Stereocontrolled 1,3-dipolar cycloadditions using Oppolzer's camphor sultam as the chiral auxiliary for carbonyl stabilized azomethine ylides

Article abstract of DOI:10.1016/S0040-4020(00)00998-4

Two complementary approaches to substituted pyrrolidines via stereocontrolled 1,3-dipolar cycloaddition reactions of chiral azomethine ylides are described. In one approach, chiral azomethine ylides were generated by thermolysis of aziridine carboxylate sultams and trapped with a variety of dipolarophiles to give good yields of the corresponding cycloadducts. In the second approach, chiral azomethine ylides were generated from glycyl sultams by 'imine tautomerization' and trapped with dipolarophiles to give good yields of the corresponding cycloadducts.

Full text of DOI:10.1016/S0040-4020(00)00998-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 71±85
Stereocontrolled 1,3-dipolar cycloadditions using Oppolzer's
camphor sultam as the chiral auxiliary for carbonyl stabilized
azomethine ylides
²
È
*
Philip Garner, Ozdemir Dogan, Wiley J. Youngs, Vance O. Kennedy, John Protasiewicz
and Rebecca Zaniewski
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-7078, USA
Received 23 August 2000; accepted 24 October 2000
AbstractÐTwo complementary approaches to substituted pyrrolidines via stereocontrolled 1,3-dipolar cycloaddition reactions of chiral
azomethine ylides are described. In one approach, chiral azomethine ylides were generated by thermolysis of aziridine carboxylate sultams
and trapped with a variety of dipolarophiles to give good yields of the corresponding cycloadducts. In the second approach, chiral azomethine
ylides were generated from glycyl sultams by `imine tautomerization' and trapped with dipolarophiles to give good yields of the correspond-
ing cycloadducts. q 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
now report the full details of our work in the context of
bimolecular azomethine ylide cycloadditions.5
Asymmetric 1,3-dipolar cycloaddition reactions of azo-
methine ylides1 (Fig. 1) offer an effective means to access
pyrrolidine substructures 1 found in many biologically
active compounds.2 Stereocontrol in these reactions can be
achieved through the use of chiral auxiliaries that are
attached either to the dipoles 2 or dipolarophiles 3. While
good stereocontrol has been reported for bimolecular
cycloadditons using both strategies, the development of a
suitable chiral auxiliary for azomethine ylides has received
less attention.3 In this context, there are ®ve issues which
need to be considered when evaluating the utility of chiral
auxiliaries for asymmetric cycloadditions. These are (1)
availability of the auxiliary, (2) diastereofacial selectivity,
(3) endo/exo selectivity, (4) geometry of 1,3-disubstituted
ylides, and (5) auxiliary removal/recovery. Suf®ce it to say
that none of the chiral systems for azomethine ylides
reported so far appears to satisfy all of these requirements.
Particularly noteworthy is the fact that all of the covalently
attached azomethine ylide auxiliaries require destructive
removal. It was in this context that we initiated studies
whose goal was to develop a recoverable chiral auxiliary
for azomethine ylides. This work has resulted in stereo-
controlled syntheses of a variety of pyrrolidine systems
using azomethine ylides which incorporate Oppolzer's
camphor sultam as a recoverable chiral auxiliary.4 We
2. Results and discussion
Our analysis of this problem led us to consider the use of
chiral auxiliaries which would exert diastereofacial bias
under purely thermal conditionsÐthat is without the need
of Lewis acids. Analysis of the transition state models put
forth by Kim and Curran6 for thermal Diels±Alder and
nitrile oxide cycloadditions to C(sp2)±COXp dienophiles
and dipolarophophiles (where XpˆOppolzer's camphor
sultam) suggested to us that azomethine ylides which incor-
porate this substructure might also bene®t from the same
diastereofacial control elements. Thus, of the 4 possible
combinations of C(a)±CO and CO±N orientations, the
(s-cis, anti) conformer should be preferred on stereoelec-
tronic grounds (Fig. 2). When the auxiliary is ultimately
derived from (2)-camphor (as in this paper), reagents
should approach the prochiral a-carbon preferentially
from its si-face (opposite the pro-S sulfonimide oxygen).
This argument presumes that potentially competing
cycloadditions through the other 3 conformers will not
proceed at signi®cantly faster rates relative to (s-cis, anti)
Keywords: cycloadditions; pyrrolidines; stereocontrol; sultams.
* Corresponding author. Tel.: 11-216-368-3696; fax: 11-216-368-3006;
e-mail: ppg@po.cwru.edu
²
Current address: Department of Chemistry, Middle East Technical
University, 06531 Ankara, Turkey
Figure 1. General approach to pyrrolidines via 1,3-dipolar cycloaddition.
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00998-4

72
P. Garner et al. / Tetrahedron 57 (2001) 71±85
Figure 2. Possible conformations of carboxyl camphor sultams. Only the s-cis, anti conformer minimizes unfavorable dipole and steric interactions.
conformer. Although the need to incorporate a carboxylic
acid into our dipole would seem to reduce the generality of
this approach, we felt that any perceived limitation would be
offset by the synthetic utility of this functional group. Such
carbonyl-stabilized azomethine ylides7 may be conveniently
generated by thermolytic ring-opening of aziridine-2-
carboxylic acid derivatives8 or condensation of a glycine
derivative with an aldehyde followed by tautomerization.9
2-step (1-pot) procedure (Scheme 1) which involved (1)
alkene bromination (!5) followed by (2) double displace-
ment by either benzylamine or p-anisidine to give 6a and
6b, respectively.11 Although not relevant here, this aziri-
dination is itself diastereoselective and can be used to
prepare enantiomerically pure aziridine-2-carboxylic acid
derivatives in high yields.12 The 7,7-dichlorosultam aziri-
dine 6c was synthesized from the known compound 7.13
Treatment of 8b with NaH and acryloyl chloride led to the
clean formation of dichlorosultam 4b in 90% yield. This
contrasts with the same reaction on the unchlorinated
sultam, where a considerable amount of the conjugate
The chiral aziridine-2-carboxamides 6a and 6b were
prepared in high yield from the known (1)-N-propenoyl-
bornane-2,10-sultam (4a, `Oppolzer's sultam')10 using a
Scheme 1.
Table 1. Dipolar cycloadditions of azomethine ylides generated by aziridine thermolysis
Entry
Azomethine ylide
Dipolarophile
Cycloadduct(s)
Stereoselectivity
Combined % yields
1
2
3
4
5
6
7
8
9
10
6a
6b
6a
6b
6c
6a
6c
6a
6b
6c
13
13
16
16
16
21
21
25
25
25
14a/15a
14b/15b
17a/18a/19a
17b/18b/19b/20b
18c/19c/20c
22a/23a
22c/23c
26a/27a
26b/27b/28b/29b
27c/28c
8:1
9:1
3:2:1
10:8:3:1
4:1:1
2:1
4:1
1:1
4:4:1:1
2:1
60
82
80
93
91
75
84
51
92
52a
a Unreacted starting material 6c was recovered.

P. Garner et al. / Tetrahedron 57 (2001) 71±85
73
Figure 3. Competing diastereomeric transition states for the addition of azomethine ylide (Z)-12 to the generic alkene dipolarophile 3.
addition product was formed in addition to 4a.10b By apply-
ing the aziridination procedure used for the synthesis of 6a
and 6b, acryloyl dichlorosultam 4b was readily converted to
the corresponding aziridine 6c in 74% yield. A variation of
Oppolzer's published route to a-amino acids was used to
synthesize the chiral glycyl sultam 10a.14 This method was
not applicable to the synthesis of 10b presumably due to the
lower nucleophilicity of dichlorinated sultam. However,
reaction of the anion of 8b with azidoacetyl chloride gave
11 in 75% yield. Reduction of this compound using
modi®ed Staudinger conditions resulted in the clean
formation of 10b in 71% yield.
model. While the analogous 1,3-dipolar cycloadditions of
12a/b to N-phenylmaleimide (16) occurred in good chemi-
cal yield, the endo-selectivity was considerably eroded with
this dipolarophile (entries 3 and 4). The major products
corresponded to bicyclic pyrrolidines 17a/b (exo-re) and
18a/b (endo-re), with former slightly predominating over
the latter. Minor cycloadducts resulting from si-face
addition (19a/b, and 20b) were also isolated. The relative
con®guration of H-1 and H-6a in these cycloadducts was
assigned by 1H NMR as described above, with H-1 appear-
ing as a doublet when they were cis to H-6a (17 and 19) and
as a singlet when they are trans to H-6a (18 and 20) (Eq.
(2)), in agreement with literature on similar compounds.15
ꢀ1†
ꢀ2†
Upon thermolysis, aziridines 6a/b underwent (presumed
conrotatory) ring-opening to produce the corresponding
N-substituted azomethine ylides which reacted with a vari-
ety of electron-de®cient alkenes via 1,3-dipolar cyclo-
addition reactions (Table 1). With dimethyl maleate (13)
as the dipolarophile, cycloadducts 14a and 14b were
obtained as the major products (Eq. (1), entries 1 and 2 in
Table 1) which conforms to exclusive endo cycloaddition to
the Z-ylide 12a/b. The trans orientation of H-2 and H-3 in
these adducts was readily deduced in the `b-series' where
Our stereochemical assignment for cycloadduct 17b was
unambiguously con®rmed by X-ray crystallography (Fig.
4).16 Interestingly, the cycloadduct corresponding to
exo-re addition product 17 was not observed when the
dichlorinated sultam auxiliary was employed (entry 5).
We believe that steric hindrance caused by pro-S chlorine
atom on the sultam disfavors exo-re addition to azomethine
ylide 12c. Thermolysis of aziridine 6a in the presence of the
unsymmetrical dipolarophile methyl acrylate (21) led to the
formation of regioisomeric adducts 22a and 23a in a ratio of
2:1 (Eq. (3), entry 6). The regiochemistry of these adducts
were easily deduced from the splitting pattern of H-2 (d in
22a versus dd in 23a). The stereochemistry of 22a was
1
H-2 appeared as a singlet (dihedral angleˆ908) in the H
NMR spectra of both 14b and what we presume to be the
minor facial diastereomer 15b. The absolute stereo-
chemistry of the major adducts conform to an endo-re TS
(Fig. 3) that would be expected from the Oppolzer±Curran

74
P. Garner et al. / Tetrahedron 57 (2001) 71±85
ꢀ3†
Repetition of the dipolar cycloaddition sequence with the
dichloroaziridine 6c resulted in a doubling of the regioselec-
tivity to 4:1 (entry 7). It should be noted that the poor endo/
exo and regioselectivity associated with dipolarophiles 16
and 21 mirror Tsuge's observations with related (achiral)
N-substituted azomethine ylides. Finally, we also examined
the thermolysis of aziridines 6a±c in the presence of vinyl-
ene carbonate 25 (Eq. (4), entries 8±10). With N-benzyl-
aziridine 6a, two major cycloadducts identi®ed as 26a and
27a were isolated in equimolar quantities, along with a
signi®cant amount of a pyrrole 30a and free sultam 8a.
All 4 possible cycloadducts 26b±29b (ratioˆ4:4:1:1) were
obtained in excellent yield in the noticeably more reactive
N-aryl series without any by-products. Once again, 1H NMR
analysis allowed assignment of relative stereochemistry of
the pyrrolidine moiety. The structures of 26a and 27a were
established by separately converting them to known
Figure 4. X-Ray crystal structure of cycloadduct 17b.
established by its conversion to and correlation with the
known17 pyrrolidine dicarboxylic acid 24 (Scheme 2).
Note that the auxiliary was recovered from this reaction in
high yield. These thiolate-mediated cleavage conditions
were necessary because the usual reagents (LiOH,
LiOOH) were found to attack the sulfoxide moiety prefer-
entially.18
Scheme 2.

P. Garner et al. / Tetrahedron 57 (2001) 71±85
75
Figure 5. Formation of by-products 8 and 30.
compounds 313g and ent-3119 (Scheme 2). A control experi-
ment showed that free sultam 9 can arise from extended
thermolysis of 6a in the absence of dipolarophile (Fig. 5).
obtaining `exo-si' 27 as a major product without the need
to abandon the Oppolzer±Curran TS model. The reaction of
chlorinated aziridine 6c with 25 apparently underwent
selective formation of endo-re cycloadduct 28 (recall
entry 5) which then undergoes epimerization to 27 and
decomposition to 30c.
ꢀ5†
ꢀ4†
We also examined 1,3-dipolar cycloadditions of chiral
azomethine ylides generated from the glycyl sultams
10a±b and benzaldehyde using the `imine tautomerization
route' of Tsuge (Table 2). With dipolarophile 13, parent
sultam auxiliary gave cycloadducts 37a and 38a in good
yield and the usual selectivity (Eq. (5), entry 1). Two
other minor compounds, which may be the remaining
Apparently, dipolar cycloaddition to the electron-rich 25 is
slow enough to allow this decomposition pathway to inter-
vene here. The formation of pyrrole 30a presumably occurs
via slow, reversible enolization followed by a fast elimi-
nation/decarboxylation sequence. Enolization of an initially
formed endo-re cycloadduct 26 would account for our
1
diastereomers, could be detected in the crude H NMR
Table 2. Dipolar cycloadditions of azomethine ylides generated by imine tautomerization
Entry
Azomethine ylide
Dipolarophile
Cycloadduct(s)
Stereoselectivity
Combined % yields
1
2
3
4
5
36a
36a
36b
36a
36b
13
16
16
21
21
37/38
7:1
8:1
1:2:1
5:1
8:1
66a
84
64
64
58
39a/40a
39b/40b/41b
42a/43a
42b/43b
1
a Two other minor diastereomers detected in the crude H NMR spectrum.

76
P. Garner et al. / Tetrahedron 57 (2001) 71±85
Figure 6. X-ray crystal structure of cycloadduct 37a.
spectrum. Free sultam 8a, which may form via azomethine
ylide decomposition or hydrolysis by the liberated H2O, was
also isolated in 15% yield. The absolute stereochemistry of
the major cycloadduct 37a was unambiguously established
by X-ray crystallography (Fig. 6) and showed that all the
pyrrolidine substituents were cis to each other. This
cycloadduct was clearly the result of endo-re addition of
the dipolarophile to the (E,E)-ylide 36a. Dipolar cyclo-
addition of 36a to N-phenylmaleimide (16) (Eq. (6)) gave
a good yield of cycloadducts 39a and 40a in a ratio of 8:1
(entry 2). These adducts presumably arose from endo-re and
endo-si addition to 36a. Once again, a small amount of the
free sultam 8a (5%) was isolated. The relative pyrrolidine
In conclusion, we have shown that Oppolzer's sultam can
serve as an effective, recoverable chiral auxiliary for stabi-
lized azomethine ylides generated by aziridine thermolysis
and imine tautomerization. These chiral azomethine ylides
undergo 1,3-dipolar cycloadditions with a variety of
dipolarophiles to give good yields of diastereomerically
enriched cycloadducts. Subsequent removal of the chiral
auxiliary provides access to a variety of enantiomerically
pure pyrrolidine derivatives.
1
stereochemistry was readily deduced from their H NMR
spectra in which H-1 and H-3 appeared as doublets, indicat-
ing the cis arrangement of these protons relative to H-6a and
H-3a respectively. This assignment was further con®rmed
by NOE experiments on 39a, wherein irradiation of H-1
resulted in enhancement of H-3 (8%) and H-6a (16%).
Conversely, irradiation of H-3 resulted in enhancement of
H-1 (8%) and H-3a (21%). When this cycloaddition was
performed using the dichlorinated glycyl sultam 10b
(entry 3), the diastereomer 40b was favored and the ratio
of 40b/39b dropped to 2:1. A new product tentatively
identi®ed as 41b was isolated as well in addition to free
sultam 8b (20%). The relative stereochemistry of the pyrro-
lidine in 41b was evident from its 1H NMR spectrum, where
H-1 appeared as a singlet and H-3 as a doublet. Formation of
this cycloadduct was rather unexpected but must occur via
epimerization of either 39b or 40b or (less likely) by
addition to the (Z,E) isomer of ylide 36b (not shown).
Finally, when unsymmetrical dipolarophile 21 was used
with both sultam auxiliaries (Eq. (7)), good yields of
cycloadducts corresponding to 42 and 43 were isolated in
the usual selectivities (5:1 and 8:1, respectively) along with
minor amounts of free sultam (entries 4 and 5). Both the
regiochemistry and relative stereochemistry of these
cycloadducts were easily determined by the characteristic
ꢀ6†
1
up®eld shift of the 3-CO2Me H NMR signal due to the
shielding effect of the cis-2-phenyl group. Once again, it
is assumed that the major product results from endo-re
addition to the corresponding azomethine ylide 36 in accord
with the Oppolzer±Curran TS model.

P. Garner et al. / Tetrahedron 57 (2001) 71±85
77
3.1. [3aR-(3aa,6a,7ab)]-3H-3a,6-Methano-2,1-benziso-
thiazole, 7,7-dichloro-4,5,6,7-tetrahydro-8,8-dimethyl-
2,2-dioxide (8b)
A solution of dichloroimine 7 (7.81 g, 27.7 mmol) in THF
(100 mL) was added to a stirring suspension of LiAlH4
(1.00 g, 27.7 mmol) in THF (20 mL) at 08C. The reaction
mixture was stirred at this temperature until judged
complete by TLC (less than 1 h) then hydrolyzed by slow
addition of 1.0N HCl over 2 h. The resulting suspension was
diluted with THF (100 mL), ®ltered and the aqueous phase
was extracted with CHCl3 (2£100 mL). The combined
organic phase was dried over MgSO4, ®ltered and concen-
trated to give crude sultam. This was recrystallized from
EtOH to give 6.40 g (89%) of 8b as a white solid. Rf 0.64
(1:1 hexanes/EtOAc); mpˆ203±2048C; [a]2D5ˆ2198 (cˆ
ꢀ7†
1
1.3, CHCl3); H NMR (CDCl3) d 4.93 (br s, 1H, N±H),
3.94 (d, Jˆ5.6 Hz, 1H, H-2), 3.22 (s, 2H, CH2SO2), 2.54
(d, Jˆ4.7 Hz, 1H), 2.32 (1H), 2.10±1.85 (2H), 1.62 (1H),
1.45 (s, 3H, CH3), 1.04 (s, 3H, CH3); 13C NMR (CDCl3) d
93.4, 77.3, 61.6, 56.1, 50.4, 49.8, 30.3, 25.8, 23.3, 23.0; IR
(CHCl3) cm21 3000 (s), 1320 (s), 1210 (s), 1140 (s), 750 (s);
HRMS calcd for C10H15NO2SCl2 (M1) 283.0201, found
283.0201.
3.2. [3aR-(3aa,6a,7ab)]-7,7-Dichloro-4-5,6,7-tetrahydro-
8,8-dimethyl-1-(1-oxo-2-propenyl)-3H-3a,6-methano-
2,1-benzisothiazole 2,2-dioxide (4b)
3. Experimental
All reactions were carried out in oven- or ¯ame-dried glass-
ware under Ar or N2 atmosphere unless otherwise stated.
Solvents and reagents were puri®ed and dried beyond
commercial reagent grade as follows: THF, benzene, and
toluene were distilled from Na/benzophenone under N2.
CHCl3, CH2Cl2, 1,2-dichloroethane, MeCN, DMF, and
Et3N were distilled from CaH2. Analytical (preparative)
TLC was performed on E. Merck 0.25 (0.5) mm precoated
silica gel 60 F-254 and visualized with UV illumination
followed by charring with either 5% anisaldehyde in
(95:5:1) EtOH±AcOH±H2SO4 (char A) or 0.3% ninhydrin
in (97:3) n-BuOH±AcOH (char B). Flash chromatography
was carried out using E. Merck silica gel 60 (230±
400 mesh). Analytical normal and reverse phase HPLC
were performed using Dynamax-60A 8 mm silica gel and
C-18 columns (4.6 mm internal diameter) respectively.
Preparative HPLC separations were performed using
columns with a 21.4 mm internal diameter. Melting points
are uncorrected. Optical rotations were measured at
lˆ589 nm (sodium D line) at room temperature and were
reported as follows: [a]D (concentration, c in g/100 mL,
To a stirred suspension of NaH (0.73 g, 30.31 mmol, 60%
dispersion in mineral oil) in toluene (10 mL) was added
sultam 8b (5.90 g, 20.8 mmol) in toluene (120 mL) under
N2 atmosphere at rt. After stirring for 30 min at the same
temperature, acryloyl chloride (3.36 mL, 41.5 mmol) was
added and the stirring continued for 1 h. At this point, the
reaction was judged complete by TLC. The mixture was
cooled to 08C, quenched with water and the organic phase
was separated. The aqueous phase was extracted with
EtOAc (2£50 mL), and the combined organic phase was
dried over MgSO4, ®ltered and concentrated to give crude
acryloyl sultam which was recrystallized from EtOH to give
6.32 g (90%) of 4b as a white solid. Rf 0.67 (4:1 benzene/
EtOAc); mpˆ213±2148C; [a]2D5ˆ 1138 (cˆ2.0, CHCl3);
1H NMR (CDCl3) d 6.84 (dd, Jˆ16.7, 10.2 Hz, 1H, H-b),
6.63 (d, Jˆ17.0 Hz, 1H, H0-b), 5.97 (d Jˆ11.2 Hz, 1H, H-a)
4.51 (s, 1H, H-2), 3.56 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2),
3.50 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2), 2.58 (d, Jˆ4.4 Hz,
1H), 2.45 (1H), 2.10±1.92 (2H), 1.62 (1H), 1.50 (s, 3H,
CH3), 1.11 (s, 3H, CH3); 13C NMR (CDCl3) d 165.3,
132.7, 127.6, 93.5, 78.6, 62.1, 52.3, 50.6, 49.6, 31.6, 25.4,
24.2, 23.0; IR (CHCl3) cm21 3010 (s), 1700 (s), 1620 (w),
1400 (s), 1340 (s), 1215 (s), 1140 (m), 1070 (m), 985 (m);
HRMS calcd for C13H17NO3SCl2 (M1) 337.0306, found
337.0302.
1
solvent). H NMR spectra were recorded at either 200 or
300 MHz and are reported in parts per million (ppm) on the
d scale relative to residual CHCl3 (d 7.25), C6D5H (d 7.15),
TMS (d 0.00) or HDO (d 4.63). 13C NMR spectra were
acquired at 75 MHz and are reported in parts per million
(ppm) on the d scale relative to CHCl3 (d 77.00). The NMR
experiments were performed at room temperature unless
3.3. [3aR-[1(Sp),3aa,6a,7ab]]-3H-3a,6-Methano-2,1-
benzisothiazole, 7,7-dichloro-4-5,6,7-tetrahydro-8,8-
dimethyl-1-[[1-(phenylmethyl)-2-aziridinyl]carbonyl]-2,2-
dioxide (6c)
1
otherwise indicated. H NMR signal assignments20 were
based on the selective homonuclear decoupling experi-
ments. High resolution mass (HRMS) data were reported
for M1 or the highest mass fragment derived from M1 in
electron impact (EI) mode. Fast atom bombardment ioni-
zation (FAB) was performed on samples in a glycerol
matrix.
Liquid bromine (1 equiv.) was added to a stirring solution of
acryloyl sultam 4c (1 equiv.) in CHCl3 (spectroscopic grade,
concentration approx. 0.3 M) under an Ar/N2 atmosphere.

78
P. Garner et al. / Tetrahedron 57 (2001) 71±85
After stirring at ,508C for 1 h, Et3N (2 equiv.) and benzyl-
amine (1.5 equiv.) were added to the reaction ¯ask and
stirring was continued at ,508C overnight. At this time,
the reaction was judged complete by TLC, and so was
diluted with CHCl3. The organic layer was washed succes-
sively with 0.1N HCl, sat. NaHCO3 soln., brine, and dried
(MgSO4). Evaporation of the solvent and puri®cation of the
residue by recrystallization from EtOAc gave the desired
aziridine 6c in 74% yield; Rf 0.23 (CHCl3); mpˆ240±
dissolved in toluene (concentration approx. 0.3 M) and
sealed in a 5 mL Pyrex tube after degassing. The sealed
tube was heated for the reported period of time (refer to
individual experiments below). The tube was then cooled,
carefully broken open, and the contents concentrated. The
1
crude reaction mixture was analyzed by H NMR then
subjected to chromatographic puri®cation.
3.5.1. [3aR-[1(2Rp,3Rp,4Sp),3aa,6a,7ab]]-3,4-Pyrrolidine-
dicarboxylic acid, 1-(phenylmethyl)-2-[(tetrahydro-8,8-
dimethyl-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)-
carbonyl]-dimethyl ester, S,S-dioxide (14a). Reaction
time: 6 h; temperature 195±2058C; ¯ash chromatography
(SiO2, 3:1 hexanes/EtOAc, further puri®cation was accom-
plished by PTLC on silica gel, eluting twice); total yield of
the cycloadducts 60%; Rf 0.26 (2:1 hexanes/EtOAc);
mpˆ51±538C; [a]D22ˆ1828 (cˆ0.88, CHCl3); 1H NMR
(CDCl3) d 7.36±7.26 (5H, Ph), 4.41 (d, Jˆ4.5 Hz, 1H,
H-2), 3.96 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.96 (dd,
Jˆ7.4, 4.6 Hz, 1H, H-7a), 3.68 (s, 3H, OCH3), 3.63 (s,
3H, OCH3), 3.65 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.50 (d,
Jˆ13.7 Hz, 1H, 1/2CH2SO2), 3.43 (d, Jˆ13.8 Hz, 1H,
1/2CH2SO2), 3.38 (dd, Jˆ14.5, 2.2 Hz, 1H, H-5), 3.29
(dd, Jˆ8.9, 4.6 Hz, 1H, H-3), 3.21 (t, Jˆ8.1 Hz, 1H, H-4),
2.97 (t, Jˆ9.3 Hz, 1H, H-5), 2.20±1.80 (5H), 1.30±1.47
(2H), 1.17 (s, 3H, CH3), 0.97 (s, 3H, CH3); 13C NMR
(CDCl3) d 172.1, 171.8, 171.5, 138.6, 128.8 (2C), 128.3
(2C), 127.1, 68.5, 65.3, 57.7, 53.5, 53.23, 52.3, 52.0, 50.6,
48.6, 47.8, 45.4, 44.7, 38.3, 32.9, 26.5, 20.8, 19.9; IR
(CHCl3) cm21 3670 (w), 3010 (m), 2950 (w), 2380 (w),
1740 (s, CvO), 1430 (w), 1330 (m), 1265 (s), (1215 (s),
1130 (m); HRMS calcd for C26H34N2O7S (M1) 519.2165,
found 519.2168.
1
2418C; [a]2D2ˆ2278 (cˆ0.73, CHCl3); H NMR (CDCl3)
d 7.40±7.20 (5H, Ph), 4.42 (s, 1H, H-7a), 3.86 (d, Jˆ
13.5 Hz, 1H, 1/2 H2Ph), 3.51 (d, Jˆ13.7 Hz, 1H, 1/
2CH2SO2), 3.45 (d, Jˆ13.8 Hz 1H, 1/2CH2SO2), 3.40 (d,
Jˆ13.6 Hz, 1H, 1/2CH2Ph), 2.78 (dd, Jˆ6.3, 3.1 Hz, 1H,
H-2), 2.51 (d, Jˆ4.4 Hz, 1H, H-3), 2.46±2.36 (2H), 2.40±
1.88 (3H), 1.55 (1H), 1.41 (s, 3H, CH3), 1.08 (s, 3H, CH3);
13C NMR (CDCl3) d 173.0, 137.9 (2C) 128.3, 128.2 (2C),
127.2, 103.4, 78.4, 63.8, 62.1, 52.7, 50.9, 49.6, 38.3, 36.7,
31.6, 25.4, 24.2, 22.9; IR (CHCl3) cm21 3010 (m), 1725 (s),
1410 (s), 1340 (s), 1215 (s), 1140 (m), 1060 (m); HRMS
calcd for C20H24N2O3SCl2 (M1) 442.0885, found 442.0885.
3.4. N-(20-Aminoacetyl)bornane-2,10-sultam (10b)
To a stirring suspension of sultam 8b (500 mg, 1.76 mmol)
and NaH (130 mg, 1.84 mmol, 60% oil dispersion) in dry
toluene (19 mL) was added azidoacetyl chloride (525 mg,
4.40 mmol) and the resulting mixture was stirred 3 h,
whereupon TLC analysis indicated complete consumption
of 8b. The reaction mixture was cooled in an ice bath and
hydrolyzed by slow addition of water. The aqueous layer
was separated, extracted with CH2Cl2 (2£25 mL), dried
(MgSO4), and concentrated to give crude azide which was
puri®ed by ¯ash chromatography on silica gel (2:1 hexanes/
EtOAc) to give 11 in 75% yield. Rf 0.5 (1:1 hexanes/
EtOAc); 1H NMR (CDCl3) d 4.50 (d, Jˆ16.8 Hz, 1H,
H-7a), 4.47 (s, 1H, H-2), 4.23 (d, Jˆ17.2 Hz, 1H, H-7a0),
3.53 (s, 2H, CH2SO2), 2.59 (d, Jˆ4.51 Hz, 1H), 2.45 (1H),
2.12±1.93 (2H), 1.68±1.54 (1H), 1.46 (s, 3H, CH3), 1.10 (s,
3H, CH3). 10b: To a stirred solution of 11 (450 mg,
1.23 mmol) in THF (20 mL) was added PPh3 (322 mg,
1.23 mmol) and H2O (0.05 mL). After stirring the mixture
at room temperature for 30 h, TLC analysis showed
complete consumption of 10. The mixture was then diluted
with THF (20 mL), and HCl (0.2N, 5 mL) was added. The
aqueous layer was separated, extracted with EtOAc
(2£15 mL), then neutralized with saturated NaHCO3 and
further extracted with CH2Cl2 (5£25 mL). The combined
organic layers were dried (MgSO4), and concentrated to
give 297 mg (71%) of 11b. Rf 0.15 (1:1 hexanes/EtOAc);
1H NMR (CDCl3) d 4.43 (s, 1H, H-2), 4.06 (d, Jˆ18.2 Hz,
1H, H-7a), 3.76 (d, Jˆ18.2 Hz, 1H, H-7a0), 3.50 (s, 2H,
CH2SO2), 2.57 (d, Jˆ4.5 Hz, 1H), 2.42 (1H), 2.10±1.90
(2H), 1.60 (2H), 1.46 (s, 3H, CH3), 1.09 (s, 3H, CH3); 13C
NMR (CDCl3) d 132.0, 128.6, 93.4, 78.6, 62.1, 52.4, 50.4,
49.6, 31.6, 30.4, 25.4, 24.1; IR (CHCl3) cm21 3010 (m),
2960 (m), 1710(s), 1340 (s),1270 (s), 1220 (s), 1130 (s),
1050 (m) HRMS calcd for C10H15NO2SCl2 ([M2
COCHNH2]1) 283.0200, found 283.0187.
3.5.2. [3aR-[1(2Sp,3Sp,4Rp),3aa,6a,7ab]]-3,4-Pyrrolidine-
dicarboxylic acid, 1-(phenylmethyl)-2-[(tetrahydro-8,8-
dimethyl-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)-
carbonyl]-dimethyl ester, S,S-dioxide (15a). Rf 0.26 (2:1
1
hexanes/EtOAc); H NMR (CDCl3) d 7.40±7.20 (5H, Ph),
4.42 (d, Jˆ3.2 Hz, 1H, H-2), 4.00 (d, Jˆ13.4 Hz, 1H,
1/2CH2Ph), 3.83 (d, Jˆ13.4 Hz, 1H, 1/2CH2Ph), 3.71 (s,
3H, OCH3), 3.65 (s, 3H, OCH3), 3.65 (dd, Jˆ6.0, 3.0 Hz,
1H, H-7a), 3.56 (dd, Jˆ9.1, 7.7 Hz, 1H, H-5), 3.50
(dd, Jˆ8.2, 3.4 Hz, 1H, H-3), 3.44 (d, Jˆ13.8 Hz, 1H,
1/2CH2SO2), 3.37 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.30
(1H, dd, Jˆ8.9, 7.3 Hz, H-4), 3.10 (1H, t, Jˆ9.2 Hz, H-5),
2.10±1.80 (5H, m), 1.40±1.20 (2H, m), 0.93 (3H, s, CH3),
0.92 (3H, s, CH3); 13C NMR (CDCl3) d 172.4, 172.1, 171.7,
138.7, 128.7 (2C), 128.4 (2C), 127.2, 67.2, 65.4, 58.3, 54.6,
53.1, 52.4, 52.0, 49.9, 45.6, 47.7, 45.5, 44.8, 38.6, 33.0,
26.4, 21.1, 19.9.
3.5.3. [3aR-[1(2Rp,3Rp,4Sp),3aa,6a,7ab]]-3,4-Pyrrolidine-
dicarboxylic acid, 1-(4-methoxyphenyl)-2-[(tetrahydro-
8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-
yl)carbonyl]-dimethyl ester, S,S-dioxide (14b). Reaction
time: 6 h; temperature 195±2058C; ¯ash chromatography
(SiO2, 2:1 hexanes/EtOAc); total yield of the cycloadducts
82%; (isolated as a 9/1 mixture); Rf 0.13 (2:1 hexanes/
1
EtOAc); [a]2D3ˆ1148 (cˆ4.0, CHCl3); H NMR (C6D6) d
6.95±6.86 (4H, arom.), 5.82 (s, 1H, H-2), 4.21 (t, Jˆ8.9 Hz,
1H, H-4), 3.88 (t, Jˆ8.6 Hz, 1H, H-5), 3.79 (d, Jˆ7.2 Hz,
1H, H-3), 3.65 (dt, Jˆ9.1, 2.0 Hz, 1H, H-5), 3.47 (dd,
3.5. General procedure for aziridine thermolyses
The starting aziridine and dipolarophile (3 equiv.) were

P. Garner et al. / Tetrahedron 57 (2001) 71±85
79
Jˆ5.9, 2.8 Hz, 1H, H-7a), 3.37 (s, 3H, OCH3), 3.53 (s, 3H,
OCH3), 3.30 (s, 3H, OCH3), 2.77 (d, Jˆ13.9 Hz, 1H,
1/2CH2SO2), 2.70 (d, Jˆ13.9 Hz, 1H, 1/2CH2SO2), 1.91
(1H), 1.78 (dd, Jˆ7.9, 6.0 Hz, 1H), 1.29 (3H), 1.22±1.10
(1H), 0.94 (s, 3H, CH3), 0.75±0.50 (2H), 0.37 (s, 3H,
CH3); 13C NMR (CDCl3) d 171.1, 170.6, 151.0, 140.1,
115.1 (2C), 113.2, 113.1 (2C), 66.3, 64.7, 55.9, 52.9,
52.8, 52.3, 48.9, 48.2, 48.0, 48.0, 44.5, 43.7, 38.3, 37.3,
26.4, 21.0, 19.9; IR (CHCl3) cm21 3680 (w), 3010 (m),
2950 (w), 2480 (w), 1735 (s, CvO), 1695 (m), 1510 (s),
1430 (m), 1330 (s), 1260 (s), (1215 (s), 1125 (m), 1030 (m);
HRMS calcd for C26H34N2O8S (M1) 535.2114, found
535.2085.
3.5.6. [3aR-[1(1Sp,3aSp,6aRp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[[octa-
hydro-4,6-dioxo-5-phenyl-2-(phenylmethyl)pyrrolo[3,4-c]-
pyrrol-1-yl]carbonyl]-2,2-dioxide (19a). Rf 0.41 (5:1
1
benzene/EtOAc); [a]2D3ˆ1188 (cˆ1.1, CHCl3); H NMR
(C6D6) d 7.63 (d, Jˆ8.8 Hz, 2H, arom.), 7.27 (d, Jˆ
8.8 Hz, 2H, arom.), 7.05±6.90 (6H, Ph), 4.29 (d, Jˆ
8.7 Hz, 1H, H-1), 3.86 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph),
3.85 (1H, H-7a), 3.75 (t, Jˆ8.4 Hz, 1H, H-6a), 3.36 (d,
Jˆ9.7 Hz, 1H, H-3), 3.32 (d, Jˆ13.4 Hz, 1H, 1/2CH2Ph),
2.86 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 2.78 (d, Jˆ13.7 Hz,
1H, 1/2CH2SO2), 2.42 (t, Jˆ7.4 Hz, 1H, H-3a), 2.05±1.85
(3H), 1.40±1.18 (3H), 1.05 (s, 3H, CH3), 0.70 (1H), 0.50
(1H), 0.50 (s, 3H, CH3); 13C NMR (CDCl3) d 177.5, 175.7,
168.2, 136.5, 132.1, 129.2 (2C), 128.9 (2C), 128.6, 128.5
(2C), 127.6, 126.8 (2C), 68.4, 66.1, 56.4, 54.0, 53.3, 48.8,
47.91, 45.0, 44.3, 38.9, 32.9, 29.8, 26.3, 21.3, 19.9; IR
(CHCl3) cm21 3010 (m), 1710 (s, CvO), 1490 (w), 1370
(m), 1335 (m), 1260 (m), 1200 (s), 1125 (m); HRMS calcd
for C19H17N2O3 ([M2C11H16NO3S]1) 305.1289, found
305.1273.
3.5.4. [3aR-[1(1Rp,3aRp,6aSp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[[octa-
hydro-4,6-dioxo-5-phenyl-2-(phenylmethyl)pyrrolo[3,4-c]-
pyrrol-1-yl]carbonyl]-2,2-dioxide (17a). Reaction time:
15 h; temperature 167±1708C; ¯ash chromatography
(SiO2, 3:1 hexanes/EtOAc); total yield of the cycloadducts
80%; Rf 0.35 (2:1 hexanes/EtOAc); mpˆ287±2898C;
1
[a]2D4ˆ11088 (cˆ1.94, CHCl3); H NMR (C6D6) d 7.42
(d, Jˆ8.2, 2H, Ph), 7.38 (d, Jˆ8.2, 2H, Ph), 6.90 (6H,
Ph), 4.31 (d, Jˆ7.6 Hz, 1H, H-1), 4.29 (d, Jˆ12.8 Hz, 1H,
1/2CH2Ph), 3.68 (dd, Jˆ7.8, 4.7 Hz, 1H, H-7a), 3.48 (t, Jˆ
8.1 Hz, 1H, H-6a), 3.31 (d, Jˆ9.5 Hz, 1H, H-3), 3.24
(d, Jˆ13.1 Hz, 1H, 1/2CH2Ph), 2.92 (d, Jˆ13.8 Hz, 1H,
1/2CH2SO2), 2.79 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 2.77
(1H), 2.43 (t, Jˆ7.9 Hz, 1H, H-3a), 1.91 (dd, Jˆ14.0,
7.9 Hz, 1H), 1.83 (dd, Jˆ9.7, 7.7 Hz, H-3), 1.47 (s, 3H,
CH3), 1.40±1.25 (2H), 1.15 (1H), 0.79 (1H), 0.63 (1H),
0.49 (s, 3H, CH3); 13C NMR (CDCl3) d 177.4, 175.4,
167.4, 137.6, 132.0, 129.3 (2C), 128.8, 128.4 (2C), 128.4
(2C), 127.4, 126.8 (2C), 68.9, 65.8, 56.7, 54.6, 53.4, 48.8,
48.0, 44.6, 43.8, 37.5, 32.9, 26.7, 20.5, 20.1; IR (CHCl3)
cm21 3660 (w), 3000 (m), 2950 (w), 2380 (w), 1710 (s,
CvO), 1490 (w), 1380 (m), 1320 (m), 1265 (m), 1200
(s), 1125 (m); HRMS calcd for C19H17N2O3 ([M2
C11H16NO3S]1) 305.1289, found 305.1292.
3.5.7. [3aR-[1(1Rp,3aRp,6aSp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[[octa-
hydro-4,6-dioxo-5-phenyl-2-(4-methoxyphenyl)pyrrolo-
[3,4-c]pyrrol-1-yl]carbonyl]-2,2-dioxide (17b). Reaction
time: 6 h; temperature 175±1808C; ¯ash chromatography
(SiO2, 3:1 hexanes/EtOAc); total yield of the cycloadducts
93%; Rf 0.33 (1:1 hexanes/EtOAc); mpˆ162±1648C;
1
[a]2D3ˆ11098 (cˆ1.2, CHCl3); H NMR (C6D6) d 7.51±
7.25 (5H, arom.), 6.97 (d, Jˆ9.0 Hz, 2H, arom.), 6.82 (d,
Jˆ8.9 Hz, 2H, arom.), 4.84 (d, Jˆ7.9 Hz, 1H, H-1), 4.12 (d,
Jˆ10.4 Hz, 1H, H-3), 4.04 (t, Jˆ8.1 Hz, 1H, H-6a), 3.96
(dd, Jˆ7.7, 4.8 Hz, 1H, H-7a), 3.74 (s, 3H, OCH3), 3.61
(d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.58 (d, Jˆ13.9 Hz, 1H,
1/2CH2SO2), 3.53 (dd, Jˆ8.8, 7.1 Hz, 1H, H-3a), 3.27 (dd,
Jˆ9.9, 8.2 Hz, 1H, H-3), 2.50 (1H), 2.01±1.83 (4H), 1.50±
1.30 (2H), 1.32 (s, 3H, CH3), 0.96 (s, 3H, CH3); 13C NMR
(C6D6) d 177.2, 174.9, 166.3, 156.4, 140.2, 131.7, 129.2
(2C), 128.8, 126.8 (2C), 121.1 (2C), 114.5 (2C), 66.0,
65.3, 57.4, 55.5, 53.3, 48.8, 48.8, 48.0, 47.9, 44.5, 43.8,
37.5, 33.0, 26.6, 20.4, 20.2; IR (CHCl3) cm21 3000 (m),
1710 (s, CvO), 1510 (s), 1380 (w), 1320 (w), 1210 (s);
HRMS calcd for C30H33N3O6S (M1) 563.2090, found
563.2073.
3.5.5. [3aR-[1(1Rp,3aSp,6aRp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[[octa-
hydro-4,6-dioxo-5-phenyl-2-(phenylmethyl)pyrrolo[3,4-c]-
pyrrol-1-yl]carbonyl]-2,2-dioxide (18a). To separate this
cycloadduct from 17a, a second ¯ash chromatography
eluting with 5:1 benzene/EtOAc, was necessary; Rf 0.28
(5:1 benzene/EtOAc); [a]2D3ˆ1378 (cˆ2.4, CHCl3); 1H
NMR (C6D6, 708C) d 7.40 (d, Jˆ8.1 Hz, 2H, Ph), 7.24±
6.95 (8H, Ph), 4.82 (br s, 1H, H-1), 4.11 (d, Jˆ13.2 Hz,
1H, 1/2CH2Ph), 3.91 (d, Jˆ13.2 Hz, 1H, 1/2CH2Ph), 3.72
(dd, Jˆ7.8, 4.8 Hz, 1H, H-7a), 3.25 (d, Jˆ9.5 Hz, 1H, H-3),
3.11 (d, Jˆ8.4 Hz, 1H, H-6a), 2.97 (t, Jˆ8.4 Hz, 1H, H-3a),
2.88 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2), 2.76 (d, Jˆ13.7 Hz,
1H, 1/2CH2SO2), 1.81 (dd, Jˆ9.5, 8.3 Hz, 1H, H-3), 1.45±
1.15 (4H), 1.08 (s, 3H, CH3), 0.90±0.70 (3H), 0.49 (s, 3H,
CH3); 13C NMR (CDCl3) d 177.6, 175.5, 171.1, 138.3,
132.2, 129.1 (2C), 128.7, 128.5 (2C), 128.4 (2C), 127.3,
126.4 (2C), 65.8, 64.5, 54.3, 53.8, 52.7, 49.5, 49.1, 47.9,
45.0, 44.4, 38.4, 33.1, 26.3, 21.0, 19.9; IR (CHCl3) cm21
3670 (w), 3010 (m), 2960 (w), 2380 (w), 1710 (s, CvO),
1490 (w), 1370 (m), 1335 (m), 1260 (m), 1200 (s), 1160
(m), 1125 (m); HRMS calcd for C19H18N2O3 ([M2
C11H15NO3S]1) 306.1368, found 306.1357.
3.5.8. [3aR-[1(1Rp,3aSp,6aRp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[[octa-
hydro-4,6-dioxo-5-phenyl-2-(4-methoxyphenyl)pyrrolo-
[3,4-c]pyrrol-1-yl]carbonyl]-2,2-dioxide (18b). Rf 0.50
1
(1:1 hexanes/EtOAc); [a]2D3ˆ1988 (cˆ0.82, CHCl3); H
NMR (C6D6) d 7.26 (d, Jˆ9.04 Hz, 2H, arom.), 7.20±
6.80 (7H, arom.), 6.10 (s, 1H, H-1), 4.16 (t, Jˆ9.6 Hz,
1H, H-3), 3.89 (dd, Jˆ9.3, 2.1 Hz, 1H, H-3), 3.38 (d,
Jˆ8.3 Hz, 1H, H-6a), 3.31 (s, 3H, OCH3), 3.22 (1H,
H-7a), 3.06 (t, Jˆ8.12 Hz, 1H, H-3a), 2.91 (d, Jˆ13.8 Hz,
1H, 1/2CH2SO2), 2.88 (d, Jˆ13.9 Hz, 1H, 1/2CH2SO2),
2.00 (1H), 1.81 (1H), 1.41±1.22 (3H), 1.13 (s, 3H, CH3),
1.12 (1H), 0.76 (1H), 0.48 (s, 3H, CH3); 13C NMR (CDCl3)
d 177.1, 172.0, 170.8, 153.0, 139.9, 131.7, 129.1 (2C),
128.8, 126.4 (2C), 115.6 (2C), 115.0 (2C), 65.1, 63.8,
55.7, 52.9, 52.4, 49.7, 49.1, 48.0, 44.7, 43.2, 38.4, 32.8,
26.4, 21.2, 19.2; IR (CHCl3) cm21 3000 (m), 1720 (s,

80
P. Garner et al. / Tetrahedron 57 (2001) 71±85
CvO), 1515 (s), 1375 (m), 1335 (m), 1230 (s); HRMS calcd
for C30H33N3O6S (M1) 563.2090, found 563.2099.
55.9, 53.4, 52.8, 50.8, 49.4, 48.1, 44.5, 31.8, 25.3, 24.7,
23.0; IR (CHCl3) cm21 3000 (m), 1710 (s, CvO), 1490
(w), 1380 (m), 1340 (m), (1200 (s); HRMS calcd for
C15H18NO3 ([M2 C11H14NO3SCl2]1) 305.1289, found
305.1298.
3.5.9. [3aR-[1(1Sp,3aSp,6aRp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[[octa-
hydro-4,6-dioxo-5-phenyl-2-(4-methoxyphenyl)pyrrolo-
[3,4-c]pyrrol-1-yl]carbonyl]-2,2-dioxide (19b). Rf 0.31
(1:1 hexanes/EtOAc); mpˆ162±1648C; [a]2D3ˆ11098 (cˆ
3.5.12. [3aR-[1(2Rp,3Rp),3aa,6a,7ab)]]-3-Pyrrolidine-
dicarboxylic acid, 1-(phenylmethyl)-2-[(tetrahydro-8,8-
dimethyl-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)-
carbonyl]-methyl ester, S,S-dioxide (22a). Reaction time:
20 h; temperature 195±1978C; ¯ash chromatography (SiO2,
2:1 hexanes/EtOAc, all the diastereomers eluted together
but most of 22a was separated by recrystallization from
3:1 hexanes/EtOAc); total yield of the cycloadducts
75.0%; Rf 0.59 (2:1 hexanes/EtOAc); mpˆ151±1528C;
1
1.2, CHCl3); H NMR (C6D6) d 7.55 (d, Jˆ8.2 Hz, 2H,
arom.), 7.20±7.05 (3H, arom.), 6.93 (d, Jˆ9.0 Hz, 2H,
arom.), 6.81 (d, Jˆ9.1 Hz, 2H, arom.), 5.26 (d, Jˆ9.2 Hz,
1H, H-1), 4.02 (dd, Jˆ9.3, 3.5 Hz, 1H, H-3), 3.83 (dd, Jˆ
7.7, 4.9 Hz, 1H, H-7a), 3.76 (t, Jˆ9.0 Hz, 1H, H-6a), 3.32
(s, 3H, OCH3), 2.91 (t, Jˆ9.2 Hz, 1H, H-3), 2.88 (d,
Jˆ13.7 Hz, 1H, 1/2CH2SO2), 2.85 (d, Jˆ13.7 Hz, 1H,
1/2CH2SO2), 2.70 (ddd, Jˆ9.1, 8.5, 3.5 Hz, 1H, H-3a),
1.93 (1H), 1.73 (dd, Jˆ8.0, 6.1 Hz, 1H), 1.40±1.14 (2H),
1.13 (s, 3H, CH3), 1.08±0.96 (1H), 0.67±0.45 (2H), 0.41 (s,
3H, CH3); 13C NMR (C6D6) d 176.0, 175.1, 169.5, 154.4,
140.6, 132.9, 128.8 (2C), 128.3, 127.5 (2C), 118.1 (2C),
114.7 (2C), 65.7, 64.7, 54.8, 54.0, 52.5, 48.5, 48.2, 47.3,
44.7, 44.4, 38.4, 32.2, 25.8, 20.9, 19.4; IR (CHCl3) cm21
3000 (m), 1720 (s, CvO), 1510 (s), 1370 (w), 1335 (w),
1240 (s), 1125 (w), 1040 (s).
1
[a]2D3ˆ11568 (cˆ2.0, CHCl3); H NMR (CDCl3) d 7.38±
7.20 (5H, Ph), 4.26 (d, Jˆ5.7 Hz, 1H, H-2), 3.93 (1H, H-7a),
3.92 (d, Jˆ12.9 Hz, 1H, 1/2CH2Ph), 3.68 (s, 3H, OCH3),
3.56 (d, Jˆ13.1 Hz, 1H, 1/2CH2Ph), 3.51 (d, Jˆ13.7 Hz,
1H, 1/2CH2SO2), 3.42 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2),
3.08 (1H, H-3), 3.02 (1H, H-5), 2.60 (q, Jˆ8.5 Hz, 1H,
H-5), 2.08 (4H), 1.89 (3H), 1.42±1.25 (2H), 1.15 (s, 3H,
CH3), 0.97 (s, 3H, CH3); 13C NMR (CDCl3) d 173.8,
172.7, 139.1, 128.8 (2C), 128.2 (2C), 127.0, 68.9, 65.4,
57.6, 53.3, 52.2, 51.9, 48.8, 48.5, 47.8, 44.7, 38.4, 33.0,
28.2, 26.5, 20.8, 20.0; IR (CHCl3) cm21 3010 (m), 1735
(s), 1700 (s), 1450 (w), 1335 (m), 1265 (m), 1200 (m),
1130 (m); HRMS calcd for C24H33N2O5S ([M1H]1)
461.2110, found 461.2105.
3.5.10. [3aR-[1(1Rp,3aSp,6aRp),3aa,6a,7ab]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, 7,7-dichloro-4,5,6,7-tetrahydro-
8,8-dimethyl-1-[[octahydro-4,6-dioxo-5-phenyl-2-(phenyl-
methyl)pyrrolo[3,4-c]pyrrol-1-yl]carbonyl]-2,2-dioxide
(18c). Reaction time: 8 h; temperature 184±1868C; ¯ash
chromatography (SiO2, 4:1 hexanes/EtOAc); total yield of
the cycloadducts 91%; Rf 0.46 (2:1 hexanes/EtOAc);
3.5.13. 3-Pyrrolidinedicarboxylic acid, 1-(phenylmethyl)-
5-[(tetrahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benz-
isothiazol-1(4H)-yl)carbonyl]-methyl ester, S,S-dioxide
(23a). Separation of this diastereomer from other minor
diastereomers was accomplished by HPLC (100 mg sample,
3:1 hexanes/EtOAc, semiprep column, rt, 10 mL/min,
Schimadzu-spectro¯ow detector) Rf 0.58 (2:1 hexanes/
EtOAc); mpˆ142±1448C; [a]2D3ˆ11308 (cˆ1.9, CHCl3);
1H NMR (CDCl3) d 7.38±7.20 (5H, Ph), 4.10 (dd, Jˆ
9.40, 6.2 Hz, 1H, H-2), 3.92 (1H, H-7a), 3.91 (d, Jˆ
12.7 Hz, 1H, 1/2CH2Ph), 3.65 (s, 3H, OCH3), 3.51 (d, Jˆ
13.8 Hz, 1H, 1/2CH2SO2), 3.47 (d, Jˆ12.9 Hz, 1H, 1/
2CH2Ph), 3.44 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.23 (t,
Jˆ8.5 Hz, 1H, H-5), 3.11 (1H, H-4), 2.68 (ddd, Jˆ9.5,
7.6, 5.8 Hz, 1H, H-3), 2.60 (t, Jˆ8.6 Hz, 1H, H-5), 2.08
(3H), 1.88 (3H), 1.40 (2H), 1.13 (s, 3H, CH3), 0.93 (s, 3H,
CH3); 13C NMR (CDCl3) d 174.0, 172.4, 138.2, 129.1 (2C),
128.3 (2C), 127.2, 65.6, 65.2, 57.6, 55.0, 53.2, 52.0, 48.7,
47.9, 44.6, 41.3, 38.3, 33.4, 32.8, 26.5, 20.9, 19.9; IR
(CHCl3) cm21 2970 (m), 1730 (s), 1700 (s), 1450 (w),
1330 (s), 1260 (s), 1210 (s), 1130 (s); HRMS m/z calcd
for C13H16NO2 ([M2C11H16NO3S]1) 218.1181, found
218.1186.
1
mpˆ225±2278C; [a]D22ˆ1128 (cˆ0.5, CHCl3); H NMR
(CDCl3) d 7.50±7.20 (10 H, 2£Ph), 5.08 (s, 1H, H-1),
4.55 (s, 1H, H-7a), 4.14 (d, Jˆ13.6 Hz, 1H, 1/2CH2Ph),
3.88 (d, Jˆ13.7 Hz, 1H, 1/2CH2Ph), 3.73 (dd, Jˆ9.1,
6.7 Hz, 1H, H-6a), 3.58 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2),
3.52 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.38 (dd, Jˆ9.0,
6.4 Hz, 1H, H-3), 3.24 (d, Jˆ8.67 Hz, 1H, H-3a), 2.60 (d,
Jˆ4.27 Hz, 1H), 2.45 (1H), 2.01 (3H), 1.62 (1H), 1.52 (s,
3H, CH3), 1.11 (s, 3H, CH3); 13C NMR (CDCl3) d 177.7,
175.3, 173.3, 138.4, 132.0, 129.2 (2C), 128.7, 128.5 (2C),
128.0 (2C), 127.2, 126.4 (2C), 94.0, 78.1, 67.5, 62.3, 53.4,
53.3, 52.7, 50.8, 50.3, 49.7, 44.0, 31.6, 25.5, 24.3, 22.9; IR
(CHCl3) cm21 3000 (m), 1715 (s, CvO), 1200 (s), 750 (s);
HRMS calcd for C15H18NO3 ([M2C11H14NO3SCl2)]1)
305.1289, found 305.1292.
3.5.11. [3aR-[1(1Sp,3aSp,6aRp),3aa,6a,7ab]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, 7,7-dichloro-4,5,6,7-tetrahydro-
8,8-dimethyl-1-[[octahydro-4,6-dioxo-5-phenyl-2-
(phenylmethyl)pyrrolo[3,4-c]pyrrol-1-yl]carbonyl]-2,2-
dioxide (19c). Rf 0.21 (2:1 hexanes/EtOAc); [a]2D2ˆ2228
1
(cˆ1.9, CHCl3); H NMR (CDCl3) d 7.50±7.23 (10 H,
2£Ph), 4.57 (s, 1H, H-7a), 4.22 (d, Jˆ8.5 Hz, 1H, H-1),
4.10 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.97 (t, Jˆ8.4 Hz
1H, H-6a), 3.59 (s, 2H, CH2SO2), 3.51 (d, Jˆ13.3 Hz, 1H,
1/2CH2Ph), 3.47 (d, Jˆ10.7 Hz, 1H, H-3), 3.32 (t,
Jˆ7.3 Hz, 1H, H-3a), 2.63 (dd, Jˆ9.6, 7.3 Hz 1H, H-3),
2.58 (d, Jˆ4.4 Hz 1H), 2.45 (1H), 2.00 (2H), 1.62 (1H),
1.55 (s, 3H, CH3), 1.12 (s, 3H, CH3); 13C NMR (CDCl3) d
177.3, 175.7, 169.9, 135.8, 132.1, 129.4,(2C), 129.1 (2C),
128.6, 128.4 (2C), 127.6, 126.8 (2C), 93.6, 79.5, 68.6, 62.4,
3.5.14. [3aR-[1(2Rp,3Rp),3aa,6a,7ab)]]-3-Pyrrolidine-
dicarboxylic acid, 1-(phenylmethyl)-2-[(7,7-dichloro-
4,5,6,7-tetrahydro-8,8-dimethyl-3H-3a,6-methano-2,1-
benzisothiazol-1(4H)-yl)carbonyl]-methyl ester, S,S-
dioxide (22c). Reaction time: 9 h; temperature 184±
1868C; ¯ash chromatography (SiO2, 3:1 hexanes/EtOAc,
this diastereomer was separated from the other one via
partial recrystallization from 1:1 hexanes/EtOAc; total
yield of the cycloadducts 84%; Rf 0.45 (2:1 hexanes/

P. Garner et al. / Tetrahedron 57 (2001) 71±85
81
EtOAc); mpˆ201±2038C; [a]2D2ˆ1278 (cˆ0.74, CHCl3);
1H NMR (CDCl3) d 7.40±7.20 (5H, Ph), 4.55 (s, 1H,
H-7a), 4.51 (d, Jˆ4.8 Hz, 1H, H-2), 4.02 (d, Jˆ13.3 Hz,
1H, 1/2CH2Ph), 3.70 (s, 3H, OCH3), 3.65 (d, Jˆ13.3 Hz,
1H, 1/2CH2Ph), 3.52 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2), 3.46
(d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.32 (1H, H-3), 3.03 (1H,
H-5), 2.65 (dd, Jˆ15.9, 8.6, 1H, H-5), 2.57 (d, Jˆ4.4 Hz,
1H), 2.45 (1H), 2.20±1.90 (4H), 1.62 (2H), 1.48 (s, 3H,
CH3), 1.09 (s, 3H, CH3); 13C NMR (CDCl3) d 174.5,
170.0, 139.2, 128.7 (2C), 122.2, 126.9 (2C), 93.7, 78.5,
69.6, 62.3, 57.1, 52.9, 52.2, 51.4, 50.6, 49.6, 48.6, 31.6,
28.6, 25.4, 23.8, 22.9; IR (CHCl3) cm21 3010 (m), 1730
(s, CvO), 1430 (w), 1340 (s), 1265 (m), (1215 (s), 1130
(m); HRMS calcd for C13H16NO2 ([M2C11H14NO3SCl2]1)
218.1181, found 218.1181.
(pyrrole 17a was formed in 22%); Rfˆ0.20 (2:1 hexanes/
EtOAc); [a]2D3ˆ11498 (cˆ2.0, CHCl3); 1H NMR (CDCl3 d
7.35±7.26 (5H, Ph), 5.47 (dd, Jˆ7.0, 5.1 Hz, 1H, H-3a),
4.97 (dd, Jˆ7.0, 4.3 Hz, 1H, H-6a), 4.11 (d, Jˆ13.2 Hz,
1H, 1/2CH2Ph), 4.00 (dd, Jˆ7.7, 4.8 Hz, 1H, H-7a), 3.88
(d, Jˆ5.1 Hz, 1H, H-4), 3.55 (d, Jˆ13.7 Hz, 1H, 1/
2CH2SO2), 3.49 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2), 3.40 (d,
Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.27 (d, Jˆ11.7 Hz, 1H, H-6),
2.38 (dd, Jˆ11.8, 4.4 Hz, 1H, H-6), 2.28±1.86 (4H), 1.89
(3H), 1.49±1.20 (3H), 1.18 (s, 3H, CH3), 0.98 (s, 3H, CH3);
13C NMR (CDCl3) d 164.64, 154.1, 135.9, 129.1 (2C), 128.2
(2C), 127.6, 80.1, 77.8, 69.6, 65.5, 56.2, 55.8, 53.3, 49.1,
48.0, 44.4, 37.9, 32.7, 26.6, 20.4, 20.0; IR (CHCl3) cm21
3000 (m), 1810 (s), 1710 (m), 1330 (m), 1260 (m), 1210
(m), 1150 (m), 1080 (m); HRMS calcd for C12H12NO3
([M2C11H16NO3S]1) 218.0817, found 218.0805.
3.5.15. 3-Pyrrolidinedicarboxylic acid, 1-(phenylmethyl)-
5-[(7,7-dichloro-4,5,6,7-tetrahydro-8,8-dimethyl-3H-3a,6-
methano-2,1-benzisothiazol-1(4H)-yl)carbonyl]-methyl
ester, S,S-dioxide (23c). Rf 0.46 (2:1 hexanes/EtOAc);
mpˆ51±538C; [a]D22ˆ1828 (cˆ0.88, CHCl3); 1H NMR
(CDCl3) d 7.40±7.20 (5H, Ph), 4.53 (s, 1H, H-7a), 4.33
(d, Jˆ9.3, 5.5 Hz, 1H, H-2), 4.02 (d, Jˆ13.2 Hz, 1H,
1/2CH2Ph), 3.64 (s, 3H, OCH3), 3.58 (d, Jˆ12.9 Hz, 1H,
1/2CH2Ph), 3.53 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2), 3.49 (d,
Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.26 (t, Jˆ8.3 Hz, 1H, H-5),
3.16 (1H, H-4), 2.68 (2H), 2.57 (d, Jˆ4.40 Hz, 1H), 2.45
(2H), 2.00 (2H), 1.62 (2H), 1.47 (s, 3H, CH3), 1.09 (s, 3H,
CH3); 13C NMR (CDCl3) d 174.3, 174.2; 138.5 128.8 (2C),
128.2, 127.1 (2C), 93.7, 78.4, 66.4, 62.2, 57.1, 54.6, 52.8,
52.0, 50.7, 49.6, 41.2, 33.5, 31.6, 25.4, 24.1, 22.9; IR
(CHCl3) cm21 3010 (m), 1730 (s), 1430 (w), 1340 (s),
1265 (m), (1215 (s), 1130 (m); HRMS calcd for
C13H16NO2 ([M2C11H14NO3SCl2]1) 218.1181, found
218.1177.
3.5.18.
[3aR-[(3aRp,4Rp,6aSp),3aa,6a,7ab)]]-3H-3a,6-
Methano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-
4-[[tetrahydro-1,3-dioxolo-5-(4-methoxyphenyl)-2-oxo-
[4,5-c]pyrrole-4-yl]carbonyl]-2,2-dioxide (26b). Rf 0.40
(1:1 hexanes/EtOAc); mpˆ322±3248C; [a]2D3ˆ2328
1
(cˆ1.4, CHCl3); H NMR (CDCl3) d 6.82 (d, Jˆ9.2 Hz,
2H, arom.), 6.76 (d, Jˆ9.2 Hz, 2H, arom.), 5.61 (dd,
Jˆ7.4, 6.7 Hz, 1H, H-3a), 5.25 (dt, Jˆ5.8, 2.3 Hz, 1H,
H-6a), 5.06 (d, Jˆ6.7 Hz, 1H, H-4), 4.03 (dd, Jˆ11.4,
2.0 Hz, 1H, H-6), 3.96 (dd, Jˆ7.6, 4.9 Hz, 1H, H-7a),
3.74 (s, 3H, OCH3), 3.60 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2),
3.55 (dd, Jˆ11.3, 5.9 Hz, 1H, H-6), 3.53 (d, Jˆ13.9 Hz, 1H,
1/2CH2SO2), 2.20±1.85 (5H), 1.48±1.28 (2H), 1.24 (s, 3H,
CH3), 0.99 (s, 3H, CH3); 13C NMR (CDCl3) d 167.3, 154.0,
153.5, 139.0, 115.8 (2C), 114.9 (2C), 78.6, 78.0, 65.7, 64.5,
55.7, 55.2, 53.2, 49.1, 47.9, 44.9, 38.3, 32.9, 26.2, 20.9,
20.0; IR (CHCl3) cm21 3680 (w), 3010 (m), 2950 (w),
2480 (w), 1735 (s, CvO), 1695 (m), 1510 (s), 1430 (m),
1330 (s), 1260 (s), (1215 (s), 1125 (m), 1030 (m); HRMS
calcd for C23H28N2O7S (M1) 476.1617, found 476.1624.
3.5.16. [3aR-[(3aRp,4Rp,6aSp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-4-[[tetra-
hydro-1,3-dioxolo-5-(phenylmethyl)-2-oxo-[4,5-c]pyrrole-
4-yl]carbonyl]-2,2-dioxide (26a). Rfˆ0.16 (2:1 hexanes/
EtOAc); [a]2D3ˆ25.88 (cˆ1.7, CHCl3); mpˆ101±1038C;
1H NMR (CDCl3 d 7.38±7.26 (5H, Ph), 5.49 (dd, Jˆ7.1,
5.4 Hz, 1H, H-3a), 4.98 (dd, Jˆ7.1, 4.2 Hz, 1H, H-6a), 4.05
(dd, Jˆ7.2, 5.5 Hz, 1H, H-7a), 3.97 (d, Jˆ5.4 Hz, 1H, H-4),
3.87 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.54 (d, Jˆ13.8 Hz,
1H, 1/2CH2SO2), 3.49 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph),
3.47 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.32 (d, Jˆ11.7 Hz,
1H, H-6), 2.50 (dd, Jˆ11.7, 4.5 Hz, 1H, H-6), 2.13 (1H),
1.89 (3H), 1.48±1.22 (3H), 1.18 (s, 3H, CH3), 0.99 (s, 3H,
CH3); 13C NMR (CDCl3) d 164.6, 154.2, 135.8, 129.1 (2C),
128.4 (2C), 127.7, 79.1, 78.0, 68.6, 66.0, 56.1, 55.7, 53.3,
48.9, 47.9, 44.8, 38.8, 33.0, 26.4, 21.2, 19.9; IR (CHCl3)
cm21 3670 (w), 3000 (m), 1820 (s), 1710 (s, CvO), 1330
(m), 1200 (s), 1150 (m), 1080 (m); HRMS calcd for
C12H12NO3 ([M2C11H16NO3S]1) 218.0817, found
218.0821.
3.5.19.
[3aR-[(3aSp,4Sp,6aRp),3aa,6a,7ab)]]-3H-3a,6-
Methano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-
4-[[tetrahydro-1,3-dioxolo-5-(4-methoxyphenyl)-2-oxo-
[4,5-c]pyrrole-4-yl]carbonyl]-2,2-dioxide (27b). Reaction
time: 5 h; temperature 188±1908C; ¯ash chromatography
(SiO2, 2:1 hexanes/EtOAc); total yield of the cycloadducts
83%; Rf 0.30 (1:1 hexanes/EtOAc); mpˆ139±1408C;
[a]2D3ˆ1388 (cˆ1.0, CHCl3); H NMR (CDCl3) d 6.79 (d,
1
Jˆ9.2 Hz, 2H, arom.), 6.71 (d, Jˆ9.2 Hz, 2H, arom.), 5.55
(t, Jˆ 7.5 Hz, 1H, H-3a), 5.30 (d, Jˆ7.2 Hz, 1H, H-4), 5.26
(1H, H-6a), 3.96 (dd, Jˆ7.9, 5.9 Hz, 1H, H-7a), 3.97 (d,
Jˆ11.0 Hz, 1H, H-6), 3.76 (dd, Jˆ10.9, 6.6 Hz, 1H, H-6),
3.74 (s, 3H, OCH3), 3.60 (d, Jˆ13.8 Hz, 1H, 1/2CH2SO2),
3.53(d, Jˆ13.9 Hz, 1H, 1/2CH2SO2), 1.98±1.75 (4H),
1.47±1.28 (3H), 1.21 (s, 3H, CH3), 0.99 (s, 3H, CH3); 13C
NMR (CDCl3) d 167.3, 153.8, 153.5, 139.1, 115.8 (2C),
114.9 (2C), 78.5, 78.1, 65.7, 64.6, 55.7, 55.2, 53.2, 49.1,
47.9, 44.9, 38.2, 32.9, 26.2, 20.9, 19.9; IR (CHCl3) cm21
3000 (m), 2640 (m), 1810 (s), 1700 (m), 1510 (s), 1330 (s),
1225 (s), 1150 (m), 1090 (s); HRMS calcd for C23H28N2O7S
(M1) 476.1617, found 476.1616.
3.5.17. [3aR-[(3aSp,4Sp,6aRp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-4-[[tetra-
hydro-1,3-dioxolo-5-(phenylmethyl)-2-oxo-[4,5-c]pyrrole-
4-yl]carbonyl]-2,2-dioxide (27a). Reaction time: 15 h;
temperature 195±1978C; ¯ash chromatography (SiO2, 3:1
hexanes/EtOAc); total yield of the cycloadducts 51%
3.5.20.
[3aR-[(3aSp,4Rp,6aRp),3aa,6a,7ab)]]-3H-3a,6-
Methano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-
4-[[tetrahydro-1,3-dioxolo-5-(4-methoxyphenyl)-2-oxo-

82
P. Garner et al. / Tetrahedron 57 (2001) 71±85
[4,5-c]pyrrole-4-yl]carbonyl]-2,2-dioxide (28b). Rf 0.19
(1:1 hexanes/EtOAc); mpˆ139±1408C; [a]2D6ˆ1398
2 h), ®ltered through a pad of Celite, and the ®ltrate concen-
trated to give crude debenzylated product in quantitative
yield. This crude product was added to a stirring solution
of 2 equiv. BnSH and 1.5 equiv. n-BuLi (2.5 M in hexanes)
at 08C in THF (concentration approx. 0.2 M). After con®rm-
ing by the TLC that the starting material was consumed, the
reaction mixture was diluted with ether and quenched with
6.0N HCl. The organic phase was separated and the aqueous
layer was extracted with 3£EtOAc. The combined organic
layers were dried (MgSO4), concentrated in vacuo and the
residue was puri®ed by ¯ash chromatography on silica gel to
give the sultam auxiliary in 80% yield. After freeze-drying
the aqueous layer, the resulting solids were dissolved in a
minimum amount of water and loaded onto an anion-
exchange column containing 2 g (wet weight) Bio Rad
Ag-1-X2 anion-exchange resin. The column was washed
with ®ve bed volumes of water, and the crude product
was eluted with 1% aqueous acetic acid. The ninhydrin
(Char B) active fractions were collected and freeze-
dried to give 24 in 72% yield; mpˆ330±3328C;
[a]D25ˆ2328 (cˆ0.3, H2O) [lit.17 mpˆ333±3358C,
1
(cˆ1.3, CHCl3); H NMR (CDCl3) d 6.77 (s, 4H, arom.),
5.48 (s, 1H, H-4), 5.34 (dd, Jˆ7.1, 4.8 Hz, 1H, H-6a), 5.25
(d, Jˆ7.1 Hz, 1H, H-3a), 3.96 (dd, Jˆ11.4, 5.0 Hz, 1H,
H-6), 3.83 (d, Jˆ11.4 Hz, 1H, H-6), 3.82 (dd, Jˆ7.3,
5.0 Hz, 1H, H-7a), 3.74 (s, 3H, OCH3), 3.59 (d,
Jˆ13.8 Hz, 1H, 1/2CH2SO2), 3.48 (d, Jˆ13.8 Hz, 1H,
1/2CH2SO2), 1.98±1.62 (4H), 1.42±1.12 (3H), 1.07 (s,
3H, CH3), 0.96 (s, 3H, CH3); 13C NMR (CDCl3) d 170.0,
153.9, 153.6, 138.9, 116.1 (2C), 114.9 (2C), 81.3, 79.2,
66.8, 65.1, 55.7, 55.6, 55.3, 53.1, 49.4, 47.9, 44.6, 44.5,
38.1, 32.9, 26.4, 20.6, 19.9, 19.9; IR (CHCl3) cm21 3000
(m), 2960 (m), 1810 (s), 1680 (m), 1510 (s), 1330 (s), 1240
(s), 1160 (s), 1050 (s).
3.5.21. [3aR-[(3aSp,4Sp,6aRp),3aa,6a,7ab)]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, 7,7-dichloro-4,5,6,7-tetrahydro-
8,8-dimethyl-4-[[tetrahydro-1,3-dioxolo-5-(phenylmethyl)-
2-oxo-[4,5-c]pyrrole-4-yl]carbonyl]-2,2-dioxide (27c). Reac-
tion time: 15 h; temperature 167±1698C; ¯ash chromato-
graphy (SiO2, 8:1 CHCl3/EtOAc); total yield of the
cycloadducts 52% (pyrrole 30c was formed in 12%); Rf
0.28 (5:1 CHCl3/EtOAc); mpˆ252±2538C; [a]2D2ˆ2618
1
[a]2D6ˆ234.38 (cˆ0.28, H2O)]; H NMR (D2O) d 4.27
(d, Jˆ5.37 Hz, 1H, H-2), 3.26 (1H), 3.13 (1H), 2.20±
2.00 (2H)-these data matched those of an authentic
sample; HRMS (FAB/glycerol) calcd for C5H8NO2
([M2CO2H]1) 114.0555, found 114.0556.
1
(cˆ, CHCl3); H NMR (CDCl3) d 7.38±7.25 (5H, Ph),
5.50 (dd, Jˆ7.0, 5.4 Hz, 1H, H-3a), 4.98 (dd, Jˆ7.0,
4.2 Hz, 1H, H-6a), 4.62 (s, 1H, H-7a), 4.10 (d, Jˆ13.3 Hz,
1H, 1/2CH2Ph), 3.98 (d, Jˆ5.3 Hz, 1H, H-4), 3.58 (s, 2H,
CH2SO2), 3.52 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.31 (d,
Jˆ11.6 Hz, 1H, H-6), 2.59 (d, Jˆ4.4 Hz, 1H), 2.49 (2H),
2.12±1.94 (2H), 1.63 (1H), 1.53 (s, 3H, CH3), 1.12 (s, 3H,
CH3); 13C NMR (CDCl3) d 166.5, 154.1, 135.4, 129.4 (2C),
128.5 (2C), 127.8, 93.3, 79.3, 78.0, 69.0, 62.3, 55.6, 55.1,
52.9, 50.9, 49.5, 31.8, 25.4, 24.5, 22.9; IR (CHCl3) cm21
2950 (w), 1810 (s), 1720 (m), 1330 (m), 1190 (m), 1130 (m),
900 (m); HRMS calcd for C12H12NO3 ([M2
C11H14NO3SCl2]1) 218.0817, found 218.0821.
3.5.24. 1,4-Dideoxy-1,4-imino-d-lyxitol hydrochloride
(ent-31). Debenzylation and auxiliary cleavage were carried
out as described above for compound 22a. The solids
obtained from the aqueous layer after freeze-drying were
dissolved in a minimum of water and loaded onto an ion-
exchange column containing 2 g (wet weight) of Amberlite-
IR-120 (H1 form). The column was eluted with aqueous
ammonia and the ninhydrin (char B) active fractions were
concentrated in vacuo, acidi®ed to pH 4 with dilute HCl
solution, and freeze-dried to afford 28 mg (65%) of
ent-31; mpˆ 158±1608C; [a]2D4ˆ1248 (cˆ0.9, H2O)
1
[lit.19 mpˆ157±1598C, [a]D20ˆ118.88 (cˆ0.16, H2O)]; H
3.5.22.
[3aR-[(3aSp,4Rp,6aRp),3aa,6a,7ab)]]-3H-3a,6-
NMR (D2O) d 4.28 (ddd, Jˆ7.3, 6.3, 4.2 Hz, 1H, H-2), 4.29
(t, Jˆ 4.1 Hz, 1H, H-3), 3,78 (dd, Jˆ5.0, 4.9 Hz, 1H, H-4),
3.68 (dd, Jˆ8.32, 12.1 Hz, 1H, H-5), 3.54 (1H, H-50), 3.33
(dd, Jˆ7.61, 7.35 Hz, 1H, H-1), 3.09 (dd, Jˆ7.38, 7.33 Hz,
Methano-2,1-benzisothiazole, 7,7-dichloro-4,5,6,7-tetra-
hydro-8,8-dimethyl-4-[[tetrahydro-1,3-dioxolo-5-(phenyl-
methyl)-2-oxo-[4,5-c]pyrrole-4-yl]carbonyl]-2,2-dioxide
(28c). Rf 0.8, 7:1 (CHCl3/EtOAc); [a]2D2ˆ1108 (cˆ0.5,
1
1H,
H-10);
HRMS
calcd
for
C4H7NO2S
CHCl3); H NMR (CDCl3) d 7.40±7.20 (5H, Ph), 5.50 (d,
([M2HClCH2OH]1) 102.0555, found 102.0551. The
Jˆ6.8 Hz, 1H, H-3a), 5.12 (dd, Jˆ6.7, 4.6 Hz, 1H, H-6a),
4.86 (s, 1H, H-4), 4.49 (s, 1H, H-7a), 4.16 (d, Jˆ13.3 Hz,
1H, 1/2CH2Ph), 3.93 (d, Jˆ13.3 Hz, 1H, 1/2CH2Ph), 3.58
(d, Jˆ 13.7 Hz, 1H, 1/2CH2SO2), 3.52 (d, Jˆ13.7 Hz, 1H,
1/2CH2SO2), 3.50 (dd, Jˆ11.5, 6.54 Hz, 1H, H-6), 3.18 (d,
Jˆ11.6 Hz, 1H, H-6), 2.60 (d, Jˆ4.52 Hz, 1H), 2.55±2.35
(1H), 2.12±1.90 (2H), 1.62 (1H), 1.47 (s, 3H, CH3), 1.12 (s,
3H, CH3); 13C NMR (CDCl3) d 170.9, 154.2, 137.7, 128.6
(2C), 128.2 (2C), 127.4, 93.7, 82.4, 79.6, 78.1, 70.2, 62.1,
55.6, 52.9, 52.6, 51.0, 49.7, 31.6, 25.4, 24.2, 22.9; IR
(CHCl3) cm21 3000 (m), 1810 (s), 1715 (m), 1200 (s),
1145 (m); HRMS calcd for C12H12NO3 ([M2
C11H14NO3SCl2]1) 218.0817, found 218.0811.
sultam auxiliary was recovered in 77% yield.
3.5.25. 1,4-Dideoxy-1,4-imino-l-lyxitol hydrochloride
(31). Following the same procedure as above, 33 was
isolated in 67% yield; mpˆ160±1628C; [a]2D4ˆ2218
(cˆ0.5, H2O) [lit.3g mpˆ162±1638C, [a]2D9ˆ220.38
1
(cˆ0.28, H2O)]; The H NMR spectrum (D2O) was same
as ent-33; HRMS calcd for C4H7NO2S ([M2HClCH2OH]1)
102.0555, found 102.0549. The recovered sultam auxiliary
was obtained in 72% yield.
3.6. General procedure for amine condensation
Ê
A mixture of 10, benzaldehyde (1.5 equiv.), and 4 A molec-
3.5.23. l-trans-2,3-Pyrrolidinedicarboxylic acid (24). A
solution of 22a (130 mg, 0.28 mmol) in MeOH (2 mL)
was treated with 10% Pd±C (130 mg), at room temperature,
under an H2 atmosphere. The reaction mixture was stirred at
this temperature until judged complete by TLC (usually
ular sieves (ca. 1 g) in toluene (concentration approx.
0.3 M) was stirred at 80±858C for 10 min at which time a
solution of dipolarophile (3 equiv.) in toluene was added.
The resulting mixture was stirred at this temperature until

P. Garner et al. / Tetrahedron 57 (2001) 71±85
83
TLC analysis indicated complete consumption of 10. The
reaction mixture was ®ltered through a pad of Celite,
concentrated, and puri®ed by ¯ash chromatography on silica
gel.
(m), 1380 (m), 1325 (m), 1260 (m), 1210 (s), 1130 (m);
HRMS calcd for C18H15N2O2 ([M2C11H16NO3S]1)
291.1133 found 291.1114.
3.6.4. [1R-[1b(3aRp,6Sp,7aSp),3b,3aa,6aa]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[(hexa-
hydro-4,6-dioxo-3,5-diphenylpyrrolo[3,4-c]pyrrol-1-yl)-
carbonyl]-2,2-dioxide (40a). Rf 0.48 (1:1 hexanes/EtOAc);
[a]2D3ˆ11318 (cˆ0.80, CHCl3); 1H NMR (CDCl3) d 7.40±
7.18 (10 H, 2£Ph), 4.72 (1H, H-3), 4.66 (m,1H, H-1), 4.23
(t, Jˆ7.8 Hz, 1H, H-6a), 4.10 (dd, Jˆ8.0, 5.0 Hz, 1H, H-7a),
3.65 (t, Jˆ8.2 Hz, 1H, H-3a), 3.56 (s, 2H, CH2SO2), 2.83 (br
s, 1H, NH), 2.33 (1H), 2.18 (dd, Jˆ7.83, 6.32 Hz, 1H), 1.91
(3H), 1.51±1.24 (2H), 1.20 (s, 3H, CH3), 1.01 (s, 3H, CH3);
13C NMR (CDCl3) d 174.9, 173.7, 168.4, 136.0, 131.7,
128.9 (2C), 128.4 (2C), 128.2 (2C), 126.9 (2C), 126.3
(2C), 66.1, 65.2, 62.9, 53.0, 50.9, 50.3, 48.9, 47.9, 44.8,
38.5, 32.8, 26.2, 21.0, 19.9; IR (CHCl3) cm21 3680 (w),
3010 (m), 2960 (w), 2380 (w), 1710 (s, CvO), 1495 (m),
1375 (m), 1330 (m), 1210 (s), 1130 (m); HRMS calcd
for C18H15N2O2 ([M2C11H16NO3S]1) 291.1133 found
291.1114.
3.6.1. [2S-[2a,3a,4a,5a(3aSp,6Rp,7aRp)]]-3,4-Pyrrolidi-
nedicarboxylic acid, 2-phenyl-5-[(tetrahydro-8,8-di-
methyl-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)-
carbonyl]-dimethyl ester, S,S-dioxide (37). Flash
chromatography (SiO2, 2:1 hexanes/EtOAc, further puri®-
cation was accomplished by PTLC on silica gel, eluting
three times with 3:1 hexanes/EtOAc); total yield of the
cycloadducts 66%; Rfˆ0.4 (1:1 hexanes/EtOAc);
1
[a]2D2ˆ1398 (cˆ0.62, CHCl3); H NMR (CDCl3) d 7.4±
7.2 (5H, Ph), 4.55 (dd, Jˆ8.6, 3.2 Hz, 1H, H-2), 4.44 (dd,
Jˆ7.3, 5.9 Hz, 1H, H-5), 4.01 (t, Jˆ8.9 Hz, 1H, H-3), 4.00
(dd, Jˆ5.01, 2.9 Hz, 1H, H-7a), 3.76 (dd, Jˆ7.5, 1.7 Hz,
1H, H-4), 3.56 (s, 3H, OCH3), 3.49 (s, 2H, CH2SO2), 3.18
(s, 3H, OCH3), 2.48±2.38 (1H), 2.12 (dd, Jˆ8.03, 5.90 Hz,
1H), 1.90 (3H), 1.50±1.35 (2H), 1.13 (s, 3H, CH3), 0.97 (s,
3H, CH3); 13C NMR (CDCl3) d 170.9, 170.7, 167.6, 136.9,
128.1 (2C), 127.5, 126.8 (2C), 65.7, 64.5, 62.6, 54.2, 53.0,
51.9, 51.9, 51.3, 48.5, 47.8, 44.6, 37.3, 32.9, 26.6, 20.1 (2C);
IR (CHCl3) cm21 3680 (w), 3015 (m), 2960 (w), 2380 (w),
1740 (s), 1325 (m), 1260 (m), (1210 (s), 1125 (m), 1050 (w);
HRMS calcd for C25H32N2O7S (M1) 504.1930, found
504.1907.
3.6.5. [1R-[1b(3aRp,6Sp,7aSp),3b,3aa,6aa]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, 7,7-dichloro-4,5,6,7-tetrahydro-
8,8-dimethyl-1-[(hexahydro-4,6-dioxo-3,5-diphenylpyr-
rolo[3,4-c]pyrrol-1-yl)carbonyl]-2,2-dioxide (39b). Flash
chromatography (SiO2 2:1 hexanes/EtOAc) total yield of
the cycloadducts 64%; Rf 0.36 (1:1 hexanes/EtOAc);
3.6.2. [2R-[2b,3b,4b,5b(3aSp,6Rp,7aRp)]]-3,4-Pyrrolidi-
nedicarboxylic acid, 2-phenyl-5-[(tetrahydro-8,8-di-
methyl-3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)-
carbonyl]-dimethyl ester, S,S-dioxide (38). Rf 10.5 (1:1
hexanes/EtOAc); [a]D23ˆ11.68 (cˆ1.4, CHCl3); H NMR
(CDCl3) d 7.35±7.20 (5H, Ph), 5.15 (d, Jˆ7.7 Hz, 1H,
H-2), 4.61 (d, Jˆ5.8 Hz, 1H, H-5), 4.23 (t, Jˆ7.5 Hz, 1H,
H-3), 4.00 (dd, Jˆ7.8, 4.9 Hz, H-7a), 3.67 (s, 3H, OCH3),
3.62 (dd, Jˆ7.3, 5.8 Hz, H-4), 3.53 (d, Jˆ13.8 Hz, 1H,
1/2CH2SO2), 3.46 (d, Jˆ13.7 Hz, 1H, 1/2CH2SO2), 3.29
(s, 3H, OCH3), 3.10 (br s, 1H, NH), 1.28±1.18 (1H),
2.10±2.02 (1H), 1.91 (2H), 1.50±1.20 (3H), 1.17 (s, 3H,
CH3), 0.96 (s, 3H, CH3); 13C NMR (CDCl3) d 171.8,
171.1, 171.0, 137.2, 128.3 (2C), 127.8, 126.3 (2C), 65.3,
65.0, 61.5, 53.47, 52.9, 52.2, 51.3, 49.1, 48.8, 47.8, 44.61,
38.1, 32.7, 26.4, 20.8, 19.9; IR (CHCl3) cm21 3670 (w),
3010 (m), 2945 (w), 2380 (w), 1730 (s), 1680 (m), 1430
(m), 1330 (s), 1270 (m), (1210 (s), 1130 (m).
1
mpˆ253±2548C; [a]D27ˆ1718 (cˆ1.2, CHCl3); H NMR
(CDCl3) d 7.45±7.20 (10 H, 2£Ph), 4.73 (d, Jˆ7.9 Hz,
1H. H-1), 4.67 (d, Jˆ8.1 Hz, 1H, H-3), 4.59 (s, 1H, H-7a),
4.21 (t, Jˆ7.9 Hz, 1H, H-6a), 3.67 (t, Jˆ8.0 Hz, 1H, H-3a),
3.61 (d, Jˆ14 Hz, 1H, 1/2CH2SO2), 3.56 (d, Jˆ14 Hz, 1H,
1/2CH2SO2), 2.89 (t, Jˆ8.0 Hz, 1H, N±H), 2.57 (d, Jˆ
4.5 Hz, 1H), 2.41 (1H), 2.02 (2H), 1.60 (1H), 1.51 (s, 3H,
CH3), 1.11 (s, 3H, CH3); 13C NMR (CDCl3) d 174.8, 173.7,
169.8, 135.6, 131.7, 129.0 (2C), 128.5 (2C), 128.3 (2C),
127.1 (2C), 126.4 (2C), 93.4, 79.3, 65.7, 63.6, 62.3, 52.67,
51.0, 50.9, 50.4, 49.5, 31.7, 25.3, 24.7, 23.0; IR (CHCl3)
cm21 3000 (m), 1720 (s), 1340 (s), 1220 (s); HRMS calcd
for C18H15N2O2 ([M2C11H14NO3SCl2]1), 291.1134 found
291.1133.
3.6.6. [1R-[1a(3aRp,6Sp,7aSp),3a,3ab,6ab]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, 7,7-dichloro-4,5,6,7-tetrahydro-
8,8-dimethyl-1-[(hexahydro-4,6-dioxo-3,5-diphenylpyr-
rolo[3,4-c]pyrrol-1-yl)carbonyl]-2,2-dioxide (40b). Rf
0.60, (1:1 hexanes/EtOAc); [a]2D7ˆ2198 (cˆ1.0, CHCl3);
1H NMR (CDCl3) d 7.60±7.28 (10 H, 2£Ph), 4.72 (d, Jˆ
6.6 Hz, 1H, H-1), 4.56 (s, 1H, H-7a), 4.53 (d, Jˆ7.7 Hz, 1H,
H-3), 3.99 (dd, Jˆ9.7, 6.8 Hz, 1H, H-6a), 3.58 (d, Jˆ14 Hz,
1H, 1/2CH2SO2), 3.54 (dd, Jˆ9.8, 7.0 Hz, 1H, H-3a), 3.51
(d, Jˆ14 Hz, 1H, 1/2CH2SO2), 3.28 (br s, 1H, N±H), 2.59
(d, Jˆ4.27 Hz, 1H), 2.45 (1H), 2.02 (2H), 1.62 (2H), 1.56 (s,
3H, CH3), 1.10 (s, 3H, CH3); 13C NMR (CDCl3) d 175.0,
173.7, 172.3, 139.6, 131.5, 129.2 (2C), 128.8 (2C), 128.7,
127.1 (2C), 126.6 (2C), 126.4, 78.7, 66.3, 62.8, 62.2, 53.8,
52.9, 52.1, 50.7, 49.7, 31.7, 29.8, 25.4, 24.3, 23.0; IR
(CHCl3) cm21 3010 (m), 1730 (s, CvO), 1340 (s), 1220
(s), 1140 (m), 1060 (m), 900 (m); HRMS calcd for
C18H15N2O2 ([M2C11H14NO3SCl2]1), 291.1134, found
291.1137.
3.6.3. [1R-[1a(3aRp,6Sp,7aSp),3a,3ab,6ab]]-3H-3a,6-Meth-
ano-2,1-benzisothiazole, hexahydro-8,8-dimethyl-1-[(hexa-
hydro-4,6-dioxo-3,5-diphenylpyrrolo[3,4-c]pyrrol-1-yl)-
carbonyl]-2,2-dioxide (39a). Flash chromatography (SiO2,
2:1 hexanes/EtOAc); total yield of the cycloadducts 84%; Rf
0.5 (1:1 hexanes/EtOAc); mpˆ270±2718C; [a]2D3ˆ123.78
(cˆ2.42, CHCl3); 1H NMR (CDCl3) d 7.46±7.13 (10H, Ph),
4.66 (2H, H-1 and H-3), 4.02 (2H, H-7a and H-6a), 3.62 (t,
Jˆ8.3 Hz, 1H, H-3a), 3.60 (d, Jˆ15.4 Hz, 1H, 1/2CH2SO2),
3.55 (d, Jˆ15.0 Hz, 1H, 1/2CH2SO2), 2.62 (2H), 2.04 (dd,
Jˆ7.9, 6.0 Hz, 1H), 1.93 (3H), 1.49±1.33 (2H), 1.32 (s, 3H,
CH3), 0.99 (s, 3H, CH3); 13C NMR (CDCl3) d 174.7, 173.7,
167.6, 136.7, 131.7, 128.9 (2C), 128.4 (2C), 128.3 (2C),
127.0 (2C), 126.3 (2C), 65.7, 63.9, 62.9, 53.2, 50.0, 49.3,
48.76, 47.9, 44.5, 37.2, 32.7, 26.6, 20.3, 20.0; IR (CHCl3)
cm21 3680 (w), 3000 (m), 2950 (w), 1710 (s, CvO), 1495

84
P. Garner et al. / Tetrahedron 57 (2001) 71±85
3.6.7. 3H-3a,6-Methano-2,1-benzisothiazole, 7,7-dichloro-
4,5,6,7-tetrahydro-8,8-dimethyl-1-[(hexahydro-4,6-dioxo-
3,5-diphenylpyrrolo[3,4-c]pyrrol-1-yl)carbonyl]-2,2-diox-
ide (41b). Rf 0.40 (1:1 hexanes/EtOAc); mpˆ170±1728C;
Education (Doctoral Fellowship to O. D.). We thank Prof.
A. R. Chamberlin (UC Irvine) for kindly providing us with
an authentic sample of compound 24.
1
[a]2D7ˆ1868 (cˆ0.9, CHCl3); H NMR (CDCl3) d 7.45±
7.10 (10 H, 2£Ph), 5.23 (s, 1H, H-1), 5.12 (d, Jˆ9.2 Hz,
1H, H-3), 4.51 (s, 1H, H-7a), 3.79 (d, Jˆ7.7 Hz, 1H, H-6a),
3.68 (dd, Jˆ9.2, 7.9 Hz, 1H, H-3a), 3.60 (d, Jˆ14 Hz, 1H,
1/2CH2SO2), 3.53 (d, Jˆ14 Hz, 1H, 1/2CH2SO2), 2.88 (br s,
1H, N±H), 2.62 (d, Jˆ4.3 Hz, 1H), 2.45 (1H), 2.04 (2H),
1.61 (1H), 1.53 (s, 3H, CH3), 1.13 (s, 3H, CH3); 13C NMR
(CDCl3) d 175.4, 174.3, 172.8, 138.5, 131.9, 129.0 (2C),
128.5 (2C), 128.4, 127.5 (2C), 126.1 (2C), 93.6, 78.7, 62.9,
62.2, 62.2, 52.7, 51.1, 50.5, 49.7, 49.2, 31.7, 29.8, 25.5,
24.4, 22.9; IR (CHCl3) cm21 3000 (m), 1720 (s), 1340 (s),
1220 (s); HRMS calcd for C18H15N2O2 ([M2
C11H14NO3SCl2]1), 291.1134, found 291.1126.
References
1. For an excellent recent review of asymmetric 1,3-dipolar
cycloaddition reactions, see: Gothelf, K. V.; Jorgensen, K. A.
Chem Rev. 1998, 98, 863.
2. Some synthetic applications of azomethine ylides:
(a) Confalone, P. N.; Huie, E. M. J. Am. Chem. Soc. 1984,
106, 7175. (b) Kraus, G. A.; Nagy, J. O. Tetrahedron 1985, 41,
3537. (c) DeShong, P.; Kell, D. A. Tetrahedron Lett. 1986, 27,
3979. (d) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am.
Chem. Soc. 1987, 109, 5523. (e) Takano, S.; Samizu, K.;
Ogasawara, K. Chem. Lett. 1990, 1239. (f) Sisko, J.; Weinreb,
S. M. J. Org. Chem. 1991, 56, 3210. (g) Garner, P.; Ho, W. B.;
Shin, H. J. Am. Chem. Soc. 1993, 115, 10742. (h) Henke, B. R.;
Kouklis, A. J.; Heathcock, C. H. J. Org. Chem. 1992, 57, 7056.
(i) Denhart, D. J.; Grif®th, D. A.; Heathcock, C. H. J. J. Org.
Chem. 1998, 63, 9616. (j) Osamu, I.; Samizu, K.; Henry, J. R.;
Weinreb, S. M. J. Org. Chem. 1999, 64, 587. (k) Coldham, I.;
Crapnell, K. M.; Fernandez, J.-C.; Haxell, T. F. N.; Treacy,
A. B.; Cole, S. J.; Hursthouse, M. B.; Moseley, J. D. Chem.
Commun. 1999, 1359.
3.6.8. [3aR-[1(2Sp,3Rp,5Rp),3aa,6a,7ab]]-3-Pyrrolidine-
carboxylic acid, 2-phenyl-5-[(tetrahydro-8,8-dimethyl-
3H-3a,6-methano-2,1-benzisothiazol-1(4H)-yl)carbonyl]-
methyl ester, S,S-dioxide (42a). Flash chromatography
(SiO2, 2:1 hexanes/EtOAc); total yield of the cycloadducts
1
64%; Rf 0.46 (1:1 hexanes/EtOAc); H NMR (CDCl3) d
7.38±7.20 (5H, Ph), 4.55 (d, Jˆ8.1 Hz, 1H, H-2), 4.45 (t,
Jˆ8.3 Hz, 1H, H-5), 3.97 (dd, Jˆ5.5, 1.7 Hz, 1H, H-7a),
3.52 (d, Jˆ14 Hz, 1H, 1/2CH2SO2), 3.45 (d, Jˆ14 Hz, 1H,
1/2CH2SO2), 3.37 (dd, Jˆ7.90, 6.84 Hz, 1H, H-3), 3.20 (s,
3H, OCH3), 2.60 (dt, Jˆ7.9, 7.9 Hz, 1H, H-4), 2.28 (ddd,
Jˆ13.1, 8.5, 1.8 Hz, 1H, H-4), 2.16 (2H), 1.90 (br s, 3H),
1.50±1.35 (3H), 1.15 (s, 3H, CH3), 0.97 (s, 3H, CH3); 13C
NMR (C6D6) d 172.9, 172.2, 139.9, 128.3 (2C), 127.6,
127.2 (2C), 66.0, 65.0, 61.4, 52.4, 50.5, 50.2, 48.2, 47.4,
44.5, 38.2, 35.7, 32.0, 26.2, 20.7, 19.4; IR (CHCl3) cm21
3680 (w), 3000 (s), 2450 (m), 2400 (w), 1720 (s, CvO),
1690 (s), 1330 (s), 1270 (m), 1210 (s), 1160 (s), 1130(s);
HRMS calcd for C23H29N2O5S ([M2H]1) 445.1797, found
445.1779.
3. (a) Padwa, A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W.
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Â
J. F.; Grisoni, S.; Carboni, B.; Courgeon, T.; Carrie, R.
Tetrahedron 1994, 50, 189. (j) Baldwin, J. E.; Turner,
S. C. S.; Moloney, M. G. Synlett 1994, 925. (k) Novello, F.;
Prato, M.; Da Ros, T.; De Amici, M.; Bianco, A.; Toniolo, C.;
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Chem. 1994, 59, 4.
3.6.9. [3aR-[1(2Sp,3Rp,5Rp),3aa,6a,7ab]]-3-Pyrrolidine-
carboxylic acid, 2-phenyl-5-[(7,7-dichloro-4,5,6,7-tetra-
hydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothia-
zol-1(4H)-yl)carbonyl]-methyl ester, S,S-dioxide (42b).
Flash chromatography (SiO2, 2:1 hexanes/EtOAc); total
yield of the cycloadducts 58%; Rf 0.40 (1:1 hexanes/
1
EtOAc); [a]2D7ˆ1148 (cˆ3, CHCl3); H NMR (CDCl3) d
7.40±7.20 (5H, Ph), 4.60 (dd, Jˆ9.3, 7.8 Hz, 1H, H-5), 4.58
(d, Jˆ8.2 Hz, 1H, H-2), 4.55 (s, 1H, H-7a), 3.54 (s, 2H,
1/2CH2SO2), 3.43 (dd, Jˆ17, 7.9 Hz, 1H, H-3), 3.21 (s,
3H, OCH3), 2.68±2.42 (5H), 2.02 (2H), 1.65 (1H), 1.48 (s,
3H, CH3), 1.10 (s, 3H, CH3); 13C NMR (CDCl3) d 173.3,
172.5, 139.3, 128.2 (2C), 127.6, 127.0 (2C), 93.5, 78.5,
65.2, 62.3, 61.6, 52.6, 51.4, 50.8, 50.4, 49.6, 34.6, 31.5,
25.4, 24.1, 22.9; IR (CHCl3) cm21 3010 (m), 1730 (s),
1340 (s), 1220 (s), 1140 (m), 1060 (m), 900 (m); HRMS
calcd for C12H14NO2 ([M2C11H14NO3SCl2]1) 204.1025,
found 204.1026.
5. Dogan, O.; Garner, P.; Turk. J. Chem. 2000, 24, 59.
6. For a review of the use of Oppolzer's sultam in this context,
see: Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293.
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1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley-
Interscience: New York, 1984; Vol. 1, p 653. (b) Tsuge, O.;
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2309.
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1987, 60, 4067. (e) Husinec, S.; Savic, V.; Porter, A. E. A.
Tetrahedron Lett. 1988, 50, 6649.
Acknowledgements
This work was supported by the National Institute of
General Medical Sciences and the Turkish Ministry of
10. (a) Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.;

P. Garner et al. / Tetrahedron 57 (2001) 71±85
85
Vullioud, C. Tetrahedron 1986, 42, 4035. (b) Improved prepa-
ration: Thom, C.; Kocienski, P. Synthesis 1992, 582.
11. Cf. Nakamura, I.; Harada, K. Heterocycles 1978, 9, 473, and
references cited therein.
similar regioselectivity problem that had been observed during
attempted cleavage of the Evans' oxazolidone auxiliaries from
sterically congested carboxylic acid imides: Damon, R. E.;
Coppola, G. M. Tetrahedron Lett. 1990, 31, 2849.
12. Garner, P.; Dogan, O.; Pillai, S. Tetrahedron Lett. 1994, 35,
1653.
19. Geoffrey, N. A.; Baird, P. D.; Fleet, G. W. J.; Peach, J. M.;
Smith, P. W.; Watkin, D. J. Tetrahedron 1987, 43, 3095.
20. The numbering system used in this paper corresponds to the
current CA index names for structures i±iv.
13. Davis, F. A.; Weismiller, M. C.; Christopher, K. M.; Reddy,
R. T.; Chen, B.-C. J. Org. Chem. 1992, 57, 7274.
14. Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 6009.
15. (a) Tsuge, O.; Kanemasa, S.; Ohe, M.; Yorozu, K.; Takenaka,
S.; Ueno, K. Bull. Chem. Soc. Jpn 1987, 60, 4067.
(b) Chastanet, J.; Roussi, G. J. Org. Chem. 1988, 53, 3808.
(c) Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkin, D.;
Wong, L. F. Tetrahedron: Asymmetry 1991, 2, 1343.
16. Inquiries concerning the X-ray structures of 17b and 37a
should be addressed to W. J. Y. and J. D. P., respectively.
The atomic coordinates and thermal parameters for compound
17b will be deposited with the Cambridge Crystallographic
Data Centre. Crystallographic data (excluding structure factor
tables) for structure of 37a have been deposited with the
CCDC as supplementary publication no. CCDC-148478.
Copies of the data can be obtained free of charge on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
(144) 1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
17. Humphrey, J. M.; Bridges, R. J.; Hart, J. A.; Chamberlin, A. R.
J. Org. Chem. 1994, 59, 2467.
18. These conditions were originally developed to circumvent a