Synthesis of Ansa-Bridged Macrocyclic Lactams Related to the Antitumor Antibiotic Geldanamycin by Ring Closing Metathesis

Abstract

The α,β,γ,δ-unsaturated 2,4,5-trimethoxyanilides 8a-e which bear a terminal alkenyl side chain at the 3-position were prepared from 1,2,4-trimethoxybenzene (2) in four steps and 25-41% overall yield. Attempted ring closing metathesis reactions were successful in the presence of catalysts 9 for the substrates 8c-e and led to the products 10c-e (66-91% yield). Substrates 8a and 8b with a shorter alkenyl side chain did not cyclize.

Key words

arenes - antitumor agents - macrocycles - metathesis - ring closure

References

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19

Representative procedure for the ring closing metathesis 8 → 10: A solution of anilide (8d, 50 mg, 113 µmol) in 5 mL of dichloromethane was slowly added to a refluxing solution of Grubbs’s catalyst (9a, 8.6 mg, 11.3 µmol) in 220 mL of dichloromethane. After 36 h at reflux, the reaction mixture was cooled and the solvent was removed in vacuo. The residue was purified by flash chromatography (pentane/EtOAc = 9:1). Compound 10d (36 mg, 87 µmol, 77%) was obtained as a colorless liquid. ¹H NMR (360 MHz, CDCl₃): δ = 1.10-1.47 (m, 2 H), 1.65-1.68 (m, 2 H), 2.04 (d, J = 0.7 Hz, 3 H), 2.21 (virt. q, J ≅ 8.0 Hz, 2 H), 2.70 (t, J = 6.5 Hz, 2 H), 3.67 (s, 3 H), 3.81 (s, 3 H), 3.87 (s, 3 H), 5.96 (virt. q, J ≅ 9.1 Hz, 1 H), 6.32 (virt. t, J ≅ 10.9 Hz, 1 H), 6.99 (d, J = 11.3 Hz, 1 H), 7.95 (s, 1 H), 8.23 (s br, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 12.6, 22.4, 27.2, 27.4, 28.1, 28.5, 28.6, 28.8, 29.4, 29.6, 29.7, 55.9, 60.9, 61.3, 101.4, 124.1, 126.7, 127.6, 128.8, 133.5, 137.9, 141.2, 143.3, 149.4, 168.4.