1,3-Dipolar cycloadditions of a 2-oxoethanenitrile oxide derived from (2R)-bornane-10,2-sultam to electronically modified 4,4′-disubstituted stilbenes

Article abstract of DOI:10.1002/hlca.200800412

Thanks to its type-II dipole nature, we were able to demonstrate the higher reactivity of the SO₂/C=O syn-conformer for the uncatalyzed 1,3-dipolar cycloaddition of the 2-oxoethanenitrile oxide 2 derived from bornane-10,2-sultam to the symmetri

Full text of DOI:10.1002/hlca.200800412

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Helvetica Chimica Acta – Vol. 92 (2009)
1,3-Dipolar Cycloadditions of a 2-Oxoethanenitrile Oxide Derived from (2R)-
Bornane-10,2-sultam to Electronically Modified 4,4’-Disubstituted Stilbenes
by Jan Romanskia), Christian Chapuis*b)1), and Janusz Jurczak*a)b)
a) Department of Chemistry, University of Warsaw, Pasteura 1, PL-02-093 Warsaw
b) Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw
(phone: þ 41227803610; fax: þ 41227803334; e-mail: christian.chapuis@firmenich.com; phone:
þ 48226320578; fax: þ 48226326681; e-mail: jurczak@icho.edu.pl)
Thanks to its type-II dipole nature, we were able to demonstrate the higher reactivity of the SO2/
C¼O syn-conformer for the uncatalyzed 1,3-dipolar cycloaddition of the 2-oxoethanenitrile oxide 2
derived from bornane-10,2-sultam to the symmetric 4,4’-disubstituted trans-stilbenes 3a – 3i. The C(a)-si
dipolarophile py approach along the C¼O bond precludes the use of the steric rules formerly expressed
for this pseudo-C2-symmetric auxiliary. The observed diastereoselectivity is related to the electronic
nature of the dipolarophile and may be predicted on the basis of its spara Hammett constant. The absolute
configuration was based on the X-ray structure analysis of cycloadduct (4S,5S)-4b, which exhibits an SO2/
C¼O anti-conformation. Finally, the results obtained with cis-stilbene suggest a nonsynchronous
mechanism.
Introduction. – Resulting from dipole interactions, N-acyl-substituted (2R)-
bornane-10,2-sultam derivatives adopt essentially, in the solid state, the thermodynami-
cally more stable SO2/C¼O anti-periplanar conformation2). More than a decade ago,
we suggested that the syn-periplanar conformation could lead to a more reactive
species in solution, and thus could eventually participate during the course of the
reaction by displacing the anti/syn equilibrium3) [8][9]. This higher reactivity is
believed to result from a better electronic alignment between the C¼O moiety and the
N lone pair (lp), favoring delocalization on the sultam moiety through a generalized
anomeric stabilization of the N lp by the anti-periplanar S¼O s* MO [2]. Indeed, we
found that the DhN pyramidal height is directly correlated with the SꢀNꢀC¼O
dihedral angle and reach local and global minima near ca. 170 and ꢀ 108, respectively
[7][8]. For syn-periplanar conformations, where the C¼O is bisecting the O¼S¼O
angle, the SꢀNꢀC¼O torsion angle only varies from ca. ꢀ 19 to ꢀ 98 and the DhN
decreases from 0.133 to 0.066 ꢀ, respectively [7]. Alternatively, in the sterically less
constrained anti-conformation, this parameter decreases from ca. 0.40 to 0.11 ꢀ, for a
dihedral angle comprised between ca. 120 and 1708, respectively [7][8]. This widely
1
)
)
)
Present address: Firmenich SA, Corporate R&D Division, P.O. Box 239, CH-1211 Geneva 8.
For the first example of a syn-conformer chelated with TiCl4, see [1].
For the first example of a nonchelated syn-conformer of 1a, see [2]. For rare further syn-examples,
see [3], as well as [4 – 7]. These latter represent ca. 3% of the N-acyl-substituted (2R)-bornane-10,2-
sultam derivatives in the CCDC database (2008).
2
3
ꢁ 2009 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 92 (2009)
1057
used chiral auxiliary [10] was earlier recognized as a disguised pseudo-C2-symmetric
promoter, reminiscent of a 2,5-disubstituted pyrrolidine [11]. As a consequence, it is
particularly difficult to define whether the anti- or syn-conformer is responsible for the
observed induction in the absence of chelation. It is indeed only very recently, by
studying the asymmetric 1,3-dipolar cycloaddition of the 2-oxoethanenitrile oxide 2
derived from (2R)-bornane-10,2-sultam to symmetric alkenes, that we have been able
to demonstrate the higher reactivity of the SO2/C¼O syn-conformer syn-2 [6]. This
evidence is supported by the fact that similar differences of energies have been
calculated by means of a B3LYP/6-31G** DFT method [12] for the approaches of
conformer anti-2 to either the C(a)-si or -re faces of trans-stilbene ((E)-3c); on the
contrary, the C(a)-si approach of this dipolarophile to conformer syn-2 is favored, thus
leading preferentially to the (4S,5S)-cycloadduct 4c, as shown by the X-ray-analysis of
its syn-conformer [6]. We also calculated that the LUMO of conformer syn-2 is slightly
lower in energy, as compared to its anti-conformer, and thus should react preferentially
with electron-rich dipolarophiles. Alternatively, with a slightly higher HOMO energy,
the type-II4) dipole anti-2 should react faster with electron-poor dipolarophiles, such as
the unreported 4,4’-dinitrostilbene 3h, and thus result in a poorer diastereoselectivity.
To confirm our hypothesis, we electronically modified the dipolarophile trans-stilbene
(3c) at C(4) and C(4’), thus minimizing the steric requirements about the reactive
centers and maintaining the symmetry, in order to avoid the formation of regioisomers.
This comparative study is now presented in detail.
Results and Discussion. – Starting from the reported N-(glyoxyloyl)bornane-10,2-
sultam 1b [15], the obtained known crystalline aldoxime 1c [16] was treated with the
commercially available 4,4’-dimethoxystilbene 3a in the presence of N-chlorosuccin-
imide (NCS) and KHCO3 in CHCl3 [17], to afford cycloadduct 4a in 88% yield and
49% d.e. (Scheme, Table 1). The diastereoselectivity of the formation of 4a – 4i was
determined with the crude reaction mixtures by 500-MHz-1H-NMR analysis of the
major d (HꢀC(4)) appearing between d 4.72 and 4.82, with respect to that of the minor
(4R,5R)-stereoisomer resonating systematically at higher field (d ca. 4.48 – 4.58) [6],
with a ꢁ 2% precision5). When 4,4’-dimethylstilbene 3b [18] was used, we isolated
cycloadduct 4b in 87% yield and 43% d.e. The sense of induction was ascertained by an
X-ray crystal-structure analysis of the main stereoisomer (4S,5S)-4b (Fig. 1), after
purification by crystallization from hexane/AcOEt 1:1, thus corroborating our
previous results obtained with analogue (4S,5S)-4c [6].
To verify, by comparison with 3c [6], that this decreasing diastereoselectivity
originates from electronic rather than steric reasons, we tested the 4,4’-difluorostilbene
4
)
Dipoles 2 are of type II according to [13], meaning that the similarity of the dipole and
dipolarophile FMO energies implies that both the HOMO – LUMO or LUMO – HOMO
interactions are important [14]. The preference may, besides the electronic nature of the
dipolarophile, also depend on the electronic influence of 2, hence, for example, on its SO2/C¼O
anti- or syn-conformation.
The ds of HꢀC(5) similarly appear at d 5.51 – 5.67 and 5.48 – 5.63 for the (4S,5S)- and (4R,5R)-
stereoisomers 4a – 4i, respectively, but were not used for quantifications since they were not always
baseline-separated.
5
)

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme
i) NCS, CHCl3. ii) KHCO3, CHCl3, 208, 6 h.
Fig. 1. ORTEP Diagram of cycloadduct (4S,5S)-4b (arbitrary atom numbering). Ellipsoids are
represented at the 50% probability level.

Helvetica Chimica Acta – Vol. 92 (2009)
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Helvetica Chimica Acta – Vol. 92 (2009)
(3d) [19]6). In this case, the selectivity reached 45% d.e. (Table 1) which was confirmed
by 19F-NMR analysis. We then used 4,4’-dichlorostilbene (3e) [21] and isolated
cycloadduct 4e in 56% yield and 40% d.e. Dipolarophile 3f (R ¼ CF3) [22] was also
chosen as a quasi-isosteric analogue of 3b, and its selectivity diminished to 36% d.e., as
also confirmed by 19F-NMR analysis. Finally, as expected from a concurrent unselective
participation of conformer anti-2, the worst selectivity (24% d.e.) was observed with
the electronically most deficient dipolarophile 3g (R ¼ CN) [23]. In this specific case,
the reaction rate was so slow that dimerization of dipole 2 became a serious
contaminating side reaction, and 4g was isolated in only 20% yield after column-
chromatography (CC; SiO2) purification. We were unable to test 3h (R ¼ NO2) as an
inverse-electron-demand partner since we failed to synthesize it by the general
procedures as earlier described for analogous substrates [24]7). Furthermore, the
chemical yield obtained from 3f and the diastereoselectivity resulting from 3g did not
encourage us to continue pursuing this direction. At this point, to optimize the
selectivity, we revisited an electron-rich dipolarophile, by testing the dibenzyl ether 3i
(R ¼ PhCH2O) [26]; in so doing, we could reach 51% d.e. As earlier emphasized, the
diastereoselectivities were constant over time, and the cycloadducts 4 were stable under
the reaction conditions [6].
Finally, we also tested pure (> 96%) cis-stilbene ((Z)-3c) as dipolarophile8) and
could isolate in 30% yield a 3 :7 mixture of trans- and cis-cycloadducts 4c. The minor
trans-pair, as well as the cis-cycloadducts were formed in ca. 44% d.e. in favor of the
diastereoisomer (4S,5S)-4c, and ca. 28% d.e. in favor of the diastereoisomer (4S,5R)-4c,
respectively. This latter ratio was determined by the integration of the 1H-NMR signals
of the ꢃbenzylꢄ ds, appearing at lower field (d 6.05 and 5.15, J ¼ 11 Hz), for the main
diastereoisomer, when compared to its minor counterpart (4R,5S)-4c (d 5.96 and 4.80,
J ¼ 10 Hz). After CC (SiO2) separation of the trans/cis mixture, the cis-adducts were
crystallized from AcOEt/hexane 1:1 to afford the enriched minor (4R,5S)-4c (cis), as
well as the analytically pure major cis-diastereoisomer (4S,5R)-4c. This latter was
suitable for X-ray analyses, and hence for absolute-configuration determination
(Fig. 2). It shows an SO2/C¼O anti-conformation with an SꢀNꢀC¼O dihedral angle
of 153.3(2)8 and a DhN of 0.230 ꢀ. As in the cases of both (4S,5S)-4b and (4S,5S)-4c,
the C¼O is anti-periplanar to the C(5’)¼N(1’) bond. cis-Stilbene ((Z)-3c) appears
isomerically stable under the reaction conditions, either in the presence or absence of
dipole 2. However, we cannot totally exclude a slow isomerization process, followed by
a rapid cycloaddition, thus explaining the apparent absence of transient (E)-
dipolarophile. Nevertheless, with respect to the absence of trans-stilbene (3c) in the
remaining excess of dipolarophile, after completion of the reaction, these results are
consistent with a nonsynchronous mechanism, as earlier suggested by calculations [6].
6
)
)
An F-atom is sterically similar to an H-atom [20].
7
Owing to the strong oxidative reactive conditions, both OH- and N-containing substrates, such as
the commercially available trans-stilbene-4,4’-diol (LUMO ꢀ 0.039; HOMO ꢀ 0.184), 4,4’-[(1E)-
ethene-1,2-diyl]bis[pyridine] (LUMO ꢀ 0.080; HOMO ꢀ 0.238), or the known trans-4,4’-
bis(dimethylamino)stilbene (¼4,4’-[(1E)-ethene-1,2-diyl]bis[N,N-dimethylbenzenamine] [25]
(LUMO ꢀ 0.024; HOMO ꢀ 0.158), proved to be unsuitable dipolarophiles in our hands, even
under milder conditions using MnO2 [6].
8
)
LUMO ꢀ 0.043 and HOMO ꢀ 0.209 Hartree.

Helvetica Chimica Acta – Vol. 92 (2009)
1061
Fig. 2. ORTEP Diagram of cycloadduct (4S,5R)-4c (arbitrary atom numbering). Ellipsoids are
represented at the 50% probability level.
In fact, we performed the X-ray structure analysis of (4S,5S)-4b (Fig. 1) because we
expected to observe, as in the case of (4S,5S)-4c [6], the rare SO2/C¼O syn-
conformation. Indeed, more than 97% of the X-ray structure analyses of bornane-10,2-
sultam derivatives exhibit an SO2/C¼O anti-conformation, and we are aware of only six
structures with syn-conformation [2][7], amongst which four possess a heteroatom lp in
the b-position, and two of them are derived from dipole 2 [5][6]. The fact that (4S,5S)-
4b9) shows an anti-conformation, in contrast to the syn-conformation of (4S,5S)-4c10),
was surprising for us, and shows for these practically identical structures, that external
secondary influences, such as the crystal-packing forces or the solvent polarity [27] are
particularly important parameters for the control of the syn/anti-stability. A second
example illustrating the differences in electronic alignments is given by the (2R)-N-
picolinoylbornane-10,2-sultam derivative [6], which shows a DhN of 0.269 ꢀ for an
SꢀNꢀC¼O angle of 144.57(15)8, as compared to 0.066 ꢀ and ꢀ 11.5(3)8, respectively,
for its thermodynamically less stable (1.8 kcal/mol) syn-conformer [7].
From a conformational point of view, the S¼O(2) substituent adopts a pseudo-
equatorial orientation due to the steric influence of the Me(9) group [28]. For both
(4S,5S)-4b and (4S,5S)-4c, the S¼O(1) bond is slightly longer than the S¼O(2) bond
(see Table 2 for (4S,5S)-4b, and Fig. 1 for atom numbering), as expected from a
stereoelectronic influence of the anti-periplanar N lone pair [29]. In the case of
(4S,5R)-4c, the steric influence of the aromatic HꢀC(19) renders, in the crystalline
state, the S¼O(1) bond both less pseudoaxial and shorter (Table 2 and Fig. 2).
Interestingly, the O¼S¼O angle remains constant between the anti-conformation of
(4S,5S)-4b and the syn-conformation of (4S,5S)-4c [6]. The F2 puckering parameters
for both five-membered sultam rings are in the range of those observed for both syn-
9
)
)
DhN ¼ 0.264 ꢀ and SꢀNꢀC¼O ¼ 148.29(11)8.
DhN ¼ 0.119 ꢀ and SꢀNꢀC¼O ¼ ꢀ17.45(18)8.
10

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Helvetica Chimica Acta – Vol. 92 (2009)
conformers (90.38 [6] to 104.88 [5]) and anti-conformers (77.48 [7][30] to 139.78 [31]).
This contrasts with fenchane-8,2-sultams, which possess a modified envelope, with an
S¼O(2) substituent in the pseudoaxial orientation (F2 ¼ 252.48), despite the presence
of a sterically more influent Me2C(3) moiety [28].
Table 2. Selected Bond Lengths [ꢀ] and Angles [8] of (4S,5S)-4b and (4S,5R)-4c. For atom numbering,
see Figs. 1 and 2.
(4S,5S)-4b
1.4298(11)
(4S,5R)-4c
1.413(3)
S¼O(1)
S¼O(2)
1.4224(12)
1.7092(12)
1.7907(15)
1.4873(18)
1.3821(18)
1.2155(17)
1.487(2)
1.428(3)
1.706(2)
1.761(4)
1.481(4)
1.378(4)
1.223(3)
1.473(5)
SꢀN
SꢀC(10)
NꢀC(2)
NꢀC(13)
C(13)¼O(3)
C(13)ꢀC(5’)
O(1)¼S¼O(2)
C(2)ꢀNꢀS
118.42(7)
112.37(9)
116.50(11)
122.21(10)
108.59(12)
108.08(10)
ꢀ 120.75(10)
139.17(11)
138.78(14)
156.84(13)
0.344
118.1(2)
112.15(19)
117.1(2)
123.75(19)
108.4(2)
110.6(2)
ꢀ 118.2(2)
138.3(2)
142.7(3)
155.5(3)
0.345
C(2)ꢀNꢀC(13)
C(13)ꢀNꢀS
C(5’)ꢀN(1’)ꢀO(2’)
C(2)ꢀNꢀS¼O(1)
C(2)ꢀNꢀS¼O(2)
C(3)ꢀC(2)ꢀNꢀS
O(3)¼C(13)ꢀC(5’)ꢀN(1’)
NꢀC(13)ꢀC(5’)ꢀC(4’)
Puckering parameter q2
SꢀNꢀC(2)ꢀC(1)ꢀC(10) F2
98.76
102.38
The rationalization for the observed diastereoselectivity is based on earlier
calculations suggesting a preferred py approach of the electron-rich (E)-dipolarophile
C(a)-si face along the C¼O bond of the more reactive dipole syn-2 [6]. The unselective
concurrent participation of nitrile oxide anti-2 decreases the selectivity with respect to
the increasing influence of its HOMO interaction with electron-deficient substrates.
Due to the linearity of the nitrile oxide, and the unusual trajectory of the dipolarophile,
the simple steric rules developed by Kim and Curran for this chiral auxiliary do not
apply here [11]. Nevertheless, the predictability of the diastereoselectivity may be
correlated with the Hammett spara electronic properties of the dipolarophiles 3a – 3i11)
[33] by using Eqn. 1 (d.r. ¼ diastereoisomer ratio). Avery similar correlation was found
by using the 4,4’-disubstituted trans-stilbene electronic parameters (Eqn. 2) [34].
log(d.r.) ¼ ꢀ0.215spara þ 0.406
(1)
(R ¼ 0.93, standard deviation ¼ 0.035, n ¼ 8)
For a correlation between the sþpara Hammett parameter and the regioselectivity in enantiomer-
catalyzed [3 þ 2] cycloadditions of electronically modified nitrones, see [32].
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Helvetica Chimica Acta – Vol. 92 (2009)
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log(d.r.) ¼ ꢀ0.222sstilbene þ 0.416
(2)
(R ¼ 0.92, standard deviation ¼ 0.036, n ¼ 8)
Nevertheless, we prefer to present the correlation with the more commonly used
and accepted simple aromatic spara constants (Fig. 3). The cis-stilbene approach follows
preferentially the same trajectory and results in the same configuration for the C(4)
center.
Fig. 3. Diastereoselectivity (log(diastereoisomer ratio)) of the uncatalyzed 1,3-dipolar cycloaddition of
dipole 2 and 4,4’-disubstituted trans-stilbenes 3a – 3i as a function of their Hammett aromatic constant spara
Conclusions. – The uncatalyzed 1,3-dipolar cycloaddition of 2-oxoethanenitrile
oxide 2 derived from (2R)-bornane-10,2-sultam to the symmetric 4,4’-disubstituted
trans-stilbenes 3a – 3i follows the Acree – Curtin – Hammett principle [35]. The higher
reactivity of the minor conformer syn-2 results from a better alignment of the electronic
p-system, between both the oxo and the N lp of the sultam moiety. The stereoelectronic
properties of such sultam derivatives differ fundamentally from those of simple chiral
amides or pyrrolidines, by their N lp anomeric stabilization with the anti-periplanar
For a correlation between the sþpara Hammett parameter and the regioselectivity in enantiomer-
catalyzed [3 þ 2] cycloadditions of electronically modified nitrones, see [32].
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Helvetica Chimica Acta – Vol. 92 (2009)
S¼O s* antibonding orbital [2][36]. Although the dipolarophile py trajectory along the
C¼O bond precludes the use of the steric rules formerly expressed for this pseudo-C2-
symmetric auxiliary [11], the observed diastereoselectivity is related to the electronic
nature of the dipolarophiles 3a – 3i and may be predicted on the basis of either their
spara or sstilbene Hammett parameters. The sense of induction resulting from a C(a)-si
approach of the trans-stilbene derivatives 3a – 3i is consistent with the X-ray structure
of cycloadduct (4S,5S)-4b, which exhibits an SO2/C¼O anti-conformation, in contrast
to the syn-conformation of (4S,5S)-4c [6]. A nonsynchronous mechanism is suggested
by both calculations [6] and experimental evidences resulting from the cycloaddition of
the dipolarophile cis-stilbene ((Z)-3c).
Financial support from the Ministry of Science and Higher Education (Grant PBZ-KBN-126/T09/06)
is gratefully acknowledged. The X-ray crystal-structure data of (4S,5S)-4b were recorded in the
Crystallographic Unit of the Physical Chemistry Laboratory at the Chemistry Department of the
University of Warsaw, and those of (4S,5R)-4c in the Crystallographic Unit Laboratory at the Institute of
Organic Chemistry, Polish Academy of Sciences of Warsaw.
Experimental Part
1. General. See [37].
2. X-Ray Crystal-Structure Analyses. All crystal measurements for (4S,5S)-4b (Fig. 1) were
performed with a KM4CCD k-axis diffractometer and graphite-monochromated MoKa radiation. The
crystal was positioned at 62 mm from the CCD camera, and 1800 frames were measured at 18 intervals
with a counting time of 5 s. The data were corrected for Lorentz and polarization effects. Empirical
correction for absorption was applied (with spherical harmonics, implemented in the SCALE3
ABSPACK scaling algorithm) [38]. All crystal measurements for (4S,5R)-4c (Fig. 2) were performed
with a Bruker-APEX-II-CCD diffractometer and graphite-monochromated CuKa radiation. The data for
both compounds are listed in Table 3. Both data and absorptions were uncorrected. Data reduction and
analysis were carried out with the Oxford Diffraction Ltd. programs [38]. The structures were solved by
direct methods [39] and refined with SHELXL [40]. The refinement was based on F2 for all reflections,
except for those with very negative F2. Weighted R factors wR and all goodness-of-fit S values were based
on F2. Conventional R factors were based on F with F set to zero for negative F2. The Fo2 > 2s(Fo2 )
criterion was used only for calculating R factors and was not relevant to the choice of reflections for the
refinement. The R factors based on F2 were about twice as large as those based on F. All H-atoms were
located geometrically, and their positions and temperature factors were not refined. Scattering factors
were taken from Tables 6.1.1.4 and 4.2.4.2 in [41]. The known configurations of the asymmetric centers
were confirmed by the Flack-parameter refinement [42]. CCDC-667773 and CCDC-697551 contain the
supplementary crystallographic data for (4S,5S)-4b and (4S,5R)-4c, resp. Copies of the data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif. The Cremer and Pople puckering
parameters [43] were calculated according to [44].
3. Cycloadditions. 3.1. General Procedure. To a soln. of aldoxime 1c (0.26 mmol) in CHCl3 (10 ml),
NCS (0.26 mmol) was added at r.t. After 15 min, the appropriate trans-stilbene 3a – 3i (0.39 mmol) and
KHCO3 (0.39 mmol) were added, and the progress of the reaction was monitored by TLC until
disappearance of the aldoxime. When the reaction was complete (max. 6 h), the mixture was washed with
H2O, the org. phase dried (MgSO4) and concentrated, and the residue purified by CC (SiO2, hexane/
AcOEt 9 :1 ! 7:3): 4a – 4i (yields in Table 1).
3.2. [(4S,5S)-4,5-Dihydro-4,5-bis(4-methoxyphenyl)isoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4a): IR: 2960,
1
2838, 1670, 1613, 1515, 1463, 1346, 1251, 1171, 1033, 829, 540. H-NMR: 7.24 – 7.14 (m, 4 H); 6.9 – 6.85
(m, 4 H); 5.53 (d, J ¼ 8.5, 1 H); 4.74 (d, J ¼ 8.5, 1 H); 4.12 (t, J ¼ 6, 1 H); 3.80 (s, 3 H); 3.37 (s, 3 H); 3.51,
3.40 (AB, J ¼ 13.5, 76.0, 2 H); 2.4 – 1.82 (m, 5 H); 1.42 – 1.23 (m, 2 H); 1.11 (s, 3 H); 0.96 (s, 3 H).

Helvetica Chimica Acta – Vol. 92 (2009)
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Table 3. Crystal Data and Structure Refinement of Compounds (4S,5S)-4b and (4S,5R)-4c
(4S,5S)-4b
(4S,5R)-4c
Empirical formula
Mr
C28H32N2O4S
492.62
C26H28N2O4S
464.57
Temp. [K]
Wavelength [ꢀ]
Crystal system
Space group
Unit-cell dimensions
a [ꢀ]
b [ꢀ]
c [ꢀ]
a [8]
b [8]
100(2)
0.71073
triclinic
P1
293(2)
1.54178
monoclinic
P21
6.8185(8)
12.5563(6)
7.6086(3)
12.9634(6)
90.00
108.200(3)
90.00
9.1335(11)
10.6932(13)
101.398(10)
104.797(11)
92.823(9)
g [8]
V [ꢀ3]
Z
627.65(13)
1
1176.51(9)
2
Density [Mg/m3]
Absorpt. coeff. [mmꢀ1
F(000) electrons
Crystal size [mm]
q Range for data [8]
Index ranges
1.303
0.166
262
1.311
1.511
492
0.83 ꢂ 0.54 ꢂ 0.50
14.88 to 55.52
ꢀ 13 ꢃ h ꢃ 10,
ꢀ 6 ꢃ k ꢃ 7,
ꢀ 10 ꢃ l ꢃ 12
1768/1666
0.0155
]
0.45 ꢂ 0.35 ꢂ 0.12
2.70 to 28.73
ꢀ 9 ꢃ h ꢃ 9,
ꢀ 12 ꢃ k ꢃ 12,
ꢀ 14 ꢃ l ꢃ 14
17980/5990
0.0193
full-matrix least-squares on F2
5990/3/321
0.989
Reflect. collected/unique
R(int)
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
R(F) (I > 2s(I))
R1
1666/1/301
0.896
0.0293
0.0635
0.0303
0.0822
wR2
wR(F2) (all data)
R1
0.0367
0.0312
wR2
0.0646
0.0828
Abs. struct. parameter
Extinction coefficient
Largest peak and holes [e · ꢀꢀ3
ꢀ 0.04(4)
0.012(2)
0.223; ꢀ 0.292
0.04(2)
0.035(5)
0.105; ꢀ 0.120
]
13C-NMR: 160.1; 159.5; 155.0; 131.0; 129.4; 127.6; 114.7; 114.4; 66.0; 61.1; 55.5; 55.4; 53.3; 48.9; 48.0; 45.5;
39.3; 33.4; 26.4; 21.6; 20.1. HR-MS: 547.1876 (C28H32N2NaO6Sþ; calc. 547.1879).
Minor stereoisomer (signals deduced from the crude mixture): 1H-NMR: 7.28 – 7.14 (m, 4 H); 6.9 –
6.85 (m, 4 H); 5.49 (d, J ¼ 7, 1 H); 4.52 (d, J ¼ 6, 1 H); 4.00 (t, J ¼ 6.5, 1 H); 3.80 (s, 3 H); 3.79 (s, 3 H);
3.55, 3.42 (AB, J ¼ 14, 2 H); 2.4 – 1.82 (m, 5 H); 1.42 – 1.23 (m, 2 H); 1.16 (s, 3 H); 0.97 (s, 3 H). 13C-NMR:
160.0; 159.4; 153.5; 131.6; 129.1; 128.9; 127.6; 114.6; 114.3; 66.0; 62.6; 55.5; 55.4; 53.6; 48.8; 47.9; 45.3;
38.8; 33.4; 26.5; 21.5; 20.1.
3.3. [(4S,5S)-4,5-Dihydro-4,5-bis(4-methylphenyl)isoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4b): Obtained
pure in ca. 44% yield after crystallization from hexane/AcOEt 1:1. M.p. 197 – 1998. [a]2D0 ¼ þ28.8 (c ¼

1066
Helvetica Chimica Acta – Vol. 92 (2009)
1.0, CHCl3). IR: 2959, 2939, 2917, 1666, 1572, 1518, 1413, 1387, 1348, 1196, 1169, 1136, 1113, 1060, 922,
1
813, 746, 559, 531. H-NMR: 7.17 – 7.14 (m, 8 H); 5.57 (d, J ¼ 9, 1 H); 4.74 (d, J ¼ 9, 1 H); 4.12 (t, J ¼ 6,
1 H); 3.50, 3.40 (AB, J ¼ 13, 2 H); 2.35 (s, 3 H); 2.32 (s, 3 H); 2.09 – 1.82 (m, 5 H); 1.42 – 1.23 (m, 2 H);
1.11 (s, 3 H); 0.96 (s, 3 H). 13C-NMR: 159.6; 154.9; 138.8; 138.0; 136.1; 134.0; 130.0; 129.7; 128.2; 93.3;
66.0: 61.7; 53.2; 48.9; 48.0; 45.5; 39.4; 33.5; 26.4; 21.6; 21.3; 20.1. HR-MS: 515.1976 C28H32N2NaO4S;calc.
515.1981).
1
Minor stereoisomer (signals deduced from the crude mixture): H-NMR: 7.17 – 7.14 (m, 8 H); 5.54
(d, J ¼ 6.5, 1 H); 4.52 (d, J ¼ 6.5, 1 H); 4.00 (t, J ¼ 6.5, 1 H); 3.54, 3.41 (AB, J ¼ 13.5, 2 H); 2.345 (s, 3 H);
2.34 (s, 3 H); 2.09 – 1.82 (m, 5 H); 1.42 – 1.23 (m, 2 H); 1.16 (s, 3 H); 0.97 (s, 3 H). 13C-NMR: 160.0; 153.4;
138.6; 137.9; 136.6; 135.4; 130.0; 129.7; 127.8; 126.0; 93.4; 66.0; 63.1; 53.6; 48.8; 48.0; 45.3; 38.9; 33.5; 26.5;
21.5; 21.4; 20.1.
3.4. [(4S,5S)-4,5-Dihydro-4,5-diphenylisoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-dimethyl-2,2-di-
oxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4c): Obtained pure after crys-
tallization from hexane/AcOEt 1:1. For data, see [6].
3.5. [(4S,5R)-4,5-Dihydro-4,5-diphenylisoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-dimethyl-2,2-di-
oxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5R)-4c): Obtained pure from (Z)-
3c after crystallization from hexane/AcOEt 1:1. M.p. 237 – 2388. [a]2D0 ¼ ꢀ76.5 (c ¼ 1.0, CHCl3).
IR(KBr): 3005, 2957, 2922, 2876, 1669, 1579, 1456, 1389, 1346, 1206, 1169, 1114, 1080, 1060, 923, 910, 772,
753, 727, 694, 550, 534. 1H-NMR: 7.09 – 7.03 (m, 8 H); 6.89 – 6.85 (m, 2 H); 6.05 (d, J ¼ 11, 1 H); 5.15 (d,
J ¼ 11, 1 H); 4.17 – 4.1 (m, 1 H); 3.55, 3.43 (AB, J ¼ 13.6, 2 H); 2.15 – 1.83 (m, 5 H); 1.42 – 1.26 (m, 2 H);
1.11 (s, 3 H); 0.98 (s, 3 H). 13C-NMR: 159.35; 156.3; 134.7; 132.8; 129.4; 128.4; 128.0; 127.9; 127.8; 126.8;
88.9; 66.1; 57.9; 53.4; 48.9; 48.0; 45.5; 39.2; 33.5; 26.4; 21.5; 20.1. HR-MS: 465.1789 (C26H29N3O4Sþ; calc.
465.5861).
1
Minor stereoisomer (signals deduced from the enriched cis-isomer mixture): H-NMR: 7.09 – 7.03
(m, 8 H); 6.89 – 6.85 (m, 2 H); 5.96 (d, J ¼ 10, 1 H); 4.80 (d, J ¼ 10, 1 H); 4.13 – 4.03 (m, 1 H); 3.11 (s,
2 H); 2.15 – 1.83 (m, 5 H); 1.42 – 1.26 (m, 2 H); 1.10 (s, 3 H); 0.97 (s, 3 H). 13C-NMR: 159.35; 156.3; 133.2;
132.8; 129.0; 128.4; 128.0; 127.9; 127.8; 127.0; 88.8; 66.1: 57.8; 53.4; 48.9; 48.0; 45.5; 39.2; 33.4; 26.4; 21.5;
20.1.
3.6. [(4S,5S)-4,5-Bis(4-fluorophenyl)-4,5-dihydroisoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4d): IR: 2960,
2940, 2887, 1668, 1606, 1512, 1388, 1347, 1228, 1169, 1160, 1136, 1114, 924, 835, 558, 539. 1H-NMR:
7.3 – 7.2 ( m, 4 H); 7.1 – 7.03 (m, 4 H); 5.57 (d, J ¼ 9, 1 H); 4.75 (d, J ¼ 9, 1 H); 4.08 (t, J ¼ 6, 1 H); 3.53, 3.41
(AB, J ¼ 13.5, 2 H); 2.07 – 1.84 (m, 5 H); 1.4 – 1.2 (m, 2 H); 1.13 (s, 3 H); 0.97 (s, 3 H). 13C-NMR: 164.1;
163.8; 162.2; 161.8; 159.8; 154.7; 134.6 (J ¼ 3); 132.4 (J ¼ 3); 130.1 (J ¼ 8.3); 127.9 (J ¼ 8.3); 116.5; 116.4;
116.3; 116.1; 92.6; 66.0; 53.4; 48.9; 48.0; 45.3; 39.1; 36.3; 33.5; 26.4; 21.6; 20.1. 19F-NMR: ꢀ 112.84 (m,
1 F); ꢀ 113.70 (m, 1 F). HR-MS: 523.1481 (C26H26F2N2NaO4Sþ; calc. 523.1479).
Minor stereoisomer (signals deduced from the crude mixture): 1H-NMR: 7.3 – 7.2 (m, 4 H); 7.1 – 7.03
(m, 4 H); 5.52 (d, J ¼ 7, 1 H); 4.52 (d, J ¼ 7, 1 H); 4.03 (t, J ¼ 6, 1 H); 3.56, 3.42 (AB, J ¼ 13.5, 2 H); 2.07 –
1.84 (m, 5 H); 1.4 – 1.2 (m, 2 H); 1.16 (s, 3 H); 0.98 (s, 3 H). 13C-NMR: 164.1; 163.8; 162.1; 161.7; 159.5;
153.1; 135.1 (J ¼ 3); 133.8 (J ¼ 3); 129.6 (J ¼ 8.3); 127.9 (J ¼ 8.3); 116.4; 116.3; 116.1; 116.0; 92.5; 61.5;
53.6; 50.5; 45.5; 44.9; 38.6; 33.5; 32.1; 26.5; 21.5; 20.1. 19F-NMR: ꢀ 113.20 (m, 1 F); ꢀ 113.94 (m, 1 F).
3.7. [(4S,5S)-4,5-Bis(4-chlorophenyl)-4,5-dihydroisoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4e): IR: 2961,
1
2884, 1668, 1599, 1493, 1347, 1219, 1169, 1092, 1015, 928, 817, 535. H-NMR: 7.37 – 7.15 (m, 8 H); 5.55
(d, J ¼ 8.9, 1 H); 4.72 (d, J ¼ 8.9, 1 H); 4.07 (t, J ¼ 6, 1 H); 3.54, 3.41 (AB, J ¼ 13.7, 2 H); 2.32 (s, 3 H); 2.27
(s, 3 H); 2.1 – 1.85 (m, 5 H); 1.4 – 1.21 (m, 2 H); 1.14 (s, 3 H); 0.97 (s, 3 H). 13C-NMR: 159.7; 154.5; 137.6;
137.1; 135.0; 134.6; 129.8; 129.7; 129.4; 127.4; 92.4; 66.1; 61.8; 53.5; 48.9; 48.0; 45.5; 39.1; 33.5; 26.4; 21.7;
20.1. MS: 555.2 (100), 557.2 (38). HR-MS: 555.0887 (C26H26Cl2N2NaO4Sþ; calc. 555.0888).
1
Minor stereoisomer (signals deduced from the crude mixture): H-NMR: 7.37 – 7.15 (m, 8 H); 5.52
(d, J ¼ 6.5, 1 H); 4.49 (d, J ¼ 6.5, 1 H); 3.98 (t, J ¼ 6.2, 1 H); 3.55, 3.41 (AB, J ¼ 13.5, 2 H); 2.32 (s, 3 H);
2.31 (s, 3 H); 2.1 – 1.85 (m, 5 H); 1.4 – 1.21 (m, 2 H); 1.16 (s, 3 H); 0.98 (s, 3 H). 13C-NMR: 159.5; 152.9;
138.0; 136.4; 135.0; 134.9; 134.4; 129.6; 129.3; 129.2; 127.4; 92.3; 66.0; 63.0; 53.6; 48.8; 48.0; 45.3; 38.6;
33.5; 26.5; 21.5; 20.1.

Helvetica Chimica Acta – Vol. 92 (2009)
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3.8. {(4S,5S)-4,5-Dihydro-4,5-bis[4-(trifluoromethyl)phenyl]isoxazol-3-yl}[(3aS,6R,7aR)-tetrahy-
dro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4f):
1
IR: 2963, 2887, 1669, 1620, 1422, 1348, 1325, 1169, 1129, 1113, 1069, 1018, 832. H-NMR: 7.68 – 7.64 (m,
4 H); 7.5 – 6.96 (m, 4 H); 5.67 (d, J ¼ 9, 1 H); 4.82 (d, J ¼ 9, 1 H); 4.06 (dt, J ¼ 4.5, 1.5, 1 H); 3.56, 3.42 (AB,
J ¼ 14, 2 H); 2.3 (m, 1 H); 2.05 – 1.85 (m, 5 H); 1.4 – 1.22 (m, 4 H); 1.15 (s, 3 H); 0.98 (s, 3 H). 13C-NMR:
159.6; 154.2; 142.4; 140.3; 138.0; 128.9; 126.3 (q, J ¼ 3.9); 92.2; 66.2; 62.3; 53.6; 48.9; 48.0; 45.6; 38.6; 33.6;
26.4; 21.7. 19F-NMR: ꢀ 62.90 (s, 3 F); ꢀ 62.94 (s, 3 F). HR-MS: 623.1415 (C28H26F6N2NaO4Sþ; calc.
623.1415).
Minor stereoisomer (signals deduced from the crude mixture): 1H-NMR: 7.68 – 7.64 (m, 4 H); 7.5 –
6.96 (m, 4 H); 5.63 (d, J ¼ 6, 1 H); 4.58 (d, J ¼ 6, 1 H); 3.97 (t, J ¼ 6, 1 H); 3.57, 3.42 (AB, J ¼ 13.5, 2 H);
2.3 (m, 1 H); 2.05 – 1.85 (m, 5 H); 1.4 – 1.22 (m, 4 H); 1.16 (s, 3 H); (0.98 (s, 3 H). 13C-NMR: 159.3; 152.6;
142.8; 141.7; 136.7; 128.4; 126.6 (q, J ¼ 3.9); 92.1; 66.0; 63.4; 53.6; 48.9; 48.0; 45.3; 39.0; 33.6; 26.5; 21.5.
19F-NMR: ꢀ 62.87 (s, 3 F); ꢀ 62.88 (s, 3 F).
3.9. [(4S,5S)-4,5-Bis(4-cyanophenyl)-4,5-dihydroisoxazol-3-yl][(3aS,6R,7aR)-tetrahydro-8,8-di-
methyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone (¼4,4’-{(4S,5S)-4,5-Dihy-
dro-3-{[(3aS,6R,7aR)-tetrahydro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano-2,1-benzothiazol-1(4H)-
yl]carbonyl}isoxazole-4,5-diyl}bis[benzonitrile]; (4S,5S)-4g): IR: 2957, 2925, 2854, 2229, 1666, 1466, 1343,
1223, 1169, 1138, 1115, 917. 1H-NMR: 7.8 – 7.6 (m, 4 H); 7.5 – 7.3 (m, 4 H); 5.66 (d, J ¼ 8.5, 1 H); 4.80 (d,
J ¼ 8.5, 1 H); 4.04 (dt, J ¼ 8, 5, 1 H); 3.58 – 3.39 (m, 2 H); 2.4 – 1.8 (m, 3 H); 1.5 – 1.2 (m, 4 H); 1.18 (s,
3 H); 1.00 (s, 3 H). 13C-NMR: 159.3; 153.7; 143.2; 141.0; 133.2; 133.0; 129.1; 126.4; 118.2; 118.1; 113.1;
112.8; 91.5; 66.0; 62.2; 53.4; 48.8; 47.8; 45.3; 38.7; 33.3; 29.7; 26.2; 21.5; 19.9. MS: 591.2 (100); 304.3 (30).
Minor stereoisomer12) (signals deduced from the crude mixture): 1H-NMR: 7.8 – 7.6 (m, 4 H); 7.5 –
7.3 ( m, 4 H); 5.62 (d, J ¼ 5.5, 1 H); 4.54 (d, J ¼ 5.5, 1 H); 3.96 (t, J ¼ 6.5, 1 H); 3.48 (m, 2 H); 2.4 – 1.8 (m,
3 H); 1.5 – 1.2 (m, 4 H); 1.12 (s, 3 H); 0.99 (s, 3 H). 13C-NMR: 158.9; 152.2; 143.6; 142.5; 133.1; 132.9;
128.5; 126.4; 118.3; 118.2; 112.9; 112.6; 91.3; 65.8; 63.2; 53.5; 48.7; 47.8; 45.2; 38.3; 33.3; 29.6; 26.3; 21.3;
19.9.
3.10. {(4S,5S)-4,5-Dihydro-4,5-bis[4-(phenylmethoxy)phenyl]isoxazol-3-yl}[(3aS,6R,7aR)-tetrahy-
dro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl]methanone ((4S,5S)-4i): IR:
2957, 2925, 1669, 1610, 1512, 1454, 1344, 1246, 1176, 1137, 1025, 828, 740, 697, 539. 1H-NMR: 6.8 – 7.5 (m,
18 H); 5.53 (d, J ¼ 8.8, 1 H); 5.05 (d, J ¼ 5.2, 2 H); 4.75 (d, J ¼ 8.8, 1 H); 4.0 – 4.14 (m, 1 H); 3.36 – 3.55 (m,
2 H); 3.10 (d, J ¼ 2.6, 2 H); 2.2 – 2.35 (m, 2 H); 1.7 – 2.1 (m, 2 H); 1.2 – 1.4 (m, 3 H); 1.13 (s, 3 H); 0.93 (s,
3 H). 13C-NMR: 159.2; 158.7; 154.8; 129.3; 128.6; 128.0; 127.5; 115.5; 115.23; 92.9; 71.0; 70.5; 65.8; 62.9;
60.9; 53.1; 50.4; 48.7; 47.8; 47.5; 45.4; 44.7; 39.2; 36.1; 33.3; 31.9; 29.7; 26.8; 26.2; 21.4; 20.5. HR-MS:
699.2506 (C40H40N2NaO6Sþ; calc. 699.2505).
Minor stereoisomer (signals deduced from the crude mixture): 1H-NMR: 6.8 – 7.5 (m, 18 H); 5.50 (d,
J ¼ 6.8, 1 H); 5.05 (d, J ¼ 5.2, 2 H); 4.52 (d, J ¼ 6.8, 1 H); 4.0 – 4.14 (m, 1 H); 3.36 – 3.55 (m, 2 H); 3.10 (d,
J ¼ 2.6, 2 H); 2.2 – 2.35 (m, 2 H); 1.7 – 2.1 (m, 2 H); 1.2 – 1.4 (m, 3 H); 1.10 (s, 3 H); 0.96 (s, 3 H).
13C-NMR: 159.1; 158.6; 153.3; 129.5; 129.0; 126.9; 126.4; 115.4; 115.1; 93.0; 72.5; 70.5; 64.4; 62.4; 60.9;
55.1; 53.4; 48.8; 47.8; 47.4; 45.1; 44.4; 38.6; 34.5; 32.8; 31.9; 29.4; 27.0; 26.3; 21.3; 20.5.
12
)
Isolated; besides ca. 50% yield of (3aS,3’aS,6R,6’R,7aR,7’aR)-1,1’-[(2-oxidofurazan-2,4-diyl)bis(car-
bonyl)]bis[hexahydro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano-2,1-benzisothiazole]: M.p.: 196 –
1978. [a]20 ¼ ꢀ198.7 (c ¼ 1.0, CHCl3). IR: 2987, 2962, 2895, 1700, 1670, 1630, 1475, 1470, 1462,
D
1380, 1350, 1300, 1250, 1175, 1150, 1075, 1062, 1050, 825, 762, 550, 500. 1H-NMR: 4.35 (dd, J ¼ 4.5, 7,
1 H); 4.04 (dd, J ¼ 5, 8, 1 H); 3.52 – 3.42 (m, 4 H); 2.42 – 2.31 (m, 2 H); 2.05 – 1.90 (m, 8 H); 1.45 – 1.36
(m, 4 H); 1.23 (s, 3 H); 1.13 (s, 3 H); 1.00 (s, 3 H); 0.96 (s, 3 H). 13C-NMR: 154.5; 151.8; 149.6; 65.3;
64.8; 52.9; 52.4; 50.0; 49.3; 48.1; 47.9; 45.5; 44.7; 39.2; 36.9; 33.3; 32.9; 26.4; 26.3; 20.9; 20.4; 20.1; 20.0.

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Helvetica Chimica Acta – Vol. 92 (2009)
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Received November 14, 2008