Highly convergent total synthesis of (+)-lithospermic acid via a late-stage intermolecular C-H olefination

Abstract

The total synthesis of (+)-lithospermic acid is reported, which exploits two successive C-H activation reactions as key steps. Rh-catalyzed carbene C-H insertion reaction utilizing Davies's catalyst was used to forge dihydrobenzofuran core, and a late-stage intermolecular C-H olefination coupled the olefin unit with the dihydrobenzofuran core to construct the molecule in a highly convergent manner.

Figure 1

(+)-Lithospermic Acid (1)

Figure 2

Retrosynthesis of (+)-Lithospermic Acid

Scheme 1

Synthesis of Dihydrobenzofuran Carboxylic Acid 4^{a a} Reagents and conditions: (a) pyrrolidinyl (S)-lactamide (1.2 equiv), PPh₃ (1.2 equiv), DEAD (1.2 equiv), toluene, 0 to 23 °C, 2 h; (b) H₂ (balloon), Pd/C (5 mol%), MeOH, 23 °C, 12 h; (c) 3,4-dimethoxybenzyl bromide (1.45 equiv), K₂CO₃ (2 equiv), THF (2 equiv), 80 °C, over night, 71% over three steps; (d) p-ABSA (2 equiv), DBU (2 equiv), MeCN, 0 to 23 °C, 24 h, 82%; (e) Rh₂(S-DOSP)₄ (0.5 mol%), CH₂Cl₂, 23 °C, 2 h, 85%, dr 8:1; (f) Ba(OH)₂·8H₂O (1.1 equiv), THF/MeOH (1:1), 0 to 23 °C, 4 h, 86%.

Scheme 2

Synthesis of Acrylate 3^{a a} Reagents and conditions: (a) Me₂SO₄ (10 equiv), K₂CO₃ (10 equiv), acetone, reflux, 10 h, 97%; (b) NaOMe (1 equiv), MeOH, 23 °C, 2 h, 88%; (c) acrylic acid (1.5 equiv), EDC-HCl (2 equiv), DMAP (2 equiv), CH₂Cl₂, 0 to 23 °C, 91%.

Scheme 3

Completion of the Synthesis of (+)-Lithospermic Acid^{a a} Reagents and conditions: (a) Me₃SnOH (3 equiv), 1,2-dichloroethane, 80 °C, 24 h, 91%; (b) 1-trimethylsilylquinolinium iodide (40 equiv), neat, 130 °C, 3 h, 31%; (c) CH₂N₂, Et₂O, 0 °C, 10 min, 96%.