Synthesis of the tetrahydroisoquinoline unit in the AB ring system of the novel antitumor-antibiotic tetrazomine

摘要

J. Chem. Soc. Perkin Trans. 1 1997 3131 Synthesis of the tetrahydroisoquinoline unit in the AB ring system of the novel antitumor-antibiotic tetrazomine Viviana L. Ponzo and Teodoro S. Kaufman* Instituto de Quiacute;mica Orgaacute;nica de Siacute;ntesis (IQUIOS) (CONICET-UNR) and Facultad de Ciencias Bioquiacute;micas y Farmaceacute;uticas Universidad Nacional de Rosario Casilla de Correo 991 2000 Rosario Repuacute;blica Argentina The elaboration of a polysubstituted 7-amino tetrahydroisoquinoline derivative which embodies the central AB ring system of the novel antitumor-antibiotic tetrazomine employing a highly selective ortho nitration and Jackson tosylamido acetal cyclisation as crucial steps is reported. Tetrazomine 1 a 7-aminotetrahydroisoquinoline derivative which is active against several Gram-positive and Gramnegative bacteria and towards P-388 and L1210 leukemia cell lines,1 belongs to a rapidly growing group of related compounds which possess potent antitumor or antibiotic properties.These include quinocarcin 2 the saframycins naphthyridinomycins ecteinascidins and bioxalomycins.2 We have reported the total synthesis of MY336-a 3,3 structurally related to the AB rings of the natural isoquinoline-based antitumor-antibiotics employing an extension of the Jackson tosylamido acetal cyclisation.4 To expand the scope of this synthetic route and taking into account the recent isolation of simple 7-aminotetrahydroisoquinolines,5 we have focused our attention on the elaboration of compound 4 which contains the AB ring system of 1 and may constitute a key intermediate for its total synthesis. Compound 4 possesses protected 7-amino and 1-hydroxymethyl groups together with appropriate substituents for C-3 functionalisation and stereochemical control N H H N MeO N OH O H O Me CH2OH * * F A B C D 1 (proposed structure) MeO N H O 2 Me CH2OH E N N Me MeO OH OH H OH N Me O H OMe OBn Ts O OMe 1 2 3 4 5 6 7 8 3 4 at this position through the neighbouring oxo moiety.6 This is important since there are only scattered references to the preparation of 7-aminotetrahydroisoquinoline derivatives and even less on the synthesis of its congeners bearing the less common and more difficult to elaborate 7,8-difunctional substitution pattern.7 Initial efforts towards the installation of the protected 1- hydroxymethyl side chain by our epoxide ring-opening methodology 4a gave poor results when applied to 2-methoxystyrene oxide 6 (Scheme 1);6b however one-pot addition of benzyloxymethyllithium 8 to o-anisaldehyde 5 followed by trapping of the resulting alkoxide with acetic anhydride gave 90 of acetate 7.Submission of the latter to nitration with potassium nitratendash; trifluoroacetic anhydride in dry chloroform9 at 220 8C afforded 92 of nitro alcohol 8 after basic hydrolysis. A reaction temperature of 220 8C was crucial for the high yield and selectivity observed whilst avoiding undesirably long reaction times; at 0 8C considerable amounts of products resulting from para nitration of both aromatic rings were observed and when the transformation was performed at 10 8C the required onitroanisole became a minor component of a complex mixture. Building of the heterocyclic ring was accomplished by Mitsunobu amination of benzylic alcohol 8 following Garciacute;a et al.10 with the DIADndash;PPh3 couple providing tosyl acetal 10 in 69 yield together with 20 of a 3 1 (E/Z) mixture of elimination products 9.The formation of these could not be suppressed or even diminished by the addition of pyridine.11 Next catalytic hydrogenation of 10 with Pd/C smoothly gave 87 of the readily oxidisable amine 11 conveniently activated for cyclisation. This was immediately exposed to Jackson cyclisation conditions to afford 1,2-dihydroisoquinoline 13 in 98 yield when 3 equivalents of aqueous 6 mol dm23 HCl were employed; this transformation seems to be general since related model compounds obtained by the same synthetic scheme were also efficiently cyclised. Noteworthy is the fact that unlike other routes reported for the elaboration of aminoisoquinolines such as the Bischlerndash; Napieralski strategy this Jackson-based sequence did not require previous protection of the amino function;12 moreover cyclisation of acetanilide 12 occurred with complete amide hydrolysis furnishing 94 of 13.Acylation of the light and air sensitive 1,2-dihydroisoquinoline 13 furnished 86 of acetanilide 14 suitable for the required double bond functionalisation by way of a catalytic dihydroxylation with osmium tetraoxide employing NMO as re-oxidant. This afforded a 3 1 inseparable mixture of compounds 15a and 15b. Molecular mechanics calculations of 14 revealed that the 1-benzyloxymethyl side chain has to adopt a quasi-axial orientation in order to relieve strain with the neighbouring toluene-p-sulfonyl group.Therefore structures 15a and 15b were assigned to the mixture of easily interconverting hemiamidals arising from osmium attack on the less hindered face of the double bond. 3132 J. Chem. Soc. Perkin Trans. 1 1997 Not surprisingly however their acetalisation with methyl orthoformate 4a quantitatively afforded 15c as a single product in agreement with results of molecular mechanics calculations and exhaustive NMR experiments. Finally 15c reacted under Swern conditions (TFAAndash;DMSO) to give ketone 4 almost quantitatively. The ability of the carbonyl to allow stereochemical inversion of the adjacent center providing 1,3-cis-disubstituted compounds was demonstrated through the synthesis of 16 by Lewis acid-promoted isomerisation of 4. Comparative analysis of NOE data of both epimeric ketones and 15c confirmed their proposed structures and that epimerisation took place during the oxidation step.In conclusion we have readily synthesised compound 4 through high-yielding chemistry and have shown the ability of the Jackson isoquinoline synthesis efficiently to provide polysubstituted 7-aminoisoquinoline derivatives. Compound 4 Scheme 1 Reagents and conditions i Me3S1HSO4 2 CH2Cl2ndash;50 NaOH TBAI (cat.) reflux 95; ii 1. NaBnO BnOH 100 8C overnight; 2. Ac2O TEA CH2Cl2 (34); iii 1. Bu3SnCH2OBn BuLi THF 278 8C 5 min then 5; 2. Ac2O 278 8CAElig;RT overnight 90; iv 1. KNO3 (F3CCO)2O CHCl3 220 8C 29 h; 2. SMe2 220 8C; 3. K2CO3 MeOHndash;H2O RT 92; v TsHNCH2CH(OMe)2 DIAD PPh3 THF reflux 3 h 9 20 10 69; vi H2 (4 atm) 10 Pd/C 2-PrOH 87; vii Ac2O TEA CH2Cl2 0 8C 92; viii 6 mol dm23 HCl dioxane reflux 15 min 12AElig;13 94 11AElig;13 98; ix Ac2O TEA CH2Cl2 0 8C 86; x 1.OsO4 (cat.) NMO acetonendash;ButOHndash;H2O (4:2:1) overnight; 2. NaHSO3 88; xi HC(OMe)3 MeOHndash;CH2Cl2 TsOH (cat.) RT 100; xii DMSO (F3CCO)2O 260 8C 15 min then TEA 98; xiii BF3? Et2O CH2Cl2 260 8C 88 N N N N N MeO CHO MeO O MeO OAc OBn O2N MeO OH OBn RHN MeO OBn Ts R MeO OMe OMe Ts OBn MeO O2N AcHN MeO Ts OBn R AcHN MeO OBn Ts O AcHN MeO O Ts OBn OH OMe OBn OMe 5 6 7 8 9 10 R = NO2 11 R = NH2 12 R = NHAc 13 R = H 14 R = Ac 15a R = OH 15b R = - - -OH 15c R = - - -OMe 4 16 i ii iii iv v vi vii ix x xi xii xiii viii possesses the AB ring system of tetrazomine and it is a potential key intermediate for its total synthesis. Further study of the C-3 functionalisation of compound 4 is in progress.Experimental N-1-Benzyloxymethyl-8-methoxy-2-(p-tolylsulfonyl)-1,2- dihydroisoquinolin-7-ylacetamide 14 A solution of tosylamide 11 (364 mg 0.708 mmol) in a mixture of anhydrous dioxane (3 cm3) and 6 mol dm23 HCl (0.35 cm3 2.1 mmol) was heated under reflux for 15 min. Then the reaction was cooled to room temperature neutralised with saturated NaHCO3 (3 cm3) and extracted with EtOAc (4 times; 25 cm3). The extract was washed with brine (5 cm3) dried (Na2SO4) concentrated under reduced pressure and chromatographed through a short column affording 13 (312 mg 98) as a highly photosensitive and readily oxidisable oil; nmax(film)/cm21 3480 3370 2920 2850 1620 1500 1350 1180 920 and 750; dH(200 MHz CDCl3) 2.29 (3 H s ArCH3) 3.36 (1 H dd J 4.6 10.7 CH2OBn) 3.57 (1 H dd J 8.3 10.7 CH2OBn) 3.62 (3 H s 8- OCH3) 3.78 (2 H br s w1/2 14 NH2) 4.48 (1 H d J 12.1 OCH2Ar) 4.59 (1 H d J 12.1 OCH2Ar) 5.66 (1 H ddd J 1.4 4.6 8.3 1-H) 5.94 (1 H d J 7.4 4-H) 6.50 (1 H dd J 1.4 7.4 3-H) 6.52 (1 H d J 8 5-H) 6.58 (1 H d J 8 6-H) 7.10 (2 H d J 8.3 ArH of toluene-p-sulfonyl) 7.25ndash;7.35 (5 H m ArH of benzyl) and 7.65 (2 H d J 8.3 ArH of toluene-p-sulfonyl);dagger; dC(50 MHz CDCl3) 21.20 51.67 59.61 69.45 72.53 113.45 115.08 120.56 121.40 121.57 121.92 126.51 (2 times; C) 127.15 127.44 (2 times; C) 128.00 (2 times; C) 129.11 (2 times; C) 136.91 138.05 139.40 142.73 and 143.17.Without further purification a solution of amine 13 (300 mg 0.67 mmol) in CH2Cl2 (12 cm3) containing triethylamine (0.8 cm3 1.96 mmol) was treated at 0 8C with Ac2O (0.2 cm3 0.98 mmol) until complete conversion of the starting material was achieved.Then the reaction was diluted with EtOAc (45 cm3) and washed successively with 1 mol dm23 HCl (5 cm3) saturated NaHCO3 (5 cm3) and brine (5 cm3). The organic phase was dried concentrated and chromatographed to afford 14 (282 mg 86) as an oil (Found C 66.01; H 5.59; N 5.74; S 6.38. C27H28N2O5S requires C 65.84; H 5.73; N 5.69; S 6.51); nmax(film)/cm21 3380 3300 2890 1690 1530 1350 1180 1040 and 700; dH(200 MHz CDCl3) 2.18 (3 H s CH3CO) 2.31 (3 H s ArCH3) 3.36 (1 H dd J 5.0 10.4 CH2OBn) 3.56 (1 H dd J 7.9 10.4 CH2OBn) 3.60 (3 H s 8-OCH3) 4.44 (1 H d J 12.2 OCH2Ar) 4.52 (1 H d J 12.2 OCH2Ar) 5.62 (1 H ddd J 1.3 5.0 7.9 1-H) 5.97 (1 H d J 7.4 4-H) 6.66 (1 H dd J 1.3 7.4 3-H) 6.76 (1 H d J 8.3 5- H) 7.12 (2 H d J 8.2 ArH of toluene-p-sulfonyl) 7.19ndash;7.35 (5 H m ArH of benzyl) 7.53 (1 H s NH) 7.64 (2 H d J 8.2 ArH of toluene-p-sulfonyl) and 8.07 (1 H d J 8.3 6-H); dC(50 MHz CDCl3) 21.24 24.45 51.59 61.18 69.47 72.66 112.18 120.56 121.00 121.14 123.30 126.44 (2 times; C) 126.76 127.25 127.35 (2 times; C) 128.02 (2 times; C) 129.32 (2 times; C) 130.42 136.66 137.79 143.60 144.89 and 168.08.Acknowledgements The authors gratefully acknowledge CONICET UNR Fundacioacute;n Antorchas and IFS for financial support and Dr A. J. Vila for the use of Hyperchem; V. L. P. thanks CONICET for a fellowship. References 1 (a) K. Suzuki T. Sato M. Morioka K. Nagai K. Abe H. Yamaguchi T. Saito Y. Ohmi and K. Susaki J. Antibiot. 1991 44 479; (b) T. Sato F. Hirayama T. Saito and H. Kaniwa J. Antibiot. 1991 44 1367. dagger; J Values are given in Hz. J. Chem. Soc. Perkin Trans. 1 1997 3133 2 (a) R.M. Williams T. Glinka M. E. Flanagan R. Gallegos H. Coffman and D. Pei J. Am. Chem. Soc. 1992 114 733 and references cited therein; (b) K. L. Rinehart T. G. Holt N. L. Fregeau J. G. Stroh P. A. Keifer F. Sun L. H. Li and D. G. Martin J. Org. Chem. 1990 55 4512 and references cited therein; (c) J. Zaccardi M. Alluri J. Ashcroft V. Bernan J. D. Korshalla G. O. Morton M. Siegel R. Tsao D. R. Williams W. Maiese and G. A. Ellestad J. Org. Chem. 1994 59 4045. 3 (a) T. S. Kaufman J. Chem. Soc. Perkin Trans. 1 1996 2497; (b) T. S. Kaufman Tetrahedron Lett. 1996 37 5329. 4 (a) A. J. Birch A. H. Jackson and P. V. R. Shannon J. Chem. Soc. Perkin Trans. 1 1974 2185; (b) A. H. Jackson and G. W. Stewart J. Chem. Soc. Chem. Commun. 1971 149. 5 (a) T. Hida M. Muroi S. Tanida and S. Harada J. Antibiot.1994 47 917; (b) Y.-E. Choi A. Park J. Schmitz and I. van Altena J. Nat. Prod. 1993 56 1431; (c) M. Kobayashi S. R. Rao R. Chavakula and N. S. Sarma J. Chem. Res. (S) 1994 282. 6 (a) R. M. Williams P. P. Ehrlich W. Zhai and J. Hendrix J. Org. Chem. 1987 52 2615; (b) R. M. Williams T. Glinka R. Gallegos P. P. Ehrlich M. E. Flanagan H. Coffman and G. Park Tetrahedron 1991 47 2629; (c) S. Danishefsky B. T. Orsquo;Neill and J. P. Springer Tetrahedron Lett. 1984 25 4203. 7 (a) S. Nakahara R. Numata Y. Tanaka and A. Kubo Heterocycles 1995 41 651; (b) Y. Kitahara S. Nakahara R. Numata K. Inaba and A. Kubo Chem. Pharm. Bull. 1985 33 823; (c) F. Zhang and G. Dryhurst Bioorg. Chem. 1993 21 221. 8 W. C. Still J. Am. Chem. Soc. 1978 100 1481. 9 (a) U. A. Spitzer and R. Stewart J. Org. Chem. 1974 39 3936; (b) J.V. Crivello J. Org. Chem. 1981 46 3056. 10 A. Garciacute;a L. Castedo and D. Domiacute;nguez Synlett 1993 271. 11 P. M. Wovkulich K. Shankaran J. Kiegiel and M. R. Uskokovic J. Org. Chem. 1993 58 832. 12 (a) T. Kametani in The Total Synthesis of Natural Products ed. J. ApSimon Wiley New York 1977 vol. 3 pp. 16ndash;22; (b) C. A. Denyer H. Bunyan D. M. Loakes J. Tucker and J. Gillam Tetrahedron 1995 51 5057. Paper 7/06070J Received 18th August 1997 Accepted 3rd September 1997 J. Chem. Soc. Perkin Trans. 1 1997 3131 Synthesis of the tetrahydroisoquinoline unit in the AB ring system of the novel antitumor-antibiotic tetrazomine Viviana L. Ponzo and Teodoro S. Kaufman* Instituto de Quiacute;mica Orgaacute;nica de Siacute;ntesis (IQUIOS) (CONICET-UNR) and Facultad de Ciencias Bioquiacute;micas y Farmaceacute;uticas Universidad Nacional de Rosario Casilla de Correo 991 2000 Rosario Repuacute;blica Argentina The elaboration of a polysubstituted 7-amino tetrahydroisoquinoline derivative which embodies the central AB ring system of the novel antitumor-antibiotic tetrazomine employing a highly selective ortho nitration and Jackson tosylamido acetal cyclisation as crucial steps is reported.Tetrazomine 1 a 7-aminotetrahydroisoquinoline derivative which is active against several Gram-positive and Gramnegative bacteria and towards P-388 and L1210 leukemia cell lines,1 belongs to a rapidly growing group of related compounds which possess potent antitumor or antibiotic properties. These include quinocarcin 2 the saframycins naphthyridinomycins ecteinascidins and bioxalomycins.2 We have reported the total synthesis of MY336-a 3,3 structurally related to the AB rings of the natural isoquinoline-based antitumor-antibiotics employing an extension of the Jackson tosylamido acetal cyclisation.4 To expand the scope of this synthetic route and taking into account the recent isolation of simple 7-aminotetrahydroisoquinolines,5 we have focused our attention on the elaboration of compound 4 which contains the AB ring system of 1 and may constitute a key intermediate for its total synthesis.Compound 4 possesses protected 7-amino and 1-hydroxymethyl groups together with appropriate substituents for C-3 functionalisation and stereochemical control N H H N MeO N OH O H O Me CH2OH * * F A B C D 1 (proposed structure) MeO N H O 2 Me CH2OH E N N Me MeO OH OH H OH N Me O H OMe OBn Ts O OMe 1 2 3 4 5 6 7 8 3 4 at this position through the neighbouring oxo moiety.6 This is important since there are only scattered references to the preparation of 7-aminotetrahydroisoquinoline derivatives and even less on the synthesis of its congeners bearing the less common and more difficult to elaborate 7,8-difunctional substitution pattern.7 Initial efforts towards the installation of the protected 1- hydroxymethyl side chain by our epoxide ring-opening methodology 4a gave poor results when applied to 2-methoxystyrene oxide 6 (Scheme 1);6b however one-pot addition of benzyloxymethyllithium 8 to o-anisaldehyde 5 followed by trapping of the resulting alkoxide with acetic anhydride gave 90 of acetate 7.Submission of the latter to nitration with potassium nitratendash; trifluoroacetic anhydride in dry chloroform9 at 220 8C afforded 92 of nitro alcohol 8 after basic hydrolysis.A reaction temperature of 220 8C was crucial for the high yield and selectivity observed whilst avoiding undesirably long reaction times; at 0 8C considerable amounts of products resulting from para nitration of both aromatic rings were observed and when the transformation was performed at 10 8C the required onitroanisole became a minor component of a complex mixture. Building of the heterocyclic ring was accomplished by Mitsunobu amination of benzylic alcohol 8 following Garciacute;a et al.10 with the DIADndash;PPh3 couple providing tosyl acetal 10 in 69 yield together with 20 of a 3 1 (E/Z) mixture of elimination products 9. The formation of these could not be suppressed or even diminished by the addition of pyridine.11 Next catalytic hydrogenation of 10 with Pd/C smoothly gave 87 of the readily oxidisable amine 11 conveniently activated for cyclisation.This was immediately exposed to Jackson cyclisation conditions to afford 1,2-dihydroisoquinoline 13 in 98 yield when 3 equivalents of aqueous 6 mol dm23 HCl were employed; this transformation seems to be general since related model compounds obtained by the same synthetic scheme were also efficiently cyclised. Noteworthy is the fact that unlike other routes reported for the elaboration of aminoisoquinolines such as the Bischlerndash; Napieralski strategy this Jackson-based sequence did not require previous protection of the amino function;12 moreover cyclisation of acetanilide 12 occurred with complete amide hydrolysis furnishing 94 of 13.Acylation of the light and air sensitive 1,2-dihydroisoquinoline 13 furnished 86 of acetanilide 14 suitable for the required double bond functionalisation by way of a catalytic dihydroxylation with osmium tetraoxide employing NMO as re-oxidant. This afforded a 3 1 inseparable mixture of compounds 15a and 15b. Molecular mechanics calculations of 14 revealed that the 1-benzyloxymethyl side chain has to adopt a quasi-axial orientation in order to relieve strain with the neighbouring toluene-p-sulfonyl group. Therefore structures 15a and 15b were assigned to the mixture of easily interconverting hemiamidals arising from osmium attack on the less hindered face of the double bond. 3132 J. Chem. Soc. Perkin Trans. 1 1997 Not surprisingly however their acetalisation with methyl orthoformate 4a quantitatively afforded 15c as a single product in agreement with results of molecular mechanics calculations and exhaustive NMR experiments.Finally 15c reacted under Swern conditions (TFAAndash;DMSO) to give ketone 4 almost quantitatively. The ability of the carbonyl to allow stereochemical inversion of the adjacent center providing 1,3-cis-disubstituted compounds was demonstrated through the synthesis of 16 by Lewis acid-promoted isomerisation of 4. Comparative analysis of NOE data of both epimeric ketones and 15c confirmed their proposed structures and that epimerisation took place during the oxidation step. In conclusion we have readily synthesised compound 4 through high-yielding chemistry and have shown the ability of the Jackson isoquinoline synthesis efficiently to provide polysubstituted 7-aminoisoquinoline derivatives.Compound 4 Scheme 1 Reagents and conditions i Me3S1HSO4 2 CH2Cl2ndash;50 NaOH TBAI (cat.) reflux 95; ii 1. NaBnO BnOH 100 8C overnight; 2. Ac2O TEA CH2Cl2 (34); iii 1. Bu3SnCH2OBn BuLi THF 278 8C 5 min then 5; 2. Ac2O 278 8CAElig;RT overnight 90; iv 1. KNO3 (F3CCO)2O CHCl3 220 8C 29 h; 2. SMe2 220 8C; 3. K2CO3 MeOHndash;H2O RT 92; v TsHNCH2CH(OMe)2 DIAD PPh3 THF reflux 3 h 9 20 10 69; vi H2 (4 atm) 10 Pd/C 2-PrOH 87; vii Ac2O TEA CH2Cl2 0 8C 92; viii 6 mol dm23 HCl dioxane reflux 15 min 12AElig;13 94 11AElig;13 98; ix Ac2O TEA CH2Cl2 0 8C 86; x 1. OsO4 (cat.) NMO acetonendash;ButOHndash;H2O (4:2:1) overnight; 2. NaHSO3 88; xi HC(OMe)3 MeOHndash;CH2Cl2 TsOH (cat.) RT 100; xii DMSO (F3CCO)2O 260 8C 15 min then TEA 98; xiii BF3? Et2O CH2Cl2 260 8C 88 N N N N N MeO CHO MeO O MeO OAc OBn O2N MeO OH OBn RHN MeO OBn Ts R MeO OMe OMe Ts OBn MeO O2N AcHN MeO Ts OBn R AcHN MeO OBn Ts O AcHN MeO O Ts OBn OH OMe OBn OMe 5 6 7 8 9 10 R = NO2 11 R = NH2 12 R = NHAc 13 R = H 14 R = Ac 15a R = OH 15b R = - - -OH 15c R = - - -OMe 4 16 i ii iii iv v vi vii ix x xi xii xiii viii possesses the AB ring system of tetrazomine and it is a potential key intermediate for its total synthesis.Further study of the C-3 functionalisation of compound 4 is in progress. Experimental N-1-Benzyloxymethyl-8-methoxy-2-(p-tolylsulfonyl)-1,2- dihydroisoquinolin-7-ylacetamide 14 A solution of tosylamide 11 (364 mg 0.708 mmol) in a mixture of anhydrous dioxane (3 cm3) and 6 mol dm23 HCl (0.35 cm3 2.1 mmol) was heated under reflux for 15 min. Then the reaction was cooled to room temperature neutralised with saturated NaHCO3 (3 cm3) and extracted with EtOAc (4 times; 25 cm3).The extract was washed with brine (5 cm3) dried (Na2SO4) concentrated under reduced pressure and chromatographed through a short column affording 13 (312 mg 98) as a highly photosensitive and readily oxidisable oil; nmax(film)/cm21 3480 3370 2920 2850 1620 1500 1350 1180 920 and 750; dH(200 MHz CDCl3) 2.29 (3 H s ArCH3) 3.36 (1 H dd J 4.6 10.7 CH2OBn) 3.57 (1 H dd J 8.3 10.7 CH2OBn) 3.62 (3 H s 8- OCH3) 3.78 (2 H br s w1/2 14 NH2) 4.48 (1 H d J 12.1 OCH2Ar) 4.59 (1 H d J 12.1 OCH2Ar) 5.66 (1 H ddd J 1.4 4.6 8.3 1-H) 5.94 (1 H d J 7.4 4-H) 6.50 (1 H dd J 1.4 7.4 3-H) 6.52 (1 H d J 8 5-H) 6.58 (1 H d J 8 6-H) 7.10 (2 H d J 8.3 ArH of toluene-p-sulfonyl) 7.25ndash;7.35 (5 H m ArH of benzyl) and 7.65 (2 H d J 8.3 ArH of toluene-p-sulfonyl);dagger; dC(50 MHz CDCl3) 21.20 51.67 59.61 69.45 72.53 113.45 115.08 120.56 121.40 121.57 121.92 126.51 (2 times; C) 127.15 127.44 (2 times; C) 128.00 (2 times; C) 129.11 (2 times; C) 136.91 138.05 139.40 142.73 and 143.17.Without further purification a solution of amine 13 (300 mg 0.67 mmol) in CH2Cl2 (12 cm3) containing triethylamine (0.8 cm3 1.96 mmol) was treated at 0 8C with Ac2O (0.2 cm3 0.98 mmol) until complete conversion of the starting material was achieved. Then the reaction was diluted with EtOAc (45 cm3) and washed successively with 1 mol dm23 HCl (5 cm3) saturated NaHCO3 (5 cm3) and brine (5 cm3). The organic phase was dried concentrated and chromatographed to afford 14 (282 mg 86) as an oil (Found C 66.01; H 5.59; N 5.74; S 6.38.C27H28N2O5S requires C 65.84; H 5.73; N 5.69; S 6.51); nmax(film)/cm21 3380 3300 2890 1690 1530 1350 1180 1040 and 700; dH(200 MHz CDCl3) 2.18 (3 H s CH3CO) 2.31 (3 H s ArCH3) 3.36 (1 H dd J 5.0 10.4 CH2OBn) 3.56 (1 H dd J 7.9 10.4 CH2OBn) 3.60 (3 H s 8-OCH3) 4.44 (1 H d J 12.2 OCH2Ar) 4.52 (1 H d J 12.2 OCH2Ar) 5.62 (1 H ddd J 1.3 5.0 7.9 1-H) 5.97 (1 H d J 7.4 4-H) 6.66 (1 H dd J 1.3 7.4 3-H) 6.76 (1 H d J 8.3 5- H) 7.12 (2 H d J 8.2 ArH of toluene-p-sulfonyl) 7.19ndash;7.35 (5 H m ArH of benzyl) 7.53 (1 H s NH) 7.64 (2 H d J 8.2 ArH of toluene-p-sulfonyl) and 8.07 (1 H d J 8.3 6-H); dC(50 MHz CDCl3) 21.24 24.45 51.59 61.18 69.47 72.66 112.18 120.56 121.00 121.14 123.30 126.44 (2 times; C) 126.76 127.25 127.35 (2 times; C) 128.02 (2 times; C) 129.32 (2 times; C) 130.42 136.66 137.79 143.60 144.89 and 168.08.Acknowledgements The authors gratefully acknowledge CONICET UNR Fundacioacute;n Antorchas and IFS for financial support and Dr A. J. Vila for the use of Hyperchem; V. L. P. thanks CONICET for a fellowship. References 1 (a) K. Suzuki T. Sato M. Morioka K. Nagai K. Abe H. Yamaguchi T. Saito Y. Ohmi and K. Susaki J. Antibiot. 1991 44 479; (b) T. Sato F. Hirayama T. Saito and H. Kaniwa J. Antibiot. 1991 44 1367. dagger; J Values are given in Hz. J. Chem. Soc. Perkin Trans. 1 1997 3133 2 (a) R. M. Williams T. Glinka M. E. Flanagan R. Gallegos H. Coffman and D. Pei J. Am. Chem. Soc. 1992 114 733 and references cited therein; (b) K. L. Rinehart T. G. Holt N. L. Fregeau J. G. Stroh P. A. Keifer F. Sun L. H. Li and D. G. Martin J. Org. Chem. 1990 55 4512 and references cited therein; (c) J.Zaccardi M. Alluri J. Ashcroft V. Bernan J. D. Korshalla G. O. Morton M. Siegel R. Tsao D. R. Williams W. Maiese and G. A. Ellestad J. Org. Chem. 1994 59 4045. 3 (a) T. S. Kaufman J. Chem. Soc. Perkin Trans. 1 1996 2497; (b) T. S. Kaufman Tetrahedron Lett. 1996 37 5329. 4 (a) A. J. Birch A. H. Jackson and P. V. R. Shannon J. Chem. Soc. Perkin Trans. 1 1974 2185; (b) A. H. Jackson and G. W. Stewart J. Chem. Soc. Chem. Commun. 1971 149. 5 (a) T. Hida M. Muroi S. Tanida and S. Harada J. Antibiot. 1994 47 917; (b) Y.-E. Choi A. Park J. Schmitz and I. van Altena J. Nat. Prod. 1993 56 1431; (c) M. Kobayashi S. R. Rao R. Chavakula and N. S. Sarma J. Chem. Res. (S) 1994 282. 6 (a) R. M. Williams P. P. Ehrlich W. Zhai and J. Hendrix J. Org. Chem. 1987 52 2615; (b) R. M. Williams T. Glinka R.Gallegos P. P. Ehrlich M. E. Flanagan H. Coffman and G. Park Tetrahedron 1991 47 2629; (c) S. Danishefsky B. T. Orsquo;Neill and J. P. Springer Tetrahedron Lett. 1984 25 4203. 7 (a) S. Nakahara R. Numata Y. Tanaka and A. Kubo Heterocycles 1995 41 651; (b) Y. Kitahara S. Nakahara R. Numata K. Inaba and A. Kubo Chem. Pharm. Bull. 1985 33 823; (c) F. Zhang and G. Dryhurst Bioorg. Chem. 1993 21 221. 8 W. C. Still J. Am. Chem. Soc. 1978 100 1481. 9 (a) U. A. Spitzer and R. Stewart J. Org. Chem. 1974 39 3936; (b) J. V. Crivello J. Org. 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