Amano PS-catalysed enantioselective acylation of (±)-α-methyl-1,3-benzodioxole-5-ethanol: An efficient resolution of chiral intermediates of the remarkable antiepileptic drug candidate, (-)-talampanel

Article abstract of DOI:10.1016/S0957-4166(02)00836-4

(S)-(+)-α-Methyl-1,3-benzodioxole-5-ethanol 5 is a chiral building block in the synthesis of the future drug (-)-talampanel 1. Amano PS-induced enantioselective acylation of (±)-3 at 50°C using vinyl acetate as acyl donor furnished (+)-5 in 53% yield and

Full text of DOI:10.1016/S0957-4166(02)00836-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 333–337
Amano PS-catalysed enantioselective acylation of
( )-a-methyl-1,3-benzodioxole-5-ethanol: an efficient resolution of
chiral intermediates of the remarkable antiepileptic drug
candidate, (−)-talampanelꢀ
Srinivasan Easwar and Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 31 October 2002; revised 5 December 2002; accepted 9 December 2002
Dedicated to Dr. B. G. Hazra, OCS, NCL, Pune, India
Abstract—(S)-(+)-a-Methyl-1,3-benzodioxole-5-ethanol 5 is a chiral building block in the synthesis of the future drug (−)-talam-
panel 1. Amano PS-induced enantioselective acylation of ( )-3 at 50°C using vinyl acetate as acyl donor furnished (+)-5 in 53%
yield and 80% e.e., and the corresponding acetyl derivative (−)-(R)-a-methyl-1,3-benzodioxole-5-ethyl acetate 6 in 44% yield and
96% e.e. The base-catalysed methanolysis of (−)-6 followed by Mitsunobu inversion and subsequent methanolysis of the product,
(+)-8 also gave the desired (+)-5 in 38% overall yield (four steps) and 96% e.e. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
5 is the first step of a new stereoselective route for the
synthesis of the new drug candidate (−)-talampanel 1.5
A group of scientists from the Hungarian Institute of
Drug Research have recently discovered an orally
active novel compound 7-acetyl-5-(4-aminophenyl)-
8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-b][2,3]-
benzodiazepine [(−)-talampanel, GYKI-53773, IDR-
53773, LY-300164, 1] with potential antiepileptic, neu-
roprotectant and skeletal muscle relaxant activities.1–3
Phase II trials of the drug (−)-talampanel 1 in patients
with severe epilepsy not responsive to other drugs have
shown efficacy and phase III studies are in progress to
confirm and use these results. Hence, (−)-talampanel 1
has been identified as a future drug.4,5 The clinical
potential of this new compound 1 has led to great
interest in developing new syntheses.5–7 The enantiose-
lective synthesis of 1 has been completed via asymmet-
ric reduction of the carbonꢀnitrogen double bond of
2,3-benzodiazepine using a borane–homochiral amino
alcohol complex.6 The stereoselective enzymatic reduc-
tion of 3,4-methylenedioxyphenylacetone to the corre-
sponding (+)-(S)-a-methyl-1,3-benzodioxole-5-ethanol
Recently, an efficient large scale enantioselective reduc-
tion of 3,4-methylenedioxyphenylacetone has been ele-
gantly accomplished by using an NAD(P)H-dependent
oxidoreductase
from
Zygosaccharomyces
rouxii
together with polymeric hydrophobic resins both to
supply substrate to the enzyme and remove the product
from the reaction mixture as it is formed.5,7 Chemical
methods for the enantioselective reduction of methyl
ꢀ NCL Communication No. 6636.
* Corresponding author. Tel.: +91-20-5893153; fax: +91-20-5893153;
e-mail: argade@dalton.ncl.res.in
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00836-4

334
S. Easwar, N. Argade / Tetrahedron: Asymmetry 14 (2003) 333–337
benzyl ketones require the stoichiometric use of costly
reagents.8 Selectivity and conversion of the correspond-
ing ketone to (+)-5 with Baker’s yeast and other com-
mon microorganisms were found to be unsatisfac-
tory.5,9 Copper(I)-catalysed reaction of (S)-propylene
oxide with the corresponding aryl Grignard reagent is
known to produce the desired alcohol (+)-5 in 91%
yield. However, the cost of this method is high as the
enantiomerically pure epoxide starting material is
expensive.5
tate (5 equiv.) as an acyl donor at 25°C took place with
12% yield of (−)-6 in 48 h. During these studies we
noticed that the enzymatic resolution is time, tempera-
ture and vinyl acetate concentration dependent. Several
experiments were carried out to obtain the maximum
yield of (+)-5 and (−)-6 with high enantiomeric excess
(Table 1). The best result from the acylation of ( )-3
afforded (−)-6 with 96% e.e. in 46% yield and (+)-5 with
80% e.e. in 54% yield (Table 1, entry 5). These results
were obtained using 5 equiv. of vinyl acetate at 50°C in
a reaction time of 72 h. Under the present set of
reaction conditions, the enzyme Amano PS had the
highest activity at 50°C and showed a decline in its
activity at 55 and 60°C (Table 1, entries 5–8). The
formed hydroxy compound (+)-5 and the acetyl deriva-
tive (−)-6 were easily separated by silica gel column
chromatography. On methanolysis in the presence of
K2CO3 as a catalyst the acetyl derivative (−)-6 gave
alcohol (−)-7 in 95% yield. The stereochemical assign-
ment of (+)-5 and (−)-7 was done on the basis of
Biotransformations are often more efficient than chemi-
cal methods10 and in continuation of our earlier
studies11 on the enzymatic resolutions of important
chiral intermediates, we planned the enantioselective
enzyme-catalysed acylation of ( )-3 and hydrolysis of
acyl derivatives of ( )-3.12 We report herein an efficient
enzyme-catalysed acylation of ( )-3 to obtain enan-
tiomerically pure (+)-5 in high yields (Scheme 1).
1
comparison with literature information.5 The H NMR
2. Results and discussion
spectrum of diastereomeric mixture of Mosher’s esters14
obtained from ( )-3 and (R)-Mosher’s acid showed a
very clean resolution of the –OCH3 and 1,3-benzodiox-
ole (-O-CH2-O-) methylene protons. The 1H NMR
spectrum of Mosher’s esters of (+)-5 and (−)-7 revealed
that (+)-5 possesses 80% e.e.15 and (−)-7 is formed with
96% e.e. Mitsunobu inversion17 of alcohol (−)-7 using
DEAD, TPP and p-nitrobenzoic acid then afforded
(+)-8 in 96% yield and subsequent alcoholysis of (+)-8
provided the desired alcohol (+)-5 in 94% yield and
The ( )-a-methyl-1,3-benzodioxole-5-ethanol
3 was
obtained in 3-steps from piperonal 2 using a known
procedure involving nitroethane condensation, reduc-
tive hydrolysis and sodium borohydride reduction.13
We prepared a systematic plan to study the enzyme-
catalysed enantioselective hydrolysis of acyl derivatives
of ( )-3 and enzyme-catalysed enantioselective
acylation of ( )-3. We first synthesised the acetyl,
chloroacetyl, p-methoxybenzoyl, p-nitrobenzoyl and
palmitoyl derivatives 4a-e from ( )-3 for screening
enzyme-catalysed hydrolysis with the enzymes Amano
PS, CCL and Amano AY but unfortunately the sub-
strates 4a–e were not recognised by these enzymes and
all attempts at biphasic enantioselective enzymatic
hydrolysis of 4a–e met with failure. Interestingly, the
Amano PS-catalysed acylation of ( )-3 using vinyl ace-
1
96% e.e. (from the H NMR spectrum of the MTPA-
ester). The conversion of the enantiomerically pure
(S)-alcohol 5 to (−)-talampanel 1 in an impressive 54%
overall yield (six steps) via exclusive generation of the
seven-membered 2,3-benzodiazepine skeleton with
inversion of configuration is
a well established
protocol.5,7
Scheme 1. Reagents and conditions: (i) Ac2O/py, rt, 24 h; (ii) RCOOH, DCC, DMAP, DCM, rt, 8 h; (iii) petroleum ether/benzene
(2:1), Amano PS or CCL or Amano AY, 50 mM sodium phosphate buffer (pH 7.0), rt, 24 h; (iv) n-hexane/benzene (2:1), Amano
PS, vinyl acetate, 50°C, 72 h; (v) K2CO3/MeOH, 0°C, 4 h; (vi) DEAD, TPP, p-NO2-C6H4COOH, THF, 0°C to rt, 8 h.

S. Easwar, N. Argade / Tetrahedron: Asymmetry 14 (2003) 333–337
335
Table 1. Amano PS-catalysed enantioselective acylation of (9)-h-methyl-1,3-benzodioxole-5-ethanol 3
(+)-5a [h]
(−)-6a [h]
(+)-5% e.e. (−)-6% e.e.
20
589
20
589
Entry
Temp. (°C)
Time (h)
Vinyl acetate (+)-5 %
(−)-6 %
(equiv.)
remained (by conversion
1H NMR)
(by 1H
NMR)
1
2
3
4
5
6
7
8
25
50
50
50
50
50
55
60
48
24
48
60
72
96
48
48
5
5
5
10
5
5
88
65
56
60
54
54
67
75
12
35
44
40
46
46
33
25
+3.1
+11.6
+26.1
+19.3
+27.6
+27.5
+10.7
+6.9
−5.3
−5.4
−5.3
−5.3
−5.4
−5.3
−5.3
−5.3
10b
34b
76c
56b
80c
80c
31b
20b
95b
96b
95d
95b
96d,e
95d
95b
95b
5
5
a Specific rotations were determined in CHCl3 (c=1 in all cases).
b E.e. determined from the specific rotation value.
c E.e. determined by MTPA-ester preparation with (R)-Mosher’s acid.
d % E.e. determined by conversion of -OAc to -OH followed by MTPA-derivatisation with (R)-Mosher’s acid.
e E value: 125.
3. Conclusion
4.3. ( )-a-Methyl-1,3-benzodioxole-5-ethyl acetate, 4a
To a stirred solution of alcohol ( )-3 (900 mg, 5 mmol)
in pyridine (10 mL) was added acetic anhydride (5 mL)
and the reaction mixture was kept in the dark at rt for
24 h. The reaction mixture was poured into water and
extracted with ethyl acetate (15 mL×5). The combined
organic layer was washed with aq. CuSO4 solution,
water and brine and dried over Na2SO4. Concentration
of the organic layer in vacuo followed by silica gel
column chromatographic purification of the residue
using petroleum ether and ethyl acetate (9:1) gave 4a
(1.01 g, 91%). Analytical and spectral data obtained
were identical with (−)-6.
In summary, we have demonstrated an efficient practi-
cal enantioselective Amano PS-catalysed acylation of
( )-a-methyl-1,3-benzodioxole-5-ethanol 3 to obtain the
potential chiral building block (+)-(S)-a-methyl-1,3-
benzodioxole-5-ethanol 5 for promising antiepileptic
future drug (−)-talampanel 1 in 53% yield and 80% e.e.
The enantiomerically pure antipode, (−)-6 was also
transformed to the desired isomer (+)-5 via Mitsunobu
inversion in 38% overall yield (four steps) with 96% e.e.
We feel that the present early stage enzymatic resolu-
tion will be of interest from a practical point of view to
both academic and industrial chemists.
4.4. General procedure for preparation of esters, 4b–e
4. Experimental
4.1. General
To a solution/slurry of carboxylic acid (1.1 mmol),
alcohol ( )-3 (180 mg, 1 mmol) and catalytic amount of
DMAP in dry CH2Cl2 (10 mL) was added a solution of
DCC (1.1 mmol) in dry CH2Cl2 (5 mL) at 0°C. The
reaction mixture was allowed to warm to rt and stirred
for 8 h. The urea formed was filtered off and the
organic layer was concentrated in vacuo. The residue
was chromatographed over silica gel using petroleum
ether and ethyl acetate (9.5:0.5) to give the desired
esters 4b–e in 86–90% yield.
Stereochemical assignments are based on the optical
rotation of known compounds.5 Melting points are
uncorrected. Amano PS-1400 U from Amano Pharma-
ceuticals, Japan was used. The activity of the lipase
powder used is expressed in terms of units, 1 unit
corresponding to micromoles of butyric acid liberated
(estimation by GC) from glyceryl tributyrate per
minute per milligram of enzyme powder.18 Column
chromatographic separations were done on ACME sil-
ica gel (60–120 mesh). Commercially available acetic
anhydride, DCC, DMAP, DEAD, TPP and (R)-Mosh-
er’s acid were used.
4.4.1. ( )-a-Methyl-1,3-benzodioxole-5-ethyl chloro acet-
1
ate, 4b. Oil; 226 mg (88% yield); H NMR (CDCl3, 200
MHz) l 1.26 (d, J=6 Hz, 3H), 2.71 (dd, J=14 and 6
Hz, 1H), 2.87 (dd, J=14 and 6 Hz, 1H), 4.01 (s, 2H),
5.13 (sextet, J=6 Hz, 1H), 5.93 (s, 2H), 6.63 (dd, J=8
and 2 Hz, 1H), 6.69 (s, 1H), 6.74 (d, J=8 Hz, 1H); IR
(Neat) wmax 1751, 1740, 1502, 1491, 1443, 1250, 1188,
1040 cm−1. Anal. calcd for C12H13ClO4: C, 56.15; H,
5.07. Found: C, 56.23; H, 5.11%.
4.2. ( )-a-Methyl-1,3-benzodioxole-5-ethanol, 3
It was prepared in three steps using known literature
procedures.13 Analytical and spectral data obtained for
( )-3 were identical with (+)-5.
4.4.2. ( )-a-Methyl-1,3-benzodioxole-5-ethyl p-methoxy-
1
benzoate, 4c. Viscous oil; 270 mg (86% yield); H NMR

336
S. Easwar, N. Argade / Tetrahedron: Asymmetry 14 (2003) 333–337
(CDCl3, 200 MHz) l 1.32 (d, J=6 Hz, 3H), 2.79 (dd,
J=14 and 6 Hz, 1H), 2.98 (dd, J=14 and 6 Hz, 1H), 3.86
(s, 3H), 5.27 (sextet, J=6 Hz, 1H), 5.91 (s, 2H), 6.60–6.80
(m, 3H), 6.91 (d, J=8 Hz, 2H), 7.98 (d, J=8 Hz, 2H);
IR (Neat) wmax 1709, 1607, 1502, 1256, 1038 cm−1. Anal.
calcd for C18H18O5: C, 68.79; H, 5.73. Found: C, 68.88;
H, 5.91%.
at 0°C with stirring. The reaction mixture was stirred at
0°C for a further 4 h and subsequently filtered through
Celite. Concentration of the organic layer in vacuo
followed by silica gel column chromatographic purifica-
tion of the residue using petroleum ether and ethyl
acetate (9:1) yielded (−)-7 (340 mg, 95%); viscous oil;
[h]25089=−34.2 (c 1.0, CHCl3). Analytical and spectral data
obtained were identical with (+)-5.
4.4.3. ( )-a-Methyl-1,3-benzodioxole-5-ethyl p-nitroben-
zoate, 4d. 289 mg (88% yield); analytical and spectral data
obtained were identical with (+)-8.
4.7. Mitsunobu inversion of (−)-7
A solution of DEAD (192 mg, 1.1 mmol) in dry THF
(5 mL) was added dropwise to a solution of TPP (288
mg, 1.1 mmol), p-nitrobenzoic acid (184 mg, 1.1 mmol)
and alcohol (−)-7 (180 mg, 1 mmol) in dry THF (10 mL)
at 0°C. The reaction mixture was allowed to warm to rt
and stirred for 8 h. Concentration of reaction mixture in
vacuo followed by silica gel column chromatographic
purification of the residue using petroleum ether and
ethyl acetate (9:1) gave (+)-8: 316 mg (96% yield); mp
57–59°C; [h]52809=+103.1 (c 1.0, CHCl3); 1H NMR
(CDCl3, 200 MHz) l 1.38 (d, J=6 Hz, 3H), 2.84 (dd,
J=14 and 6 Hz, 1H), 3.00 (dd, J=14 and 6 Hz, 1H), 5.34
(sextet, J=6 Hz, 1H), 5.92 (s, 2H), 6.60–6.80 (m, 3H),
8.17 (d, J=8 Hz, 2H), 8.29 (d, J=8 Hz, 2H); 13C NMR
(CDCl3, 50 MHz) l 19.4, 41.9, 73.5, 100.9, 108.2, 109.7,
122.4, 123.5, 130.6, 130.8, 136.0, 146.3, 147.7, 150.4,
164.1; IR (Nujol) wmax 1720, 1607, 1526, 1493, 1443, 1281
cm−1. Anal. calcd for C17H15NO6: C, 62.00; H, 4.56; N,
4.26. Found: C, 62.11; H, 4.60; N, 4.11%.
4.4.4. ( )-a-Methyl-1,3-benzodioxole-5-ethyl hexadec-
1
anoate, 4e. Viscous oil; 376 mg (90% yield); H NMR
(CDCl3, 200 MHz) l 0.88 (t, J=8 Hz, 3H), 1.20 (d, J=6
Hz, 3H), 1.25 (bs, 24H), 1.45–1.65 (m, 2H), 2.24 (t, J=8
Hz, 2H), 2.66 (dd, J=14 and 6 Hz, 1H), 2.83 (dd, J=14
and 8 Hz, 1H), 5.06 (sextet, J=6 Hz, 1H), 5.92 (s, 2H),
6.63 (dd, J=6 and 2 Hz, 1H), 6.69 (s, 1H), 6.73 (d, J=6
Hz, 1H); IR (Neat) wmax 1732, 1504, 1491, 1443, 1248,
1042 cm−1. Anal. calcd for C26H42O4: C, 74.64; H, 10.05.
Found: C, 74.51; H, 10.13%.
4.5. Amano PS-catalysed acylation of ( )-3
A solution of alcohol ( )-3 (900 mg, 5 mmol) in n-hex-
ane/benzene (2:1) (25 mL) was added to Amano PS lipase
(300 mg) followed by vinyl acetate (2.3 mL, 25 mmol).
The reaction mixture was stirred at 50°C for 72 h and
then allowed to reach rt. The enzyme was filtered off,
washed with ethyl acetate and the organic layer was
concentrated in vacuo. The residue was chro-
matographed over silica gel using petroleum ether and
ethyl acetate (9:1) to obtain (+)-5 (474 mg, 53%) and (−)-6
(498 mg, 44%), respectively.
4.8. (+)-(S)-a-Methyl-1,3-benzodioxole-5-ethanol, 5
(+)-8 On repetition of above procedure for conversion of
(−)-6 to (−)-7 gave (+)-5 in 94% yield. [h]25809=+34.0 (c 1.0,
CHCl3).
4.5.1. Alcohol (+)-5. Oil; [h]25809=+27.6 (c 1.0, CHCl3); 1H
NMR (CDCl3, 200 MHz) l 1.23 (d, J=6 Hz, 3H), 1.63
(bs, 1H), 2.59 (dd, J=14 and 8 Hz, 1H), 2.72 (dd, J=14
and 4 Hz, 1H), 3.96 (sextet, J=6 Hz, 1H), 5.93 (s, 2H),
6.66 (d, J=8 Hz, 1H), 6.70 (s, 1H), 6.76 (d, J=8 Hz, 1H);
13C NMR (CDCl3, 50 MHz) l 22.3, 45.0, 68.5, 100.5,
107.9, 109.4, 122.0, 132.2, 145.7, 147.3; MS (m/e) 180,
148, 135, 121, 106, 91, 77, 63, 51, 45; IR (Neat) wmax 3398,
1609, 1502, 1490, 1443, 1248, 1040 cm−1. Anal. calcd for
C10H12O3: C, 66.67; H, 6.67. Found: C, 66.52; H, 6.55%.
4.9. General procedure for MTPA-ester preparation
To a solution of (R)-Mosher’s acid (26 mg, 0.11 mmol),
alcohol ( )-3 or (+)-5 or (−)-7 (18 mg, 0.1 mmol) and
DMAP (cat.) in dry CH2Cl2 (3 mL) was added a solution
of DCC (23 mg, 0.11 mmol) in dry CH2Cl2 (2 mL) at 0°C.
The reaction mixture was allowed to warm to rt and
stirred for 8 h. The formed urea was filtered off and the
organic layer was concentrated in vacuo. Silica gel
column chromatographic purification of the residue
using petroleum ether and ethyl acetate (9.5:0.5) gave the
MTPA-ester in quantitative yield.
1
4.5.2. Acetate (−)-6. Oil; [h]25809=−5.4 (c 1.0, CHCl3); H
NMR (CDCl3, 200 MHz) l 1.21 (d, J=6 Hz, 3H), 2.01
(s, 3H), 2.66 (dd, J=14 and 6 Hz, 1H), 2.84 (dd, J=14
and 6 Hz, 1H), 5.05 (sextet, J=6 Hz, 1H), 5.93 (s, 2H),
6.64 (d, J=8 Hz, 1H), 6.69 (s, 1H), 6.74 (d, J=8 Hz, 1H);
13C NMR (CDCl3, 50 MHz) l 19.1, 21.0, 41.7, 71.3,
100.6, 107.9, 109.5, 122.1, 131.1, 146.0, 147.4, 170.3; MS
(m/e) 222, 162, 147, 135, 121, 104, 91, 77, 69, 63; IR
(Neat) wmax 1736, 1609, 1505, 1491, 1443, 1373, 1246,
1042 cm−1. Anal. calcd for C12H14O4: C, 64.86; H, 6.31.
Found: C, 65.02; H, 6.49%.
4.9.1. MTPA-ester of ( )-a-methyl-1,3-benzodioxole-5-
1
ethanol, 3. Viscous oil; H NMR (CDCl3, 200 MHz) l
1.31 (d, J=6 Hz, 3H), 1.34 (d, J=6 Hz, 3H), 2.60–3.00
(m, 4H), 3.42 (s, 3H), 3.50 (s, 3H), 5.20–5.45 (m, 2H),
5.91 (s, 2H), 5.93 (s, 2H), 6.45–6.80 (m, 6H), 7.20–7.50
(m, 10H).
4.9.2. MTPA-ester of (+)-(S)-a-methyl-1,3-benzodioxole-
1
5-ethanol, 5. Viscous oil; H NMR (CDCl3, 200 MHz)
4.6. (−)-(R)-a-Methyl-1,3-benzodioxole-5-ethanol, 7
l 1.30 (d, J=6 Hz, 0.30H), 1.34 (d, J=8 Hz, 2.70H),
2.60–2.95 (m, 2H), 3.42 (s, 0.30H), 3.51 (s, 2.70H), 5.34
(sextet, J=6 Hz, 1H), 5.92 (s, 1.80H), 5.93 (s, 0.20H),
6.45–6.80 (m, 3H), 7.25–7.55 (m, 5H).
To a solution of acetate (−)-6 (444 mg, 2 mmol) in dry
methanol (10 mL) was added anhydrous K2CO3 (5 mg)

S. Easwar, N. Argade / Tetrahedron: Asymmetry 14 (2003) 333–337
337
4.9.3. MTPA-ester of (−)-(R)-a-methyl-1,3-benzodiox-
ole-5-ethanol, 7. Viscous oil; 1H NMR (CDCl3, 200
MHz) l 1.31 (d, J=6 Hz, 3H), 2.70–3.00 (m, 2H), 3.42
(s, 2.94H), 3.51 (s, 0.06H), 5.32 (sextet, J=6 Hz, 1H),
5.93 (s, 2H), 6.60–6.80 (m, 3H), 7.15–7.50 (m, 5H).
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Chem. Soc. 1973, 95, 512.
S.E. thanks UGC, New Delhi, for the award of a
research fellowship. N.P.A. thanks the Department of
Science and Technology, New Delhi, for financial sup-
port. We thank Amano Pharmaceuticals Co., Japan for
a generous gift of enzyme Amano PS. We thank Dr. K.
N. Ganesh, Head, Division of Organic Chemistry (Syn-
thesis), for constant encouragement.
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