The synthesis of epiboxidine and related analogues as potential pharmacological agents

Article abstract of DOI:10.1002/hlca.201100140

Methyl epiboxidine-N-carboxylate (8) was synthesized from 7 under reductive Heck conditions (Scheme 2). The C-C coupling of the new epiboxidine analog 9 with aryl and heteroaryl halides gave by hydroarylation C-aryl, N-(3-methylisoxazol-5-yl)-substituted

Full text of DOI:10.1002/hlca.201100140

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Helvetica Chimica Acta – Vol. 94 (2011)
The Synthesis of Epiboxidine and Related Analogues as Potential
Pharmacological Agents
by Irem Kulu and Nuket Ocal*
Yildiz Technical University, Faculty of Art and Sciences, Department of Chemistry, Davutpasa Campus,
TR-34210, Istanbul
(phone: þ 90-212-3834214; e-mail: nocal@yildiz.edu.tr)
Methyl epiboxidine-N-carboxylate (8) was synthesized from 7 under reductive Heck conditions
(Scheme 2). The CꢀC coupling of the new epiboxidine analog 9 with aryl and heteroaryl halides gave by
hydroarylation C-aryl, N-(3-methylisoxazol-5-yl)-substituted tricyclic imides 10a – 10f (Table). The [3 þ
2] cycloaddition of 9 with nitrile oxides yielded the bridged dihydroisoxazole derivatives 11a – 11d with
potential biological activity (Scheme 4).
Introduction. – The discovery of the natural product epibatidine (¼(1R,2R,4S)-2-
(6-chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane; 1) in 1992 [1] and recognition of its
powerful analgesic properties has led to a remarkable level of synthetic interest. The
fact that epibatidine acts as the nicotinic acetylcholine receptor 2 (nAChR) and is a
much more effective ligand than nicotine (¼ 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine)
itself has prompted a substantial reappraisal of this receptor [2].
The toxicity of epibatidine itself has encouraged work on structurally related
analogues in the search for lower toxicity and also higher discrimination between
receptor sub-types. Daly and co-workers [3] reported that replacement of the
chloropyridinyl moiety of 1 by a methylisoxazolyl moiety gave epiboxidine (¼ rac-2-
(3-methylisoxazol-5-yl)-7-azabicyclo[2.2.1]heptane; 3), which behaved as a potent
a4b2 nicotinic receptor agonist, 10-fold less potent than epibatidine (1) as antinoci-
ceptive agent but ca. 20-fold less toxic. The presence of the 3-methylisoxazol-5-yl
moiety was similarly effective in the structure of (S)-ABT-418 (4) and represents a
relatively accessible modification that could be also applied to 1. The exciting biological
properties and unique structure of 3, combined with its scarcity in nature have aroused
the interest of synthetic chemists around the world. So far, some syntheses of
epiboxidine and related analogues have been published [4][5]. These syntheses are
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
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based on an acetone oxime derivative allowing to construct later on the isoxazole ring
at the bicylic system (Scheme 1).
Scheme 1. Synthesis of Racemic 3
Seeden and Kaufmann have reported the synthesis of some new epibatidine
analogues by the reductive Heck reaction, but their compounds were not including the
isoxazole ring [6][7]. We therefore became interested in the synthesis of 3 involving
the reductive Heck reaction in a single synthetic operation with 5-iodo-3-methylisox-
azole as reactant in the present work, i.e., we prepared the analog 8. We then focused on
reductive Heck reactions of tricyclic molecule containing a strained C¼C bond and an
N-(3-methylisoxazol-5-yl)-substituted imide group (9) possessing potential biological
activity as epiboxidine analogues. In our previous works, we had already accomplished
Pd-catalyzed reductive Heck reactions with bicyclic and tricyclic precursors of
epibatidine analogues [8 – 10]. In the present work, we also planned to synthesize
dihydroisoxazole derivatives of 9 via 1,3-dipolar cycloadditions leading to possibly
biologically active molecules including two isoxazole moieties.
Results and Discussion. – Our synthesis of epiboxidine analog 8 started with the
reaction of methyl 1H-pyrrole-1-carboxylate (5) and p-toluenesulfonylacetylene (6)
followed by two reduction steps by using Kaufmannꢂs procedure [7] to give methyl 7-
azabicyclo[2.2.1]hept-2-ene-7-carboxylate (7; Scheme 2). The reagent for the subse-
quent reductive Heck reaction, 5-iodo-3-methylisoxazole, was obtained from 3-methyl-
5-(tributylstannyl)isoxazole by using the procedure of Yamanaka and co-workers [11],
followed by chromatographic purification (silica gel). Finally, treatment of 7 with 5-
Scheme 2. Synthesis of Compound 8

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Helvetica Chimica Acta – Vol. 94 (2011)
iodo-3-methylisoxazole under reductive Heck conditions and subsequent chromatog-
raphy (silica gel) gave methyl 2-exo-(3-methylisoxazol-5-yl)-7-azabicyclo[2.2.1]hep-
tane-7-carboxylate (¼ methyl exo-epiboxidine-N-carboxylate; 8) in a yield of 61%.
We also synthesized 9 as a new epiboxidine analog from the cyclic anhydride of
bicyclo[2.2.1]hept-5-ene-2-endo,3-endo-dicarboxylic acid (¼ 3a,4,7,7a-tetrahydro-4,7-
methanoisobenzofuran-1,3-dione) and 3-methylisoxazol-5-amine in good yield (90%)
after crystallization (Scheme 3).
Scheme 3. Synthesis of Compound 9
Treatment of 9 with 5-iodo-3-methylisoxazole, 1-iodobenzene, 4-chloro-1-iodo-
benzene, 2-chloro-5-iodopyridine, 2-iodothiophene, and 4-methoxy-1-iodobenzene
under reductive Heck conditions and subsequent column chromatography (silica gel)
gave 10a – 10f as single diastereoisomers in yields of 42 – 66% after purification
(Table). The relative configuration for each Heck product was inferred from NMR
spectra including diagnostic spinꢀspin interactions. The exo-position of the C(5)
substituent was confirmed by the fact that HendoꢀC(5) showed no significant interaction
with HꢀC(7). The geminal H-atoms at C(8) were identified by their vicinal coupling to
1
HꢀC(7). Additionally, the H,1H-COSY plots showed cross-peaks between HꢀC(3a)
and HꢀC(7a) and between HꢀC(5) and HꢀC(6), respectively. In addition to the
13C-NMR, HSQC, and FT-IR data and elemental analyses, which were in agreement
with the proposed structures, the mass spectra of all new compounds 10a – 10f showed
the expected molecular-ion peaks.
Table. Exploration of Product Formation under Reductive Heck Conditions
Entry
Ar(Hetar)
Product
Yield [%]
1
2
3
4
5
6
3-Methylisoxazol-5-yl
Ph
10a
10b
10c
10d
10e
10f
42
66
58
45
52
60
4-ClꢀC6H4
6-Chloropyridin-3-yl
Thiophen-2-yl
4-MeOꢀC6H4

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Trinorbornene and its derivatives due to their rigid bicyclic skeleton give rise to
stereoisomers with fixed spatial orientation of substitutents. The C¼C bond in
substituted trinorbornenes is quite reactive toward cycloadditions, in particular toward
nitrile oxides in 1,3-dipolar additions. We carried out the [3 þ 2] cycloaddition of 9 with
in situ formed nitrile oxides to obtain the target compounds 11a – 11d (Scheme 4). The
1H-NMR spectra of 11a – 11d were in accord with the proposed structures. To identify
the configuration of the dihydroisoxazole moiety of the adducts, we studied selective
1H,1H-COSY plots obtained from these compounds.
Scheme 4. Synthesis of Compounds 11a – 11d
In conclusion, epiboxidine analog 8 was synthesized with 5-iodo-3-methylisoxazole
under reductive Heck conditions in the presence of Ph3As as a ligand in a simple way.
The Pd-catalyzed hydroarylation of the easily accessible unsaturated tricyclic N-(3-
methylisoxazol-5-yl)imide 9 was a stereoselective, versatile, and high-yield conversion
for the synthesis of aryl and heteroaryl derivatives 10a – 10f. Our results also
demonstrate that the cycloaddition of 9 to give aryl-substituted bridged dihydroisox-
azole derivatives 11b – 11d will be useful for the construction of novel heterocycles of
potential pharmacological interest.
We gratefully acknowledge the financial support of this work by the Scientific and Technological
Research Council of Turkey (Tubitak Project No. 109T380). We thank Prof. Dr. Dieter E. Kaufmann,
Clausthal Technical University, for helping us.
Experimental Part
1. General. All reactions were conducted under N2 and carried out in a Schlenk system. Column
chromatography (CC): silica gel 60. TLC: silica gel pre-coated (0.2 mm layer) aluminium sheets
(Merck). M.p.: Gallenkamp melting-point apparatus; uncorrected. IR Spectra: PerkinꢀElmer FT-IR
spectrometer; KBr pellets; ˜n in cmꢀ1. NMR Spectra: Varian Inova (500 MHz) spectrometers; in CDCl3; d
in ppm rel. to Me4Si as internal standard, J in Hz. GC/MS: Agilent 6890N GC system 5973 IMSD; in m/z.
2. Compounds 8 and 9. Methyl 2-exo-(3-Methylisoxazol-5-yl)-7-azabicyclo[2.2.1]heptane-7-carbox-
ylate (8). As described in Sect. 3, from 7 and 5-iodo-3-methylisoxazole. CC (AcOEt/hexane 1:2). Yield
61%. Colorless oil. IR: 3012, 2922, 1709, 1605, 1512, 1437, 1396, 1254, 1198, 1024, 880, 772, 737. 1H-NMR:
1.56 – 1.60 (m, HꢀC(5), HꢀC(6)); 1.75 – 1.83 (m, HꢀC(5), HꢀC(6), HexoꢀC(3)); 1.98 – 2.01 (m,
HendoꢀC(3)); 2.29 (s, Me); 2.93 (dd, J ¼ 4.8; 8.8, HendoꢀC(2)); 3.75 (s, MeO); 4.11 (br. s, HꢀC(1)); 4.40
(br. s, HꢀC(7)); 5.77 (s, ¼CH). 13C-NMR: 10.85; 28.71; 29.62; 40.25; 44.78; 52.40; 58.15; 62.11; 97.76;
133.80; 153.92; 161.15. GC/MS: 236 (Mþ), 178, 110, 82, 69, 55.
rel-(3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-2-(3-methylisoxazol-5-yl)-4,7-methano-1H-isoindole-
1,3(2H)-dione (9). Synthesized from 3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione and 3-
methylisoxazol-5-amine. CC (AcOEt/hexane 2 :1). Yield 90%. White crystals. m.p. 135 – 1378. IR: 3134,

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Helvetica Chimica Acta – Vol. 94 (2011)
3009, 2977, 2940, 2870, 1794, 1717, 1625, 1495, 1414, 1352, 1381, 1165, 1109, 709, 666. 1H-NMR: 1.53 (d, J ¼
8.8, HantiꢀC(8)); 1.72 (dt, J ¼ 1.9, 10.7, HsynꢀC(8)); 2.24 (s, Me); 3.40 (br. s, HꢀC(4), HꢀC(7)); 3.43 – 3.44
(m, HꢀC(3a), HꢀC(7a)); 6.06 (s, ¼CH); 6.17 (s, CH¼CH). 13C-NMR: 10.85; 44.78; 45.29; 51.26; 97.76;
133.80; 153.92; 159.73; 172.48. GC-MS: 244 (Mþ), 179, 119, 82, 66.
3. Reductive Heck Reactions. General Procedure: A soln. of [Pd(OAc)2] (5.6 mg, 0.025 mmol) and
Ph3As (33.7 mg, 0.11 mmol) in anh. DMF or DMSO (3 ml) was stirred under N2 at 658 for 15 min. Then,
compound 10 (244 mg, 1 mmol), Et3N (488 ml, 3.5 mmol), aryl(heteroaryl) iodide (1.5 mmol), and
HCOOH (138 mg, 3 mmol) were added. The mixture was stirred for 8 – 24 h. After cooling to r.t., AcOEt
and brine were added. The org. layer was dried (MgSO4) and concentrated, and the residue purified by
CC (SiO2).
rel-(3aR,4S,5S,7R,7aS)-Hexahydro-2,5-bis(3-methylisoxazol-5-yl)-4,7-methano-1H-isoindole-
1,3(2H)-dione (10a): CC (AcOEt/hexane 1:1). Yield 42%. Colorless oil. IR: 3169, 3009, 2970, 1795, 1727,
1618, 1600, 1493, 1415, 1346, 1252, 1155, 727, 690. 1H-NMR: 1.65 (d, J ¼ 10.7, HantiꢀC(8)); 1.88 – 1.90 (m,
CH2(6)); 1.94 (d, J ¼ 10.7, HsynꢀC(8)); 2.18 (s, Me); 2.29 (s, Me); 2.93 – 2.96 (m, HꢀC(7), HendoꢀC(5));
3.01 (d, J ¼ 4.8, HꢀC(4)); 3.27 – 3.31 (m, HꢀC(3a)); 3.33 – 3.36 (m, HꢀC(7a)); 5.77 (s, ¼CH); 6.21 (s,
¼CH). 13C-NMR: 11.60; 12.14; 31.71; 35.61; 40.03; 40.44; 45.25; 48.64; 48.84; 99.60; 154.84; 155.99;
161.22; 173.43; 173.58; 174.26. GC/MS: 327 (Mþ), 179, 148, 82, 66.
rel-(3aR,4S,5S,7R,7aS)-Hexahydro-2-(3-methylisoxazol-5-yl)-5-phenyl-4,7-methano-1H-isoindole-
1,3(2H)-dione (10b): CC (AcOEt/hexane 2 :1). Yield 66%. White crystals. M.p. 118 – 1198. IR: 3148,
3009, 2922, 1790, 1724, 1607, 1494, 1416, 1349, 1255, 1058, 731, 698. 1H-NMR: 1.55 (d, J ¼ 10.7,
HantiꢀC(8)); 1.86 – 1.90 (m, HsynꢀC(8), CH2(6)); 2.29 (s, Me); 2.89 – 2.93 (m, HꢀC(4), HꢀC(7),
HendoꢀC(5)); 3.25 – 3.28 (m, HꢀC(3a)); 3.31 – 3.34 (m, HꢀC(7a)); 6.21 (s, ¼CH); 7.11 – 7.14 (m, 3 arom.
H); 7.22 – 7.25 (m, 2 arom. H). 13C-NMR: 12.15; 32.83; 39.63; 40.64; 42.15; 46.71; 48.90; 49.47; 99.46;
126.60; 127.24; 128.77; 144.13; 155.12; 161.16; 174.13; 174.21. GC/MS: 322 (Mþ), 281, 239, 180, 142, 128,
104, 82, 66.
rel-(3aR,4S,5S,7R,7aS)-5-(4-Chlorophenyl)hexahydro-2-(3-methylisoxazol-5-yl)-4,7-methano-1H-
isoindole-1,3(2H)-dione (10c): CC (AcOEt/hexane 3 :1). Yield 58%. White crystals. M.p. 117 – 1198. IR:
3135, 3009, 2963, 1794, 1724, 1621, 1493, 1415, 1346, 1256, 1012, 741, 715, 667. 1H-NMR: 1.57 (d, J ¼ 10.5,
HantiꢀC(8)); 1.81 – 1.93 (m, HsynꢀC(8), CH2(6)); 2.29 (s, Me); 2.86 – 2.95 (m, HꢀC(4), HꢀC(7),
HendoꢀC(5)); 3.26 – 3.29 (m, HꢀC(3a)); 3.32 – 3.35 (m, HꢀC(7a)); 6.21 (s, ¼CH); 7.04 (d, J ¼ 8.8, 2 arom.
H); 7.18 (d, J ¼ 8.8, 2 arom. H). 13C-NMR: 10.92; 31.66; 38.29; 39.33; 40.39; 45.35; 47.52; 48.09; 98.28;
127.36; 127.57; 131.10; 141.39; 153.77; 160.00; 172.82; 172.95. GC/MS: 356.5 (Mþ), 331, 315, 273, 176, 139,
103, 82, 66.
rel-(3aR,4S,5S,7R,7aS)-5-(6-Chloropyridin-3-yl)hexahydro-2-(3-methylisoxazol-5-yl)-4,7-methano-
1H-isoindole-1,3(2H)-dione (10d): CC (AcOEt/hexane 2 :1). Yield 45%. White crystals. M.p. 147 – 1488.
IR: 3151, 3094, 2964, 2886, 1792, 1726, 1621, 1497, 1419, 1349, 1249, 1151, 751, 739, 683, 671. 1H-NMR: 1.63
(d, J ¼ 10.7, HantiꢀC(8)); 1.79 – 1.85 (m, HsynꢀC(8), HexoꢀC(6)); 1.92 – 1.98 (ddd, J ¼ 1.9, 8.8, 14.6,
HendoꢀC(6)); 2.29 (s, Me); 2.87 – 2.92 (m, HꢀC(7), HendoꢀC(5)); 2.98 (br. s, HꢀC(4)); 3.29 – 3.32 (m,
HꢀC(3a)); 3.36 – 3.39 (m, HꢀC(7a)); 6.22 (s, ¼CH); 7.19 (s, 1 arom. H); 7.40 (dd, J ¼ 2.9, 8.8, 1 arom. H);
8.17 (d, J ¼ 2.9, 1 arom. H). 13C-NMR: 12.15; 32.85; 39.58; 39.60; 40.62; 46.19; 48.64; 49.23; 99.58; 124.27;
137.87; 138.39; 148.54; 149.91; 153.90; 154.89; 161.23; 173.61; 173.78. GC/MS: 356 (Mþ), 276, 178, 139, 99,
66.
rel-(3aR,4S,5S,7R,7aS)-Hexahydro-2-(3-methylisoxazol-5-yl)-5-(thiophen-2-yl)-4,7-methano-1H-
isoindole-1,3(2H)-dione (10e): CC (AcOEt/hexane 3 :1). Yield 52%. White crystals. M.p. 1278. IR: 3148,
3009, 2978, 2950, 1792, 1721, 1611, 1492, 1415, 1349, 1253, 1162, 1141, 741, 697, 674. 1H-NMR: 1.60 (d, J ¼
10.7, HantiꢀC(8)); 1.85 – 2.01 (m, HsynꢀC(8), CH2(6)); 2.28 (s, Me); 2.92 (br. s, HꢀC(4), HꢀC(7)); 3.11
(dd, J ¼ 4.8, 8.8, HendoꢀC(5)); 3.24 – 3.28 (m, HꢀC(3a)); 3.30 – 3.34 (m, HꢀC(7a)); 6.21 (s, ¼CH); 6.74 (d,
J ¼ 3.9, 1 arom. H); 6.85 (dd, J ¼ 4.8, 8.8, 1 arom. H); 7.07 (d, J ¼ 4.8, 1 arom. H). 13C-NMR: 12.15; 35.23;
38.34; 40.00; 40.29; 48.04; 48.63; 49.04; 99.48; 123.78; 123.92; 127.06; 148.97; 154.99; 161.16; 173.85;
173.87. GC/MS: 327 (Mþ), 179, 148, 82, 66.
rel-(3aR,4S,5S,7R,7aS)-Hexahydro-5-(4-methoxyphenyl)-2-(3-methylisoxazol-5-yl)-4,7-methano-
1H-isoindole-1,3(2H)-dione (10f): CC (AcOEt/hexane 2 :1). Yield 60%. White crystals. M.p. 1228. IR:
3169, 3066, 3009, 2963, 2888, 2836, 1787, 1719, 1594, 1510, 1494, 1419, 1345, 1249, 1034, 821, 741, 726.

Helvetica Chimica Acta – Vol. 94 (2011)
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1H-NMR: 1.53 (d, J ¼ 10.7, HantiꢀC(8)); 1.84 – 1.87 (m, HsynꢀC(8), CH2(6)); 2.28 (s, Me); 2.84 – 2.86 (m,
HꢀC(7), HendoꢀC(5)); 2.92 (br. s, HꢀC(4)); 3.24 – 3.27 (m, HꢀC(3a)); 3.30 – 3.33 (m, HꢀC(7a)); 3.71 (s,
MeO); 6.21 (s, ¼CH); 6.77 (d, J ¼ 8.8, 2 arom. H); 7.03 (d, J ¼ 8.8, 2 arom. H). 13C-NMR: 10.93; 31.67;
38.28; 39.38; 40.21; 45.78; 47.66; 48.21; 54.27; 98.21; 112.89; 126.99; 134.99; 153.90; 157.11; 159.92; 172.93;
173.03 GC/MS: 352 (Mþ), 334, 311, 269, 231, 199, 172, 158, 121, 103, 82, 65.
4. 1,3-Dipolar Cycloaddition Reactions: General Procedure. To a soln. of oxime (1.3 mmol) in CH2Cl2
was added 9 (1 mmol), and the soln. was cooled to 08. Aq. NaOCl soln. (5.25%; 3.5 g, 2.5 mmol) was
added dropwise over 30 min, and the mixture was stirred overnight (08 to r.t.). The mixture was extracted
with either CH2Cl2 (3 ꢁ 10 ml) or Et2O and dried (MgSO4). The solvent was evaporated and the residue
purified by CC.
rel-(3aR,4R,4aS,7aR,8R,8aR)-3a,4,4a,7a,8,8a-Hexahydro-3-methyl-6-(3-methylisoxazol-5-yl)-4,8-
methano-5H-isoxazolo[4,5-f]isoindole-5,7(6H)-dione (11a): CC (AcOEt/hexane 3 :1). Yield 64%. White
crystals. M.p. 199 – 2038. IR: 3143, 3008, 2976, 2939, 1794, 1718, 1624, 1495, 1414, 1352, 1323, 1240, 1164,
1
752, 710, 666. H-NMR: 1.56 (d, J ¼ 10.7, HantiꢀC(9); 1.75 (d, J ¼ 10.7, HsynꢀC(9)); 1.88 (s, Me); 2.28 (s,
Me); 2.90 (d, J ¼ 4.8, HꢀC(3a)); 3.09 – 3.12 (m, HꢀC(4), HꢀC(8)); 3.25 – 3.32 (m, HꢀC(4a), HꢀC(7a));
4.51 (d, J ¼ 7.8, HꢀC(8a)); 6.18 (s, ¼CH). 13C-NMR: 11.90; 12.13; 36.08; 41.72; 44.84; 46.39; 47.06; 56.40;
81.56; 99.74; 154.45; 154.49; 161.25; 172.13; 172.82. GC/MS: 304 (Mþ), 282, 207, 178, 113, 85, 57.
rel-(3aR,4R,4aS,7aR,8R,8aR)-3-(4-Chlorophenyl)-3a,4,4a,7a,8,8a-hexahydro-6-(3-methylisoxazol-
5-yl)-4,8-methano-5H-isoxazolo[4,5-f]isoindole-5,7(6H)-dione (11b): CC (AcOEt/hexane 2 :1). Yield
60%. White crystals. M.p. 247 – 2488. IR: 3154, 3009, 2974, 2951, 1797, 1720, 1610, 1592, 1494, 1417, 1350,
1
1268, 1090, 830, 749, 713. H-NMR: 1.59 (d, J ¼ 10.7, HantiꢀC(9)); 1.83 (d, J ¼ 10.7, HsynꢀC(9)); 2.29 (s,
Me); 3.01 (br. s, HꢀC(8)); 3.21 (br. s, HꢀC(4)); 3.32 – 3.38 (m, HꢀC(4a), HꢀC(7a)); 3.62 (d, J ¼ 7.8,
HꢀC(3a)); 4.73 (d, J ¼ 7.8, HꢀC(8a)); 6.22 (s, ¼CH); 7.32 (d, J ¼ 8.8, 2 arom. H); 7.53 (d, J ¼ 8.8, 2 arom.
H). 13C-NMR: 10.91; 35.02; 41.54; 43.62; 45.29; 46.02; 51.60; 82.20; 98.55; 125.35; 127.07; 128.33; 135.55;
153.20; 154.12; 160.06; 170.81; 171.81. GC/MS: 317 (Mþ), 301, 287, 271, 216, 191, 151, 111, 82, 66.
rel-(3aR,4R,4aS,7aR,8R,8aR)-3a,4,4a,7a,8,8a-Hexahydro-6-(3-methylisoxazol-5-yl)-3-(thiophen-2-
yl)-4,8-methano-5H-isoxazolo[4,5-f]isoindole-5,7(6H)-dione (11c): CC (AcOEt/hexane 2 :1). Yield
42%. Yellow crystals. M.p. 1488. IR: 3136, 3073, 2963, 1796, 1720, 1612, 1570, 1493, 1417, 1350, 1255,
1056, 713, 677, 665. 1H-NMR: 1.60 (d, J ¼ 10.7, HantiꢀC(9)); 1.88 (d, J ¼ 10.7, HsynꢀC(9)); 2.29 (s, Me); 3.15
(br. s, HꢀC(8)); 3.21 (br. s, HꢀC(4)); 3.31 – 3.41 (m, HꢀC(4a), HꢀC(7a)); 3.62 (d, J ¼ 7.8, HꢀC(3a)); 4.72
(d, J ¼ 7.8, HꢀC(8a)); 6.21 (s, ¼CH); 7.00 (dt, J ¼ 4.8, 8.8, 1 arom. H); 7.34 (d, J ¼ 4.8, 1 arom. H); 7.65 (dd,
J ¼ 4.8, 10.7, 1 arom. H). 13C-NMR: 10.90; 35.11; 41.91; 43.58; 44.77; 45.20; 52.83; 82.14; 98.53; 126.54;
127.16; 127.64; 150.98; 153.25; 153.53; 160.04; 171.70; 172.48. GC/MS: 369 (Mþ), 355, 281, 207, 179, 163,
82, 66.
rel-(3aR,4R,4aS,7aR,8R,8aR)-3-(2,5-Dimethoxyphenyl)-3a,4,4a,7a,8,8a-hexahydro-6-(3-methyli-
soxazol-5-yl)-4,8-methano-5H-isoxazolo[4,5-f]isoindole-5,7(6H)-dione (11d). CC (AcOEt/hexane 2 :1).
Yield 60%. White crystals. M.p. 178 – 1808. IR: 3158, 3009, 2962, 2840, 1793, 1728, 1616, 1597, 1491, 1462,
1342, 1261, 1020, 800, 741, 729. 1H-NMR: 1.51 (d, J ¼ 8.8, HantiꢀC(9)); 1.83 (d, J ¼ 11.7, HsynꢀC(9)); 2.29 (s,
Me); 2.88 (br. s, HꢀC(8)); 3.15 (br. s, HꢀC(4)); 3.25 – 3.31 (m, HꢀC(4a), HꢀC(7a)); 3.71 (s, MeO); 3.79
(s, MeO); 4.04 (d, J ¼ 8.8, HꢀC(3a)); 4.65 (d, J ¼ 8.8, HꢀC(8a)); 6.22 (s, ¼CH); 6.81 (d, J ¼ 8.8, 1 arom.
H); 6.88 (dd, J ¼ 2.9, 8.8, 1 arom. H); 7.33 (d, J ¼ 2.9, 1 arom. H). 13C-NMR: 10.92; 34.77; 42.03; 43.99;
45.32; 46.13; 53.77; 54.77; 54.80; 81.67; 98.40; 112.01; 112.16; 115.80; 117.53; 150.58; 152.47; 153.53;
154.55; 160.01; 171.24; 171.60. GC/MS: 423 (Mþ), 394, 270, 205, 176, 148, 82, 66.
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Received April 7, 2011