(2S,3R,4S,5R)-Diethyl 2-(10,10-dimethyl-3,3-dioxo-3λ6- thia-4-azatricyclo[5.2.1.01'5]decan-4-ylcarbonyl)5-phenylpyrrolidine- 3,4-dicarboxylate: A novel isomorphous-by-addition compound

Article abstract of DOI:10.1107/S0108270108040584

A structural study was undertaken to confirm the relative conformation of the 3,4-ester groups, given that the absolute configuration was established by the stereochemistry of the starting (+)-camphor enantiomer. Benzaldehyde was dissolved in tetrahydrofu

Full text of DOI:10.1107/S0108270108040584

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
cally the potential of chiral auxiliary-assisted 1,3-dipolar
cycloaddition of azomethine ylids to various dipolarophiles
(see first reaction scheme).
ISSN 0108-2701
Our work sought to capitalize upon the findings of Garner
and co-workers (Garner & Kaniskan, 2005; Garner et al., 2001,
2006) and others (Padwa et al., 1985), who demonstrated that a
diastereofacial bias was indeed possible utilizing a chiral
auxiliary on an ylid dipole. The synthetic route to (I)
employed the glycyl sultam chiral auxiliary, (2), which was
prepared from enantiomerically pure (+)-camphor 10-sulfonic
acid (Davis et al., 1988; Oppolzer et al., 1989; Hoppe &
Beckmann, 1979). The 1,3-dipolar cycloaddition was carried
out with diethyl maleate and benzaldehyde in the presence of
silver acetate (see second reaction scheme) to yield the title
compound, (I). This structural study was undertaken to
confirm the relative conformation of the 3,4-ester groups,
given that the absolute configuration was established by the
stereochemistry of the starting (+)-camphor enantiomer. In
this case, the absolute configuration was successfully
confirmed by the observed X-ray anomalous dispersion effects
[4033 Bijvoet pairs, Flack x parameter = 0.00 (7) (Flack, 1983);
Hooft y parameter = 0.00 (4) (Hooft et al., 2008)].
(2S,3R,4S,5R)-Diethyl 2-(10,10-di-
methyl-3,3-dioxo-3k6-thia-4-azatri-
cyclo[5.2.1.01,5]decan-4-ylcarbonyl)-
5-phenylpyrrolidine-3,4-dicarboxyl-
ate: a novel isomorphous-by-addition
compound
Graeme J. Gainsford,* Simon P. H. Mee and Andreas
Luxenburger
Industrial Research Limited, PO Box 31-310, Lower Hutt, New Zealand
Correspondence e-mail: g.gainsford@irl.cri.nz
Received 2 December 2008
Accepted 2 December 2008
Online 13 December 2008
The title compound, C27H36N2O7S, (I), is isomorphous by
addition with the dimethyl ester analogue [Garner, Dogan,
Youngs, Kennedy, Protasiewicz & Zaniewski (2001). Tetra-
hedron, 57, 71–85], (II), by replacing two methyl ester H atoms
with two methyl groups. With the exception of the conforma-
tion of one of the ester groups, the molecules are almost
superimposable. Likewise, apart from a slightly larger c axis in
(I), few differences in the cell packing of (I) and (II) are found,
with both dominated by the same C—Hꢀ ꢀ ꢀO hydrogen bonds.
Full synthetic and spectroscopic details of (I) are given. The
molecular synthesis is important as an example of chiral
auxiliary-assisted 1,3-dipolar cycloaddition of an azomethine
ylid.
Comment
Pyrrolidine substructures are found in many biologically
active compounds, leading to a point where there is a clear
need for an arsenal of ‘decorated’ scaffolds that will enable
modern combinatorial access to refined libraries of
compounds for (bio)assay and drug development (Schreiber,
2000). The title compound, (I), was prepared as part of a
The asymmetric unit of (I) is shown in Fig. 1, with selected
dimensions compared with the dimethyl ester analogue, (II)
[Garner et al., 2001; Cambridge Structural Database (Version
5.29, with November 2007 updates; Allen, 2002) refcode
MIPPOQ], in Table 2. The cell dimensions, molecular packing
and alignment of (I) are closely related to those of the
dimethyl analogue (Figs. 2 and 3). As the opposite enantiomer
was reported for (II), all comparisons here involve using the
inverted molecule [conversion (x, 1 ꢁ y, z)] for (II); atom
labelling here does not match the arbitrary labelling found in
the archived CIF of (II) (there were no labels given in the
original paper). The two structures are isomorphous through
replacement of one H atom of each of the ester methyl groups
with a methyl group (Fig. 2). To the best of our knowledge, this
is a novel case; more usual isomorphous organic crystals
involve larger group ‘interchanges’, such as Cl for CH3 in 2,20-
derivatives of 50,50-dipropoxybenzidines (El-Shafei et al., 2004)
broader research programme designed to explore preparative
routes to chiral pyrrolidine scaffolds and to address specifi-
Acta Cryst. (2009). C65, o15–o18
doi:10.1107/S0108270108040584
# 2009 International Union of Crystallography o15

organic compounds
Figure 1
The molecular structure of the asymmetric unit of (I). Displacement
ellipsoids are drawn at the 30% probability level and H atoms are shown
as small spheres of arbitrary radii.
or, more commonly, of related transition metals such as CoII/
NiII (e.g. Li et al., 2007). It is possible that our literature survey
has not picked up previous cases of this phenomenon, though
we note there have been many studies of polymorphs of the
Figure 2
Overlapped view of (I) (thick bonds, shaded) and the inverted
enantiomer of (II) (thin bonds). Selected labels are given. Note the
conformational difference along the C4—C9—O5—C10—C11 ester
chain.
´
´
same compound (e.g. Kalman et al., 2004).
The definition of isomorphicity is well tested by these two
structures. It is obvious that (I) and (II) have different
conformations with respect to rotation about the C4—C9
bond, as shown by the dihedral angles (Table 2) and in Fig. 2.
Minor ‘displacement’ differences involving the phenyl ring
(C12–C17) and the location of the N1 H atom are noted,
although in the latter case the position in (II) was a calculated
one rather than its refined position in (I). Indeed, the position
of the N1 H atom (H1) in (I) seems to fulfil the distance
criteria, but not the expected N—Hꢀ ꢀ ꢀO interaction angle
criteria based on normal intermolecular interactions [at
110 (2)ꢂ; see Desiraju & Steiner, 1999]. Atom H1 is also under
the influence of atom O4, with an intramolecular H1ꢀ ꢀ ꢀO4
Figure 3
˚
distance of 2.60 (4) A. The five- and six-membered rings in (I)
Cell packing diagram of (I) and the inverted cell of (II), using the same
bond styles as in Fig. 2. The axes of (I) and (II) are unprimed and primed,
respectively. The view with overlap of the ac diagonal and the b axis
illustrates that the cell expansion is mainly along the c axis in (I).
and (II), as expected from the close overlap (Fig. 2), are
almost identical, e.g. the N1/C2–C5 ring in (I) is in an envelope
conformation, with Cremer & Pople (1975) parameters Q2 =
ꢂ
˚
0.391 (2) A and ’2 = 150.3 (3) , whilst the inverted molecule of
˚
(II) has a slight twist on C5—N1, with Q2 = 0.397 (4) A and
conformation is rotated; see Fig. 2). One final difference
involves a close intramolecular interaction in (I) (entry 9,
Table 2) which is missing from (II). The remaining five inter-
and intramolecular interactions (Table 1) are duplicated in
both structures, under the same symmetry designations, with
’2 = 160.8 (6)ꢂ. The S1/N2/C18/C19/C24 rings are similar, each
being in a twisted C18—C19 bond conformation.
Examination of Fig. 3 shows how the a and b cell axes of (I)
and (II) are similar, with a relatively minor alteration in the
direction and size of the c axis, consistent with the molecular
orientation and addition of the extra methyl group. The
molecules are in the same relative orientation in the unit cells
and details of the three-dimensional cell packing illustrate
only minor differences between the two cells. The interactions
are mainly of the C—Hꢀ ꢀ ꢀO type (the acceptor O atom being
either a carboxyl O atom or an O atom bound to S), with one
C—Hꢀ ꢀ ꢀꢀ interaction (Table 1). We note the differences first.
The orientation of the O5—C10 bond in (II) allows a C10—
Hꢀ ꢀ ꢀO2 interaction which is missing in (I). Likewise, the
orientation and presence of methyl C8 only in (I) sets up an
interaction with O2 (entry 2, Table 1). The phenyl C16—
H16ꢀ ꢀ ꢀO5 interaction in (I) (entry 3, Table 1) is found in (II),
but changed, with the acceptor atom being O4 (since the ester
˚
an average difference in Hꢀ ꢀ ꢀacceptor distance of 0.10 (7) A.
Similar methylene C—Hꢀ ꢀ ꢀO
S distances have been
˚
observed before (e.g. Hꢀ ꢀ ꢀO = 2.330 A; James et al., 2005).
In summary, the relationship between the title compound,
(I), and the antipode of the previously reported compound,
(II), can be described as being a novel case of ‘isomorphous by
addition’, given the subtle though distinct differences in the
molecules and packing.
Experimental
Benzaldehyde (69.0 ml, 0.68 mmol) was dissolved in tetrahydrofuran
(1 ml) and added to a solution of the glycyl sultam (2) (Davis et al.,
1988; Oppolzer et al., 1989; Hoppe & Beckmann, 1979) (185 mg,
ꢃ
o16 Gainsford et al.
C27H36N2O7S
Acta Cryst. (2009). C65, o15–o18

organic compounds
0.68 mmol) in tetrahydrofuran (1 ml) (see second reaction scheme in
Comment). Diethyl maleate (329 ml, 2.04 mmol) was added to the
reaction solution, followed by silver acetate (5.70 mg, 34.0 mmol).
After being stirred under argon in the dark for 3 h, the reaction
mixture was diluted with dichloromethane (100 ml) and washed with
saturated ammonium chloride solution (50 ml). The organic layer was
dried over magnesium sulfate and the solvent was removed under
reduced pressure. The residue was purified by flash column chro-
matography (silica gel, ethyl acetate–petroleum spirit 3:7 v/v, then 4:6
and 1:1 v/v) to give (I) (182 mg, 50%) as a pale-yellow solid. Analysis:
RF = 0.18 (ethyl acetate–petroleum spirit 3:7 v/v); [ꢁ]22 = ꢁ39.9 (c =
1.5, CHCl3); HRMS (ES+): calculated for C27H36N223NaO7S (MNa+):
555.2141; found: 555.2127; microanalysis requires: C 60.88, H 6.81,
Table 2
Comparison of selected bond lengths and angles (A, ) in (I) and (II).
ꢂ
˚
(I)
(II)
S1—O6
S1—N2
O3—C6
O3—C7
N1—C2
1.426 (2)
1.6733 (18)
1.335 (3)
1.463 (3)
1.473 (3)
1.423 (4)
1.687 (3)
1.341 (5)
1.441 (5)
1.454 (5)
O6—S1—O7
C1—N2—S1
116.45 (15)
124.26 (16)
116.4 (2)
122.8 (3)
N2—C1—C2—N1
O1—C1—C2—C3
S1—N2—C1—O1
C2—C3—C6—O3
C3—C6—O3—C7
C6—O3—C7—C8
C2—C3—C6—O2
C5—C4—C9—O5
C10—O5—C9—C4
C5—C4—C9—O4
148.7 (2)
90.5 (3)
148.2 (3)
89.2 (5)
151.1 (4)
153.6 (2)
ꢁ166.8 (2)
175.5 (2)
ꢁ129.8 (3)
15.8 (3)
ꢁ104.7 (2)
177.9 (2)
73.7 (3)
1
N 5.26%; found: C 60.57, H 6.99, N 5.17%. For details of H and
13C NMR data, see the archived CIF. The crystallization solvent was
ethanol.
ꢁ165.2 (3)
ꢁ179.4 (3)
17.1 (6)
69.8 (4)
Crystal data
ꢁ177.7 (4)
ꢁ107.4 (5)
3
˚
C27H36N2O7S
Mr = 532.64
Monoclinic, P21
V = 1363.25 (14) A
Z = 2
Mo Kꢁ radiation
ꢃ = 0.17 mmꢁ1
T = 122 (2) K
˚
a = 13.7194 (9) A
˚
b = 6.9464 (4) A
parameter. All C-bound H atoms were constrained to their expected
˚
geometries, with C—H = 0.98, 0.99 or 1.00 A. Methyl H atoms were
˚
c = 14.9703 (9) A
0.45 ꢄ 0.24 ꢄ 0.06 mm
ꢂ = 107.148 (2)ꢂ
refined with Uiso(H) = 1.5Ueq(C); all other H atoms were refined with
Uiso(H) = 1.2Ueq(C).
Data collection
Data collection: SMART (Bruker, 2006); cell refinement: SAINT
(Bruker, 2006); data reduction: SAINT and SADABS (Bruker, 2006);
program(s) used to solve structure: SHELXS97 (Sheldrick, 2008);
program(s) used to refine structure: SHELXL97 (Sheldrick, 2008);
molecular graphics: ORTEP-3 (Farrugia, 1997) and Mercury (Macrae
et al., 2006); software used to prepare material for publication:
SHELXL97, PLATON (Spek, 2003) and Mercury.
Bruker–Nonius APEXII CCD area-
detector diffractometer
Absorption correction: multi-scan
(Blessing, 1995)
Tmin = 0.665, Tmax = 1.000
(expected range = 0.658–0.990)
28357 measured reflections
9045 independent reflections
6778 reflections with I > 2ꢄ(I)
Rint = 0.058
Refinement
R[F2 > 2ꢄ(F2)] = 0.056
wR(F2) = 0.152
S = 1.03
8865 reflections
342 parameters
1 restraint
H atoms treated by a mixture of
independent and constrained
refinement
The authors thank Dr J. Wikaira of the University of
Canterbury for her assistance in the data collection.
ꢁ3
˚
Áꢅmax = 0.44 e A
ꢁ3
˚
Áꢅmin = ꢁ0.23 e A
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: SK3280). Services for accessing these data are
described at the back of the journal.
Absolute structure: Flack (1983),
with 4033 Friedel pairs
Flack parameter: 0.00 (7)
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Hydrogen-bond geometry (A, ) for (I).
ꢂ
˚
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Cg1 represents the centroid of the C12–C17 phenyl ring.
D—Hꢀ ꢀ ꢀA
D—H
Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA
D—Hꢀ ꢀ ꢀA
C7—H7Bꢀ ꢀ ꢀO1i
C8—H8Bꢀ ꢀ ꢀO2ii
C16—H16ꢀ ꢀ ꢀO5iii
C24—H24Aꢀ ꢀ ꢀO6iv
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0.99
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159
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110 (2)
103
164
C7—H7Aꢀ ꢀ ꢀO2
C26—H26Bꢀ ꢀ ꢀO2
1
2
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1
2
1
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1
2
y ꢁ ; ꢁz þ 1; (v) ꢁx; y þ ; ꢁz þ 1; (vi) ꢁx; y þ ; ꢁz þ 2.
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ꢃ
Acta Cryst. (2009). C65, o15–o18
Gainsford et al. C27H36N2O7S o17

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´ ´ ´ ´ ´
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ꢃ
o18 Gainsford et al.
C27H36N2O7S
Acta Cryst. (2009). C65, o15–o18