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Synlett 2002(12): 2089-2091
DOI: 10.1055/s-2002-35568
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of the Naturally Occurring Endothelin Converting Enzyme (ECE) Inhibitor WS 75624 A

Thorsten Bach*, Stefan Heuser
Lehrstuhl für Organische Chemie I, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
Fax: +49(892)8913315; e-Mail: thorsten.bach@ch.tum.de;
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Publication History

Received 20 August 2002
Publication Date:
20 November 2002 (online)

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Abstract

The ECE inhibitor WS 75624 A (1a) was synthesized following a convergent strategy. 2,4-Dibromothiazole (2) served as the central building block, which underwent consecutive cross-coupling reactions. In the first C-C bond formation step, it was substituted at carbon atom C-2 by a C7-alkylzinc chloride derived from iodide 8 (85% yield). In the second step, the intermediate 4-bromothiazole 9 was converted to the corresponding stannane 10 which was coupled at carbon atom C-4 to the 2-iodopyridine 6 (75% yield).

Key words

cross-coupling - heterocycles - palladium - pyridines - total synthesis

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A 1.5 M solution of t-BuLi (2.30 mL, 3.45 mmol) in pentane was slowly added to a cooled (-78 °C) solution of the primary alkyl iodide 8 (575 mg, 1.62 mmol) in diethyl ether (4 mL). After 1 h at -78 °C, a 1.0 M solution of zinc chloride (2.50 mL, 2.50 mmol) in THF was added and the resulting solution was stirred for 30 min at r.t. This solution was added to a mixture of 2,4-dibromothiazole (2, 157 mg, 0.65 mmol), Pd2(dba)3 (15.0 mg, 33 µmol) and dppf (18.0 mg, 33 µmol) in THF (5 mL). After stirring at r.t. for 16 h the reaction was quenched by addition of a saturated NH4Cl solution (3 mL). The aqueous layer was extracted with diethyl ether (3 × 20 mL). The combined organic layers were washed with a saturated NaCl solution (20 mL) and dried over Na2SO4. After filtration and removal of the solvent in vacuo the residue was purified by flash chromatography (pentane-diethyl ether = 95:5). Compound 9 (215 mg, 54.8 µmol, 85%) was obtained as an orange oil. 1H NMR (360 MHz, CDCl3) δ = 0.53 (q, 3 J = 7.9 Hz, 6 H), 0.93 (t, 3 J = 7.9 Hz, 9 H), 1.17 (s, 6 H), 1.42-1.46 (m, 4 H), 1.70-1.83 (m, 2 H), 2.99 (t, 3 J = 7.7 Hz, 2 H), 7.05 (s, 1 H, CHar). 13C NMR (90 MHz, CDCl3) δ = 6.8, 7.1, 23.8, 29.9, 30.4, 33.7, 44.6, 73.2, 115.6, 124.2, 172.7.

21

A 1.5 M solution of t-BuLi (1.80 mL, 2.70 mmol) in pentane was slowly added to a cooled (-78 °C) solution of the 4-bromothiazole 9 (511 mg, 1.30 mmol) in diethyl ether (10 mL). After 10 min at -78 °C, a 1.0 M solution of chlorotrimethyltin (2.60 mL, 2.60 mmol) in THF was added and the resulting mixture was stirred for 2 h at r.t. Subsequently, diethyl ether (20 mL) and water (5 mL) were added. The organic layer was dried over Na2SO4. After removal of the solvent in vacuo crude stannane 10 (620 mg, 1.30 mmol, quant.) was obtained as an yellow oil. The stannane (90.0 mg, 186 µmol) was added to a solution of iodopyridine 6 (60.0 mg, 186 µmol) and PdCl2(PPh3)2 (6.5 mg, 9.3 µmol) in dioxane (25 mL). After stirring at reflux for 24 h the solvent was removed in vacuo and the residue was purified by flash chromatography (pentane-EtOAc-triethylamine = 80:20:5). Compound 11 (71.0 mg, 140 µmol, 75%) was obtained as a yellow oil. 1H NMR (360 MHz, CDCl3) δ = 0.53 (q, 3 J = 7.9 Hz, 6 H), 0.91 (t, 3 J = 7.9 Hz, 9 H), 1.17 (s, 6 H), 1.42-1.52 (m, 4 H), 1.76-1.88 (m, 2 H), 3.10 (t, 3 J = 7.8 Hz, 2 H), 3.87 (s, 3 H), 3.95 (s, 3 H), 4.00 (s, 3 H), 7.71 (s, 1 H), 7.89 (s, 1 H). 13C NMR (90 MHz, CDCl3) δ = 6.5, 7.0, 24.0, 29.7, 30.4, 33.6, 44.5, 52.7, 56.1, 60.4, 73.0, 108.3, 120.1, 143.9, 145.8, 146.0, 149.8, 159.4, 165.5, 170.9.