Convergent Synthesis of the Central Heterocyclic Domain of Micrococcin P1

Abstract

The heterocyclic domain of micrococcin P1 has been prepared from N-Boc-(2S,3R)-threonine in 15 steps and 9% overall yield utilising a microwave-assisted enamine formation in mono- or multimode instruments, Bohlmann-Rahtz pyridine synthesis to form the 2,3,6-trisubstituted pyridine motif, and two-directional elaboration of the 3- and 6-thiazole substituents.

Key words

micrococcin - thiopeptide antibiotics - pyridines - thi­azoles - Bohlmann-Rahtz

References and Notes

• 1 Bagley MC. Dale JW. Merritt EA. Xiong X. Chem. Rev.  2005,  105:  685 
• 2a Nicolaou KC. Safina BS. Zak M. Lee SH. Nevalainen M. Bella M. Estrada AA. Funke C. Zécri FJ. Bulat S. J. Am. Chem. Soc.  2005,  127:  11159 
• 2b Nicolaou KC. Zak M. Safina BS. Estrada AA. Lee SH. Nevalainen M. J. Am. Chem. Soc.  2005,  127:  11176 
• 3 Su TL. Brit. J. Exp. Path.  1948,  29:  473 
• 4 Fuller AT. Nature (London)  1955,  175:  722 
• 5 Heatley NG. Doery HM. Biochem. J.  1951,  50:  247 
• 6a Dean BM. Mijović MPV. Walker J. J. Chem. Soc.  1961,  3394 
• 6b Walker J. Olesker A. Valente L. Rabanal R. Lukacs G. J. Chem. Soc., Chem. Commun.  1977,  706 
• 6c Bycroft BW. Gowland MS. J. Chem. Soc., Chem. Commun.  1978,  256 
• 6d Ciufolini MA. Shen Y.-C. Org. Lett.  1999,  1:  1843 
• 6e Okumura K. Ito A. Yoshioka D. Shin C.-G. Heterocycles  1998,  48:  1319 
• 6f Fenet B. Pierre F. Cundliffe E. Ciufolini MA. Tetrahedron Lett.  2002,  43:  2367 
• 6g Bagley MC. Merritt EA. J. Antibiot.  2004,  57:  829 
• 7a Bohlmann F. Rahtz D. Chem. Ber.  1957,  90:  2265 
• 7b Bagley MC. Brace C. Dale JW. Ohnesorge M. Phillips NG. Xiong X. Bower J. J. Chem. Soc., Perkin Trans. 1  2002,  1663 
• 8 Bagley MC. Glover C. Chevis D. Synlett  2005,  649 
• 9 Bagley MC. Chapaneri KC. Glover C. Merritt EA. Synlett  2004,  2615 

10

The enol tautomer of 8 accounts for 22% of the material by ¹H NMR integration in CDCl₃.

11

tert -Butyl 4-{4-[2-(ethoxycarbonyl)-1-aminovinyl]thi-azol-2-yl}-2,2,5-trimethyloxazolidine-3-carboxylate (4) β-Ketoester 8 (100 mg, 0.24 mmol) was dissolved in toluene-AcOH (5:1, 3 mL) and NH₄OAc (2.24 g, 29.09 mmol, 120 equiv) was added. The mixture was irradiated in a sealed tube at 150 °C with continuous cooling for 10 min using a CEM Discover^® single-mode microwave synthesiser (initial power 300 W). The mixture was cooled to r.t., evaporated in vacuo and partitioned between H₂O (20 mL) and EtOAc (10 mL). The aqueous layer was further extracted with EtOAc (2 × 10 mL) and the combined organic extracts were washed sequentially with sat. aq NaHCO₃ (15 mL) and brine (15 mL), dried (Na₂SO₄) and evaporated in vacuo. Purification by column chromatography on silica, eluting with PE-EtOAc (3:1) gave the title compound 4 ¹² as a viscous yellow oil.
Methyl 2-(propynoyl)thiazole-4-carboxylate (5)
To a stirred solution of methyl 2-[1-(1-hydroxyprop-2-ynyl)]thiazole-4-carboxylate (882 mg, 4.47 mmol) in CH₂Cl₂ (50 mL), activated manganese(IV) oxide (1.94 g, 22.36 mmol, 5 equiv) was added and the mixture was stirred at r.t. for 30 min. A further portion of activated manga-nese(IV) oxide (1.94 g, 22.36 mmol, 5 equiv) was added and the solution was stirred at r.t. for 2 h, and then filtered through a pad of Celite^®. The pad was washed with CH₂Cl₂ (25 mL) and the filtrate was evaporated under a stream of nitrogen. The residue (672 mg, 77%) was used immediately without further purification. Purification by recrystallisation afforded the title compound 5 ¹³ as a yellow solid.
MP1 domain (3)
Bisthioamide 13 (140 mg, 0.24 mmol) was dissolved in anhyd DME (20 mL) and anhyd KHCO₃ (389 mg, 3.88 mmol, 16 equiv) was added. Ethyl bromopyruvate (0.183 mL, 284 mg, 1.46 mmol, 6 equiv) was added and the mixture was stirred at r.t. for 36 h. The solvent was removed in vacuo and the residue was partitioned between H₂O (50 mL) and Et₂O (50 mL). The organic extract was dried (MgSO₄) and evaporated in vacuo, and the residue was dissolved in anhyd DME (20 mL). The solution was cooled to 0 °C and pyridine (0.353 mL, 346 mg, 4.37 mmol, 18 equiv) and TFAA (0.275 mL, 408 mg, 1.94 mmol, 8 equiv) were added slowly and sequentially. The solution was stirred at 0 °C for 3 h, allowed to warm to r.t. and Et₃N (0.135 mL, 98 mg, 0.97 mmol, 4 equiv) was added. The solution was stirred at r.t. for 3 h, and then evaporated in vacuo. Purification of the residue by column chromatography on silica eluting with 5% MeOH in CHCl₃ afforded the title compound 3 ¹⁴ as a yellow solid.

12

tert -Butyl 4-{4-[2-(ethoxycarbonyl)-1-aminovinyl]thi-azol-2-yl}-2,2,5-trimethyloxazolidine-3-carboxylate (4) R _f 0.34 (PE-EtOAc, 3:1). HRMS: m/z [MH⁺] calcd for C₁₉H₃₀N₃O₅S: 412.1901; found: 412.1899. IR (film): 3488, 3407, 3146, 2975, 1694, 1478, 1368, 1258, 1217, 1167, 1132, 1087 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.54 (br s, 1 H, thz), 6.60-7.10 (br s, 1 H, NH), 5.12 (br s, 1 H, Thr-α), 4.68 (br s, 0.4 H, Thr-β), 4.57 (br d, J = 6.2 Hz, 0.6 H, Thr-β), 4.14 (s, 1 H, C=CH), 4.12 (q, J = 7.0 Hz, 2 H, OCH ₂CH₃), 1.64 (br s, 7 H), 1.40 (br s, 3 H), 1.34 (br d, J = 6.2 Hz, 3 H, Thr-Me), 1.24 (t, J = 7.0 Hz, 3 H, OCH₂CH ₃), 1.10 (br s, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 171.9 (C), 170.4 (C), 151.8 (C), 151.2 (C), 150.6 (C), 124.9 (CH), 116.9 (CH), 95.2 (C), 81.4 (CH), 80.6 (C), 65.9 (CH), 58.9 (CH₂), 28.1 (CH₃), 26.5 (CH₃), 25.5 (CH₃), 17.7 (CH₃), 14.6 (CH₃). MS (APCI): m/z (%) = 412 (7) [M + H⁺], 356 (17), 312 (30), 241 (30), 227 (23), 183 (15), 134 (100).

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Methyl 2-(propynoyl)thiazole-4-carboxylate (5)
mp 152 °C (dec.) (CHCl₃); R _f 0.47 (PE-EtOAc, 1:1). HRMS: m/z [MH⁺] calcd for C₈H₆NO₃S: 196.0068; found: 196.0059. IR (CH₂Cl₂): 3209, 3128, 2360, 1742, 1641, 1480, 1461, 1427, 1341, 1265, 1240, 1109, 993, 960, 911, 827 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 8.46 (s, 1 H, 5-H), 3.93 (s, 3 H, CO₂Me), 3.66 (s, 1 H, 3′-H). ¹³C NMR (125 MHz, CDCl₃): δ = 169.01 (C), 166.16 (C), 161.06 (C), 149.18 (C), 133.81 (CH), 84.93 (CH), 78.94 (C), 52.84 (CH₃). MS (ES+): m/z (%) = 196 (100) [M + H⁺], 156 (15), 135 (3).

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MP1 domain (3)
R _f 0.69 (5% MeOH in CHCl₃). HRMS: m/z [MH⁺] calcd for C₃₄H₃₇N₆O₇S₄: 769.1601; found: 769.1604. IR (CH₂Cl₂): 3438, 2966, 2915, 1734, 1700, 1579, 1464, 1438, 1363, 1298, 1258, 1091, 1022 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.25 (s, 1 H, thz), 8.24 (app. br s, 1 H, py-4), 8.20 (s, 1 H, thz), 8.17 (s, 1 H, thz), 7.95 (app. br s, 1 H, py-5), 6.91 (s, 1 H, thz), 4.95 (s, 0.6 H, Thr-α), 4.83 (d, J = 11.0 Hz, 0.4 H, Thr-α), 4.39 (q, J = 7.0 Hz, 2 H, OCH ₂CH₃), 4.36 (q, J = 7.0 Hz, 2 H, OCH ₂CH₃), 4.35 (br s, 1 H, Thr-β), 1.61 (br s, 3 H), 1.51 (br s, 6 H), 1.45 (br s, 3 H), 1.38 (t, J = 7.0 Hz, 3 H, OCH₂CH ₃), 1.31 (t, J = 7.0 Hz, 3 H, OCH₂CH ₃), 1.18 (br s, 6 H). MS (ES+): m/z (%) = 786 (45) [M + Na⁺], 769 (100) [M + H⁺], 656 (8), 639 (8), 224 (8), 141 (8).