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

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).

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

References

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10b

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18

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, CH_ar). 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.

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20 Kelly TR. Lang F. J. Org. Chem.  1996,  61:  4623 

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.

22 Nicolaou KC. Webber SE. Synthesis  1986,  453