An efficient chemoenzymatic approach to enantiomerically pure 4-[2-(difluoromethoxy)phenyl] substituted 1,4-dihydropyridine-3,5-dicarboxylates

Article abstract of DOI:10.1016/S0957-4166(02)00022-8

An efficient chemoenzymatic synthesis of (-)-3-methyl 5-(2-propoxyethyl) (4R)-4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3, 5-pyridinedicarboxylate has been achieved. The key step is a highly stereoselective Candida rugosa lipase (CRL)-mediate

Full text of DOI:10.1016/S0957-4166(02)00022-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3251–3256
An efficient chemoenzymatic approach to enantiomerically pure
4-[2-(difluoromethoxy)phenyl] substituted
1,4-dihydropyridine-3,5-dicarboxylates
Arkadij Sobolev,a,b Maurice C. R. Franssen,a,* Brigita Vigante,b Brigita Cekavicus,b
Natalija Makarova,b Gunars Dubursb and Aede de Groota
aLaboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
bLatvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
Received 14 November 2001; accepted 14 January 2002
Abstract—An efficient chemoenzymatic synthesis of (−)-3-methyl 5-(2-propoxyethyl) (4R)-4-[2-(difluoromethoxy)phenyl]-2,6-
dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate has been achieved. The key step is a highly stereoselective Candida rugosa lipase
(CRL)-mediated asymmetrisation of the prochiral bis[(isobutyryloxy)methyl]-4-[2-(difluoromethoxy)phenyl]-1,4-dihydro-2,6-
dimethyl-3,5-pyridinedicarboxylate. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
biologically active substances. Compound 3 was used to
prepare (−)-3-methyl 5-(2-propoxyethyl) (4R)-4-[2-
(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-
pyridinedicarboxylate, which is an asymmetric analogue
of cerebrocrast, a compound with cognition and mem-
ory enhancing, neuroprotective properties.1,2
1,4-Dihydropyridines (1,4-DHPs) remain important
because of their wide spectrum of biological activities,
these include antidiabetic, nootropic, neuromodulatory,
cognition and memory enhancing, neuroprotective (at
age-related neuronal damage, anti-hypoxic, anti-alco-
hol) properties, regulatory mode action and neuropep-
tide effects.1,2 When substituents on the left side differ
from those on the right side of a 1,4-DHP, the molecule
is chiral, with C(4) as the stereogenic centre. The enan-
tiomers of an unsymmetrical 1,4-DHP usually differ in
their biological activities and could even have an
exactly opposite activity profile. Chiral 4-aryl-1,4-DHPs
have been the subject of extensive investigation as
calcium antagonists for the last two decades3–8 and the
chemoenzymatic synthesis of chiral 1,4-DHPs has been
reported by several research groups, including us.9–14
Herein, we present the Candida rugosa lipase-catalysed
enantioselective hydrolysis of bifunctional prochiral bis
[(isobutyryloxy)methyl] 4-[2-(difluoromethoxy)phenyl]-
1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate 3,
which is a building block for the synthesis of potentially
2. Results and discussion
The main task of our studies was to reach the best
enantioselectivity for the enzyme-mediated hydrolysis
of prochiral 4-[2-(difluoromethoxy)phenyl] substituted
dihydropyridines. Since ester groups which are directly
attached to the heterocyclic ring are not cleaved by
most enzymes, the readily cleavable acyloxymethyl
esters were introduced at the 3 and 5 positions of the
1,4-DHP. It has been observed previously14,15 that the
size of the transformed acyloxymethyl ester group of a
1,4-DHP exerts a significant influence on the enantiose-
lectivity of the enzymatic hydrolysis. The enantioselec-
tivity of CRL-mediated hydrolysis increased together
with the steric hindrance of the acyloxymethyl ester
group and the highest enantiomeric ratio (E=21) was
reached for racemic 3-[(isobutyryloxy)methyl] 5-methyl
4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-
3,5-pyridinedicarboxylate.14 For this reason, the iso-
butyryloxymethyl and pivaloyloxymethyl derivatives 3a
and 3b were synthesised.
* Corresponding author. Tel.: +31 (0)317 482976; fax: +31 (0)317
484914; e-mail: maurice.franssen@bio.oc.wag-ur.nl
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00022-8

3252
A. Sobole6 et al. / Tetrahedron: Asymmetry 12 (2001) 3251–3256
using Candida rugosa lipase as a catalyst in water-satu-
rated IPE at rt, as shown in Scheme 1. It is necessary to
monitor the reaction carefully by HPLC because of the
subsequent hydrolysis to the diacid 2. The reaction was
interrupted when the ratio between the substrate, diacid
2 and 4b was about 1:1:3. The enantioselectivity of the
reaction was excellent (>95%).
Substrates 3a and 3b were prepared in a three-step
sequence as depicted in Scheme 1. Bis cyanoethyl ester
1 was synthesised starting from 2-cyanoethyl aceto-
acetate, 2-(difluoromethoxy)benzaldehyde and ammonia
by a Hantzsch cyclisation in 38% yield. The hydrolysis
of the diester 1 with KOH gave dicarboxylic acid 2 in
73% yield. The substrate 3a was obtained by the treat-
ment of 2 with pivaloyloxymethyl (POM) chloride in
the presence of K2CO3 in 57% yield. Compound 3b was
obtained by the treatment of the in situ generated
diacid 2 with isobutyryloxymethyl (i-BOM) chloride in
48% yield.
The enantiomeric excess of 4b was determined by an
enantioselective HPLC method using a mixture of (+)-
4b and (−)-4b as a reference standard. This (almost
racemic) reference standard was prepared by hydrolysis
of 3b with the lipases of Rhizomucor miehei and Can-
dida antarctica B. The first enzyme gave 4b with 11%
e.e., whereas Candida antarctica lipase B gave 4b in 13%
e.e. with opposite stereopreference.
The bis POM ester 3a was first tested for hydrolysis
with lipase AH, as this enzyme has been used for the
asymmetrisation of its 4-(3-nitrophenyl) analogue.16
The hydrolysis of 3a with lipase AH in aqueous media
at 45°C occurred with formation of 4a in 25% e.e.
When Candida rugosa lipase (CRL) was applied for the
hydrolysis of 3a in water-saturated diisopropyl ether
(IPE) at 45°C, the e.e. of monoacid 4a was not constant
and increased from 45% (25% conversion after 1 day)
until 84% of e.e. (34% of conversion in 9 days), together
with concomitant hydrolysis to the diacid 2 (9% in 9
days). Apparently, the enantiomeric excess of 4a was
improved by the CRL-catalysed kinetic resolution of
enantiomerically enriched 4a to achiral diacid 2, as the
second hydrolytic step.17,18 Longer reaction time led to
higher enantiomeric purity but also to a lower chemical
yield of the product 4a and therefore this method is not
practical.
The monoacid (−)-(R)-4b was converted into the corre-
sponding methyl ester (−)-(R)-5b by esterification with
MeI in DMF with 87% yield (Scheme 2). The asymmet-
ric analogue of Cerebrocrast (−)-(R)-7 was obtained
after removal of i-BOM group, treatment with SOCl2,
and a subsequent reaction with 2-propoxyethanol
(propylcellosolve®) as reported before.14
The absolute configuration of (−)-4b was proven to be
R. It was determined by the conversion of (−)-4b to
(−)-5b, (−)-6 and (−)-7 which showed the same sign of
optical rotation as that of (−)-(R)-5b, (−)-(S)-6 and
(−)-(R)-7 as reported earlier.14 The absolute configura-
tion was also proven by the coupling of (−)-(S)-6 with
(R)-(a)-methylbenzylamine and comparing their order
of elution on a reversed phase HPLC column with the
literature data.14
A better way to asymmetrise 3 involves hydrolysis of
the bis i-BOM ester 3b, which could be performed
Scheme 1.

A. Sobole6 et al. / Tetrahedron: Asymmetry 12 (2001) 3251–3256
3253
Scheme 2.
CRL lipase prefers to hydrolyse the pro-R ester group
of substrate 3b which is in agreement with previously
obtained data, in which this enzyme reacts preferen-
tially with the S-form of the racemic mixture of unsym-
metrical analogues of compound 3, producing
R-monoacids.14
trimethylsilane (l 0.00). Mass spectral data and accu-
rate mass measurements were determined on a Finni-
gan MAT 95 mass-spectrometer. Melting points were
determined on a Boetius apparatus and are uncor-
rected. Optical rotation values were measured with a
Perkin–Elmer 241 digital polarimeter. Elemental analy-
ses were determined on a Carlo-Erba elemental analy-
ser. The reaction mixtures were analysed by HPLC on
a 4.6×250 mm column packed with 5 mm Spherisorb
ODS-2 (Phase Separations) with solvent system aceto-
nitrile/water/acetic acid (60:40:0.1) as mobile phase at a
flow rate of 1.0 mL/min using a Gynkotek 480 pump
and Applied Biosystems 758A programmable
absorbance detector at 254 nm. Determination of enan-
tiomeric excesses of 4a and 4b was performed by analy-
sis on an enantioselective column Chirex 3011, 4.6×250
mm, 5 mm (Phenomenex) using a Ginkotek 580A pump
and an Applied Biosystems 759A absorbance detector
at 254 nm. The eluent was methanol/dichloromethane
(1:2) at a flow rate of 1.0 mL/min. Peak areas were
determined electronically with the Chromeleon chro-
matography data system, Dionex Softron GmbH (Ger-
mering, Germany). The enantiomeric purity of
(−)-(R)-6b was measured after coupling to (R)-(+)-a-
3. Conclusion
The present study demonstrates the usefulness of Can-
dida rugosa lipase for the asymmetrisation of 3b with
excellent enantiomeric purity. The enantioselectivity of
the CRL-catalysed asymmetrisation of prochiral
bifunctional substrates 3a and 3b to the monoacids 4a
and 4b was enhanced by the second hydrolysis to
achiral diacid 2 which is highly stereoselective. The
synthesis of (−)-3-methyl 5-(2-propoxyethyl) (4R)-4-[2-
(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-
pyridinedicarboxylate (−)-(R)-7 with ]99% e.e. was
achieved. The synthesis of other potentially biologically
active chiral dihydropyridine derivatives using the
building block (−)-(R)-4b is currently underway.
methylbenzylamine on
a
reversed phase ODS-2
4. Experimental
4.1. General
column.14 The enantiomeric excess of (−)-(R)-7 has
been determined by 1H NMR using a chiral shift
reagent.14 The enantiomeric excesses of the intermediate
(−)-(R)-5b was assumed to be the same as for (−)-(R)-
4b, (−)-(S)-6b and (−)-(R)-7.
All reagents were purchased from Aldrich, Acros or
Merck and used without further purification. HPLC
grade solvents were from Labscan (Dublin, Ireland).
Flash column chromatography was performed on
Merck silica gel 60 (230–400 mesh or 70–230 mesh).
Preparative TLC was performed on 20×20 cm silica gel
TLC-PET F254 foils (Fluka). Candida rugosa lipase
(lipase (EC 3.1.1.3) Type VII from Candida rugosa) was
purchased from Sigma. Lipase AH was supplied by
Amano Pharmaceutical Co., Ltd (Japan). Immobilised
Candida antarctica lipase B (Novozym 435) was a gift
from Novo Nordisk A/S (Bagsvaerd, Denmark). Rhi-
zomucor miehei lipase (CHIRAZYME L-9, c-f, lyo.)
was a gift from Boehringer–Mannheim (Mannheim,
Germany). Enzymatic reactions were carried out in a
New Brunswick Scientific Innova 4080 incubatory
4.2. Bis(2-cyanoethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-
dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, 1
A solution of 2-(difluoromethoxy)benzaldehyde (10 g,
58 mmol), 2-cyanoethyl acetoacetate (18.2 g, 117 mmol)
and 25% aqueous ammonium solution (10 mL, 130
mmol) in ethanol (50 mL) was stirred under reflux for
6 h. After cooling the mixture, the precipitate was
filtered off and crystallised from ethanol to give yellow
crystals of 1 (10 g, 38%): mp 138–139°C; 1H NMR
(CDCl3, 200 MHz): l 2.31 (s, 6H, 2,6-CH3), 2.65 (t, 4H,
J=6.8 Hz, 3,5-CH2CN), 4.22 (t, 4H, J=6.8 Hz, 3,5-
OCH2-), 5.25 (s, 1H, 4-CH), 5.95 (br s, 1H, NH), 6.60
(t, 1H, JH-F=78.0 Hz, OCHF2), 7.00–7.19 (m, 3H,
Ar-H), 7.37 (dd, 1H, J=2.2, 7.3 Hz, Ar-H); 13C NMR
(CHCl3, 50 MHz): l 17.95 (2×CH2); 19.66 (2×CH3);
35.33 (CH); 58.27 (2×CH2); 101.94 (2×C); 116.97, (t,
CH, J=274.2 Hz, OCHF2); 117.34 (2×CN); 117.99
(CH), 125.28 (CH), 128.04 (CH), 131.57 (CH), 137.91
1
orbital shaker at 25°C. H NMR spectra were recorded
on a Varian Mercury 200BB (200 MHz) or a Bruker
AC-E 200 (200 MHz) or a Bruker Avance DPX 400
(400 MHz) spectrometer. 13C NMR spectra were
recorded on a Bruker AC-E 200 (50 MHz). Chemical
shifts are reported in parts per million (ppm) relative to

3254
A. Sobole6 et al. / Tetrahedron: Asymmetry 12 (2001) 3251–3256
(C), 146.06 (2×C), 149.15 (C), 166.66 (2×C); MS m/z
(rel. abund.): 445 (M+, 6); 375 (6), 347 (11), 303 (17),
302 (100), 278 (6), 277 (33), 249 (8), 205 (13), 196 (8);
HRMS calcd for C22H21F2N3O5 445.1449, found
445.1442. Anal. calcd for C22H21F2N3O5: C, 59.32; H,
4.75; N, 9.43; found: C, 59.33; H, 4.73; N, 9.40%.
4.5. Bis[(isobutyryloxy)methyl] 4-[2-(difluoromethoxy)-
phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxy-
late, 3b
To a stirred solution of 1 (2.00 g, 4.5 mmol) in etha-
nol (50 mL) was added a solution of KOH (0.55 g,
10 mmol) in ethanol (5 mL). After stirring the mix-
ture at rt for 2 h the solvent was evaporated. The
residue was diluted with dry DMF (5 mL), after
which isobutyryloxymethyl chloride19 (1.41 g, 10.35
mmol) was added. The reaction mixture was stirred
for 18 h, then diluted with water and extracted with
chloroform. The organic layer was washed succes-
sively twice with water and twice with brine, dried
and evaporated. The resulting product was flash chro-
matographed on silica gel [3:1 petroleum ether (bp
40–60°C)/EtOAc] to give 3b as a yellow oil (1.17 g,
48%): 1H NMR (CDCl3, 200 MHz): l 1.03 (d, 6H,
J=6.8 Hz, 2×CH3), 1.06 (d, 6H, J=6.8 Hz, 2×CH3),
2.27 (s, 6H, 2,6-CH3), 2.44 (septet, 2H, J=6.8 Hz,
3,5-CH(CH3)2), 5.18 (s, 1H, 4-CH), 5.69 (s, 4H, 3,5-
4.3. 4-[2-(Difluoromethoxy)phenyl]-2,6-dimethyl-1,4-
dihydro-3,5-pyridinedicarboxylic acid, 2
To a stirred solution of 1 (2 g, 4.5 mmol) in ethanol
(50 mL) was added a solution of KOH (0.55 g, 10
mmol) in ethanol (5 mL). After stirring the mixture
at rt for 2 h the solvent was evaporated and the
residue was dissolved in water. After cooling down
the solution was adjusted to pH 4–5 by adding dilute
aqueous HCl. The precipitate was filtered off and
washed thoroughly with water to give 2 in pure form
(1.11 g, 73%), mp 138–140°C; 1H NMR (DMSO-d6,
200 MHz): l 2.19 (s, 6H, 2,6-CH3), 5.08 (s, H, 4-
CH), 6.78 (t, 1H, J=75.4 Hz, OCHF2), 6.9–7.3 (m,
4H, Ar-H), 8.52 (br s, H, NH), 11.38 (br s, 2H,
3,5-COOH); 13C NMR (DMSO-d6, 200 MHz): l
18.29 (2×CH3); 34.90 (CH), 101.71 (2×C); 117.26 (t,
CH, J=246.5 Hz, OCHF2), 117.96 (CH), 125.23
(CH), 127.31 (CH), 131.15 (CH), 139.89 (C), 145.05
(2×C), 148.28 (C), 168.87 (2×C). Anal. calcd for
C16H15F2NO5: C, 56.64; H, 4.46; N, 4.13; found: C,
56.32; H, 4.45; N, 4.20%.
COOCH2O), 6.24 (br s, 1H, NH), 6.76 (t, 1H, JH-F
=
74.0 Hz, OCHF2), 6.92–7.12 (m, 3H, Ar-H); 7.32 (dd,
1H, J=2.0, 7.3 Hz, Ar-H); 13C (CDCl3, 50 MHz): l
18.53 (4×CH3), 19.83 (2×CH3), 33.61 (2×CH), 36.20
(CH), 78.70 (2×CH2), 101.59 (2×C), 116.74 (t, CH,
J=255.29 Hz, OCHF2), 117.41 (CH), 124.60 (CH),
127.76 (CH), 132.21 (CH), 136.82 (C), 146.20 (2×C)
150.18 (C), 165.86 (2×C), 175.74 (2×C); MS m/z (rel.
abund.): 539 (M+, 11), 422 (30), 397 (20), 396 (100),
322 (7), 297 (8), 296 (54), 294 (18), 196 (43), 71 (8),
43 (11). HRMS calcd for C26H31NO9F2 (M+) m/z
539.1967, found 539.1963.
4.4. Bis[(pivaloyloxy)methyl] 4-[2-(difluoromethoxy)-
phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxy-
late, 3a
4.6. (−)-4-[2-(Difluoromethoxy)phenyl]-2,6-dimethyl-1,4-
dihydro-5-{[(pivaloyloxy)methoxy]carbonyl}-3-pyridine-
carboxylic acid, 4a
Compound 2 (3.66 g, 10.8 mmol) was dissolved in
DMF (10 mL), after which K2CO3 (3.70 g, 26.9
mmol) was added. The mixture was stirred for 2 h at
rt and pivaloyloxymethylchloride (3.74 mL, 25.92
mmol) was added and the resulting mixture was
stirred for an additional 24 h. The reaction mixture
was diluted with chloroform (100 mL), washed suc-
cessively twice with water and twice with brine, dried
and evaporated. The residue was triturated with
methanol and crystallised from diluted methanol to
give 3a (3.5 g, 57%), mp 105–107°C; 1H NMR
(CDCl3, 200 MHz): l 1.06 (s, 18H, 3,5-C(CH3)3), 2.26
(s, 6H, 2,6-CH3), 5.18 (s, H, 4-CH), 5.68 (s, 4H, 3,5-
COOCH2O), 6.04 (br s, H, NH), 6.51 (t, 1H, J=75.0
Hz, OCHF2), 6.88–7.11 (m, 3H, Ar-H), 7.31 (dd, 1H;
J=2.0, 7.3 Hz, Ar-H); 13C (CDCl3, 50 MHz): l 19.79
(2×CH3), 26.73 (6×CH3), 36.33 (CH), 38.61 (2×C),
78.90 (2×CH2), 101.62 (2×C), 116.79 (t, CH, J=255.5
Hz, OCHF2), 117.54 (CH), 124.73 (CH), 127.78 (CH),
132.25 (CH), 136.94 (C), 146.13 (2×C), 150.22 (C),
162.84 (2×C), 177.14 (2×C). MS m/z (rel. abund.):
567 (M+, 11); 437 (8), 436 (33), 425 (22), 424 (100),
394 (11), 364 (7), 294 (9), 196 (17), 57 (14); HRMS
calcd for C28H35F2NO9 567.2288, found 567.2273.
Anal. calcd for C28H35F2NO9: C, 59.25; H, 6.22; N,
2.47; found: C, 58.96; H, 6.22; N, 2.41%.
A solution of 3a (200 mg, 0.35 mmol) in acetonitrile (30
mL) was added to K2HPO4/KH2PO4 buffer (20 mM,
pH 7.5, 500 mL) and heated to 45°C, after which
Lipase AH (600 mg) was added. The resulting mixture
was shaken at 350 rpm and 45°C for 5 days, then the
pH of the solution was adjusted to 5.0 by adding 1 M
aqueous HCl and extracted three times with ethyl ace-
tate. The organic layers were dried and concentrated
under reduced pressure. The residue was crystallised
from methanol to give 4a (140 mg, 87%), mp 175–
1
177°C, [h]2D0 +1.3 (c 1.0, MeOH), e.e.=25%; H NMR
(DMSO-d6, 200 MHz): l 1.02 (s, 9H, C(CH3)3), 2.21 (s,
6H, 2,6-CH3), 5.09 (s, H, 4-CH), 5.62 (s, 2H,
COOCH2O), 6.93 (t, 1H, J=75.0 Hz, OCHF2), 6.93–
7.25 (m, 4H, Ar-H), 8.92 (br s, H, NH); 13C NMR
(DMSO-d6, 50 MHz): 18.24 (CH3), 18.65 (CH3); 26.56
(3×CH3), 35.12 (CH), 38.09 (C), 78.86 (CH2), 99.21 (C),
102.43 (C), 117.11 (t, CH, J=254.74 Hz, OCHF2),
117.61 (CH), 124.98 (CH), 127.62 (CH), 131.32 (CH),
138.55 (C), 144.68 (C), 148.20 (C), 148.84 (C), 165.66
(C), 168.75 (C), 176.40 (C); MS m/z (rel. abund.): 453
(M+, 2), 409 (23), 310 (18), 294 (25), 278 (55), 267 (16),
266 (100), 250 (14), 236 (35), 152 (71), 57 (20); HRMS
calcd for C22H25NO7F2 (M+) m/z 453.1599, found
453.1592. Anal. calcd for C22H25NO7F2: C, 58.27; H,
5.56; N, 3.09; found: C, 57.95; H, 5.54; N, 3.00%.

A. Sobole6 et al. / Tetrahedron: Asymmetry 12 (2001) 3251–3256
3255
4.7. (−)-(4R)-4-[2-(Difluoromethoxy)phenyl]-5-
{[(isobutyryloxy)methoxy]carbonyl}-2,6-dimethyl-1,4-
dihydro-3-pyridinecarboxylic acid, (−)-R-4b
ing: mp 78–79°C triturated from ether-hexane, e.e.
]99% (lit.14 mp 87–89°C, 79% e.e.); [h]2D0 −51.7 (c 1.0,
1
CHCl3) (lit.14 [h]2D0 −46.9 (c 1.0, CHCl3); the H NMR
was in accordance with the literature.14
To a solution of 3b (0.539 g, 1 mmol) in water-satu-
rated IPE (50 mL) was added Candida rugosa lipase
(0.200 g) and the resulting mixture was shaken for 3.5 h
at rt. After removal of the enzyme by filtration, the
filtrate was concentrated under reduced pressure. The
residue was flash chromatographed on silica gel with
petroleum ether (bp 40–60°C)/chloroform/isopropyl
alcohol (100:40:5“100:100:20) to give unreacted 3b
(0.125 g, 23%) and (−)-(R)-4b (0.240 g (55%), mp
149–151°C or 129–130°C (dec.), from ether–hexane;
[h]2D0 +26.5 (c 1.0, CHCl3), −24.0 (c 1.0 MeOH); e.e.
4.10. (−)-3-Methyl 5-(2-propoxyethyl) (4R)-4-[2-
(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3,5-
pyridinedicarboxylate, (−)-(R)-7
This compound was prepared by the same method used
in the literature.14 The oily product was characterised
giving: e.e. ]99%, [h]D20 −19.7 (c 1.0, CHCl3) (lit.14 88%
e.e., [h]D20 −17.0 (c 1.0, CHCl3)). The 1H NMR and mass
spectral data were in accordance with the literature.14
1
]99%; H NMR (CDCl3, 400 MHz): l 1.08 (d, 3H,
J=6.8 Hz, CH3), 1.11 (d, 3H, J=6.8 Hz, CH3), 2.31 (s,
3H, CH3), 2.32 (s, 3H, CH3), 2.48 (septet, 1H, J=6.8
Hz, CH(CH3)2), 5.21 (s, 1H, 4-CH), 5.73 (ABq, 2H,
Acknowledgements
COOCH2O), 6.45 (dd, 1H,
JH-F=74.4, 76.0 Hz,
OCHF2), 7.00–7.16 (m, 3H, Ar-H), 7.37 (dd, 1H, J=
2.0, 7.6 Hz, Ar-H); 13C (CDCl3+CD3OD, 50 MHz): l
18.45 (2×CH3), 18.69 (CH3), 19.03 (CH3), 33.73 (CH),
35.72 (CH), 78.77 (CH2), 100.66 (C), 102.71 (C), 117.10
(t, CH, J=254.95 Hz, OCHF2), 118.07 (CH), 124.98
(CH), 127.67 (CH), 131.88 (CH), 138.46 (C), 145.87
(C), 148.26 (C), 149.58 (C), 166.62 (C), 170.45 (C),
176.28 (C); MS m/z (rel. abund.): 439 (M+, 2) 395 (17),
296 (12), 294 (19), 278 (28), 253 (9), 252 (64), 250 (11),
196 (13), 152 (100), 44 (18); HRMS calcd for
C21H23F2NO7 439.1443, found 439.1438. Anal. calcd
for C21H23NO7F2: C, 57.40; H, 5.28; N, 3.19; found: C,
57.69; H, 5.12; N, 3.00%.
Financial support by the Copernicus programme (ERB-
CIPA-CT 94 0121), NATO (Linkage grant LST.CLG
974948), the PhD programme of Wageningen Univer-
sity and a PhD Grant of the Latvian Council of Science
are gratefully acknowledged. We are indebted to Mr.
A. van Veldhuizen for recording the NMR spectra, to
Mr. C. J. Teunis and Mr. H. Jongejan for the mass
spectral analyses and to Mr. E. J. C. van der Klift and
Emma Sarule for the elemental analyses.
References
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4.8. (−)-3-[(Isobutyryloxy)methyl] 5-methyl (4R)-4-[2-
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To a solution of (−)-(R)-4b (0.77 g, 1.75 mmol) in
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This compound was prepared by the same method used
in the literature.14 The product was characterised giv-

3256
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