First Total Synthesis of Jomthonic Acid A^[1]

Abstract

A stereoselective total synthesis of jomthonic acid A is described. The key features of the synthetic strategy are a Sharpless asymmetric epoxidation, a Gilmann reagent-induced methylation, a Mitsunobu reaction, a Yamaguchi esterification, and an O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)-mediated amide coupling. Jomthonic acid A is an architecturally rare amino acid containing a β-methylphenylalanine residue and a 4-methyl-(2E,4E)-hexa-2,4-dienoate moiety. It shows antidiabetic and antiatherogenic activities when tested against mouse ST-13 preadiopocytes.

Key words

Gilmann reaction - Mitsunobu reaction - Yamaguchi esterification - amide coupling - total synthesis - jomthonic acid A

• References and Notes

• 1 Communication No. IICT/Pubs./2019/237.
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• 9 {[(2S,3R)-2-Azido-3-phenylbutyl]oxy}(tert-butyl)dimethyl­silane (12)To a solution of compound 11 (1.7 g, 6.0 mmol) in THF (20 mL) at 0 °C were added DIAD (2.39 mL, 12.1 mmol) and TPP (3.1 g, 12.1 mmol), and the mixture was stirred for 5 min. DPPA (2.61 g, 9.5 mmol) was added at 0 °C, and the mixture was allowed to warm to rt, stirred for 3 h, then warmed to 35 °C for 24 h. The mixture was then concentrated and purified by flash column chromatography [silica gel, EtOAc–hexane (8:92)] to give a pale-yellow oil; yield: 1.48 g (80%).¹H NMR (400 MHz, CDCl₃): δ = 7.33–7.26 (m, 2 H), 7.24–7.16 (m, 3 H), 3.60 (dd, J = 10.4, 3.1 Hz, 1 H), 3.4–3.40 (m, 1 H), 3.39–3.33 (m, 1 H), 2.91 (dq, J = 14.1, 7.0 Hz, 1 H). 1.35 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), –0.02 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.5, 128.6, 127.55, 126.5, 69.2, 64.9, 40.3, 25.8, 18.4, 18.2, –5.6. EI-ESI: m/z = 323 [M + NH₄]⁺.
• 10 (2S,3R)-2-Azido-3-phenylbutan-1-ol (13)A 1.0 M solution of TBAF in THF (1.54 g, 8.85 mL, 5.9 mmol) was added to a solution of compound 12 (1.2 g, 3.9 mmol) in anhyd THF (10 mL) at 0 °C, and the mixture was stirred at rt for 2 h. When the reaction was complete, the mixture was diluted with H₂O (5 mL), and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried (Na₂SO₄). Filtration, and evaporation of the solvent under reduced pressure, followed by column chromatography [silica gel, EtOAc–hexane (20:80)] gave a colorless liquid; yield: 0.676 g (90%); [α]_D ²⁵ –9.1 (c 0.7, CHCl₃).¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.30 (m, 2 H), 7.27–7.19 (m, 3 H), 3.60–3.50 (m, 2 H), 3.46–3.37 (m, 1 H), 2.94–2.83 (m, 1 H), 1.40 (d, J = 6.9 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 142.8, 128.7, 127.3, 127.0, 70.3, 64.0, 41.4, 18.4. EI-ESI: m/z = 209 [M + NH₄]⁺.
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• 13 (1R,2S)-3-{[tert-Butyl(diphenyl)silyl]oxy}-1,2-dimethyl­propyl (2S,3R)-2-Azido-3-phenylbutanoate (15)To a stirred solution of azide 5 (0.200 g, 0.9 mmol), alcohol 6 (0.333 g, 0.9 mmol), and Et₃N (0.4 mL, 2.9 mmol) in THF (5 mL) was added 2,4,6-trichlorobenzoyl chloride (0.2 mL, 1.1 mmol) at rt, and the mixture was stirred for 2 h. DMAP (0.238 g, 1.6 mmol) was added at rt, and the mixture was stirred for 6 h. When the reaction was complete, the mixture was quenched with sat. aq NaHCO₃ and washed with brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel, EtOAc–hexane (20:80)] to give a colorless oil; yield: 0.349 g, (68%); [α]_D ²⁵ +22.0 (c 0.5, CHCl₃).¹H NMR (500 MHz, CDCl₃): δ = 7.67–7.62 (m, 4 H), 7.45–7.35 (m, 6 H), 7.25–7.17 (m, 5 H), 5.02–4.95 (m, 1 H), 3.80 (dd, J = 7.2, 14.9 Hz, 1 H), 3.56–3.40 (m, 2 H), 3.28–3.20 (m, 1 H), 1.93–1.74 (m, 1 H), 1.34 (d, J = 7.0 Hz, 3 H), 1.05 (d, J = 5.1 Hz, 3 H), 1.04 (s, 9 H), 0.87 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.1, 141.4, 135.5, 129.6, 128.5, 127.7, 127.6, 127.2, 73.6, 67.6, 65.1, 41.7, 39.9, 26.8, 19.2, 17.0, 15.7, 12.3. HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₃₁H₄₃N₄O₃Si: 547.3104; found: 547.3104.
• 14 Matsumoto A, Sada K, Tashiro K, Miyata M, Tsubouchi T, Tanaka T, Odani T, Nagahama S, Tanaka T, Inoue K, Saragai S, Nakamoto S. Angew. Chem. Int. Ed. 2002; 41: 2502
• 15 (1R,2S)-3-Hydroxy-1,2-dimethylpropyl (βR)-β-Methyl-N-[(2E,4E)-4-methylhexa-2,4-dienoyl]-l-phenylalaninate (16)HF·pyridine (0.09 mL) was added dropwise to a stirred solution of 2 (0.070 g, 0.1 mmol) in anhyd CH₃CN (2 mL) at 0 °C, and the mixture was stirred for 12 h. The reaction was then quenched by adding sat. aq NaHCO₃ (1 mL) and the mixture was extracted with EtOAc (3 × 5 mL). The organic extracts were washed with brine (5 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica gel, EtOAc–hexane (25:75)] to give a pale-yellow liquid; yield: 0.030 g (85%); [α]_D ²⁵ +20.33 (c 0.3, CHCl₃).¹H NMR (500 MHz, CDCl₃): δ = 7.33–7.23 (m, 5 H), 7.23 (d, J = 7.0 Hz, 1 H), 5.95 (q, J = 7.0 Hz, 1 H), 6.15–6.10 (m, 1 H), 5.77 (d, J = 15.2 Hz, 1 H), 4.82–4.70 (m, 2 H), 3.54 (dd, J = 7.0, 11.4 Hz, 1 H), 3.40 (dd, J = 6.7, 11.4 Hz, 1 H), 3.26–3.20 (m, 1 H), 3.13 (dq, J = 7.4, 7.7 Hz, 1 H), 1.86–1.80 (m, 1 H), 1.80 (d, J = 7.0 Hz, 3 H), 1.76 (s, 3 H), 1.40 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3 H), 0.78 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.0, 166.7, 146.9, 141.2, 135.6, 133.3, 128.4, 127.9, 127.2, 116.6, 73.6, 64.2, 58.2, 43.0, 40.4, 18.1, 16.8, 14.4, 13.2, 11.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₃₂NO₄: 374.2331; found: 374.2328.