Effect of acyl chain length and branching on the enantioselectivity of Candida rugosa lipase in the kinetic resolution of 4-(2-difluoromethoxyphenyl)-substituted 1,4-dihydropyridine 3,5-diesters

Article abstract of DOI:10.1021/jo0104025

Since 2,6-dimethyl-4-aryl-1,4-dihydropyridine 3,5-diesters themselves are not hydrolyzed by commercially available hydrolases, derivatives with spacers containing a hydrolyzable group were prepared. Seven acyloxymethyl esters of 5-methyl- and 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)-pheny]l-2,6-dimethyl-1,4-dihydro-3, 5-pyridinedicarboxylate were synthesized and subjected to Candida rugosa lipase (CRL) catalyzed hydrolysis in wet diisopropyl ether. A methyl ester at the 5-position and a long or branched acyl chain at C3 gave the highest enantiomeric ratio (E values). The most stereoselective reaction (E = 21) was obtained with 3- [(isobutyryloxy)methyl] 5-methyl 4-(2-difluoromethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylate, and this compound was used to prepare both enantiomers of 3-methyl 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-3, 5-pyridinedicarboxylate. The absolute configuration of the enzymatically produced carboxylic acid was established to be 4R by X-ray crystallographic analysis of its 1-(R)-phenylethyl amide.

Full text of DOI:10.1021/jo0104025

J . Org. Chem. 2002, 67, 401-410
401
Effect of Acyl Ch a in Len gth a n d Br a n ch in g on th e
En a n tioselectivity of Ca n d id a r u gosa Lip a se in th e Kin etic
Resolu tion of 4-(2-Diflu or om eth oxyp h en yl)-Su bstitu ted
1,4-Dih yd r op yr id in e 3,5-Diester s
Arkadij Sobolev,†,‡ Maurice C. R. Franssen,*,† Brigita Vigante,‡ Brigita Cekavicus,‡
Raivis Zhalubovskis,‡ Huub Kooijman,§ Anthony L. Spek,§,| Gunars Duburs,‡ and
Aede de Groot†
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8,6703 HB Wageningen,
The Netherlands; Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia;
and Bijvoet Center for Biomolecular Research, Crystal and Structural Chemistry, Utrecht University,
Padualaan 8, 3584 CH Utrecht, The Netherlands
Maurice.Franssen@bio.oc.wag-ur.nl
Received April 17, 2001
Since 2,6-dimethyl-4-aryl-1,4-dihydropyridine 3,5-diesters themselves are not hydrolyzed by
commercially available hydrolases, derivatives with spacers containing a hydrolyzable group were
prepared. Seven acyloxymethyl esters of 5-methyl- and 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)-
phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate were synthesized and subjected to
Candida rugosa lipase (CRL) catalyzed hydrolysis in wet diisopropyl ether. A methyl ester at the
5-position and a long or branched acyl chain at C3 gave the highest enantiomeric ratio (E values).
The most stereoselective reaction (E ) 21) was obtained with 3-[(isobutyryloxy)methyl] 5-methyl
4-(2-difluoromethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and this compound
was used to prepare both enantiomers of 3-methyl 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)phenyl]-
2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate. The absolute configuration of the enzymatically
produced carboxylic acid was established to be 4R by X-ray crystallographic analysis of its 1-(R)-
phenylethyl amide.
In tr od u ction
damages, antihypoxic, antialcohol) properties; regulatory
mode action; and neuropeptide effects.5,6
The pharmacology of 1,4-dihydropyridine (1,4-DHP)
derivatives is at the eve of a novel boom. After the
synthesis, study, and development of a set of antihyper-
tensive and antianginal drugs,1,2 the interest is growing
toward pharmacological activities that are not connected
with their calcium antagonist properties, like neurotropic
(antiamnestic, anticonvulsant, neuroregulatory), antidia-
betic, and membrane protecting as well as anticancer,
antibacterial, and antiviral activities.3-6
2,6-Dimethyl-3,5-bis[2-(propoxy)ethoxycarbonyl]-4-[2-
(difluoromethoxy)phenyl]-1,4-dihydropyridine (cerebro-
crast) is a novel, highly active preparation with antidi-
abetic, nootropic, neuromodulatory, cognition and memory
enhancing, neuroprotective (for age-related neuronal
* To whom correspondence should be addressed. Tel: +31-317-
482976. Fax: +31-317-484914.
† Wageningen University.
‡ Latvian Institute of Organic Synthesis.
Pharmaceutical evaluations of chiral 1,4-DHPs re-
vealed that their stereoisomers usually have different
biological activities. Sometimes the undesired enantiomer
caused serious side effects, while in other cases enanti-
omers were reported to even have the opposite action
profile (calcium antagonist-calcium agonist; hypotensive
activity-hypertensive activity).7 Ever since the differ-
ences in biological action and toxicity for a number of
unsymmetrical dihydropyridines were reported for the
§ Utrecht University
|| Address correspondence concerning crystallography to this author.
(1) Peri, R.; Padmanabhan, S.; Rutledge, A.; Singh, S.; Triggle, D.
J . J . Med. Chem. 2000, 43, 2906-2914.
(2) Alajarin, R.; Vaquero, J . J .; Alvarez-Builla, J .; Pastor, M.; Sunkel,
C.; Fau de Casa-J uana, M.; Priego, J .; Statkow, P. R.; Sanz-Aparicio,
J .; Fonseca, I. J . Med. Chem. 1995, 38, 2830-2841.
(3) Misane, I.; Klusa, V.; Dambrova, M.; Germane, S.; Duburs, G.;
Bisenieks, E.; Rimondini, R.; Ogren, S. O. Eur. Neuropsychopharmacol.
1998, 8, 329-347.
(4) Krauze, A.; Germane, S.; Eberlins, O.; Sturms, I.; Klusa, V.;
Duburs, G. Eur. J . Med. Chem. 1999, 34, 301-310.
(5) Klusa, V. Drugs Future 1995, 20, 135-138.
(6) Briede, J .; Daija, D.; Stivrina, M.; Duburs, G. Cell. Biochem.
Func. 1999, 17, 89-96.
(7) Vo, D.; Matowe, W. C.; Ramesh, M.; Iqbal, N.; Wolowyk, M. W.;
Howlett, S. E.; Knaus, E. E. J . Med. Chem. 1995, 38, 2851-2859.
10.1021/jo0104025 CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/03/2002

402 J . Org. Chem., Vol. 67, No. 2, 2002
Sch em e 1. P r ep a r a tion of th e Dih yd r op yr id in e Su bstr a tes 6
Sobolev et al.
first time,8 the demand for enantiopure dihydropyridines
appeared, and in 1991, the first successful enantioselec-
tive chemoenzymatic transformation of a prochiral dihy-
dropyridine-3,5-dicarboxylic diester was carried out.9 The
chemoenzymatic synthesis of some biological active DHPs,
(e.g., Nicardipine, Nilvadipine) was recently achieved in
several laboratories.10,11
but this spacer group is not easy to remove. The acyl-
oxymethyl moieties were introduced by the groups of
Sih16 and Achiwa17 and have the advantage that, after
enzymatic hydrolysis, a free carboxyl group is liberated
due to the spontaneous loss of formaldehyde. This
versatile spacer has also been applied for the kinetic
resolution of sterically hindered tertiary alcohols.18
Hydrolytic enzymes are not capable of hydrolyzing
alkyl esters at the position 3 and 5 of 4-aryl-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylates, presumably be-
cause of steric and electronic factors.9,12 To overcome this
difficulty, spacers have been introduced at these posi-
tions. The spacer should contain a group that is easily
hydrolyzed by enzymes (e.g., an ester group) in order to
allow kinetic resolution or enzymatic asymmetrization.
The ethoxycarbonylmethyl spacer has been used to
asymmetrize a number of 4-aryl-1,4-DHPs by us13 and
others.14,15 Moderate to excellent ee values were obtained,
To investigate the differences in biological activities
of both enantiomers of an asymmetric analogue of cere-
brocrast, two chemoenzymatic approaches to the synthe-
sis of both enantiomers of 3-methyl 5-(2-propoxyethyl)
4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydro-
3,5-pyridinedicarboxylate (1) using various acyloxy-
methyl spacers are described in this paper. The relation-
ship between the structure of the substrates and the rate
and selectivity of the enzymatic transformation is stud-
ied.
Resu lts a n d Discu ssion
(8) Tamazawa, K.; Arima, H.; Kojima, T.; Isomura, Y.; Okada, M.;
Fujita, M.; Furuya, T.; Takenaka, T.; Inagaki, O.; Terai, M. J . Med.
Chem. 1986, 29, 2504-2511.
The racemic substrates 6a -g were synthesized as
depicted in Scheme 1. These compounds have one of the
desired ester groups at the 5-position and a variety of
acyloxymethyl esters at the 3-position that are amenable
(9) Holdgrun, X. K.; Sih, C. J . Tetrahedron Lett. 1991, 32, 3465-
3468.
(10) Achiwa, K.; Kato, T. Curr. Org. Chem. 1999, 3, 77-106.
(11) de Castro, M. S.; Salazar, L.; Sinisterra, J . V. Tetrahedron:
Asymmetry 1997, 8, 857-858.
(12) Ebiike, H.; Terao, Y.; Achiwa, K. Tetrahedron Lett. 1991, 32,
5805-5808.
(13) Sobolev, A.; Franssen, M. C. R.; Makarova, N.; Duburs, G.; de
Groot, Ae. Tetrahedron: Asymmetry 2000, 11, 4559-4569.
(14) Hirose, Y.; Kariya, K.; Sasaki, I.; Kurono, Y.; Achiwa, K.
Tetrahedron Lett. 1993, 34, 3441-3444.
(15) Hirose, Y.; Kariya, K.; Sasaki, I.; Kurono, Y.; Achiwa, K.
Tetrahedron Lett. 1993, 34, 5915-5918.
(16) Salazar, L.; Sih, C. J . Tetrahedron: Asymmetry 1995, 6, 2917-
2920.
(17) Ebiike, H.; Maruyama, K.; Yamazaki, Y.; Hirose, Y.; Kariya,
K.; Sasaki, I.; Kurono, Y.; Terao, Y.; Achiwa, K. Chem. Pharm. Bull.
1997, 45, 863-868.
(18) Franssen, M. C. R.; Goetheer, E. L. V.; J ongejan, H.; de Groot,
Ae. Tetrahedron Lett. 1998, 39, 8345-8348.

Kinetic Resolution of 1,4-Dihydropyridine 3,5-Diesters
J . Org. Chem., Vol. 67, No. 2, 2002 403
Sch em e 2. En zym a tic Resolu tion of th e
Dih yd r op yr id in es 6
to enzymatic hydrolysis. The first step is the reaction of
the benzylidene acetoacetates 2a ,b and 2-cyanoethyl
3-aminocrotonate 3 by a modified Hantzsch cyclization.
3,5-Bis(2-cyanoethyl) 1,4-dihydropyridinedicarboxy-
lates have already been transformed by seaprose S
(Aspergillus melleus) with good enantioselectivity.14,15
Unfortunately, this enzyme is not commercially available.
Furthermore, in our hands, enzymes from the same
species or genus such as protease P6 (Aspergillus melleus)
and acylase 30 000 (Aspergillus sp.) hardly showed any
activity toward compounds 4a ,b. However, the 2-cyano-
ethyl ester group can be easily removed under basic
conditions19 to give the monoacids 5a ,b in good yields.
The substrates 6a -g were synthesized from the isolated
or in situ generated monoacids by treatment with the
corresponding acyloxymethyl chloride prepared according
to reported methods.20,21 The alkylation occurred smoothly
in the case of 6g, but in the other cases, the products
6a -f were isolated from mixtures of byproducts in 10-
70% yield. The low yield of the propionyloxymethyl
derivatives 6a and 6d is due to their instability. The set
of derivatives 6a -g differing in the bulkiness of the
acyloxymethyl ester and alkyl ester at positions 3 and 5
allowed us to establish the relationship between the
structure of the substrate and the reactivity and enan-
tioselectivity of the enzyme.
Screening of the transformation of 6c and 6f with
lipase AH, lipase PS, Candida antarctica B lipase (CAL-
B), Burkholderia cepacia lipase, and Mucor miehei lipase
showed that these enzymes can catalyze the hydrolysis
of the substrates in wet diisopropyl ether. However, the
enantiopreference was rather moderate, and these en-
zymes were not investigated further. Candida rugosa
lipase (CRL) was found to be the most active and
enantioselective of all the tested enzymes, and this
enzyme was used for all subsequent experiments (see
Scheme 2).
According to the literature, CRL together with CAL-B
are the most universal enzymes for different purposes
and were already widely applied because of their unique
stereoselectivity.13,22,23
The enantioselectivity of Candida rugosa lipase cata-
lyzed kinetic resolution of racemic substrates 6a -g in
water-saturated diisopropyl ether (IPE) was investigated,
and the obtained data are summarized in Table 1. From
this table it is clear that increasing the steric bulk of the
acyl group in compounds 6 decreases the reaction rates.26
The pivaloyloxymethyl derivative 6g is not reactive
toward CRL. Only CAL-B and Mucor miehei lipase were
able to hydrolyze 6g: in 8 days of incubation with Mucor
Ta ble 1. En a n tiom er ic Ra tio24 (E) a n d Rea ction Ra te of
th e Ca n d id a r u gosa Lip a se Ca ta lyzed Kin etic Resolu tion
of Ra cem ic 1,4-Dih yd r op yr id in e Su bstr a tes 6a -g in
Wa ter -Sa tu r a ted Diisop r op yl Eth er a
enantiomeric
time of 50%
conversion, h
compd
ratio (E value)b
6a
6b
6c
6d
6e
6f
1.7 ( 0.07
3.0 ( 0.1
11.0 ( 0.6
4.0 ( 0.2
6.0 ( 0.1
21.0 ( 1.3
4
6
6
4.0
4.5
5
6g
no reaction
a
b
For the details, see the Experimental Section. The data were
fitted using the computer program EIVFIT.25
miehei lipase, the conversion to monoacid 5b was 35%
with 13% ee.
Substrates having a methyl ester at C5 give higher E
values than those having 2-propoxyethyl esters. Further-
more, the enantioselectivity of CRL increased together
with the steric hindrance of acyloxymethyl ester group.
The highest enantiomeric ratio (E ) 21) was reached for
the isobutyryloxymethyl ester 6f. This rather high enan-
tioselectivity is remarkable, since there are no less than
six single bonds between the chiral center and the
carbonyl group where the serine residue of the enzyme
attacks. This means that there is much conformational
flexibility in the substrate, which increases the chance
that both enantiomers will fit in the enzyme active site
(in different conformations). Increasing the size and
branching of the acyloxymethyl group may limit the
available space for the 4-aryl-1,4-DHP moiety inside the
enzyme and therefore enhance the steric recognition.
Furthermore, it should be noted that the reaction is
(19) Ogawa, T.; Hatayama, K.; Maeda, H.; Kita, Y. Chem. Pharm.
Bull. 1994, 42, 1579-1589.
(20) Rasmussen, M.; Leonard, N. L. J . Am. Chem. Soc. 1967, 89,
5439-5445.
(21) Sum, F. W.; Gilbert, A.; Venkatesan, A. M.; Lim, K.; Wong, V.;
O’Dell, M.; Francisco, G.; Chen, Z.; Grosu, G.; Baker, J .; Ellingboe, J .;
Malamas, M.; Gunawan, I.; Primeau, J .; Largis, E.; Steiner, K. Bioorg.
Med. Chem. Lett. 1999, 9, 1921-1926.
(22) Anderson, E. M.; Larsson, K. M.; Kirk, O. Biocatal. Biotrans-
form. 1998, 16, 181-204.
(23) Lehmann, S. V.; Breinholt, J .; Bury, P. S.; Nielsen, T. E.
Chirality 2000, 12, 568-573.
(24) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am.
Chem. Soc. 1982, 104, 7294-7299.
(25) J ongejan, J . A.; van Tol, J . B. A.; Geerlof, A.; Duine, J . A. Recl.
Trav. Chim. Pays-Bas 1991, 110, 247-254.
(26) Morgan, B.; Zaks, A.; Dodds, D. R.; Liu, J .; J ain, R.; Megati,
S.; Njoroge, F. G.; Girijavallabhan, V. M. J . Org. Chem. 2000, 65, 5452-
5459.

404 J . Org. Chem., Vol. 67, No. 2, 2002
Sobolev et al.
Sch em e 3. Ch em oen zym a tic Rou tes to Both En a n tiom er s of th e Cer ebr ocr a st An a logu e 1
performed in an organic solvent and it is well-appreciated
that reactions in nonaqueous solvents have increased
enantioselectivity.27
more preferable from a synthetic point of view because
2-propoxyethanol (propylcellosolve) was already intro-
duced to the dihydropyridine ring; however, pathway B
gives higher ee values for the products.
Our goal was the preparative synthesis of both enan-
tiomers of 1. Several synthetic roads can be envisaged
for this purpose. The two isobutyryloxymethyl derivatives
6c and 6f have been chosen as the starting materials, as
in these cases the highest enantioselectivity of CRL was
observed. The CRL-catalyzed kinetic resolution was
stopped halfway to give the optically active monoacid
5a ,b and the remaining optically active substrates 6c,f
(Scheme 3, Table 2). The remaining substrates (+)-(R)-
6c and (-)-(R)-6f were hydrolyzed chemically to the
monoacids (+)-(S)-5a and (-)-(S)-5b. The pathway A is
The yield of esterification of the monoacid (+)-(R)-5b
with 2-propoxyethanol (propylcellosolve) using 2-chlo-
romethylpyridinium iodide (Mukaiyama reagent)28 was
22%, together with unconverted starting material. This
forced us to look for a better method of esterification,
which was found in treatment of (-)-(S)-5b with 4 equiv
of SOCl2 and a subsequent reaction with propylcellosolve
to give (-)-(R)-6 in 45% yield. Using less SOCl2 (1-2
equiv) leads to decarboxylation instead of esterifica-
tion.
(27) Koskinen, A. M. P.; Klibanov, A. M. Enzymatic reactions in
organic media; Blackie Academic & Professional: Glasgow, UK, 1996.
(28) Saton, Y.; Okumura, K.; Shiokawa, Y. Chem. Pharm. Bull.
1994, 42, 950-952.

Kinetic Resolution of 1,4-Dihydropyridine 3,5-Diesters
J . Org. Chem., Vol. 67, No. 2, 2002 405
Ta ble 2. Syn th esis of Both En a n tiom er s of 3-Meth yl
5-(2-P r op oxyeth yl) 4-[2-(Diflu or om eth oxy)p h en yl]-
2,6-d im eth yl-1,4-d ih yd r o-3,5-p yr id in ed ica r boxyla tes,
(+)-(S)-1 a n d (-)-(R)-1
to be strong enough for the ab initio determination of the
absolute configuration of an enantiopure sample.30 The
Flack x-parameter31 amounted to -0.04(8); the x param-
eter for the inverted structure was 1.03(8), indicating a
correct assignment of absolute structure.
pathway
compound
ee, %
[R]20 (solvent)
D
A
A
A
A
A
B
B
(+)-(R)-6c
(-)-(R)-5a
(+)-(S)-5a
(+)-(S)-1
(-)-(R)-1
(-)-(R)-6f
(+)-(R)-5b
62
88a
62
62
88
79
77
+16.0 (MeOH)
-32.6 (MeOH)
+29.8 (MeOH)
+13.0 (CHCl3)
-17.0 (CHCl3)
-15.0 (CHCl3)
+42.7 (CHCl3)
-12.7 (MeOH)
-46.9 (CHCl3)
+16.6 (MeOH)
+16.8 (CHCl3)
-18.7 (CHCl3)
The acid (-)-(S)-5b, derived from the remaining
substrate (-)-(R)-6f, was converted to the corresponding
amide 7 and appeared to have the same retention time
as the (+)-(R,S)-isomer that was subjected to X-ray
analysis. In the same way, the amide derived from the
enzymatic product (+)-(R)-5b coeluted with (-)-(R,R)-
7. So, in the hydrolysis of 6f, CRL preferentially reacts
with the S-isomer. The same enantiopreference of CRL
was observed for the hydrolysis of 6c and other deriva-
tives.
B
(-)-(S)-5b
79
B
B
(+)-(S)-1
(-)-(R)-1
71b
89b
a
b
Determined after crystallization. Obtained from another
experiment, where the degree of conversion of the enzymatic
reaction was higher than 50%.
Con clu sion s
The chemoenzymatic synthesis of both enantiomers
of 3-methyl 5-(2-propoxyethyl) 4-[2-(difluoromethoxy)-
phenyl]-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarbox-
ylate has been performed in moderate to good optical
yields, depending on the strategy of the synthesis. The
reaction of Candida rugosa lipase was dependent on
the structure of the substrates: increasing the steric bulk
of the hydrolyzed acyloxymethyl ester leads to lower
reaction rates until the substrate becomes unreactive
toward this enzyme at all. At the same time, the
enantioselectivity of CRL increases until an enantiomeric
ratio (E) of 21 is reached for the isobutyryloxymethyl
ester. This fine-tuning of the structure of the acyl moiety
on the spacer provides a useful method to perform kinetic
resolution of hindered or unreactive carboxylic acids.
Using this strategy, the CRL-catalyzed hydrolysis of the
isobutyryloxymethyl derivative 6f yielded a practical
method for the synthesis of both enantiomers of a chiral
1,4-dihydropyridine. The absolute configuration of the
enzymatic product was assigned by X-ray analysis of its
(R)-(+)-1-phenylethylamine derivative.
Determination of optical yields of the products of the
enzymatic reactions has been performed in several ways.
The most convenient analysis using HPLC on chiral
stationary phases was applied for compound 5a , since
the separation of enantiomers (Rs) was ∼1.2. In other
cases (5b, 6c, 6f, 1) the optimal conditions of separation
using different chiral HPLC columns were not found, and
Rs was at best ∼0.6-0.8, which was not sufficient for the
determination of the ee of the enzymatic products. So,
the data obtained by this method were only used to
determine the approximate ee. The determination of ee
of 5b has been done via coupling to (R)-(+)-R-methylben-
zylamine;29 analysis of the obtained diastereomers on a
reversed phase column gave Rs >1.2. Enantiomeric
excesses of the intermediates 6c,f and target compound
1 derived from 6c were assumed to be the same as for
5a and 5b. The enantiomeric excess of 1 obtained from
1
5b has been determined by H NMR using a chiral shift
reagent.
Initial attempts to synthesize derivatives suitable for
the determination of the absolute configuration by X-ray
diffraction analysis failed. A number of esters of 5b and
optically active or heavy atom containing alcohols were
synthesized, but none of them led to enantiopure crystal-
line material. Even when the racemic mixtures were
crystalline, the enantiopure materials were found to be
oils, until the derivative of (()-5b and (R)-(+)-R-meth-
ylbenzylamine was synthesized. The epimers of 7 (Scheme
4) were separated on reversed-phase silica gel, and both
diastereomers appeared to be crystalline. The crystals
of the first eluted amide (+)-(R,S)-7 were submitted to
X-ray analysis. An ORTEP plot of (+)-(R,S)-7 is given
in the Supporting Information. Besides the indicated
intramolecular hydrogen bond, the structure also con-
tains an intermolecular hydrogen bond, donated by
N1-H to O32, creating an infinite one-dimensional chain
of hydrogen-bonded molecules, running in the a-direction.
The asymmetric unit contains one molecule of cocrystal-
lized chloroform, involved in a short C-H‚‚‚O interaction
with O11. Further details of intra- and intermolecular
geometry are given in the Supporting Information.
The absolute configuration was initially chosen to be
in accordance with the known configuration of C24. The
anomalous signal of the cocrystallized chloroform proved
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. 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) and Baker bond phase
C18 for flash from J . T. Baker (Deventer, The Netherlands).
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 and lipase PS were supplied by Amano
Pharmaceutical Co., Ltd. (J apan). Immobilized Candida ant-
arctica lipase B (Novozym 435) was a gift from Novo Nordisk
A/S (Bagsvaerd, Denmark). Lipase from Burkholderia cepacia
(CHIRAZYME L-1, c.-f., lyo.) and Mucor miehei lipase (CHIRA-
ZYME L-9, c.-f, lyo.) were gifts from Boehringer-Mannheim
(Mannheim, Germany). Enzymatic reactions were carried out
1
in a orbital shaker at 25 °C (250 rpm). H NMR spectra were
recorded at 90, 200, or 400 MHz. 13C spectra were recorded at
50 MHz. Melting points are uncorrected. The conversions and
E-values of the enzymatic reactions were analyzed by HPLC
on a 4.6 × 250 mm column packed with 5 µm Spherisorb,
ODS-2 (Phase Separations) with the solvent system acetoni-
trile/water/acetic acid (60:40:0.1) as the mobile phase at a flow
rate of 1.0 mL/min. Alternatively, a 4.6 × 250 mm Alltima
(30) Flack, H. D.; Bernardinelli, G. J . Appl. Crystallogr. 2000, 33,
1143-1148.
(31) Flack, H. D. Acta Crytallogr. 1983, A39, 876-881.
(29) Bergot, B. J .; Anderson, R. J .; Schooley, D. A.; Henrick, C. A.
J . Chromatogr. 1978, 155, 97-105.

406 J . Org. Chem., Vol. 67, No. 2, 2002
Sch em e 4. Deter m in a tion of th e Ster eoch em istr y of th e En zym a tic Rea ction
Sobolev et al.
C18 5U (Alltech) column was used with the eluent methanol/
water/acetic acid (68:38:0.01) equipped with a detector set at
254 nm. Determination of enantiomeric excesses of 5a was
performed by direct analysis on the chiral column Chirex 3011,
4.6 × 250 mm, 5 µm (Phenomenex) with detection at 254 nm.
The eluent was methanol/dichloromethane (1:2) at a flow rate
of 1.0 mL/min.
Enantiomeric excesses of (-)-(R)-1 and (+)-(S)-1 were
determined by 1H NMR (400 MHz) using Eu(hfc)3 in CDCl3
solution. The ee was calculated from the splitting of the
resonance of one of the 2,6-CH3 groups into two singlets.
2-[2-(Diflu or om eth oxy)ben zylid en e]m eth yl Acetoa c-
eta te (2b). 2-(Difluoromethoxy)benzaldehyde (26.15 g, 0.15
mol) and methyl acetoacetate (21.37 g, 0.18 mol) were added
to a mixture of 2-propanol (10 mL), piperidine (1 mL), and
acetic acid (1 mL). After being stirred at room temperature
for 6 h, the solvent was removed in vacuo. The residue was
twice crystallized from diethyl ether-hexane mixture to give
21.80 g (53.2%) of 2b as white crystals: mp 51-53 °C; 1H NMR
(CDCl3, 200 MHz) δ 2.44 (3H, s), 3.77 (3H, s), 6.53 (1H, t, J H-F
) 73.2 Hz), 7.20-7.45 (4H, m), 7.82 (1H, s).
2.38 (3H, s), 3.30 (2H, t, J ) 7.0 Hz), 3.40-3.70 (2H, m), 4.15-
4.35 (2H, m), 6.48 and 6.50 (1H, t, J ) 72.5 Hz), 6.95-7.50
(4H, m), 7.80 and 7.82 (1H, s).
Crude 2a (18.2 g, 0.53 mol) and 8.15 g (0.53 mol) of
2-cyanoethyl 3-aminocrotonate 3 were refluxed in 50 mL of
isopropyl alcohol for 6 h. After cooling until -5 °C overnight,
the precipitate containing 90% of the main product was filtered
off. The precipitate was flash chromatographed with chloroform/
hexane/acetone (9:7:1) to give 17.5 g (85%) of 4a as pale yellow
1
crystals: mp 123-124 °C; H NMR (CDCl3, 200 MHz) δ 0.86
(3H, t, J ) 7.0 Hz), 1.53 (2H, sextet, J ) 7.0 Hz), 2.27 (3H, s),
2.28 (3H, s), 2.63 (2H, t, J ) 6.5 Hz), 3.32 (CH2, t, J ) 7.0 Hz),
3.55 (2H, t, J ) 5.1 Hz), 4.12 (2H, t, J ) 5.3 Hz), 4.19 (2H, t,
J ) 6.5 Hz), 5.23 (1H, s), 6.03 (1H, br s), 6.58 (1H, dd, J H-F
)
73.8, 76.8 Hz), 6.96-7.18 (3H, m), 7.37 (1H, dd, J ) 2.0, 7.0
Hz); 13C NMR (CDCl3, 50 MHz) δ 10.50 (CH3), 17.85 (CH2),
19.55 (CH3), 19.73 (CH3), 22.78 (CH2), 35.55 (CH), 58.18 (CH2),
63.06 (CH2), 68.56 (CH2), 72.72 (CH2), 101.57 (C), 103.10 (C),
116.91 (CN), 117.30 (CH, t, J ) 264.6 Hz, OCHF2), 118.22
(CH), 125.18 (CH), 127.81 (CH), 131.71 (CH), 138.25 (C),
144.53 (C), 146.16 (C), 149.29 (C), 166.78 (C), 167.46 (C); IR
(Nujol) 2260 cm-1 (CN); MS m/z 478 (M+); HRMS calcd for
Anal. Calcd for C13H12F2O4: C, 57.78; H, 4.47. Found: C,
57.87; H, 4.28.
C
24H28F2N2O6 478.1915, found: 478.1910.
2-Cya n oeth yl 3-a m in ocr oton a te (3)32 was prepared by
a modified method: To 10.00 g (0.06 mol) of 2-cyanoethyl
acetoacetate were added 15 mL (0.20 mol) of 25% aqueous
ammonia and 0.3 mL of acetic acid with stirring. The reaction
mixture was maintained at room temperature for 2 h, after
which the white precipitate was filtered off. Crystallization
from methanol gave 6.50 g (71%) of 3 as white crystals: mp
88 °C; H NMR (DMSO-d6, 90 MHz) δ 1.85 (3H, s), 2.60 (2H,
t, J ) 6.5 Hz), 4.00 (2H, t, J ) 6.5 Hz), 4.45 (1H, s), 7.20 (2H,
br s).
Anal. Calcd for C24H28F2N2O6: C, 60.24; H, 5.89; N, 5.85.
Found C, 59.88; H, 5.90; N, 5.78;
3-(2-Cyan oeth yl) 5-Meth yl 4-[2-(Diflu or om eth oxy)ph en -
yl]-2,6-d im et h yl-1,4-d ih yd r o-3,5-p yr id in ed ica r b oxyla t e
(4b). A solution of 5.00 g (19 mmol) of 2b and 2.86 g (19 mmol)
of 2-cyanoethyl 3-aminocrotonate was refluxed in 20 mL of
ethanol for 6 h. After cooling until -5 °C, the precipitate was
filtered off. Crystallization from ethanol gave 5.20 g (69%) of
4b as pale yellow crystals: mp 124-125 °C; 1H NMR (CDCl3,
200 MHz) δ 2.29 (3H, s), 2.30 (3H, s), 2.64 (2H, t, J ) 6.4 Hz),
3.59 (3H, s), 4.20 (2H, t, J ) 6.4 Hz), 5.25 (1H, s,), 5.86 (1H,
br s), 6.52 (1H, dd, J H-F ) 73.7, 76.6 Hz), 6.96-7.19 (3H, m),
7.36 (1H, dd, J ) 2.0, 7.0 Hz); 13C NMR (CDCl3, 50 MHz) δ
17.81 (CH2), 19.49 (CH3), 19.80 (CH3), 35.11 (CH), 50.92 (CH3),
58.19 (CH2), 101.71 (C), 103.32 (C), 116.91 (CN), 117.23 (CH,
t, J ) 279.7 Hz, OCHF2), 117.89 (CH), 125.23 (CH), 127.83
(CH), 131.47 (CH), 138.24 (C), 144.16 (C), 146.10 (C), 149.02
(C), 166.64 (C), 167.85 (C); IR (Nujol) 2260 cm-1 (CN); MS m/z
406 (M+); HRMS calcd for C20H20F2N2O5 406.1440, found
406.1333.
1
Anal. Calcd for C7H10N2O2: C, 54.53; H, 6.53; N, 18.17.
Found: C, 54.35; H, 6.51; N, 17.95.
3-(2-Cya n oet h yl) 5-(2-P r op oxyet h yl) 4-[2-(Diflu or o-
m eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p yr id in e-
d ica r boxyla te (4a ). 2-(Difluoromethoxy)benzaldehyde (17.21
g, 0.10 mol) and propoxyethyl acetoacetate (18.82 g, 0.10 mol)
were added to a mixture of 2-propanol (150 mL), a catalytic
amount of piperidine, and acetic acid (0.5 mL). After being
stirred at reflux for 5 h, the solvent was removed in vacuo.
The residue was dissolved in ether and washed with water
twice, dried over MgSO4, and concentrated under reduced
pressure to give 18.2 g (0.53 mol) of crude (E,Z)-2-[2-(difluo-
romethoxy)benzylidene]propoxyethyl acetoacetate (2a ), which
was used without further purification: 1H NMR (CDCl3, 90
MHz) δ (major peaks) 1.46 (2H, sextet, J ) 7.0 Hz), 2.25 and
Anal. Calcd for C20H20F2N2O5: C, 59.11; H, 4.96; N, 6.89.
Found: C, 59.00; H, 5.05; N, 6.72.
4-[2-(Diflu or om eth oxy)p h en yl]-2,6-d im eth yl-5-[(2-p r o-
p oxyeth oxy)ca r bon yl]-1,4-d ih yd r o-3-p yr id in eca r boxyl-
ic Acid (5a ). Crushed KOH (0.73 g, 13 mmol) was added to a
solution of 4.78 g (10 mmol) of 4a in 40 mL of ethanol. The
reaction mixture was stirred at 40 °C for 3 h and then 6 h at
(32) Grohe, K.; Heitzer, H. Liebigs Ann. Chem. 1973, 1025-1035.

Kinetic Resolution of 1,4-Dihydropyridine 3,5-Diesters
J . Org. Chem., Vol. 67, No. 2, 2002 407
room temperature. Then the reaction mixture was evaporated
and the residue was dissolved in water and washed twice with
30 mL of chloroform. The ice-cooled aqueous layer was acidified
with HCl to pH 4.0-5.0. The precipitated product was filtered
off, washed with water, and dried over MgSO4 to give 2.90 g
(86%) of 4a as a pale yellow powder: mp 138-140 °C; 1H NMR
(DMSO-d6, 200 MHz) δ 0.82 (3H, t, J ) 7.0 Hz), 1.46 (2H,
sextet, J ) 7.0 Hz), 2.22 (6H, s), 3.30 (2H, t, J ) 7.0 Hz), 3.45-
3.51 (2H, m), 3.95-4.06 (2H, m), 5.12 (1H, s), 6.93 (1H, t, J H-F
)76.6 Hz), 6.92-7.30 (4H, m), 8.75 (1H, br s), 11.63 (1H, br
s); 13C NMR (DMSO-d6, 50 MHz) δ 10.46 (CH3), 18.28 (2 ×
CH3), 22.39 (CH2), 34.85 (CH), 62.35 (CH2), 67.95 (CH2), 71.81
(CH2), 100.70 (C), 101.80 (C), 117.10 (CH, t, J ) 254.6 Hz,
OCHF2), 117.66 (CH), 125.00 (CH), 127.39 (CH), 131.17 (CH),
139.17 (C), 145.04 (C), 145.94 (C), 148.43 (C), 167.04 (C),
168.74 (C).
br s), 6.55 (1H, dd, J H-F ) 74.1, 76.2 Hz), 6.93-7.15 (3H, m),
7.33 (1H, J ) 2.1, 7.3 Hz); 13C NMR (CDCl3, 50 MHz) δ 10.50
(CH3), 18.57 (2 × CH3), 19.34 (CH3), 19.91 (CH3), 22.79 (CH2),
33.63 (CH), 36.00 (CH), 62.97 (CH2), 68.45 (CH2), 72.89 (CH2),
78.51 (CH2), 101.01 (C), 103.14 (C), 117.00 (CH, t, J ) 250.1
Hz, OCHF2), 117.62 (CH), 124.75 (CH), 127.65 (CH), 132.08
(CH), 137.65 (C), 144.06 (C), 146.98 (C), 149.84 (C), 166.05 (C),
167.50 (C), 172.85 (C); MS m/z 525 (M+); HRMS calcd for
C
26H33F2NO8 525.2174, found 525.2175.
3-[(Isob u t yr yloxy)m et h yl] 5-Met h yl 4-[2-(Diflu or o-
m eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p yr id in e-
d ica r boxyla te (6f). To a solution of 3.00 g (8.5 mmol) of 5b
in 6 mL of dry DMF was added 1.41 g (10.2 mmol) of K2CO3
at room temperature, and the reaction mixture was stirred
for 2 h, after which 1.50 g (11.0 mmol) of isobutyryloxymethyl
chloride was added. The mixture was stirred overnight, diluted
with CHCl3, washed with water (three times) and brine, dried
over MgSO4, and evaporated. The remaining residue was flash
chromatographed on silica gel with petroleum ether (bp 40-
60 °C)/ethyl acetate (2:1) followed by crystallization from
ethanol to give 2.67 g (71%) of 6f as white crystals: mp 112-
113 °C; 1H NMR (CDCl3, 200 MHz) δ 1.04 (3H, d, J ) 6.7 Hz),
1.06 (3H, d, J ) 6.7 Hz), 2.27 (3H, s), 2.31 (3H, s), 2.44 (1H,
septet, J ) 6.7 Hz), 3.58 (1H, s), 5.23 (1H, s), 5.69 (2H, s),
5.81 (1H, br s), 6.53 (1H, dd, J H-F ) 74.2, 76.1 Hz), 6.93-7.16
(3H, m), 7.32 (1H, dd, J ) 2.1, 7.3 Hz); 13C NMR (CDCl3, 50
MHz) δ 18.57 (2 × CH3), 19.28 (CH3), 19.93 (CH3), 35.65 (CH),
35.73 (CH), 50.90 (CH3), 78.50 (CH2), 101.11 (C), 103.31 (C),
116.84 (CH, t, J ) 256.7 Hz, OCHF2), 117.57 (CH), 124.82
(CH), 127.70 (CH), 131.78 (CH), 137.69 (C), 143.98 (C), 147.01
(C), 149.70 (C), 166.05 (C), 167.99 (C), 175.88 (C); MS m/z 453
(M+); HRMS calcd for C22H25NO7F2 (M+) m/z 453.1599, found
453.1597.
Anal. Calcd for C21H25F2NO6: C, 59.29; H, 5.92; N, 3.29.
Found C, 59.38; H, 6.00; N, 3.85.
4-[2-(Diflu or om eth oxy)p h en yl]-5-(m eth oxyca r bon yl)-
2,6-d im eth yl-1,4-d ih yd r o-3-p yr id in eca r boxylic Acid (5b).
This compound was prepared via the same method used for
compound 5a , but beginning with 2.20 g (5.0 mmol) of 4b, after
addition of 0.30 g (5.3 mmol) of KOH, the reaction mixture
was stirred for 6 h at room temperature, and the washing step
with chloroform was omitted. Compound 5b was obtained in
86% (1.65 g), as a pale yellow powder: mp 153-154 °C; 1H
NMR (DMSO-d6, 200 MHz) δ 2.21 (3H, s), 2.24 (3H, s), 3.49
(3H, s), 5.14 (1H, s), 6.97 (1H, t, J H-F ) 76.0 Hz), 6.99-7.28
(4H, m) 8.76 (1H, br s), 11.61 (1H, br s); 13C NMR (DMSO-d6,
50 MHz) δ 18.12 (CH3), 18.21 (CH3), 34.23 (CH), 50.42 (CH3),
100.96 (C), 101.85 (C), 117.07 (CH, t, J ) 254.6 Hz, OCHF2),
117.43 (CH), 125.14 (CH), 127.42 (CH), 130.79 (CH), 139.30
(C), 145.14 (C), 145.63 (C), 148.05 (C), 167.51 (C), 168.68 (C).
Anal. Calcd for C17H17NF2O5: C, 57.79; H, 4.85; N, 3.96.
Found C, 57.65, H, 4.82, N, 3.85.
Anal. Calcd for C22H25NO7F2: C, 58.28; H, 5.56; N, 3.09.
Found: C, 58.12; H, 5.53; N, 3.03.
3-[(P r op ion yloxy)m eth yl] 5-(2-P r op oxyeth yl) 4-[2-(Di-
flu or om eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p y-
r id in ed ica r boxyla te (6a ). To a solution of 478 mg (2.0 mmol)
of 4a in 5 mL of ethanol was added a solution of 135 mg (2.4
mmol) of KOH in 1 mL of ethanol at room temperature. The
resulting mixture was stirred for 1 h, after which the reaction
mixture was evaporated until the solvent was completely
removed. The residue was diluted with 2 mL of dry DMF, after
which 139 mg (2.6 mmol) of propionyloxymethyl chloride was
added. The reaction mixture was stirred overnight and then
diluted with CHCl3 and washed successively twice with water
and twice with brine, dried over MgSO4, and evaporated. The
remaining residue was flash chromatographed on silica gel
with petroleum ether (bp 40-60 °C)/ethyl acetate (7:3) to give
683 mg (67%) of 90% pure 6a as a yellow oil, which can be
purified on a preparative TLC silica gel plate with petroleum
ether (bp 40-60 °C)/acetone (5:2): 1H NMR (CDCl3, 200 MHz)
δ 0.89 (3H, t, J ) 7.5 Hz), 1.05 (3H, t, J ) 7.5 Hz), 1.60 (2H,
sextet, J ) 7.5 Hz), 2.15-2.30 (2H, m), 2.24 (3H, s), 2.27 (3H,
s), 3.36 (2H, t, J ) 7.4 Hz), 3.53-3.63 (2H, m), 4.11-4.17 (2H,
m), 5.22 (1H, s), 5.69 (2H, s), 6.16 (1H, s), 6.53 (1H, t, J H-F
)74.7 Hz), 6.91-7.16 (3H, m), 7.35 (1H, dd, J ) 2.1, 7.4 Hz);
13C NMR (CDCl3, 50 MHz) δ 8.65 (CH3), 10.50 (CH3), 19.38
(CH3), 19.88 (CH3), 22.80 (CH2), 27.23 (CH2), 36.09 (CH), 62.98
(CH2), 68.47 (CH2), 72.88 (CH2), 78.41 (CH2), 100.93 (C), 103.12
(C), 116.90 (CH, t, J ) 254.7 Hz, OCHF2), 117.71 (CH), 124.70
(CH), 127.65 (CH), 132.15 (CH), 137.56 (C), 144.12 (C), 147.06
(C), 149.85 (C), 166.10 (C), 167.46 (C), 173.23 (C); MS m/z 511
(M+); HRMS calcd for C25H31F2NO8 511.2018, found 511.2022.
3-[(Isobu tyr yloxy)m eth yl] 5-(2-P r op oxyeth yl) 4-[2-(Di-
flu or om eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p y-
r id in ed ica r boxyla te (6c). This compound was prepared via
the same method used for compound 6a . Beginning with 957
mg (2 mmol) of 4a , 135 mg (2.4 mmol) of KOH, and 355 mg
(2.6 mmol) of isobutyryloxymethyl chloride, 6c was obtained
in 72% (762 mg): 1H NMR (CDCl3, 200 MHz) δ 0.89 (3H, t, J
) 7.4 Hz), 1.01 (3H, d, J ) 6.8 Hz), 1.05 (3H, d, J ) 6.8 Hz),
1.56 (2H, sextet, J ) 7.4 Hz), 2.25 (3H, s), 2.29 (3H, s), 2.42
(1H, septet, J ) 6.8 Hz), 3.36 (CH2, t, J ) 6.7 Hz), 3.50-3.64
(2H, m), 4.04-4.20 (2H, m), 5.22 (1H, s), 5.68 (2H, s), 6.01 (1H,
3-[(Bu t yr yloxy)m et h yl] 5-(2-P r op oxyet h yl) 4-[2-(Di-
flu or om e t h oxy)p h e n yl]-2,6-d im e t h yl-1,4-d ih yd r o-3,5-
p yr id in ed ica r boxyla te (6b). This compound was prepared
via the same method used for compound 6f, but beginning with
213 mg (0.5 mmol) of 5a , 35 mg (0.25 mmol) of K2CO3, and
889 mg (0.65 mmol) of butyryloxymethyl chloride in 0.5 mL of
dry DMF. Flash chromatography on silica gel with petroleum
ether (bp 40-60 °C)/ethyl acetate (7:3) gave 137 mg (52%) of
6b as a yellow oil: 1H NMR (CDCl3, 200 MHz) δ 0.86 (3H, t,
J ) 7.6 Hz), 0.88 (3H, t, J ) 7.6 Hz), 1.53 (2H, sextet, J ) 7.6
Hz), 1.55 (2H, sextet, J ) 7.6 Hz), 2.18 (2H, t, J ) 7.6 Hz),
2.27 (3H, s), 2.29 (3H, s), 3.35 (2H, t, J ) 7.6 Hz), 3.50-3.62
(2H, m), 4.05-4.19 (2H, m), 5.21 (1H, s), 5.69 (2H, ABq), 5.92
(1H, s), 6.53 (1H, dd, J H-F ) 74.3, 75.9 Hz), 6.92-7.15 (3H,
m), 7.33 (1H, dd, J ) 2.1, 7.4 Hz); 13C NMR (CDCl3, 50 MHz)
δ 10.50 (CH3), 13.51 (CH3), 18.03 (CH2), 19.45 (CH3), 19.98
(CH3), 22.80 (CH2), 35.77 (CH2), 36.11 (CH), 62.98 (CH2), 68.46
(CH2), 72.88 (CH2), 78.39 (CH2), 101.02 (C), 103.19 (C), 116.97
(CH, t, J ) 250.1 Hz, OCHF2), 117.73 (CH), 124.72 (CH),
127.67 (CH), 132.14 (CH), 137.57 (C), 144.03 (C), 146.91 (C),
149.93 (C), 166.07 (C), 167.42 (C), 172.39 (C); MS m/z 525 (M+);
HRMS calcd for C26H33F2NO8 525.2174, found 525.2182.
3-[(P r op ion yloxy)m eth yl] 5-Meth yl 4-[2-(Diflu or o-
m eth oxy)ph en yl]-2,6-dim eth yl-1,4-dih ydr o-3,5-pyr idin edi-
ca r boxyla te (6d ). This compound was prepared via the same
method used for compound 6f, but beginning with 1.06 g (3.0
mmol) of 5b, 0.62 g (4.5 mmol) of K2CO3, and 0.55 g (4.5 mmol)
of propionyloxymethyl chloride in 2 mL of dry DMF. Flash
chromatography on silica gel with petroleum ether (bp 40-60
oC)/chloroform/isopropyl alcohol (10:10:1) followed by crystal-
lization from hexanes-ethyl acetate and recrystallization from
methanol gave 0.13 g (10%) of 6d as a pale yellow powder:
mp 115-116 °C; 1H NMR (CDCl3, 200 MHz) δ 1.04 (3H, t, J )
7.4 Hz), 2.22 (2H, q, J ) 7.4 Hz), 2.25 (3H, s), 2.29 (3H, s),
3.58 (3H, s), 5.21 (1H, s), 5.63 (2H, s), 5.94 (1H, br s), 6.54
(1H, t, J H-F ) 75.0 Hz), 6.88-7.32 (4H, m); 13C NMR (CDCl3,
50 MHz) δ 8.66 (CH3), 19.34 (CH3), 19.42 (CH3), 27.24 (CH2),
35.78 (CH), 50.91 (CH3), 78.40 (CH2), 101.06 (C), 103.31 (C),
116.84 (CH, t, J ) 255.4 Hz, OCHF2), 117.59 (CH), 124.79
(CH), 127.7 (CH), 131.85 (CH), 137.66 (C), 143.98 (C), 147.07

408 J . Org. Chem., Vol. 67, No. 2, 2002
Sobolev et al.
(C), 149.74 (C), 166.10 (C), 167.97 (C), 173.29 (C); MS m/z 439
as a colorless viscous oil; 62% ee; [R]20 +16.0 (c 1.0, MeOH);
D
(M+); HRMS calcd for C21H23F2NO7 439.1443, found 439.1437.
the 1H NMR and mass spectral data were identical to those
described for its racemic precursor (()-5c; HRMS calcd for
3-[(Bu tyr yloxy)m eth yl]
5-Meth yl
4-[2-(Diflu or o-
C
26H33F2N1O8 525.2174, found 525.2171.
m eth oxy)ph en yl]-2,6-dim eth yl-1,4-dih ydr o-3,5-pyr idin edi-
ca r boxyla te (6e). This compound was prepared via the same
method used for compound 6f, but beginning with 71 mg (0.20
mmol) of 5b, 33 mg (0.24 mmol) of K2CO3, and 35 mg (0.26
mmol) of butyryloxymethyl chloride in 0.5 mL of dry DMF.
Purification by flash chromatography on silica gel with petro-
leum ether (bp 40-60 °C)/ethyl acetate (7:3) followed by
crystallization from ethanol gave 64 mg (70%) of 6e, a pale
(+)-(4R)-4-[2-(Diflu or om et h oxy)p h en yl]-5-(m et h oxy-
ca r bon yl)-2,6-d im et h yl-1,4-d ih yd r o-3-p yr id in eca r b oxy-
lic Acid ((+)-(R)-5b): yield 127 mg (45%) as a colorless viscous
oil, which was triturated from the mixture of chloroform-
hexane to give 90 mg (32%) of a white solid; mp 82-84 °C;
77% ee; [R]20D +42.7 (c 1.0, CHCl3); [R]20D -12.7 (c 1.0, MeOH);
1H NMR (CDCl3, 200 MHz) δ 2.28 (3H, s), 2.29 (3H, s), 3.58
(3H, s), 5.21 (1H, s,), 5.71 (1H, br s), 6.39 (1H, dd, J H-F ) 73.1,
77.4 Hz), 6.95-7.17 (3H, m), 7.33 (1H, dd, J ) 2.0, 7.2 Hz);
mass spectral data were identical to those described for its
racemic precursor (()-5b; HRMS calcd for C17H17NO5F2 (M+)
m/z 353.1075, found 353.1074.
1
yellow powder: mp 98-99 °C; H NMR (CDCl3, 200 MHz) δ
0.84 (3H, t, J ) 7.4 Hz), 1.49 (2H, sextet, J ) 7.4 Hz), 2.13
(2H, t, J ) 7.4 Hz), 2.17 (3H, s), 2.20 (3H, s), 3.52 (1H, s), 5.23
(1H, s), 5.63 (2H, s), 5.99 (1H, s), 6.46 (1H, dd, J H-F ) 74.4,
75.7 Hz), 6.84-7.20 (3H, m), 7.26 (1H, dd, J ) 2.1, 7.3 Hz);
13C NMR (CDCl3, 50 MHz) δ 13.50 (CH3), 18.03 (CH2), 19.28
(CH3), 19.91 (CH3), 35.72 (CH), 35.77 (CH2), 50.90 (CH3), 78.36
(CH2), 101.04 (C), 103.30 (C), 116.84 (CH, t, J ) 255.4 Hz,
OCHF2), 117.60 (CH), 124.82 (CH), 127.70 (CH), 131.80 (CH),
137.71 (C), 144.04 (C), 147.13 (C), 149.00 (C), 166.10 (C),
167.99 (C), 172.47 (C); MS: m/z 453 (M+); HRMS calcd for
(-)-3-[(Isobu tyr yloxy)m eth yl] 5-Meth yl (4R)-4-[2-(Di-
flu or om eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p y-
r id in ed ica r boxyla te ((-)-(R)-6f): yield 164 mg (45%) as a
colorless viscous oil; 79% ee; [R]20 -15.0 (c 1.0, CHCl3); the
D
1H NMR and mass spectral data were identical to those
described for its racemic precursor (()-6f; HRMS calcd for
C
22H25NO7F2 (M+) m/z 453.1599, found 453.1592.
C
22H25NO7F2 453.1599, found 453.1596.
(+)-(4S)-4-[2-(Diflu or om eth oxy)p h en yl]-2,6-d im eth yl-
3-Meth yl 5-[(P iva loyloxy)m eth yl]
4-[2-(Diflu or o-
5-[(2-p r op oxyet h oxy)ca r b on yl]-1,4-d ih yd r o-3-p yr id in e-
ca r boxylic Acid ((+)-(S)-5a ). To a stirred solution of 158 mg
(0.30 mmol) of (+)-(R)-6c in 3 mL of ethanol was added a
solution of 19 mg (0.33 mmol) of KOH in 0.5 mL of ethanol.
After being stirred at room temperature for 1.5 h, the reaction
mixture was evaporated, diluted with water, acidified with
diluted HCl until pH 5.0, and extracted with chloroform three
times. The organic layer was washed with water and evapo-
rated. The residue was chromatographed on silica gel with
petroleum ether (bp 40-60 °C)/dichloromethane/isopropyl
alcohol (5:5:1) to give 87 mg (68%) of (+)-(S)-5a as a white
m eth oxy)ph en yl]-2,6-dim eth yl-1,4-dih ydr o-3,5-pyr idin edi-
ca r boxyla te (6g). This compound was prepared via the same
method used for compound 6f, but beginning with 0.35 g (1
mmol) of 5b, 0.20 g (1.5 mmol) of K2CO3, and 0.30 mL (2 mmol)
of pivaloyloxymethyl chloride in 3 mL of dry DMF. The mixture
was poured into water, and the precipitate was filtered off and
crystallized from methanol to give 0.32 g (69%) of 6f as a white
1
powder: mp 153-155 °C; H NMR (CDCl3, 200 MHz) δ 1.05
(9H, s), 2.25 (3H, s), 2.29 (3H, s), 3.58 (1H, s), 5.22 (1H, s),
5.69 (2H, ABq), 5.92 (1H, br s, NH), 6.52 (1H, dd, J H-F ) 74.0,
76.3 Hz), 6.92-7.16 (3H, m), 7.31 (1H, dd, J ) 2.1, 7.4 Hz);
13C NMR (CDCl3, 50 MHz) δ 19.33 (CH3), 19.98 (CH3), 26.71
(3 × CH3), 35.81 (CH), 38.60 (C), 50.87 (CH3), 78.67 (CH2),
101.23 (C), 103.31(C), 116.87 (CH, t, J ) 256.0 Hz, OCHF2),
117.60 (CH), 124.84 (CH), 127.69 (CH), 131.78 (CH), 137.79
(C), 143.89 (C), 146.74 (C), 149.76 (C), 165.93 (C), 167.97 (C),
177.22 (C); MS: m/z 467 (M+); HRMS calcd for C23H27F2NO7
467.1756, found 467.1748.
precipitate from ether: mp 86-87 °C; 62% ee; [R]20 +29.8 (c
D
1.0, MeOH). The 1H NMR (CDCl3, 200 MHz) and mass spectral
data were identical to those described for (()-5a and (-)-(R)-
5a ; HRMS calcd for C21H25F2N1O6 425.1650, found 425.1645.
(-)-(4S)-4-[2-(Diflu or om et h oxy)p h en yl]-5-(m et h oxy-
ca r bon yl)-2,6-d im et h yl-1,4-d ih yd r o-3-p yr id in eca r b oxy-
lic Acid ((-)-(S)-5b). This compound was prepared via the
same method used for compound (+)-(S)-5a , without purifica-
tion by flash chromatography. After pH adjustment to 5, the
precipitated product was filtered off and thoroughly washed
with water to give 84 mg (79%) of (-)-(S)-5b as a white
precipitate: mp 87-89 °C; 79% ee; [R]20D -46.9 (c 1.0, CHCl3);
Anal. Calcd for C23H27F2NO7: C, 59.09; H, 5.82; N, 2.99.
Found: C, 58.95; H, 5.79; N, 3.11.
Gen er a l P r oced u r e of Ca n d id a r u gosa Lip a se Ca ta -
lyzed Kin etic Resolu tion of Ra cem ic (()-6c a n d (()-6f.
To a solution of 0.80 mmol of (()-6c,f in 80 mL of water-
saturated diisopropyl ether was added 200 mg of Candida
rugosa lipase, and the resulting mixture was shaken for 6 h
at 25 °C and monitored by HPLC. When the conversion
reached 50%, the enzyme was removed by filtration and
washed additionally with chloroform. The filtrate was concen-
trated under reduced pressure. The residue was flash chro-
matographed on silica gel with chloroform/petroleum ether (bp
40-60 °C)/isopropyl alcohol (10:20:1 w 5:5:1) to give the
monoacids (-)-(R)-5a and (+)-(R)-5b and the remaining
substrates (+)-(R)-6c and (-)-(R)-6f, respectively.
1
the H NMR (CDCl3, 200 MHz) and mass spectral data were
identical to those described for (()-5b and (+)-(R)-5b; HRMS
calcd for C17H17NO5F2 (M+) m/z 353.1075, found 353.1069.
Gen er a l P r oced u r e for th e Deter m in a tion of th e
En a n tiom er ic Ra tio (E Va lu e) of th e Ca n d id a r u gosa
Lip a se Med ia ted Kin etic Resolu tion of Ra cem ic Su b-
str a tes 6a -f. To a solution of 0.04 mmol of (()-6a -d in 4
mL of water-saturated diisopropyl ether was added 10 mg of
Candida rugosa lipase, and the resulting mixture was shaken
at 25 °C. During the investigated period, several samples of
50 µL each were taken. The solvent was removed by passing
a gentle stream of nitrogen. The samples taken from the
reactions of 6a -c were analyzed for the conversion and
enantiomeric excess on the chiral column Chirex 3011. The
rate of the reactions of 6d -f were analyzed on a reversed-
phase HPLC column, and enantiomeric excesses were deter-
mined after conversion to diastereomers of amide 7: the
sample was diluted with 50 µL of DMF, treated with an excess
of (R)-(+)-R-methylbenzylamine, and kept for 0.5 h at room
temperature, after which a small excess of chloromethylpyri-
dinium iodide was added. The reaction mixture was kept for
another 2 h, evaporated, and diluted with mobile phase, and
the pH of the sample was adjusted by adding acetic acid. The
ee values of the reactions of 6e,f were analyzed on a HPLC
column packed with Spherisorb, ODS-2. The ee of the reaction
of 6d was analyzed on an Alltima HPLC column.
(4R)-4-[2-(Diflu or om eth oxy)p h en yl]-2,6-d im eth yl-5-[(2-
p r op oxye t h oxy)ca r b on yl]-1,4-d ih yd r o-3-p yr id in e ca r -
boxylic Acid ((-)-(R)-5a ): yield 139 mg (41%) as a white
precipitate from ether; mp 62-65 °C; 88% ee (determined after
crystallization), [R]20 -32.6 (c 1.0, MeOH); H NMR (CDCl3,
1
D
200 MHz) δ 0.90 (3H, t, J ) 7.4 Hz), 1.57 (2H, sextet, J ) 7.4
Hz), 2.26 (3H, s), 2.29 (3H, s), 3.38 (CH2, t, J ) 7.4 Hz), 3.51-
3.63 (CH2, m), 4.08-4.24 (CH2, m), 5.21 (1H, s), 5.85 (1H, br
s), 6.39 (1H, dd, J H-F ) 72.8, 77.8 Hz), 6.98-7.15 (3H, m), 7.35
(1H, dd, J ) 2.0, 7.6 Hz). The mass spectral data were identical
to those described for (()-5a and (+)-(S)-5a ; HRMS calcd for
C
21H25F2N1O6 425.1650, found 425.1647.
(+)-3-[(Isobu tyr yloxy)m eth yl] 5-(2-P r op oxyeth yl) (4S)-
4-[2-(Diflu or om eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-
3,5-p yr id in ed ica r boxyla te ((+)-(R)-6c): yield 194 mg (46%)

Kinetic Resolution of 1,4-Dihydropyridine 3,5-Diesters
J . Org. Chem., Vol. 67, No. 2, 2002 409
Gen er a l P r oced u r e for P r ep a r a tion of (-)-(R)-1 a n d
(+)-(S)-1 fr om th e Mon oa cid s (-)-(R)-5a a n d (+)-(S)-5a .
To a stirred solution of 64 mg (0.15 mmol) of (-)-(R)-5 or (+)-
(S)-5 in 0.4 mL of dry DMF was added 21 mg (0.15 mmol) of
K2CO3 at room temperature, and the resulting mixture was
stirred for 2 h, after which 0.028 mL (0.45 mmol) of MeI was
added. The reaction mixture was stirred for another 2 h,
diluted with water and extracted with chloroform. The organic
layer was washed with water and brine (twice) and dried over
MgSO4. After removal of the solvent in vacuo, the residue was
chromatographed on a silica gel coated preparative TLC plate
with petroleum ether (bp 40-60 °C)/chloroform/isopropyl
alcohol (10:1:1) to give the following.
Syn t h esis a n d Ch r om a t ogr a p h ic Sep a r a t ion of
Ep im er s of Meth yl 4-[2-(Diflu or om eth oxy)p h en yl]-2,6-
d im et h yl-5-({[(1R)-1-p h en ylet h yl]a m in o}ca r b on yl)-1,4-
d ih yd r o-3-p yr id in eca r boxyla te (R,S)-(+)-7 a n d (R,R)-
(-)-7. To a solution of 141 mg (0.4 mmol) of (()-5b in 0.2 mL
of dry DMF was added 0.309 mL (2.4 mmol) of (R)-(+)-R-
methylbenzylamine at room temperature, and the reaction
mixture was stirred for 1 h, after which 180 mg (0.8 mmol) of
2-chloromethylpyridinium iodide was added. The reaction
mixture was stirred overnight, diluted with chloroform, washed
with water (three times) and brine, dried over MgSO4, and
evaporated. The remaining residue was flash chromatographed
on silica gel with chloroform/petroleum ether (bp 40-60 °C)/
isopropyl alcohol (9:7:1) to give 84 mg (46%) of 7 as a colorless
viscous oil. The mixture of two diastereomers was separated
by flash chromatography on Baker bond phase C18 with
acetonitrile/water/acetic acid (60:40:0.1) to give the following.
Meth yl (4S)-4-[2-(Diflu or om eth oxy)ph en yl]-2,6-dim eth -
yl-5-({[(1R)-1-ph en yleth yl]am in o}car bon yl)-1,4-dih ydr o-3-
p yr id in eca r boxyla te ((R,S)-(+)-7): yield 29 mg (16%) as
colorless needles from a mixture of EtOH, CHCl3, and hexane;
(-)-3-Met h yl 5-(2-P r op oxyet h yl) (4R)-4-[2-(Diflu or o-
m eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p yr id in e-
d ica r boxyla te ((-)-(R)-1): yield 42 mg (63%) as a yellow oil;
88% ee; [R]20D -17.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz)
δ 0.88 (3H, t, J ) 7.4 Hz), 1.54 (2H, sextet, J ) 7.4 Hz), 2.27
(3H, s), 2.28 (3H, s), 3.35 (CH2, t, J ) 7.4 Hz), 3.55 (2H, t, J )
4.8 Hz), 3.58 (3H, s), 4.13 (2H, t, J ) 5.1 Hz), 5.26 (1H, s),
5.74 (1H, br s), 6.88 (1H, t, J H-F ) 75.3 Hz), 6.98-7.16 (3H,
m), 7.35 (1H, J ) 2.2, 7.2 Hz); 13C NMR (CDCl3, 50 MHz) δ
10.45 (CH3), 19.43 (CH3), 19.56 (CH3), 22.76 (CH2), 35.71 (CH),
50.76 (CH3), 62.89 (CH2), 68.47 (CH2), 72.79 (CH2), 102.58 (C),
102.70 (C), 116.97 (CH, t, J ) 255.0 Hz, OCHF2), 118.04 (CH),
124.96 (CH), 127.57 (CH), 131.69 (CH), 138.31 (C), 144.37 (C),
144.68 (C), 149.43 (C), 167.50 (C), 168.05 (C); MS m/z 439 (M+);
mp 101-103 °C; [R]20 +63.2 (c 1.0, MeOH); 1H NMR (CDCl3,
D
200 MHz) δ 1.29 (3H, d, J ) 7.0 Hz), 2.19 (3H, s), 2.22 (3H, s),
3.51 (3H, s), 4.96 (1H, quintet, J ) 7.0 Hz), 5.03 (1H, s), 5.65
(1H, br s), 6.51 (1H, dd, J H-F ) 69.8, 79.6 Hz), 6.51 (1H, br d,
J ) 7.0 Hz), 6.00-7.37 (9H, m); 13C NMR (50 MHz, CDCl3 +
CD3OD) δ 17.29 (CH3), 18.38 (CH3), 21.51 (CH3), 33.69 (CH),
48.66 (CH), 50.31 (CH3), 100.07 (C), 105.65 (C), 116.8 (CH, dd,
J ) 254.4, 259.4 Hz, OCHF2), 117.79 (CH), 125.46 (two CH
from the phenyl), 126.16 (CH), 126.49 (CH), 127.67 (CH),
128.04 (two CH from the phenyl), 130.52 (CH), 138.85 (C),
139.73 (C), 143.40 (C), 146.53 (C), 147.03 (C), 167.67 (C),
168.34 (C). MS m/z 456 (M+); HRMS calcd for C25H26F2N2O4
456.1861, found 456.1860. This isomer was the first to elute
from the C18 column.
HRMS calcd for
439.1800.
C
22H27NO6F2 (M+) m/z 439.1806, found
(+)-3-Met h yl 5-(2-P r op oxyet h yl) (4S)-4-[2-(Diflu or o-
m eth oxy)p h en yl]-2,6-d im eth yl-1,4-d ih yd r o-3,5-p yr id in e-
d ica r boxyla te ((+)-(S)-1): yield 45 mg (68%) as a yellow oil;
1
62% ee; [R]20 +13.0 (c 1.0, CHCl3); the H NMR (CDCl3, 200
D
MHz) and mass spectral data were identical to those described
for (-)-(R)-1; HRMS calcd for C22H27NO6F2 (M+) m/z 439.1806,
found 439.1801.
Meth yl (4R)-4-[2-(Diflu or om eth oxy)ph en yl]-2,6-dim eth -
yl-5-({[(1R)-1-ph en yleth yl]am in o}car bon yl)-1,4-dih ydr o-3-
p yr id in eca r boxyla te ((R,R)-(-)-7): yield 29 mg (16%) as
colorless needles from a mixture of CHCl3 and hexane; mp
142-145 °C; [R]20 -112.2 (c 1.0, MeOH) or [R]20 -146.0 (c
(+)-(S)-1 fr om (+)-(R)-5b. To a stirred solution of 91 mg
(0.26 mmol) of (+)-(R)-5b in 0.2 mL of dry DMF was added
0.107 mL (0.77 mmol) of triethylamine at room temperature.
After the solution was stirred for 30 min, 0.053 mL (0.46 mmol)
of 2-propoxyethanol and 64 mg (0.28 mmol) of 2-chlorometh-
ylpyridinium iodide were added, and the reaction mixture was
stirred overnight. The reaction mixture was diluted with water
and extracted with dichloromethane two times. The organic
layer washed with water twice, dried over MgSO4, and
evaporated. The residue was flash chromatographed on silica
gel with petroleum ether (bp 40-60 °C)/dichloromethane/
isopropyl alcohol (5:5:1) to give 53 mg (58%) of unreacted (+)-
(R)-5b and 25 mg (22%) of (+)-(S)-1 as a yellow oil: 71% ee;
D
D
1.0, CHCl3), 1H NMR (CDCl3, 200 MHz) δ 1.40 (3H, d, J ) 7.0
Hz), 2.16 (3H, s), 2.20 (3H, s), 3.53 (3H, s), 4.96 (1H, quintet),
5.06 (1H), 5.82 (1H, br s), 6.42 (1H, dd, J H-F ) 70.2, 79.2 Hz),
6.52 (1H, br d, J ) 7.0 Hz), 6.88-7.33 (9H, m); 13C NMR
(CDCl3, 50 MHz) 19.36 (CH3), 19.92 (CH3), 22.17 (CH3), 33.69
(CH), 49.07 (CH), 50.94 (CH3), 101.87 (C), 105.74 (C), 116.8
(CH, dd, J ) 254.1; 260.2 Hz, OCHF2), 118.05 (CH), 125.92
(two CH from the phenyl), 126.68 (two CH from the phenyl),
128.15 (CH), 128.30 (two CH from the phenyl), 131.04 (CH),
139.11 (C), 140.98 (C), 144.04 (C), 145.74 (C), 146.51 (C),
166.56 (C), 168.00 (C); MS m/z 456 (M+); HRMS calcd for
[R]20 +16.6 (c 1.0, CHCl3). The 1H NMR and mass spectral
D
data were identical to those described for (-)-(R)-1 above.
Please note: (+)-(R)-5b was obtained from another CRL-
catalyzed hydrolysis of 6f where the degree of conversion was
higher than 50%.
C
25H26F2N2O4 456.1861, found 456.1863. This isomer was the
second to elute from the C18 column.
Cr ysta l d a ta for com p ou n d (R,S)-(+)-7: C25H26F2N2O4·
CHCl3, Mr ) 575.85, colorless crystal (0.05 × 0.10 × 0.30 mm),
orthorhombic, space group P212121 (no. 19) with a ) 7.8831(10)
Å, b ) 14.619(2) Å, c ) 23.101(3) Å, V ) 2662.2(6) Å3,
Z ) 4, Dx ) 1.437 g cm-3, 17 412 reflections measured, 6034
independent, Rint ) 0.0651 (1.5° < θ < 27.5°, T ) 150 K,
Mo KR radiation, λ ) 0.71073 Å) on a Nonius KappaCCD
diffractometer on rotating anode. The structure was solved
by automated direct methods (SHELXS86) and refined on F2
(SHELXL-97) for 344 parameters. Refinement converged at a
final wR2 value of 0.1415, R1 ) 0.0578 (for 3626 reflections
with I > 2σ(I)), S ) 1.061. The N-H hydrogen atom coordi-
nates were included as parameters in the refinement; all other
hydrogen atoms were included on calculated positions, riding
on their carrier atoms. A final difference Fourier showed no
(-)-(R)-1 fr om (-)-(S)-5b. To a stirred solution of 77 mg
(0.22 mmol) of (-)-(R)-5b in 0.2 mL of dry DMF at 0 °C was
added 0.064 mL (0.88 mmol) of SOCl2, after which the reaction
mixture was allowed to come to room temperature. After the
solution was stirred for 2 h, 0.05 mL (0.44 mmol) of 2-pro-
poxyethanol was added, and the reaction mixture was stirred
for another 1 h. The reaction mixture was diluted with water
and extracted with chloroform. The organic layer was washed
with water (twice) and brine, dried over MgSO4, and evapo-
rated. The residue was flash chromatographed on silica gel
with ethyl acetate/petroleum ether (bp 40-60 °C) (2:3) and
purified again on a TLC silica plate with petroleum ether (bp
40-60 °C)/chloroform/isopropyl alcohol (10:1:1) to give 43 mg
(45%) of (-)-(R)-1 as a yellow oil: 89% ee; [R]20 -18.7 (c 1.0,
residual density outside -0.61 and 0.48 e Å-3
.
D
CHCl3). The 1H NMR (CDCl3, 200 MHz) and mass spectral
data were identical to those described for (-)-(R)-1. HRMS
calcd for C22H27F2NO6 439.1806, found 439.1800. Please note:
the starting material (-)-(R)-5b was obtained from another
CRL-catalyzed hydrolysis of 6f where the degree of conversion
was higher than 50%.
Ack n ow led gm en t. Financial support by the Coper-
nicus program (ERB-CIPA-CT 94 0121), NATO (Link-
age grant LST.CLG 974948), The Netherlands Ministry
of Agriculture, Nature Management and Fisheries (IAC

410 J . Org. Chem., Vol. 67, No. 2, 2002
Sobolev et al.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 1, 4a ,b, 5b, 6a -g, (+)-(R,R)-7,
grant), the Ph.D. program of Wageningen University
and a Ph.D. Grant of the Latvian Council of Science are
gratefully acknowledged. This work was supported in
part (A.L.S.) by the Council for Chemical Sciences of
The Netherlands Organization for Scientific Research
(CW-NWO). We are indebted to Mr. A. van Veldhuizen
for recording the NMR spectra, to Mr. C. J . Teunis and
Mr. H. J ongejan for the mass spectral analyses, and to
Mr. E. J . C. van der Klift and Emma Sarule for the
elemental analyses.
1
(-)-(R,S)-7 and a copy of the H NMR spectrum of compound
5a ; a Crystallographic Information File of compound (+)-
(R,S)-7; an ORTEP(PLATON) plot of (+)-(R,S)-7, drawn at
50% probability level; and a drawing of the crystal lattice
structure of this compound. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0104025