Synthesis and analytical properties of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid

Article abstract of DOI:10.1016/S0957-4166(03)00348-3

2-Methoxy-2-(9-phenanthryl)propionic acid was synthesized as a novel chiral resolving agent. The absolute configuration of (+)-2-methoxy-2-(9-phenanthryl)propionic acid was determined to be S by using X-ray structural analysis of the (1R,2S,5R)-menthyl ester. In the crystal, the methoxyl and carbonyl groups of the ester are in a syn-periplanar position. The syn-periplanar conformations of (1R,2S,5R)-menthyl esters were also observed by the NMR analyses in CDCl₃. The utility of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid was exemplified by the resolution of (±)-3-octanol.

Full text of DOI:10.1016/S0957-4166(03)00348-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1593–1597
Synthesis and analytical properties of
(S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid
Akio Ichikawa,a,* Hiroshi Onob and Nobuyuki Haradac,*
aNational Institute of Agrobiological Sciences, 1-2 Owashi, Tsukuba, Ibaraki 305-8634, Japan
bNational Food Research Institute, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan
cInstitute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba,
Sendai 980-8577, Japan
Received 23 January 2003; accepted 22 April 2003
Abstract—2-Methoxy-2-(9-phenanthryl)propionic acid was synthesized as a novel chiral resolving agent. The absolute configura-
tion of (+)-2-methoxy-2-(9-phenanthryl)propionic acid was determined to be S by using X-ray structural analysis of the
(1R,2S,5R)-menthyl ester. In the crystal, the methoxyl and carbonyl groups of the ester are in a syn-periplanar position. The
syn-periplanar conformations of (1R,2S,5R)-menthyl esters were also observed by the NMR analyses in CDCl3. The utility of
(S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid was exemplified by the resolution of ( )-3-octanol. © 2003 Elsevier Science
Ltd. All rights reserved.
Mosher’s
2-methoxy-2-(trifluoromethyl)phenylacetic
of acid 3 were corroborated using (1R,2S,5R)-menthyl
esters. Finally, acid 3 was applied to the enantioresolu-
tion of ( )-3-octanol.
acid (MTPA acid) 1 is widely used to determine the
absolute configurations of secondary alcohols1,2 (Fig.
1). We have been studying the use of 2-methoxy-2-(1-
naphthyl)propionic acid (MaNP acid) 23–7 for the stereo-
chemical studies of biologically active natural
products. Acid 2 is a non-racemizable chiral acid that is
useful for preparing pure enantiomers3–7 and for deter-
mining the absolute configuration of each enantiomer.4
Herein we report the synthesis and absolute configura-
tion of 2-methoxy-2-(9-phenanthryl)propionic acid 3,
which possesses a large aryl substituent 9-phenanthryl
group (Fig. 1). The spectral and separation properties
( )-Methyl 2-hydroxy-2-(9-phenanthryl)propionate ( )-
4 was synthesized by the Grignard reaction of 9-
phenanthrylmagnesium bromide and methyl pyruvate
in THF (Scheme 1). The hydroxyl group of ( )-4 was
methylated with NaH and CH3I in THF to give ( )-
methyl 2-methoxy-2-(9-phenanthryl)propionate ( )-5.
Alkaline hydrolysis (NaOCH3/methanol) of ( )-5 gave
( )-2-methoxy-2-(9-phenanthryl)propionic acid ( )-3.
The racemic acid ( )-3 was then condensed with
(1R,2S,5R)-(−)-menthol using N,N%-dicyclohexylcarbo-
diimide (DCC) and 4-(N,N-dimethylamino)pyridine
(DMAP) in CH2Cl2. The crude product was purified by
preparative LC (silica gel, hexane/EtOAc 19:1) to give
(+)-6a {[h]3D0 +2.7 (c 1.45, chloroform)} as the first-
eluted ester and (−)-6b {[h]3D1 −46 (c 1.21, ethanol)} as
the second-eluted in 43 and 37% yield, respectively.
Alkaline hydrolysis (KOH/aq. ethanol) of ester (+)-6a
gave enantio-pure (+)-3 {[h]3D0 +101 (c 0.982, ethanol)}.
Therefore, (+)-6a and (−)-6b are (1R,2S,5R)-menthyl
esters of (+)- and (−)-3, respectively. Acid (+)-3 was
methylated with trimethylsilyldiazomethane affording
methyl ester (+)-5 {[h]D29 +86 (c 0.97, ethanol)}. Acid
(−)-3 {[h]2D8 −100 (c 0.914, ethanol)}, and methyl ester
(−)-5 {[h]2D8 −86 (c 0.90, ethanol)} were also prepared
from ester (−)-6b.
Figure 1. The structures of chiral resolving agents.
* Corresponding authors. Tel.: +81-29-838-6267; fax: +81-29-838-
6028.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00348-3

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A. Ichikawa et al. / Tetrahedron: Asymmetry 14 (2003) 1593–1597
Scheme 1. Synthesis and resolution of 2-methoxy-2-(9-phenanthryl)propionic acid 3.
1
ƒ(O2ꢁC19ꢁC18ꢁO3)=11.8°. The crystalline structure
of ester (+)-6a suggests that 5- and 6-positions of
(1R,2S,5R)-menthyl group are located above aromatic
The H NMR signals of esters (+)-6a and (−)-6b (600
and 800 MHz, CDCl3) were assigned from DQF
COSY, HSQC, and HMBC spectra (Fig. 2). The Dl
(=l((−)-6b)−l((+)-6a)) values are shown in Figure 2.
The chemical shifts of esters (+)-6a and (−)-6b, and
their Dl values are close to those of the (S)- and
(R)-MaNP esters of (1R,2S,5R)-(−)-menthol,5,6 in spite
of the difference between the 9-phenanthryl and 1-
naphthyl groups. High field shifts were observed at the
6-b proton of ester (+)-6a (0.48 ppm), and at the
isopropyl group of ester (−)-6b (0.15, 0.18, 0.49 ppm).
Negative Dl values were observed at 2- and 3-positions,
and the isopropyl group. Conversely, positive Dl values
1
were observed at 5- and 6-positions (Fig. 2). The H
NMR spectra also revealed that esters (+)-6a and (−)-6b
are both >99.8% d.e.
Recently, Kitamura et al. discussed inter- and
intramolecular OH···OꢀC hydrogen bonds and the lim-
its of empirical NMR studies for determining the rela-
tive stereochemistry of aldols.8 They noted that X-ray
diffraction is the only reliable spectroscopic method.8
Although the MaNP esters of (1R,2S,5R)-(−)-menthol
are not crystalline, ester (+)-6a is readily crystallized
from ethyl acetate. Consequently, the relative stereo-
chemistry of ester (+)-6a was determined by X-ray
structural analysis (Fig. 3 and Table 1). The absolute
configuration of the acyl group was assigned as S,
because (1R,2S,5R)-(−)-menthol was used for ester (+)-
6a. Therefore, the absolute stereochemistry of acid (+)-
3 was determined to be S. The crystalline structure of
ester (+)-6a shows that hydrogen atom H22 and the
carbonyl group of ester (+)-6a are in a syn-periplanar
position: the dihedral angles ƒ(H22ꢁC22ꢁO1ꢁC19)=
6.6°; ƒ(C22ꢁO1ꢁC19ꢁO2)=−6.8°. The two oxygen
atoms of the methoxyl and carbonyl groups are also in
1
Figure 2. The H NMR chemical shift data and Dl values for
a
syn-periplanar position: the dihedral angle
(+)-6a and (−)-6b (800 MHz, CDCl3).

A. Ichikawa et al. / Tetrahedron: Asymmetry 14 (2003) 1593–1597
1595
Figure 4. The preferred conformation of (+)-6a and (S)-O-
methylmandelic acid ester.
Figure 3. The stereochemistry of ester (+)-6a determined by
X-ray crystallography.
Table 1. Crystallographic data for (+)-6a
Figure 5. The orientation of the 9-phenanthryl group in ester
(+)-6a.
Mol. formula
Crystal system
Space group
Z
C28H34O3
Monoclinic
P21
Esters (+)-6a and (−)-6b were remixed, and analyzed by
HPLC (Fig. 6). The separation factor (h value) was 1.64
in a SILICA SG80 column (4.6 ƒ×250 mm, hexane/
EtOAc, T0: solvent peak), and 1.16 in a CAPCELL-
PAK C18 MG column (4.6 ƒ×150 mm, methanol/water
97:3, T0: uracil). These separation factors (h=1.64 and
1.16) are equivalent to those for the enantioresolution
of rac-menthol using single-enantiomer 3.
2
,
a (A)
12.253(4)
9.973(4)
10.082(3)
1214.1(7)
99.74(3)
1.145
,
b (A)
,
c (A)
3
,
V (A )
i (°)
zcalcd
R
4.27
Rw
4.58
Finally, the utility of acid (S)-(+)-3 was exemplified by
the enantioresolution of ( )-3-octanol, both enan-
tiomers of which are known as the ant pheromones.10
Acid (S)-(+)-3 was condensed with ( )-3-octanol using
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro-
chloride (WSCI·HCl) and DMAP in CH2Cl2. The crude
product of diastereomeric esters was separated by
preparative LC (silica gel, hexane/EtOAc 47:3) to give
(+)-7a {38%, [h]3D1 +21 (c 0.44, ethanol)} and (+)-7b
{40%, [h]3D2 +59 (c 0.42, ethanol)}: the separation factor
h=1.57 with the SILICA SG80 column (Fig. 7). The
1H NMR chemical shift data of (+)-7a and (+)-7b are
shown in Figure 8 together with the Dl values, from
which the absolute configuration of the first-eluted frac-
tion (+)-7a was unambiguously determined as X=R.
(See Ref. 4 for the definition of Dl and the sector rule
for the assignment of absolute configuration.) There-
fore, the absolute configurations of these esters are
described as (S,R)-(+)-7a and (S,S)-(+)-7b, respectively.
The ester (S,S)-(+)-7b was treated with NaOCH3/
methanol to yield enantiopure (S)-(+)-3-octanol {81%,
[h]3D1 +9.7 (c 0.11, chloroform)}; this assignment of the
absolute configuration is consistent with the previous
one {Ref. 10, (S)-(+)-3-octanol: [h]2D2 +10.1 (c 0.82,
chloroform)}. Namely, the enantioresolution of alco-
hols using acid (S)-(+)-3 and the following determina-
tion of absolute configuration by the 1H NMR
anisotropy method are thus powerful.
rings X and Y (Fig. 3). These conformational features
in the crystal are consistent with those determined from
1
the H NMR analyses of ester (+)-6a in CDCl3 (Fig. 2).
We have already reported the syn-periplanar conforma-
tion of MaNP esters in CDCl3.3–7
The preferred conformation of O-methylmandelic acid
esters has been studied by Trost et al.,9 who reported
that in the O-methylmandelates, the methoxyl group
eclipses the ester carbonyl group. The esters of acid 3
have the structure and conformation similar to those of
O-methylmandelates as shown in Figure 4: (1) the
methyl group replaces the a hydrogen atom of O-
methylmandelate to prevent epimerization; (2) the 9-
phenanthryl group replaces the phenyl group to
1
enhance the H NMR anisotropy effect.
Conformer L, which was observed in the crystal,
explained the H NMR high field shifts observed at 5-
1
and 6-positions of the (1R,2S,5R)-menthyl group of
ester (+)-6a (Fig. 5). The repulsion between the 3%
methyl group and hydrogen atom Ha at the 10-position
of the 9-phenanthryl group is not crucial in conformer
L. By contrast, conformer M is not plausible because of
the repulsion between the 3% methyl group and hydro-
gen atom Hb at the 8-position (Fig. 5).
As discussed above, 2-methoxy-2-(9-phenanthryl)-
propionic acid 3 was synthesized as a novel chiral
resolving agent. The absolute configuration of (+)-3 was

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A. Ichikawa et al. / Tetrahedron: Asymmetry 14 (2003) 1593–1597
determined to be S via X-ray structural analysis of ester
(+)-6a. The large aryl substituent 9-phenanthryl group
contributed to the formation of the crystal. The crys-
talline structure of (+)-6a revealed that the two oxygen
atoms of the carbonyl and methoxyl groups are in the
syn-periplanar position. A similar conformation has
been proposed for MaNP esters, although the mecha-
nism is not clear.4,11 The syn-periplanar conformations
of the methoxyl and carbonyl groups were also sup-
ported by the NMR analyses of esters (+)-6a and (−)-6b
in CDCl3. Acid (S)-(+)-3 was used in the enantioresolu-
tion of ( )-3-octanol. The novel chiral carboxylic acid
(S)-(+)-3 could be used to prepare single-enantiomer
agrochemicals12 and pharmaceuticals, and for stereo-
chemical studies of natural products along with other
chiral resolving agents.
Figure 6. The HPLC separation of diastereomeric esters (+)-6a and (−)-6b (SILICA SG80, hexane/EtOAc 9:1, UV 300 nm,
h=1.64).
Figure 7. The HPLC separation of diastereomeric esters formed from ( )-3-octanol and (S)-(+)-3 (SILICA SG80, hexane/EtOAc
9:1, UV 300 nm, h=1.57).
1
Figure 8. The H NMR chemical shift data and Dl values for esters (+)-7a and (+)-7b (600 MHz, CDCl3).

A. Ichikawa et al. / Tetrahedron: Asymmetry 14 (2003) 1593–1597
1597
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