Conformational analysis of MαNP esters, powerful chiral resolution and 1H NMR anisotropy tools - aromatic geometry and solvent effects on Δδ values

FULL PAPER

DOI: 10.1002/ejoc.200600856

1

Conformational Analysis of MαNP Esters, Powerful Chiral Resolution and H

NMR Anisotropy Tools – Aromatic Geometry and Solvent Effects on ∆δ

Values

Yusuke Kasai,^[a]Akinori Sugio,^[a]Satoshi Sekiguchi,^[a]Shunsuke Kuwahara,^[a]

Takatoshi Matsumoto,^[a]Masataka Watanabe,^[a]Akio Ichikawa,^[b]and

Nobuyuki Harada*^[a][‡]

Keywords: Conformational analysis / ¹H NMR anisotropy effect / MαNP and related esters / Chirality / Aromatic geometry

and solvent effects

The MαNP acid method is very powerful for the preparation

of enantiopure alcohols by resolution and the simultaneous

determination of their absolute configurations by the ¹H

NMR anisotropy effect, where the syn-syn conformation is

taken as the preferred conformation of MαNP esters. How-

ever, the syn-syn conformation of MαNP esters looks un-

stable, because two electronegative oxygen atoms (CH₃O

and C=O) are close to each other. To solve the problem of

why the MαNP esters take such a syn-syn conformation, the

aromatic geometry and solvent effects on the ¹H NMR anisot-

ropy data were studied, leading to the following conclusions:

i) the hydrogen-bonding-like interaction among the H-8Ј of

the naphthyl group, the ester carbonyl oxygen, and the

methoxy oxygen supports a triangular intramolecular force

to stabilize the syn-syn conformation; ii) triangular hydrogen

bonding among a hydrogen atom of protic solvents, the ester

carbonyl oxygen, and the methoxy oxygen also supports the

syn-syn conformation. This hydrogen bonding, as the sol-

vation effect implies, suggests that a similar hydrogen bond-

ing between a MαNP ester and a hydroxy group of the silica

gel surface would make a dominant contribution to the excel-

lent discrimination of diastereomeric MαNP esters observed

in the HPLC on silica gel.

Germany, 2007)

dition, this method does not need derivatives containing so-

called heavy atoms. For example, the absolute configura-

tions of chiral C₆₀fullerene cis-3 bisadducts were first estab-

lished by a combination of this X-ray method and CD spec-

troscopy.^[2]For such internal reference compounds, we have

developed the chiral auxiliaries of camphorsultam-phthalic

(CSP) and camphorsultam-dichlorophthalic (CSDP) ac-

ids,^[3–5]which are very powerful for the enantioresolution

of racemic alcohols and for the simultaneous determination

of their absolute configurations by X-ray crystallography.

However, X-ray crystallography has a disadvantage in that

it needs single crystals suitable for X-ray diffraction experi-

ments, while such single crystals are not always available.

For non-crystalline compounds, the relative and empiri-

Introduction

It is well known that in 1951, J. M. Bijvoet and co-

workers first succeeded in determining the absolute config-

uration of a chiral compound, sodium rubidium tartrate,

using the anomalous dispersion effect of heavy atoms in X-

ray crystallography.^[1]Since then, the absolute configura-

tions of many compounds containing heavy atoms have

been determined by the Bijvoet method. Once the absolute

configuration of a compound has been determined by the

Bijvoet method, the compound can be used as an internal

reference of absolute configuration in the X-ray crystal-

lography of derivatives of the compound. In our opinion,

this relative method with the internal reference in X-ray

crystallography is the most reliable, because the absolute

configuration in question is automatically determined from

the stereoview provided by X-ray crystallography. In ad-

1

cal H NMR anisotropy method is useful. For such chiral

¹H NMR anisotropy reagents, many chiral acids have been

developed for determining the absolute configurations of

alcohols and other chiral compounds: α-methoxy-α-(tri-

fluoromethyl)phenylacetic acid (MTPA),^[6]2-methoxy-2-

phenylacetic acid (MPA),^[7]2-methoxy-2-(1-naphthyl)acetic

acid (1NMA), 2-methoxy-2-(2-naphthyl)acetic acid

(2NMA), 2-(9-anthryl)-2-methoxyacetic acid (9AMA),^[8,9]

α-cyano-α-fluoro-p-tolylacetic acid (CFTA),^[10]and other

acids.^[11]By using these chiral anisotropy reagents, the abso-

lute configurations of many chiral alcohols and natural

[a] Institute of Multidisciplinary Research for Advanced Materials,

Tohoku University,

2-1-1 Katahira, Aoba, Sendai 980-8577, Japan

[b] National Institute of Agrobiological Sciences,

1-2 Owashi, Tsukuba, Ibaragi 305-8634, Japan

[‡] Present address: Nobuyuki Harada, Department of Chemistry,

Columbia University,

3000 Broadway, MC3114, New York, NY 10027, USA

Fax: +1-212-932-8273

E-mail: nh2212@columbia.edu

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N. Harada et al.

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Figure 1. General scheme of enantioresolution and determination of the absolute configuration of the first eluted diastereomeric ester

with chiral MαNP acid (S)-(+)-1.

products have been successfully determined.^[8,9]As another periplanar to the methine proton of the alcohol moiety, and

1

chiral H NMR anisotropy reagent, we have developed 2- these three atoms form the MαNP plane as shown in Fig-

methoxy-2-(1-naphthyl)propionic (MαNP) acid 1,^[12–14]ure 1 (b). These two planes are perpendicular to each other

which is also powerful for determining the absolute config- because of the tetrahedral configuration of the quaternary

urations of chiral secondary alcohols (Figure 1). This chiral stereogenic center. In this preferred conformation of the

¹H NMR anisotropy reagent is unique in the sense that first eluted ester 3A, the substituent R²is in proximity to

diastereomeric MαNP esters prepared from enantiopure the plane of the naphthalene moiety, falling in its field of

acid (S)-(+)-1 and racemic alcohols are easily separable by diamagnetic anisotropy and leading to the high-field shifts

HPLC on silica gel. In addition, acid 1 has a chiral quater- of R²protons. On the other hand, in the second eluted ester

nary carbon atom, and therefore, does not racemize. There- 3B, the substituent R¹is located above the naphthalene

fore, enantiopure alcohols are easily prepared from sepa- plane, and, therefore, high-field shifts of R¹protons are ob-

rated esters. We have developed a new methodology for the served.

enantioresolution of alcohols and the simultaneous deter-

mination of their absolute configurations with MαNP acid nally defined as ∆δ = δ(R,X) – δ(S,X). In the case of enantio-

1.^[12–15]

resolution with the (S)-(+)-MαNP acid, this equation is

The parameter representing the anisotropy effect is origi-

The procedure of the MαNP acid method is outlined in transformed to ∆δ = δ(S,–X) – δ(S,X) = δ(2nd fraction) –

1

Figure 1 (a). Racemic alcohol (Ϯ)-(2) is esterified with (S)- δ(1st fraction).^[12,14]From the observed H NMR spectro-

(+)-MαNP acid 1, yielding diastereomeric esters, which are scopic data, the ∆δ value of each proton is calculated and

easily separable by HPLC on silica gel. The absolute config- plotted according to the sector rule shown in Figure 1 (c),

uration of the first eluted fraction 3A is designated as (S,X), where the substituent R²with positive ∆δ values is placed

where X represents the absolute configuration of the on the right side, while the substituent R¹with negative ∆δ

alcohol part to be determined, while S indicates that of the values is placed on the left side. By this displacement of

MαNP acid part. From the logic for the enantioresolution, substituents, the absolute configuration X of the first eluted

the absolute configuration of the second eluted fraction 3B ester 3A is determined; it is obvious that the second eluted

is naturally designated as (S,–X), where –X represents the ester 3B takes the opposite absolute configuration –X. The

opposite absolute configuration of X. As shown in Figure 1 hydrolysis of esters 3A and 3B gives enantiopure alcohols

(b), diastereomeric MαNP esters (S,X)-3A and (S,–X)-3B (X)-2 and (–X)-2, respectively, as shown in Figure 1 (d).

adopt the preferred conformation, where the terminal

The MαNP acid method has several advantages: (1) in

methyl group of the propionic acid part is synperiplanar to general, diastereomeric esters 3A and 3B are clearly separa-

the H-2 of the naphthalene group, which forms the Me/ ble by HPLC on silica gel indicating that MαNP acid has a

naphthyl plane as shown with dotted lines. On the other great ability to discriminate the chirality of alcohols, (2) the

hand, the oxygen atom of the methoxyl group is synperi- chiral center of MαNP acid is a quaternary carbon atom,

planar to the ester carbonyl oxygen atom, which is also syn- and therefore, does not racemize during the derivatization

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Chiral Conformation and H NMR Anisotropy of MαNP Esters

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reaction, the separation by HPLC, and the hydrolysis to

recover the alcohol. This is essential for the preparation of

an enantiopure alcohol, and (3) although the MαNP acid

method for determining the absolute configuration is an

empirical rule, we have not encountered any exception dur-

ing our many studies.^[12]This is an important advantage of

the MαNP acid method and makes the method reliable.

Why has the method no exception? It indicates that in all

cases, the conformations shown in Figure 1 (b) are always

stable and preferred, leading to the distribution of ∆δ values

obeying the sector rule. So, the next question is why the

conformations depicted in Figure 1 (b) are so stable. At first

glance, the conformations look unstable, because the oxy-

gen atom of the methoxyl group is synperiplanar to the car-

bonyl oxygen atom of the ester moiety. Why are two electro-

negative oxygen atoms close to each other? The objective

of these three serial papers^[16,17]is to solve these problems.

Results and Discussion

Synthesis of Racemic Carboxylic Acids with Various

Aromatic Groups Related to MαNP Acid and Preparation

of Their Menthol Esters

To study the dependence of the anisotropy effect, ∆δ, on

the geometry of the aromatic group, carboxylic acids with

various aromatic groups were synthesized as shown in Fig-

ure 2. The Grignard reagents prepared from aryl bromides

(14, 15, 17–22) were allowed to react with methyl pyruvate,

yielding methyl 2-aryl-2-hydroxypropionates 24, 25, and

27–32, respectively, which were further converted to methyl

2-aryl-2-methoxypropionates 34, 35, and 37–42, respec-

tively, by treating with NaH and iodomethane (Scheme 1).

Scheme 1. Preparation of diastereomeric esters from (–)-menthol

and racemic carboxylic acids. The preparation of MαNP acid esters

43a/43b and M9PP acid esters 46a/46b has been reported.^[12l,19]

Figure 2. MαNP acid (S)-(+)-1 and related acids.

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N. Harada et al.

Table 1. HPLC separation of diastereomeric esters formed from (–)-menthol with racemic MαNP acid and related acids.^[a]

FULL PAPER

Chiral acid recovered

from 1st fraction

Entry

Acid

Solvent^[b]

α

Rs

Ester (1st fraction)

1^[c]

2

(Ϯ)-1

(Ϯ)-4

(Ϯ)-5

(Ϯ)-6

(Ϯ)-7

(Ϯ)-8

(Ϯ)-9

(Ϯ)-10

(Ϯ)-11

(Ϯ)-12

H/EA = 10:1

H/EA = 20:1

H/EA = 9:1

H/EA = 10:1

H/EA = 20:1

H/EA = 10:1

1.83

1.93

1.37

1.64

1.71

1.41

1.59

1.09

1.53

1.27

4.55

3.31

1.86

–

2.55

3.30

3.97

0.90

1.72

1.57

(S;1R,3R,4S)-(–)-43a

(S)-(+)-1

44a

–

3

45a

(S;1R,3R,4S)-(+)-46a

(–)-47a

–

4^[d]

5

(S)-(+)-6

(S)-(+)-7

6

7

8

9

(–)-48a

–

(–)-49a

50a

(–)-51a

10

52a

[a] Glass column (Ø 22 mmϫ300 mm, or Ø 25 mmϫ400 mm) of silica gel (particle size 5–10 µm). [b] H = n-hexane, EA = ethyl acetate.

[c] Taken from ref.^[12l][d] Taken from ref.^[19]

The methyl esters were hydrolyzed with KOH in methanol, ¹H NMR Anisotropy Effects of (1R,3R,4S)-Menthol

giving 2-aryl-2-methoxypropionic acids 4, 5, and 7–12, MαNP Acid Esters and Related Esters

respectively. The racemic acids obtained were allowed to

To clarify the dependence of ¹H NMR anisotropy effects

react with (–)-menthol by stirring with 1,3-dicyclohexylcar-

1

on the geometry of the aromatic groups, the H NMR sig-

bodiimide (DCC), 4-(dimethylamino)pyridine (DMAP),

and 10-camphorsulfonic acid (CSA) in dichloromethane,

yielding a mixture of diastereomeric esters 44, 45, and 47–

nals of menthol esters 44a, 45a, and 47a–52a were fully as-

signed with ¹H NMR, ¹³C NMR, ¹H-¹H COSY, ¹H-¹³C

COSY, and HMBC spectra. From the observed data, ∆δ

52, respectively.

values were calculated as ∆δ = δ(2nd fraction) – δ(1st frac-

As in the case of menthol MαNP ester 43, the dia-

tion) for the protons of the menthol moiety; the distribution

stereomeric esters 44, 45, and 47–52 were subjected to

HPLC on silica gel with hexane/EtOAc (10:1 or 20:1); as

listed in Table 1, these diastereomeric esters were effectively

separated. For example, ester 44 with the 2-methyl-1-naph-

of ∆δ values are shown in Figure 3 together with those of

menthol MαNP esters 43a/43b and menthol 2-methoxy-2-

(9-phenanthryl)propionic acid (M9PP acid) 46a/46b. In the

case of menthol MαNP esters 43a/43b, their absolute con-

thyl group was largely separated to 44a and 44b with a sepa-

figurations are already known, and ∆δ {= δ(2nd fraction) –

ration factor α = 1.93. Such a large separation factor en-

ables one to make a separation on a large scale. In the case

of 2-methoxyphenyl derivative 50, the α value was 1.09,

which is smaller than in other cases, but it was still possible

δ(1st fraction)} is equal to δ(R,X) – δ(S,X), in agreement

with the original definition of ∆δ as described in the Intro-

duction. The same is true for the case of M9PP esters 46a/

46b. In the case of esters 44a/44b, 45a/45b, and 47a/47b–

to make the complete separation.

52a/52b, however, the absolute configurations of carboxylic

In the case of menthyl 2-methoxy-2-phenylpropionate 47,

acid parts are unknown, except for 47a/47b, and therefore,

the diastereomeric esters were effectively separated with α

we have adopted ∆δ values as ∆δ = δ(2nd fraction) – δ(1st

= 1.71. The first eluted ester, (–)-47a, was hydrolyzed with

fraction); there is no guarantee that ∆δ = δ(R,X) – δ(S,X).

KOH in methanol, giving (+)-2-methoxy-2-phenylpropionic

1

To evaluate the H NMR anisotropy effects here, it is suf-

acid (7), the absolute configuration of which was deter-

ficient to use the definition of ∆δ = δ(2nd fraction) – δ(1st

mined as S by comparison of the sign of optical rotation

fraction).

with that reported in the literature (Scheme 2).^[18]

In Figure 3 (a), the ∆δ values of menthol MαNP acid

esters 43a/43b are listed as the standard, where CDCl₃was

1

used as the H NMR solvent. A new parameter D repre-

senting the strength of the anisotropy effect is defined as D

= ∆δ(max) – ∆δ(min), where ∆δ(max) indicates the maxi-

mum value of ∆δ in the alcohol moiety, while ∆δ(min) indi-

cates the minimum value of ∆δ (largest negative value). In

the case of menthol esters, ∆δ(max) was determined by the

proton at the 2ax-position, H-2ax, and ∆δ(min) was deter-

mined by H-8Ј. Therefore D = ∆δ(max) – ∆δ(min) = ∆δ(H-

2ax) – ∆δ(H-8Ј); this definition was used for menthol esters

44a/44b–52a/52b. In the case of menthol MαNP acid esters

43a/43b, D = +0.31 – (–1.23) = 1.54.

The observed ∆δ values representing anisotropy effects

Scheme 2. Recovery of enantiopure carboxylic acid (S)-(+)-7.

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are very sensitive to the geometry of aromatic groups. When

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an extra methyl group is placed at the 2-position of the some specific position, and therefore, the naphthalene plane

naphthalene group, the observed ∆δ values are almost zero is randomly oriented toward the menthol moiety, and

as seen in esters 44a/44b [Figure 3 (a)]; small negative ∆δ hence, no anisotropy effect is observed.

values are obtained even on the right side. This result indi-

Menthol 2-methoxy-2-(2-naphthyl)propionic (MβNP)

cates that the conformation of esters 44a/44b is not fixed at acid esters 45a/45b, containing 2-naphthyl group, also show

Figure 3. (a) ¹H NMR anisotropy effects of (1R,3R,4S)-menthol MαNP acid esters 43a (first eluted fraction), 43b (second eluted fraction),

and related acid esters 44. ∆δ {= δ(2nd fraction) – δ(1st fraction)} and D values are shown in ppm. Spectra were recorded at 600 MHz

in CDCl₃. For esters 44, the D value was not calculated because of overlap of proton signals. The ∆δ values of esters 43a/43b were taken

from ref.^[12l](b) ¹H NMR anisotropy effects of (1R,3R,4S)-menthol esters 45 and 46. ∆δ {= δ(2nd fraction) – δ(1st fraction)} and D

1

values are given in ppm. Spectra were recorded at 600 MHz in CDCl₃. The ∆δ values of esters 46a/46b were taken from ref.^[19](c) H

NMR anisotropy effects of (1R,3R,4S)-menthol esters 47, 48, and 49. ∆δ {= δ(2nd fraction) – δ(1st fraction)} and D values are given in

ppm. Spectra were recorded at 600 MHz in CDCl₃. (d) ¹H NMR anisotropy effects of (1R,3R,4S)-menthol esters 50, 51, and 52. ∆δ

{= δ(2nd fraction) – δ(1st fraction)} and D values are given in ppm. Spectra were recorded at 600 MHz in CDCl₃.

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Figure 3. (continued).

nil ∆δ values [D = 0.05 in Figure 3 (b)]. This is in strong

It is interesting to compare the behavior of menthol

contrast with the case of menthol 2NMA acid esters, for MβNP acid esters 45a/45b with that of menthol M9PP acid

which moderately large ∆δ values were reported;^[8b]from esters 46a/46b [Figure 3 (b)]. Although esters 46a/46b, with

the data, the D value was calculated as D = 0.87. Why are the 9-phenanthryl group, show large ∆δ values (D =

the anisotropy effects of menthol MβNP acid esters 45a/ 1.57),^[19]esters 45a/45b, with the 2-naphthyl group, give no

45b and menthol 2NMA acid esters so different? The anisotropy effect (D = 0.05). The shape of the 9-phenan-

MβNP esters 45a/45b are propionic acid derivatives, while thryl group looks like a hybrid of 1-naphthyl and 2-naph-

2NMA acid esters are acetic acid derivatives; this difference thyl groups, and the results clearly indicate that the 1-naph-

is solely due to the existence of a methyl group. The data thyl part is essential for the anisotropy effect.

indicate that menthol MβNP acid esters 45a/45b do not oc-

No anisotropy effect was observed in the cases of men-

cupy any specific stable conformation leading to large ∆δ thol esters of 2-methoxy-2-phenylpropionic (MPP) acid

values. The mechanism of different D values will be dis- 47a/47b, 2-methoxy-2-(4-methoxyphenyl)propionic acid

cussed below.

48a/48b, and 2-methoxy-2-(3-methoxyphenyl)propionic

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acid 49a/49b [D = 0.02 for 47a/47b, D = 0.11 for 48a/48b,

It was surprising to find that less polar solvents such as

and D = 0.05 for 49a/49b, Figure 3 (c)]. The result of MPP [D₂]dichloromethane and [D]chloroform gave larger D val-

esters 47a/47b also contrasts strongly with the menthol es- ues than [D₆]DMSO as shown in Figure 4 (b) {D = 1.38 in

ters of MPA acid, which show a moderately large D value [D₂]dichloromethane and D = 1.54 in [D]chloroform}.

of 0.86.^[20]The presence of an extra methyl group prevents These results indicate that the anisotropy effect (∆δ) is not

the appearance of the anisotropy effect, implying that the proportional to the solvent polarity. A plausible interpret-

phenyl group is randomly oriented toward the menthol ation of these results is that the hydrogen of halomethane

moiety under the averaged conformations. To study the ef- molecules may stabilize the syn-syn conformation by a hy-

fect of electron-donating substituents on a phenyl group, drogen-bonding-like interaction. This mechanism was sup-

4-methoxyphenyl (48a/48b) and 3-methoxyphenyl (49a/49b) ported by the data with protic solvents, such as [D₄]acetic

esters were prepared, and ∆δ values were calculated. The acid, [D₄]methanol, and [D₃]-2,2,2-trifluoroethanol, as

results indicate that there is no effect of the electron-donat- shown in Figure 4 (b) {D = 1.57 in [D₄]acetic acid, D =

ing substituents on ∆δ values.

1.85 in [D₄]methanol, and D = 2.07 in 2,2,2-[D₃]-

The studies were further continued. In the case of 2- trifluoroethanol}. These ∆δ values are much larger than

methoxyphenyl esters 50a/50b, the distribution pattern of those with [D₆]DMSO. It is now clear that the proton of

∆δ values matches with the sector rule shown in Figure 1 protic solvents effectively stabilizes the syn-syn conforma-

(c), although the observed ∆δ values are small (D = 0.27); tion by its participation in hydrogen bonding. This is dis-

the right half of the menthol moiety gives positive ∆δ val- cussed below in detail.

ues, while the left half gives negative ∆δ values [Figure 3

The [D₄]methanol solvent gives a larger D value than

(d)]. This is a good indication of the effect of the substituent that of [D]chloroform, and therefore, when ∆δ values ob-

at the 2-position. We next checked 2-methylphenyl esters served in [D]chloroform are small, it is advised to use [D₄]-

51a/51b; it was surprising to find that the distribution of ∆δ methanol. However, in our opinion, the ∆δ values observed

values obeys the sector rule despite the nonpolar substitu- in [D]chloroform are large enough for absolute configura-

ent, and the observed anisotropy effect (D = 0.61) was tional assignment, and therefore, the use of [D]chloroform,

much larger than the case of 2-methoxyphenyl esters 50a/ in which most compounds are easily soluble, is recom-

50b. This result implies that the hydrogens of a methyl mended.

group may participate in the stabilization of the conforma-

tion matching the sector rule [i.e. the syn-syn conformation

shown in Figure 1 (b)]. We next studied the case of 2-(meth-

Intramolecular Hydrogen-Bonding-Like Interaction

oxymethyl)phenyl esters 52a/52b, which also showed a sim-

Stabilizing the syn-syn Conformation

ilar anisotropy effect (D = 0.66), suggesting the contri-

bution of hydrogen atoms to the stabilization of the syn-syn

conformer.

What kind of mechanism for stabilizing the syn-syn con-

formation can be deduced from the data described above?

In the case of 2-hydroxy-2-(1-naphthyl)propionic acid ester

shown in Figure 5 (a), the intramolecular hydrogen bonding

between the hydroxy proton and the ester carbonyl oxygen

makes the syn-syn conformation stable. Similarly, we had

1

The Solvent Dependency of the H NMR Anisotropy of

(1R,3R,4S)-Menthol MαNP Acid Esters

To clarify the solvent dependency of anisotropy effects, first considered that the proton of the methoxyl group par-

¹H NMR spectra of menthol MαNP acid esters 43a/43b ticipates in an intramolecular hydrogen-bonding-like inter-

were measured with various solvents as shown in Figure 4. action as shown in Figure 5 (b). However, this mechanism

In all cases, the distribution of ∆δ values obeys the sector is easily ruled out, because the anisotropy effect (∆δ value)

rule; even in nonpolar solvents such as [D₁₂]cyclohexane sharply depends on the geometry of the aromatic moiety;

and [D₆]benzene, small but non-zero and moderately large only MαNP esters 43a/43b, M9PP esters 46a/46b, and 2-

D values were obtained, respectively [Figure 4 (a), D = 0.43 methoxy-(2-substituted phenyl)propionic acid esters, 50a/

in C₆D₁₂and D = 0.83 in C₆D₆]. These results indicate that 50b, 51a/51b, and 52a/52b, gave non-zero and meaningful

molecules 43a/43b have, to some extent, an intramolecular ∆δ values.

force to stabilize the syn-syn conformation depicted in Fig-

We next considered the intramolecular hydrogen-bond-

ure 1 (b). With polar solvents, such as [D₅]pyridine, [D₆]- ing-like interaction among H-8Ј of the naphthalene group,

acetone, [D₃]acetonitrile, and [D₆]DMSO, the ∆δ value be- the methoxy oxygen (O-7), and the ester carbonyl oxygen

comes larger in the order of solvent polarity {D = 1.14 in (O-6) as shown in Figure 5 (c). Namely, these three atoms

[D₅]pyridine, D = 1.18 in [D₆]acetone, D = 1.36 in [D₃]ace- could form a triangular hydrogen-bonding-like interaction,

tonitrile, and D = 1.36 in [D₆]DMSO}. However, the D where H-8Ј is partially positively charged and interacts with

value in [D₆]DMSO is equal to that in [D₃]acetonitrile, al- the lone pair orbitals of O-6 and O-7. Such interaction sta-

though the dielectric constants and dipole moments of bilizes the syn-syn conformation as shown. This mechanism

1

DMSO are larger than those of acetonitrile. These data is supported by the H NMR spectroscopic data of esters

indicate that the solvent polarity also contributes to the sta- 43a, 43b, and related compounds listed in Table 2. In

bilization of the syn-syn conformation, but it is not the MαNP acid ester 43a, the H-8Ј signal (δ = 8.37 ppm) is

major factor.

shifted downfield compared to those of H-4Ј (δ = 7.81 ppm)

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Figure 4. (a) Solvent effect on the ¹H NMR anisotropy data of (1R,3R,4S)-menthol MαNP acid esters 43a and 43b. ∆δ {= δ(2nd

fraction) – δ(1st fraction)} and D values are given in ppm. Spectra were recorded at 600 MHz. (b) Solvent effect on the ¹H NMR

anisotropy data of (1R,3R,4S)-menthol MαNP acid esters 43a and 43b. ∆δ {= δ(2nd fraction) – δ(1st fraction)} and D values are given

[a]

in ppm. Spectra were recorded at 600 MHz. Dielectric constant at 25 °C. The ∆δ values in [D]chloroform were taken from ref.^[12l]

1

and H-5Ј (δ = 7.84 ppm), indicating that H-8Ј is more posi- original positions. The H NMR chemical shift data thus

tively charged by the hydrogen-bonding-like interaction. support the triangular hydrogen-bonding-like interaction

Similar phenomena were observed in the case of menthol stabilizing the syn-syn conformation.

MαNP acid ester 43b and methyl MαNP acid ester 33. On

This mechanism is strongly supported by comparing the

the other hand, in the case of methyl 2-(1-naphthyl)propi- ∆δ data of menthol MβNP acid esters 45a/45b with those

onic acid ester 53, which lacks a methoxyl group, the H-8Ј of menthol M9PP acid esters 46a/46b. As described above,

signal (δ = 8.07 ppm) is shifted upfield, while those of H-4Ј esters 46a/46b show large ∆δ values (D = 1.57), while esters

(δ = 7.77 ppm) and H-5Ј (δ = 7.86 ppm) remained near their 45a/45b show no anisotropy effect (D = 0.05). H-8Ј of the

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Chiral Conformation and H NMR Anisotropy of MαNP Esters

FULL PAPER

52a/52b, where the proton of the methyl group or meth-

oxymethyl group can participate in the triangular hydrogen-

bonding-like interaction stabilizing the syn-syn conforma-

tion. The polarization of the C–H bond in this case is

smaller than that in the case of MαNP ester, because in

esters 51a/51b and 52a/52b, the relevant C is sp³-hybridized,

while in MαNP esters 43a/43b, the relevant C is sp²hy-

bridized. Therefore, the ∆δ values observed for esters 51a/

51b and 52a/52b, are smaller than those of MαNP esters

43a/43b.

1

Interpretation of the H NMR Anisotropy Difference

Between 2-Methoxy-2-arylpropionates and 2-Methoxy-2-

arylacetates

As shown above, the ¹H NMR anisotropy effects of men-

thol MβNP acid esters 45a/45b are nil (D = 0.05), while

menthol 2NMA acid esters give moderate anisotropy effects

(D = 0.87). Similarly, menthol MPP acid esters 47a/47b give

no anisotropy effects (D = 0.02), while menthol MPA acid

esters show a moderate D value (D = 0.86). Although propi-

onic acid esters give no anisotropy effect, acetic acid esters

show moderate D values. Why are their anisotropy effects

so much different? At the moment, we interpret the phe-

nomena as follows: propionic acid esters are sterically more

hindered because of the extra methyl group, and therefore,

the aromatic group cannot take any specific orientation

causing anisotropy effects. On the other hand, acetic acid

esters are less hindered, and therefore, aromatic groups can

take an orientation generating anisotropy effects.

Figure 5. The possible conformers of MαNP and related acid esters

stabilizing the syn-syn conformation.

Table 2. ¹H NMR chemical shift data (600 MHz, CDCl₃) for the

naphthalene protons of MαNP and related esters.

On the contrary, in the case of esters with the 1-naphthyl

group, both propionic and acetic acid esters show larger ∆δ

values. Menthol 1NMA acid esters give larger ∆δ values,^[8b]

from which a D value was calculated (D = 1.42). Menthol

MαNP esters 43a/43b show a similar D value as described

above (1.54). In these cases, the triangular hydrogen-bond-

ing-like interaction among H-8Ј, the methoxy oxygen, and

the ester carbonyl oxygen stabilizes the syn-syn conforma-

tion despite the existence of the extra methyl group. So,

large anisotropy effects are observable for esters with a 1-

naphthyl group.

δ values (ppm) for compounds

Naphthyl-H

(S)-43a

(R)-43b

(S)-33

53

4-H

5-H

8-H

7.81

7.84

8.37

7.81

7.83

8.49

7.84

7.86

8.35

7.77

7.86

8.07

Trianglular Hydrogen Bonding with Protic Solvents

Stabilizing the syn-syn Conformation

In the study of the solvent effect on the ∆δ value, it was

9-phenanthryl group is close to O-6 and O-7, and therefore, found that protic solvents such as [D₄]methanol give larger

participates in the triangular intramolecular hydrogen- ∆δ values, indicating more stabilization of the syn-syn con-

bonding-like interaction, stabilizing the syn-syn conforma- formation. This is easily understandable by invoking the tri-

tion. On the other hand, MβNP esters 45a/45b have no pro- angular hydrogen bonding among O-6/alcoholic D/O-7 as

ton in such a position, and hence, no anisotropy effect was shown in Figure 6 (a). Therefore, the syn-syn conformation

observed.

is stabilized. The triangular hydrogen bonding among O-6/

The mechanism can be extended to the cases of 2-meth- alcoholic proton/O-7 was proved by X-ray crystallography

oxy-(2-methylphenyl)propionic acid esters 51a/51b and 2- of MαNP ester with a tertiary alcohol as described in part

methoxy-(2-methoxymethylphenyl)propionic acid esters 2 of this series.^[16]

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1819

N. Harada et al.

FULL PAPER

43b are easily separable by HPLC on silica gel. This is a

great advantage of the MαNP acid compared to other chi-

ral anisotropy reagents. Why are MαNP acid esters so easily

separable? We propose a plausible mechanism in Figure 7.

In the holes of silica gel, hydroxy groups at the surface par-

ticipate in triangular hydrogen bonding with MαNP esters,

which fixes the molecular conformations. Therefore dia-

stereomeric esters take different shapes and are adsorbed

on silica gel in a different manner, leading to large separa-

tions by HPLC on silica gel.

Conclusions

To clarify the mechanism of the anisotropy effect of

1

MαNP acid esters, we studied their H NMR spectra and

those of related carboxylic acid esters and found that the

observed ∆δ values are very sensitive to the geometry of

the aromatic groups. These results indicate that the syn-syn

conformation generating larger ∆δ values is stabilized by a

triangular hydrogen-bonding-like interaction among O-6/

H-8Ј/O-7 [Figure 5 (c)]. Larger ∆δ values are also observ-

able in protic solvents such as [D₄]methanol. These results

suggest that the syn-syn conformation is also stabilized by

triangular hydrogen bonding among O-6/proton of a protic

solvent/O-7 [Figure 6 (a)]. This mechanism can be extended

to the case of halomethane solvents such as [D]chloroform.

The mechanisms stabilizing the syn-syn conformation dis-

cussed here are further supported by the X-ray crystallogra-

phy of many MαNP acid esters as reported in the following

part 2,^[16]and also by the ab initio calculations of the con-

formational energy surface of MαNP acid ester as described

in part 3.^[17]

Figure 6. The possible syn-syn conformation of MαNP esters stabi-

lized by solvation: hydrogen bonding or hydrogen-bonding-like in-

teraction.

How about the case of [D]chloroform? Here we propose

an O-6/D(CCl₃)/O-7 triangular hydrogen-bonding-like in-

teraction, where the D atom of [D]chloroform is also par-

tially positively charged because of the strong electron-with-

drawing nature of the CCl₃moiety, and therefore, the D

participates in the hydrogen-bonding-like interaction as an

electron accepter. A similar mechanism is applicable to the

case of [D₂]dichloromethane. By this mechanism, the syn-

syn conformation is stabilized in [D]chloroform and [D₂]-

dichloromethane, and larger ∆δ values are observable.

The Easy Separation of Diastereomeric MαNP Esters by

HPLC on Silica Gel

Experimental Section

General Methods: Melting points were uncorrected. IR spectra

were obtained as neat liquids, as a film on KBr, or as KBr disks

with a Jasco FT/IR-410 spectrophotometer. ¹H NMR spectra were

recorded with a Jeol JNM-LA400 (400 MHz) and/or a Jeol JNM-

In general, it is hard to separate diastereomeric esters

prepared from a racemic alcohol and a chiral organic acid

by HPLC on silica gel. However, as reported in our earlier

papers,^[12–14]most diastereomeric MαNP esters such as 43a/ LA600 (600 MHz) spectrometer. ¹³C NMR spectra were obtained

on a Jeol JNM-LA400 (100 MHz) and/or a Jeol JNM-LA600

(150 MHz) spectrometer. All NMR spectroscopic data of [D]chlo-

roform, [D₁₂]cyclohexane, [D₆]benzene, [D₅]pyridine, [D₆]acetone,

[D₃]acetonitrile, [D₆]DMSO, [D₂]dichloromethane, [D₄]acetic acid,

[D₄]methanol, and 1,1,1-[D₃]trifluoroethanol solutions are re-

ported in ppm (δ) downfield from TMS. Optical rotations {[α]_D}

were measured with a Jasco DIP-1000 spectropolarimeter. Silica

gel 60 F₂₅₄precoated plates on glass from Merck Ltd. were used

for thin-layer chromatography (TLC). HPLC separation and purifi-

cation were performed with

a prepacked glass column (Ø

22 mmϫ300 mm, or Ø 25 mmϫ400 mm) of silica gel (particle size

5–10 µm) from Kusano Co., Ltd, and a UV/RI detector (Shima-

mura YRU-880). The purities of the title compounds were shown

1

to be Ն99% by H NMR, TLC, HPLC, and/or elemental analysis.

Preparation of Methyl 2-Aryl-2-hydroxypropionates 24, 25, and 27–

32 by Grignard Reaction: For example, to a mixture of magnesium

(0.486 g, 20.0 mmol) and a catalytic amount of iodine in dried THF

(50 mL), 1-bromo-2-methylnaphthalene (14, 4.422 g, 20.0 mmol)

was added dropwise, and the mixture was stirred at room tempera-

Figure 7. The plausible mechanism of the diastereomeric discrimi-

nation of MαNP esters in the holes of silica gel, where ester mole-

cules are adsorbed by hydrogen bonding.

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1

Chiral Conformation and H NMR Anisotropy of MαNP Esters

FULL PAPER

ture for a few hours. To a solution of methyl pyruvate (2.25 g,

22.0 mmol) in THF (50 mL), cooled to 0 °C, was added dropwise

the mixture of the Grignard reagent formed above, and the reaction

mixture was stirred at room temperature overnight. After the ad-

dition of aqueous NH₄Cl at 0 °C and removal of the organic sol-

vent under reduced pressure, the mixture was extracted with EtOAc

three times. The combined organic layers were washed with brine,

dried with anhydrous MgSO₄, and the solvent was evaporated to

dryness. The oily residue was purified by HPLC on silica gel (hex-

ane/EtOAc = 5:1), yielding hydroxy ester 24 as a colorless solid.

128.2, 131.9, 136.9, 139.1, 177.5 ppm. C₁₁H₁₄O₃(194.23): calcd. C

68.02, H 7.27; found C 67.82, H 7.22.

Methyl 2-Hydroxy-2-(2-methoxymethylphenyl)propionate (32):

Yield 27%, colorless oil. IR (neat): ν = 3468, 3391, 2987, 2950,

˜

2894, 2827, 1736, 1452, 1370, 1254, 1191, 1133, 1099, 977, 933, 753

cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.86 (s, 3 H), 3.37 (s, 3 H),

3.73 (s, 3 H), 4.48 (d, J = 11.7 Hz, 1 H), 4.54 (d, J = 11.7 Hz, 1

H), 5.00 (s, 1 H), 7.29–7.38 (m, 3 H), 7.50–7.53 (m, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 26.8, 52.8, 58.0, 73.9, 76.1, 126.8,

128.2, 128.5, 131.5, 135.2, 141.1, 176.8 ppm.

Methyl 2-Hydroxy-2-(2-methyl-1-naphthyl)propionate (24): Yield

Preparation of Methyl Ethers 34, 35, and 37–42: For example, to a

mixture of hydroxy ester 24 (1.037 g, 4.25 mmol) and iodomethane

(0.40 mL, 6.37 mmol) in dried THF (21 mL), sodium hydride (60%

dispersion in mineral oil, 0.204 g, 5.09 mmol) was added portion-

wise, and the mixture was stirred at room temperature overnight.

After addition of aqueous NH₄Cl and removal of the organic sol-

vent under reduced pressure, the mixture was extracted with EtOAc

three times. The combined organic layers were washed with brine,

dried with anhydrous MgSO₄, and the solvent was evaporated to

dryness. The oily residue was purified by HPLC on silica gel (hex-

ane/EtOAc = 5:1), yielding methyl ether 34 as a yellow oil.

1.58 g, 32%. IR (KBr): ν = 3471, 3049, 2993, 2949, 1732, 1253,

˜

1

1119, 1089, 813, 744 cm^–1. H NMR (400 MHz, CDCl₃): δ = 2.01

(s, 3 H), 2.54 (s, 3 H), 2.89 (s, 1 H), 3.71 (s, 3 H), 3.93 (s, 1 H),

7.22 (d, J = 8.6 Hz, 1 H), 7.37–7.44 (m, 2 H), 7.67 (d, J = 8.6 Hz,

1 H), 7.76–7.81 (m, 1 H), 8.38–8.41 (m, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 22.5, 24.8, 52.7, 79.5, 124.6, 124.8, 125.7,

128.3, 128.7, 130.8, 131.2, 133.0, 135.6, 175.5 ppm.

Methyl 2-Hydroxy-2-(2-naphthyl)propionate (25): Yield 47%. IR

(neat): ν = 3501, 3058, 2984, 2952, 1733, 1599, 1507, 1436, 1374,

˜

1246, 1212, 1184, 1139, 1094, 1064, 1017, 976, 934, 904, 860, 822,

752, 725 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.88 (s, 3 H), 3.77

(s, 3 H), 3.93 (s, 1 H), 7.44–7.51 (m, 2 H), 7.64 (dd, J = 8.6, 1.7 Hz,

1 H), 7.82 (br. d, J = 8.6 Hz, 1 H), 7.78–7.87 (m, 2 H), 8.02 (br. d,

J = 1.7 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 26.6,

53.3, 75.9, 123.3, 124.0, 126.2, 127.5, 128.1, 128.3, 132.8, 132.9,

139.9, 176.0 ppm.

Methyl 2-Methoxy-2-(2-methyl-1-naphthyl)propionate (34): Yield

0.741 g, 68%. IR (neat): ν = 2992, 2943, 2831, 1733, 1509, 1437,

˜

1371, 1255, 1116, 953, 813, 784, 744 cm^–1. ¹H NMR (400 MHz,

CDCl₃): δ = 1.99 (s, 3 H), 2.53 (s, 3 H), 3.26 (s, 3 H), 3.70 (s, 3 H),

7.23 (d, J = 8.3 Hz, 1 H), 7.35–7.42 (m, 2 H), 7.66 (d, J = 8.3 Hz,

1 H), 7.74–7.79 (m, 1 H), 8.23–8.27 (m, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 22.9, 22.9, 51.9, 52.3, 83.9, 124.4, 124.6,

125.6, 128.2, 128.6, 131.0, 131.6, 132.8, 133.7, 134.4, 172.9 ppm.

Methyl 2-Hydroxy-2-phenylpropionate (27): Yield 29%, colorless

oil. IR (neat): ν = 3500, 3061, 3027, 2986, 2954, 1731, 1600, 1494,

˜

1447, 1374, 1256, 1213, 1148, 1097, 1071, 976, 941, 784, 699, 657

cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.79 (s, 3 H), 3.78 (s, 3 H),

7.25–7.38 (m, 3 H), 7.53–7.56 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 26.7, 53.2, 75.7, 125.1, 127.8, 128.3, 142.6, 176.1 ppm.

C₁₀H₁₂O₃(180.20): calcd. C 66.65, H 6.71; found C 66.85, H 6.68.

Methyl 2-Methoxy-2-(2-naphthyl)propionate (35): Yield 78%. IR

(neat): ν = 3057, 2989, 2951, 2831, 1734, 1600, 1507, 1436, 1372,

˜

1255, 1185, 1131, 1078, 1050, 978, 952, 897, 858, 821, 752 cm^–1. ¹H

NMR (400 MHz, CDCl₃): δ = 1.90 (s, 3 H), 3.31 (s, 3 H), 3.73 (s,

3 H), 7.45–7.52 (m, 2 H), 7.59 (dd, J = 8.8, 1.9 Hz, 1 H), 7.84 (br.

d, J = 8.8 Hz, 1 H), 7.80–7.87 (m, 2 H), 7.95 (br. d, J = 1.9 Hz, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.8, 52.0, 52.6, 81.8,

123.8, 125.1, 126.2, 126.3, 127.5, 128.2, 128.3, 132.9, 133.0, 138.0,

173.5 ppm.

Methyl 2-Hydroxy-2-(4-methoxyphenyl)propionate (28): Pale yellow

1

oil. H NMR (400 MHz, CDCl₃): δ = 1.76 (s, 3 H), 3.76 (s, 3 H),

3.80 (s, 3 H), 6.87–6.91 (m, 2 H), 7.44–7.47 (m, 2 H) ppm.

Methyl 2-Hydroxy-2-(3-methoxyphenyl)propionate (29): Yield 65%,

colorless oil. IR (neat): ν = 3502, 2954, 1734, 1602, 1489, 1435,

˜

Methyl 2-Methoxy-2-phenylpropionate (37): Yield 75%, colorless

1259, 1146, 1045, 792, 735, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 1.77 (s, 3 H), 3.74 (s, 1 H), 3.78 (s, 3 H), 3.82 (s, 3 H), 6.84

(ddd, J = 8.3, 2.4, 1.0 Hz, 1 H), 7.10–7.13 (m, 2 H), 7.27 (dd, J =

8.3, 8.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 26.7,

53.3, 55.3, 75.7, 111.1, 113.1, 117.5, 129.4, 144.4, 159.6, 176.0 ppm.

oil. IR (neat): ν = 2990, 2951, 2831, 1735, 1494, 1448, 1372, 1258,

˜

1196, 1116, 1076, 1049, 976, 864, 770, 729, 699, 645, 559, 519 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 1.80 (s, 3 H), 3.28 (s, 3 H), 3.72

(s, 3 H), 7.26–7.38 (m, 3 H), 7.46–7.52 (m, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 21.9, 51.9, 52.5, 81.6, 125.8, 127.9, 128.3,

140.6, 173.5 ppm.

Methyl 2-Hydroxy-2-(2-methoxyphenyl)propionate (30): Yield 53%,

colorless needles. M.p. 89–90 °C. IR (KBr): ν = 3482, 2995, 2951,

˜

Methyl 2-Methoxy-2-(4-methoxyphenyl)propionate (38): Total yield

2840, 1740, 1602, 1587, 1492, 1464, 1437, 1370, 1243, 1134, 1057,

1

1025, 982, 930, 803, 757, 654 cm^–1. H NMR (400 MHz, CDCl₃):

from 18: 25%, colorless oil. IR (neat): ν = 2989, 2952, 2834, 1734,

˜

1610, 1583, 1510, 1457, 1372, 1302, 1252, 1179, 1111, 1031, 978,

δ = 1.79 (d, J = 0.7 Hz, 3 H), 3.71 (s, 3 H), 3.82 (s, 3 H), 4.02 (q,

J = 0.7 Hz, 1 H), 6.90 (dd, J = 8.2, 1.0 Hz, 1 H), 7.00 (ddd, J =

7.6, 7.6, 1.0 Hz, 1 H), 7.32 (ddd, J = 8.2, 7.6, 1.6 Hz, 1 H), 7.45

(dd, J = 7.6, 1.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

24.2, 52.6, 55.5, 74.1, 111.1, 120.9, 126.3, 129.5, 131.0, 156.6, 176.6

ppm. C₁₁H₁₄O₄(210.23): calcd. C 62.85, H 6.71; found C 62.68, H

6.62.

1

833, 803, 608, 509 cm^–1. H NMR (400 MHz, CDCl₃): δ = 1.78 (s,

3 H), 3.25 (s, 3 H), 3.72 (s, 3 H), 3.80 (s, 3 H), 6.89 (d, J = 8.8 Hz,

2 H), 7.39 (d, J = 8.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 21.7, 51.7, 52.5, 55.2, 81.2, 113.7, 127.3, 132.5, 159.2, 173.7

ppm. C₁₂H₁₆O₄(224.26): calcd. C 64.27, H 7.19; found C 64.04, H

7.14.

Methyl 2-Hydroxy-2-(2-tolyl)propionate (31): Yield 42%, colorless Methyl 2-Methoxy-2-(3-methoxyphenyl)propionate (39): Colorless

solid. IR (KBr): ν = 3491, 2993, 2952, 1732, 1458, 1437, 1291,

oil. IR (neat): ν = 2993, 2952, 2834, 1736, 1600, 1585, 1489, 1453,

˜

1259, 1214, 1190, 1128, 1093, 779, 767, 745, 726 cm^–1. ¹H NMR

(400 MHz, CDCl₃): δ = 1.84 (s, 3 H), 2.31 (s, 3 H), 3.48 (s, 1 H),

3.75 (s, 3 H), 7.14–7.24 (m, 3 H), 7.45–7.47 (m, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 20.2, 26.9, 53.2, 75.8, 125.7, 126.0,

1434, 1372, 1261, 1194, 1135, 1116, 1046, 979, 878, 827, 788, 727,

697, 542, 451 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.78 (s, 3 H),

3.28 (s, 3 H), 3.73 (s, 3 H), 3.81 (s, 3 H), 6.84 (ddd, J = 7.9, 2.4,

1.0 Hz, 1 H), 7.04 (m, 2 H), 7.27 (ddd, J = 7.9, 7.9, 0.5 Hz, 1 H)

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ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.9, 51.9, 52.5, 55.2, 81.6,

2-Methoxy-2-(4-methoxyphenyl)propionic Acid (8): Yield 99%, col-

111.6, 113.4, 118.2, 129.3, 142.3, 159.6, 173.4 ppm.

orless solid. IR (KBr): ν = 3467, 3401, 2996, 2962, 2908, 2837,

˜

1704, 1610, 1511, 1457, 1371, 1298, 1254, 1179, 1145, 1097, 1025,

874, 831, 736, 603, 523 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

1.83 (s, 3 H), 3.24 (s, 3 H), 3.81 (s, 3 H), 6.91 (d, J = 8.8 Hz, 2 H),

7.38 (d, J = 8.8 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

20.4, 51.4, 55.3, 81.0, 114.0, 127.6, 130.5, 159.7, 175.0 ppm.

Methyl 2-Methoxy-2-(2-methoxyphenyl)propionate (40): Colorless

oil. IR (neat): ν = 2993, 2949, 2835, 1740, 1602, 1587, 1491, 1463,

˜

1437, 1367, 1290, 1256, 1192, 1119, 1104, 1078, 1047, 1026, 982,

1

873, 802, 757, 643, 592, 504, 458, 427 cm^–1. H NMR (400 MHz,

CDCl₃): δ = 1.67 (s, 3 H), 3.28 (s, 3 H), 3.71 (s, 3 H), 3.77 (s, 3 H),

6.88 (dd, J = 8.3, 1.2 Hz, 1 H), 7.01 (ddd, J = 7.6, 7.6, 1.2 Hz, 1

H), 7.29 (ddd, J = 8.3, 7.6, 1.7 Hz, 1 H), 7.56 (dd, J = 7.6, 1.7 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.4, 51.7, 52.0, 55.4,

79.0, 111.0, 120.6, 126.3, 128.9, 130.3, 155.9, 173.1 ppm.

2-Methoxy-2-(3-methoxyphenyl)propionic Acid (9): Yield 93%, pale

1

yellow oil. H NMR (400 MHz, CDCl₃): δ = 1.83 (s, 3 H), 3.28 (s,

3 H), 3.81 (s, 3 H), 6.87 (ddd, J = 8.3, 2.7, 1.0 Hz, 1 H), 7.02 (dd,

J = 2.7, 1.7 Hz, 1 H), 7.05 (ddd, J = 7.8, 1.7, 1.0 Hz, 1 H), 7.30

(dd, J = 8.3, 7.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

20.6, 51.7, 55.3, 81.2, 112.2, 113.7, 118.6, 129.6, 140.4, 159.8, 175.1

ppm.

Methyl 2-Methoxy-2-(2-tolyl)propionate (41): Yield 88%, colorless

oil. IR (neat): ν = 3062, 2991, 2949, 2830, 1735, 1487, 1456, 1435,

˜

1368, 1294, 1256, 1228, 1190, 1128, 1068, 1048, 977, 874, 803, 764,

743, 661, 643 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.82 (s, 3 H),

2.30 (s, 3 H), 3.10 (s, 3 H), 3.73 (s, 3 H), 7.15–7.26 (m, 3 H), 7.40–

7.43 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.9, 21.6,

50.7, 52.5, 81.3, 125.6, 127.1, 128.2, 131.8, 137.1, 137.4, 174.2 ppm.

2-Methoxy-2-(2-methoxyphenyl)propionic Acid (10): Yield 73%,

colorless crystals. M.p. 91–92 °C. IR (KBr): ν = 3164, 2942, 2837,

˜

1715, 1602, 1492, 1463, 1438, 1252, 1125, 1101, 1075, 1047, 1025,

1

758 cm^–1. H NMR (400 MHz, CDCl₃): δ = 1.78 (s, 3 H), 3.12 (s,

3 H), 3.80 (s, 3 H), 6.92 (dd, J = 8.3, 1.0 Hz, 1 H), 7.00 (ddd, J =

7.5, 7.5, 1.0 Hz, 1 H), 7.36 (ddd, J = 8.3, 7.5, 1.7 Hz, 1 H), 7.44

(dd, J = 7.5, 1.7 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

20.3, 51.2, 55.6, 78.9, 111.8, 120.5, 126.1, 128.2, 130.4, 157.3, 175.4

ppm. C₁₁H₁₄O₄(210.23): calcd. C 62.85, H 6.71; found C 62.86, H

6.67.

Methyl 2-Methoxy-2-(2-methoxymethylphenyl)propionate (42):

Yield 82%, colorless oil. IR (neat): ν = 2949, 1737, 1451, 1255,

˜

1

1193, 1132, 752 cm^–1. H NMR (400 MHz, CDCl₃): δ = 1.85 (s, 3

H), 3.10 (s, 3 H), 3.36 (s, 3 H), 3.70 (s, 3 H), 4.48 (d, J = 12.4 Hz,

1 H), 4.58 (d, J = 12.4 Hz, 1 H), 7.31 (ddd, J = 7.6, 7.6, 1.7 Hz, 1

H), 7.36 (ddd, J = 7.6, 7.6, 1.4 Hz, 1 H), 7.42 (dd, J = 7.6, 1.7 Hz,

1 H), 7.52 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.8,

50.8, 52.5, 58.4, 71.6, 81.3, 127.3, 127.4, 128.5, 129.5, 137.0, 137.4,

174.0 ppm.

2-Methoxy-2-(2-tolyl)propionic Acid (11): Yield 99%, colorless

prisms from hexane/EtOAc. M.p. 96.5–97.5 °C. IR (KBr): ν =

˜

2989, 1721, 1231, 1143, 1130, 1097, 1065, 729 cm^–1. ¹H NMR

(400 MHz, CDCl₃): δ = 1.88 (s, 3 H), 2.34 (s, 3 H), 3.10 (s, 3 H),

7.17–7.29 (m, 3 H), 7.40–7.42 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 20.2, 21.4, 50.7, 81.3, 125.8, 128.1, 129.0, 132.0, 135.0,

137.4, 174.9 ppm.

Preparation of 2-Aryl-2-methoxypropionic Acids 4, 5, and 7–12: For

example, to a solution of ester 34 (0.590 g, 2.28 mmol) in methanol

(21 mL), was added a solution of KOH (1.40 g, 25.0 mmol) in water

(2.3 mL), and the mixture was gently refluxed for 1–2 d. After re-

moval of the organic solvent under reduced pressure, the mixture

was extracted with diethyl ether. The remaining aqueous layer was

acidified with 6  HCl at 0 °C, giving a precipitate, which was ex-

tracted with EtOAc three times. The combined EtOAc layers were

washed with brine, dried with anhydrous MgSO₄, and the solvent

was evaporated to dryness, yielding carboxylic acid 4 as a colorless

solid.

2-Methoxy-2-(2-methoxymethylphenyl)propionic Acid (12): Yield

90%, colorless oil. IR (KBr): ν = 3502, 3065, 2988, 2938, 2830,

˜

1731, 1453, 1373, 1228, 1193, 1141, 1096, 1065, 1046, 894, 754, 662

cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.88 (s, 3 H), 3.17 (s, 3 H),

3.35 (s, 3 H), 4.43 (d, J = 12.2 Hz, 1 H), 4.78 (d, J = 12.2 Hz, 1 H),

7.30–7.37 (m, 2 H), 7.42–7.48 (m, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 21.6, 51.1, 58.0, 72.8, 82.0, 127.9, 128.1, 128.7, 130.1,

136.2, 136.6, 175.2 ppm.

2-Methoxy-2-(2-methyl-1-naphthyl)propionic Acid (4): Yield

Preparation of Diastereomeric (1R,3R,4S)-Menthyl 2-Aryl-2-meth-

oxypropionates 44, 45, and 47–52: For example, a solution of race-

mic acid (Ϯ)-4 (0.101 g, 0.411 mmol), (1R,3R,4S)-(–)-menthol

(0.071 g, 0.45 mmol), 1,3-dicyclohexylcarbodiimide (DCC, 0.102 g,

0.512 g, 92%. IR (KBr): ν = 3851, 2939, 1708, 1131, 1096, 1051,

˜

812, 785, 745 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.03 (s, 3 H),

2.59 (s, 3 H), 3.26 (s, 3 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.38–7.44 (m,

2 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.76–7.80 (m, 1 H), 8.34–8.37 (m,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 23.3, 23.5, 52.0, 83.9,

124.7, 124.8, 125.9, 128.7, 131.0, 132.2, 132.9, 135.0, 176.4 ppm.

C₁₅H₁₆O₃(244.29): calcd. C 73.75, H 6.60; found C 73.58, H 6.61.

0.49 mmol),

4-(dimethylamino)pyridine

(DMAP,

0.025 g,

0.21 mmol), and 10-camphorsulfonic acid (CSA, 0.010 g,

0.041 mmol) in dichloromethane (0.4 mL) was stirred at room tem-

perature for 1 d. After the addition of a small amount of water,

stirring for 1 h, and the addition of diethyl ether and anhydrous

MgSO₄, the mixture was filtered with Celite, which was washed

with EtOAc. The combined organic layers were evaporated under

reduced pressure, and the residue was subjected to a short column

of silica gel (hexane/EtOAc = 20:1). The crude diastereomeric es-

ters obtained were separated by HPLC on silica gel (Ø

25 mmϫ300 mm column, Table 1), giving the first eluted ester 44a

and the second eluted one 44b.

2-Methoxy-2-(2-naphthyl)propionic Acid (5): Yield 98%, faintly yel-

1

low powder. H NMR (400 MHz, CDCl₃): δ = 1.95 (s, 3 H), 3.30

(s, 3 H), 7.47–7.52 (m, 2 H), 7.55 (dd, J = 8.8, 2.0 Hz, 1 H), 7.85

(br. d, J = 8.8 Hz, 1 H), 7.80–7.88 (m, 2 H), 7.95 (br. d, J = 2.0 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.7, 51.8, 81.4,

123.7, 125.8, 126.4, 126.6, 127.5, 128.3, 128.5, 133.0, 133.1, 136.2,

175.6 ppm.

2-Methoxy-2-phenylpropionic Acid (7): Yield 96%, pale yellow oil.

IR (neat): ν = 3183, 3062, 2989, 2942, 2834, 1716, 1600, 1495, 1448,

(1R,3R,4S)-Menthyl 2-Methoxy-2-(2-methyl-1-naphthyl)propionate

˜

1373, 1339, 1223, 1196, 1142, 1123, 1075, 1047, 889, 770, 721, 699, (44a): Yield 0.085 g, 49%; colorless solid. ¹H NMR (600 MHz,

658, 638, 430 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.84 (s, 3 H),

3.27 (s, 3 H), 7.31–7.40 (m, 3 H), 7.47–7.49 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 20.7, 51.7, 81.3, 126.2, 128.4, 128.6,

138.9 ppm.

CDCl₃): δ = 0.57 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.65 (d, J = 7.0 Hz,

3 H, iPr CH₃), 0.79 (dddd, J = 13.0, 12.8, 11.9, 3.2 Hz, 1 H, 6ax-

H), 0.88 (d, J = 6.6 Hz, 3 H, 1-CH₃), 0.90 (ddd, J = 11.9, 11.9,

11.0 Hz, 1 H, 2ax-H), 0.98 (dddd, J = 13.0, 13.0, 12.8, 3.5 Hz, 1

1822

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Eur. J. Org. Chem. 2007, 1811–1826

1

Chiral Conformation and H NMR Anisotropy of MαNP Esters

FULL PAPER

H, 5ax-H), 1.23–1.39 (m, 2 H, 4-H, iPr CH), 1.47 (m, 1 H, 1-H),

1.58 (dddd, J = 13.4, 3.3, 3.3, 3.2 Hz, 1 H, 5eq-H), 1.63 (dddd, J

H, 3-H), 7.38–7.49 (m, 2 H, 6Ј-H, 7Ј-H), 7.58 (dd, J = 8.5, 2.0 Hz,

1 H, 3Ј-H), 7.82 (d, J = 8.5 Hz, 1 H, 4Ј-H), 7.80–7.84 (m, 2 H, 5Ј-

= 13.0, 5.3, 3.3, 3.3 Hz, 1 H, 6eq-H), 1.99 (s, 3 H, CH₃), 2.07 (dddd, H, 8Ј-H), 7.93 (d, J = 2.0 Hz, 1 H, 1Ј-H) ppm. ¹³C NMR

J = 11.9, 4.2, 3.7, 2.0 Hz, 1 H, 2eq-H), 2.57 (s, 3 H, aromatic CH₃),

(150 MHz, CDCl₃): δ = 15.6, 20.5, 21.6, 22.0, 22.9, 25.6, 31.3, 34.1,

3.25 (s, 3 H, OCH₃), 4.66 (ddd, J = 11.0, 11.0, 4.4 Hz, 1 H, 3-H), 40.4, 46.9, 52.0, 75.4, 81.7, 124.0, 125.3, 126.1, 127.5, 127.9, 128.2,

7.22 (d, J = 8.2 Hz, 1 H, 3Ј-H), 7.33–7.38 (m, 2 H, 6Ј-H, 7Ј-H),

7.64 (d, J = 8.2 Hz, 1 H, 4Ј-H), 7.73–7.76 (m, 1 H, 5Ј-H), 8.23–

8.26 (m, 1 H, 8Ј-H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 16.0,

20.7, 22.0, 23.0, 23.5, 25.2, 31.3, 34.1, 40.1, 46.6, 51.7, 75.4, 84.3,

124.3, 124.7, 125.6, 127.9, 128.5, 131.1, 131.7, 132.7, 133.9, 134.6,

171.4 ppm.

132.9, 133.0, 138.2, 172.6 ppm. UV (EtOH): λ (ε, Lmol^–1cm^–1) =

275.4 (5,470), 267.8 (5,220), 224.8 (78,710) nm. CD (EtOH): λ (∆ε,

Lmol^–1cm^–1) = 286.2 (–1.3), 276.4 (–2.2), 266.8 (–2.0), 230.4

(–21.2), 217.2 (+22.1) nm.

(1R,3R,4S:S)-(–)-Menthyl 2-Methoxy-2-phenylpropionate (47a):

Yield 43%, colorless oil. [α]²_D²= –84.0 (c = 1.26, CHCl₃). IR (neat):

(1R,3R,4S)-Menthyl 2-Methoxy-2-(2-methyl-1-naphthyl)propionate

(44b): Yield 0.066 g, 42%; colorless solid. ¹H NMR (600 MHz,

CDCl₃): δ = 0.53 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.65 (d, J = 7.0 Hz,

3 H, iPr CH₃), 0.76 (dddd, J = 13.0, 12.8, 11.9, 3.2 Hz, 1 H, 6ax-

H), 0.79 (ddd, J = 11.9, 11.9, 11.0 Hz, 1 H, 2ax-H), 0.85 (d, J =

ν = 2954, 2932, 2870, 1725, 1493, 1449, 1371, 1253, 1195, 1118,

˜

1077, 1050, 982, 962, 917, 843, 773, 726, 698, 647, 543 cm^–1. ¹H

NMR (600 MHz, CDCl₃): δ = 0.58 (d, J = 7.0 Hz, 3 H, iPr CH₃),

0.73 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.84 (dddd, J = 13.0, 13.0, 11.9,

3.5 Hz, 1 H, 6ax-H), 0.88 (d, J = 6.4 Hz, 3 H, 1-CH₃), 0.95 (ddd,

6.6 Hz, 3 H, 1-CH₃), 0.95 (dddd, J = 13.0, 13.0, 12.8, 3.5 Hz, 1 H, J = 12.1, 12.1, 11.0 Hz, 1 H, 2ax-H), 0.99 (dddd, J = 13.4, 13.0,

5ax-H), 1.20 (m, 1 H, 4-H), 1.34 (sept.d, J = 7.0, 2.8 Hz, 1 H, iPr

CH), 1.44 (m, 1 H, 1-H), 1.56 (dddd, J = 13.4, 3.3, 3.3, 3.2 Hz, 1

H, 5eq-H), 1.61 (dddd, J = 13.0, 5.3, 3.3, 3.3 Hz, 1 H, 6eq-H), 1.98

(dddd, J = 11.9, 4.2, 3.7, 2.0 Hz, 1 H, 2eq-H), 2.01 (s, 3 H, CH₃),

2.61 (s, 3 H, aromatic CH₃), 3.21 (s, 3 H, OCH₃), 4.65 (ddd, J =

11.0, 11.0, 4.4 Hz, 1 H, 3-H), 7.21 (d, J = 8.2 Hz, 1 H, 3Ј-H), 7.34–

7.39 (m, 2 H, 6Ј-H, 7Ј-H), 7.64 (d, J = 8.2 Hz, 1 H, 4Ј-H), 7.73–

12.5, 3.3 Hz, 1 H, 5ax-H), 1.35 (dddd, J = 12.5, 11.0, 3.3, 2.9 Hz,

1 H, 4-H), 1.46 (ddqdd, J = 12.1, 11.9, 6.4, 3.7, 3.3 Hz, 1 H, 1-H),

1.48 (sept.d, J = 7.0, 2.9 Hz, 1 H, iPr CH), 1.61 (dddd, J = 13.4,

3.5, 3.3, 3.3 Hz, 1 H, 5eq-H), 1.65 (ddddd, J = 13.0, 3.3, 3.3, 3.1,

2.0 Hz, 1 H, 6eq-H), 1.77 (s, 3 H, CH₃), 1.93 (dddd, J = 12.1, 4.4,

3.7, 2.0 Hz, 1 H, 2eq-H), 3.31 (s, 3 H, OCH₃), 4.70 (ddd, J = 11.0,

11.0, 4.4 Hz, 1 H, 3-H), 7.26–7.28 (m, 1 H, 4Ј-H), 7.31–7.35 (m, 2

7.76 (m, 1 H, 5Ј-H), 8.34–8.36 (m, 1 H, 8Ј-H) ppm. ¹³C NMR H, 3Ј-H), 7.46–7.48 (m, 2 H, 2Ј-H) ppm. ¹³C NMR (150 MHz,

(150 MHz, CDCl₃): δ = 15.7, 20.6, 22.0, 23.0, 23.9, 23.9, 25.4, 31.3,

34.1, 40.1, 46.8, 51.4, 75.2, 84.1, 124.4, 125.3, 125.7, 128.1, 128.4,

131.2, 132.2, 132.8, 133.2, 134.9, 172.0 ppm.

CDCl₃): δ = 15.7, 20.6, 22.0, 22.1, 23.0, 25.6, 31.4, 34.2, 40.4, 46.9,

52.1, 75.3, 81.9, 125.6, 126.1, 127.7, 128.1, 141.3, 172.5 ppm. UV

(EtOH): λ (ε, Lmol^–1cm^–1) = 263.6 (170), 258.2 (210) nm. CD

(EtOH): λ (∆ε, Lmol^–1cm^–1) = 238.4 (–2.7), 213.8 (+2.6) nm.

C₂₀H₃₀O₃(318.46): calcd. C 75.43, H 9.50; found C 75.46, H 9.34.

(1R,3R,4S)-Menthyl 2-Methoxy-2-(2-naphthyl)propionate (45a):

Yield 49%, colorless oil. IR (neat): ν = 2954, 2870, 1725, 1507,

˜

1456, 1371, 1254, 1184, 1119, 962, 897, 858, 819, 749, 477 cm^–1. ¹H

(1R,3R,4S:R)-(–)-Menthyl 2-Methoxy-2-phenylpropionate (47b):

NMR (600 MHz, CDCl₃): δ = 0.56 (d, J = 7.0 Hz, 3 H, iPr CH₃), Yield 43%, colorless oil. [α]²_D³= –68.5 (c = 1.26, CHCl₃). IR (neat):

0.64 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.80 (dddd, J = 12.8, 12.8, 11.9, ν = 2955, 2870, 1725, 1495, 1450, 1371, 1253, 1195, 1138, 1116,

˜

3.5 Hz, 1 H, 6ax-H), 0.86 (d, J = 6.6 Hz, 3 H, 1-CH₃), 0.95 (ddd, 1078, 1050, 982, 962, 916, 846, 773, 727, 699, 646, 569, 508 cm^–1.

J = 11.9, 11.9, 11.2 Hz, 1 H, 2ax-H), 0.98 (dddd, J = 13.4, 12.8, ¹H NMR (600 MHz, CDCl₃): δ = 0.56 (d, J = 7.0 Hz, 3 H, iPr

12.8, 3.3 Hz, 1 H, 5ax-H), 1.33 (dddd, J = 12.8, 11.0, 3.5, 3.3 Hz, CH₃), 0.71 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.81 (dddd, J = 13.0,

1 H, 4-H), 1.46 (ddqdd, J = 12.8, 11.9, 6.6, 3.4, 3.4 Hz, 1 H, 1-H),

1.47 (sept.d, J = 7.0, 3.3 Hz, 1 H, iPr CH), 1.59 (dddd, J = 13.4,

6.8, 3.5, 3.5 Hz, 1 H, 5eq-H), 1.63 (ddddd, J = 12.8, 6.8, 3.3, 3.3,

1.5 Hz, 1 H, 6eq-H), 1.86 (s, 3 H, CH₃), 1.94 (dddd, J = 11.9, 4.2,

3.4, 1.5 Hz, 1 H, 2eq-H), 3.35 (s, 3 H, OCH₃), 4.74 (ddd, J = 11.2,

12.8, 12.4, 3.5 Hz, 1 H, 6ax-H), 0.87 (d, J = 6.6 Hz, 3 H, 1-CH₃),

0.90 (ddd, J = 12.1, 11.0, 11.0 Hz, 1 H, 2ax-H), 0.97 (dddd, J =

12.8, 12.8, 12.8, 3.5 Hz, 1 H, 5ax-H), 1.29 (dddd, J = 12.8, 11.0,

3.2, 2.9 Hz, 1 H, 4-H), 1.41 (sept.d, J = 7.0, 2.9 Hz, 1 H, iPr CH),

1.47 (ddqdd, J = 12.4, 11.0, 7.0, 3.7, 3.3 Hz, 1 H, 1-H), 1.60 (dddd,

11.0, 4.2 Hz, 1 H, 3-H), 7.45–7.49 (m, 2 H, 6Ј-H, 7Ј-H), 7.56 (dd, J = 12.8, 3.5, 3.2, 3.2 Hz, 1 H, 5eq-H), 1.64 (ddddd, J = 13.0, 3.5,

J = 8.6, 1.9 Hz, 1 H, 3Ј-H), 7.81 (d, J = 8.6 Hz, 1 H, 4Ј-H), 7.80– 3.3, 3.2, 2.0 Hz, 1 H, 6eq-H), 1.79 (s, 3 H, CH₃), 1.94 (dddd, J =

7.84 (m, 2 H, 5Ј-H, 8Ј-H), 7.95 (d, J = 1.9 Hz, 1 H, 1Ј-H) ppm. 12.1, 4.4, 3.7, 2.0 Hz, 1 H, 2eq-H), 3.27 (s, 3 H, OCH₃), 4.65 (ddd,

¹³C NMR (150 MHz, CDCl₃): δ = 15.7, 20.6, 22.0, 22.1, 22.9, 25.6,

31.4, 34.1, 40.4, 46.8, 52.1, 75.4, 82.0, 123.7, 126.1, 126.1, 127.5,

J = 11.0, 11.0, 4.4 Hz, 1 H, 3-H), 7.26–7.29 (m, 1 H, 4Ј-H), 7.32–

7.35 (m, 2 H, 3Ј-H), 7.45–7.47 (m, 2 H, 2Ј-H) ppm. ¹³C NMR

127.9, 128.3, 132.8, 133.0, 138.7, 172.5 ppm. UV (EtOH): λ (ε, (150 MHz, CDCl₃): δ = 15.7, 20.7, 21.4, 22.0, 23.0, 25.6, 31.3, 34.2,

Lmol^–1cm^–1) = 275.2 (5,530), 224.4 (80,340) nm. CD (EtOH): λ

(∆ε, Lmol^–1cm^–1) = 239.0 (–6.7), 222.0 (+18.6) nm.

40.4, 46.9, 51.9, 75.3, 81.5, 126.1, 127.8, 128.1, 140.8, 172.6 ppm.

UV (EtOH): λ (ε, Lmol^–1cm^–1) = 263.8 (160), 258.2 (200) nm. CD

(EtOH): λ (∆ε, Lmol^–1cm^–1) = 269.2 (+0.05), 263.6 (+0.07), 243.8

(+0.57), 224.4 (–3.78), 215.4 (–3.29) nm. C₂₀H₃₀O₃(318.46): calcd.

C 75.43, H 9.50; found C 75.26, H 9.41.

(1R,3R,4S)-Menthyl 2-Methoxy-2-(2-naphthyl)propionate (45b):

Yield 42%, colorless oil. IR (neat): ν = 2954, 1725, 1507, 1456,

˜

1

1371, 1251, 1184, 1114, 961, 819, 749 cm^–1. H NMR (600 MHz,

CDCl₃): δ = 0.52 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.59 (d, J = 7.0 Hz,

3 H, iPr CH₃), 0.79 (dddd, J = 13.0, 13.0, 11.8, 3.5 Hz, 1 H, 6ax-

H), 0.86 (d, J = 6.6 Hz, 3 H, 1-CH₃), 0.91 (ddd, J = 12.0, 12.0,

11.0 Hz, 1 H, 2ax-H), 0.96 (dddd, J = 13.4, 13.0, 12.8, 3.5 Hz, 1

H, 5ax-H), 1.27 (dddd, J = 12.8, 10.8, 3.5, 2.8 Hz, 1 H, 4-H), 1.38

(sept.d, J = 7.0, 2.8 Hz, 1 H, iPr CH), 1.46 (ddqdd, J = 12.0, 11.8,

6.6, 3.7, 3.5 Hz, 1 H, 1-H), 1.57 (dddd, J = 13.4, 6.8, 3.5, 3.5 Hz,

1 H, 5eq-H), 1.63 (ddddd, J = 13.0, 6.8, 3.5, 3.5, 1.6 Hz, 1 H, 6eq-

H), 1.89 (s, 3 H, CH₃), 1.96 (dddd, J = 12.0, 4.4, 3.7, 1.6 Hz, 1 H,

2eq-H), 3.31 (s, 3 H, OCH₃), 4.68 (ddd, J = 11.0, 10.8, 4.4 Hz, 1

(1R,3R,4S)-(–)-Menthyl 2-Methoxy-2-(4-methoxyphenyl)propionate

(48a): Yield 41%, colorless solid. [α]²_D²= –65.1 (c = 1.20, CHCl₃).

IR (KBr): ν = 2954, 2870, 2833, 1725, 1611, 1583, 1510, 1456, 1370,

˜

1302, 1249, 1178, 1118, 1079, 1051, 1035, 1009, 981, 962, 918, 885,

1

833, 808, 791, 740, 614, 545 cm^–1. H NMR (600 MHz, CDCl₃): δ

= 0.61 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.76 (d, J = 7.0 Hz, 3 H, iPr

CH₃), 0.82 (dddd, J = 13.0, 12.7, 12.5, 3.3 Hz, 1 H, 6ax-H), 0.87

(d, J = 6.6 Hz, 3 H, 1-CH₃), 0.93 (ddd, J = 12.1, 12.1, 11.0 Hz, 1

H, 2ax-H), 1.00 (dddd, J = 13.4, 12.7, 12.3, 3.2 Hz, 1 H, 5ax-H),

1.36 (dddd, J = 12.3, 11.0, 3.4, 2.9 Hz, 1 H, 4-H), 1.47 (ddqdd, J

Eur. J. Org. Chem. 2007, 1811–1826

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1823

N. Harada et al.

FULL PAPER

= 12.5, 12.1, 6.6, 3.7, 3.2 Hz, 1 H, 1-H), 1.56 (sept.d, J = 7.0,

2.9 Hz, 1 H, iPr CH), 1.62 (dddd, J = 13.4, 3.3, 3.3, 3.3 Hz, 1 H,

5eq-H), 1.65 (ddddd, J = 13.0, 3.3, 3.2, 3.2, 2.0 Hz, 1 H, 6eq-H),

1.75 (s, 3 H, CH₃), 1.92 (dddd, J = 12.1, 4.4, 3.7, 2.0 Hz, 1 H, 2eq-

H), 3.28 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃), 4.70 (ddd, J = 11.0,

11.0, 4.4 Hz, 1 H, 3-H), 6.85–6.88 (m, 2 H, 3Ј-H), 7.37 (m, 2 H,

2Ј-H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.7, 20.7, 22.0,

3.5 Hz, 1 H, 6ax-H), 0.88 (d, J = 6.5 Hz, 3 H, 1-CH₃), 0.91 (ddd,

J = 12.1, 12.1, 11.0 Hz, 1 H, 2ax-H), 0.98 (dddd, J = 13.0, 12.8,

12.4, 3.3 Hz, 1 H, 5ax-H), 1.29 (dddd, J = 12.4, 11.0, 3.3, 2.8 Hz,

1 H, 4-H), 1.41 (sept.d, J = 7.0, 2.8 Hz, 1 H, iPr CH), 1.47 (ddqdd,

J = 12.1, 11.9, 6.5, 3.6, 3.1 Hz, 1 H, 1-H), 1.60 (dddd, J = 12.8,

3.5, 3.3, 3.1 Hz, 1 H, 5eq-H), 1.64 (ddddd, J = 13.0, 3.3, 3.1, 3.1,

2.0 Hz, 1 H, 6eq-H), 1.77 (s, 3 H, CH₃), 1.95 (dddd, J = 12.1, 4.4,

22.0, 23.0, 25.7, 31.4, 34.2, 40.4, 46.9, 51.9, 55.3, 75.2, 81.4, 113.5, 3.6, 2.0 Hz, 1 H, 2eq-H), 3.27 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃),

127.1, 133.3, 159.1, 172.7 ppm. UV (EtOH): λ (ε, Lmol^–1cm^–1) =

4.65 (ddd, J = 11.0, 11.0, 4.4 Hz, 1 H, 3-H), 6.82–6.84 (m, 1 H, 4Ј-

280.8 (1,300), 274.0 (1,500), 229.8 (10,100) nm. CD (EtOH): λ (∆ε, H), 7.02–7.03 (m, 1 H, 6Ј-H), 7.03–7.04 (m, 1 H, 2Ј-H), 7.23–7.26

Lmol^–1cm^–1) = 246.4 (–2.62), 225.2 (+4.36), 208.0 (+2.49) nm.

C₂₁H₃₂O₄(348.48): calcd. C 72.38, H 9.26; found C 72.45, H 9.26.

(m, 1 H, 5Ј-H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.7, 20.7,

21.3, 22.0, 23.0, 25.6, 31.3, 34.2, 40.5, 46.9, 51.8, 55.3, 75.3, 81.4,

111.7, 113.6, 118.5, 129.1, 142.4, 159.6, 172.4 ppm. UV (EtOH): λ

(ε, Lmol^–1cm^–1) = 276.0 (2,400), 218.0 (8,700) nm. CD (EtOH): λ

(∆ε, Lmol^–1cm^–1) = 245.6 (+0.42), 229.8 (–4.94), 202.4 (+9.05) nm.

C₂₁H₃₂O₄(348.48): calcd. C 72.38, H 9.26; found C 72.33, H 9.22.

(1R,3R,4S)-(–)-Menthyl 2-Methoxy-2-(4-methoxyphenyl)propionate

(48b): Yield 40%, colorless oil. [α]²_D⁴= –65.8 (c = 0.88, CHCl₃). IR

(neat): ν = 2954, 2870, 1725, 1610, 1510, 1455, 1370, 1302, 1249,

˜

1179, 1115, 1035, 962, 833, 539 cm^–1. ¹H NMR (600 MHz, CDCl₃):

δ = 0.57 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.72 (d, J = 7.0 Hz, 3 H,

iPr CH₃), 0.81 (dddd, J = 13.2, 13.0, 11.9, 3.5 Hz, 1 H, 6ax-H),

0.84 (d, J = 6.6 Hz, 3 H, 1-CH₃), 0.91 (ddd, J = 12.1, 12.1, 11.0 Hz,

1 H, 2ax-H), 0.98 (dddd, J = 13.3, 13.2, 12.6, 3.5 Hz, 1 H, 5ax-H),

1.29 (dddd, J = 12.6, 11.0, 3.3, 2.8 Hz, 1 H, 4-H), 1.43 (sept.d, J =

(1R,3R,4S)-Menthyl

2-Methoxy-2-(2-methoxyphenyl)propionate

(50a): Colorless crystal. M.p. 97–98 °C. ¹H NMR (600 MHz,

CDCl₃): δ = 0.69 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.74 (d, J = 7.0 Hz,

3 H, iPr CH₃), 0.81 (dddd, J = 13.0, 12.1, 12.1, 3.5 Hz, 1 H, 6ax-

H), 0.89 (d, J = 6.5 Hz, 3 H, 1-CH₃), 0.93 (ddd, J = 12.1, 12.1,

7.0, 2.9 Hz, 1 H, iPr CH), 1.47 (ddqdd, J = 12.1, 11.9, 6.6, 3.5, 10.8 Hz, 1 H, 2ax-H), 1.01 (dddd, J = 13.0, 13.0, 12.7, 3.3 Hz, 1

3.3 Hz, 1 H, 1-H), 1.60 (dddd, J = 13.3, 3.5, 3.3, 3.3 Hz, 1 H, 5eq-

H), 1.65 (ddddd, J = 13.0, 3.5, 3.3, 3.3, 2.0 Hz, 1 H, 6eq-H), 1.77

(s, 3 H, CH₃), 1.94 (dddd, J = 12.1, 4.4, 3.5, 2.0 Hz, 1 H, 2eq-H),

3.24 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃), 4.65 (ddd, J = 11.0, 11.0,

H, 5ax-H), 1.29 (dddd, J = 12.7, 10.9, 3.1, 3.1 Hz, 1 H, 4-H), 1.49

(ddqdd, J = 12.1, 12.1, 6.5, 3.5, 3.3 Hz, 1 H, 1-H), 1.61 (dddd, J =

13.0, 3.5, 3.3, 3.1 Hz, 1 H, 5eq-H), 1.63 (sept.d, J = 7.0, 3.1 Hz, 1

H, iPr CH), 1.65 (ddddd, J = 12.1, 3.3, 3.3, 3.3, 2.0 Hz, 1 H, 6eq-

4.4 Hz, 1 H, 3-H), 6.85–6.88 (m, 2 H, 3Ј-H), 7.37–7.39 (m, 2 H, 2Ј- H), 1.67 (s, 3 H, CH₃), 2.10 (dddd, J = 12.1, 4.4, 3.5, 2.0 Hz, 1 H,

H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.7, 20.7, 21.3, 22.0,

2eq-H), 3.30 (s, 3 H, OCH₃), 3.74 (s, 3 H, OCH₃), 4.66 (ddd, J =

23.0, 25.6, 31.3, 34.2, 40.5, 46.9, 51.7, 55.3, 75.2, 81.0, 113.5, 127.5, 10.9, 10.8, 4.4 Hz, 1 H, 3-H), 6.82 (dd, J = 8.2, 1.1 Hz, 1 H, 3Ј-H),

132.8, 159.2, 172.8 ppm. UV (EtOH): λ (ε, Lmol^–1cm^–1) = 281.0

6.98 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H, 5Ј-H), 7.27 (ddd, J = 8.2, 7.5,

(1,500), 274.2 (1,700), 231.0 (10,900) nm. CD (EtOH): λ (∆ε, 1.6 Hz, 1 H, 4Ј-H), 7.58 (dd, J = 7.5, 1.6 Hz, 1 H, 6Ј-H) ppm. ¹³C

Lmol^–1cm^–1) = 281.8 (–0.49), 273.8 (–0.59), 249.6 (+0.41), 234.6

NMR (150 MHz, CDCl₃): δ = 15.9, 20.7, 21.1, 22.1, 23.0, 25.5,

(–5.01), 219.6 (+0.31), 207.0 (–2.97) nm. C₂₁H₃₂O₄(348.48): calcd. 31.3, 34.2, 40.4, 46.5, 51.5, 54.9, 75.0, 79.4, 110.1, 120.4, 126.4,

C 72.38, H 9.26; found C 72.43, H 9.31. 126.4, 128.7, 130.4, 155.8, 171.8 ppm.

(1R,3R,4S)-(–)-Menthyl 2-Methoxy-2-(3-methoxyphenyl)propionate (1R,3R,4S)-Menthyl

2-Methoxy-2-(2-methoxyphenyl)propionate

1

(49a): Yield 43%, colorless oil. [α]²_D⁵= –82.7 (c = 1.22, CHCl₃). IR

(50b): Colorless solid. H NMR (600 MHz, CDCl₃): δ = 0.75 (d, J

(KBr): ν = 2954, 2870, 1725, 1600, 1488, 1455, 1371, 1255, 1179, = 6.9 Hz, 3 H, iPr CH₃), 0.80 (m, 1 H, 6ax-H), 0.81 (d, J = 6.9 Hz,

˜

1117, 1045, 962, 913, 783, 725, 696 cm^–1. ¹H NMR (600 MHz,

CDCl₃): δ = 0.59 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.74 (d, J = 7.0 Hz,

3 H, iPr CH₃), 0.82 (dddd, J = 13.0, 13.0, 11.9, 3.5 Hz, 1 H, 6ax-

H), 0.88 (d, J = 6.4 Hz, 3 H, 1-CH₃), 0.96 (ddd, J = 12.1, 11.9,

11.0 Hz, 1 H, 2ax-H), 0.99 (dddd, J = 13.1, 13.0, 12.3, 3.5 Hz, 1

H, 5ax-H), 1.36 (dddd, J = 12.3, 11.0, 3.3, 2.9 Hz, 1 H, 4-H), 1.47

(ddqdd, J = 12.1, 11.9, 6.4, 4.2, 3.5 Hz, 1 H, 1-H), 1.51 (sept.d, J

= 7.0, 2.9 Hz, 1 H, iPr CH), 1.62 (dddd, J = 13.1, 3.5, 3.3, 3.3 Hz,

1 H, 5eq-H), 1.65 (ddddd, J = 13.0, 3.5, 3.5, 3.3, 2.0 Hz, 1 H, 6eq-

H), 1.75 (s, 3 H, CH₃), 1.94 (dddd, J = 11.9, 4.4, 4.2, 2.0 Hz, 1 H,

3 H, iPr CH₃), 0.85 (ddd, J = 12.1, 11.9, 10.8 Hz, 1 H, 2ax-H),

0.88 (d, J = 6.6 Hz, 3 H, 1-CH₃), 1.03 (dddd, J = 13.5, 13.0, 12.5,

3.3 Hz, 1 H, 5ax-H), 1.30 (dddd, J = 12.5, 11.0, 3.1, 3.1 Hz, 1 H,

4-H), 1.49 (m, 1 H, 1-H), 1.62 (dddd, J = 13.0, 3.3, 3.3, 3.1 Hz, 1

H, 5eq-H), 1.65 (m, 1 H, 6eq-H), 1.67 (s, 3 H, CH₃), 1.82 (sept.d,

J = 6.9, 2.8 Hz, 1 H, iPr CH), 2.04 (dddd, J = 11.9, 4.4, 3.7, 2.0 Hz,

1 H, 2eq-H), 3.26 (s, 3 H, OCH₃), 3.74 (s, 3 H, OCH₃), 4.70 (ddd,

J = 10.8, 10.8, 4.4 Hz, 1 H, 3-H), 6.84 (dd, J = 8.3, 1.0 Hz, 1 H,

3Ј-H), 6.98 (ddd, J = 7.7, 7.7, 1.0 Hz, 1 H, 5Ј-H), 7.27 (ddd, J =

8.3, 7.7, 1.6 Hz, 1 H, 4Ј-H), 7.53 (dd, J = 7.7, 1.6 Hz, 1 H, 6Ј-H)

2eq-H), 3.31 (s, 3 H, OCH₃), 3.80 (s, 3 H, OCH₃), 4.70 (ddd, J = ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 16.1, 20.7, 21.3, 22.1, 23.2,

11.0, 11.0, 4.4 Hz, 1 H, 3-H), 6.82 (ddd, J = 8.0, 2.4, 1.0 Hz, 1 H, 25.7, 31.3, 40.3, 46.6, 51.5, 54.9, 74.7, 79.5, 110.3, 120.3, 126.7,

4Ј-H), 7.03 (ddd, J = 8.0, 1.7, 1.0 Hz, 1 H, 6Ј-H), 7.05 (dd, J = 2.4, 128.7, 130.3, 156.0, 171.9 ppm.

1.7 Hz, 1 H, 2Ј-H), 7.24 (dd, J = 8.0, 8.0 Hz, 1 H, 5Ј-H) ppm. ¹³C

(1R,3R,4S)-(–)-Menthyl 2-Methoxy-2-(2-methylphenyl)propionate

NMR (150 MHz, CDCl₃): δ = 15.7, 20.7, 22.0, 22.2, 23.0, 25.6,

31.4, 34.2, 40.5, 46.9, 52.1, 55.2, 75.4, 81.8, 111.2, 113.5, 118.0,

129.1, 143.0, 159.6, 172.4 ppm. UV (EtOH): λ (ε, Lmol^–1cm^–1) =

274.8 (1,700), 219.2 (6,400) nm. CD (EtOH): λ (∆ε, Lmol^–1cm^–1)

= 286.0 (–0.14), 264.0 (+0.02), 239.8 (–2.62), 230.0 (–1.12), 223.6

(–2.11), 201.2 (+3.84) nm. C₂₁H₃₂O₄(348.48): calcd. C 72.38, H

9.26; found C 72.29, H 9.12.

(51a): Yield 49%, colorless oil. [α]²_D⁴= –28.4 (c = 1.07, CHCl₃). IR

(neat): ν = 2955, 2870, 1726, 1455, 1386, 1369, 1252, 1187, 1129,

˜

1

1049, 982, 962, 918, 889, 845, 761, 740, 644, 593 cm^–1. H NMR

(600 MHz, CDCl₃): δ = 0.72 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.79

(dddd, J = 13.9, 13.9, 11.9, 4.3 Hz, 1 H, 6ax-H), 0.82 (d, J = 7.0 Hz,

3 H, iPr CH₃), 0.83 (ddd, J = 12.1, 12.1, 11.0 Hz, 1 H, 2ax-H),

0.86 (d, J = 6.6 Hz, 3 H, 1-CH₃), 1.01 (dddd, J = 13.9, 13.1, 12.4,

(1R,3R,4S)-(–)-Menthyl 2-Methoxy-2-(3-methoxyphenyl)propionate 3.3 Hz, 1 H, 5ax-H), 1.31 (dddd, J = 12.4, 11.0, 3.1, 2.9 Hz, 1 H,

(49b): Yield 39%, colorless oil. [α]²_D⁵= –56.0 (c = 1.02, CHCl₃). ¹H

NMR (600 MHz, CDCl₃): δ = 0.56 (d, J = 7.0 Hz, 3 H, iPr CH₃),

4-H), 1.47 (ddqdd, J = 12.1, 11.9, 6.6, 3.5, 3.1 Hz, 1 H, 1-H), 1.62

(dddd, J = 13.1, 4.3, 3.1, 3.1 Hz, 1 H, 5eq-H), 1.64 (ddddd, J =

0.71 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.81 (dddd, J = 13.0, 13.0, 11.9, 13.9, 3.3, 3.1, 3.1, 1.8 Hz, 1 H, 6eq-H), 1.77 (sept.d, J = 7.0, 2.9 Hz,

1824

www.eurjoc.org

Eur. J. Org. Chem. 2007, 1811–1826

1

Chiral Conformation and H NMR Anisotropy of MαNP Esters

FULL PAPER

1 H, iPr CH), 1.81 (s, 3 H, CH₃), 1.96 (dddd, J = 12.1, 4.4, 3.5,

1.8 Hz, 1 H, 2eq-H), 2.34 (s, 3 H, CH₃), 3.10 (s, 3 H, OCH₃), 4.71

(dddd, J = 13.2, 12.8, 12.6, 3.5 Hz, 1 H, 5ax-H), 1.20 (dddd, J =

12.6, 10.8, 3.1, 2.7 Hz, 1 H, 4-H), 1.23 (sept.d, J = 7.0, 2.7 Hz, 1

(ddd, J = 11.0, 11.0, 4.4 Hz, 1 H, 3-H), 7.14 (m, 1 H), 7.18 (m, 1 H, iPr CH), 1.47 (ddqdd, J = 12.1, 11.9, 6.6, 3.7, 3.3 Hz, 1 H, 1-

H), 7.21 (ddd, J = 7.0, 7.0, 1.6 Hz, 1 H), 7.39 (dd, J = 7.5, 1.6 Hz,

H), 1.57 (dddd, J = 13.2, 3.5, 3.3, 3.1 Hz, 1 H, 5eq-H), 1.64 (ddddd,

J = 12.8, 3.5, 3.3, 3.3, 2.0 Hz, 1 H, 6eq-H), 1.84 (s, 3 H, CH₃), 2.03

1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.8, 20.2, 20.8, 21.4,

22.0, 22.9, 25.8, 31.3, 34.1, 40.1, 46.6, 50.7, 75.2, 81.6, 125.4, 127.2, (dddd, J = 11.9, 4.4, 3.7, 2.0 Hz, 1 H, 2eq-H), 3.13 (s, 3 H, OCH₃),

127.9, 131.6, 137.0, 137.7, 173.1 ppm. UV (EtOH):

λ

(ε,

3.41 (s, 3 H, OCH₃), 4.48 (d, J = 13.2 Hz, 1 H, OCH), 4.62 (ddd,

J = 10.8, 10.8, 4.4 Hz, 1 H, 3-H), 4.66 (d, J = 13.2 Hz, 1 H, OCH),

Lmol^–1cm^–1) = 272.2 (260), 265.2 (310), 209.6sh (7,800) nm. CD

(EtOH): λ (∆ε, Lmol^–1cm^–1) = 272.8 (–0.26), 266.6 (–0.29), 242.8 7.26 (m, 1 H), 7.32 (ddd, J = 7.8, 7.8, 1.3 Hz, 1 H), 7.35 (dd, J =

(–0.41), 216.0 (+5.35) nm. C₂₁H₃₂O₃(332.48): calcd. C 75.86, H

9.70; found C 75.71, H 9.70.

7.8, 1.3 Hz, 1 H), 7.57 (m, 1 H) ppm. ¹³C NMR (150 MHz,

CDCl₃): δ = 16.0, 20.7, 21.9, 22.2, 23.3, 25.7, 31.5, 34.4, 40.5, 47.0,

51.0, 58.7, 71.6, 75.6, 81.7, 127.0, 127.7, 128.3, 128.4, 136.6, 138.2,

172.9 ppm. UV (EtOH): λ (ε, Lmol^–1cm^–1) = 264.6 (370), 210.2sh

(9,600) nm. CD (EtOH): λ (∆ε, Lmol^–1cm^–1) = 272.4 (+0.41), 265.8

(+0.48), 229.8 (–3.23), 215.8 (–8.68) nm.

(1R,3R,4S)-(–)-Menthyl 2-Methoxy-2-(2-methylphenyl)propionate

(51b): Yield 48%, colorless oil. [α]²_D⁴= –83.2 (c = 1.04, CHCl₃). IR

(neat): ν = 2954, 2870, 1747, 1455, 1386, 1369, 1250, 1189, 1134,

˜

1

1098, 1039, 982, 963, 918, 889, 844, 761, 740, 664 cm^–1. H NMR

Recovery of Enantiopure Carboxylate: For example, to a solution

of ester (–)-47a (0.0253 g, 0.0794 mmol) in MeOH (1.2 mL) was

added a solution of KOH (0.201 g, 3.58 mmol) in water (0.3 mL),

and the mixture was gently refluxed for 27 h. After the addition of

water, the mixture was extracted with diethyl ether, and the aqueous

layer was acidified with 2  HCl at 0 °C and then extracted with

EtOAc. The organic layer was washed with brine, dried with anhy-

drous MgSO₄, and the solvent was evaporated to dryness, yielding

carboxylic acid (S)-(+)-7 as a colorless syrup.

(600 MHz, CDCl₃): δ = 0.57 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.64

(d, J = 7.0 Hz, 3 H, iPr CH₃), 0.80 (dddd, J = 13.2, 13.0, 11.9,

3.5 Hz, 1 H, 6ax-H), 0.89 (d, J = 6.6 Hz, 3 H, 1-CH₃), 0.92 (ddd,

J = 12.1, 12.1, 10.8 Hz, 1 H, 2ax-H), 0.96 (dddd, J = 13.3, 13.0,

12.4, 3.5 Hz, 1 H, 5ax-H), 1.20 (dddd, J = 12.4, 10.8, 2.9, 2.8 Hz,

1 H, 4-H), 1.25 (sept.d, J = 7.0, 2.8 Hz, 1 H, iPr CH), 1.48 (ddqdd,

J = 12.1, 11.9, 6.6, 3.7, 3.3 Hz, 1 H, 1-H), 1.57 (dddd, J = 13.3,

3.5, 3.5, 2.9 Hz, 1 H, 5eq-H), 1.64 (ddddd, J = 13.2, 3.5, 3.5, 3.3,

2.0 Hz, 1 H, 6eq-H), 1.83 (s, 3 H, CH₃), 2.04 (dddd, J = 12.1, 4.4,

3.7, 2.0 Hz, 1 H, 2eq-H), 2.34 (s, 3 H, CH₃), 3.10 (s, 3 H, OCH₃),

4.64 (ddd, J = 10.8, 10.8, 4.4 Hz, 1 H, 3-H), 7.12–7.13 (m, 1 H),

7.16–7.19 (m, 1 H), 7.20 (ddd, J = 7.1, 7.1, 1.5 Hz, 1 H), 7.35–7.37

(m, 1 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 15.8, 20.2, 20.5,

21.4, 22.0, 23.0, 25.4, 31.3, 34.2, 40.3, 46.8, 50.5, 75.1, 81.3, 125.4,

127.5, 127.9, 131.6, 137.3, 137.5, 172.9 ppm. UV (EtOH): λ (ε,

Lmol^–1cm^–1) = 272.4 (320), 265.2 (380), 208.6sh (9,500) nm. CD

(EtOH): λ (∆ε, Lmol^–1cm^–1) = 273.0 (+0.64), 266.2 (+0.68), 227.2

(–5.40), 215.4 (–8.81) nm. C₂₁H₃₂O₃(332.48): calcd. C 75.86, H

9.70; found C 75.64, H 9.70.

(S)-(+)-2-Methoxy-2-phenylpropionic Acid (7): Yield 0.0135 g, 94%.

[α]²_D⁷= +51.1 (c = 0.68, CHCl₃); ref.^[18a][α]_D= +31.5 (neat, 0.1 dm)

and [α]_D= +25 (c = 1, MeOH); ref.^[18b]methyl ester, α²_D⁵= +50

(neat, 1 dm). Other spectroscopic data agreed with those of carbox-

ylic acid (Ϯ)-7.

(R)-(–)-2-Methoxy-2-phenylpropionic Acid (7): From ester (–)-47b,

yield 85%, colorless syrup. [α]²_D⁷–50.6 (c = 0.82, CHCl₃); ref.^[18a]

[α]_D= –32.5 (neat, 0.1 dm) and [α]_D= –26 (c = 1, MeOH); ref.^[18b]

methyl ester, α²_D⁴= –52.2 (neat, 1 dm). Other spectroscopic data

agreed with those of carboxylic acid (Ϯ)-7.

(1R,3R,4S)-Menthyl 2-Methoxy-2-(2-methoxymethylphenyl)propi-

onate (52a): Yield 39%, colorless oil. IR (neat): ν = 2955, 2870,

˜

Acknowledgments

2829, 1726, 1455, 1371, 1250, 1192, 1132, 1097, 1068, 962, 918, 844,

1

748 cm^–1. H NMR (600 MHz, CDCl₃): δ = 0.73 (d, J = 7.0 Hz, 3

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

Mazda Foundation (to S. K.), and the Inamori Foundation (to

S. K.).

H, iPr CH₃), 0.78 (m, 1 H, 6ax-H), 0.81 (ddd, J = 12.1, 12.1,

10.9 Hz, 1 H, 2ax-H), 0.83 (d, J = 7.0 Hz, 3 H, iPr CH₃), 0.85 (d,

J = 6.6 Hz, 3 H, 1-CH₃), 1.01 (dddd, J = 12.8, 12.8, 12.5, 3.3 Hz,

1 H, 5ax-H), 1.31 (dddd, J = 12.5, 10.9, 3.1, 2.9 Hz, 1 H, 4-H),

1.46 (m, 1 H, 1-H), 1.61–1.65 (m, 2 H, 5eq-H, 6eq-H), 1.77 (sept.d,

J = 7.0, 2.9 Hz, 1 H, iPr CH), 1.83 (s, 3 H, CH₃), 1.92 (dddd, J =

12.1, 4.4, 3.5, 1.9 Hz, 1 H, 2eq-H), 3.12 (s, 3 H, OCH₃), 3.40 (s, 3

H, OCH₃), 4.52 (d, J = 13.0 Hz, 1 H, OCH), 4.63 (d, J = 13.0 Hz,

1 H, OCH), 4.70 (ddd, J = 10.9, 10.9, 4.4 Hz, 1 H, 3-H), 7.26 (ddd,

J = 8.0, 7.5, 1.4 Hz, 1 H), 7.34 (ddd, J = 7.5, 7.5, 1.3 Hz, 1 H),

7.36 (dd, J = 8.0, 1.3 Hz, 1 H), 7.57 (m, 1 H) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 15.8, 20.7, 21.8, 21.9, 23.0, 25.9, 31.3, 34.1,

40.1, 46.6, 50.8, 58.4, 71.4, 75.5, 81.8, 126.9, 127.2, 128.2, 128.5,

136.9, 137.7, 172.9 ppm. UV (EtOH): λ (ε, Lmol^–1cm^–1) = 264.6

(270), 210.6sh (8,100) nm. CD (EtOH): λ (∆ε, Lmol^–1cm^–1) = 272.4

(–0.25), 265.2 (–0.29), 242.8 (–0.67), 227.8 (+1.65), 215.0 (+5.95)

nm.

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Received: September 29, 2006

Published Online: January 25, 2007

1826

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Eur. J. Org. Chem. 2007, 1811–1826

Article Doi

Conformational analysis of MαNP esters, powerful chiral resolution and 1H NMR anisotropy tools - aromatic geometry and solvent effects on Δδ values

DOI: 10.1002/ejoc.200600856

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