Supporting Information

Supporting Information Efficient Short Step Synthesis of Corey s Tamiflu Intermediate Nsiama Tienabe Kipassa, Hiroaki kamura, * Kengo Kina, Tetsuo Iwagawa, and Toshiyuki Hamada Department of Chemistry and Bioscience, Faculty of Science, Kagoshima University 1-21-35 Korimoto, Kagoshima 890-0065, Japan okam@sci.kagoshima-u.ac.jp Table of Contents General methods... S2 N-nosyl-3-hydroxy-2-pyridone (3b)... S2 Diels-Alder reaction of N-Ns- and N-Ts-pyridone 3b and 3c with acrylate ester... S3 Ethyl N-(2 -nitrobenzenesulfonyl)-2-aza-4-hydroxy-3-oxo-bicyclo[2.2.2]oct-5-ene-8-carboxylate (4b)... S3 Ethyl 2-hydroxy-2-hydroxymethyl-5-(2 -nitrobenzensulfonamido)-3-enecarboxylate (5b)... S4 Ethyl 5-(2 -nitrobenzenesulfonyl)-2-oxocyclohex-3-enylcarboxylate (6b) and its enol tautomer (6b)... S4 The equivalent of Corey s intermediate (2b)... S4 Ethyl 5-(tert-butoxycarbamoyl)-2-hydroxy-2-(hydroxymethyl)cyclohex-3-enecarboxylate (5b)... S5 Corey s intermediate (2a)... S5 1H NMR of 3b... S6 13C NMR of 3b... S7 1H NMR of 4b... S8 13C NMR of 4b... S9 1H NMR of 5b...S10 13C NMR of 5b... S11 1H NMR of 2b...S12 13C NMR of 2b...S13 1H NMR of 5a...S14 13C NMR of 5a...S15 1H NMR of 2a...S16 13C NMR of 2a...S17 S1

General methods Except the preparation of 3b that has been carried out under N 2 atmosphere, all reactions were performed directly in the air atmosphere. THF was distilled from Na-benzophenone. CH 3 CN and Me were also distilled before use. All the other chemicals were used as commercially available forms. Thin-layer chromatography (TLC) was performed using silica gel 60 F 254 precoated plates (Merck, thickness, 0.25 mm). Column chromatography was performed using silica gel 60 (Wako gel, 70-230 mesh). NMR spectra were recorded on JEL FX-400 instrument in CDCl 3 or DMS using TMS as an internal reference. IR spectra were recorded on JASC FT/IR 5300. ESI-TFMS measurements were performed on a Bruker Daltonics micro TF-KS1focus. Typical procedures Ns N N-nosyl-3-hydroxy-2-pyridone (3b) The compound 3b was prepared by a modified procedure reported by Posner for the preparation of N-Ts-3-hydroxy-2-pyridone. 1 3b A solution of 3-(tert-butyldimethylsilyloxy)-2-pyridone (318 mg, 1.4 mmol) in THF (16 ml) was prepared under N 2 atmosphere at 0 ºC, and n-buli (1.6 N in hexane, 0.90 ml) was then added carefully and stirred for 20 min at the temperature. While stirring, 2-nitrobenzensulfonyl chloride (NsCl, 315 mg) was added and the temperature maintained at 0 ºC. After 24 h, the solution was warmed to room temperature and distilled water (15 ml) was added. The mixture was extracted with EtAc (3 x 10 ml) and the organic layer was dried over MgS 4. The solvent was removed under vacuo and the residue was purified by silica gel column chromatography using hexane-acet (4:1) to give a light yellow powder of 3-tert-butyldimethylsilyloxy-1-(2 -nitorobenzensulfonyl)-2-pyridone (515 mg, 89%). To the solution of the resulting product (526 mg, 1.3 mmol) in aqueous CH 3 C (1:1 mixture, 10.5 ml), two drops of conc. H 2 S 4 were added and the mixture was stirred for 30 h at room temperature. After the addition of water (1 ml), almost pure product 3b was obtained as a crystalline product by simple filtration (307 mg, 81%). M. p. 218-221 C; Elemental anal.: calcd for C 11 H 8 N 2 6 S: C, 44.60; N, 9.46; H, 2.72, found: C, 44.54; N, 9.27; H, 2.86; ESI-TFMS: m/z [M-H] - calcd for C 11 H 9 N 2 6 S: 295.0019, found 295.0307; IR (KBr): 3322, 3125, 2363, 1658, 1624, 1534, 1390, 1350, 904, 858, 743, 652; 1 H NMR (400 MHz, DMS) 9.93 (1H, s), 8.44 (1H, dd, J = 7.6, 2.1 Hz), 8.09 (1H, dd, J = 8.1, 1.6), 8.05-7.97 (2H, m), 7.40 (1H, dd, J = 7.8, 1.4), 6.79 (1H, dd, J = 7.3, 1.8 Hz), 6.36 (1H, t, J = 7.3); 13 C NMR (100 MHz, DMS) 156.3, 147.6, 147.5, 137.1, 135.0, 132.8, 128.7, 125.4, 121.3, 116.8, 107.1. (1) Posner, H. G.; Vinader, V.; Afarinkia, K. J. rg. Chem. 1992, 57, 4088-4097. S2

Diels-Alder reaction of N-Ns- and N-Ts-pyridone 3b and 3c with acrylate ester N-Nosyl protected pyridone 3b showed very different reactivity from N-tosyl pyridone 3c that was used for preparation of the starting material of validamine. 2 Compound 3c smoothly reacted with acrylate in CH 2 Cl 2 using Et 3 N as a catalyst (Table 1, entry 1). Under the same condition however, 3b gave only 3-hydroxy-2-(2 -nitrobenzensulfonyloxy)-pyridine and no desired DA adduct (entry 2). To prevent the Ns migration, several reaction conditions were examine, and finally a heterogeneous reaction of aqueous alkaline solution of 3b and excess ethyl acrylate was found to be an appropriate condition to give the corresponding DA adduct 4b in good yield without the migration (entry 3). Table 1. Base-Catalyzed DA reaction of 3 N-X 3b: X = Ns 3c: X = Ts + C 2 R base X N C2 R 4b: X = Ns 4c: X = Ts entry dienophile 1 R = Me, 1.1 eq. 2 R = Et, 1.1 eq. 3 R = Et, excess condition Et 3 N, CH 2 Cl 2, RT, 24 h Et 3 N, CH 2 Cl 2, RT, 24 h Na, H 2, RT, 24 h in suspension yeild (%) 66 a 0 b 83 a) ref. 2. b) N Ns was formed in 30 %. Ethyl N-(2 -nitrobenzenesulfonyl)-2-aza-4-hydroxy-3-oxo-bicyclo[2.2.2]oct-5-ene-8- Ns N carboxylate (4b) To a suspension of compound 3b (325 mg, 1.1 mmol) in water (12 ml), aqueous Na solution (2N, 1.1 ml) and ethyl acrylate (4.5 ml) were successively added, and the resulting 4b mixture was stirred vigorously at room temperature. After 24 h, the reaction mixture was extracted by CH 2 Cl 2 (3 x 10 ml) and the combined organic layer was dried over MgS 4 and concentrated under vaccuo to give crude crystalline product. Recrystallization in ether provided pure 4b as a single isomer (361 mg, 83% yield). M. p. 149-151 C; Elemental Anal.: calcd for C 16 H 16 N 2 8 S: C, 48.48; N, 7.07; H, 4.07, found: C, 48.49; N, 7.05; H, 4.14; ESI-TFMS: m/z [M-H] - calcd for C 16 H 16 N 2 8 S: 395.0544, found 395.0660; IR (KBr): 3315, 3102, 2899, 1746, 1717, 1591, 1365, 1304, 960, 881; 1 H NMR (400 MHz, CDCl 3 ) 8.50 (1H, m), (2) kamura, H.; Nagaike, H.; Kipassa, N. T.; Iwagawa, T.; Nakatani, M. Heterocycles 2006, 68, 2587-2594. S3

7.79-7.82 (3H, m), 6.70 (1H, t, J = 6.6 Hz), 6.26 (1H, dd, J = 8.0, 1.1 Hz), 5.53 (1H, m), 4.19 (2H, q, J = 7.3 Hz), 3.90 (1H, s), 2.93 (1H, dd, J = 9.6, 5.0 Hz), 2.69 (1H, m), 1.99 (1H, dd, J = 13.3, 5.0 Hz), 1.71 (1H, s), 1.25 (3H, t, J = 7.3 Hz); 13 C NMR (100 MHz, CDCl 3 ) 171.4, 171.3, 147.8, 135.3, 134.2, 134.0, 132.4, 131.6, 131.4, 124.6, 77.9, 61.6, 53.6, 43.2, 33.4, 14.1. NHNs Ethyl 2-hydroxy-2-hydroxymethyl-5-(2 -nitrobenzensulfonamido)-3-enecarboxylate (5b) To a solution of 4b (294 mg, 0.74 mmol) in THF (8.0 ml), NaBH 4 (42 mg, 1.1 mmol) was added at 0 ºC. After stirring for two hours, the reaction was quenched by some drops of H 3 P 4 solutiojn (5%). The whole mixture was extracted with EtAc (3 x 5 ml) and the resulting organic layer was washed with brine and dried over Mg S 4. The solvent was 5b removed under vaccuo and the obtained residue was purified by silica gel column chromatography with Me-CH 2 Cl 2 (1:50) to afford the diol 5b as a pale yellow oil (229 mg, 77% yield). ESI-TFMS: m/z [M-H] - calcd for C 16 H 20 N 2 8 S 399.0857, found 399.0865; IR (film): 3466, 2982, 2361, 1715, 1593, 1539, 1343, 855; 1 H NMR (400 MHz, CDCl 3 ) 8.17 (1H, m), 7.89 (1H, dd, J = 6.0, 3.2 Hz), 7.79-7.76 (2H, m), 5.79 (1H, dd, J = 10.1, 1.4 Hz), 5.65 (1H, dd, J = 10.1, 4.6 Hz), 5.54 (1H, d, J = 7.8 Hz), 4.38 (1H, s), 4.20-4.11 (3H, m), 3.59-3.53 (2H, m), 2.96 (1H, dd, J = 10.3, 3.4 Hz), 2.36 (1H, br s), 2.29 (1H, m), 1.99 (1H, dt, J = 14.2, 4.1 Hz), 1.74 (2H, s), 1.25 (3H, t, J = 7.1 Hz); 13 C NMR (100 MHz, CDCl 3 ) 174.8, 147.8, 134.6, 133.7, 133.7, 133.0, 130.8, 128.5, 125.5, 70.3, 68.0, 61.4, 48.4, 41.2, 29.7, 14.1. Ethyl 5-(2 -nitrobenzenesulfonyl)-2-oxocyclohex-3-enylcarboxylate NHNs NHNs (6b) and its enol tautomer (6b) To a solution of diol 5b (205 mg, 0.51 mmol) in THF:H 2 (1:1, 8.0 ml), NaI 4 (163.6 mg) was added at 0 ºC. The solution was stirred for 6b three hours at the temperature, warmed to room temperature and then 6b' diluted by addition of water (5 ml). The resulting clear solution was extracted with ethyl acetate (3 x 5 ml). The combined organic layer was washed with brine and dried over anhydrous MgS 4, then filtered and concentrated. The residue was purified by silica gel chromatography with Hexane:EtAc (7:3) to afford the desired product as nearly 1:1 mixture of the enone 6b and its enol tautomer 6b (151 mg, 80% yield). Since the resulting mixture was relatively unstabele, it was used for next step without detailed spectra examinations. NHNs The equivalent of Corey s intermediate (2b) The mixture of 6b and 6b (160 mg, 0.44 mmol) and cerium trichloride (148 mg) were dissolved in Me (4.0 ml) at 0 ºC and NaBH 4 (27 mg) was added. The reaction mixture was 2b stirred at this temperature for 2 h, and then quenched by adding saturated aqueous solution of NH 4 Cl (ca. 1 ml). After removing Me under reduced pressure, the residue was diluted in water (ca. 5 ml) and extracted with ethyl acetate (3 x 10 ml). The organic layer was washed with brine, dried over MgS 4, filtered through celite, and concentrated. The resulting syrup containing corresponding alcohol was dissolved in THF (9.0 ml) with Et 3 N (290 µl) and DMAP (80 mg). The solution was cooled to 0 ºC, and then MsCl (112 mg) was added. The resulting white suspension was left to slowly warm to S4

room temperature while stirring for 4 h. After adding water (ca. 5 ml), the whole mixture was extracted with AcEt (3 x 10 ml). The combined organic layer was dried over MgS 4, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography with hexane-acet (7:3) to yield the desired product 2b as a pale yellow oil (87 mg, 76% yield over two steps). ESI-TFMS: m/z [M-H] - calcd for C 15 H 16 N 2 6 S: 351.0645, found 351.0743; IR (film): 3297, 3098, 2984, 1701, 1642, 1578, 1537, 1346, 1165, 1100, 854; 1 H NMR (400 MHz, CDCl 3 ) 8.20 (1H, m), 7.89 (1H, m), 7.81-7.74 (2H, m), 6.21 (1H, dd, J = 9.4, 5.7), 6.00 (1H, dd, J = 9.6, 5.0), 5.53 (1H, d, J = 9.2), 4.31 (1H, m), 4.16 (2H, q, J = 6.9 Hz), 2.75 (1H, dd, J = 18.1, 5.8), 2.51 (1H, ddd, J = 18.1, 8.0, 2.5), 1.26 (3H, t, J = 7.1); 13 C NMR (100 MHz, CDCl 3 ) 166.1, 147.7, 135.2, 133.7, 133.2, 131.5, 130.6, 130.3, 126.7, 126.3, 125.6, 125.5, 60.7, 47.5, 28.6, 14.2. NHBoc Ethyl 5-(tert-butoxycarbamoyl)-2-hydroxy-2-(hydroxymethyl)cyclohex-3-enecarboxylate (5a) To a solution of the 5b (338 mg, 0.85 mmol) in MeCN (4.0 ml) was added K 2 C 3 (152 mg) and PhSH (130 µl), and the resulting reaction mixture was stirred for 3 h at room temperature. The solution was diluted with water (10 ml) and washed with AcEt (2 x 5 ml). 5a To the aqueous layer, Boc 2 (204 mg) was added. The mixture was stirred for 24 h and extracted with AcEt (3 8 ml). The combined organic layer were dried over MgS 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography with hexane-acet (4:1) to give 5a as a colorless oil (124 mg, 55% yield). ESI-TFMS: m/z [M+Na] + calcd for C 15 H 25 N 6 Na: 338.1574, found: 338.1547; IR (film): 3362, 2978, 2936, 1689, 1522, 1456, 1393, 1248, 1171, 995, 779; 1 H NMR (400 MHz, CDCl 3 ) 5.84 (1H, dd, J = 10.1, 3.7 Hz), 5.76 (1H, dd, J = 10.1, 1.4 Hz), 4.57 (1H, br s), 4.46 (1H, s), 4.26 (1H, br s), 4.21 (2H, q, J = 7.3 Hz), 3.59-3.51 (2H, m), 2.91 (1H, dd, J = 9.6, 2.7 Hz), 2.38-2.31 (2H, m), 1.91 (1H, dt, J = 13.3, 4.1 Hz), 1.70 (2H, s), 1.45 (9H, s), 1.30 (3H, t, J = 7.1 Hz); 13 C NMR (100 MHz, CDCl 3 ) 175.3, 155.0, 132.2, 130.5, 108.7, 70.5, 68.2, 61.4, 41.7, 29.4, 28.4, 14.1. NHBoc Corey s intermediate (2a) The experimental procedures for the conversions from 5a to 2a were essentially same with the above mentioned method. The spectra data of 2a showed good agreement with that of reported values. 3 ESI-TFMS: m/z [M+Na] + calcd for C 14 H 21 N 4 Na: 290.1363, found 2a 290.1340; IR (film): 3353, 2978, 2361, 1707, 1512, 1368, 1254, 1167, 1098, 478, 444; 1 H (400 MHz, CDCl 3 ): 7.06 (1H, d, J = 4.1 Hz), 6.18-6.08 (2H, m), 4.64 (1H, br s), 4.44 (1H, br s), 4.22 (2H, q, J = 7.1), 2.77-2.63 (2H, m), 1.40 (9H, s), 1.31 (3H, t, J = 7.1 Hz); 13 C (100 MHz, CDCl 3 ): 166.9, 154.9, 132.5, 131.8, 128.9, 127.0, 124.8, 60.6, 53.4, 28.9, 28.4, 14.3. (3) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310-6311. S5

1 H NMR of 3b N 3b Ns S6

13 C NMR of 3b N 3b Ns S7

1 H NMR of 4b Ns N 4b S8

13 C NMR of 4b Ns N 4b S9

1 H NMR of 5b NHNs 5b S10

13 C NMR of 5b NHNs 5b S11

1 H NMR of 2b NHNs 2b S12

13 C NMR of 2b NHNs 2b S13

1 H NMR of 5a NHBoc 5a S14

13 C NMR of 5a NHBoc 5a S15

1 H NMR of 2a NHBoc 2a S16

13 C NMR of 2a NHBoc 2a S17