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).

Key words

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

References

• 1a Tsurumi Y. Ueda H. Hayashi K. Takase S. Nishikawa M. Kiyoto S. Okuhara M. J. Antibiot.  1995,  48:  1066 
• 1b Yoshimura S. Tsurumi Y. Takase S. Okuhara M. J. Antibiot.  1995,  48:  1073 
• 2 Patt WC. Massa MA. Tetrahedron Lett.  1997,  38:  1297 
• 3 Huang ST. Gordon DM. Tetrahedron Lett.  1998,  39:  9335 
• 4 Synthesis of analogues: Patt WC. Massa MA. Ahn K. Sisneros AM. Doherty A. Bioorg. Med. Chem. Lett.  1998,  8:  2117 
• 5 Synthesis of the structurally related antibiotic karnamicin B₁: Umemura K. Watanabe K. Ono K. Yamaura M. Yoshimura J. Tetrahedron Lett.  1997,  38:  4811 
• 6a Bach T. Krüger L. Tetrahedron Lett.  1998,  39:  1729 
• 6b Bach T. Krüger L. Synlett  1998,  1185 
• 6c Bach T. Krüger L. Eur. J. Org. Chem.  1999,  2045 
• 7 Bach T. Bartels M. Synlett  2001,  1284 
• 8 Bach T. Heuser S. Tetrahedron Lett.  2000,  41:  1707 
• 9 Bach T. Heuser S. J. Org. Chem.  2002,  67:  5789 
• 10a Bach T. Heuser S. Angew. Chem. Int. Ed.  2001,  40:  3184 
• 10b

  Bach, T.; Heuser, S. Chem.-Eur. J., 2002, 6, in press.

• Selected references on regioselective cross-coupling reactions of five-membered heterocycles:
• 11a Minato A. Tamao K. Hayashi T. Suzuki K. Kumada M. Tetrahedron Lett.  1980,  21:  845 
• 11b Minato A. Tamao K. Suzuki K. Kumada M. Tetrahedron Lett.  1980,  21:  4017 
• 11c Karlsson JO. Gronowitz S. Fried T. J. Org. Chem.  1982,  47:  845 
• 11d Minato K. Suzuki A. Tamao K. Kumada M. J. Chem. Soc., Chem. Commun.  1984,  511 
• 11e Carpita A. Rossi R. Gazz. Chim. Ital.  1985,  115:  575 
• 11f Gronowitz S. Svensson A. Isr. J. Chem.  1986,  27:  25 
• 11g Kaswasaki I. Yamashita M. Ohta S. J. Chem. Soc., Chem. Commun.  1994,  2085 
• 11h Wang D. Haseltine J. J. Heterocycl. Chem.  1994,  31:  1637 
• 11i Bussenius J. Laber N. Müller T. Eberbach W. Chem. Ber.  1994,  127:  247 
• 11j Pereira R. Iglesias B. de Lera AR. Tetrahedron  2001,  57:  7871 
• 11k Bellina F. Anselmi C. Viel S. Mannina L. Rossi R. Tetrahedron  2001,  57:  9997 
• For general references on cross-coupling reactions of heterocycles, see:
• 12a Li JJ. Gribble GW. Palladium in Heterocyclic Chemistry   Pergamon Press; Oxford: 2000. 
• 12b Brandsma L. Vasilevsky SF. Verkruijsse HD. Application of Transition Metal Catalysts in Organic Synthesis   Springer; Berlin: 1999. 
• 12c Diederich F. Stang PJ. Metal-Catalyzed Cross-coupling Reactions   Wiley-VCH; Weinheim: 1998. 
• 13 Reynaud P. Robba M. Moreau RC. Bull. Soc. Chim. Fr.  1962,  1735 
• For regioselective Suzuki and Sonogashira cross-coupling reactions on substrate 2, see:
• 14a Wellmar U. Gronowitz S. Hörnfeldt A.-B. J. Heterocycl. Chem.  1995,  32:  1159 
• 14b Nicolaou KC. He Y. Roschangar F. King NP. Vourloumis D. Li T. Angew. Chem. Int. Ed.  1998,  37:  84 
• 14c Nicolaou KC. King NP. Finlay RV. He Y. Roschangar F. Vourloumis D. Vahlberg H. Sarabia F. Ninkovic S. Hepworth D. Bioorg. Med. Chem.  1999,  7:  665 
• 14d See also: Langille NF. Dakin LA. Panek JS. Org. Lett.  2002,  4:  2485 
• 15 Koch V. Schnatterer S. Synthesis  1990,  497 
• 16 Compound 7 was obtained from methyl 5-bromopentanoate in 95% yield: Larsen SD. Spilman CH. Yagi Y. Dinh DM. Hart KL. Hess GF. J. Med. Chem.  1994,  37:  2343 
• 17 Negishi E. Swanson DR. Rousset CJ. J. Org. Chem.  1990,  55:  5406 
• 19 The methods we tried included Pd(0)-catalyzed cross-coupling reactions with bis(pinacolato)diboron or hexamethyldistannane, halogen-metal exchange reactions and reductive metalations. For a review on this topic, see: Mongin F. Quéginer G. Tetrahedron  2001,  57:  4059 
• 20 Kelly TR. Lang F. J. Org. Chem.  1996,  61:  4623 
• 22 Nicolaou KC. Webber SE. Synthesis  1986,  453 

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.

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.