7-Mesityl-2,2-dimethylindan-1-ol: A novel alcohol which serves as both a chiral auxiliary and a protective group for carboxy functions

Article abstract of DOI:10.1039/b109396g

A novel chiral indanol 11 is conveniently synthesized by using a stepwise displacement of the methoxy groups of 2,6-dimethoxybenzoic ester 1 by a vinyl and then an aryl Grignard reagent as the key step. The racemic indanol 11 is optically resolved as the diastereomeric (S_a)-2′-methoxy-1,1′-binaphthyl-2-carboxylic esters 12 by column chromatography. The absolute stereochemistry of the indanol (+)-11 is established to be S by an X-ray crystallographic analysis of the ester (S_a,S)-12. Performance of the indanol 11 as a chiral auxiliary, and as a protective group for the carboxy function, is examined in the atrolactic acid synthesis from phenylglyoxylic ester 13 and methylmagnesium iodide and in the biphenyl coupling reaction of 2,3-dimethoxybenzoic ester 15 with 2-methoxy-4,6-dimethylphenylmagnesium bromide, resulting in quantitative formations of atrolactic ester 14 with up to 83% de and biphenyl 16 with 72% de, respectively.

Full text of DOI:10.1039/b109396g

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7-Mesityl-2,2-dimethylindan-1-ol: a novel alcohol which serves as
both a chiral auxiliary and a protective group for carboxy
functions
1
Eiji Koshiishi, Tetsutaro Hattori,* Naoki Ichihara and Sotaro Miyano*
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University,
Aramaki-Aoba 07, Aoba-ku, Sendai 980-8579, Japan.
E-mail: hattori@orgsynth.che.tohoku.ac.jp; miyano@orgsynth.che.tohoku.ac.jp;
Fax: ϩ81-22-217-7293; Tel: ϩ81-22-217-7263
Received (in Cambridge, UK) 16th October 2001, Accepted 4th December 2001
First published as an Advance Article on the web 11th January 2002
A novel chiral indanol 11 is conveniently synthesized by using a stepwise displacement of the methoxy groups of
2,6-dimethoxybenzoic ester 1 by a vinyl and then an aryl Grignard reagent as the key step. The racemic indanol 11
is optically resolved as the diastereomeric (Sa)-2Ј-methoxy-1,1Ј-binaphthyl-2-carboxylic esters 12 by column
chromatography. The absolute stereochemistry of the indanol (ϩ)-11 is established to be S by an X-ray crystal-
lographic analysis of the ester (Sa,S)-12. Performance of the indanol 11 as a chiral auxiliary, and as a protective group
for the carboxy function, is examined in the atrolactic acid synthesis from phenylglyoxylic ester 13 and methyl-
magnesium iodide and in the biphenyl coupling reaction of 2,3-dimethoxybenzoic ester 15 with 2-methoxy-4,6-
dimethylphenylmagnesium bromide, resulting in quantitative formations of atrolactic ester 14 with up to 83% de
and biphenyl 16 with 72% de, respectively.
tect the carboxy group with the 1- and 8-substituent (b).5
Although they showed intrinsically high chiral induction
ability, their esters were found to readily racemize via the cyclo-
pentadienyl anions under basic conditions. We assumed that
a 2,2-dialkyl-7-arylindan-1-ol skeleton would embody similar
structural features to the fluorenols but resist racemization (c).
Here, we report a convenient synthesis of such an indanol 11
and its optical resolution. Also reported are the performances
Introduction
In the last three decades, diastereoselective asymmetric syn-
theses have enjoyed much success, a large part of which resulted
from the continuing efforts to develop novel chiral auxiliaries.1
Among such entities, cyclohexanol-based chiral auxiliaries,2
especially those bearing an aryl substituent, such as Corey’s 8-
phenylmenthol2b and Whitesell’s trans-2-phenylcyclohexanol,2c
fulfil big roles because of their high stereoselectivity and wide
of the indanol 11 as a chiral auxiliary, as well as a protective
group for the carboxy function.
applicability.1,3 These auxiliaries were designed, when used to
derivatize a carboxylic acid such as an α-keto acid or an α,β-
unsaturated acid, to prevent nucleophiles from attacking from
Results and discussion
one side of the diastereotopic faces of the resulting ester by
virtue of the aryl substituent as schematically visualized in
Fig. 1(a).The auxiliaries, however, will not always be applicable
Synthesis of indanol 11
In previous papers,6,7 we reported that an ester function sub-
stantially activates an ortho alkoxy group for nucleophilic
aromatic substitution (SNAr) reaction by various nucleophiles,
providing a convenient substitute for the oxazoline-mediated
ortho-alkoxy displacement from aryloxazolines (the Meyers
reaction).8 The reaction was advantageously utilized for the
synthesis of the indanol 11 (Scheme 1). Thus, the 2,6-di-tert-
butyl-4-methoxyphenyl ester (BHA ester) of 2,6-dimethoxy-
benzoic acid, ester 1, was allowed to react with 1.4 equiv. of
prop-1-enylmagnesium bromide at room temperature to give
the vinyl benzene 2 in good yield. It has been shown that con-
trol of steric bulk of the ester alkoxy moiety corresponding to
the bulkiness of the Grignard reagents is crucial to obtaining
good results in the ester-mediated SNAr reaction.9 For example,
the BHA ester of 2-methoxybenzoic acid reacted readily with
phenylmagnesium bromide to afford the corresponding bi-
phenyl in almost quantitative yield, but the ester did not react
with bulkier mesitylmagnesium bromide at all. Thus, the BHA
moiety of the ester 2 was replaced with a 2,6-diisopropylphenyl
(DIPP) group to give ester 4 via a transesterification–hydrolysis
sequence9a,10 to acid 3, followed by its esterification with 2,6-
diisopropylphenol. The SNAr reaction of the DIPP ester 4 with
the mesityl Grignard reagent gave the biphenyl 5, which was
Fig. 1 Schematic views of α-keto esters of 8-phenylmenthol a, 1-
methyl-8-phenylfluoren-9-ol b and 2,2-dimethyl-7-phenylindan-1-ol c.
to the system where the nucleophiles are so highly reactive as to
attack the ester carbonyl group, because they are not designed
to work as a protective group for the carboxy function.4
To address this limitation, we recently designed fluoren-9-ols
bearing an alkyl and an aryl substituent at the 1- and 8-
position, respectively, which provide a steric environment quite
similar to those offered by the arylcyclohexanols and may pro-
DOI: 10.1039/b109396g
J. Chem. Soc., Perkin Trans. 1, 2002, 377–383
This journal is © The Royal Society of Chemistry 2002
377

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Scheme
2
Reagents: i, (Sa)-2Ј-methoxy-1,1Ј-binaphthyl-2-carbonyl
chloride, 4-pyrrolidinopyridine, PhMe–pyridine, ii, LAH, THF.
perature but were reductively cleaved with LAH to give the
corresponding enantiomers 11, the optical purities of which
were determined to be 99% ee by chiral HPLC analyses. On the
other hand, the absolute stereochemistry of indanol 11 was
determined to be S-(ϩ) by an X-ray crystallographic analysis
of the ester of indanol (ϩ)-11 [(Sa,S)-12] (Fig. 2).
Scheme 1 Reagents: i, prop-1-enylmagnesium bromide, THF–PhH;
ii, NaOMe, PhMe–HMPA; iii, water; iv, DIPPOH, TFAA, PhH;
v, mesitylmagnesium bromide, Et2O–PhH; vi, SOCl2; vii, SnCl4, PhH;
viii, Et3N, PhH; ix, SiH2Ph2, Pd(PPh3)4, ZnCl2, CHCl3; x, NaH, MeI,
PhH; xi, LAH, THF.
hydrolyzed without purification to give acid 6 in good yield.
It should be noted that an alternative route to the biphenyl 5,
that is, first, mesitylation of the DIPP ester of 2,6-dimethoxy-
benzoic acid and then vinylation of the resulting biphenyl,
resulted in failure because of preferential attack of the prop-1-
enyl Grignard reagent on the ester carbonyl moiety of the
biphenyl during the latter transformation. The vinyl acid 6 was
then subjected to an intramolecular Friedel–Crafts acylation11
after conversion into the acyl chloride. The reaction gave a
mixture of the indenone 7 and its hydrochloric acid adduct 8;
the latter could be converted into the former by treatment
of the mixture with triethylamine. The indenone 7 was then
reduced to the indanone 9 via a palladium-catalyzed hydro-
silylation by using ZnCl2 as the Lewis acid co-catalyst.12
Methylation of the indanone 9, followed by LAH reduction of
the resulting dimethylindanone 10, gave the desired racemic
indanol 11 in 31% yield based on the starting benzoic ester 1.
Fig. 2 ORTEP drawing of ester (Sa,S)-12.
The ORTEP14 drawing of ester (Sa,S)-12 shows that the
carbinyl C–H bond and the carbonyl moiety adopt an almost
eclipsed conformation, the torsion angle being 26.7Њ. As a
result, the 7-mesityl group and the 2,2-dimethyl groups are
positioned on opposite sides of the carbonyl plane to each
other so as to prevent nucleophilic attack at the carbonyl
carbon. In addition, the mesityl group seems to be substantially
bulkier than the dimethyl groups, which allows high diastereo-
selectivity in the auxiliary-based asymmetric reactions to be
achieved.
Optical resolution of the indanol 11 and determination of the
absolute configuration
Recently, we and others have shown that axially chiral 2Ј-
methoxy-1,1Ј-binaphthyl-2-carboxylic acid is very useful as a
chiral auxiliary for enantiomeric resolution of alcohols and
amines, as well as for determination of their absolute stereo-
chemistry by HPLC, 1H NMR or X-ray crystallographic
analysis.5,13 The acid was adopted as a chiral resolving agent
for the indanol 11 (Scheme 2). Thus, racemic indanol 11
was treated with (Sa)-2Ј-methoxy-1,1Ј-binaphthyl-2-carbonyl
chloride to afford a diastereomeric mixture of esters 12, which
could be separated well by column chromatography on silica
gel. The first-eluted fraction was evaporated to give the ester
of indanol (Ϫ)-11 [(Sa,R)-12] in 47% yield, while the second
gave the ester of (ϩ)-11 [(Sa,S)-12] in 42% yield. The diastereo-
merically pure esters 12 could not be hydrolyzed by treatment
with potassium hydroxide in aqueous ethanol at room tem-
Utilization of the indanol 11 as a chiral auxiliary
Atrolactic acid synthesis. Diastereoselective 1,2-addition of
organometallics to α-keto acid derivatives with the aid of
a chiral auxiliary provides an easy access to chiral α,α-
disubstituted α-hydroxy acid derivatives, which are important
intermediates for the synthesis of biologically active natural
products.15 Therefore, a considerable number of studies have
been made to clarify the relationship between the structure
of the auxiliary employed and the diastereoselectivity in the
reaction, and the reaction has sometimes been used to estimate
the intrinsic asymmetric induction ability of an alcohol as a
378
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chiral auxiliary.2 Phenylglyoxylic ester (R)-13 derived from
indanol (R)-11 was treated with methylmagnesium iodide in
diethyl ether–toluene at room temperature to give atrolactic
ester 14, the optical purity of which was determined to be
71% de by 1H NMR analysis (Scheme 3). The de value increased
magnesium bromide was conducted in diethyl ether–toluene
at lower temperature to give the biphenyl 16 in 91% yield with
fairly good diastereoselectivity (72% de) (Scheme 4). The
Scheme 4 Reagents and conditions: i, 2-methoxy-4,6-dimethylphenyl-
magnesium bromide, Et2O–PhMe, Ϫ10
0 ЊC.
induced axis was assigned to be Ra by chemical correlation to
the corresponding carboxylic acid.20c In order to gain insight
into the mechanism of the asymmetric induction, a binaphthyl
coupling reaction was carried out. Thus, the 1-methoxy-2-
naphthoic ester derived from the indanol (R)-11 was allowed to
react with 2-methoxy-1-naphthylmagnesium bromide in diethyl
ether–benzene at room temperature to give the binaphthyl 12
in 85% yield with 49% de. The direction of the preferentially
1
induced binaphthyl axis was determined to be Sa by H NMR
analysis. This agrees with the previous result that (S)-1-
phenylethyl 1-methoxy-2-naphthoate induced an Ra axis in the
binaphthyl coupling reaction.20a Therefore, it may be concluded
that an identical mechanism operates in both cases.20a
In conclusion, we have shown here a convenient method
for the synthesis of the novel indanol 11 by using the
ester-mediated SNAr reaction as the key step. Optical resolu-
tion of the racemic indanol could be achieved by column
chromatography after conversion into the diastereomeric
esters of 2Ј-methoxy-1,1Ј-binaphthyl-2-carboxylic acid. The
indanol showed good performance as a chiral auxiliary, as
well as a protective group, in diastereoselective asymmetric
reactions.
Scheme 3 Reagents: i, MeMgI, Et2O–PhMe.
to 83% when the reaction was carried out at Ϫ78 ЊC. The R
absolute stereochemistry of the induced quaternary carbon
center was established by comparison of the sign of the specific
rotation with that reported in the literature after hydrolysis of
the ester 14. The auxiliary 11 was recovered from the ester 14
without loss of chiral integrity by hydrolysis. The stereo-
chemical course of the reaction can be rationalized by a steric
model depicted in Scheme 3. The crystal structure of ester 12
(Fig. 2) suggests that the O᎐C–O–C–H bonds of the ester 13 lie
᎐
in the same plane, where the carbinyl hydrogen is oriented syn
to the carbonyl group. The two carbonyl groups will adopt a
syn-coplanar conformation due to formation of a magnesium
chelate16 and/or a stabilizing interaction between the mesityl
HOMO and the glyoxyl LUMO,17,18 as suggested in the related
reactions of 8-phenylmenthyl esters.19 Accordingly, the
Grignard reagent will attack the keto carbonyl group from
the opposite face to the mesityl substituent to avoid steric
repulsion, leading to the preferential formation of atrolactic
ester (R,R)-14.
Experimental
Mps were taken using a Mitamura Riken MP-P apparatus and
are uncorrected. Optical rotations were measured on a JASCO
DIP-100 polarimeter and [α]D-values are given in units of
10Ϫ1 deg cm2 gϪ1. Microanalyses were carried out in the Micro-
analytical Laboratory of the Institute of Multidisciplinary
Research for Advanced Materials, Tohoku University. IR
spectra were recorded on a Shimadzu FTIR-8300 spectro-
photometer. 1H NMR spectra were recorded on a Bruker
DPX-400 or DRX-500 spectrometer using tetramethylsilane as
the internal standard and CDCl3 as the solvent. J-Values
are given in Hz. X-ray data† were collected on a Rigaku
AFC7R diffractometer with graphite-monochromated Mo-Kα
radiation and a rotating anode generator, and the structure was
solved by direct methods (SIR9225) and expanded using Fourier
techniques (DIRDIF-9426). Merck silica gel 60GF254 was used
for analytical and preparative TLC (PLC). Silica gel columns
were prepared by use of Merck silica gel 60 (63–200 µm).
Water- and air-sensitive reactions were routinely carried out
under nitrogen. Diethyl ether, THF, benzene and toluene were
distilled from sodium diphenyl ketyl just before use. Other
solvents for experiments requiring anhydrous conditions were
purified by usual methods. Grignard reactions were performed
by a similar procedure to that described in the previous
papers.10,20a
Biphenyl coupling reaction. It has been reported that in the
ester-mediated biaryl coupling reaction, axial chirality of the
biaryl unit can be efficiently induced by central chirality of
the leaving alkoxy20 or sulfinyl 21 group, as well as by planar
chirality of the substrate, such as cyclophanes22 or arene–
chromium complexes.23 However, only poor to moderate
asymmetric induction (up to 56% de) has been achieved by
using a chiral ester group,20a,24 due to the remote location of
the chiral center from the reaction site. In addition, the known
cyclohexanol-based auxiliaries could scarcely be applied to
the asymmetric synthesis of biphenyls, because these alkoxy
moieties cannot protect the ester carbonyl function from
attack by the aryl Grignard reagents (vide supra). To our
pleasure, the reaction of the mesityldimethylindanyl ester of
2,3-dimethoxybenzoic acid, ester 15, with phenylmagnesium
bromide proceeded smoothly in diethyl ether–benzene at room
temperature to give the corresponding biphenyl in 95% yield,
while a control reaction of isopropyl 2,3-dimethoxybenzoate
gave the SNAr product in only 13% yield, accompanied by
formation of the carbonyl addition product, (2,3-dimethoxy-
phenyl)diphenylmethanol, in 31% yield. Asymmetric coupling
of the indanyl ester (R)-15 with 2-methoxy-4,6-dimethylphenyl-
† CCDC reference number(s) 172909. See http://www.rsc.org/suppdata/
p1/b1/b109396g/ for crystallographic files in .cif or other electronic
format.
J. Chem. Soc., Perkin Trans. 1, 2002, 377–383
379

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Synthesis of the indanol 11
s, ArMe), 6.30 (1 H, dq, J 15.6 and 6.6, CH᎐CHMe), 6.55
᎐
(1 H, dd, J 15.6 and 1.5, CH᎐CHMe), 6.87 (2 H, s, ArH), 6.97
᎐
Vinylation of ester 1 to the vinylbenzene 2. To a solution of
ester 15 (24.4 g, 60.9 mmol) in benzene (200 cm3) was added a
solution of prop-1-enylmagnesium bromide, which had been
prepared from 1-bromopropene (10.3 g, 85.1 mmol) and
magnesium turnings (3.32 g) in THF (200 cm3) and diluted
with benzene (200 cm3). The mixture was stirred at room
temperature for 12 h. After usual work-up, the crude product
was chromatographed on a silica gel column with hexane–ethyl
acetate (40 : 1) as eluent to give the vinylbenzene 2 (19.6 g, 78%)
as colorless crystals, mp 110–111 ЊC (Found: C, 76.15; H, 8.2.
Calc. for C26H34O4: C, 76.1; H, 8.4%); νmax (KBr)/cmϪ1 1713;
δH(400 MHz) 1.35 (18 H, s, But × 2), 1.79 (3 H, dd, J 6.6 and
(1 H, d, J 7.6, ArH), 7.40 (1 H, t, J 7.6, ArH) and 7.52 (1 H, d,
J 7.6, ArH).
Cyclization of acid 6 to the indenone 7. Acid 6 (6.60 g,
23.5 mmol) was refluxed for 2 h in thionyl dichloride (15 cm3)
in the presence of several drops of DMF and volatiles were
removed under reduced pressure to give the acid chloride, which
was dissolved in benzene (30 cm3). To the ice-cold solution was
added dropwise SnCl4 (12.2 g, 46.8 mmol) and the mixture was
stirred at 0 ЊC for 20 min. The reaction was quenched by succes-
sive additions of water (30 cm3) and 2 M HCl (30 cm3) and the
two layers were separated. The water layer was extracted with
diethyl ether and the combined organic layer was washed
successively with 2 M HCl, 1 M NaOH and water, dried
(MgSO4), and evaporated to give a mixture of the indenone
7 and its hydrochloric acid adduct 8. To a solution of the
mixture in benzene (40 cm3) was added triethylamine (2.90 g,
28.7 mmol) and the mixture was refluxed for 3 h. After cooling,
the mixture was poured into 2 M HCl (20 cm3) and the resulting
mixture was extracted with diethyl ether. The extract was
washed with water, dried (MgSO4), and evaporated. The residue
was chromatographed on a silica gel column with hexane–ethyl
acetate (6 : 1) as eluent to give the indenone 7 (5.27 g, 85%) as
pale yellow crystals, mp 76.9–78.3 ЊC (Found: C, 87.2; H, 6.9.
Calc. for C19H18O: C, 87.0; H, 6.9%); νmax(KBr)/cmϪ1 1701;
δH(500 MHz) 1.79 (3 H, d, J 1.8, Me), 1.95 (6 H, s, ArMe × 2),
2.32 (3 H, s, ArMe), 6.84 (1 H, d, J 7.6, ArH), 6.92 (2 H, s,
ArH), 6.92 (1 H, d, J 7.6, ArH), 7.14 (1 H, q, J 1.8, ArCH) and
7.29 (1 H, t, J 7.6, ArH).
1.8, CH᎐CHMe), 3.81 (3 H, s, OMe), 3.91 (3 H, s, OMe), 6.03
᎐
(1 H, dq, J 15.5 and 6.6, CH᎐CHMe), 6.90 (2 H, s, ArH),
᎐
6.92 (1 H, dd, J 7.9 and 0.8, ArH), 7.04 (1 H, dq, J 15.5 and 1.8,
CH᎐CHMe), 7.13 (1 H, dd, J 7.9 and 0.8, ArH) and 7.40 (1 H,
᎐
t, J 7.9, ArH).
Hydrolysis of the vinylbenzene 2 to acid 3. Vinylbenzene
derivative 2 (18.5 g, 45.1 mmol) was added to a solution of
10 equiv. of sodium methoxide in toluene (60 cm3)–dry HMPA
(20 cm3) and the mixture was refluxed for 1 day. To the mixture
was added water (5.0 cm3) and the resulting mixture was
refluxed for a further 2 h. After cooling, the mixture was diluted
with water, washed with diethyl ether, and acidified by the
addition of conc. HCl to liberate the free acid, which was
extracted with diethyl ether and the extract was washed succes-
sively with 2 M HCl and water, dried (MgSO4), and evaporated.
The residue was recrystallized from hexane–dichloromethane
to give acid 3 (7.02 g, 81%) as colorless crystals, mp 107–108 ЊC
(Found: C, 68.4; H, 6.3. Calc. for C11H12O3: C, 68.7; H, 6.3%);
νmax(KBr)/cmϪ1 1647 and 2839; δH(400 MHz) 1.90 (3 H, d, J 6.6,
Reduction of the indenone 7 to the indanone 9. A mixture
of the indenone 7 (5.19 g, 19.8 mmol), diphenylsilane (8.75 g,
47.5 mmol), ZnCl2 (2.08 g, 15.3 mmol), Pd(PPh3)4 (32.0 mg,
27.7 µmol) and chloroform (120 cm3) was stirred at room
temperature for 4 h. Precipitates were filtered off on a silica gel
plug and the filtrate was evaporated. The residue was chroma-
tographed on a silica gel column with hexane–ethyl acetate
(30 : 1) as eluent to give the indanone 9 (4.71 g, 90%) as an
amorphous solid (Found: C, 86.5; H, 7.7. Calc. for C19H20O: C,
86.3; H, 7.6%); νmax(KBr)/cmϪ1 1707; δH(500 MHz) 1.24 (3 H, d,
J 6.7, Me), 1.87 (3 H, s, ArMe), 1.88 (3 H, s, ArMe), 2.33 (3 H,
s, ArMe), 2.64 (1 H, dqd, J 8.1, 6.7 and 4.4, CHMe), 2.75 (1 H,
dd, J 17.0 and 4.4, ArCH2), 3.41 (1 H, dd, J 17.0 and 8.1,
ArCH2), 6.92 (1 H, s, ArH), 6.93 (1 H, s, ArH), 7.06 (1 H, dd,
J 7.5 and 0.9, ArH), 7.42 (1 H, dd, J 7.5 and 0.9, ArH) and 7.59
(1 H, t, J 7.5, ArH).
CH᎐CHMe), 3.90 (3 H, s, OMe), 6.25 (1 H, dq, J 15.3 and
᎐
6.6, CH᎐CHMe), 6.67 (1 H, d, J 15.3, CH᎐CHMe), 6.83 (1 H,
᎐
᎐
d, J 8.0, ArH), 7.14 (1 H, d, J 8.0, ArH) and 7.33 (1 H, t, J 8.0,
ArH).
Esterification of acid 3 to ester 4. This compound was pre-
pared by the same procedure as used for the preparation of
similar esters before.10 A mixture of acid 3 (7.02 g, 36.5 mmol),
2,6-diisopropylphenol (6.52 g, 36.6 mmol), TFAA (10 cm3) and
benzene (25 cm3) was stirred at room temperature for 1 day.
After work-up, the crude product was purified by column
chromatography on silica gel and elution with hexane–ethyl
acetate (9 : 1) to give ester 4 (12.5 g, 97%) as colorless crystals,
mp 73.5–74.5 ЊC (Found: C, 78.5; H, 8.0. Calc. for C23H28O3:
C, 78.4; H, 8.0%); νmax(KBr)/cmϪ1 1736; δH(400 MHz) 1.23
(12 H, br, CHMe × 2), 1.90 (3 H, d, J 6.6, CH᎐CHMe), 3.39
᎐
2
Methylation of the indanone 9 to the dimethylindanone 10. A
mixture of the indanone 9 (4.47 g, 16.9 mmol), NaH (1.14 g,
47.5 mmol), iodomethane (11.2 g, 78.9 mmol) and benzene
(50 cm3) was refluxed for 2 days. The cooled mixture was
poured into 2 M HCl and extracted with diethyl ether. The
extract was washed successively with 1 M NaHSO3 and water,
dried (MgSO4), and evaporated. The residue was purified by
column chromatography on silica gel with hexane–ethyl acetate
(10 : 1) as eluent to give the dimethylindanone 10 (4.67 g, 99%)
as pale yellow crystals, mp 82.3–84.1 ЊC (Found: C, 86.5; H, 7.7.
Calc. for C20H22O: C, 86.3; H, 8.0%); νmax(KBr)/cmϪ1 1710;
δH(400 MHz) 1.17 (6 H, s, Me × 2), 1.87 (6 H, s, ArMe × 2), 2.32
(3 H, s, ArMe), 3.01 (2 H, s, ArCH2), 6.92 (2 H, s, ArH), 7.08
(1 H, d, J 7.5, ArH), 7.40 (1 H, d, J 7.5, ArH) and 7.60 (1 H, t,
J 7.5, ArH).
(2 H, sept, J 6.6, CHMe2 × 2), 3.90 (3 H, s, OMe), 6.28 (1 H, dq,
J 15.4 and 6.6, CH᎐CHMe), 6.73 (1 H, d, J 15.4, CH᎐CHMe),
᎐
᎐
6.87 (1 H, d, J 8.1, ArH), 7.17 (1 H, d, J 8.1, ArH), 7.17 (1 H, d,
J 7.9, ArH), 7.21–7.28 (2 H, m, ArH) and 7.35 (1 H, t, J 8.1,
ArH).
Conversion of ester 4 into acid 6. To a solution of ester 4
(12.5 g, 35.5 mmol) in benzene (125 cm3) was added a solution
of mesitylmagnesium bromide, which had been prepared from
2-bromomesitylene (12.9 g, 64.8 mmol) and magnesium
turnings (2.51 g) in diethyl ether (125 cm3) and diluted with
benzene (125 cm3). The mixture was refluxed for 1 day. Work-up
gave the biphenyl 5, which was hydrolyzed without further
purification by the same procedure as mentioned for ester 2.
Column chromatography of the crude product on silica gel with
hexane–ethyl acetate (2 : 1) as eluent gave acid 6 (6.69 g, 67%) as
colorless crystals. The sample sublimed at around 145 ЊC
(Found: C, 81.3; H, 7.2. Calc. for C19H20O2: C, 81.4; H, 7.2%);
νmax(KBr)/cmϪ1 1693 and 2916; δH(500 MHz) 1.90 (3 H, dd,
Reduction of the dimethylindanone 10 to the indanol rac-11.
To a cooled solution of the dimethylindanone 10 (1.90 g,
6.83 mmol) in THF (50 cm3) was added LAH (1.30 g, 34.3
mmol) portionwise at 0 ЊC and the mixture was stirred at this
temperature for 2 h. The reaction was quenched by successive
J 6.6 and 1.5, CH᎐CHMe), 1.96 (6 H, s, ArMe × 2), 2.30 (3 H,
᎐
380
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additions of ethanol (5.0 cm3), water (5.0 cm3) and 1 M HCl
(20 cm3), and the two layers was separated. The water layer was
extracted with diethyl ether and the organic layer was washed
successively with 1 M Na2CO3 and brine, dried (MgSO4), and
evaporated. The residue was chromatographed on a silica gel
column with hexane–ethyl acetate (10 : 1) as eluent to give the
indanol 11 (1.91 g, 100%) as colorless crystals, mp 47.7–49.0 ЊC
(Found: C, 85.8; H, 8.5. Calc. for C20H24O: C, 85.7; H, 8.6%);
νmax(KBr)/cmϪ1 2954 and 3384; δH(400 MHz) 1.04 (3 H, s,
Me), 1.10 (3 H, s, Me), 1.30 (1 H, s, OH), 1.93 (3 H, s, ArMe),
2.01 (3 H, s, ArMe), 2.32 (3 H, s, ArMe), 2.63 (1 H, d, J 15.6,
ArCH2), 2.94 (1 H, d, J 15.6, ArCH2), 4.26 (1 H, s, CHOH),
6.90 (1 H, dd, J 7.5 and 0.8, ArH), 6.93 (2 H, s, ArH), 7.18 (1 H,
dd, J 7.5 and 0.8, ArH) and 7.28 (1 H, t, J 7.5, ArH).
room temperature for 2 h. After work-up, the crude product
was purified by column chromatography with hexane–ethyl
acetate (10 : 1) as eluent to give the indanol (S)-(ϩ)-11 of 99%
ee (236 mg, 100%) as colorless crystals; [α]2D5 ϩ4.29 (c 1.02,
CHCl3).
Determination of the absolute configuration of ester 12
The slower-running counterpart of the diastereomeric indanyl
esters 12 on a silica gel column (vide supra) was crystallized
from ethyl acetate to give prismatic crystals, one of which was
subjected to X-ray crystallographic analysis. The absolute
stereochemistry of the indanyl moiety was assigned to be S
by using the (Sa)-binaphthyl axis as an internal reference. See
Fig. 2 for the ORTEP drawing.
Optical resolution of indanol 11
Crystal data. C42H38O3, M = 590.76, orthorhombic, a =
15.260(2), b = 16.228(2), c = 13.263(2) Å, V = 3284.6(7) Å3,
T = 22 ЊC, space group P212121 (no. 19), Z = 4, µ (Mo-Kα) =
0.73 cmϪ1, 4223 unique reflections, R(F) = 0.0329 [wR(F) =
0.029].
Esterification of the indanol 11 to esters 12 and their chroma-
tographic separation. Enantiomerically pure (Sa)-2Ј-methoxy-
1,1Ј-binaphthyl-2-carboxylic acid20a (1.50 g, 4.57 mmol) was
refluxed for 2 h in thionyl dichloride (5.0 cm3) in the presence
of several drops of DMF and volatiles were removed under
reduced pressure to give the acid chloride, which was dissolved
in toluene (10 cm3) along with the racemic indanol 11 (802 mg,
2.86 mmol), 4-pyrrolidinopyridine (848 mg, 5.72 mmol) and
dry pyridine (2.0 cm3). The mixture was refluxed for 12 h. The
cooled mixture was poured into 1 M HCl and extracted with
diethyl ether. The extract was washed successively with 1 M
HCl, 1 M Na2CO3 and brine, dried (MgSO4), and evaporated.
The residue was chromatographed on a silica gel column with
hexane–ethyl acetate (30 : 1) as eluent to give the diastereo-
merically pure esters 12.
Ester (Sa,R)-(Ϫ)-12. As the first-eluted fraction; yield 794
mg, 47%; [α]2D8 Ϫ46.1 (c 1.40, CHCl3) (Found: C, 85.4; H, 6.6.
Calc. for C42H38O3: C, 85.4; H, 6.5%); νmax(KBr)/cmϪ1 1705 and
2959; δH(400 MHz) 0.15 (3 H, s, Me), 0.82 (3 H, s, Me), 1.64
(3 H, s, Me), 1.79 (3 H, s, Me), 2.24 (3 H, s, Me), 2.29 (1 H, d,
J 15.6, ArCH2), 2.36 (1 H, d, J 15.6, ArCH2), 3.26 (3 H, s,
OMe), 5.34 (1 H, s, ArCH ) and 6.66–7.95 (17 H, m, ArH).
Ester (Sa,S)-(Ϫ)-12. As the second-eluted fraction; yield
710 mg, 42%; [α]3D0 Ϫ30.4 (c 1.01, CHCl3) (Found: C, 85.35; H,
6.7. Calc. for C42H38O3: C, 85.4; H, 6.5%); νmax(KBr)/cmϪ1 1703
and 2993; δH(500 MHz) 0.37 (3 H, s, Me), 0.77 (3 H, s, Me), 1.73
(3 H, s, Me), 1.82 (3 H, s, Me), 1.96 (1 H, d, J 15.5, ArCH2),
2.18 (1 H, d, J 15.5, ArCH2), 2.29 (3 H, s, Me), 3.63 (3 H,
s, OMe), 5.37 (1 H, s, ArCH ) and 6.78–7.95 (17 H, m, ArH).
The absolute stereochemistry was established by an X-ray
crystallographic analysis (vide infra).
Atrolactic acid synthesis
Preparation of phenylglyoxylic ester 13. Phenylglyoxylic
acid (182 mg, 1.21 mmol) was treated with oxalyl dichloride
(290 mg, 2.28 mmol) in the presence of several drops of DMF
in dry dichloromethane (1.0 cm3) at room temperature for 2 h
and volatiles were removed under reduced pressure to give the
acid chloride, which was dissolved in dry pyridine (5.0 cm3). To
the solution was added the indanol (R)-(Ϫ)-11 (170 mg, 0.606
mmol) and the mixture was stirred at room temperature for
12 h. The reaction was quenched with 1 M HCl (30 cm3) and
the mixture was extracted with diethyl ether. The extract was
washed successively with 1 M HCl, saturated aq. Na2CO3 and
brine, dried (MgSO4), and evaporated. The residue was purified
by column chromatography on silica gel with hexane–ethyl
acetate (25 : 1) as eluent to give phenylglyoxylic ester (R)-13
(230 mg, 92%) as an oil, [α]2D6 Ϫ7.41 (c 0.940, CHCl3) (Found: C,
81.65; H, 6.6. Calc. for C28H28O3: C, 81.5; H, 6.8%); νmax(neat)/
cmϪ1 1686, 1724 and 2960; δH(400 MHz) 1.17 (3 H, s, Me), 1.22
(3 H, s, Me), 1.72 (3 H, s, ArMe), 1.99 (3 H, s, ArMe), 2.28 (3 H,
s, ArMe), 2.73 (1 H, d, J 15.8, ArCH2), 3.13 (1 H, d, J 15.8,
ArCH2), 5.72 (1 H, s, ArCH ), 6.69 (1 H, s, ArH), 6.93 (1 H, d,
J 7.5, ArH), 6.96 (1 H, s, ArH), 7.22 (1 H, d, J 7.5, ArH), 7.35
(1 H, t, J 7.5, ArH), 7.44–7.49 (2 H, m, ArH), 7.62–7.66 (1 H,
s, ArH) and 7.73–7.76 (2 H, m, ArH).
Typical procedure for the Grignard reaction of ester 13.
Methylmagnesium iodide was prepared from iodomethane
(233 mg, 1.64 mmol) and magnesium turnings (65 mg) in
diethyl ether (7.0 cm3). One-fifth portion of the Grignard
reagent was added dropwise to a cooled solution of ester (R)-13
(113 mg, 0.274 mmol) in toluene (2.7 cm3) over a period of
10 min at Ϫ78 ЊC and the mixture was stirred at this tempera-
ture for 5 min before being quenched with saturated aq. NH4Cl
(10 cm3). After warming to room temperature, the mixture was
extracted with diethyl ether and the extract was washed with
water, dried (MgSO4), and evaporated. The residue was purified
by PLC with hexane–ethyl acetate (20 : 1) as the developer to
give atrolactic ester 14 (117 mg, 100%) as an oil (Found: C, 81.5;
H, 7.2. Calc. for C29H32O3: C, 81.3; H, 7.5%); δH(400 MHz)
0.55, 0.77 [3 H: s, Me (minor); s, Me (major)], 0.96, 0.98 [3 H:
s, Me (minor); s, Me (major)], 1.52, 1.53 [3 H: s, Me (minor); s,
Me (major)], 1.71, 1.84 [3 H: s, Me (major); s, Me (minor)],
1.94, 1.95 [3 H: s, Me (minor); s, Me (major)], 2.29, 2.32 [3 H: s,
Me (minor); s, Me (major)], 2.55, 2.64 [1 H: d, J 15.7, ArCH2
(minor); d, J 15.7, ArCH2 (major)], 2.84, 2.91 [1 H: d, J 15.7,
ArCH2 (minor); d, J 15.7, ArCH2 (major)], 2.95, 3.68 [1 H: s,
OH (major); s, OH (minor)], 5.59, 5.69 [3 H: s, ArCH (minor);
Reduction of esters 12 to the indanols 11. To a solution of the
diastereomerically pure ester (Sa,R)-12 (506 mg, 0.857 mmol) in
THF (8.5 cm3) was added LAH (326 mg, 8.59 mmol) portion-
wise at 0 ЊC and the mixture was stirred at this temperature for
1 h and then allowed to warm to room temperature. After being
stirred for 30 h, the mixture was cooled to 0 ЊC and quenched by
successive additions of ethanol (1.0 cm3), water (1.0 cm3) and
1 M HCl (10 cm3). The resulting mixture was extracted with
diethyl ether and the extract was washed successively with 1 M
Na2CO3 and brine, dried (MgSO4), and evaporated. The residue
was chromatographed on silica gel and eluted with benzene to
give the indanol (R)-(Ϫ)-11 (228 mg, 95%) as colorless crystals;
[α]2D5 Ϫ4.27 (c 1.04, CHCl3). The spectral data of the sample
were identical with those of racemic 11 (vide supra). Optical
purity of the sample was determined to be 99% ee by an HPLC
analysis on a Daicel Chiralcel OD-H with 0.3% propan-2-ol in
hexane as the eluent.
The dextrorotatory counterpart of the indanol 11 was
obtained from the diastereomerically pure ester (Sa,S)-12 by a
similar procedure. Ester (Sa,S)-12 (498 mg, 0.843 mmol) was
treated with LAH (320 mg, 8.43 mmol) in THF (8.5 cm3) at
J. Chem. Soc., Perkin Trans. 1, 2002, 377–383
381

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1
s, ArCH (major)] and 6.73–7.44 (10 H, m, ArH). H NMR
The major isomer (ϩ)-16 was hydrolyzed by a similar pro-
cedure to that used for the preparation of acid 3. Thus, the ester
(ϩ)-16 (135 mg, 0.246 mmol) was heated at 120 ЊC with 10
equiv. of sodium methoxide in toluene (2.0 cm3)–dry HMPA
(1.0 cm3) for 12 h. To this mixture was added water (1.0 cm3)
and the resulting mixture was heated at 110 ЊC for 2 h.
After work-up, the crude product was purified by column
chromatography on silica gel with hexane–ethyl acetate (2 : 1)
as eluent to give (ϩ)-2Ј,6-dimethoxy-4Ј,6Ј-dimethylbiphenyl-2-
carboxylic acid (63.4 mg, 90%), [α]2D7 ϩ98.6 (c 1.34, CHCl3)
{lit.,20c [α]2D2 ϩ66.9 (c 1.02, CHCl3) for (Ra)-isomer of 79% ee}.
This determined the absolute stereochemistry of the acid to be
Ra. Thus, the Ra,R absolute configuration of the ester (ϩ)-16
was established. The chiral auxiliary 11 (63.0 mg, 91%) was
recovered from the ester 16 by hydrolysis without appreciable
loss of chiral integrity (98% ee).
analysis of the sample easily differentiated the methyl
signal resonating at the highest magnetic field, between the
diastereomers, which determined the optical purity to be
83% de.
The ester 14 (116 mg, 0.271 mmol) was boiled with KOH
(400 mg) in aq. ethanol (10 cm3) for 1 day. After usual work-up,
the crude product was purified by column chromatography on
silica gel with hexane–ethyl acetate (1 : 2) as eluent to give
atrolactic acid (39.3 mg, 87%), [α]3D0 Ϫ29.5 (c 1.75, EtOH) {lit.,27
[α]2D5 ϩ36.3 (c 2.7, EtOH) for (S)-enantiomer}. This determined
the absolute stereochemistry of the ester 14 to be R,R. The
chiral auxiliary 11 (73.1 mg, 96%) was recovered from the ester
14 by hydrolysis without loss of chiral integrity (99% ee).
Biphenyl coupling reaction
Preparation of ester 15. This compound was prepared by a
similar procedure to that employed for the preparation of ester
12. The acyl chloride prepared from 2,3-dimethoxybenzoic acid
(590 mg, 3.24 mmol) was allowed to react with the indanol (R)-
11 (227 mg, 0.810 mmol) in dry pyridine (4.0 cm3) at 90 ЊC for
1 day. After work-up, the crude product was purified by column
chromatography on silica gel with hexane–ethyl acetate (40 : 1
to 20 : 1) to give ester (R)-15 (306 mg, 85%) as an amorphous
solid (Found: C, 78.15; H, 7.0. Calc. for C29H32O4: C, 78.4; H,
7.3%); δH(400 MHz) 1.16 (3 H, s, Me), 1.19 (3 H, s, Me), 1.69
(3 H, s, ArMe), 1.96 (3 H, s, ArMe), 2.24 (3 H, s, ArMe), 2.73
(1 H, d, J 15.7, ArCH2), 3.09 (1 H, d, J 15.7, ArCH2), 3.68 (3 H,
s, OMe), 3.85 (3 H, s, OMe), 5.77 (1 H, s, ArCH ), 6.64 (1 H,
s, ArH), 6.90 (1 H, s, ArH), 6.92 (1 H, d, J 7.5, ArH), 6.98–7.03
(3 H, m, ArH), 7.22 (1 H, d, J 7.5, ArH) and 7.33 (1 H, t, J 7.5,
ArH).
Acknowledgements
This work was partly supported by Grants-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan (No. 07555587 and No.
10555318).
References
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Typical procedure for the Grignard reaction of ester 15. The
Grignard reagent was prepared from 1-bromo-2-methoxy-4,6-
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acetate (20 : 1) as eluent to give the diastereomerically pure
esters 16.
Ester (Ra,R)-(ϩ)-16. As the major isomer; yield 186 mg,
78%; [α]3D0 ϩ28.7 (c 0.685, CHCl3) (Found: C, 81.2; H, 7.2. Calc.
for C37H40O4: C, 81.0; H, 7.4%); δH(400 MHz) 0.69 (3 H, s, Me),
0.95 (3 H, s, Me), 1.70 (3 H, s, Me), 1.77 (3 H, s, Me), 1.84 (3 H,
s, Me), 2.26 (3 H, s, Me), 2.34 (3 H, s, Me), 2.44 (1 H, d, J 15.6,
ArCH2), 2.66 (1 H, d, J 15.6, ArCH2), 3.23 (3 H, s, OMe), 3.66
(3 H, s, OMe), 5.41 (1 H, s, ArCH ), 6.45 (1 H, s, ArH), 6.63
(1 H, s, ArH), 6.71 (1 H, s, ArH), 6.84 (1 H, s, ArH), 6.89 (1 H,
d, J 7.4, ArH), 7.05 (1 H, dd, J 8.0 and 1.3, ArH), 7.17 (1 H, d,
J 7.4, ArH), 7.22 (1 H, dd, J 8.0 and 1.3, ArH), 7.28 (1 H, t,
J 8.0, ArH) and 7.29 (1 H, t, J 7.4, ArH).
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Me), 0.92 (3 H, s, Me), 1.64 (3 H, s, Me), 1.67 (3 H, s, Me), 1.86
(3 H, s, Me), 2.28 (3 H, s, Me), 2.33 (3 H, s, Me), 2.41 (1 H, d,
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382
J. Chem. Soc., Perkin Trans. 1, 2002, 377–383

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J. Chem. Soc., Perkin Trans. 1, 2002, 377–383
383