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1 An Improved ynthesis of the Pyridine-Thiazole Cores of Thiopeptide Antibiotics Virender. Aulakh, Marco A. Ciufolini* Department of Chemistry, University of British Columbia 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada upporting Information

2 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 2 Table of Contents A. Experimental Protocols 3 B. Experimental Procedures and Characterization Data 3 4-Carbethoxythiazole (8) 3 Bithiazole 11 3 Alkynone 22 4 Pyridine 23 4 Pyridines 24 and 25 5 C. HPLC Traces of Pyridines 18 and 19 6 Pyridine 18 6 Pyridine 19 6 D. 1 H and 13 C MR spectra 7 Aldehyde 7 4-Carbethoxythiazole (8) Bithiazole 11 Aldehyde 12 Compound 14 Compound 15 Compound 16 Compound 18 Compound 19 Compound 22 Compound 23 Compound 24 Compound

3 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 3 A. Experimental Protocols. Melting points are uncorrected. Unless otherwise indicated, 1 H (300 MHz) and 13 C (75 MHz) MR spectra were recorded at room temperature from CDCl 3 solutions. Chemical shifts are reported as ppm on the δ scale and coupling constants, J, are in Hz. Multiplicities are described as s (singlet), d / dd / dt (doublet / doublet of doublets / doublet of triplets), t (triplet), q (quartet), m (multiplet). Low and high resolution mass spectra were obtained in the EI mode. Infrared spectra (cm -1 ) were recorded from neat films of analyte deposited on acl plates. Chromatographic separations were effected over Fluka 60 silica gel. Tetrahydrofuran was freshly distilled from a/benzophenone. All other commercial reagents and solvents were used without further purification. All reactions were performed under argon in flasks equipped with Teflon stirring bars and fitted with rubber septa for the introduction of substrates, reagents, and solvents via syringe. B. Experimental Procedures and Characterization Data. 4-Carbethoxythiazole (8). m.p C (lit. 1 H (CDCl 3 ): 8.86 (d, 1H, J = 1.7), 8.26 (d, 1H, J = 1.7), 4.45 (q, 2H, J = 7.1), 1.43 (t, 3H, J = 7.1). 13 C (CDCl 3 ): 161.3, 153.4, 148.2, 127.2, 61.6, EIM: [M+H] +, [M+a] +. HRM : calc for C 6 H 7 2 a [M+a] +, , found Bithiazole 11. Ethyl 2-methylthiazole-4-carboxylate (8.7 g, 51.1 mmol) was dissolved in commercial aq. conc. H 4 H solution (40 ml) and the solution was heated to 70 C for 2 h. The solution was cooled to rt and extracted with EtAc (3 x 30 ml). The combined extracts were evaporated to leave a residue of 2-methylthiazole-4-carboxamide, which was directly treated with the Lawesson reagent (10.3 g, 25.6 mmol) in refluxing toluene (40 ml) for 2 h. Upon cooling to 0 C, the thioamide precipitated as a brown solid. The toluene was decanted and the thioamide was treated with ethyl bromopyruvate (10.0 g, 51.1 mmol) in refluxing ethanol (40 ml) for 2 hours. The cooled reaction mixture was evaporated and the residue was suspended in

4 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 4 EtAc (10 ml). eutralization with aq sat ahc 3 sol (40 ml) caused the precipitation of a white solid, which was filtered and washed with small amounts of cold hexane to give 11 (10.6g, 80% over 3 steps), white solid, m.p C. 1 H (CDCl 3 ): 8.17 (s, 1H), 8.01 (s, 1H), 4.45 (q, 2H, J = 7.14), 2.78 (s, 3H), 1.43 (t, 3H, J = 7.14). 13 C (CDCl 3 ): 166.8, 163.4, 161.5, 148.0, 147.9, 127.6, 117.0, 61.5, 19.2, EIM: [M+1] +, 277.1[M+a] +. HRM: calc for C 10 H a [M+a] , found Alkynone 22. A solution of benzaldehyde (1.0 g, 9.2 mmol) in THF (3mL) was added dropwise to a commercial 0.5 M solution of ethynylmagnesium bromide (28.3 ml, 14.1 mmol) in THF at rt. The mixture was stirred for 10 min at 0 C, then it was quenched with aq sat H 4 Cl sol (10 ml). The organic layer were separated and the aqueous phase was extracted with EtAc (2 x 10 ml). The combined extracts were evaporated to give the propargyl alcohol as yellowish oil. Without purification, this material was added to a solution of IBX (5.3 g, 18.8 mmol) in DM and the solution was heated to 35 C for 12 h. The cooled reaction mixture was diluted with EtAc (20 ml) and water (30 ml) and stirred vigorously for 10 min, then it was filtered over celite. The organic layer was separated and the aqueous phase was extracted with ether (3 x 20 ml). The combined extracts were sequentially washed with aq sat ahc 3 (20 ml) and acl (20 ml) solutions, dried (a 2 4 ) and concentrated to give 22 (1.2 g, 95% over 2 steps), white solid, m.p.: C (lit C). 1 H (CDCl 3 ): 8.16 (m, 2H), 7.65 (m, 1H), 7.51 (m, 2H), 3.44 (s, 1H). 13 C (CDCl 3 ): 177.4, 136.1, 134.5, 129.7, 128.7, 80.7, EIM: [M + H] +, 153.0[M +a] +. Pyridine 23. A solution of ethyl acetoacetate (229 µl, 1.8 mmol), alkynone 22 (234 mg, 1.8 mmol), and H 4 Ac (208 mg, 2.7 mmol) in AcH (5 ml) was refluxed for 12 h, then it was cooled to rt and evaporated. The residue was treated with aq sat ahc 3 sol (10 ml) and 1 Um, I-H.; Lee, E.-J; eok, J.-A.; Kim, K.-H. J. rg. Chem. 2005, 70, 7530.

5 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 5 extracted with EtAc (2 x 20 ml). The combined extracts were dried (a 2 4 ) and evaporated and the residue was purified by chromatography (10% EtAc/ hexanes) to give 23 (369 mg, 85%), white solid, m.p C (lit C). 1 H (CDCl 3 ): 8.28 (d, 1H, J = 8.3), (m, 2H), 7.64 (d, 1H, J = 8.3), (m, 3H), 4.41 (q, 2H, J = 7.1), 2.92 (s, 3H), 1.43 (t, 3H, J = 7.1). 13 C (CDCl 3 ): 166.5, 159.1, 158.9, 139.3, 138.4, 129.6, 128.8, , 123.6, 117.3, 61.1, 25.3, M: [M+H] +. HRM: calc for C 15 H 16 2 [M+H] +, , found Pyridines 24 and 25. A solution of 1,3-cyclohexanedione (276 mg, 2.5 mmol), alkynone 22 (321 mg, 2.5 mmol), and H 4 Ac (285 mg, 3.7 mmol) in AcH (7 ml) was refluxed for 8 hours, then it was cooled to rt and evaporated. The residue was neutralized with aq sat ahc 3 sol (10 ml) and extracted with EtAc (2 x 20 ml). The combined extracts were dried (a 2 4 ) and evaporated and the residue was purified by chromatography (10% EtAc/hexanes) to give 24 (341 mg, 62%), white solid, m.p C (lit C) and 25 (139 mg, 22 %), pale yellow solid, m.p C (lit C). Pyridine H (CDCl 3 ): 8.34 (d, 1H, J = 8.2), (m, 2H), 7.72 (d, 1H, J = 8.2), (m, 3H), 3.23 (t, 2H, J = 6.3), 2.73 (t, 2H, J = 6.3), 2.24 (p, 2H, J = 6.3). 13 C (CDCl 3 ): 197.9, 163.8, 160.8, 138.4, 135.8, 130.0, 128.9, 127.5, 126.5, 119.0, 38.6, 32.9, EIM: 224.3[M+1] +. HRM: calc for C 15 H [M+H] +, found Pyridine H (CDCl 3 ): 9.08 (dd, 1H, J = 2.4, 0.6), 8.22 (dd, 1H, J = 8.3, 2.2), 8.15 (m, 2H), 7.88 (m, 3H), 7.65 (tt, 1H, J = 7.41, 2.31), 7.54 (m, 5H). 13 C (CDCl 3 ): 194.7, 160.4, 151.2, 138.2, 137.0, 133.0, 131.2, , , 129.0, 128.6, 127.4, EIM [M+1] +. HRM calc for C 18 H 14 [M+H] +, found Bagley, M. C.; Jenkins, R. L.; Lubinu, M. C.; Mason, C.; Wood, R. J. rg. Chem. 2005, 70, chroeder, E.; Lehmann, M.; Boettcher, I. Eur. J. Med. Chem. 1979, 14, Benary, E.; Psille, H. Ber. Deut. Chem. Ges. B 1924, 57B, 828.

6 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 6 B. HPLC Traces of Pyridines 18 and 19. Column: Agilent ZRBAX Bonus-RP, 3.5 µm, 4.6 mm x 150 mm olvent: A = MeH, B = H 2, 50 mmol (H 4 ) 4, ph = 5.5 Detection: UV, 254 nm Time (min) Flow (ml/min) %A %B Gradient: Pyridine Ac U A H H H 18 CEt Minutes Pyridine Ac U A H H H 19 CEt Minutes

7 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 7 D. 1 H and 13 C MR pectra. Aldehyde 7 HC 7 CEt

8 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 8 4-Carbethoxythiazole (8) 8 CEt

9 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 9 Bithiazole CEt

10 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 10 Aldehyde 12 HC 12 CEt

11 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 11 Compound CEt

12 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 12 Compound 15 H 15 CEt

13 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 13 Compound CEt

14 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 14 Compound 18 Ac H 18 Et

15 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 15 Compound 19 Ac H 19 Et

16 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 16 Compound 22 22

17 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 17 Compound 23 Et 23

18 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 18 Compound 24 24

19 Aulakh, V..; Ciufolini, M.A. Pyridine Cores of Thiopeptide 19 Compound 25 25