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TETRAHEDRON

Pergamon Tetrahedron 57 (2001) 3425±3433

Stereoselective synthesis of homochiral annulated sultams via
intramolecular cycloaddition reactions
Ugo Chiacchio,a,p Antonino Corsaro,a Antonio Resci®na,a Majdi Bkaithan,b Giovanni Grassi,b
Anna Piperno,b Tindara Priviterab and Giovanni Romeob
a
Dipartimento di Scienze Chimiche, UniversitaÁ di Catania, 95125 Catania, Italy
b
Dipartimento Farmaco-Chimico, UniversitaÁ di Messina, Messina, Italy
Received 3 November 2000; revised 25 January 2001; accepted 8 February 2001

AbstractÐDifferent homochiral dipoles containing a sulfonamido group have been synthesized, starting from l-amino acids, and used for
the construction of functionalized and enantiomerically pure annulated sultams. q 2001 Elsevier Science Ltd. All rights reserved.

1. Introduction In this paper we have investigated the intramolecular
cycloaddition process of different dipoles, where the sulfon-
The synthetic versatility of the intramolecular cycloaddition amido group is located in a-position with respect to the
of nitrones, containing additional oxygen, nitrogen or sulfur reactive center, i.e. the aldehydic moiety on which different
atoms in a tether connecting the dipole to the dipolarophile dipoles have been built.
moiety, has been widely exploited.1 Applications of this
methodology are seen in the synthetic routes towards func- The presence of a stereocenter at C2 furnishes a valid tool
tionalized furan, pyrrole and thiophene nuclei, some of for the diastereoselective synthesis of isoxazole-, pyrazole-,
which occur in natural and biologically active compounds. pyrrolo-fused isothiazole-1,1-dioxides, some of which have
In some cases these syntheses start from homochiral also been accessible in enantiopure forms (Scheme 1).
educts.2
The synthetic potential of this kind of sulfonamido-based
Factors controlling the stereochemical outcome of the reac- dipoles has not been fully exploited; moreover, sultams
tion have been elucidated on the basis of a kinetic control of have acquired good interest for the biological activity of
the process and the stability of the different transition states some members of this class of compounds6 and as chiral
leading to different diastereoisomers.3 A chiral center in the auxiliaries in asymmetric syntheses.7
starting nitrone could cause asymmetric induction giving
rise to the formation of new chiral centers with de®nite
con®guration in the obtained cycloadducts, so extending 2. Results and discussion
the synthetic potential of the reaction.
The different synthetic approaches which lead to the target
In this context, we have previously reported the intramo- molecules are based on the sulfonamido aldehydes 4, which
lecular 1,3-dipolar cycloaddition of suitably substituted a- have been obtained as reported in Scheme 2.
and b-sulfonamides, which leads to isoxazole and pyrazole
annulated g- and d-sultams: the obtained isothiazole 1,1- Starting from l-amino acids 1, aminoalcohols 2 have been
dioxide derivatives belong to a class of heterocycles obtained according to standard procedures.8 Compounds 2
which exhibit interesting pharmacological properties;4 have been treated with trans 2-phenylethenesulfonyl
in particular, the 2-methyl-5,6-diphenylperhydro-1l6- chloride to give the corresponding sulfonamido alcohols
pyrazolo[3,4-d]isothiazole-1,1-dioxide shows antimicotic 3, which have been converted into the a-sulfonamido alde-
activity.5 hydes 4a±d by oxidation with Dess±Martin periodinane
(DMP).9 Subsequent treatment with N-substituted hydroxyl-
amines 5 (RˆMe or PhCH2) furnished nitrones 6a, b, d, e,
which immediately underwent intramolecular cycloaddition
Keywords: sultams; Dess±Martin periodinane; intramolecular cyclo-
addition.
to bicyclo compounds 7a, b, d, e in good yields (Scheme 3).
p
Corresponding author. Tel.: 139-095-738-5014; fax: 139-095-580138;
e-mail: uchiacchio@dipchi.unict.it Similar treatment of 4a, c with hydroxylamine produces the

0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0040-402 0(01)00186-7

3426 U. compound 8c is converted into Scheme 3. 12a. which spontaneously aromatizes into isoxazole deriva- over. which gives rise to intramolecular induced oxime-nitrone 8!9 isomerization. On the contrary. the oxime 8a is converted by NaOCl oxidation to tive 13a. . bicyclo compounds 10a. Chiacchio et al. Scheme 2. More. c which result from the thermally nitrile oxide 11a. followed by cycloaddition at the styryl group to afford intermediate subsequent intramolecular cyloaddition (Scheme 4). / Tetrahedron 57 (2001) 3425±3433 Scheme 1.

In fact. patible with a (3S. e. compound 12c. is the consequence of the racemization process. Thus. racemic phenylhydrazone 14 (see Section 3).43%).3-dipolar cycloadditions showed high The stereocenter at the a-position effectively controls the regioselectivity. while H3a protons between H3a and H6a. c. b. stereoselective process. zone±azomethine imine isomerization. Irradiation of H3a gives rise to a appear at 3.95 ppm. occurring in mation present in the dipolarophile moiety is completely the hydrazone formation.56 ppm. 5).34±5. in compound 7a.64 ppm. as evidenced in the 1H NMR spectrum of the reagent [Eu(tfc)3]. By considering that compound 13a the diagnostic resonance of H6 proton is at the C6 con®guration is S.76 ppm. performed in ethanol 12 and 13 from homochiral starting material. thermal hydra- metric induction furnishing homochiral compounds 7. The absolute stereochemistry of the cycloadducts 7. 10 and Compound 17 was obtained as a racemic mixture: this result 12 was elucidated by 1H NMR. Furthermore. 10a. . The 1H NMR spectra of compounds coupling constant for the cis ring junction protons (J3a. Structures of obtained cycloadducts were assigned on the the ring junction between the two fused rings in compounds basis of analytical and spectroscopic data. as con®rmed by coupling constants mass spectra gave the correct molecular ions for all the and NOE measurements. d. H6a protons. For instance. indicative of a nearly eclipsed dihedral angle of H3 protons in the range 5.39±4. For cis relationship between these protons. 10. generates the 1. U. Chiacchio et al. The investigated 1. reaction of 4a with phenylhydrazine afforded the isomers. The stereochemical infor. The cycloaddition process has also been found to proceed The syntheses of pyrazolo-fused g-sultams have also been with complete diasteroselectivity: the NMR spectra or tlc of investigated. which does not aromatize in our reaction retained in the cycloadducts and the relative stereochemistry conditions. which originates from a rapid air oxidation of 16.4 Hz.54%) and for benzylic protons at C6.98±4. for compounds 7a. The attempts to isolate this compound resonances. according to similar intramolecular formation of the three new contiguous stereocenters and one processes. for at C3 (3. recorded in taneously underwent intramolecular cycloaddition to cyclo- the presence of increasing amounts of the chiral shift adduct 16.3aR. which spon- NMR spectra of the above reported compounds. the examined compounds. for aromatic protons e and 10a. c and 12c showed the diagnostic resonances 8. the obtained data are only com- 4. positive NOE effect for H6a (9. starting from sulfonamido aldehyde 1 (Scheme crude products do not show evidence of any diastereo. do not show any change of the single crude reaction mixture.14 ppm. so indicating a compound 7d the H8b proton results at 3. no bridged adducts have been detected in the of the eight possible stereoisomers is produced in a highly crude reaction mixture.3-dipole 15. resonate in the range 3. The chiral center at C2 induces a complete asym. High-resolution 7 and 10 is always cis. / Tetrahedron 57 (2001) 3425±3433 3427 Scheme 4. 17.6S.6aS) stereochemistry. b. the 1H at re¯ux temperature. apart from the expected shifts induced by the by ¯ash chromatography led to the isolation of compound paramagnetic reagent.6a) is 7a. at C3 and C3a in the formed isoxazolidine and isoxazoline ring is predetermined by the alkene geometry.

2 investigated approach towards bicyclic sultams. which undergoes only to enhancement of H6a and the methyl group at C3. 20 and 21 as racemic mixtures.10 also examined the synthesis of pyrrolidino-isothiazole dioxide fused systems. so indicating a cis spatial relationship presence of 6 equiv. in a 3:1 relative ratio. H6a and the Reaction with glycine methyl ester hydrochloride in the methyl group at C3. In the attempt to establish the scope and limitations of the a thermal imine±azomethine ylide 19 isomerization by 1. the basis of NOE measurements. we have prototropic shift. . in compound 21. thus. The stereochemical assignments have been performed on hyde 4c (Scheme 6). Scheme 6. / Tetrahedron 57 (2001) 3425±3433 Scheme 5. irradiation of H3a in 20 resulted in NOE enhancements for H5. Chiacchio et al. starting from the sulfonamido alde. of triethylamine afforded compounds between these protons. Figure 1. Conversely.3428 U. no NOE effect has been The reaction pathway is rationalized on the basis of the detected between H3a and H5: irradiation of H3a gives rise initial formation of imino derivative 18.

3. 4.40 (bs. 6. 2H).74 (d.41 (dd. 128.2 and 11. 1600. spectra were measured on a 500 MHz Varian Unity Inova 863. 1060.2. [a ]D25ˆ isomeric azomethine ylides 19a and 19b. CHCl3). 1600. 6. First elution gave N-benzyl-N-[(1S)-2-hydroxy- Melting points were measured on a Ko¯er apparatus and are 1-methylethyl]-(E)-2-phenyleth-1-ene-1-sulfonamide 3c uncorrected.6 Hz).75 (bs.8 Hz). 3. construction of functionalized isothiazoloisoxazole-4. 11H). 1H). 1330.96 (m. 3.41. Jˆ15. 1H.78.0 and isothiazole-1. Reaction of 2d with trans 2-phenylethenesulfonyl 3. 1. 1H.4. 3058.25.74.1 Hz).0929. 127.17 (d.65. CDCl3) 15. 56. 1H).81. 128. Moreover.31 (d. Jˆ6.48 (m. Chemical shifts are in ppm Jˆ6. First elution gave N-benzyl-N-[(1S)-1-benzyl-2- by the basic reaction medium.44 g. 10.52. 1H).1242. n max In conclusion.5 Hz). 137. Jˆ15. 65. lations directed towards the synthesis of biologically active 128.00.19. d H (500 MHz.65 (dd. CDCl3) 36. 2. 3H). Experimental 3. hydroxyethyl]-(E)-2-phenyleth-1-ene-1-sulfonamide 3b (18. 129.27.98.1. n max (KBr) 3524. In particular.63. Found: 331. 3030.6 and 14. instrument in CDCl3 as solvent.4 Hz). the homochiral aldehyde 4 has been used as a (KBr) 3380. Jˆ15.83 (dd. enantiomerically Jˆ15. 127. 3.0932. 238.3-dipolar cycloaddition.96. that compound 21 originates 2. 128.1-dioxides and pyrrolo. 1H). 1615. 3H. 1140.55 (m. 6H).68. 130. 129.35 g.59. CDCl3) 27.1 Hz).80. NOE difference spectra 11.6 Hz). 127.1240. Jˆ5.94. starting material was recovered 62.10. 2. 137. can be ruled out: in fact.79 (d. 3.9 Hz). from 20 by epimerization. 12 and 13 with speci®c 16H). Exact mass calculated for C24H25NO3S: 407.1 (c 1. formation of 20 and 21 as racemic mixtures is explainable on the basis of a racemization process occurring 3.56 g. 3062. 817.71 (t. / Tetrahedron 57 (2001) 3425±3433 3429 The absence of any diastereomeric control in the examined ethyl]-N-methyl-(E)-2-phenyleth-1-ene-1-sulfonamide 3a process could be ascribed to the existence of two stereo. 1021. 124. Chiacchio et al. 920. CDCl3) 2. Merck silica gel 60H was used for 11H). Preparation of trans sulfonamido alcohols 3a±dÐ chloride. d C (125 MHz. 79%) as a white solid. at 08C.6. Infrared spectra were 122.94. reported. CDCl3) 1.62.45 (d. Found: with 10% aqueous NaHCO3 and dried (Na2SO4). 60. and 14.08 g. 1H. absolute stereochemistry have been obtained. 128.37 (m.84. mp 110±1138C. 3035.5 mL. 55 mmol) of trans 2-phenylethene. 143. First elution gave ((2S)-1-{[(E)-2-phenyleth-1- general procedure enyl]sulfonyl}tetrahydro-1H-pyrrol-2-yl)methanol 3d. 128. compounds 2 (50 mmol) and triethylamine (5.0 and 14.58.19±7. 128.48 (m. d C (125 MHz. 4. d C 53.30 (d.1550.27. 126. promoted chloride. i. Jˆ5. 2.99. pendently undergo the cycloaddition reaction (Fig.17 (q.4 Hz) 6.35 (m.0 Hz.1 Hz). 7. 6.99. n max (neat) 3375. 1H.85. Found: 331.64. 1H NMR 2978. tions were measured on a PF 241 MC Polarimeter 132. 1H).45 nance free induction decays (FIDS) from right-on-reso. 2. 132.81. (d. Jˆ9. 128. 1320. 3030. 3H).13 (d. 1650.99.56. 6. Found: 407.81 (m. Jˆ6. valid source of different homochiral dipoles for the 920.70 (dd. at re¯ux temperature. 2.77. Jˆ6.1-dioxides by exploiting the intramolecular 7.1245.47 (dd.2 dioxides.3. 128. pure annulated sultams 7.1 Hz).82.3 Hz).15. CDCl3) 29. Jˆ15. 3.e. 2940. 4.8 Hz). 1H.6 Hz). Jˆ15. 48.79. 2995. Jˆ15. were obtained by subtracting alternatively right-off-reso.66. 1H. 1H. 1490. 64.1. Exact mass calculated for (Perkin±Elmer). 1H. OH). CHCl3). 128. 128.2 and 14. 141. 700 cm21. unaltered.32. 126. Jˆ7.71 (m.42±7. 7.80. 1). n max (KBr) 3380. 130. compounds. 129. 20 mL H2O in 20 mL CH2Cl2) chloride.25. 62. d H (500 MHz.17. 1H. First elution gave N-[(1S)-1-benzyl-2-hydroxy. 750. 1330.26. Reaction of 2a with trans 2-phenylethenesulfonyl Wet CH2Cl2 (20 mL. 141.57. 750. was added dropwise.6 (c 1. 1H.82. d H (500 MHz.7 Hz). 1H. 2H. 70%) as a yellow oil.75 (d. 94%) as a yellow solid.1. was added slowly to a vigorously stirring solution of .1242. Jˆ7. 3029. CDCl3) 1. 747 cm21. 2H).1555. 126. 61. solvent was removed and the crude residue was puri®ed by silica gel ¯ash chromatography (2% methanol/chloro. 2960.59.95. 123. A solution (11. closures offer the possibility of usefully synthetic manipu. 47.4. pyrazoloisothiazole-1. 4. mp 89±918C.2 Hz). to a stirred solution containing 1H.20. 1H. Elemental analyses were performed with a (13.03 (ddd. CDCl3) 2.66. 1H).1.57 (m. d C (125 MHz.69 (d. 30 min and then at 258C for 6 h.8 mmol). 140.80 (s. 1. 137. Exact the mixture was extracted with dichloromethane. 128. 1600. Jˆ5. 700 cm21. Compounds 2a±d have already been C18H21NO3S: 331.09. Reaction of 2c with trans 2-phenylethenesulfonyl chloride. 130.97. 90%) as a yellow solid. OH). 1060. The 267. Reaction of 2b with trans 2-phenylethenesulfonyl in the initial step leading to the imino derivative. 1060. 128. 1H.75±7. 3.6 and (d ) from TMS as internal standard. 4. Preparation of trans sulfonamido aldehydes 4a±dÐ form). The possible alternative. Optical rota. 129. 1450. 1H. 2995.61.1620. 137.95. 7. which inde. 137. 7. 1324.1.23 (bs.37. 4.20.14 g.1. Exact mass calculated for C18H21NO3S: 331. washed mass calculated for C13H17NO3S: 267. 1063.24. U. 3.47 (m. 1H. Jˆ15.4 Hz).19± when 20 was treated with triethylamine for several hours 7. 3. 2H. 29. The reaction mixture was stirred at 08C for (125 MHz. [a ]D25ˆ Perkin±Elmer elemental analyzer. 128.08.39. 49. 128. preparative short-column chromatography. 132.41.85 (dd. 35. nance-induced FIDS. 2.62.2.32 g.11. (9. 1H. general procedure 3. 760 cm21.05.16. 128.73. 5.2 Hz).11 3. Jˆ8.46 (m. 128.68. recorded on a Perkin±Elmer 377 instrument. At the end of this time 128.25. (15. d H sulfonyl chloride in anhydrous dichloromethane (50 mL) (500 MHz. 125. mp 90±928C. 1496. 980. These ring 62. 4.46.2a.88.9 and 8.

(dd. 66. 1H. Jˆ6.49.2. 1.43 g. 80. 67. 5H). 128.0773. phenylperhydro-4l6-isothiazolo[4. 47. 2980. Jˆ7. The residue was taken up in ether (50 mL) and then washed with a 1:1 solution of 10% aqueous 3. Reaction of 4a with N-methyl hydroxylamine.08.11.23.95. 3.99.4 Hz).28 (s.5 Hz).55.76. 3.74.0777. .0 and elution gave (3S.95 (d. 9. The combined triethylamine (5. 2750.57.11. CDCl3) 29. 2995.08±7. 129. 12. 1500. 4.19±7. 1490. 1740.66 mL.4-dioxide 9.4 and 141.67. 46. 760 cm21. 131. 1600.45.1085.0 Hz). At the end of this time subjected to silica gel ¯ash chromatography (2% methanol/ the solvent was removed and the residue extracted with chloroform).40. 934. Chiacchio et al. 65%) as a yellow oil.62.42± (125 MHz.6aS)-6-benzyl-1. 5. Jˆ7.70. 126. 3.1620. Jˆ7. elution gave (3S. 1239. 1H. concentrated into a few milliliters of solvent by rotary evaporator. 760 cm21.51. 1H. Jˆ5.81. d C (125 MHz.61. CDCl3) 2. Jˆ7.2. 1H.1 Hz).34. 1H. 750.28. n max (KBr) 3050. 6. Jˆ7. 142.17. 1H. 7. 4. d.14. 129. d C 3. mp 15H). 2. 980.75.3]isothiazolo[4.98. Jˆ15. Jˆ5.1396. 1H). 760 cm21. 980. Reaction of 4b with N-methyl hydroxylamine. CDCl3) 1. Oxidation of 3d with DMP. 2960. 132.10 (dd. 8. 132. H6.43 (s. Jˆ2.3 and 9.18. 7. H6a. 760 cm21.4 and 3. 130.10.85.5 (c 1.04. 130. 142.83. 1740.74. and this organic A mixture containing compound 4 (a. 7.18.26. 136. 142. 1060.5 and 128.50.0 Hz). 1H). Jˆ 434.10. 830.4-dioxide Exact mass calculated for C18H19NO3S: 329. eÐgeneral procedure by H2O (10 mL) and brine (10 mL).3 and 9.3. 81. CDCl3) 32. 128. 2.5-c]isoxazole-4. 198.62.96. 126. 1H. H3. 2755. 49. Jˆ8. 1H.5-c]isoxazole-4. 127.5-c]isoxazole-4.80.3 Hz). Jˆ15. dichloromethane. 7. 3020.3 Hz). 2980. 3050. n max 124. d H (500 MHz. 1350.1351. 2982.9 and 10.2 Hz).6-dibenzyl-1-methyl-3- 10. 10H). 1H. H3a. Jˆ7. CDCl3) 29.83.1 (c 5. sulfonamide 4b (324 mg.3 (c 0.23±7. 1050.0 3. 128. 129.47 (m. 128.3aR.81 (dd. Jˆ15. d C (125 MHz.44 (m. 2. CDCl3) 25.9 Hz). 67. 1H.6 Hz).34. mp 152±1538C.6 Hz).60 (s.69 (s. 2H). 1 mmol) in dry CH2Cl2 (6 mL) and allowed to stir for 143. 135. 132. d C 3. First n max (neat) 3060.73 (dd. 1H. CDCl3) 2. 1050.41 (d. 7b (18. 1H. Jˆ6.50.26. 128.25 (dd. 127. CHCl3). 198.36.82.38 (s. 2833. H8b.3. 70%) as a yellow solid.8aS. 1735.56 (m. Jˆ5. d H (500 MHz.0 Hz). 980.45. 27.84. n max (KBr) 3058.33. d H (500 MHz. 126.80 (s.35. 136.8 (c 0.4 Hz). 4. H6.03.24 (s.76.74 (m.20. Jˆ9. 750.95.0 and 15. 977. CHCl3). Oxidation of 3a with DMP. 1H. 128. 3. The residue was then subjected to silica gel ¯ash chroma- 3. and 265.99. Jˆ14.61.1 Hz).33.05 (m.2 Hz). 1490.1 Hz). 2H).99. layer was washed with H2O and brine.90.13.4. 1H.55 (m. 3.80. 128. 2H. 1490. C19H22N2O3S: 358. 44. 2850.4- Na2S2O3 in saturated aqueous NaHCO3 (30 mL). 1H.88. 129. 9.93. 760 cm21. 63. 3020.5-dimethyl-3- 1315. 136. 920. 132. b.4-dioxide 2. 11H).56 g. 980. 55 mmol) and N-substituted organic layers were dried (Na2SO4) and the solvent hydroxylamine hydrochloride (55 mmol) in absolute etha- removed under reduced pressure.38.79 (d. n max 130.05 (m.39. 3. 1H.3. CHCl3). Jˆ10.1.23 (dt. H6a.9 and 13.5-c]isoxazole-4. 980.6 Hz).1350. 3H). First elution gave N. d C (125 MHz. d H 3. 75%) as a white solid.23. 4. 16H). 31. 329. 134. 1H). 1320. H3a. First and 15.0 Hz). 70. 5. Found: 265. pyrrole-2-carbaldehyde 4d (172 mg. (KBr) 3070.55.65 (s. H7a. 199. 1315. 3.36. [a ]D25ˆ27. Jˆ10. 1H. 1H.5 and 11. 128.44 (d. 120. d C (125 MHz. 6H). [a ]D25ˆ129.2. 70. CHCl3).5 Hz). 3. Jˆ7. (2S)-1-{[(E)-2-phenyleth-1-enyl]sulfonyl}tetrahydro-1H.3 Hz). 920.32.06.78 198. d H (500 MHz.24 (d. Jˆ17.67.05 (dd.97 (m.45 (m. 1060.35.1. 1050.2. 128.74 (dd. 126. 3.3aR. 3030.39 (d.8bS)-1-methyl-3-phenylperhydro- 128. 3020.9 and 15. d C (125 MHz. 700 cm21. [a ]D25ˆ18. 1320. H3. 3. Jˆ10. 1H. H7a. CDCl3) 2. 3H). 48. 2850. 131.6 Hz).4 Hz).8 and 13.0 Hz). 80%) as a white solid. The mixture was then diluted with ether. 126. First elution gave N-ben. 1H.18 (m.51.15.8 Hz). 1600. 36. Exact mass calculated for (neat) 3035.03. 1H).34 (d.87 (dd.1086. CDCl3) phenylperhydro-4l6-isothiazolo[4. 3H). 129.69. 128.4 and 10.3 and 15.42 (d. 1H. 3. Found: 358.42 (dd.4 Hz).3 Hz). 4.92. 127.6S.2 and 8. 1H. 85%) as a white sticky oil. CDCl3) 24. 6.27 (m. 7. 1H). 132.40. 1H.6S. 78±808C. 59. 129.09 (q. 1H. 1H). washed with water and dried (Na2SO4).54. 4. Oxidation of 3c with DMP. 128. 128. 124. 128. 42. H8b.62.66.36. 1H.3. 3025. H3a.25±7.19.54. 72. 4l6-pyrrolo[1 0 . 1H. 1615. [a ]D25ˆ27.84. 128. Reaction of 4d with N-methyl hydroxylamine. (125 MHz. b or d) (50 mmol). 1H. 3H). 3. Exact mass calculated for C25H26N2O3S: Jˆ7. 2.1663.1086. 1H). CDCl3) 36.3 Hz). Exact mass calculated for C13H15NO3S: 30 min. 52. 128. 1H.97.88. 134. 80%) as a yellow sticky oil. 1H. 1330.23 (dd. 129. 7. 4. 1600. 59.1399. Found: 7d (10.29 g. H6a. 85%). 15. 2. CDCl3) 2. Jˆ8.37 (dd. 1760. The residue was then nol (50 mL) was re¯uxed for 24 h.58 (m.97±7. 4. 49.10.2. Jˆ14.29. 129. First CDCl3) 12. 3H).45 g. 2750.28 (dd. 2730. 63. mp 142±1448C. 7. ene-1-sulfonamide 4c (263 mg. 3. Found: 434. Oxidation of 3b with DMP. 1650. N-[(1S)-1-benzyl-2-oxoethyl]-N-methyl-(E)-2-phenyleth-1- ene-1-sulfonamide 4a (280 mg. The aqueous washings were back-extracted with ether (20 mL).15. 1H. 81. 2. 2970.83. 61.33 (d.5 and 9. 700 cm21.94. Jˆ Found: 405. 1H.35 (dd. 4. 1030. 4.14.63.92. Found: 329.16. 135.1350. 1500.56.1664.3aR.31.53.2 Hz).43.79 (m. Jˆ4.88 (s.2. H7b.39 (d.3430 U.7 Hz).98 (dd. H3. / Tetrahedron 57 (2001) 3425±3433 sulfonamido alcohol 4 (1 mmol) and DMP9 (640 mg.2 Hz). 128. First elution gave tography (2% methanol/chloroform). 130. Jˆ7.88. n max (KBr) 3075. Exact mass calculated for C18H19NO3S: 12. Preparation of isothiazolo[4. 1350.19. 5. elution gave (3S. 70. zyl-N-[(1S)-1-benzyl-2-oxoethyl]-(E)-2-phenyleth-1-ene-1. 31.75. 2H). benzyl-N-[(1S)-1-methyl-2-oxoethyl]-(E)-2-phenyleth-1.17 (m.33±7.68 (d. 127. 7.42.6aS)-5. 4. 11H).63 (d.07.06 (dd. d H (500 MHz. 4. 4H).56 (dd. CDCl3) 1. 7a (13. followed dioxides 7a. d H (500 MHz.3.54 (d. H8a.51. n max (neat) 3050. Jˆ5.2 0 :2. Exact mass calculated for C24H23NO3S: 405.10. 5. 73. 126. 329. 137. 1143.2 Hz). First elution gave (500 MHz. H7b. 6.44.5 Hz).3. H6b and H8a). 1H. Jˆ 15. 2980. 9. 5.05. 128.1090. 1449. 3.47 (m.75 (d.

4.23±7. 126.03.7 Hz).2 and dropwise sodium hypochlorite (6 mL. 1H. 3.8 Hz). (3S. 3.33.78. 128. 2980. Exact mass calculated for C18H20N2O3S: methyl-3-phenyl-3a. Reaction of oxime 8c.5 Hz). white solid. 1.20.1189.36. 7. 4.0 Hz). and 8. 4. H3a. 127.07 (d. Found: 344.3. 135.5. 7.8 Hz). Jˆ6.66 (d. 129.03. 1H. 1H. Jˆ2.33. Jˆ14.06. 4.5. CHCl3). 130. CDCl3) 16. 3.3 Hz). 1H. 70.97.99 (ddd. Jˆ1. 3H). 3H). H5 0 b.5. and 9. Jˆ6.4. Exact mass calculated for 1128C.60. Exact mass calculated for 4. zyl-N-[(1S)-2-hydroxyimino-1-methylethyl]-(E)-2-phenyl. Major 74. H6.67.98 (dd.75.6S)-5-Benzyl-6- 141. 7. CDCl3) 30.4-dioxides 10a. 1H.09. Jˆ7. 3.82 (c 0. 69.c [a ]D25ˆ24. with vigorous stirring.14 (c 1.1190. d H (500 MHz. 127. 3. Preparation of sulfonamido oximes 8a. [a ]D25ˆ222. 1H. Major isomer: d H (2.81.71.5. 128.39 (m. 59. CDCl3) 16. 2H.7 and 4.38.53. [a ]D25ˆ21. 129. 126.cÐgeneral procedure 3.3 and 13. and 13. mp 132±1358C.15 (dd.4-dioxide 13a (609 mg. d H (500 MHz. Jˆ6.3 8.8 mmol) and sodium acetate (390 mg.8 Hz).41 (d.64 (t. 128. [a ]D25ˆ 27.09 (q.8 Hz). 1H. 128. phenyl-5.35 (m.37 (d.6. 10H). 136. 127. First A solution containing sulfonamido oxime 8a. 10H). mp 157±1588C.3.65. 4.04.4-dioxide 10a (539 mg. 126.71. 4. 1H.23±7. 1H. C18H20N2O3S: 344. 11H).0 Hz). CHCl3).31 methyl-3-phenylperhydro-4l6-isothiazolo[4.13. Jˆ6. 1H. sticky oil.66. d C (125 MHz. Jˆ6.3 mmol).70 (dd. CDCl3) 2. 128.62. in absolute ethanol (100 mL) was re¯uxed for 60 h. 95% 4.6 Hz). Jˆ4. 2.16±7.6. 4.2 (c 1. Found: 344.30 (d.48 (m.1194.52 (bs. 1H. Exact mass calculated for ethyl acetate).7 Hz). [4. isoxazole-4.6aS)-6-Benzyl-5- 2. 129. 1490. Reaction of oxime 8c.1041. H8a.5-c]isoxazole- A mixture containing compound 4a. 6.7. [a ]D25ˆ215. 4.2 Hz).2. Jˆ1. washed 4. 3.2 and (dd. 4.28.01 (dd. 68.5 Hz). 5. 3H.57 (d.3aR.5-c]- Found: 294.0 Hz). 10H).2 Hz).97. H8b. Reaction of 4a with N-benzyl hydroxylamine.38.3aR. 70%). (330 mg. 3. 128. H3. H6a.19 (dd.14.26 (d. 1H. 4.36. 69.39 (m. 1H. d H (500 MHz. 125. Jˆ4. c (3. Jˆ9.61.49 (m. 127. 5. 5. n max (KBr) 3080. H7a. CDCl3) 1.40. First eluted product gave a syn±anti mixture (1:3) of N-ben.3 Hz).63. Jˆ6. 434. 3H). 132. NH. 3. H3.95 (d. d C (125 MHz.8 Hz). 4.52. Jˆ8.7 Hz). 7. 1H.92. d H (500 MHz.41 (c 2.5-c]isoxazole- 128. 7% solution) at 08C 14. Jˆ4. The phenylperhydro-4l6-isothiazolo[4. 7. OH).17.27.97.76 (dd.6 (c aqueous ethanol (30 mL).cÐgeneral procedure 3. CDCl3) 1.6 Hz). 1H. Jˆ15. C18H20N2O3S: 344. Jˆ6. 4. 135.1194. 760 cm21. Found: 33.55. 128.2 and 8. 137. 980. 4. Jˆ7.42 (m.4.89 (c 0. hydroxylamine hydrochloride 0. 70%). H6a.99.6-dihydro-4H-4l6-isothiazolo[4.05.61. Preparation of sultams 12c and 13aÐgeneral First eluted product was a syn±anti mixture (1:3) of N-[(1S). 4. H3a.16.2 and 7.46.1194.26. Jˆ4.23. Jˆ7. 3. Exact mass calculated for C18H20N2O3S: 344. 5.53. 1H. procedure 1-benzyl-2-hydroxyiminoethyl]-N-methyl-(E)-2-phenyleth- 1-ene-1-sulfonamide 8a (1.81.4.2 Hz). 2. isomer: d H (500 MHz. 3.94. 1H.49 (dd. Jˆ6. 128. (dd. [a ]D25ˆ22. 1H.1194.5-c]isoxazole-4. 125. NH). Jˆ7. 80%).6aS)-5-Benzyl-6- methyl-3-phenylperhydro-4l6-isothiazolo[4. 158. H3a. CDCl3) Exact mass calculated for C25H26N2O3S: 434. and 7. (3% MeOH/CHCl3).32. CDCl3) 2.9 and 13. 44. 1H.24 mmol) in dichloromethane (250 mL) was added (500 MHz. 128. CDCl3) 1.06. H3.92. 1H. solvent was removed and the crude residue was 68.7 Hz).5 and 13.3 Hz).54.1039. mp 109± 132. 128.6S.20 (dq.7 and 14. Jˆ1.20 (c 8. d C (125 MHz. At the end of this 6. 86. 1H.4.5-c]isoxazole-4. 1H. 1H. 3.16.4 Hz). To a solution containing sulfonamido oxime 8a.34. 128.39.57 (d. 1H. H6. 1H.78 (s. 1H. 12H).9 and 8. Jˆ15. Chiacchio et al. 57. 151.49. 85. Reaction of oxime 8a.354. Jˆ16.78 (s. 70.64. 46.30 (d.62.6 Hz). H5 0 a.6.3 Hz). 129.12.1192. 77%).4-dioxide reaction mixture was evaporated under reduced pressure 7e (18.34 (d. 134.72.3 Hz).27 (d. d H (500 MHz. 1H. 1H. 87%) as a white solid.05 g. (dq. CHCl3).55 C18H18N2O3S: 342. OH). Found: 344. 93%) as a white solid. 128. 1050. 136. 128. 90%) as a sticky oil. H7b.1.49. 149. 82.61. with 10% aqueous NaHCO3 and dried (Na2SO4).6aS)-1. H3.4 Hz). 128.3 Hz).6 Hz).06 (d.31 (d.03 (dd.3aR. 36.33.34.08. 5. 7.27 (d.6S. 130.8 Hz). 132. 7. CHCl3).09.1195.83 (s. and the residue puri®ed by silica gel ¯ash chromatography [a ]D25ˆ118.2. 126. the residue was extracted with dichloromethane. CDCl3) 2. (6S)-6-Benzyl-5-methyl-3- CDCl3) 16.3.36.04. (3S. Found: 342. U.15. Found: 344. 4. 4.95. time the solvent was evaporated at reduced pressure and 1H.36.0 70. 3. d C (125 MHz.11 (bs.1664. Jˆ7. 1H. / Tetrahedron 57 (2001) 3425±3433 3431 Exact mass calculated for C14H18N2O3S: 294.13 (dd. 128.7 and 10. CDCl3) 2.56 (d.6-dibenzyl-5-methyl-3. 1320. 128. Jˆ10. 3H). 3H.4-dioxide 10c (539 mg.24± evaporated and the residue subjected to silica gel ¯ash 7. 129. d C (125 MHz.08.09. Jˆ10. 3. chromatography (40% CCl4/ethyl ether). H6. 65. H7. 5. After 3 h the reaction mixture was Jˆ4.94 (dd. 1H. H6. . 3040. sticky oil.2.98.5.00. CDCl3) 29.1. 52. 141.1038. Jˆ14.74.91.1665. 1H. Jˆ15. Reaction of 4c with hydroxylamine hydrochloride.0 Hz).65 (d. 48.39.1038.4 Jˆ13. Reaction of oxime 8a. Jˆ16. (3S.1. 8. 1H. 37.12.4 and 8.2 Hz).97. 3. H7a. 1H. 4. 1H. 81. Reaction of 4a with hydroxylamine hydrochloride. CHCl3). Jˆ6. 136.4 Hz).83. 3025. 1H.05± eth-1-ene-1-sulfonamide 8c (1. Jˆ13. Jˆ1. 53.77 (s.5 and 7.2 Hz).02 g. 1H. 3.6-tetrahydro-3H-4l6-isothiazolo- 344.5-c]isoxazole- (ddd.6S.99 (d. 35.27.53. 135. H3a.21. 128. 129. Jˆ5.20 (dd. puri®ed by silica gel ¯ash chromatography (70% CCl4/ 129.0 Hz). Preparation of 1-N-unsubstituted isothiazolo[4. H7b.29.2 and 10. 3. 1H.92.62. H6a.65.14 d C (125 MHz. CHCl3).3 Hz).31.8 mmol) was stirred at 08C for 6 h.4-dioxide 12c (590 mg. 136.75.14.16.37. 135.86. 128. 5.53 (d. 3.24 mmol) elution gave (3S. 6. 129. 15H). 1H.15 (bs.88 g. 7. CHCl3).91. 3.3 Hz). 123. 125.2 Hz).0 Hz).57.41. 3. 64. Jˆ15. The 7. c (2. 128.3aR.52 (d.72 (dd.12±7.

5 Hz).67.92. Romeo. Jˆ6. 144.. Wienen.50 (d.74.2 Hz).70 (s. Found: 400. addition of C-alkenyl nitrones and nitrile oxides. Chem. 114. 163.. 1788.3aSR. Meri®eld. ene-1-sulfonamide 14 (2. 1171±1178. as ®rst eluted product.42 (m.28 (dq. Bruggini.13.71. 6. Stereoselective synthesis of (500 MHz.6SR.5 Hz).. 51. G.3 and 6. 330 mmol) and glycine methyl ester NY. 7. 143.33 (d.04 g. Resci®na. 112.. dioxo-6-phenylperhydro-1l6-pyrrolo[2. 130. [2. 4040±4051. 225±276. 134.0 and 14.90 g. Chem.20 mmol) and p-toluenesulfonic acid (10 mg) was stirred 2960. Exact mass calculated for C18H16N2O3S: 66.5SR.. 2900. U. 8.. Piperno.. At the end of this time 750 cm21.20 mmol).21.77. Jˆ1. Jˆ4. 7.. 69. 1140. d H (500 MHz. 44.42.46.69 (s. CDCl3) 1. 36.6aSR)-2- benzyl-3-methyl-1. Hellmchen. Eds. 10H). 129. 1997. V.S.32. CDCl3) 37. (dd.20.04. 128. 35. A. We thank the M. at 08C for 6 h. 15H).12. M.39 (m. mp 110± 7. Pizzimenti. 4. 1H.00 g. (125 MHz. CDCl3) 16.6RS. 5. A.4-d]isothiazole-1. Tetrahedron 1118C. Chiacchio. the solvent was evaporated at reduced pressure and the 2. Jˆ14. 44. 3H. 7.. V. Resci®na.1457.83. SocietaÁ Jˆ1.26.. 67.6. A. R. 697 cm21. 1H. 3020. E. (b) AuÈrich. Bochet. 1773± 1H.5 and 7.21.5 Hz). Jˆ8. 73. d H (500 MHz. 134. Lin. 127. 62. D. n max (KBr): 3337.. 2. Tetrahedron 1997..24.31 (d.29 (d. 4. F. 748.60 g. Vol.76. 13855±13866.01 Romeo. 3. Romeo. 3H.98 (ddd.06. 6. CDCl3) 2.37.. 5.0881. Romeo. 138. 145. H6a. 855.98. 1H. 127.2 Hz).6. K.. Jˆ6.6 Hz). H.93.8 Hz). 127.. 126. CDCl3) 17. U. Unpublished results. Romeo.. 135.1. G. 51. 4.1456. In Targets in 5.08 (d. F..39.0 and 7. J. 1600..14 (d.3 and 8. 4. mp 118±1218C. (a) Chiacchio. 55.8 Hz).51. 138. (c) Curran. 1218. 50 mmol). 128.. 4. G. G. 132. C. Jˆ2. 1H.19.41 (d. In Methods in Organic Chemistry: Stereoselective Synthesis. white 95% aqueous ethanol (30 mL). R. 53. subjected to silica gel ¯ash chromatography Romeo.5 Hz). 1H.. 129. Piperno. Hoffman. Gumina. H6. 53. giving (3SR.28 (dd. Eds.. 2.3 Hz).3. D.1507. A.29±7. 1310. 85%) as a white solid.50.T. A. Jˆ14.26 (dd.2. Lett. J. 910. G. Resci®na. d H O.68.. 6.0 and 8.3-d]isothiazole-5. B.02 (dd.1-dioxo-6-phenylperhydro-1l6-pyrrolo- A mixture containing compound 4a (2.8. the solvent was removed and the residue extracted with Tetrahedron 1997. CDCl3) 1.37. Jˆ1. 56. Chiacchio. H6. 38.5 Hz). 128.3aSR. J. 2. 129. Tetrahedron 1994.. 3.. Corsaro.74..59. (33. 1. 403± 425. N. (c) Frederikson.21 with 10% aqueous NaHCO3 and dried (Na2SO4). 128. Jˆ6.. 128.16 (dq. 3. residue was extracted with dichloromethane. Jˆ6. Entzeroth.41. Attanasi. (50 mL) was stirred at rt for 16 h. 7015±7018.50. 50. A mixture containing 4c (16.93 (m. 1130. U. Jˆ2... Found: 340.83 (dd.99. pp.66. 3H).05. 50. 135. Corsaro. U.39 g. 128. 2H. 800. A solution of 14 (914 mg.2 Hz). 1.57. 3H). 3. Buemi.74. 417. Romeo. G.70.47.2 Hz). 1H. Alessi.53. van Meel. 1H.5 Hz). H6.83. Jˆ7. Jˆ4.. W. for its partial ®nancial support.27 (d. 127.40.2 Hz). 156.0 and 400.77. 1H.0877.6 and 8. Cozzi.51. 1H. H6a. 36. 1280. C. evaporated and the residue References subjected to ¯ash chromatography (40% CCl4/ethyl ether). P. J.56. 12H).6 Hz)..96 (dd.3432 U.6a-hexahydro-1l6-pyrazolo[3.7.. (b) Zecchi.6 Hz). 61. H5.. Evaporation of the solvent and silica gel ¯ash chromato. 340. 4. E21c (Chapter 1. Acknowledgements 135. methyl (3SR. 4.. d C (125 MHz. d C 127. 1H. 128. hydrochloride (6. Resci®na. 127. The residue. S.73 (s.1511.46 (m. Preparation of sultam 17 eluted product was methyl (3SR.6 Hz). 3026. G.30 (dt.5 Hz). 5.59. 53. Biesemeier.39.70. 1H.. Schaumann.. 17 (636 mg. H3. n max (KBr): 3350. H6a.26 (d. 1600.33. 127.57.67 (d. 7..42 (bs. H.3-d]isothiazole-5-carboxylate 21 (3. H3. Jˆ15. Exact mass calculated for C21H24N2O4S: 1H. graphy (70% CCl4/ethyl acetate) gave N-(1SR)-1-benzyl. 56.81. 3.01.50 (dd. Jˆ6. 165.47 (bs.5 Hz).18 mmol) in ethanol (100 mL) was heated under nitrogen at re¯ux temperature for 72 h.86 (d.01.3 Hz). 128. 66.6-diphenyl-1. 170. A. 51. Synthesis 1999. (a) Chiacchio. Jˆ3.56.86. 1994. mp 180±1828C. d C (125 MHz. W. Found: 419.29. 3. Exact mass calcu- lated for C24H25N3O2S: 419. 1H. H6. 126..83. 1450. Luning.1. H. 127.6aSR)-3-benzyl-2-methyl-5. Med..U. (a) Oppolzer. Jˆ1.25±7. Ries. / Tetrahedron 57 (2001) 3425±3433 1H. 1730. 1H. 1995. Exact mass calcu- lated for C21H24N2O4S: 400. G. 129.83.28 (bs.54. CDCl3) 31. 3H).8 and 4.59. G.79. The solution was cooled off. Gieb. Acta 1495.. mp 120±1228C. H. 5503±5514.57. A. J. W. Hasselbach. triethylamine Mulzer. 61.1667. R. .6 and 14. Shen. 116. 1H. 128.6 and 6. Wittneben. 3H). A.2). M. 2-(2-phenylhydrazono)ethyl-N-methyl-(E)-2-phenyleth-1. 124. 1993. Vol.98 (dd. carboxylate 20 (8.. CDCl3) 29. 6. d C (125 MHz. 15%). E. 129. Jˆ15. 128. under nitrogen. 1H. Mihm. F.74.0 Hz). 1741.05±7. solid. d H (500 MHz. 1H. NH). 2990.. 151. Found: 400. 54±57.1669. 1350.0 Hz). N.34. Spinelli. Heterocycles 1994. (dd. 52.99. Chiacchio. Thieme (Georg): Stuttgart.. 70%) as a white solid. phenylhydrazine (670 mg. Procopio. 125. 55 mmol) in absolute ethanol 4. 1450.84±7. Exact mass calculated for C24H23N3O2S: 417.13. G. Librando. 1H.46.. Scand. Narr.06. Hauel. Jˆ4. F. 113. 10H). 1H.04.34. 2. 2. 128.. E. Zhang. (b) Larsson.5RS.18. W..21 g.6. 65.61. B.5 and 7. 3015. PistaraÁ. 1H. (2% methanol/chloroform). 68. 10H). R. Found: 5689±5700.02.1457. NH). d C (125 MHz. 4. 144. 46 mL. U. Jˆ7. H3a.40 Chimica Italiana: Italia.68. 3.8 and 7. NH). H3a.25. C.84.69. 1H. M. Jˆ9.. 1H. functionalized heterocyclic systems via intramolecular cyclo- 3. 905±917..2 Hz). 860. gave. 4. U.89 (s. J. 3. H3. Cinquini. 121. Jˆ 15.1459. CDCl3) 1. washed 3.43. dichloromethane. 6. washed with water and dried (Na2SO4). 125. 137.6 Hz). Preparation of sultams 20 and 21 3. H5.81. 9. A. Tetrahedron 1995. H. 37.. Resci®na. Further 3. G.R. Chiacchio et al. 43%) as a white solid.28±7.. 1996. 125.74. Jˆ6. 4. G.84. 1H. 171. At the end of this time A.6RS. Casuscelli.6aSR)-2-benzyl-3-methyl-1.94. A. (m..1-dioxide Heterocyclic Systems: Chemistry and Properties. 66. Synthesis 1995. 3. 4.45 g.

C. B.. C. 4155± 10. 48. 113. Schreiber. B. L. 52. / Tetrahedron 57 (2001) 3425±3433 3433 9. 15157±15170. Abdaoui. 56. Chiacchio et al. Tetrahedron 2000.. N. Tetrahedron 1996. J. Org.. Dewynter. Chem. E. D. Z. J. Monneret. C. 89±121. S. M. R. 1991. Chiaroni. G. (b) Dess.. 1983. Aouf.-L. 59. 1994. 16. Y. J.-E. L. Am. Chem. Chem. Aubertin. J. (c) Ireland. 7277±7287. Grigg. R. Martin.. 1993. 7549±7552. 381±387.. 1987. . A. 4156. Soc.-M.. Org.. Liu. U. C. 58. D. Chem. Soc. S. J. Martin. 11.. Chem. J. (a) Dess.. 2899. (b) Regainia. (a) Janin. Org. Montero. Rev. A.. D. Riche.. (d) Meyer. J.