Franssen, M.C.R.

Jongejan, H.

Kooijman, H.

Sobolev, A.

Spek, A.L.

Acta Crystallographica Section E

English

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Universiteit Utrecht

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3-methyl 5-[(S)-2-methylbutyl] 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Utrecht University Repository

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3-Methyl 5-[(S)-2-methylbutyl] 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Wageningen Yield 

organic papers
o532 Huub Kooijman et al.  C22H27F2NO5 DOI: 10.1107/S1600536802006487 Acta Cryst. (2002). E58, o532±o534
Acta Crystallographica Section E
Structure Reports
Online
ISSN 1600-5368
3-Methyl 5-[(S)-2-methylbutyl] 4-[2-(difluoro-
methoxy)phenyl]-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate
Huub Kooijman,a* Anthony L.
Spek,a Arkadij Sobolev,b²
Hugo Jongejanc and
Maurice C. R. Franssenc
aBijvoet Center for Biomolecular Research,
Department of Crystal and Structural Chemistry,
Utrecht University, Padualaan 8, 3584 CH
Utrecht, The Netherlands, bLatvian Institute of
Organic Synthesis, Aizkraukles 21, Riga
LV-1006, Latvia, and cLaboratory of Organic
Chemistry, Wageningen University,
Dreijenplein 8, 6703 HB Wageningen, The
Netherlands
² Visiting scientist at Wageningen University.
Correspondence e-mail:
h.kooijman@chem.uu.nl
Key indicators
Single-crystal X-ray study
T = 150 K
Mean (C±C) = 0.005 AÊ
R factor = 0.046
wR factor = 0.095
Data-to-parameter ratio = 8.4
For details of how these key indicators were
automatically derived from the article, see
http://journals.iucr.org/e.
# 2002 International Union of Crystallography
Printed in Great Britain ± all rights reserved
The crystal structure of the title compound, C22H27F2NO5,
contains two diastereomers, related by a pseudo-glide plane.
Owing to the addition of the di¯uoromethoxyphenyl moiety,
the dihydropyridine ring is somewhat deformed from
planarity. The packing involves a two-dimensional network
created by CÐH  O and NÐH  O hydrogen bonds.
Comment
In order to investigate the stereochemical course of the
Candida rugosa lipase mediated kinetic resolution of 3-acyl-
oxymethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylates, a
derivative containing a second chiral centre of known
con®guration was prepared. This would allow the determin-
ation of the relative con®guration of the chiral centre at C4
(labelled C3 and C25 in Fig. 1). The enzymatically prepared
carboxylic acid (1) was esteri®ed to (S)-2-methyl-1-butanol,
giving the title compound, (2), whose crystal structure has
been determined. However, since the starting material was not
entirely stereochemically pure, there was a risk that the two
diastereomers would preferentially crystallize together. This
indeed proved to be the case, as is shown in Fig. 1. Later,
compound (2) was prepared in stereochemically pure form.
Unfortunately, we could not obtain crystals suitable for a
structure determination from this material.
The asymmetric unit contains two molecules, which are
diastereomers with con®guration (R,S) and (S,S) at (C3,C9)
and (C25,C31), respectively. These con®gurations have been
assigned with reference to the known (S)-con®guration of
atoms C9 and C31. The diastereomers have adopted confor-
mations which are related by an inversion operation, with the
exception of the 2-methylbutyl moiety. This is illustrated in
Fig. 2, which displays a ®t of molecule (1) and the inverted
molecule (2). In the crystal, the molecules are related by a
pseudo-c-glide plane, with the exception of the 2-methylbutyl
moiety. The unit cell displays a pseudo-monoclinic geometry,
with the pseudo-glide plane parallel to the a and c axes. The
best-®t between the molecules is obtained by a rotation of
ÿ176 over the rotary-inversion axis [ÿ0.018, ÿ1.000, 0.042],
combined with a shift of 7.226 AÊ (i.e. 0.48c) in the direction
Received 27 March 2002
Accepted 11 April 2002
Online 19 April 2002
[0.002, ÿ0.096, ÿ1.000]. The unit weight r.m.s. ®t is 0.31 AÊ ,
with the largest deviations for atoms C9, C10 and C12 of
molecule (1).
Addition of the di¯uoromethoxyphenyl moiety to the di-
hydropyridine ring results in a slight deformation from
planarity towards a sofa conformation in both diastereomers.
The relevant asymmetry parameters (Duax & Norton, 1975)
are Cs[N1] = 2.2 (4)
 for molecule (1) and Cs[N2] = 1.8 (4)
for molecule (2); all other asymmetry parameters are at least
10. The total puckering amplitude (Cremer & Pople, 1975) of
the dihydropyridine ring is 0.177 (3) AÊ in molecule (1) and
0.173 (3) AÊ in molecule (2). The phenyl rings show total
puckering amplitudes of 0.029 (3) and 0.019 (3) for molecules
(1) and (2), respectively. For these rings, all asymmetry para-
meters are less then 5. Hydrogenation of the pyridine N atom
apparently has no in¯uence on its hybridization (sp2) or the
planarity of this part of the six-membered ring. The bond
distances in the dihydropyridine rings indicate delocalization
of the formal double bonds of the C CÐNÐC C fragment
(see Table 1).
Crystal packing involves the formation of chains, parallel to
the c axis, consisting of molecules connected by NÐH  O
hydrogen bonds (see Fig. 3 and Table 2). Each chain consists
of an alternation of both diastereomers. The unitary graph set
is DD, the binary graph set is C22(12) (Bernstein et al., 1995).
Two neighbouring chains are connected by CÐH  O
hydrogen bonds linking the F2OCH moiety to the O C
acceptor of the carboxylate moiety. These hydrogen bonds
form links between equal stereoisomers. Both types of
hydrogen bond together create a two-dimensional network of
hydrogen-bonded molecules, with main axes a and c.
Experimental
The title compound was prepared from 284 mg (0.808 mmol) of 4-[2-
(di¯uoromethoxy)phenyl]-5-(methoxycarbonyl)-2,6-dimethyl-1,4-di-
hydro-3-pyridinecarboxylic acid, (1), by reaction of its acid chloride
with 0.262 ml (2.41 mmol) of (S)-2-methyl-1-butanol, using the
Acta Cryst. (2002). E58, o532±o534 Huub Kooijman et al.  C22H27F2NO5 o533
organic papers
Figure 1
View of the title compound, with the atom-numbering scheme. H atoms
have been omitted for clarity. Displacement ellipsoids for non-H atoms
are drawn at the 50% probability level. (a) molecule (1), the (R,S)-
stereoisomer; (b) molecule (2), the (S,S)-stereoisomer.
Figure 2
Fit of molecule (1) [con®guration (R,S), green] on the inverted molecule
(2) [con®guration (R,R), red; NB this con®guration is not present in the
crystal]. H atoms have been omitted for clarity.
Figure 3
NÐH  O bonded chains (parallel to c) of alternating diasteromers,
linked into a two-dimensional network by soft CÐH  O interactions
(parallel to a).
organic papers
o534 Huub Kooijman et al.  C22H27F2NO5 Acta Cryst. (2002). E58, o532±o534
method of Sobolev et al. (2002). The crude product was ¯ash chro-
matographed on silica gel with ethyl acetate/petroleum ether (b.p.
313±333 K, 1:3), puri®ed again on silica gel with petroleum ether (b.p.
313±333 K)/chloroform/isopropyl alcohol (20:5:2) and crystallized
from ethanol to give 276 mg (81%) as pale-yellow crystals: m.p. 406±
407 K; 1H NMR (CDCl3, 200 MHz):  0.83 (t, 3H, J = 7.3 Hz, CH3),
0.85 (d, 3H, J = 7.4 Hz, CH3), 0.95±1.16 (m, 1H, CH2), 1.19±1.40 (m,
1H, CH2), 1.60±1.76 (m, 1H, CH), 2.28 (s, 3H, CH3), 2.30 (s, 3H, CH3),
3.59 (s, 3H, CH3), 3.77 (dd, 1H, J = 10.8, 6.9 Hz, CH2), 3.89 (dd, 1H, J
= 10.8, 6.4 Hz, CH2), 5.25 (s, 1H, CH), 5.60 (br s, 1H, NH), 6.46 (dd,
1H, JHÐF = 75.6, 75.8 Hz, OCHF2), 6.95±7.13 (m, 3H, Ar±H), 7.35 (dd,
1H, J = 2.2, 7.3 Hz, ArÐH). MS m/z: 423 (M+, 9), 352 (10), 336 (5),
308 (9), 284 (6), 281 (15), 280 (100), 211 (4), 210 (36); HRMS calcu-
lated for C22H27F2O5: 423.1857, found 423.1853. Crystals suitable for
X-ray analysis were obtained by recrystallization from hexane
containing a small amount of methanol.
Crystal data
C22H27F2NO5
Mr = 423.45
Triclinic, P1
a = 8.2340 (16) AÊ
b = 8.7827 (18) AÊ
c = 14.9145 (18) AÊ
 = 89.299 (11)
 = 78.697 (11)
 = 89.906 (7)
V = 1057.6 (3) AÊ 3
Z = 2
Dx = 1.330 Mg m
ÿ3
MoKa radiation
Cell parameters from 367 re¯ections
 = 1.6±25.0
 = 0.11 mmÿ1
T = 150 K
Needle, colourless
0.3  0.1  0.1 mm
Data collection
Nonius KappaCCD area-detector
diffractometer
’ scans, and ! scans with  offsets
Absorption correction: none
21160 measured re¯ections
4617 independent re¯ections
3257 re¯ections with I > 2(I)
Rint = 0.084
max = 27.5

h = ÿ10! 10
k = ÿ11! 11
l = ÿ19! 19
Re®nement
Re®nement on F 2
R[F 2 > 2(F 2)] = 0.046
wR(F 2) = 0.095
S = 1.02
4617 re¯ections
549 parameters
H atoms treated by a mixture of
independent and constrained
re®nement
w = 1/[2(Fo
2) + (0.0468P)2]
where P = (Fo
2 + 2Fc
2)/3
(/)max = 0.002
max = 0.17 e AÊ
ÿ3
min = ÿ0.23 e AÊ ÿ3
Table 1
Selected geometric parameters (AÊ , ).
N1ÐC1 1.381 (4)
N1ÐC5 1.374 (5)
C1ÐC2 1.354 (4)
C2ÐC3 1.532 (5)
C3ÐC4 1.521 (5)
C4ÐC5 1.360 (4)
N2ÐC23 1.372 (4)
N2ÐC27 1.371 (4)
C23ÐC24 1.362 (4)
C24ÐC25 1.522 (5)
C25ÐC26 1.520 (5)
C26ÐC27 1.356 (4)
C7ÐO2ÐC8ÐC9 ÿ159.7 (3)
O2ÐC8ÐC9ÐC10 ÿ57.5 (4)
C8ÐC9ÐC10ÐC11 173.1 (4)
C29ÐO7ÐC30ÐC31 ÿ170.7 (3)
O7ÐC30ÐC31ÐC32 ÿ60.9 (3)
C30ÐC31ÐC32ÐC33 174.9 (3)
Table 2
Hydrogen-bonding geometry (AÊ , ).
DÐH  A DÐH H  A D  A DÐH  A
N1ÐH1  O6i 0.96 (4) 2.13 (4) 3.080 (4) 171 (4)
N2ÐH2  O1 0.88 (4) 2.19 (4) 3.060 (3) 171 (4)
C19ÐH19  O4ii 1.00 2.20 3.155 (5) 159
C41ÐH41  O9ii 1.00 2.24 3.160 (4) 153
Symmetry codes: (i) x; y; 1 z; (ii) xÿ 1; y; z.
Owing to the absence of signi®cant anomalous dispersion, the
absolute con®gurations could not be determined reliably. The
con®guration of C9 and thereby also that of C31 was set equal to S,
consistent with the starting materials used. The measured re¯ections
reduced to 9040 unique re¯ections with an Rint of 0.074. After
merging of the Friedel pairs, the 4617 re¯ections reported above
remained. H atoms of the NÐH moieties were located in a difference
Fourier map and their coordinates and isotropic displacement para-
meters were re®ned. All other H atoms were included at calculated
positions, riding on their carrier atoms. Isotropic displacement
parameters of H atoms bonded to C atoms were coupled to the
equivalent isotropic displacement parameter of their carrier atoms by
a ®xed factor of 1.5 (methyl H atoms) or 1.2 (other H atoms).
Data collection: COLLECT (Nonius, 1998); cell re®nement:
DENZO (Otwinowski & Minor, 1997); data reduction: DENZO;
program(s) used to solve structure: SHELXS86 (Sheldrick, 1985);
program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997);
molecular graphics: PLATON (Spek, 2002); software used to prepare
material for publication: PLATON.
This work was supported in part (ALS) by the Council for
the Chemical Sciences of the Netherlands Organization for
Scienti®c Research (CW-NWO).
References
Bernstein, J., Davis, R. E., Shimoni, L., & Chang, N.-L. (1995). Angew. Chem.
Int. Ed. Engl. 34, 1555±1573.
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354±1358.
Duax, W. L. & Norton, D. A. (1975). Atlas of Steroid Structures, Vol. 1. New
York: Plenum.
Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276,
Macromolecular Crystallography, Part A, edited by C. W. Carter Jr and R.
M. Sweet, pp. 307±326. New York: Academic Press.
Sheldrick, G. M. (1985). SHELXS86. University of GoÈ ttingen, Germany.
Sheldrick, G. M. (1997). SHELXL97. University of GoÈ ttingen, Germany.
Sobolev, A., Franssen, M. C. R., Vigante, B., Cekavicus, B., Zhalubovskis, R.,
Kooijman, H., Spek, A. L., Duburs, G. & de Groot, A. (2002). J. Org. Chem.
67, 401±410.
Spek, A. L. (2002). PLATON. Utrecht University, The Netherlands. URL:
http://www.Cryst.Chem.uu.nl/platon/.


COLLECT. Nonius BV,

Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by

3-Methyl 5-[(S)-2-methylbutyl] 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

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