Stereoselectivity in the TiCl4-catalyzed [4 + 2] cycloaddition of cyclopentadiene to (2R)-bornane-10,2-sultam derivatives of fumaric acid monoesters

Article abstract of DOI:10.1002/(SICI)1522-2675(19990210)82:2<182::AID-HLCA182>3.0.CO;2-P

The [4 + 2] cycloaddition of cyclopentadiene to the (2R)-bornane-10,2- sultam derivative (-)-1b of fumaric monomethyl ester proceeds with high endo and π-facial diastereoselectivity in the presence of 0.5 mol-equiv. of TiCl₄. The major diastere

Full text of DOI:10.1002/(SICI)1522-2675(19990210)82:2<182::AID-HLCA182>3.0.CO;2-P

182
Helvetica Chimica Acta ± Vol. 82 (1999)
Stereoselectivity in the TiCl4-Catalyzed [4 ‡ 2] Cycloaddition
of Cyclopentadiene to (2R)-Bornane-10,2-sultam Derivatives
of Fumaric Acid Monoesters1)
a
a
b
a b
2
by Michal Achmatowicz ), Christian Chapuis ) )*, Piotr Rzepecki ), and Janusz Jurczak ) )*
a) Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-01-224 Warsaw
b) Department of Chemistry, University of Warsaw, Pasteura 1, PL-02-093 Warsaw
The [4 ‡ 2] cycloaddition of cyclopentadiene to the (2R)-bornane-10,2-sultam derivative ( )-1b of fumaric
monomethyl ester proceeds with high endo and p-facial diastereoselectivity in the presence of 0.5 mol-equiv. of
TiCl4. The major diastereoisomer endo-(2R,3R)-2b, isolated in 87% yield by crystallization, was subjected to X-
ray crystal-structure analysis. Steric influence of ethyl- and benzyl-ester analogues ( )-1c and ( )-1d,
respectively, is also reported.
Introduction. ± We recently presented the complete p-facial selectivity observed in
the TiCl4-catalyzed [4 ‡ 2] cycloaddition of cyclopentadiene to N,N'-fumaroylbis[(2R)-
bornane-10,2-sultam] (( )-1a) [1] under the influence of diverse Lewis acids, as well as
its application to diverse dienes [2]. Although these kinds of cycloadducts have been
employed for the synthesis of several natural products [3] and analogues [4], their use is
usually limited to symmetric or specific targets where the two carbonyl moieties can be
distinguished by either iodolactonization [5] or selective steric approach of the
reagent3). For this reason, nonsymmetrical chiral fumarates were earlier developed
[9]4), where one carbonyl moiety may be chemoselectively transposed into a suitable
functionality, either by selective saponification [9b], acidic hydrolysis [12], hydro-
genation [13], or hydride reduction [14]5). With respect to this methodology, we now
would like to present our results obtained with (2R)-bornane-10,2-sultam derivatives
( )-1b ± d of fumaric acid monoesters as dienophiles.
Results and Discussion. ± The syntheses of crystalline ( )-1b,c were earlier
reported [15][16], while ( )-1d was obtained in 83% yield, after crystallization from
CCl4, by addition of the corresponding crude acid chloride (fumaric acid monobenzyl
1
)
)
)
Diploma and part of Ph. D. work of M. A. and P. R., respectively.
2
3
Present address: Firmenich SA, Corporate R & D Division, P.O. Box 239, CH-1211 Geneva 8.
For asymmetric [4 ‡ 2] cycloadditions of symmetrical fumarates, see ref. cited in [1] and [2]; for more
recent ref., see [6]. For the cycloaddition of achiral symmetric fumarates catalyzed by chiral catalysts, see
[7]. For a recent review of asymmetric intermolecular homo- and hetero-Diels-Alder reactions, see [8].
For achiral dienophiles of this type catalyzed by chiral catalysts, see [10]; for nonsymmetric maleates, see
[11].
The [4 ‡ 2] cycloadditions of analogous dienophiles derived from nonsymmetrical (2R)-bornane-10,2-
sultam derivatives ( )-1 of fumaric acid (R1 ˆ H, OH, tBuO, 1H-imidazol-1-yl, achiral N-substituted
toluenesultam) are also envisaged and will be reported in due time.
4
5
)
)

Helvetica Chimica Acta ± Vol. 82 (1999)
183
i) CH2Cl2, 788, 20 h, 0.0 ± 2.0 mol-equiv. of TiCl4, 10.0 mol-equiv. of cyclopenta-1,3-diene. ii) LiAlH4, THF.
iii) H2, 10% (w/w) Pd/C, EtOH.
ester [17], (COCl)2 (2.0 mol-equiv.), toluene, 808) to the deprotonated free camphor-
derived sultam (NaH, 1.1 mol-equiv., toluene, 0 ± 208 [18]).
For a detailed study of the [4 ‡ 2] cycloaddition, dienophile ( )-1b was selected,
anticipating a simpler 1H-NMR analysis of the cycloadducts, as well as a potential Sn2'
chemospecific saponification of the methoxycarbonyl moiety [19]. The uncatalyzed
[4 ‡ 2] cycloaddition of ( )-1b to cyclopentadiene (10 mol-equiv.) in CH2Cl2 at 208
afforded after 20 h, quantitatively, a 51 : 29 : 12 : 8 mixture of diastereoisomers, as
determined by integration of the olefinic protons in the 1H-NMR spectrum of the crude
material6). Purification by chromatography (SiO2, hexane/AcOEt 9 : 1) allowed the
isolation of a faster eluting minor pair of diastereoisomers as an 8 : 7 mixture (16%;
resulting from the 12 : 8 mixture) as well as a more polar major pair of diastereoisomers
as a 5 : 2 mixture (75%; resulting from the 51 : 29 mixture).
The 1H-NMR analysis of the pure major diastereoisomer shows signals at 6.34 and 5.86 ppm, while its
diastereoisomeric partner resonates at 6.34 and 6.14 ppm. The large difference between the two olefinic
signals suggests an endo orientation of the large sultam moiety for the major diastereoisomer [20]. The
third most abundant isomer exhibits signals at 6.31 and 6.17 ppm, as compared to its paired (not isolated
pure) diastereoisomer, which shows signals at 6.31 and 6.06 ppm, thus suggesting an endo-orientation of
the chiral auxiliary in this latter case.
6
)

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Helvetica Chimica Acta ± Vol. 82 (1999)
We then decided to perform the reaction at 788 in the presence of increasing
quantities of TiCl4. The results, summarized in Table 1, show several noteworthy
aspects. For example, the uncatalyzed reaction of ( )-1b gave a 61 : 24 : 8 : 7 mixture in
46% yield (Entry 4), while the diastereoselectivity and the chemical yield were greatly
improved by addition of TiCl4 (0.25 mol-equiv., Entry 7). The optimal diastereoisomer
efficiency was reached for 0.5 mol-equiv. of Lewis acid, thus affording in 98% yield a
94 : 3 : 1 : 2 mixture (Entry 8). The two major isomers, separated by chromatography
from the two minor ones, were further purified by crystallization in EtOH, and the most
abundant isomer endo-(2R,3R)-2b was obtained pure in 87% yield. The LiAlH4
reduction of the 8 : 7 minor pair of diastereoisomers obtained from the first described
reaction at room temperature (Entry 1) resulted in the formation of optically pure diol
( )-(2S,3S)-37), after crystallization of the concomitantly formed free sultam (91%)
from hexane. The relative and absolute configuration of the main crystalline cycloadduct
endo-(2R,3R)-2b was confirmed by X-ray crystal-structure analysis showing both the
endo-orientation of the sultam moiety and the (2R,3R)-configuration (see Fig.).
Table 1. Cyclopentadiene [4 ‡ 2] Cycloaddition to ( )-1b ± d in CH2Cl2 at 788 for 20 h
Entry Dienophile Equiv. of endo-
exo-
exo-
endo-
endo/
Yield Global endo exo
[%] de de de
[%] [%] [%]
TiCl4
(2R,3R)-2 (2R,3R)-2 (2S,3S)-2 (2S,3S)-2 exo
[%]
[%]
[%]
[%]
[%]
1a)
2a)
3a)
4
5
6
7
8
9
10
11
12
13
14
15
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
)-1b
)-1c
)-1d
)-1b
)-1c
)-1d
)-1b
)-1b
)-1c
)-1d
)-1b
)-1b
)-1d
)-1b
)-1b
0.00
0.00
0.00
0.00
0.00
0.00
0.25
0.50
0.50
0.50
0.75
1.00
1.00
1.25
2.00
51
54
49
61
63
54
92
94
92
86
93
88
84
85
75
29
23
22
24
21
20
5
3
3
3
4
12
12
16
8
8
14
1
1
2
5
1
8
11
13
7
8
12
2
2
3
6
2
59 : 41 98
65 : 35 97
62 : 38 96
68 : 32 46
71 : 29 36
66 : 34 42
60
54
42
70
68
48
94
94
90
78
94
86
74
82
68
73
41
31
16
50
45
18
67
50
25
25
60
25
40
0
66
58
79
77
64
95
96
94
87
96
91
87
93
88
94 :
96 :
95 :
92 :
95 :
92 :
6
4
5
8
5
8
97
98
96
98
98
95
5
3
6
9
3
7
6
11
4
6
3
5
90 : 10 95
88 : 12 96
80 : 20 95
10
a) Reaction performed at 208.
Similarly, using 0.5 mol-equiv. of TiCl4, 2c,d were obtained as 92 :3 :2 :3 and
86 :3 :5 :6 mixtures (Table 1, Entry 9 and 10, resp.). In both cases, the chromato-
graphically purified major more polar inseparable pair of diastereoisomers was
recrystallized from EtOH to afford pure endo-(2R,3R)-2c,d in 80 and 73% yield,
respectively8).
)-(2S,3S)-3: [a]D20
ˆ
23.1 (c ˆ 1.01, CHCl3) ([21]: [a]D20
ˆ
24.7 (c ˆ 0.8)). Similarly, reduction of the
7
)
(
96 : 4 mixture obtained after chromatographic purification of the most abundant pair (Entry 8; 95%),
afforded (‡)-(2R,3R)-3; [a]D20 ˆ‡ 23.6 (c ˆ 1.1, CHCl3) ([22]: [a]2D0 ˆ‡ 23.0 (c ˆ 0.6)).
Reduction to optically pure (‡)-(2R,3R)-3 ([a]2D0 ˆ‡ 23.8 (c ˆ 1.2, CHCl3)) confirmed the absolute
configuration of endo-(2R,3R)-2c,d. That of the other diastereoisomers of 2c,d was based on 1H-NMR
comparison with the diastereoisomers of 2b (see Exper. Part).
8
)

Helvetica Chimica Acta ± Vol. 82 (1999)
185
Figure. ORTEP Diagram of 2b showing endo-(2R,3R)-configuration. Thermal ellipsoids at 50% probability
level; arbitrary numbering.
In the case of the symmetrical dienophile ( )-1a, a mixture of diastereoisomers
(85% de) was observed at 208, while this ratio increased to 89% de at 788 for the
uncatalyzed reaction in CH2Cl2 [1]. Thus, the 73% de observed during the endo
addition of dienophile ( )-1b at 208 (Entry 1), bearing a single prosthetic group, is
much higher than the theoretical (92.5 : 7.5)1/2 ˆ 56% de expected according to the
cooperative postulate of Tolbert and Ali [23]. This difference is even accentuated at
788, since the 79% de obtained for endo-2b (Entry 4) should be compared with the
theoretical (94.5 : 5.5)1/2 ˆ 61% de expected. As recently shown, this difference may
depend on either the solvent [24] or the steric/electronic influence of the residual group
branched to the C(b)-atom of the dienophile [15a]. Thus, the diastereoselectivity
observed for the endo attack on the ethyl- and benzyl-ester analogues ( )-1c,d
decreases for these sterically more demanding esters9). This is logical, since the p-face
selectivity of this kind of dienophile is partially steric in origin [18][25]; thus, such a
trend is also observed for both endo and exo (catalyzed) [4 ‡ 2] cycloaddition to ( )-
1b ± d (Entries 8 ± 10). The ester substituent may not only sterically influence the
approach of the diene, but may also modify the coplanarity of the dienophile as well as
its intrinsic electronic properties. Intuitively, from a purely steric point of view, the
endo/exo ratio should increase with increasing steric bulk of the ester substituent.
Nevertheless, the contrary is observed, at least in the case of the catalyzed reactions
(Entries 8 ± 10), indicating a possible electronic contribution.
For ( )-1b, the endo/exo ratio proportionally increases until the addition of
0.5 mol-equiv. of Lewis acid, and then starts to decrease with concomitant weakening of
9
)
For the endo approach to ( )-1c, the diastereoselectivity of 66% at 208 (Entry 2) and of 77% at 788
(Entry 5) diminishes, while for ( )-1d, the diastereoselectivity of 58% at 208 (Entry 3) and of 64% at
788 (Entry 6) is even closer to the theoretical value. Formally, the correct comparison should be done
with an achiral sultam residue for R1.

186
Helvetica Chimica Acta ± Vol. 82 (1999)
the global p-facial selectivity (Entries 4, 7, 8, 11, 12, 14, and 15). This ratio even reaches,
for 2.0 mol-equiv. of TiCl4 (Entry 15), a similar global diastereoselectivity (global de)
as observed for the uncatalyzed reaction (Entry 4). At catalytic levels, we assume that
TiCl4 prefers to be chelated to the SO2/CˆO functionalities of the bornane-10,2-sultam
auxiliary [18][26], rather than simply coordinated to the methoxycarbonyl
moiety10), thus promoting endo addition with respect to the sultam carbamoyl moiety.
By increasing the Lewis-acid concentration to 1 equiv. and above, the methoxycarbonyl
group starts to be coordinated, and the differences in the second-order orbital
interactions between cyclopentadiene and both carbonyl moieties decreases, resulting
in a sterically more favorable competitive endo attack with respect to the methox-
ycarbonyl substituent. The diene, thus removed from the prosthetic group, shows much
lower p-facial discrimination in the exo approach11). Based on earlier work
[18][25][27] as well as on X-ray analysis of a TiCl4-sultam complex [26], we propose
that the CˆC bond is conformationally s-cis-restricted with respect to the CˆO/SO2
syn-chelated moieties of the sultam, thus offering its C(a)-re face to the sterically and
stereoelectronically preferred endo attack [28]. In the uncatalyzed case, the same face
is prone to endo addition [28]12), the methoxycarbonyl group, being slightly more
stable in a s-cis-conformation with respect to the reactive CˆC bond, may change to a
s-trans conformation in case of competitive coordination with TiCl4. This supplemen-
tary/competitive coordination may even destabilize the conformational equilibrium or
sterically interfere with the incoming diene, thus additionally providing a tentative
explanation for the lower diastereoselectivity observed in the presence of more than
1.0 mol-equiv. of TiCl4 for both endo and exo modes of addition. In the latter case, the
diastereoselectivity even starts to reverse in the presence of 2.0 mol-equiv. of TiCl4
(Entry 15), or for the sterically more demanding benzyl ester ( )-1d (Entries 10 and
13).
Finally, we hydrogenated (H2, 10% (w/w) Pd/C, 98% EtOH) endo-(2R,3R)-2d to
the saturated mono-acid (2R,3R)-4, thus demonstrating the clear synthetic advantage
of nonsymmetrical fumaric-acid-derived dienophiles of type ( )-1b ± d5).
The X-ray analysis of endo-(2R,3R)-2b (see Table 2 for selected structural
parameters) exhibits the usual features of such N-acylbornane-10,2-sultams [18], such
as the anti-periplanar disposition of the SO2/C(ˆO) moieties, with concomitant
anomeric pyramidalization of the N-atom [28]13).
Conclusion. ± High diastereoselectivity (87 ± 96%) was obtained during the TiCl4-
catalyzed (0.5 mol-equiv.) endo addition of ( )-1b ± d to cyclopentadiene. Chromato-
10
)
)
Chelation is also entropically more favorable than the intermolecular dicoordination to two
methoxycarbonyl functionalities.
In case of the catalyzed cyclopentadiene [4 ‡ 2] cycloaddition to monomenthyl methyl fumarate,
preferential endo attack with respect to the sterically less demanding methoxycarbonyl group was earlier
observed [9d]; this selectivity was even increased to 98.4% in the presence of a sterically demanding
catalyst.
11
12
13
)
)
Recent PM3 calculations of ( )-1b LUMO suggest that the steric/stereoelectronic effects are cooperative
only for the C(a)-atom in its syn-s-cis-conformation [15a].
For a recent discussion of the influence of the pyramidalization on the sp3 N overlap with the carbonyl
moiety and resultant reactivity in anomeric amides and sultams, see [29].

Helvetica Chimica Acta ± Vol. 82 (1999)
187
Table 2. Selected Bond Lengths [Š] and Angles [8] for endo-(2R,3R)-2b (lp ˆ lone electron pair)
DhN
0.200(4)
1.430(2)
1.422(3)
1.692(2)
S
N
C(13) O(3)
154.6(3)
107.1(2)
123.2(2)
151.5(2)
21.8(2)
S
S
S
O(1)
O(2)
N
O(1)
O(2)
O(1)
O(2)
S
S
S
S
N
N
N
N
C(2)
C(2)
lp
O(1)
S
O(2)
117.2(2)
lp
graphic separation of the endo/exo-(2R,3R)-2b ± d from the minor endo/exo-(2S,3S)
pair of diastereoisomers led, after crystallization and reduction with LiAlH4, to
optically pure (2R,3R)-3 in 91 ± 93% yield, with non-destructive removal of the chiral
auxiliary (89 ± 91%). Nonsymmetric, optically pure cycloadducts of type endo-2b ± d
are ideal building blocks for the synthesis of diverse molecules possessing potent
antithrombotic [30] or A2/prostaglandin endoperoxide receptor antagonist properties
[31], as well as of loganin [32] and nitraraine alkaloids [33]. This methodology may
also be applied to the preparation of the hexahydrobenzofuran subunit of the
avermectins and milbemycins [34] and to the marine diterpene fuscol [35].
We are indebted to Dr. Zofia UrbanÄczyk-Lipkowska for X-ray analysis and structure determination of
(2R,3R)-2b. Financial support from the Polish Academy of Sciences and from the University of Warsaw (BST/
592/18/98) is gratefully acknowledged.
Experimental Part
General. See [15a].
X-Ray Crystal-Structure Determination of endo-(2R,3R)-2b. Crystal data and measurement conditions are
given in Table 3. Diffraction data were collected at r.t. on a four-circle Enraf-Nonius-MACH3 diffractometer
using ꢀExpressꢁ software, without absorption correction. Monochromated CuKa radiation (l 1.54178 Š) was
applied, and the w-2q scan technique was used during measurements. In the final steps of the least-squares
procedure, all but the Me group H-atoms were kept fixed at their calculated positions. The structure was solved
by the SHELXS [36] and refined with the SHELXL [37] programs. Crystallographic data for endo-(2R,3R)-2b
have been deposited at the Cambridge Crystallographic Data Center as supplementary publication No CCDC-
102389.
Table 3. Crystal Data and Structure Refinement of endo-(2R,3R)-2b
Empirical formula
Formula weight
Crystal system
Space group
C20H27NO5S
393.49
orthorhombic
P212121
q-Range [8]
Index ranges
Reflex. collected
Independent reflex
3.51 to 73.65
0 < h < 9, 0 < k < 12, 0 < l < 31
2073
2070 (R(int) ˆ 0.0335)
Completeness to 2q ˆ 73.65 91.8%
Unit cell dimension a [Š] 7.889(6)
b [Š] 9.7412(4)
2
Refinement method
Full-matrix least-square on F
2070/0/245
1.053
Data/restraints/parameters
goodness of fit on F2
Final R indices (I > 2s(I))
R indice (all data)
Absolute structure parameter 0.07(3)
Extinction coeff.
c [Š] 25.2030(10)
Volume [Š3]
Z
Density calc. [Mg m
Absorption coeff. [mm
F(000)
1936.7(15)
4
1.350
1.751
R1 ˆ 0.0371, wR2 ˆ 0.1094
R1 ˆ 0.0379, wR2 ˆ 0.1105
3
]
1
]
0.0014(3)
0.229 and 0.207
840
Largest diff. peak and
hole [e ´ Š
Crystal size [mm]
0.7 Â 0.63 Â 0.56
3
]
(
)-(2R)-N-[(E)-3-[(Benzyloxy)carbonyl]prop-2-enoyl]bornane-10,2-sultam (ˆ( )-Benzyl (E)-4-[(3aS,6R,
7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano[2,1]benzisothiazol-1-yl]-4-oxobut-2-
enoate; ( )-1d). To a stirred suspension of NaH (225 mg, 4.52 mmol; 50% in mineral oil, washed 3 Â with dry
pentane) in dry toluene (35 ml) (2R)-bornane-10,2-sultam (972 mg, 4.52 mmol) in toluene (15 ml) was added.

188
Helvetica Chimica Acta ± Vol. 82 (1999)
After 30 min at r.t., freshly prepared crude benzyl (E)-4-chloro-4-oxobut-2-enoate in toluene (10 ml) (obtained
after distillative concentration of an excess of oxalyl chloride (1370 mg, 10.8 mmol) and fumaric acid
monobenzyl ester [17] (1120 mg, 5.4 mmol) in toluene (15 ml), 808, 1 h) was added dropwise at 08, and the
mixture was stirred at r.t. for 18 h. The reaction was quenched by addition of sat. aq. NH4Cl soln. (40 ml) and
extracted with toluene (4 Â 20 ml). The org. phase was dried (MgSO4) and evaporated and the residue purified
by CC (cyclohexane/AcOEt 9 : 1): pure ( )-1d (85%). White solid. M.p. 126 ± 1288 (CCl4, 83%). [a]D20
ˆ
111.1
(c ˆ 1.5, CCl4). IR: 2957, 1724, 1679, 1292, 1161, 1134, 1066, 971. 1H-NMR: 0.98 (s, 3 H); 1.17 (s, 3 H); 1.4
(m, 2 H); 1.9 (m, 3 H); 2.15 (m, 2 H); 3.51 (q, J ˆ 14, 2 H); 3.96 (dd, J ˆ 6, 8, 1 H); 5.24 (AB, J ˆ 12, 16, 2 H);
6.95 (d, J ˆ 16, 1 H); 7.37 (m, 5 H); 7.6 (d, J ˆ 16, 1 H). 13C-NMR: 19.9 (q); 20.8 (q); 26.5 (t); 32.9 (t); 38.3 (t);
44.7 (d); 47.9 (s); 48.8 (s); 53.0 (t); 65.1 (d); 67.1 (t); 128.3 (2d); 128.4 (d); 128.6 (2d); 132.8 (d); 133.7 (d); 135.3
.
‡
(s); 162.4 (s); 164.4 (s). MS: 403 (0, M ), 358(4), 297(26), 233(25), 135(21), 91(100), 79(6).
(2R,3R)-3-{[(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano[2,1]benziso-
thiazol-1-yl]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Methyl Ester (endo-(2R,3R)-2b). To a soln. of
(
)-1b (327 mg, 1.0 mmol) in CH2Cl2 (20 ml), 1m TiCl4 in CH2Cl2 (0.5 ml, 0.5 mmol) was added. The mixture
was cooled to 788 and pre-cooled 1m cyclopenta-1,3-diene in CH2Cl2 (10 ml, 10 mmol) was added dropwise
and slowly along the interior cold surface of the reaction flask. After 18 h, the reaction was quenched with NH4F
and equilibrated. After addition of H2O, the mixture was extracted with CH2Cl2 and the extract dried (MgSO4)
and evaporated under medium and then high vacuum. 1H-NMR analysis showed full conversion and a
94 : 3 : 1 : 2 mixture of cycloadducts. Chromatography (SiO2, hexane/AcOEt 95 : 5 ! 8 : 2) afforded a faster
eluting pair of diastereoisomers (8 : 7 mixture; 1.8%) and a more polar pair of diastereoisomers (96 : 4 mixture;
95%) which was recrystallized to afford pure endo-(2R,3R)-2b (87%). White solid, M.p. 190 ± 1928 (EtOH).
[a]2D0
ˆ
219.94 (c ˆ 1.03, CHCl3). IR: 3060, 3000, 2953, 2913, 2881, 1733, 1687, 1328, 1136, 551. 1H-NMR: 0.97
(s, 3 H); 1.19 (s, 3 H); 1.30 ± 1.75 (m, 5 H); 1.80 ± 2.1 (m, 4 H); 2.88 (dd, J ˆ 1.4, 4.4, 1 H); 3.18 (m, 1 H); 3.48
(AB, J ˆ 13.7, 2 H); 3.51 (m, 1 H); 3.68 (s, 3 H); 3.86 (m, 2 H); 5.86 (dd, J ˆ 2.5, 5.3, 1 H); 6.34 (dd, J ˆ 3.2, 5.3,
1 H). 13C-NMR: 20.1 (q); 20.9 (q); 26.6 (t); 32.9 (t); 38.7 (t); 44.8 (d); 45.8 (t); 46.3 (d); 47.7 (s); 48.1 (d); 48.5
(s); 48.7 (d); 49.3 (d); 52.2 (q); 53.3 (t); 65.5 (d); 133.0 (d); 138.5 (d); 172.0 (s); 174.6 (s). HR-MS: 393.16074
(C20H27NO5S ; calc 393.16099). MS: 393 (1, M ), 362(3), 328(18), 296(14), 178(65), 150(25), 135(35),
113(100), 66(30).
.
‡
‡
(2R,3R)-3-{[(3aS,6R,7aR)-1,4,5,6,7,7a-Hexahydro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano[2.1]benziso-
thiazol-1-yl]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Ethyl Ester (endo-(2R,3R)-2c). Obtained in
80% yield, similarly to endo-(2R,3R)-2b. M.p. 170 ± 1728 (EtOH). [a]D20
ˆ
209.3 (c ˆ 0.7, CCl4). IR: 2957, 1726,
1688, 1456, 1392, 1327, 1234, 1209, 1039. 1H-NMR: 0.99 (s, 3 H); 1.21 (s, 3 H); 1.25 (t, J ˆ 7, 3 H); 1.30 ± 1.75
(m, 5 H); 1.80 ± 2.1 (m, 4 H); 2.88 (dd, J ˆ 1.4, 4.4, 1 H); 3.22 (br. s, 1 H); 3.48 (AB, J ˆ 14, 2 H); 3.51 (m, 1 H);
3.87 (m, 2 H); 4.16 (m, 2 H); 5.86 (dd, J ˆ 2.5, 5.3, 1 H); 6.34 (dd, J ˆ 3.2, 5.3, 1 H). 13C-NMR: 14.2 (q); 19.9
(q); 20.8 (q); 26.5 (t); 32.7 (t); 38.5 (t); 44.6 (d); 45.8 (t); 46.3 (d); 47.5 (d); 47.8 (s); 47.9 (d); 48.5 (s); 49.2 (d);
.
‡
53.2 (t); 60.8 (t); 65.3 (d); 132.8 (d); 138.4 (d); 172.0 (s); 174.0 (s). MS: 407 (0, M ), 341(4), 296(21), 268(22),
231(21), 204(45), 150(29), 135(35), 127(100), 99(32), 55(16).
The paired diastereoisomer exo-(2R,3R)-2c exhibits signals at 6.34 and 6.14 ppm in the 1H-NMR spectrum,
while the exo-(2S,3S)-2c diastereoisomer resonates at 6.32 and 6.19 ppm, when compared to its inseparable
endo-(2S,3S)-2c counterpart (6.32 and 6.03 ppm for olef. H).
(2R,3R)-3-{[(3aS,6R,7aR)-1,4,5,6,7,7a-hexahydro-8,8-dimethyl-2.2-dioxido-3H-3a,6-methano[2,1]benziso-
thiazol-1-yl]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Benzyl Ester (endo-(2R,3R)-2d). Obtained in
73% yield, similarly to endo-(2R,3R)-2b. M.p. 143 ± 1448 (EtOH). [a]D20
ˆ
148.4 (c ˆ 2.6, CHCl3). IR: 2957,
1730, 1688, 1330, 1269, 1234, 1209, 1163, 1132, 1053, 782, 754. 1H-NMR: 0.98 (s, 3 H); 1.19 (s, 3 H); 1.35
(m, 2 H); 1.47 (m, 1 H); 1.71 (br. d, J ˆ 8, 1 H); 1.9 (m, 4 H); 2.0 (m, 1 H); 2.94 (dd, J ˆ 3, 6, 1 H); 3.2
(br. s, 1 H); 3.5 (q, J ˆ 14, 2 H); 3.53 (br. s, 1 H); 3.86 (dd, J ˆ 4, 8, 1 H); 3.95 (t, J ˆ 4, 1 H); 5.14 (AB, J ˆ 12,
2 H); 5.88 (dd, J ˆ 3, 6, 1 H); 6.34 (dd, J ˆ 3, 6, 1 H); 7.35 (m, 5 H). 13C-NMR: 19.9 (q); 20.8 (q); 26.5 (t); 32.7
(t); 38.5 (t); 44.6 (d); 46.3 (d); 47.8 (d); 47.8 (s); 48.0 (d); 48.3 (s); 48.4 (t); 49.1 (d); 53.1 (t); 65.3 (d); 66.6 (t);
.
‡
128.0 (d); 128.1 (2d); 128.5 (2d); 132.9 (d); 136.0 (s); 138.3 (d); 171.8 (s); 173.8 (s). MS: 469 (0, M ), 358(3),
297(26), 233(25), 135(23), 91(100), 79(7).
The paired diastereoisomer exo-(2R,3R)-2d exhibits signals at 6.34 and 6.04 ppm in the 1H-NMR spectrum,
while the exo-(2S,3S)-2d diastereoisomer resonates at 6.32 and 6.12 ppm, when compared to its inseparable
endo-(2S,3S)-2d counterpart (6.32 and 6.02 ppm for olef. H).
Cycloadduct exo-(2R,3R)-2b. 1H-NMR (deduced from the mixture): 0.99 (s, 3 H); 1.20 (s, 3 H); 3.09
(m, 1 H); 3.26 (m, 1 H); 3.62 (s, 3 H); 6.14 (dd, J ˆ 2.4, 5.4, 1 H); 6.34 (dd, J ˆ 2.4, 5.4, 1 H). 13C-NMR (deduced

Helvetica Chimica Acta ± Vol. 82 (1999)
189
from the mixture): 20.1 (q); 21.0 (q); 26.6 (t); 33.0 (t); 38.8 (t); 45.5 (d); 45.9 (t); 46.9 (d); 47.9 (s); 48.0 (d); 48.5
(s); 49.1 (d); 49.8 (d); 51.9 (q); 53.2 (t); 65.5 (d); 135.9 (d); 137.7 (d); 172.6 (s); 173.6 (s).
1
Cycloadduct exo-(2S,3S)-2b. H-NMR (deduced from the mixture): 0.97 (s, 3 H); 1.17 (s, 3 H); 1.20 ± 1.50
(m, 4 H); 1.70 (m, 1 H); 1.8 ± 2.0 (m, 2 H); 2.0 ± 2.2 (m, 2 H); 3.10 (dd, J ˆ 1.4, 5.0, 1 H); 3.15 ± 3.25 (m, 2 H);
3.605 (s, 3 H); 6.17 (dd, J ˆ 1.9, 5.6, 1 H); 6.31 (dd, J ˆ 2, 5.6, 1 H). 13C-NMR (deduced from the mixture): 20.1
(q); 20.9 (q); 26.6 (t); 33.1 (t); 38.8 (t); 44.9 (d); 46.1 (t); 47.2 (d); 48.1 (s); 48.4 (d); 48.5 (s); 48.6 (d); 50.0 (d);
51.9 (q); 53.3 (t); 65.7 (d); 136.1 (d); 138.1 (d); 172.7 (s); 173.7 (s).
Cycloadduct endo-(2S,3S)-2b. 1H-NMR (deduced from the mixture): 0.96 (s, 3 H); 1.15 (s, 3 H); 1.2 ± 1.5
(m, 4 H); 1.7 (m, 1 H); 1.8 ± 2.0 (m, 2 H); 2.0 ± 2.2 (m, 2 H); 2.60 (dd, J ˆ 2, 5.3, 1 H); 3.15 ± 3.25 (m, 2 H); 3.675
(s, 3 H); 6.06 (dd, J ˆ 3, 5.5, 1 H); 6.31 (dd, J ˆ 3, 5.5, 1 H). 13C-NMR (deduced from the mixture): 20.1 (q); 20.8
(q); 26.6 (t); 32.9 (t); 38.6 (t); 44.7 (d); 45.1 (t); 47.1 (d); 48.0 (s); 48.5 (d); 48.6 (s); 48.8 (d); 50.3 (d); 52.1 (q);
53.2 (t); 65.6 (d); 134.6 (d); 137.0 (d); 172.7 (s); 173.6 (s).
(2R,3R)-3-{[(3aS,6R,7aR)-1,4,5,6,7,7a-hexahydro-8,8-dimethyl-2,2-dioxido-3H-3a,6-methano[2.1]benziso-
thiazol-1-yl]carbonyl}bicyclo[2.2.1]heptane-2-carboxylic Acid ((2R,3R)-4).
A soln. of endo-(2R,3R)-2d
(470 mg, 1.0 mmol) in EtOH (10 ml) was hydrogenated in the presence of 10% Pd/C (47 mg). After 4 h, the
soln. was filtered and evaporated under medium and then high vacuum to give quantitatively (2R,3R)-4. White
solid. M.p. 250 ± 2518 (98% EtOH). [a]D20
ˆ
138.2 (c ˆ 1.3, CHCl3). IR: 3150, 2954, 1697, 1680, 1458, 1407,
1388, 1296, 1265, 1181, 1040, 930, 848. 1H-NMR: 0.98 (s, 3 H); 1.14 (s, 3 H); 0.8 ± 1.45 (m, 7 H); 1.55 (m, 1 H);
1.68 (br. d, J ˆ 16, 1 H); 1.88 (m, 2 H); 2.05 (m, 2 H); 2.64 (br. d, J ˆ 5, 1 H); 2.88 (br. t, J ˆ 3, 1 H); 3.04
(br. d, J ˆ 5, 1 H); 3.48 (AB, J ˆ 14, 2 H); 3.75 (m, 1 H); 3.92 (dd, J ˆ 6, 11, 1 H); 8.6 (br. s, 1 H). 13C-NMR:
19.9 (q); 20.8 (q); 23.6 (t); 26.5 (t); 28.6 (t); 32.7 (t); 38.8 (t); 39.0 (t); 41.5 (d); 41.6 (d); 44.7 (d); 47.7 (d); 48.3
.
‡
(2 s); 50.7 (d); 53.0 (t); 65.3 (d); 172.0 (s); 179.4 (s). EI-MS: 381 (1.5, M ), 315(74), 297(20), 216(100),
167(71), 139(41), 121(13), 93(21), 67(40).
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Received December 18, 1998