Enantiomerically pure α-methoxyaryl acetaldehydes as versatile precursors: a facile chemo-enzymatic methodology for their preparation

Article abstract of DOI:10.1016/j.tetasy.2008.10.023

A facile and efficient synthesis of optically active α-methoxyaryl acetic acids (up to 95% ee), α-methoxyaryl ethanols (up to 93% ee) and α-methoxyaryl acetonitriles (up to 93% ee) was achieved via Arthrobacter sp. lipase-catalyzed kinetic resolution of masked aldehydes as the key synthons, that is, α-hydroxyaryl acetaldehyde acetals.

Full text of DOI:10.1016/j.tetasy.2008.10.023

Tetrahedron: Asymmetry 19 (2008) 2579–2588
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Tetrahedron: Asymmetry
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Enantiomerically pure a-methoxyaryl acetaldehydes as versatile precursors:
a facile chemo-enzymatic methodology for their preparation
Buddh Singh a, Pankaj Gupta a, Asha Chaubey a, Rajinder Parshad a, Shiromani Sharma b, Subhash C. Taneja a,
*
a Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi 180 001, India
b D.N. College, Chaudhary Charan Singh University, Meerut 250 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient synthesis of optically active
aryl ethanols (up to 93% ee) and a-methoxyaryl acetonitriles (up to 93% ee) was achieved via Arthrobacter
sp. lipase-catalyzed kinetic resolution of masked aldehydes as the key synthons, that is,
acetaldehyde acetals.
a
-methoxyaryl acetic acids (up to 95% ee),
a
-methoxy-
Received 9 October 2008
Accepted 23 October 2008
Available online 19 November 2008
a-hydroxyaryl
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
yields utilizing uneconomical protection–deprotection methodolo-
gies and low enantiomeric purity of the final products.
Enantiomerically pure
a-alkoxy/hydroxyl aryl acetaldehydes
The absence of any simple and general methodology for the
are very versatile chiral synthons for the preparation of natural
products, such as rhodinose,1 rocellaric acid,2 lipoxine A,3 brevico-
min,4 goniodiol analogues5 and amino sugars.6 These molecules are
preparation of optically active a-methoxyaryl acetaldehyde pre-
cursors capable of producing downstream products, such as
nitriles, alcohols and carboxylic acids, prompted us to look for an
alternative synthesis. Herein, we report a facile chemo-enzymatic
methodology, wherein the formation of masked aldehyde is the
key step. The aldehyde synthon can easily be converted into other
important downstream products, such as nitriles, alcohols and car-
boxylic acids in both the enantiomeric forms with high enantio-
meric purity.
the precursors of a-alkoxy arylacetic acids, which are also used as
chiral auxiliaries in Diels–Alder reactions7 and for chiral recogni-
tion by NMR in the method known as ‘Mosher’s method’.8
Moreover, MPA (methoxyphenyl acetic acid) and MTPA (methoxy-
trifluoromethyl phenylacetic acid) have been the most widely used
reagents for the determination of absolute configuration of second-
ary alcohols, amines and sulfoxides by 1H NMR,9,10 even though
some novel auxiliaries and reagents based on
a-alkoxy aryl acetic
acids are also reported.11
a-Alkoxyphenyl acetic acids are extre-
2. Results and discussion
mely useful in the resolution of amines via diastereoisomer forma-
tion; as a consequence of differentiation in the physio-chemical
properties of these diastereoisomers they can easily be crystallized
Substituted b-bromostyrenes (prepared by known meth-
ods21,22) were used as the starting material for the preparation of
racemic acetals as described in Scheme 1. Our strategy initiated
with the synthesis of racemic 2,2-dimethoxy-1-aryl ethanol
(masked aldehyde) 3 via a simple and novel route involving hydro-
halogenation of substituted b-bromostyrene 1 followed by a nucle-
ophilic substitution reaction in 2, providing 3a–d in ꢀ80% overall
isolated yields (Scheme 1).
and separated.12 Analogues of mandelic acid and
a-methoxy-
phenyl acetic acid have been reported to behave as plant growth
regulators,13 calcium antagonists,14 and also as apoptosis
inhibitors.15
Due to numerous biological and pharmacological properties of
these molecules, a number of routes for the synthesis of
a-
For the synthesis of the target molecules, acetyl derivatives of
2,2-dimethoxy-1-aryl ethanols 4a–d were subjected to enzymatic
hydrolysis in biphasic systems, since in the lipase-catalyzed hydro-
lysis of acylates, biphasic reaction media have been found to pro-
methoxyaryl acetaldehydes and -methoxy aryl acetic acids are
a
available in the literature; for example, (a) from (S)-(+)-p-tolyl-thi-
omethylsulfoxide;16 (b) by asymmetric microbial reduction of
a
-keto acetals17 and -keto thioacetals;18 (c) by Sharpless asym-
a
vide rapid conversion and improved enantioselectivity.23
A
metric dihydroxylation as a key step19 and (d) from tartaric acid.20
However, most of these synthetic routes suffer from low overall
number of lipases from the institutes microbial repository were
screened for enantioselective hydrolysis and out of these, a native
strain Arthrobacter sp.24 lipase designated as ABL (MTCC No. 5125)
in a biphasic system (buffer/ACN = 4:1) was identified to be the
best, in terms of both rate of hydrolysis and enantioselectivity, as
depicted in Scheme 2 and Table 1. The kinetic resolution reactions
* Corresponding author. Tel.: +91 191 2569111/2569011; fax +91 191 2569222/
2569333.
E-mail address: sc_taneja@yahoo.co.in (S.C. Taneja).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.023

2580
B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
OH
OH
R1
R2
OMe
R1
R2
Br
R1
R2
Br
ii
i
OMe
Br
1
2
3
a, R1 = R2 = H; b, R1 = H, R2 = OMe; c, R1 = R2 = OMe; d, R1 + R2 = -OCH2O-.
Scheme 1. Synthesis of racemic 2,2-dimethoxy-1-aryl ethanol. Reagents and conditions: (i) NBS, acetonitrile/water (1:1); (ii) methanol/KOH.
OH
OCOCH3
OCH3 R1
OH
OCOCH3
OCH3
R1
R2
OCH3
R1
R2
OCH3
R1
R2
ii
i
OCH3
rac-3
OCH3
)-4
OCH3
(S)-3
OCH3
rac-4
R2
(
R
a, R1 = R2 = H; b, R1 = H, R2 = OMe; c, R1 = R2 = OMe; d, R1 + R2 = -OCH2O-.
Scheme 2. Enzymatic hydrolysis of 4a, 4b, 4c and 4d. Reagents and conditions: (i) Ac2O, Py, CH2Cl2; (ii) lipase, 0.1 M-phosphate buffer, pH 7.1.
Table 1
Enzymatic hydrolysis of 4a, 4b, 4c and 4d in a biphasic system using 20% co-solvent with respect to the buffera
R1
R2
Co-solvent
Convn. (%)
Time (h)
eep (%) {Abs conf.}
ees (%) {Abs conf.}
E
H
H
H
OCH3
OCH3
ACN
ACN
Tol
50
50
50
50
2
2
12
3
99 (S)
99 (S)
99 (S)
99 (S)
99 (R)
99 (R)
99 (R)
99 (R)
1059
1059
1059
1059
OCH3
R1 + R2 = –OCH2O–
ACN
a
All the reactions were performed at 25 °C using Arthrobacter simplex lipase (enzyme/substrate; 1.5:1) at 20 g/L concentration.
of 4a–d were carried out in an aqueous phosphate buffer (0.1 M,
pH 7.0), using 20% co-solvent such as acetonitrile/toluene. It was
observed that the pH of the reaction mixture had a profound effect
on rate as well as on enantioselectivity. Thus, in order to maintain
the pH at 7.1, a 0.1 M solution of disodium hydrogen phosphate
was added at regular intervals during the hydrolysis with ABL.
The conversion and enantiomeric excess (ee%) of enzyme (ABL)-
catalyzed hydrolysis of 4a, 4b, 4c and 4d was measured by HPLC
using a chiral stationary phase (R,R)-whelk-01 column.
After the synthesis of enantiomerically pure
a-hydroxyaryl
acetaldehydes in masked form, our next aim was to synthesize
the downstream products such as
a-methoxyaryl acetic acids,
OMe
R1
CH2OH
R2
(S)-7 ee 87-93%,
yield 90-95%
iii
OMe
CN
OMe
CHO
OMe
OH
iv
R1
R2
R1
R2
ii
R1
R2
OMe
R1
R2
OMe
i
OMe
OMe
(S
)-8 ee 89- 93%,
(S
)-6 yield 80-90%
(S
)-5 ee >95%,
(S)-3 ee = 99%
yield 60-70%
yield 90-95%
v
OMe
COOH
R1
R2
(S
)-9 ee 80-95%,
yield 85-90%
a, R1 = R2 = H; b, R1 = H, R2 = OMe; c, R1 = R2 = OMe; d, R1 + R2 = -OCH2O-.
Scheme 3. Synthetic scheme for the preparation of downstream products. Reagents and conditions: (i) sodium hydride/methyl iodide in dry THF; (ii) dilute HCl in acetone;
(iii) sodium borohydride in methanol; (iv) (a) hydroxylamine hydrochloride/NaOH; (b) acetic anhydride, 80 °C; (v) ammonical silver nitrate in toluene.

B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
2581
a
-methoxyaryl ethanols and
tiomerically enriched form. To achieve this, the methyl ether of
optically active (S)- -hydroxyaryl acetaldehyde acetals (prepared
after methylation of (S)- -hydroxyaryl acetaldehyde acetals with
methyl iodide) was subjected to acid hydrolysis to obtain (S)-
methoxy aryl acetaldehyde in >95% ee, which on oxidation with
Tollen’s reagent afforded (S)-
a
-methoxyaryl acetonitriles in enan-
During the synthesis of enantiomerically pure
acetonitriles from enantiomerically pure
a
-methoxyaryl
a
-methoxyaryl acetalde-
a
hydes, it was observed that after the formation of an oxime with
hydroxylamine hydrochloride, heating with acetic anhydride at a
temperature higher than 100 °C would result in a significant
loss of enantiomeric purity of the product; therefore, the reaction
was carried out under controlled reaction conditions (70–80 °C)
to avoid racemization (Scheme 3, Table 2). Herein, it was recog-
nized that electron-donating substituents on the benzene ring
did not have any significant effect on the rate as well as on
enantioselectivity.
a
a
-
a
-methoxyaryl acetic acids (ꢀ95%
ee) in good yields without any significant loss in enantioselec-
tivity. On reduction with NaBH4, (S)-6a–d provided optically active
(S)-a-methoxyaryl ethanols in quantitative yields (up to 93%
ee). However, no attempts were made to optimize the condi-
tions for improving the enantiomeric excess in these transfor-
mations.
The enantiomeric purities of all of the optically active com-
pounds were determined by using chiral stationary phased ODH,
Table 2
Synthesized downstream products from
a-methoxyaryl acetaldehydes
Product
Yielda (%)
ee (%)
½
a 2D5
ꢁ
Product
Yielda (%)
ee (%)
93
½ ꢁ
a 2D5
OMe
OMe
CN
>95
+104
90
CH2OH
64
ꢂ43
MeO
OMe
(S)-7a
(S)-8c
OMe
CN
OMe
CH2OH
94
87
+92.4
70
89
ꢂ54
O
O
MeO
(S)-7b
OMe
(S)-8d
OMe
COOH
CH2OH
93
93
+98
82
80
+105
MeO
OMe
(S)-9a
(S)-7c
OMe
OMe
COOH
CH2OH
92
87
+87.5
85
90
+108
O
O
MeO
MeO
(S)-9b
(S)-7d
OMe
COOH
OMe
CN
60
93
ꢂ67
ꢂ57
86
91
+93.2
OMe
(S)-8a
(S)-9c
OMe
COOH
OMe
CN
68
89
90
89
+106
O
MeO
O
(S)-8b
(S)-9d
a
Isolated yield.

2582
B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
OJH and (R,R)-whelk-01 columns. The absolute configurations of
optically active compounds, such as 7a, 7b, 7c, 9a, 9b and 9c, were
assigned on the basis of comparison the sign of specific rotation
with that reported in the literature,17,20 whereas for unknown
compounds, a correlation was made with the absolute configura-
tions of the resolved alcohols and esters and similar types of com-
pounds based on the selectivity profile of Arthrobacter sp. lipase.
was kept overnight at room temperature. The contents of the reac-
tion mixture were poured into ice-cold water and extracted with
dichloromethane. The organic layer was washed, dried and evapo-
rated to get crude acetic acid-2,2-dimethoxy-1-arylethyl esters 4a–
d, which were purified by CC using a gradient of ethylacetate and
hexane as eluent (90–95% yields).
4.5. General method for the preparation of 1-(aryl)-1,2,2-
trimethoxy ethanes 5a–d
3. Conclusion
Sodium hydride (15 mmol) was added to a solution of 2,2-
dimethoxy-1-arylethanols 3a–d (10 mmol) in dry THF at 0–5 °C.
After stirring for 5 min, methyl iodide was added to the reaction
mixture. The reaction, after completion (as indicated by TLC),
was worked up by quenching the excess of NaH with ethyl ace-
tate, the contents were diluted with water and the organic layer
was separated. The aqueous layer was extracted twice with ethyl
acetate, and combined organic layers were washed with water,
dried over sodium sulfate and concentrated under vacuo to give
a crude product, which on column chromatography over silica
gel gave1-(aryl)-1,2,2-trimethoxy ethanes 5a–d in 90–95% yields.
In conclusion,
a series of enantiomerically pure masked
a
-methoxyaryl acetaldehydes, key synthons and their optically
enriched downstream products, such as nitriles, alcohols and
carboxylic acids (ee up to 95%), were prepared by a simple and
efficient synthetic methodology via an ABL-catalyzed kinetic reso-
lution step.
4. Experimental
4.1. General
1H NMR spectra in CDCl3 were recorded on Bruker 200 MHz
spectrometers with TMS as the internal standard. Chemical shifts
were expressed in parts per million (d ppm). Reagents and solvents
used were mostly of LR grade. Silica gel coated aluminium plates
coated on alumina from M/s Merck were used for TLC. MS were
recorded on Jeol MSD-300 and Bruker Esquire 3000 GC-Mass spec-
trometer. IR was recorded on a FT-IR Bruker (270-30) spectropho-
tometer. Optical rotations were measured on Perkin–Elmer 241
polarimeter at 25 °C using sodium D light. Enantiomeric excess
(ee) was determined on a chiral stationary phase HPLC column.
4.6. General method for the preparation of
acetaldehydes 6a–d
a-methoxyaryl
Hydrochloric acid (100 mL of 1 M) was added to a solution of 1-
aryl-1,2,2-trimethoxy ethanes 5a–d (10 mmol) in 100 mL acetone.
The solution was stirred at 80–90 °C and after completion of the
reaction as indicated by TLC (benzene/ethyl acetate; 95:5), acetone
was removed under vacuo and residue was extracted with ethyl
acetate. The pH was made neutral by sodium bicarbonate solution,
washed with water and concentrated in vacuo to give crude
a-
methoxyaryl acetaldehydes 6a–d in 80–90% yields.
4.2. General method for the preparation of substituted
(dibromomethyl)aryl methanols 2a–d
a-
4.7. General method for the preparation of
acetic acids 9a–d
a-methoxyaryl
Freshly prepared NBS (12 mmol) was added in small install-
ments to solution of substituted b-bromostyrenes 1a–d
a
To a solution of a-methoxyaryl acetaldehyde (3 mmol) in
(10 mmol) in 50 mL acetonitrile/water (1:1) in a reaction vessel,
and the mixture was stirred at ambient temperature. After comple-
tion of the reaction as indicated by TLC, acetonitrile was removed
at reduced pressure and the residue was extracted twice with ethyl
acetate. The combined organic layers were washed with water and
100 mL toluene was added Tollen’s reagent (prepared from 1 g
AgNO3) dropwise, and the solution was stirred at room tempera-
ture. After completion of the reaction as indicated by TLC, the solu-
tion was diluted with distilled water and the toluene layer
containing unwanted impurities was removed. The aqueous layer
after washing with ethyl acetate was separated and acidified to
pH 6.0. It was then extracted with ethylacetate (2 ꢃ 30 mL). The
combined organic layer was dried and concentrated under reduced
concentrated under reduced pressure to give
a-(dibromometh-
yl)aryl methanols 2a–d in quantitative yield.
pressure to give a-methoxyaryl acetic acids 9a–d (85–90% yields).
4.3. General method for the preparation of 2,2-dimethoxy-1-
aryl ethanols 3a–d
4.8. General method for the preparation of
acetonitriles 8a–d
a-methoxyaryl
A solution of KOH (12 mmol) in methanol (50 mL) was added
dropwise to a stirred solution of a-(dibromomethyl)-arylmethanol
Hydroxylamine hydrochloride (150 mg) was added to a stirred
solution of -methoxyaryl acetaldehyde (1 mmol) in 50 mL etha-
2a–d (10 mmol) in dry methanol (100 mL) at room temperature.
The progress of the reaction was monitored by TLC. After comple-
tion of the reaction, potassium bromide was filtered off and meth-
anol was evaporated at reduced pressure. The residue was purified
by column chromatography using a gradient of ethyl acetate in
hexane as eluent to give 2,2-dimethoxy-1-aryl ethanols 3a–d in
75–80% yields.
a
nol/water (1:1), and the solution was made slightly basic by the
addition of 10% aq NaOH solution. After stirring for 0.5–1 h at room
temperature, the progress of the reaction was monitored by TLC.
The pH was adjusted to 6.5 by the addition of more hydroxylamine
hydrochloride. The solution was concentrated under vacuo, and
the residue was extracted with ethyl acetate. The organic layer
was dried and concentrated under reduced pressure to give a crude
oxime, which was heated with acetic anhydride in dry conditions
at 70–80 °C until completion of the reaction. The acetic anhydride
4.4. General method for the preparation of acetic acid-2,2-
dimethoxy-1-arylethyl esters 4a–d
was removed under vacuo at low temperature to give crude
methoxy arylacetonitriles 8a–d, which were purified by column
chromatography (pet. ether/ethyl acetate; 96:4) (60–70% yields).
a-
Acetic anhydride (12 mmol) and a catalytic amount of DMAP
were added to a solution of racemic 2,2-dimethoxy-1-aryl ethanols
3a–d (10 mmol) in dry dichloromethane, and the reaction mixture

B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
2583
4.9. General method for the preparation of
ethanols 7a–d
a-methoxyaryl
4.14. Preparation of optically active (S)-(ꢂ)-2-methoxy-2-
phenyl acetonitrile 8a
NaBH4 (2 mmol) in small installments was added at 0–5 °C to a
solution of -methoxyaryl acetaldehyde (1 mmol) in 20 mL meth-
The compound was prepared using the same procedure as ap-
a
plied for racemic 8a, ee 93%, ½a D25
¼ ꢂ67 (c 1.0, CHCl3); HPLC con-
ꢁ
anol. After completion of the reaction as indicated by TLC, the pH
was made neutral by the addition of dil HCl and the contents were
concentrated under reduced pressure. The residue was extracted
with diethyl ether. The combined extracts were dried over anhy-
drous sodium sulfate and concentrated under reduced pressure.
ditions: OJH chiral column, eluent 2-propanol/hexane (1.0:99),
flow rate: 0.8 mL/min.
4.15. Preparation of optically active (S)-(+)-a-methoxy phenyl
acetic acid 9a
The product was purified on a silica gel column to give a-methoxy-
aryl ethanols 7a–d (90–95% yields).
The compound was prepared using the same procedure as ap-
plied for racemic 9a, (S)-9a, ee 80%, ½a D25
¼ þ105 (c 0.5, EtOH);
ꢁ
(lit.19 (S)-isomer, ½a 2D5
¼ þ146:0 (c 1.04, EtOH), HPLC conditions
ꢁ
4.10. Kinetic resolution of acetic acid-2,2-dimethoxy-1-
phenylethyl ester 4a
for its methyl ester: (R,R)-whelk-01, chiral column, eluent 2-propa-
nol/hexane (2.0:98.0), flow rate: 0.8 mL/min.
Racemic acetic acid-2,2-dimethoxy-1-phenylethyl ester 4a
(1 g), aqueous phosphate buffer (75 mL, 0.1 M, pH 7.0), acetoni-
trile (15 mL) and whole cells of Arthrobacter sp. lipase (1.35 g)
were stirred continuously at 25 1 °C. The pH of the reaction mix-
ture was adjusted at 7.1 with aqueous solution of disodium
4.16. Kinetic resolution of acetic acid-2,2-dimethoxy-1-(4-
methoxyphenyl)ethyl ester 4b
Racemic acetic acid-2,2-dimethoxy-1-(4-methoxyphenyl)ethyl
ester 4b (1 g), aqueous phosphate buffer (75 mL, 0.1 M, pH 7.0),
acetonitrile (15 mL) and whole cells of Arthrobacter sp. lipase
(1.5 g) were stirred continuously at 25 1 °C. The pH of the reac-
tion mixture was adjusted at 7.1 with aqueous solution of diso-
dium hydrogen phosphate. After a certain degree of conversion
(ꢀ50%) as indicated by thin layer chromatography (TLC) and chiral
high performance liquid chromatography (HPLC), the reaction was
terminated by adding ethyl acetate and centrifuging the mixture at
10,000–15,000g to remove the enzyme and the suspended parti-
cles. The clear solution was decanted, and the centrifuged mass
was extracted separately with ethyl acetate (3 ꢃ 25 mL). The or-
ganic layer was combined and washed with water. The combined
organic layer was then dried and evaporated under reduced pres-
sure to furnish a mixture comprising hydrolyzed alcohol and unhy-
drolyzed ester, which was separated by column chromatography
(60–120 mesh) using a gradient of ethyl acetate and hexane as elu-
hydrogen phosphate. After
a certain degree of conversion
(ꢀ50%) as indicated by thin layer chromatography (TLC) and chi-
ral high performance liquid chromatography (HPLC), the reaction
was terminated by adding ethyl acetate and centrifuging the mix-
ture at 10,000–15,000g to remove the enzyme and the suspended
particles. The clear solution was decanted, and the centrifuged
mass was extracted separately with ethyl acetate (3 ꢃ 25 mL).
The organic layer was combined and washed with water. The
combined organic layer was then dried and evaporated under re-
duced pressure to furnish a mixture comprising hydrolyzed alco-
hol and unhydrolyzed ester, which was separated by column
chromatography (60–120 mesh) using a gradient of ethyl acetate
and hexane as eluent to give (R)-(ꢂ)-4a, (432 mg), ee = 99%,
½
½
½
a 2D5
a 2D5
a 2D5
ꢁ
¼ ꢂ45:0 (c 0.5, CHCl3) and (S)-(+)-3a, (386 mg), ee = 99%,
¼ þ10:5 (c 1.0 CHCl3), lit.;17 (S)-(+)-3a, ee = 46%,
¼ þ4:7 (c 5, CHCl3,), HPLC conditions: (R,R)-Whelk-01, chiral
ꢁ
ꢁ
ent to give R-(ꢂ)-4b, (480 mg), ee = 99%, ½a D25
ꢁ
¼ ꢂ61:0 (c 0.5,
column, eluent 2-propanol/hexane (0.5:99.5), flow rate: 0.8 mL/
CHCl3) and (S)-(+)-3b, (410 mg), ee = 99%, ½a D25
ꢁ ¼ þ14:5 (c 1.0
min.
CHCl3), HPLC conditions: (R,R)-whelk-01, chiral column, eluent 2-
propanol/hexane (5:95), flow rate: 0.8 mL/min.
4.11. Preparation of optically active (S)-(+)-1-(phenyl)-1,2,2-
trimethoxy ethane 5a
4.17. Preparation of optically active (S)-(+)-1-(4-
methoxyphenyl)-1,2,2-trimethoxy ethane 5b
Compound 5a was prepared using the same procedure as ap-
plied for the synthesis of racemic 1-(phenyl)-1,2,2-trimethoxy eth-
ane 5a: ½a 2D5
¼ þ55:2 (c 1, CHCl3), ee = 95%, HPLC conditions: ODH
ꢁ
The compound was prepared from (S)-(+)-3b using the same
procedure as applied for racemic 5b. Ee = 95%, ½a D25
¼ þ52 (c 0.5,
ꢁ
chiral column, eluent 2-propanol/hexane (0.5:99.5), flow rate:
0.8 mL/min.
CHCl3), HPLC conditions: Chiralcel OJH chiral column, eluent 2-pro-
panol/hexane (1.5:98.5), flow rate: 0.8 mL/min.
4.12. Preparation of optically active (S)-(+)-a-methoxyphenyl
acetaldehyde 6a
4.18. Preparation of optically active (S)-(+)-a-methoxy-2-(4-
methoxyphenyl)acetaldehyde 6b
The compound was prepared using the method described for
The compound was prepared from (S)-(+)-5b using the same
racemic 6a, ½a 2D5
¼ þ52 (c 0.5, CHCl3) for crude (S)-6a.
ꢁ
procedure as applied for racemic 6b. ½a D25
¼ þ68:1 (c 1.0, CHCl3)
ꢁ
for crude (S)-(+)-6b.
4.13. Preparation of optically active (S)-(+)-2-methoxy-2-
phenyl ethanol 7a
4.19. Preparation of optically active (S)-(+)-2-methoxy-2-(4-
methoxyphenyl)ethanol 7b
The compound was prepared using the same procedure as ap-
plied for racemic 7a; Ee 95%, ½a D25
¼ þ104 (c 1.0, acetone); HPLC
ꢁ
It was prepared from (S)-(+)-6b using the same procedure as ap-
plied for racemic 7b. Ee = 87%, ½a D25
¼ þ92:4 (c 1.0, CHCl3), HPLC
ꢁ
conditions: OJH chiral column, eluent 2-propanol/hexane
(0.5:99.5), flow rate: 0.8 mL/min; (lit.19; (S)-7a, ½a D25
¼ þ108:5 (c
ꢁ
conditions for its acetyl derivative: Chiralcel OJH chiral column,
eluent 2-propanol/hexane (0.5:99.5), flow rate: 0.8 mL/min.
0.11 CHCl3).

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B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
4.20. Preparation of optically active (S)-(ꢂ)-2-methoxy-2-(4-
4.26. Preparation of optically active (S)-(ꢂ)-2-methoxy-2-(3,4-
methoxyphenyl)acetonitrile 8b
dimethoxyphenyl)acetonitrile 8c
The compound was prepared from (S)-(+)-6b using the same
The compound was prepared from (S)-(+)-6c using the same
procedure as applied for racemic 8b. Ee = 89%, ½a D25
ꢁ
¼ ꢂ57 (c 1.0,
procedure as applied for racemic 8c. Ee ꢀ93%, ½a D25
¼ ꢂ43 (c 1.0,
ꢁ
CHCl3), HPLC conditions: Chiralcel OJH chiral column, eluent, 2-
propanol/hexane (2.0:98.0), flow rate: 0.8 mL/min.
CHCl3), HPLC conditions: Chiralcel OJH chiral column, eluent 2-pro-
panol/hexane (0.5:99.5), flow rate: 0.8 mL/min.
4.21. Preparation of optically active S-(+)-a-methoxy-2-(4-
4.27. Preparation of optically active (S)-(+)-2-methoxy-2-(3,4-
methoxyphenyl)acetic acid 9b
dimethoxyphenyl)acetic acid 9c
The compound was prepared from (S)-(+)-6b using the same
The compound was prepared from (S)-(+)-6c using the same
procedure as applied for racemic 9b. Ee = 90%, ½a D25
ꢁ
¼ þ108 (c
procedure as applied for racemic 9c. Ee = 91%, ½a D25
¼ þ93:2 (c
ꢁ
0.5, EtOH). HPLC conditions for its methyl ester: (R,R)-whelk-01,
chiral column, eluent, 2-propanol/hexane (2.0:98.0), flow rate:
0.8 mL/min.
0.5, EtOH); HPLC conditions for its methyl ester: (R,R)-whelk-01,
chiral column, eluent 2-propanol/hexane (5:95), flow rate:
0.8 mL/min.
4.22. Kinetic resolution of acetic acid-2,2-dimethoxy-1-(3,4-
dimethoxyphenyl)ethyl ester 4c
4.28. Kinetic resolution of acetic acid-2,2-dimethoxy-1-(3,4-
methylenedioxyphenyl)ethyl ester 3d
Racemic acetic acid-2,2-dimethoxy-1-(3,4-dimethoxyphenyl)-
ethyl ester 4c (1 g), aqueous phosphate buffer (75 mL, 0.1 M, pH
7.0), acetonitrile (15 mL) and whole cells of Arthrobacter sp. lipase
(1.5 g) were stirred continuously at 25 1 °C. The pH of the reac-
tion mixture was adjusted at 7.1 with an aqueous solution of diso-
dium hydrogen phosphate. After a certain degree of conversion
(ꢀ50%) as indicated by thin layer chromatography (TLC) and chiral
high performance liquid chromatography (HPLC), the reaction was
terminated by adding ethyl acetate and centrifuging the mixture at
10,000–15,000g to remove enzyme and the suspended particles.
The clear solution was decanted, and the centrifuged mass was ex-
tracted separately with ethyl acetate (3 ꢃ 25 mL). The organic layer
was combined and washed with water. The combined organic layer
was then dried and evaporated under reduced pressure to furnish a
mixture comprising hydrolyzed alcohol and unhydrolyzed ester,
which was separated by column chromatography (60–120 mesh)
using a gradient of ethyl acetate and hexane as eluent to give
Racemic acetic acid-2,2-dimethoxy-1-(3,4-methylenedioxy-
phenyl)ethyl ester 4d (1 g), aqueous phosphate buffer (75 mL,
0.1 M, pH 7.0), acetonitrile (15 mL) and whole cells of Arthrobacter
sp. lipase (1.5 g) were stirred continuously at 25 1 °C. The pH of
the reaction mixture was adjusted at 7.1 with an aqueous solution
of disodium hydrogen phosphate. After a certain degree of conver-
sion (ꢀ50%) as indicated by thin layer chromatography (TLC) and
chiral high performance liquid chromatography (HPLC), the reac-
tion was terminated by adding ethyl acetate and centrifuging the
mixture at 10,000–15,000g to remove enzyme and the suspended
particles. The clear solution was decanted, and the centrifuged
mass was extracted separately with ethyl acetate (3 ꢃ 25 mL).
The organic layer was combined and washed with water. The com-
bined organic layer was then dried and evaporated under reduced
pressure to furnish a mixture comprising hydrolyzed alcohol and
unhydrolyzed ester, which was separated by column chromatogra-
phy (60–120 mesh) using a gradient of ethyl acetate and hexane as
(R)-(ꢂ)-4c, (470 mg), ee = 99%, ½a D25
ꢁ
¼ ꢂ52:2 (c 1.0, CHCl3) and
eluent to give (R)-(ꢂ)-4d, (503 mg), ee = 99%, ½a D25
ꢁ
¼ ꢂ62 (c 1.0,
(S)-(+)-3c, (400 mg), ee = 99%, ½a D25
ꢁ
¼ þ8:2 (c 1.0 CHCl3), HPLC con-
CHCl3) and (S)-(+)-3d, (455 mg), ee = 99%, ½a D25
ꢁ
¼ þ5:7 (c 1.0
ditions: (R,R)-whelk-01, chiral column, eluent 2-propanol/hexane
CHCl3), HPLC conditions: (R,R)-whelk-01, chiral column, eluent 2-
(5:95), flow rate: 0.8 mL/min.
propanol/hexane (5:95), flow rate: 0.8 mL/min.
4.29. Preparation of optically active (S)-(+)-1-(3,4-
methylenedioxyphenyl)-1,2,2-trimethoxy ethane 5d
4.23. Preparation of optically active (S)-(+)-1-(3,4-
dimethoxyphenyl)-1,2,2-trimethoxy ethane 5c
The compound was prepared from (S)-(+)-3d using the same
The compound was prepared from (S)-(+)-3c using the same
procedure as applied for racemic 5d, ee = 95%, ½a D25
¼ þ51 (c 1.0,
ꢁ
procedure as applied for racemic 5c. Ee = 95%, ½a D25
¼ þ40:4 (c
ꢁ
CHCl3). HPLC conditions: Chiralcel ODH chiral column, eluent 2-
propanol/hexane (0.5:99.5), flow rate: 0.8 mL/min.
0.5, CHCl3), HPLC conditions: Chiralcel ODH chiral column, eluent
2-propanol/hexane (1.5:98.5), flow rate: 0.8 mL/min.
4.30. Preparation of optically active S-(+)-a-methoxy-2-(3,4-
methylenedioxyphenyl)acetaldehyde 6d
4.24. Preparation of optically active (S)-(+)-a-methoxy-2-(3,4-
dimethoxyphenyl)acetaldehyde 6c
The compound was prepared from (S)-(+)-5d using the same
procedure as applied for racemic 6d. ½a D25
ꢁ
¼ þ52:3 (c 1.0, CHCl3)
The compound was prepared from (S)-(+)-5c using the same
procedure as applied for racemic 6c. ½a D25
¼ þ54:5 (c 1.0, CHCl3)
ꢁ
for crude (S)-(+)-6d.
for crude (S)-(+)-6c.
4.31. Preparation of optically active (S)-(+)-2-methoxy-2-(3,4-
4.25. Preparation of optically active (S)-(+)-2-methoxy-2-(3,4-
methylenedioxyphenyl)-ethanol 7d
dimethoxyphenyl)ethanol 7c
The compound was prepared from (S)-(+)-6d using the same
procedure as applied for racemic 7d, ee = 87%, ½a D25
¼ þ87:5 (c
ꢁ
The compound was prepared from (S)-(+)-6c using the same
procedure as applied for racemic 7c. Ee ꢀ93%, ½a D25
¼ þ98 (c 0.5,
ꢁ
0.5, CHCl3), HPLC conditions for its acetyl derivative: Chiralcel
OJH chiral column, eluent 2-propanol/hexane (0.5:99.5), flow rate:
0.8 mL/min.
CHCl3). HPLC conditions: Chiralcel OJH chiral column, eluent 2-
propanol/hexane (5:95), flow rate: 0.8 mL/min.

B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
2585
4.32. Preparation of optically active S-(ꢂ)-2-methoxy-2-(3,4-
3064.9, 3033.2, 2936.9, 1726, 1197.1, 1105.5, 722 cmꢂ1
(m/z): 164.6, 148.7, 120.7, 92.7.
;
MS
methylenedioxyphenyl)acetonitrile 8d
The compound was prepared from (S)-(+)-6d using the same
4.34.7. 2-Methoxy-2-phenyl acetonitrile C9H9ON 8a
procedure as applied for racemic 8d, ee = 89%, ½a D25
¼ ꢂ54:0 (c
ꢁ
Colourless viscous liquid, 1H NMR (500 MHz): d; 3.52 (3H, s,
OCH3), 5.18 (1H, s, CH), 7.25–7.89 (5H, m, ArH); 13C NMR: d;
56.8, 72.3, 117.0, 127.1, 127.3, 129.9, 133.5; IR (neat) NaCl:
1.0, CHCl3), HPLC conditions: Chiralcel OJH chiral column, eluent
2-propanol/hexane (5:95), flow rate: 0.8 mL/min.
3390.1, 3001.0, 1454.2, 1193.8, 1088.1, 758.5, 698.2 cmꢂ1
MS (m/z) (%); 147 (27.3), 146 (9.9), 132 (10.8), 121 (100), 116
(59.3).
;
4.33. Preparation of optically active (S)-(+)-a-methoxy-2-(3,4-
methylenedioxyphenyl)acetic-acid 9d
The compound was prepared from (S)-(+)-6d using the same
procedure as applied for racemic 9d, ee = 89%, ½a D25
¼ þ106:0 (c
ꢁ
4.34.8. Acetic acid-2,2-dimethoxy-1-phenylethyl ester
C12H16O4 4a
0.5, EtOH), HPLC conditions for its methyl ester: (R,R)-whelk-01,
chiral column, eluent 2-propanol/hexane (2:98), flow rate:
0.8 mL/min.
Colourless viscous liquid, 1H NMR (200 MHz): d; 2.11 (3H, s,
OC(O)CH3), 3.29 (3H, s, OCH3), 3.43 (3H, s, OCH3), 4.54 (1H, d,
J = 6.3 Hz, CH(OCH3)2), 5.83 (1H, d, J = 6.3 Hz, CHOAc), 7.32–7.42
(5H, m, ArH); 13C NMR: d; 21.5, 55.1, 55.9, 74.7, 105.5, 128.1,
128.6, 129.2, 137.2; IR (neat) NaCl: 2939.1, 2835.2, 1741.7,
1372.0, 1077.9, 700.5 cmꢂ1; MS (m/z) (%); 224, 193 (40.6), 165
(24.1), 75 (100).
4.34. Spectral data of synthesized compounds
4.34.1.
a-(Dibromomethyl)benzene methanol C8H8OBr2 2a
Colourless viscous liquid, 1H NMR (500 MHz): d; 5.38 (1H, d,
J = 7.4 Hz, CHBr2), 6.0 (1H, d, J = 7.4 Hz, CHOH), 7.35–7.37 (3H, m,
ArH), 7.45–7.47 (2H, m, ArH); 13CNMR: d; 45.6, 58.7, 128.6,
128.6, 129.5, 137.5; IR (neat) NaCl: 3406.2, 3029.1, 1584, 1494.7,
1141.5, 769.5, 693, 601.7 cmꢂ1; MS (m/z) (%); 280 (2.0), 263
(100), 261 (49.8), 184 (65.9), 182 (70.2), 171 (9.1), 169 (10.5),103
(73.2), 102 (34.6),77 (21.6).
4.34.9.
a,a-Dibromomethyl-(4-methoxyphenyl)methanol
C9H10O2Br2 2b
Light yellow viscous liquid, 1H NMR (200 MHz): d; 3.91 (1H,
OH), 3.81 (3H, s OCH3), 4.99 (1H, d, J = 5.3 Hz, CHBr2), 5.74 (1H, d,
J = 5.2 Hz, CHOH), 6.90 (2H, d, J = 8.6 Hz, ArH), 7.34 (2H, d,
J = 8.6 Hz, ArH), 13C NMR: d; 52.4, 55.3, 78.5, 113.8, 130.0, 131.5,
159.9; IR (neat) NaCl: 3446.2, 3002.9, 2836.9, 1611.2, 1513.0,
1252.8, 1030.6, 833.4 cmꢂ1; MS (m/z) (%); 310 (1.9), 150 (1.8),
149 (2.9), 138 (9.7), 137 (100), 135 (6), 122 (1.5), 109 (15.3), 108
(1.5), 94 (14.5), 77 (22.9).
4.34.2. 2,2-Dimethoxy-1-(phenyl)ethanol C10H14O3 3a
Colourless viscous liquid, 1H NMR (200 MHz): d; 3.25 (3H, s,
OCH3), 3.46 (3H, s, OCH3), 4.28 (1H, d, J = 6.4 Hz, CH(OMe)2), 4.61
(1H, d, J = 6.4 Hz, CHOH), 7.25–7.44 (5H, m, ArH); 13C NMR: d;
55.0, 56.0, 74.1, 107.7, 127.2, 127.9, 128.3, 139.5; IR (neat) NaCl:
3446.1, 3032.5, 2932.4, 2833.8, 1691.2, 1453.4, 1190.9, 1125.8,
4.34.10. 2,2-Dimethoxy-1-(4-methoxyphenyl)ethanol C11H16O4
3b
1068.9, 976.7, 762.4, 701 cmꢂ1
; MS (m/z) (%); 165 (17.10)
(M+ꢂOH), 151 (27.1).
Colourless viscous liquid, 1H NMR (200 MHz): d; 3.26 (3H, s,
OCH3), 3.47 (3H, s, OCH3), 3.8 (3H, s, OCH3), 4.27 (1H, d,
J = 6.5 Hz, CH(OCH3)2), 4.56 (1H, d, J = 6.5 Hz, CHOCH3), 6.89 (2H,
d, J = 8.5 Hz, ArH), 7.33 (2H, d, J = 8.5 Hz, ArH); 13C NMR: d; 54.7,
55.1, 55.7, 73.4, 107.6, 113.5, 128.2, 131.6, 159.1; IR (neat) NaCl,
3457.9, 2936.6, 2835.3, 1613, 1515.1, 832.0, 574.5 cmꢂ1; MS (m/
z) (%); 212 (1.4), 152 (2.1), 149 (10.9), 137 (13.5), 135 (39.7), 121
(16.6), 105 (1.2), 94 (11), 77 (31.4), 75 (100), 66 (8.9).
4.34.3. 1-(Phenyl)-1,2,2-trimethoxy ethane C11H16O3 5a
Colourless viscous liquid, 1H NMR (500 MHz): d; 3.18 (3H, s,
OCH3), 3.23 (3H, s, OCH3), 3.43 (3H, s, OCH3), 4.16 (1H, d, J = 6.2
Hz, CH(OMe)2), 4.36 (1H, d, J = 6.2 Hz, CHOMe), 7.25–7.35 (m, 5H,
ArH); 13C NMR: d; 54.4, 55.7, 56.9, 83.9, 106.5, 128.1, 128.3,
128.5, 138.0; IR (neat) NaCl: 2934.8, 2801, 1722.8, 1493.6,
1453.5, 1189.1, 1111.2, 701 cmꢂ1; MS (m/z) (%): 165 (M+ꢂOMe)
(39.5), 121 (17.6), 77 (11.9), 75 (100).
4.34.11. 1-(4-Methoxyphenyl)-1,2,2-trimethoxyethane
C12H18O4 5b
4.34.4.
a-Methoxyphenyl acetaldehyde C9H10O2 6a
Colourless viscous liquid,1H NMR (200 MHz): d; 3.20 (3H, s,
OCH3), 3.23 (3H, s, OCH3), 3.46 (3H, s, OCH3), 3.82 (3H, s, OCH3),
4.14 (1H, d, J = 5.6 Hz, CH(OCH3)2), 4.37 (1H, d, J = 5.6 Hz, CHOCH3),
6.91 (2H, d, J = 7.5 Hz, ArH), 7.28 (2H, d, J = 7.3 Hz, ArH); 13C NMR:
d; 55.4, 55.7, 56.0, 56.5, 83.2, 106.3, 113.5, 129.0, 129.8, 159.3; IR
(neat) NaCl, 2936.2, 2832.7, 1612.4, 1513.0, 1302.1, 1246.7,
1108.7, 831.5, 637.4 cmꢂ1; MS (m/z) (%); 226 (2), 195 (4.3), 164
(1.6), 135 (29), 121 (15), 108 (5), 92 (5), 91 (6), 78 (7), 75 (100),
49 (23).
Colourless viscous liquid, 1H NMR (500 MHz): d; 3.46 (3H, s,
OCH3), 4.64 (1H, d, J = 1.2 Hz, CHOCH3), 7.1–7.4 (5H, m, ArH), 9.6
(1H, d, J = 1.6 Hz, CHO); 13C NMR: d; 57.3, 88.3, 125.4, 127.5,
129.0, 129.1, 198.3; IR (neat) NaCl: 3439.1, 2925.8, 2853.8, 1735,
1454, 1108, 700 cmꢂ1; MS (m/z) (%); 151 (5.8) (M++1), 134 (6.3),
167.3 (13), 121 (100), 92 (7.1).
4.34.5. 2-Methoxy-2-phenyl ethanol C9H12O2 7a
Colourless viscous liquid, 1H NMR (500 MHz): d; 3.31 (3H, s,
OCH3), 3.56–3.68 (2H, m, CH2OH), 4.31 (1H, dd, J = 4.4 Hz,
7.83 Hz, CHOMe), 7.34 (5H, ArH); 13C NMR: d; 56.9, 67.4, 84.7,
126.9, 127.8, 128.2, 138.3; IR (neat) NaCl: 3425.6, 2933.1, 1454.3,
4.34.12.
a-Methoxy-2-(4-methoxyphenyl)acetaldehyde
C10H12O3 6b
Colourless liquid, 1H NMR (200 MHz): d; 3.40 (3H, s, OCH3), 3.80
(3H, s, OCH3), 4.59 (1H, d, J = 1.5 Hz, CHOMe), 6.93 (2H, d, J = 2.1 Hz,
ArH), 7.25 (2H, d, J = 1.9 Hz, ArH), 9.55 (1H, d, J = 1.6 Hz, CHO); 13C
NMR: d; 54.9, 56.9, 87.5, 114.2, 125.2, 128.68, 159.0, 199.1; IR
(neat) NaCl, 3449.5, 2963.2, 2836.4, 1735.5, 1610.1, 1511.0,
1250.9, 1106.4, 831.9 cmꢂ1; MS (m/z) (%); 180 (0.3), 164 (1.8),
151 (100), 150 (0.4).
1112.0, 1065.1, 759.3, 702.2 cmꢂ1
; MS (m/z) (%); 121 (100)
(M+ꢂOMe), 91 (19.9), 77 (7.1).
4.34.6.
a-Methoxyphenyl acetic acid C9H10O3 9a
Colourless viscous liquid, 1H NMR (200 MHz): d; 3.41 (3H, s,
OCH3), 4.78 (1H, s, CHOCH3), 7.26–7.45 (m, 5H, ArH); 13C NMR:
d; 57.7, 82.4, 127.7, 129.2, 129.4, 135.7, 175.7; IR (neat) NaCl:

2586
B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
4.34.13. 2-Methoxy-2-(4-methoxyphenyl)ethanol C10H14O3 7b
Colourless liquid, 1H NMR (200 MHz): d; 3.28 (3H, s, OCH3), 3.82
(3H, s, OCH3), 3.61–3.73 (2H, m, CH2OH), 4.26 (1H, dd, J = 4.1 Hz,
8.2 Hz, CHOMe), 6.91(2H, d, J = 8.6 Hz, ArH), 7.24 (2H, d,
J = 8.6 Hz, ArH); 13C NMR: d; 54.2, 54.7, 66.4, 83.1, 86.6, 112.9,
127.1, 159.6; IR (neat) NaCl: 3422.5, 2934.9, 1611.6, 1513.2,
1247.7, 1108.7, 1033.9, 832 cmꢂ1; MS (m/z) (%), 182 (1.4), 183
(1.5), 152 (100), 135 (20.4), 122 (3.6), 108 (6.2), 91 (6), 77 (7), 66
(3.6), 52 (4).
4.34.19. 1-(3,4-Dimethoxyphenyl)-1,2,2-trimethoxy ethane
C13H20O5 5c
White solid, mp 43 °C, 1H NMR (200 MHz): d; 3.22 (3H, s, OCH3),
3.24 (3H, s, OCH3), 3.45 (3H, s, OCH3), 3.88 (6H, s, OCH3), 4.1 (1H, s,
J = 6.1 Hz, CH(OCH3)2), 4.35 (1H, s, J = 6.1 Hz, CHOCH3), 6.8–6.9 (3H,
m, ArH); 13C NMR: d; 54.4, 55.6, 55.8, 55.9, 56.8, 83.5, 106.4, 110.4,
110.6, 120.6, 130.3, 148.7, 148.9; IR(KBr), 3529.3, 2936.7, 2832.5,
1594, 1516, 1464, 1261, 1108.5, 1028, 812.5, 752 cmꢂ1; MS (m/z)
(%); 257 (1.70) (M++1), 226 (1.5), 182 (32.5), 181 (32), 166 (7.2),
165 (6.2), 151 (6.2), 135 (1.2), 121 (1.1), 107 (1.3), 95 (1.8), 75
(100).
4.34.14.
a-Methoxy-2-(4-methoxyphenyl)acetic acid
C10H12O4 9b
White solid, mp 64 °C, 1H NMR (200 MHz): d; 3.39 (3H, s, OCH3),
3.80 (3H, s, OCH3), 4.72 (1H, s, CHOMe), 6.90 (2H, d, J = 8.2 Hz, ArH),
7.34 (2H, d, J = 8.3 Hz, ArH); 13C NMR: d; 54.3, 56.0, 80.5, 113.4,
126.9, 127.6, 167.8, 180.4; IR (neat) NaCl; 3423.1, 2936.3, 2837.2,
1734.5, 1610.4, 1512.7, 1249.9, 1176.0, 1101.1, 1031.2, 988.5,
830.7 cmꢂ1; MS (m/z) (%); 195 (M+ꢂ1), 181, 165, 134.
4.34.20.
C11H14O4 6c
colourless liquid, 1H NMR (200 MHz): d; 3.43 (3H, s, OCH3), 3.89
(6H, s, 2 ꢃ OCH3), 4.60 (1H, d, J = 1.5 Hz, CHOCH3), 6.85–6.97 (3H,
m, ArH), 9.57 (1H, d, J = 1.6 Hz, CHO); 13C NMR: d; 55.2, 55.5,
56.9, 87.5, 110.3, 111.3, 120.1, 126.5, 148.9, 149.2, 197.5; IR (neat)
NaCl; 3449.8, 2935.8, 2835.7, 1733, 1594.0, 1515.1, 1265.4, 1026.4,
811.5 cmꢂ1; MS (m/z) (%); 210 (2.3), 182 (9.2), 181 (100), 166
(31.7), 165 (21.1), 151 (14.3), 137 (5), 121 (2.5), 77 (7.9).
a-Methoxy-2-(3,4-dimethoxyphenyl)acetaldehyde
4.34.15. 2-Methoxy-2-(4-methoxyphenyl)acetonitrile
C10H11O2N 8b
Colourless liquid, 1H NMR (200 MHz): d; 3.50 (3H, s, OCH3), 3.83
(3H, s, OCH3), 5.15 (1H, s, CHOMe), 6.94 (2H, d, J = 8.6 Hz, ArH), 7.41
(2H, d, J = 8.7 Hz, ArH); 13C NMR: d; 55.3, 56.8, 73.3, 115.8, 118.5,
126.8, 130.3, 162.1; IR (neat) NaCl; 2936.0, 2838.2, 2558.3,
2037.4, 1612.0, 1513.9, 1463.5, 1253.8, 1178.4, 1082.8,
829.5 cmꢂ1; MS (m/z) (%); 177 (23), 151 (5.9), 147 (13), 146
(100), 135 (9.5), 103 (12.7), 91 (14.4), 77 (15.3), 76 (16.4), 64
(11.3), 53 (12.6), 45 (22.3).
4.34.21. 2-Methoxy-2-(3,4-dimethoxyphenyl)ethanol
C11H16O4 7c
White solid, mp 45 °C, 1H NMR (200 MHz): d; 3.30 (3H, s, OCH3),
3.80 (6H, s, 2 ꢃ OCH3), 3.63–3.71 (2H, m, CH2OH), 4.25 (1H, dd,
J = 4.2 Hz, 8.0 Hz, CHOMe), 6.84–6.86 (3H, m, ArH); 13C NMR: d;
54.1, 54.5, 55.1, 65.1, 82.1, 107.3, 108.8, 117.3, 128.6, 144.3,
146.9; IR (neat) NaCl; 3423.0, 2934.9, 2835.5, 1594.1, 1517.1,
1464.7, 1262.5, 1110.6, 1027.2, 812.6 cmꢂ1; MS (m/z) (%); 213 (4)
(M++1), 212 (3.2), 183 (11.4), 182 (100), 167 (22), 166 (10.9), 151
(8.3), 137 (3.4), 95 (3.2).
4.34.16. Acetic acid-2,2-dimethoxy-1-(4-methoxyphenyl)ethyl
ester C13H18O5 4b
Colourless liquid, 1H NMR (200 MHz): d; 2.10 (3H, s, OCOCH3),
3.3 (3H, s, OCH3), 3.42 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.52 (1H,
d, J = 6.3 Hz, CH(OCH3)2), 5.78 (1H, d, J = 6.28 Hz, CHOAc), 6.88
(2H, d, J = 4.8 Hz, ArH), 7.33 (2H, d, J = 4.8 Hz, ArH); 13C NMR: d;
20.8, 54.3, 55.3, 56.1, 74.0, 105.0, 114.5, 128.3, 128.6, 159.5,
169.8; IR (neat) NaCl, 3450.2, 2938.4, 2836.8, 1740.8, 1613.3,
1516.2, 1238.8, 1072.7, 1032.0, 831.6 cmꢂ1; MS (m/z) (%); 254
(.3), 223 (.2), 195 (.3), 181 (.5), 149 (1.7), 137 (3), 135 (1.9), 121
(3.7), 91 (.8), 77 (2.4), 75 (100), 49 (7.7).
4.34.22.
C11H14O5 9c
White solid, mp 92 °C, 1H NMR (200 MHz): d; 3.40 (3H, s, OCH3),
3.87 (6H, s, OCH3), 4.70 (1H, s, CHOCH3), 6.85 (1H, d, J = 8.1 Hz,
ArH), 6.90 (1H, d, J = 8.2 Hz, ArH), 7.01 (1H, s, ArH); 13C NMR: d;
56.3, 56.5, 57.6, 82.2, 110.1, 111.4, 120.6, 125.5, 146.4, 147.6,
177.2; IR (neat) NaCl, 3488.8, 2952.0, 2853.5, 1735.9, 1599.1,
1496.3, 1467.7, 1418.4, 1259.6, 1097.1, 803.0 cmꢂ1; MS (m/z);
226, 224, 194.8, 164.9.
a-Methoxy-2-(3,4-dimethoxyphenyl)acetic acid
4.34.17.
C10H12O3Br2 2c
a,a-Dibromomethyl-(3,4-dimethoxyphenyl)methanol
4.34.23. 2-Methoxy-2-(3,4-dimethoxyphenyl)acetonitrile
C11H13O3N 8c
White crystalline solid, mp 97 °C, 1H NMR (200 MHz): d; 3.04
(1H, d, J = 3.70 Hz, OH), 3.88 (3H, s, OCH3), 3.87 (3H, s, OCH3),
4.94–4.98 (1H, m, CHBr2), 5.75 (1H, d, J = 5.3 Hz, CHOH), 6.82–
6.96 (3H, m, ArH); 13C NMR: d; 52.3, 55.8, 78.7, 109.8, 110.8,
119.6, 130.4, 148.9, 149.4; IR (neat) NaCl; 3467.3, 3078.4, 2979.4,
2913.3, 1592.4, 1325.0, 1102.3, 814.3 cmꢂ1; MS (m/z) (%); 340
(4.8), 180 (2.9), 167 (100), 165 (4.2), 151 (3.8), 139 (33.3), 107
(3.5), 77 (10.2).
Colourless liquid, 1H NMR (200 MHz): d; 3.52 (3H, s, OCH3), 3.92
(6H, s, 2 ꢃ OCH3), 5.14 (1H, s, CHOMe), 6.85 (1H, d, J = 8.2 Hz, ArH),
6.99–7.07 (2H, m, ArH); 13C NMR: d; 56.3, 56.4, 57.4, 72.5, 110.4,
111.4, 115.3, 120.6, 123.3, 149.2, 150.5; IR (neat) NaCl; 3081.0,
3003.7, 2605.7, 2226.2, 2863.7, 1751.6, 1715.4, 1596.4, 1518.0,
1464.4, 1420.8, 1262.1, 1082.9, 1052.0, 813.1, 783.2, 746.5 cmꢂ1
;
MS (m/z) (%); 208 (3.6) (M++1), 207 (27), 177 (13), 176 (100),
131 (6.9), 103 (5), 90 (8.1), 79 (6.8), 64 (15.4).
4.34.18. 2,2-Dimethoxy-1-(3,4-dimethoxyphenyl)ethanol
C12H18O5 3c
4.34.24. Acetic acid-2,2-dimethoxy-1-(3,4-
dimethoxyphenyl)ethylester C14H20O6 4c
White solid, mp 48 °C, 1H NMR (200 MHz): d; 3.26 (3H, s, OCH3),
3.46 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.26 (1H,
d, J = 6.5 Hz, CH(OCH3)2), 4.54 (1H, d, J = 6.5 Hz, CHOH), 6.8 (1H, d,
J = 8.8 Hz, ArH), 6.90 (2H, d, J = 8.9 Hz, ArH); 13C NMR: d; 54.9, 55.8,
56.0, 73.8, 107.7, 110.1, 110.8, 119.5, 131.9, 148.6, 148.8; IR (KBr);
3380.2, 3081.7, 2993.6, 2966.5, 2835.3, 1594.4, 1514.6, 1464.6,
1263.9, 812.0, 747.9 cmꢂ1; MS (m/z) (%); 242 (3.2), 179 (5.5), 167
(4.7), 165 (1.66), 151 (5.3), 139 (8.2), 124 (3.3), 121 (1.3), 108
(3), 79 (2.2), 75 (100), 65 (2.9), 49 (17.7), 47 (3.6).
White solid, mp 98 °C, 1H NMR (200 MHz): d; 2.13 (3H, s,
C(O)CH3), 3.32 (3H, s, OCH3), 3.44 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 3.91 (3H, s, OCH3), 4.54 (1H, d, J = 6.2 Hz, CH(OMe)2), 5.78
(1H, d, J = 6.2 Hz, CHOAc), 6.86 (1H, d, J = 8.1 Hz, ArH), 6.90 (1H,
d, J = 8.2 Hz, ArH), 7.0 (1H, s, ArH); 13C NMR: d; 21.3, 54.8, 55.5,
56.3, 56.8, 74.9, 104.9, 110.7, 110.9, 120.2, 129.2, 148.6, 148.9,
169.8; IR (KBr); 3082.7, 1734.1, 1593.2, 1519.4, 1192.9,
1237.1 cmꢂ1; MS (m/z) (%); 284 (1.1), 195 (.5), 180 (.3), 166 (.8),
165 (1.2), 151 (2.4), 125 (4), 121 (.5), 107 (.5), 75 (100).

B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
2587
4.34.25.
methanol C9H8O3Br2 2d
a
,
a
-Dibromomethyl-(3,4-methylenedioxyphenyl)-
4.34.31. 2-Methoxy-2-(3,4-methylenedioxyphenyl)acetonitrile
C10H9O3N 8d
Colourless liquid, 1H NMR (200 MHz): d; 2.94 (1H, d, J = 3.6 Hz,
OH), 4.94 (1H, d, J = 5.2 Hz, CHBr2), 5.7 (1H, d, J = 5.2 Hz, CHOH),
5.97 (2H, s, OCH2O), 6.71–6.92 (3H, m, ArH); 13C NMR: d; 52.6,
79.2, 101.7, 107.6, 108.6, 121.3, 131.7, 147.7, 147.9; IR (neat) NaCl;
3513.8, 3004.9, 2829.1, 1503.4, 1444.7, 1247.6, 1038.3,
932.6 cmꢂ1; MS (m/z) (%); 326 (15.4), 324 (30), 322 (14.9), 164
(16.4), 152 (100), 149 (15.4), 135 (34), 123 (31), 122 (12.8), 121
(22.9), 93 (100), 77 (38), 65 (100).
Colourless liquid, 1H NMR (200 MHz): d; 3.50 (3H, s, OCH3), 5.0
(1H, s, CHOMe), 6.01 (2H, s, OCH2O), 6.81–6.98 (3H, m, ArH); 13C
NMR: d; 57.2, 72.2, 101.4, 107.9, 108.6, 117.2, 121.7, 127.2,
148.5, 149.1; IR (neat) NaCl; 3077.5, 3001.4, 2933.6, 2617.7,
2237.6, 504.6, 1489.2, 1446.9, 1253.5, 1080.9, 833.0, 810.2 cmꢂ1
;
MS (m/z) (%); 191 (32.6), 165 (16.6), 160 (99.5), 104 (10.4), 102
(15.5), 87 (23.7), 77 (13.8), 76 (14.8), 75 (27.9), 74 (45.2), 64
(18.8), 57 (19.5), 46 (100), 45 (95).
4.34.26. 2,2-Dimethoxy-1-(3,4-methylenedioxyphenyl)ethanol
C11H14O5 3d
4.34.32. Acetic acid-2,2-dimethoxy-1-(3,4-
methylenedioxyphenyl)ethyl ester C13H16O6 4d
White solid, mp 55 °C, 1H NMR (200 MHz): d; 2.67 (1H, br s,
OH), 3.29 (3H, s, OCH3), 3.47 (3H, s, OCH3), 4.25 (1H, d, J = 6.4 Hz,
CH(OCH3)2), 4.52 (1H, d, J = 6.4 Hz, CHOH), 5.95 (2H, s, OCH2O),
6.78 (1H, d, J = 7.9 Hz, ArH), 6.88 (1H, d, J = 8.0 Hz, ArH), 6.92 (1H,
s, ArH); 13C NMR: d; 55.3, 56.3, 74.2, 101.3, 107.9, 108.0, 108.4,
121.1, 133.7, 148.0, 148.5; IR (neat) NaCl; 3451.2, 2902.3, 2781.2,
1489.7, 1443.7, 1249.3, 1077.0, 929.0 cmꢂ1; MS (m/z) (%); 226
(15.5), 165 (4.7), 151 (15.2), 150 (8.7), 135 (28.3), 123 (5.3), 105
(5.3), 91 (4), 76 (100), 49 (100).
White solid, mp 63 °C, 1H NMR (200 MHz): d; 2.03 (3H, s,
OCOCH3), 3.20 (3H, s, OCH3), 3.31 (3H, s, OCH3), 5.61 (1H, d,
J = 6.1 Hz, CHOAc), 5.80 (2H, s, OCH2O), 6.61–90 (3H, m, ArH);
13C NMR: d; 21.5, 54.8, 55.8, 74.6, 101.5, 105.3, 109.4, 112.9,
122.1, 130.8, 147.4, 147.9, 170.1; IR (neat) NaCl; 2914.7, 2835.7,
1742.0, 1480.5, 1233.6, 1037.2 cmꢂ1; MS (m/z) (%); 268 (3.4),
209 (2.2), 178 (3.2), 147 (7.2), 133 (9.3), 121 (3.1), 77 (11.4),
76(100).
Acknowledgement
4.34.27. 1-(3,4-Methylenedioxyphenyl)-1,2,2-trimethoxy
ethane C12H16O5 5d
One of the authors P.G. is thankful to CSIR, New Delhi, for the
award of SRF.
Semi solid, 1H NMR (200 MHz): d; 3.24 (3H, s, OCH3), 3.25 (3H, s,
OCH3), 3.45 (3H, s, OCH3), 4.09 (1H, d, J = 6.1 Hz, CH(OMe)2), 4.34
(1H, d, J = 6.1 Hz, CHOMe), 5.96 (2H, s, OCH2O), 6.79–6.86 (3H, m,
ArH); 13C NMR: d; 54.8, 56.0, 57.1, 84.0, 101.4, 106.7, 108.3,
108.4, 122.1, 132.2, 148.2, 148.9; IR (neat) NaCl; 2934.0, 2900.1,
2830.7, 1488.6, 1442.6, 1243.1, 1108.3, 943.9 cmꢂ1; MS (m/z) (%);
240 (2.7), 209 (5), 178 (2.1), 165 (35.1), 166 (23.1), 121 (2.9), 75
(100), 77 (10).
References
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Lindvquist, B. Acta Chem. Scand. B 1985, 39, 589.
4.34.28.
C10H10O4 6d
a-Methoxy-(3,4-methylenedioxyphenyl)acetaldehyde
Semisolid, 1H NMR (200 MHz): d; 3.42 (3H, s, OCH3), 4.54 (1H, s,
CHOMe), 5.98 (2H, s, OCH2O), 6.78–6.81 (3H, m, ArH), 9.55 (1H, d,
J = 1.0 Hz, CHO); 13C NMR: d; 57.4, 88.2, 101.7, 107.9, 108.7, 121.9,
127.8, 148.4, 148.8, 198.3; IR (neat) NaCl; 3448.3, 2901.9, 1735.0,
1487.8, 1246.7, 1037.9, 812.1 cmꢂ1; MS (m/z) (%); 194 (2.7), 167
(1.2), 166 (11), 165 (100), 150 (27.5), 149 (24.8), 133 (2.6), 121
(32), 119 (4.6), 79 (5.4), 77 (9.4), 64 (8.2).
7. (a) Trost, B. M.; O’Krongly, D.; Belletire, J. L. J. Am. Chem. Soc. 1980, 102, 7595;
(b) Siegel, C.; Thornton, E. R. Tetrahedron Lett. 1988, 29, 5225; (c) Tucker, J. A.;
Houk, K. N.; Trost, B. M. J. Am. Chem. Soc. 1990, 112, 5465.
8. (a) Raban, M.; Mislow, K. Tetrahedron Lett. 1965, 48, 4249; (b) Raban, M.;
Mislow, K. Top. Stereochem. 1967, 2, 199; (c) Dale, J. A.; Mosher, H. S. J. Am.
Chem. Soc. 1968, 90, 3732; (d) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512; (e) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.
J. Org. Chem. 1986, 51, 2370.
9. Seco, J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915.
10. (a) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59, 4202; (b)
Brust, P. H.; Marecak, D.; Hollend, H. L.; Brown, F. M. Tetrahedron: Asymmetry
1995, 6, 7.
11. (a) Latypov, Sh. K.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1995, 60, 504;
(b) Seco, J. M.; Latypov, Sh. K.; Quinoa, E.; Riguera, R. Tetrahedron 1997, 53,
8541.
12. Ho, P. T.; Ngu, K.-Y. J. Org. Chem. 1993, 58, 2313.
13. Chamberlain, V. K.; Wain, R. L. Ann. Appl. Biol. 1971, 68, 307.
14. Ulrich, R.; Martin, D. J. Med. Chem. 1992, 35, 2238.
15. Lee, C.; Kim, J.; Lee, H.; Lee, S.; Kho, Y. J. Nat. Prod. 2001, 64, 659.
16. Colombo, L.; Gennari, C.; Scolastico, C.; Guanti, G.; Narisano, E. J. Chem. Soc.,
Perkin Trans. 1 1981, 1278.
17. Ferraboschi, P.; Santaniello, E.; Tingoli, M.; Aragozzini, F.; Molinari, F.
Tetrahedron: Asymmetry 1993, 4, 1931.
18. (a) Fujisawa, T.; Kojima, E.; Itoh, T.; Sato, T. Chem. Lett. 1985, 1751; (b) Guanti,
G.; Banfi, L.; Narisano, E. Tetrahedron Lett. 1986, 27, 3547.
19. Dorado, F. J. M.; Guerra, F. M.; Ortega, M. J.; Zubia, E.; Massanet, G. M.
Tetrahedron: Asymmetry 2003, 14, 503.
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21. Naskar, D.; Roy, S. Tetrahedron 2000, 56, 1369.
4.34.29. 2-Methoxy-2-(3,4-methylenedioxyphenyl)ethanol
C10H12O4 7d
White solid, mp 38 °C, 1H NMR (200 MHz): d; 2.33 (1H, br s,
OH), 3.28 (3H, s, OCH3), 3.41–3.60 (2H, m, CH2OH), 4.21 (1H, dd,
J = 4.4 Hz, 7.8 Hz, CHOMe), 5.90 (2H, s, OCH2O), 6.72–6.81 (3H, m,
ArH); 13C NMR: d; 56.9, 67.5, 84.5, 101.3, 107.2, 108.5, 120.7,
132.4, 147.7, 148.1; IR (neat) NaCl; 3423.2, 2931.7, 2902.1,
1487.3, 1439.9, 1246.1, 1109.4, 1038.7, 930.0, 843.2 cmꢂ1; MS
(m/z) (%); 196 (6.6), 166 (10.2), 165 (100), 150 (24), 149
(18.6), 119 (3.6), 107 (4.8), 77 (10.2), 64 (7.5), 55 (4.4), 46 (13.8),
45 (8.7).
4.34.30.
C10H10O5 9d
a-Methoxy-(3,4-methylenedioxyphenyl)acetic acid
White solid, mp 74 °C, 1H NMR (200 MHz): d; 3.40 (3H, s, OCH3),
4.69 (1H, s, CHOMe), 5.97 (2H, s, OCH2O), 6.78–6.93 (3H, m,
ArH); 13C NMR: d; 57.1, 81.7, 101.3, 107.4, 108.4, 121.4, 129.1,
148.1, 148.2, 174.2; IR (neat) NaCl; 3394.1, 2923.0, 1731.8,
1503.8, 1245.0, 1101.9, 1038.1 cmꢂ1; MS (m/z) (%); 208.6, 176.9,
121.
22. Dass, J. P.; Roy, S. J. Org. Chem 2002, 67, 7861.
23. (a) Gupta, P.; Shah, B. A.; Parshad, R.; Qazi, G. N.; Taneja, S. C. Green Chem. 2007,
9, 1120; (b) Kato, K.; Gong, Y.; Saito, T.; Kimoto, H. J. Biosci. Bioeng. 2000, 90,
332; (c) Anand, N.; Kapoor, M.; Ahmad, K.; Koul, S.; Parshad, R.; Manhas, K. S.;
Sharma, R. L.; Qazi, G. N.; Taneja, S. C. Tetrahedron: Asymmetry 2007, 18,
1059.
24. (a) Arthrobacter sp. cell biomass was prepared in shake flasks and in 10 L
fermentor-containing medium (1% peptone, and 0.5% NaCl and 0.5% beef

2588
B. Singh et al. / Tetrahedron: Asymmetry 19 (2008) 2579–2588
extract, pH 7.0). The medium was inoculated with an overnight preculture
has been deposited in MTCC culture collection under Budapest Treaty (2004);
(b) Johri, S.; Verma, V.; Parshad, R.; Koul, S.; Taneja, S. C.; Qazi, G. N. Bioorg.
Med. Chem. 2001, 9, 269; (c) Koul, S.; Taneja, S. C.; Parshad, R.; Qazi, G. N.
Tetrahedron: Asymmetry 1998, 9, 3395; (d) Chaubey, A.; Parshad, R.; Koul, S.;
Taneja, S. C.; Qazi, G. N. J. Mol. Catal. B: Enzym. 2006, 42, 39.
prepared in the same broth. The culture was grown at 30 °C for 16–18 h at
200 rpm. The cell pellet was separated from the broth by centrifugation at
10,000g for 15 min at 4 °C, and was preserved at ꢂ20 °C till further use.
Arthrobacter sp. microbial culture (ABL, MTCC No. 5125), isolated at institute