophores, leading
to the (3S,4R) configuration in the steroidal skeleton. The absolute configuration of
diol systems is thus determinable by the CD exciton chirality method.
The exciton coupling is the most effective in the case of a degenerate system
having two identical chromophores, because the UV absorption maxima ꢁmax of
both chromophores are the same. However, even in a nondegenerate system having
two different chromophores, the CD spectrum is still governed by the exciton
coupling mechanism. As shown in Fig. 4, the excited state has two energy levels,
and the excitations to these levels give rise to exciton split CD Cotton effects as in
the case of a degenerate case. For example, in the system of cholest-5-ene-3ꢃ,4ꢃ-
diol 3-benzoate 4-(4-methoxybenzoate) shown in Fig. 5, the 257 nm transition of
4-methoxybenzoate and the 230 nm transition of benzoate couple with each
other generating bisignate Cotton effects with typical pattern of exciton coupling,
although their CD amplitude, A-value, is smaller than that of 3,4-dibenzoate
(230=230 nm). The absolute configurations of nondegenerate system are thus deter-
minable from the observed exciton CD spectra.

416
J. Naito et al.
Fig. 4. (a) Exciton coupling between two nonidentical chromophores (nondegenerate system), as
exemplified by the system of 1,2-diol 4-methoxybenzoate=benzoate (257 nm–230 nm); (b) the CD
exciton chirality method is still applicable to the nondegenerate system composed of two different
chromophores having similar UV ꢁmax values; namely, exciton split bisignate CD Cotton effects are
observable, and the absolute configuration of the system can be determined (adapted from Ref. [2])
Fig. 5. CD spectrum of cholest-5-ene-3ꢃ,4ꢃ-diol 3-benzoate 4-methoxybenzoate in EtOH (adapted
from Ref. [2])
The exciton chirality method is extensible to chiral compounds which already
possess a chromophore suitable for exciton coupling. One typical example is
shown in Fig. 6, where the original compound has a naphthalene chromophore
ꢀ
which exhibits intense ꢀ–ꢀ transition at 226 nm polarized along the long axis
of the chromophore. As a partner of exciton coupling, the unsubstituted benzoate
ꢀ
polarized along the long axis of the chromophore. Namely in such a case, it is
was selected, because benzoate chromophore exhibits ꢀ–ꢀ transition at 230 nm

Exciton CD of Phenylacetylene Alcohol Benzoates
417
Fig. 6. Nondegenerate system having two different chromophores, where one chromophore is al-
ready present in the molecule in question: 226 nm transition of naphthalene chromophore polarized
along the long axis and 230 nm transition of benzoate chromophore polarized along long axis; the
two transition dipole moments constitute positive exciton chirality generating positive first and
negative second Cotton effects (adapted from Ref. [2])
Fig. 7. CD spectra of estra-1,3,5,7,9-pentaene-3,17ꢃ-diol 3-methyl ether and its benzoate in EtOH
(adapted from Ref. [2])
important to choose a chromophore having ꢁmax similar to that of the chromophore
contained in the molecule. As expected, the exciton coupling between naphthalene
and benzoate chromophores generates intense exciton split CD Cotton effects (Fig. 7),
from which the absolute configuration of the original compound is determinable.
In this paper, we report the application of the CD exciton chirality method to
phenylacetylene alcohol benzoates, where phenylacetylene and benzoate chromo-
phores effectively couple with each other (Fig. 8). From the exciton CD data, the
absolute configurations of original phenylacetylene alcohols were determined.

418
J. Naito et al.
Fig. 8. Application of the CD exciton chirality method to nondegenerate systems of phenylacetylene
alcohol benzoates
Furthermore, by combining with the Sonogashira reaction, a novel methodology
for determining the absolute configurations of acetylene alcohols having the
HCꢁCCH(OH)-moiety was developed as described below.
Results and Discussion
Preparation of Enantiopure Phenylacetylene Alcohols
We have previously reported that the chiral acids listed in Fig. 9 are very powerful
for enantioresolution of racemic alcohols and also for determination of their abso-
lute configurations [5, 6, 13, 14]. Namely, camphorsultam dichlorophthalic acid
(CSDP acid) (1S,2R,4R)-(ꢂ)-1 was condensed with racemic alcohols to yield dia-
stereomeric esters, which were easily separated by HPLC on silica gel. In general,
the CSDP esters have high probability to crystallize as large single crystals suitable
for X-ray diffraction experiments. Therefore their stereostructures were determined
by X-ray crystallography. Since the absolute configuration of CSDP acid is already
known, the absolute configuration of the alcohol part was easily determined from
the ORTEP drawing of X-ray analysis. From the CSDP esters, enantiopure alcohols
were recovered by hydrolysis or solvolysis [5, 6].
Fig. 9. Chiral molecular tools for preparation of enantiopure alcohols and determination of absolute
configurations

Exciton CD of Phenylacetylene Alcohol Benzoates
419
Another method is to use 2-methoxy-2-(1-naphthyl)propionic acids (MꢂNP
acids) (R)-(ꢂ)-2 and (S)-(þ)-2 [13–15]. For example, racemic alcohol was ester-
ified with MꢂNP acid (S)-(þ)-2, and the diastereomeric esters obtained were easily
1
separated by HPLC on silica gel. By applying the H NMR anisotropy method of
MꢂNP acid to diastereomeric esters, their absolute configurations were empirically
determined. From the MꢂNP esters, enantiopure alcohols were recovered by sol-
volysis [13, 14].
The MꢂNP acid method is also useful for determination of absolute configura-
tions of chiral alcohols, as exemplified below. Namely, chiral alcohol was con-
1
densed with MꢂNP acid (R)-(ꢂ)-2 and also with (S)-(þ)-2. From the H NMR
anisotropy data of both MꢂNP esters, the absolute configuration of the original
alcohol was determined [13, 14].
As target compounds, the enantiopure phenylacetylene alcohols (3–6, 8, 10)
listed in Fig. 10 were synthesized; alcohol (S)-(ꢂ)-3 had been previously prepared
by the MꢂNP acid method, and its absolute configuration also had been deter-
mined by the 1H NMR anisotropy method [13o]. For alcohols 4, 5, and 6, racemic
alcohols were synthesized as shown in Scheme 1; all reactions proceeded well in
good yields. To enantioresolve racemic alcohol 4, we have first tried to use the
MꢂNP acid method. However, it was difficult to separate diastereomeric MꢂNP
esters formed from alcohol 4. Instead, we have applied the CSDP acid method
as shown in Scheme 2; alcohol (ꢅ)-4 was esterified with CSDP acid (1S,2R,4R)-
(ꢂ)-1, 4-dimethylaminopyridine (DMAP), and 1,3-dicyclohexylcarbodiimide
Fig. 10. Chiral acetylene alcohols and their absolute configurations

420
J. Naito et al.
Scheme 1
(DCC) yielding diastereomeric esters, which were separated by HPLC on silica
gel: n-hexane=EtOAc 3=1, ꢂ ¼ 1.06, Rs ¼ 0.82 (Table 1). In this case, it was not
easy to separate diastereomeric esters, because of small ꢂ value. However, we
performed HPLC separation several times to obtain enough amounts of both
esters: the first-eluted ester (ꢂ)-15a, 49%, and the second-eluted ester (ꢂ)-15b,
46%. To apply the X-ray crystallographic analysis, those esters were subjected to
crystallization; however, both compounds were obtained as amorphous solids. The
first-eluted ester (ꢂ)-15a was treated with K2CO3 in MeOH yielding enantiopure
alcohol (ꢂ)-4.
The CSDP acid method was similarly applied to racemic alcohols 5 and 6. The
esters formed from alcohol (ꢅ)-5 were separated by HPLC on silica gel in a
moderate extent: n-hexane=EtOAc 3=1, ꢂ ¼ 1.13, Rs ¼ 1.75 (Table 1). The first-
eluted ester (S)-(ꢂ)-16a was subjected to solvolysis giving enantiopure alcohol
(S)-(ꢂ)-5 (Scheme 3). Alcohol (ꢅ)-6 was esterified with CSDP acid yielding a dia-
stereomeric mixture, which was separated by HPLC on silica gel: n-hexane=EtOAc
2=1, ꢂ ¼ 1.08, Rs ¼ 1.26 (Table 1). The first-eluted ester (S)-(ꢂ)-17a was treated
with K2CO3 in MeOH giving enantiopure alcohol (þ)-6 (Scheme 3).

Exciton CD of Phenylacetylene Alcohol Benzoates
421
Scheme 2
Table 1. Silica gel-HPLC separation of diastereomeric esters formed from racemic acetylene alcohols
with (ꢂ)-CSDP acid, recovery of chiral alcohols, and determination of their absolute configurations
1
by the H NMR anisotropy method
Acid
Alcohol
Solventa
ꢂ
Rs
Ester
Chiral alcohol
(from 1st Fr.)
1H NMR
Dꢄb
(1st Fr.)
(ꢂ)-1
(ꢂ)-1
(ꢂ)-1
(ꢅ)-4
(ꢅ)-5
(ꢅ)-6
H=EA ¼ 3=1
H=EA ¼ 3=1
H=EA ¼ 2=1
1.06
1.13
1.08
0.82
1.75
1.26
(S)-(ꢂ)-15a
(S)-(ꢂ)-16a
(S)-(ꢂ)-17a
(S)-(ꢂ)-4
(S)-(ꢂ)-5
(S)-(þ)-6
yesc
yesc
yesc
H ¼ n-hexane, EA ¼ ethyl acetate; Dꢄ ¼ 1H NMR anisotropy effect; absolute configuration
a
b
c
determined by the 1H NMR anisotropy method agreed with that by the CD exciton chirality method
Determination of the Absolute Configurations of Phenylacetylene
1
Alcohols by the H NMR Anisotropy Method
To determine the absolute configurations of the phenylacetylene alcohols obtained,
we have next applied the 1H NMR anisotropy method using MꢂNP acids (R)-(ꢂ)-2
and (S)-(þ)-2. The general procedure of the method is summarized as follows
(Fig. 11); i) chiral alcohol, whose unknown absolute configuration is defined as
X, is esterified with (R)-MꢂNP acid and (S)-MꢂNP acid separately; ii) the 1H NMR
spectra of (R,X)- and (S,X)-esters are measured, and the chemical shift data of
alcohol moieties in each ester are obtained as ꢄ(R,X) and ꢄ(S,X); iii) the chemical

422
J. Naito et al.
Scheme 3
shift difference values are calculated as Dꢄ ¼ ꢄ(R,X) – ꢄ(S,X); iv) in the projection
of the sector rule shown in Fig. 11, the group R1 with protons exhibiting positive
Dꢄ values is placed in the right sector and the group R2 with protons showing
negative Dꢄ values in the left sector. In the sector rule, the OMꢂNP group is located
in the down and front side, and the methine proton of the secondary alcohol in the
down and rear side. From this projection, the absolute configuration X of chiral
alcohol can be determined [13, 14].
This 1H NMR anisotropy method using MꢂNP acid is based on the anisotropy
effect of the naphthyl group generated by the ring current induced under the external
magnetic field. The MꢂNP esters take preferred conformations as shown in Fig. 11,
where the ester carbonyl oxygen atom is synperiplanar (syn) to the OMe group
in MꢂNP acid moiety and also to the methine proton of the secondary alcohol.
Therefore in the (R,X)-ester, the group R2 faces the naphthyl group and hence the
proton NMR signals of group R2 are moved to a higher magnetic field (high field
shift). On the other hand, the group R1 faces the naphthyl group in the (S,X)-ester,

Exciton CD of Phenylacetylene Alcohol Benzoates
423
1
Fig. 11. The H NMR anisotropy method using MꢂNP acid for determining the absolute config-
uration of chiral alcohols
leading to high field shift. The group R1 thus takes positive Dꢄ values, while the
group R2 takes negative Dꢄ values. Based on this mechanism, the absolute config-
uration of a chiral alcohol is determinable. The 1H NMR anisotropy method using
MꢂNP acid is an empirical rule, but it is very useful and extensively applicable to
various chiral secondary alcohols [13, 14].
Scheme 4

424
J. Naito et al.
The application of the MꢂNP acid method to chiral phenylacetylene alcohol
(ꢂ)-4 was executed as follows. Chiral alcohol (X)-(ꢂ)-4 was esterified with MꢂNP
acids (R)-(ꢂ)-2 and (S)-(þ)-2 yielding esters (R,X)-(þ)-18 and (S,X)-(ꢂ)-18
1
(Scheme 4). Their H NMR signals of alcohol part were easily assigned and then
Dꢄ (¼ꢄ((R,X)-18) ꢂ ꢄ((S,X)-18)) values were calculated as shown in Fig. 12. Since
the ortho- and meta-protons of phenyl group show positive Dꢄ values, þ0.15 and
þ0.03, the 4-methoxyphenylacetylene group was placed in the right side. On the
other hand, the methyl group protons exhibit a negative Dꢄ value, ꢂ0.21, and
therefore it was placed in the left side. So, the absolute configuration of alcohol
(ꢂ)-4 was explicitly determined as X ¼ S. The observed Dꢄ values are distributed in
Fig. 12. 1H NMR chemical shifts of MꢂNP esters (R,X)-18 and (S,X)-18, and Dꢄ values leading to
the absolute configuration of the chiral alcohol, X ¼ S, i.e. (S)-(ꢂ)-4
Scheme 5

Exciton CD of Phenylacetylene Alcohol Benzoates
425
a reasonable manner; more remote protons from the OMꢂNP group show smaller
Dꢄ values. The distribution pattern indicates that the determination of the absolute
configuration of (ꢂ)-4 is reliable.
Fig. 13. Dꢄ Values leading to the absolute configuration of the chiral alcohol, X ¼ S, i.e. (S)-(ꢂ)-5
and (S)-(þ)-6
Fig. 14. CD and UV spectra of alcohol (S)-(ꢂ)-3 in EtOH

426
J. Naito et al.
The remaining alcohols (ꢂ)-5 and (þ)-6 were similarly converted to MꢂNP
esters (Scheme 5) and then Dꢄ values were calculated as shown in Fig. 13; the
Dꢄ values of MꢂNP esters 19 are similar to those of 18 leading to the (S)
absolute configuration of alcohol (ꢂ)-5. In the case of MꢂNP esters 20, the
phenyl group shows negative Dꢄ values, while 3,4,5-trimethoxyphenylacetylene
group shows a positive Dꢄ value, indicating the (S) absolute configuration of
alcohol (þ)-6.
Determination of the Absolute Configurations of Phenylacetylene
Alcohols by the CD Exciton Chirality Method
Next the CD exciton chirality method was applied to phenylacetylene alcohols 3–6
to determine their absolute configurations. Figure 14 illustrates the CD and UV
spectra of (ꢂ)-3; the 4-methoxyphenylacetylene group exhibits intense UV absorp-
3
tion band of ꢀ–ꢀ transition at 252 nm (" ¼ 25600 molꢂ1 dm cmꢂ1), which is
ꢀ
polarized along the long axis of the chromophore [16]. Although the 252 nm tran-
sition is allowed, it is almost silent in the CD spectrum of (ꢂ)-3. To generate the
most effective exciton split CD Cotton effects, the 4-methoxybenzoate chromo-
ꢀ
phore having a ꢀ–ꢀ transition at 257 nm was selected, because the ꢁmax value of
4-methoxybenzoate is close to that of 4-methoxyphenylacetylene chromophore. So
4-methoxybenzoate (þ)-21 was prepared (Scheme 6) and its CD and UV spectra
were measured as shown in Fig. 15. As expected, the CD spectrum of (þ)-21
shows very intense bisignate Cotton effects due to the exciton coupling between
4-methoxyphenylacetylene and 4-methoxybenzoate chromophores: ꢁext ¼ 266.0 nm
(D" ¼ þ30.9 molꢂ1 dm3 cmꢂ1), 246.4 (ꢂ22.7), A ¼ þ53.6. The positive first and
negative second Cotton effects observed indicate the positive exciton chirality
between the two chromophores.
The preferred conformation of benzoate (S)-21 is depicted in Fig. 16, where
the carbonyl oxygen atom of benzoate group is synperiplanar (syn) to the alcohol
methine proton. The 257 nm transition of 4-methoxybenzoate is polarized along
the long axis of the chromophore, and the 252 nm of 4-methoxyphenylacetylene is
Scheme 6

Exciton CD of Phenylacetylene Alcohol Benzoates
427
Fig. 15. CD and UV spectra of benzoate (S)-(þ)-21 in EtOH
Fig. 16. Positive exciton chirality between two long axes of 4-methoxybenzoate and 4-methoxy-
phenylacetylene chromophores

428
J. Naito et al.
also polarized along the long axis of the group as illustrated in Fig. 16. Since the
4-methoxyphenylacetylene group is linear in its form, the direction of the transi-
tion moment is invariant, even if the phenylacetylene group rotates around C–C
single bonds. In the stereostructure of (S)-21, the long axis of 4-methoxybenzoate
is located in the front side and that of 4-methoxyphenylacetylene is in the rear
side. Namely, the two long axes constitute a clockwise screw sense, i.e., positive
Scheme 7

Exciton CD of Phenylacetylene Alcohol Benzoates
429
exciton chirality. Therefore the observed bisignate Cotton effects of positive exci-
ton chirality lead to the (S) absolute configurations of ester (þ)-21 and alcohol
1
(ꢂ)-3, which agree with the previous determination by the H NMR anisotropy
method.
Other phenylacetylene alcohols 4–6 were similarly converted to benzoates
22–25 (Scheme 7). In the case of benzoate (þ)-22, its CD spectrum exhibits posi-
tive first and negative second Cotton effects leading to the (S) absolute configuration
(Fig. 17). Its A-value is comparable to that of (þ)-21 indicating that the CD sign
and intensity are mostly governed by the exciton coupling between 4-methoxy-
benzoate and 4-methoxyphenylacetylene groups, and the contribution of aliphatic
side chain is relatively small. Benzoate (þ)-23 is a unique compound having
3,4,5-trimethoxyphenylacetylene chromophore; although its CD spectrum shows
bisignate Cotton effects of positive exciton chirality leading to the (S) absolute
Fig. 17. CD and UV spectra of benzoate (S)-(þ)-22 in EtOH

430
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Fig. 18. CD and UV spectra of benzoate (S)-(þ)-23 in EtOH
configuration, its A-value is smaller than those of 4-methoxyphenylacetylene=
4-methoxy-benzoates 21 and 22 (Fig. 18). It may be interpreted as follows; two
methoxyl groups at the 3- and 5-positions weaken the long-axis polarized transi-
tion of the phenylacetylene chromophore as judged from the UV data of alcohol
(S)-(ꢂ)-5, ꢁmax ¼ 265.2 nm (" ¼ 15700 molꢂ1 dm3 cmꢂ1) (see Experimental Sec-
tion), and hence the exciton coupling CD becomes weaker. This effect is more
emphasized in the CD spectrum of 24; its A-value is ca. one third of that of 22
(Fig. 19). Therefore, chromophores having substituents, which strengthen the
long-axis polarized transition, are more appropriate for the CD exciton chirality
method. Compound 25 is also unique in the sense that it has the third chromo-
phore in addition to a pair of the exciton coupling chromophores; it may be
worried that the third phenyl chromophore disturbs the exciton coupling between
4-methoxybenzoate and 3,4,5-trimethoxyphenylacetylene groups. However, the
CD spectrum of (þ)-25 shows a clear pattern of positive exciton chirality lead-
ing to the (S) absolute configuration (Fig. 20). The A-value of (þ)-25 is almost

Exciton CD of Phenylacetylene Alcohol Benzoates
431
Fig. 19. CD and UV spectra of benzoate (S)-(þ)-24 in EtOH
comparable to that of (þ)-23 indicating that the contribution of phenyl group is
relatively small.
Determination of the Absolute Configurations of Acetylene Alcohols
by Combination of the Sonogashira Reaction and the CD
Exciton Chirality Method
As discussed above, the CD exciton chirality method is useful for determining the
absolute configuration of phenylacetylene alcohols. As an extension of the results,
we have developed a general methodology for determining the absolute configu-
rations of chiral acetylene alcohols having the HCꢁCCH(OH)-moiety by com-
bination of the Sonogashira reaction and the CD exciton chirality method as
shown in Fig. 21. To determine the absolute configuration of acetylene alcohols,
the CD exciton chirality method had been applied to their benzoates [17]. However,
it is difficult to observe bisignate CD Cotton effects due to the exciton coupling
ꢀ
between acetylene and benzoate chromophores, because the ꢀ–ꢀ transition of

Fig. 20. CD and UV spectra of benzoate (S)-(þ)-25 in EtOH
Fig. 21. A general methodology for determining the absolute configuration of acetylene alcohols by
combination of the Sonogashira reaction and the CD exciton chirality method

J. Naito et al.: Exciton CD of Phenylacetylene Alcohol Benzoates
433
Scheme 8
Fig. 22. CD and UV spectra of benzoate (S)-(þ)-26 in EtOH

434
J. Naito et al.
acetylene triple bond is located below 180 nm. To observe the ideal exciton split
Cotton effects necessary for the unambiguous determination of absolute configura-
tion, we have taken the strategy to convert the acetylene group to 4-methoxyphe-
nylacetylene moiety by the Sonogashira reaction (Fig. 21) [18, 19]. As reported
above, 4-methoxyphenylacetylene chromophore is ideal for generating the exciton
coupling CD Cotton effects together with 4-methoxybenzoate group leading to the
unambiguous determination of absolute configuration of chiral acetylene alcohols.
The method was applied to chiral acetylene alcohols as follows.
Enantiopure 1-octyn-3-ol ((S)-(ꢂ)-7), which had been previously prepared
by the MꢂNP acid method [13o], was converted to 4-methoxyphenylacetylene
alcohol (þ)-8 by the Sonogashira reaction; a mixture of (ꢂ)-7, 4-iodoanisole,
CuI, Et3N, and PdCl2(PPh3)2 was stirred overnight and then worked up yielding
(þ)-8 in a good yield (Scheme 8). Alcohol (þ)-8 was then esterified with
4-methoxybenzoic acid giving benzoate (þ)-26, the CD spectrum of which showed
bisignate Cotton effects of positive exciton chirality as expected: ꢁext ¼ 266.2 nm
(D" ¼ þ27.4 molꢂ1 dm3 cmꢂ1), 246.6 (ꢂ20.2), A ¼ þ47.6 (Fig. 22). From the data,
the absolute configuration of benzoate (þ)-26 was determined as (S), confirming
the previous absolute configurational assignment of alcohol (S)-(ꢂ)-7 by the
1H NMR anisotropy method using MꢂNP acid [13o].
As shown in Scheme 9, the same method was applied to 1-dodecyn-3-ol ((R)-(þ)-
9) [20], which was similarly converted to 4-methoxyphenylacetylene alcohol (ꢂ)-
10 in a good yield. Alcohol (ꢂ)-10 was benzoylated giving 4-methoxybenzoate
(ꢂ)-27, the CD spectrum of which showed exciton Cotton effects of negative
chirality leading to the (R) absolute configuration: ꢁext ¼ 266.0 nm (D" ¼
ꢂ27.9 molꢂ1 dm3 cmꢂ1), 246.2 (þ21.0), A ¼ ꢂ48.9 (Fig. 23). The (R) absolute
Scheme 9

Exciton CD of Phenylacetylene Alcohol Benzoates
435
Fig. 23. CD and UV spectra of benzoate (R)-(ꢂ)-27 in EtOH
configuration of benzoate (ꢂ)-27 determined by the CD exciton chirality method
thus agreed with the (R) absolute configuration of acetylene alcohol (þ)-9 assigned
1
by the H NMR anisotropy method using MꢂNP acid [20].
Conclusion
The absolute configurations of phenylacetylene alcohols were determined by observ-
ing intense bisignate CD Cotton effects due to the exciton coupling between phenyl-
acetylene and benzoate chromophores. As an extension of the results, we developed a
general methodology for determining the absolute configurations of chiral acetylene
alcohols having the HCꢁCCH(OH)-moiety by combination of the Sonogashira reac-
tion and the CD exciton chirality method. The absolute configurations determined by
the CD exciton chirality method agreed with those by the 1H NMR anisotropy method
using MꢂNP acid. Further applications of the Sonogashira=CD exciton chirality
method to other acetylene alcohols are now in progress.

436
J. Naito et al.
Experimental
IR spectra were obtained as neat, film on KBr, or KBr disks 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) spectrometer. 13C NMR spectra were obtained on a Jeol JNM-LA400 (100MHz) and=or
a Jeol JNM-LA600 (150MHz) spectrometer. All NMR data are reported in ppm (ꢄ) downfield from
TMS. Optical rotations [ꢂ]D were measured on a Jasco DIP-1000 spectropolarimeter. Silica gel 60 F254
precoated plates on glass from Merck Ltd. were used for thinlayer chromatography (TLC). HPLC
separation was performed using prepacked glass columns (22ꢄ300 mm, or 25ꢄ400 mm) of silica gel
(particle size 5–10ꢅm) from Kusano Co., Ltd. The purities of the title compounds were shown to be
1
ꢆ99% by H NMR, TLC, HPLC, and=or elemental analyses, which matched the calculated values
within experimental errors.
1-(4-Methoxyphenyl)-2,2-dibromoethylene (12, C9H8Br2O)
To a mixture of 5.72g PPh3 (21.8 mmol), 3.63g CBr4 (10.9 mmol) in 20 cm3 of CH2Cl2 was added
dropwise at room temperature 0.742 g of 4-methoxybenzaldehyde (5.45 mmol). After being stirred for
10min at room temperature, the mixture was treated with aqueous NaHCO3 solution and stirred for
10min. The mixture was extracted with EtOAc, and the organic layer was filtered with Celite, washed
with brine, and evaporated under reduced pressure. The residue was subjected to a short column
chromatography on silica gel (n-hexane=EtOAc¼ 4=1) giving 1.78 g 12 (99%): colorless solid; mp
34ꢇC; IR (KBr): ꢆꢀ¼ 3285, 2940, 2838, 1578, 1504, 1412, 1334, 1237, 1129 cmꢂ1
;
1H NMR
(400 MHz, CDCl3): ꢄ ¼ 3.82 (s, 3H), 6.89 (d, J ¼ 8.7 Hz, 2H), 7.41 (s, 1H), 7.51 (d, J ¼ 8.7Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3): ꢄ ¼ 55.3, 87.3, 113.8, 127.8, 129.9, 136.3, 159.6 ppm.
4-(4-Methoxyphenyl)-3-butyn-2-ol (4, C11H12O2)
To a solution of 1.00 g 12 (3.43 mmol) in 10cm3 of dried THF cooled at ꢂ78ꢇC, was added a
solution of n-BuLi (1.54 M hexane solution, 5.34cm3, 8.23mmol) dropwise. After stirring for 15min
at ꢂ78ꢇC, 1.00 g of acetaldehyde (22.7 mmol) was added, and the mixture was stirred at room
temperature for 20min. Aqueous NH4Cl solution was added at 0ꢇC, and the mixture was extracted
with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and evaporated
under reduced pressure. The residue was subjected to a short column chromatography on silica gel
(n-hexane=EtOAc ¼ 2=1) giving 0.475 g 4 (79%): colorless solid; mp 46ꢇC; IR (KBr): ꢆꢀ¼ 3365,
2980, 2934, 2838, 1607, 1510, 1290, 1250, 1174, 1106, 1031, 833 cmꢂ1 1H NMR (400MHz,
;
CDCl3): ꢄ ¼ 1.54 (d, J ¼ 6.3Hz, 3H), 2.04 (d, J ¼ 5.2 Hz, 1H), 3.80 (s, 3H), 4.74 (qd, J ¼ 6.3,
5.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): ꢄ ¼ 22.4, 55.2, 58.9, 83.9, 89.6, 113.9, 114.6,
133.1, 159.6ppm.
3-(3,4,5-Trimethoxyphenyl)propynal (14, C12H12O4)
A mixture of 0.666 g of 3-(3,4,5-trimethoxyphenyl)propynol (13, 3.00 mmol) and 1.35g of pyridinium
dichlorochromate (PDC, 3.60 mmol) in 30cm3 CH2Cl2 was stirred at room temperature for 1 h. After
addition of aqueous Na2SO3, the mixture was evaporated under reduced pressure. The residue was
subjected to a short column chromatography on silica gel (n-hexane=EtOAc¼ 2=1) giving 0.427 g 14
(65%): colorless crystals; mp 92ꢇC; IR (KBr): ꢆꢀ¼ 2981, 2945, 2863, 2837, 2186, 1666, 1578, 1498,
1
1415, 1345, 1247, 1120, 1059, 1020, 996, 869, 831 cmꢂ1; H NMR (400MHz, CDCl3): ꢄ ¼ 3.88 (s,
6H), 3.90 (s, 3H), 6.86 (s, 2H), 9.40 (s, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 56.2, 61.0, 88.0,
95.7, 110.6, 113.9, 141.5, 153.2, 176.6 ppm.

Exciton CD of Phenylacetylene Alcohol Benzoates
437
4-(3,4,5-Trimethoxyphenyl)-3-butyn-2-ol (5, C13H16O4)
To a solution of 0.220 g 14 (1.00 mmol) in 10 cm3 of dried THF cooled at 0ꢇC, was added a solution
of MeMgBr (1.4M in THF, 1.00 cm3, 1.4 mmol) dropwise, and the mixture was stirred at room
temperature for 1 h. After addition of aqueous saturated NH4Cl, the mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over anhydrous MgSO4, and evaporated under re-
duced pressure. The residue was subjected to a column chromatography on silica gel (n-hexane=
EtOAc¼ 2=1) giving 0.225 g 5 (95%): colorless crystals; mp 74.5ꢇC; IR (KBr): ꢆꢀ¼ 3445, 2981,
1
2936, 2840, 1579, 1505, 1452, 1411, 1236, 1129cmꢂ1; H NMR (400MHz, CDCl3): ꢄ ¼ 1.56 (d,
J ¼ 6.6 Hz, 3H), 2.31 (d, J ¼ 4.9 Hz, 1H), 3.84 (s, 6H), 3.85 (s, 3H), 4.76 (qd, J ¼ 6.6, 4.9 Hz, 1H), 6.66
(s, 2H) ppm; 13C NMR (100 MHz, CDCl3): ꢄ ¼ 24.3, 56.0, 58.7, 60.9, 83.8, 90.0, 108.8, 117.5, 138.7,
152.9ppm.
1-Phenyl-3-(3,4,5-trimethoxyphenyl)propynol (6, C18H18O4)
To a solution of 0.050g 14 (0.28 mmol) in 3 cm3 of dried THF cooled at 0ꢇC, was added a solution of
PhMgBr (1.0M in THF, 0.5cm3, 0.5 mmol) dropwise, and the mixture was stirred at room temperature
for 1 h. After addition of aqueous saturated NH4Cl, the mixture was extracted with EtOAc. The organic
layer was washed with brine, dried over anhydrous MgSO4, and evaporated under reduced pressure.
The residue was subjected to a column chromatography on silica gel (n-hexane=EtOAc¼ 2=1) giving
0.061 g 6 (84%): colorless oil; IR (neat): ꢆꢀ¼ 3444, 2940, 2838, 2190, 1579, 1504, 1452, 1412, 1237,
1
1128, 1001, 834, 700 cmꢂ1; H NMR (400MHz, CDCl3): ꢄ ¼ 2.31 (d, J ¼ 5.9 Hz, 1H), 3.85 (s, 6H),
3.85 (s, 3H), 5.70 (d, J ¼ 5.9 Hz, 1H), 6.71 (s, 2H), 7.34–7.46 (m, 3H), 7.60–7.64 (m, 2H) ppm;
13C NMR (100 MHz, CDCl3): ꢄ ¼ 56.1, 61.0, 65.1, 86.6, 87.7, 108.9, 117.3, 126.7, 128.5, 128.7, 139.0,
140.6, 153.0 ppm.
Enantioresolution of Racemic Phenylacetylene Alcohols 4–6 as CSDP Acid Esters
A mixture of 0.340 g (ꢅ)-4 (1.93 mmol), 1.00 g CSDP acid (2.32 mmol), 0.556 g DCC (2.70 mmol),
and 0.047 g DMAP (0.39 mmol) in 10 cm3 CH2Cl2 was stirred at room temperature overnight. After
addition of 0.3 cm3 of water, the mixture was stirred for 1 h, diluted with EtOAc, and filtered with
Celite, which was washed with EtOAc. The organic layer was evaporated under reduced pressure, and
the residue was subjected to a short column chromatography on silica gel (n-hexane=EtOAc¼ 3=1).
The crude diastereomeric esters were separated by HPLC on silica gel (25ꢄ300 mm column,
n-hexane=EtOAc ¼ 3=1) giving 0.554 g of the first-eluted ester 15a (49%) and 0.530 g of the second-
eluted one 15b (46%) (Table 1).
4-(4-Methoxyphenyl)-3-butyn-2-ol CSDP ester ((S)-(ꢂ)-15a, C29H29Cl2NO6S)
28
Amorphous solid; ½ꢂꢈD ¼ ꢂ99.8ꢇcm3 gꢂ1 dmꢂ1 (c ¼ 1.22, CHCl3); IR (KBr): ꢆꢀ¼ 2963, 1728, 1686,
1606, 1510, 1337, 1292, 1247, 1169, 1142, 1091, 1022, 834, 762cmꢂ1; 1H NMR (400MHz, CDCl3):
ꢄ ¼ 0.96 (s, 3H), 1.21 (s, 3H), 1.30–1.41 (m, 2H), 1.65 (d, J ¼ 6.6Hz, 3H), 1.87–1.95 (m, 3H),
2.13 (br s, 1H), 2.47 (br d, J ¼ 12.7Hz, 1H), 3.37 (d, J ¼ 13.7Hz, 1H), 3.43 (d, J ¼ 13.7Hz, 1H), 3.80
(s, 3H), 4.07 (br dd, J ¼ 12.7, 5.2Hz, 1H), 5.84 (q, J ¼ 6.6 Hz, 1H), 6.83 (d, J ¼ 8.8 Hz, 2H), 7.40
(d, J ¼ 8.8 Hz, 2H), 7.53 (s, 1H), 8.13 (s, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 20.0, 20.6,
21.5, 26.4, 33.1, 37.5, 44.7, 47.7, 48.4, 53.0, 55.2, 62.8, 65.7, 85.4, 85.4, 113.9, 114.0, 128.5, 131.1,
131.6, 133.4, 134.8, 134.8, 136.8, 159.9, 162.4, 165.2ppm; UV (EtOH): ꢁmax(") ¼ 254.0 (33300),
206.8 (52000) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 264.8 (ꢂ6.1), 244.4 (ꢂ5.5), 213.2
(þ16.5) nm (molꢂ1 dm3 cmꢂ1).

438
J. Naito et al.
4-(4-Methoxyphenyl)-3-butyn-2-ol CSDP ester ((R)-(ꢂ)-15b, C29H29Cl2NO6S)
30
Amorphous solid; ½ꢂꢈD ¼ ꢂ48.2ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.10, CHCl3); IR (KBr): ꢆꢀ¼ 2960, 1730, 1686,
1607, 1510, 1337, 1296, 1248, 1170, 1142, 1061, 1025, 834, 761cmꢂ1; 1H NMR (400MHz, CDCl3):
ꢄ ¼ 0.91 (s, 3H), 1.20 (s, 3H), 1.31–1.36 (m, 2H), 1.68 (d, J ¼ 6.6 Hz, 3H), 1.83–1.90 (m, 3H), 2.14 (br
dd, J ¼ 12.6, 7.8 Hz, 1H), 2.50 (br d, J ¼ 12.6 Hz, 1H), 3.34 (d, J ¼ 13.8 Hz, 1H), 3.39 (d, J ¼ 13.8Hz,
1H), 3.80 (s, 3H), 4.07 (br dd, J ¼ 5.9, 5.9 Hz, 1H), 5.85 (q, J ¼ 6.6 Hz, 1H), 6.83 (d, J ¼ 9.0 Hz, 2H),
7.39 (d, J ¼ 9.0 Hz, 2H), 7.51 (s, 1H), 8.15 (s, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 19.9, 20.7,
21.6, 26.4, 32.9, 37.6, 44.7, 47.7, 48.5, 52.8, 55.2, 62.8, 65.6, 85.2, 85.5, 113.8, 114.2, 128.2, 130.8,
131.8, 133.3, 134.7, 134.9, 136.8, 159.8, 162.3, 165.1ppm; UV (EtOH): ꢁmax(") ¼ 253.4 (33400),
206.4 (52800) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 249.4 (ꢂ12.6), 220.8 (þ3.7), 215.6
(ꢂ2.3), 212.8 (ꢂ2.0), 204.0 (þ19.7), 201.6 (þ23.4) nm (molꢂ1 dm3 cmꢂ1).
4-(4-Methoxyphenyl)-3-butyn-2-ol ((S)-(ꢂ)-4, C11H12O2)
A mixture of 0.292 g (S)-(ꢂ)-15a (0.494mmol) and 0.500g K2CO3 (excess) in 6 cm3 MeOH
was stirred at room temperature overnight. After filtration with Celite, the organic layer was evapo-
rated under reduced pressure, and the residue was subjected to a short column chromatography
on silica gel (n-hexane=EtOAc¼ 2=1). The crude alcohol was further purified by HPLC on silica
gel (25ꢄ300 mm column, n-hexane=EtOAc¼ 4=1) giving 0.072g (S)-(ꢂ)-4 (83%): colorless oil;
26
½ꢂꢈD ¼ ꢂ29.6ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.44, CHCl3); IR (neat): ꢆꢀ¼ 3365, 2980, 2934, 2838, 1607, 1510,
1
1290, 1250, 1174, 1106, 1031, 833 cmꢂ1; H NMR (400MHz, CDCl3): ꢄ ¼ 1.54 (d, J ¼ 6.3 Hz, 3H),
2.04 (d, J ¼ 5.2 Hz, 1H), 3.80 (s, 3H), 4.74 (qd, J ¼ 6.3, 5.2Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3): ꢄ ¼ 22.4, 55.2, 58.9, 83.9, 89.6, 113.9, 114.6, 133.1, 159.6ppm; UV (EtOH): ꢁmax(") ¼ 252.0
(23700), 202.4 (28500) nm (molꢂ1 dm3 cmꢂ1).
Enantioresolution of Racemic Acetylene Alcohols 5 by the CSDP Acid Method
In a similar way, 0.150 g (ꢅ)-5 were converted to CSDP esters, which were separated by HPLC on
silica gel (25ꢄ300 mm column, n-hexane=EtOAc¼ 3=1) giving 0.179g of the first-eluted ester 16a
(43%) and 0.168 g of the second-eluted one 16b (41%) (Table 1).
4-(3,4,5-Trimethoxyphenyl)-3-butyn-2-ol CSDP ester ((S)-(ꢂ)-16a, C31H33Cl2NO8S)
32
Amorphous solid; ½ꢂꢈD ¼ ꢂ93.7ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 0.970, CHCl3); IR (KBr): ꢆꢀ¼ 2941, 1730, 1687,
1
1579, 1505, 1412, 1335, 1298, 1242, 1130, 1092, 910, 732, 539 cmꢂ1; H NMR (400MHz, CDCl3):
ꢄ ¼ 0.98 (s, 3H), 1.22 (s, 3H), 1.31–1.44 (m, 2H), 1.67 (d, J ¼ 6.6 Hz, 3H), 1.90–1.96 (m, 3H), 2.15
(br s, 1H), 2.46 (br d, J ¼ 12.7 Hz, 1H), 3.38 (d, J ¼ 13.9Hz, 1H), 3.44 (d, J ¼ 13.9Hz, 1H), 4.07 (dd,
J ¼ 12.7, 7.6 Hz, 1H), 5.84 (q, J ¼ 6.6 Hz, 1H), 6.70 (s, 2H), 7.54 (s, 1H), 8.14 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): ꢄ ¼ 20.0, 20.7, 21.5, 26.4, 33.1, 37.6, 44.8, 47.7, 48.4, 53.0, 56.2, 60.9, 62.6, 65.7,
85.4, 85.8, 109.1, 117.0, 128.4, 131.1, 131.6, 134.9, 134.9, 136.9, 139.2, 153.0, 162.4, 165.2ppm; UV
(EtOH): ꢁmax(") ¼ 256.6 (23600), 216.6 (77200) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 246.2
(ꢂ9.20), 221.6 (þ35.0), 209.0 (ꢂ19.6) nm (molꢂ1 dm3 cmꢂ1).
4-(3,4,5-Trimethoxyphenyl)-3-butyn-2-ol CSDP ester ((R)-(ꢂ)-16b, C31H33Cl2NO8S)
26
Colorless crystals; mp 157ꢇC; ½ꢂꢈD ¼ ꢂ52.6ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.05, CHCl3); IR (KBr): ꢆꢀ¼ 2941,
1
1731, 1686, 1578, 1505, 1335, 1298, 1241, 1129, 1091, 731 cmꢂ1; H NMR (400 MHz, CDCl3):
ꢄ ¼ 0.92 (s, 3H), 1.21 (s, 3H), 1.33–1.41 (m, 2H), 1.69 (d, J ¼ 6.6Hz, 3H), 1.87–1.92 (m, 3H),
2.15 (br dd, J ¼ 12.6, 7.8 Hz, 1H), 2.51 (br d, J ¼ 12.6Hz, 1H), 3.37 (d, J ¼ 13.9Hz, 1H), 3.38
(d, J ¼ 13.9Hz, 1H), 3.85 (s, 6H), 3.85 (s, 3H), 4.07 (br s, 1H), 5.85 (q, J ¼ 6.6 Hz, 1H), 6.70 (s, 2H),

Exciton CD of Phenylacetylene Alcohol Benzoates
439
7.52 (s, 1H), 8.16 (s, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 20.0, 20.8, 21.5, 26.4, 32.9, 37.7,
44.7, 47.7, 48.5, 52.9, 56.2, 60.9, 62.6, 65.7, 85.3, 85.9, 109.1, 117.1, 128.0, 130.9, 131.8, 134.8, 134.9,
137.0, 139.1, 153.0, 162.3, 165.1 ppm; UV (20% dioxane=EtOH): ꢁmax(") ¼ 256.2 (24400), 217.0
(79100) nm (molꢂ1 dm3 cmꢂ1); CD (20% dioxane=EtOH): ꢁext(D") ¼ 250.2 (ꢂ10.8), 222.6 (ꢂ29.9),
211.0 (þ38.8) nm (molꢂ1 dm3 cmꢂ1).
4-(3,4,5-Trimethoxyphenyl)-3-butyn-2-ol ((S)-(ꢂ)-5, C13H11O)
Similarly 0.165 g (S)-(ꢂ)-16a were treated with K2CO3 in MeOH yielding 0.050 g (S)-(ꢂ)-5 (84%):
25
colorless oil; ½ꢂꢈD ¼ ꢂ21.0ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.00, CHCl3); IR (neat): ꢆꢀ¼ 2981, 2945, 2863, 2837,
2186, 1666, 1578, 1498, 1415, 1345, 1247, 1120, 1059, 1020, 996, 869, 831cmꢂ1 1H NMR
;
(400 MHz, CDCl3): ꢄ ¼ 3.88 (s, 6H), 3.90 (s, 3H), 6.86 (s, 2H), 9.40 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3): ꢄ ¼ 56.2, 61.0, 88.0, 95.7, 110.6, 113.9, 141.5, 153.2, 176.6ppm; UV (EtOH):
ꢁ
max(") ¼ 265.2 (15700), 215.8 (40500) nm (molꢂ1 dm3 cmꢂ1).
Enantioresolution of Racemic Acetylene Alcohols 6 by the CSDP Acid Method
Similarly 0.200 g (ꢅ)-6 were converted to CSDP esters, which were separated by HPLC on silica gel
(25ꢄ300 mm column, n-hexane=EtOAc¼ 2=1) giving 0.200g of the first-eluted ester 17a (42%) and
0.209 g of the second-eluted one 17b (44%) (Table 1).
1-Phenyl-3-(3,4,5-trimethoxyphenyl)propynol CSDP ester ((S)-(ꢂ)-17a, C36H35Cl2NO8S)
31
Amorphous solid; ½ꢂꢈD ¼ ꢂ53.1ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 0.962, CHCl3); IR (KBr): ꢆꢀ¼ 2961, 1731, 1687,
1
1579, 1504, 1336, 1298, 1239, 1130, 757 cmꢂ1; H NMR (400MHz, CDCl3): ꢄ ¼ 0.95 (s, 3H), 1.17
(s, 3H), 1.30–1.34 (m, 2H), 1.85–1.91 (m, 3H), 2.11 (br dd, J ¼ 13.5, 7.6 Hz, 1H), 2.48 (br d,
13.5Hz, 1H), 3.31 (d, J ¼ 13.8Hz, 1H), 3.40 (d, J ¼ 13.8Hz, 1H), 3.85 (s, 6H), 3.85 (br s, 1H), 3.85
(s, 3H), 6.73 (s, 2H), 6.80 (s, 1H), 7.35–7.47 (m, 3H), 7.52 (s, 1H), 7.65 (dd, J ¼ 7.3, 1.3 Hz, 2H), 8.15
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3): ꢄ ¼ 20.0, 20.7, 26.4, 32.9, 37.6, 44.7, 47.7, 48.4, 53.0, 56.2,
60.9, 65.5, 67.7, 83.8, 88.0, 109.2, 116.8, 127.4, 128.0, 128.1, 128.7, 129.1, 131.1, 131.9, 134.9,
136.2, 137.1, 139.3, 153.0, 162.5, 165.0 ppm; UV (EtOH): ꢁmax(") ¼ 256.8 (21300), 216.8
(70500) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 255.0 (ꢂ5.6), 224.2 (ꢂ3.2), 208.0 (þ10.8) nm
(molꢂ1 dm3 cmꢂ1).
1-Phenyl-3-(3,4,5-trimethoxyphenyl)propynol CSDP ester ((R)-(ꢂ)-17b, C36H35Cl2NO8S)
31
Amorphous solid; ½ꢂꢈD ¼ ꢂ58.9ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 0.822, CHCl3); IR (KBr): ꢆꢀ¼ 2961, 1731, 1686,
1
1579, 1504, 1336, 1299, 1240, 1130, 758 cmꢂ1; H NMR (400MHz, CDCl3): ꢄ ¼ 0.92 (s, 3H), 1.22
(s, 3H), 1.31–1.36 (m, 2H), 1.85–1.96 (m, 3H), 2.11 (br dd, J ¼ 13.2, 7.6Hz, 1H), 2.48 (br d, J ¼
13.2Hz, 1H), 3.34 (d, J ¼ 13.8Hz, 1H), 3.38 (d, J ¼ 13.8Hz, 1H), 3.85 (s, 6H), 3.85 (s, 3H), 3.93
(br s, 1H), 6.73 (s, 2H), 6.82 (s, 1H), 7.37–7.47 (m, 3H), 7.52 (s, 1H), 7.65 (dd, J ¼ 8.1, 1.4Hz, 2H),
8.10 (s, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 20.0, 20.8, 26.4, 32.9, 37.7, 44.7, 47.7, 48.5,
52.9, 56.2, 61.0, 65.6, 67.7, 84.0, 87.8, 109.2, 117.0, 128.0, 128.1, 128.8, 129.2, 130.9, 131.9,
134.9, 134.9, 136.3, 137.0, 139.3, 153.0, 162.4, 165.0ppm; UV (EtOH): ꢁmax(") ¼ 256.8 (17000),
216.8 (54600) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 255.0 (ꢂ7.2), 224.2 (ꢂ4.1), 208.0
(þ13.9) nm (molꢂ1 dm3 cmꢂ1).
1-Phenyl-3-(3,4,5-trimethoxyphenyl)propynol ((S)-(þ)-6, C18H18O4)
Similarly 0.502 g (S)-(ꢂ)-17a were treated with K2CO3 in MeOH yielding 0.182 g (S)-(ꢂ)-5
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(87%): colorless solid; ½ꢂꢈD ¼ þ2.8ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.29, CHCl3); IR (KBr): ꢆꢀ¼ 3444, 2940,

440
J. Naito et al.
2838, 2190, 1579, 1504, 1452, 1412, 1237, 1128, 1001, 834, 700cmꢂ1; 1H NMR (400MHz, CDCl3):
ꢄ ¼ 2.31 (d, J ¼ 5.9 Hz, 1H), 3.85 (s, 6H), 3.85 (s, 3H), 5.70 (d, J ¼ 5.9 Hz, 1H), 6.71 (s, 2H), 7.34–
7.46 (m, 3H), 7.60–7.64 (m, 2H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 56.1, 61.0, 65.1, 86.6, 87.7,
108.9, 117.3, 126.7, 128.5, 128.7, 139.0, 140.6, 153.0ppm; UV (EtOH): ꢁmax(") ¼ 262.6 (20200),
216.8 (42000) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 296.4 (ꢂ0.5), 226.2 (ꢂ1.8) nm
(molꢂ1 dm3 cmꢂ1).
4-(4-Methoxyphenyl)-3-butyn-2-ol MꢂNP ester ((R,S)-(þ)-18, C25H24O4)
A mixture of 0.020 g (ꢂ)-4 (0.11 mmol), 0.036 g (R)-MꢂNP acid (0.16 mmol), 0.046 g DCC
(0.22 mmol), 0.014 g DMAP (0.11 mmol), and 0.005g of 10-camphorsulfonic acid (CSA, 0.02 mmol)
in 1 cm3 CH2Cl2 was stirred at room temperature overnight. After addition of 0.1 cm3 of water, the
mixture was stirred for 1 h, diluted with EtOAc, and filtered with Celite, which was washed with
EtOAc. The organic layer was evaporated under reduced pressure, and the residue was purified by
HPLC on silica gel (n-hexane=EtOAc¼ 3=1) giving 0.037 g (R,S)-(þ)-18 (86%): colorless syrup;
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½ꢂꢈD ¼ þ15.9ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 0.822, CHCl3); IR (neat): ꢆꢀ¼ 3051, 2989, 2937, 2835, 2229,
1738, 1606, 1510, 1291, 1250, 1174, 1135, 1107, 1025, 834, 781cmꢂ1; 1H NMR (400MHz, CDCl3):
ꢄ ¼ 1.25 (d, J ¼ 6.8 Hz, 3H), 2.03 (s, 3H), 3.11 (s, 3H), 3.80 (s, 3H), 5.71 (q, J ¼ 6.8 Hz, 1H), 6.81 (d,
J ¼ 8.9 Hz, 2H), 7.30 (d, J ¼ 8.9 Hz, 2H), 7.40–7.70 (m, 3H), 7.62 (dd, J ¼ 7.3, 1.0 Hz, 1H), 7.83 (d,
J ¼ 7.8 Hz, 1H), 7.84 (d, J ¼ 9.5 Hz, 1H), 8.42 (m, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 21.0,
21.7, 51.0, 55.3, 61.9, 81.6, 84.8, 85.6, 113.8, 114.3, 124.6, 125.3, 125.6, 125.8, 126.4, 128.6, 129.5,
131.3, 133.3, 134.1, 134.8, 159.8, 173.1ppm; UV (EtOH): ꢁmax(") ¼ 292.2 (6400), 281.2 (10200),
256.4 (26800), 224.2 (75000), 207.6 (48400) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 291.0
(þ4.0), 281.0 (þ6.6), 271.2 (þ5.7), 256.0 (ꢂ1.8), 228.2 (ꢂ3.2), 214.0 (þ11.5), 208.8 (þ12.3) nm
(molꢂ1 dm3 cmꢂ1).
4-(4-Methoxyphenyl)-3-butyn-2-ol MꢂNP ester ((S,S)-(ꢂ)-18, C25H24O4)
Similarly 0.017 g (ꢂ)-4 were esterified with 0.032 g (S)-MꢂNP acid yielding 0.037 g of (S,S)-(ꢂ)-18
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(97%): colorless syrup; ½ꢂꢈD ¼ ꢂ31.5ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.42, CHCl3); IR (neat): ꢆꢀ¼ 3053, 2987,
2936, 2836, 1734, 1606, 1510, 1250, 1134, 1107, 1026, 834, 781cmꢂ1; 1H NMR (400MHz, CDCl3):
ꢄ ¼ 1.46 (d, J ¼ 6.8 Hz, 3H), 2.01 (s, 3H), 3.15 (s, 3H), 3.80 (s, 3H), 5.71 (q, J ¼ 6.8 Hz, 1H), 6.78 (d,
J ¼ 9.0 Hz, 2H), 7.15 (d, J ¼ 9.0 Hz, 2H), 7.39–7.47 (m, 3H), 7.64 (dd, J ¼ 7.1, 1.0 Hz, 1H), 7.81–7.86
(m, 2H), 8.39 (m, 1H) ppm; 13C NMR (100MHz, CDCl3): ꢄ ¼ 21.1, 22.1, 51.2, 55.2, 62.0, 81.8, 84.7,
85.4, 113.7, 114.3, 124.7, 125.2, 125.6, 125.6, 126.3, 128.7, 129.5, 131.2, 133.2, 134.1, 135.1, 159.7,
173.0ppm; UV (EtOH): ꢁmax(") ¼ 292.4 (6400), 281.2 (9900), 256.2 (26200), 224.2 (74600), 207.2
(48200) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼ 281.8 (þ6.3), 256.6 (ꢂ8.2), 226.0 (þ6.2),
215.6 (ꢂ7.7), 204.4 (þ9.1) nm (molꢂ1 dm3 cmꢂ1).
4-(3,4,5-Trimethoxyphenyl)-3-butyn-2-ol MꢂNP ester ((R,S)-(þ)-19, C27H28O6)
Similarly 0.014 g (ꢂ)-5 were esterified with 0.019 g (R)-MꢂNP acid yielding 0.030 g (R,S)-(þ)-19
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(99%): colorless crystals; mp 159ꢇC; ½ꢂꢈD ¼ þ9.5ꢇcm3 g ꢂ1 dmꢂ1 (c ¼ 1.41, CHCl3); IR (KBr):
ꢆꢀ¼ 2994, 2939, 2831, 1740, 1578, 1505, 1452, 1412, 1237, 1130 cmꢂ1; 1H NMR (400MHz, CDCl3):
ꢄ ¼ 1.28 (d, J ¼ 6.8 Hz, 3H), 2.04 (s, 3H), 3.10 (s, 3H), 3.82 (s, 6H), 3.85 (s, 3H), 5.71 (q, J ¼ 6.8 Hz,
1H), 6.60 (s, 2H), 7.40–7.48 (m, 3H), 7.63 (dd, J ¼ 7.3, 1.0 Hz, 1H), 7.83–7.87 (m, 2H), 8.41 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3): ꢄ ¼ 20.9, 21.7, 51.0, 56.1, 60.9, 61.7, 81.6, 84.8, 85.9, 109.1,
117.2, 124.6, 125.2, 125.6, 125.8, 126.4, 128.6, 129.5, 131.3, 134.0, 134.7, 139.0, 152.9, 173.1ppm;
UV (EtOH): ꢁmax(") ¼ 262.6 (17900), 220.6 (77000) nm (molꢂ1 dm3 cmꢂ1); CD (EtOH): ꢁext(D") ¼
280.8 (þ4.5), 257.0 (ꢂ1.1), 219.6 (þ7.6) nm (molꢂ1 dm3 cmꢂ1).