Download PDF
Synlett 2007(6): 0954-0958  
DOI: 10.1055/s-2007-973870
LETTER
© Georg Thieme Verlag Stuttgart · New York

Convergent Synthesis of the Central Heterocyclic Domain of Micrococcin P1

Eleanor A. Merritt, Mark C. Bagley*
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax: +44(29)20874030; e-Mail: Bagleymc@cf.ac.uk;
Further Information

Publication History

Received 9 January 2007
Publication Date:
26 March 2007 (online)

    Permissions and Reprints All articles of this category

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

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).

13

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).

14

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).