Synlett 2020; 31(01): 69-72
DOI: 10.1055/s-0039-1691503
letter
© Georg Thieme Verlag Stuttgart · New York

First Total Synthesis of Jomthonic Acid A[1]

Mohan Dumpala
,
Batthula Srinivas
,
D-211, Discovery Laboratory, Organic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India   Email: prkgenius@iict.res.in
› Author Affiliations
Further Information

Publication History

Received: 14 October 2019

Accepted after revision: 07 November 2019

Publication Date:
29 November 2019 (online)


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.

Supporting Information

 
  • References and Notes

  • 1 Communication No. IICT/Pubs./2019/237.
    • 2a Igarashi Y, Yu L, Ikeda M, Oikawa T, Kitani S, Nihira T, Bayanmunkh B, Panbangred W. J. Nat. Prod. 2012; 75: 986
    • 2b García-Salcedo R, Álvarez-Álvarez R, Olano C, Cañedo L, Braña AF, Méndez C, De la Calle F, Salas JA. Mar. Drugs 2018; 16: 259
    • 2c Yu L, Oikawa T, Kitani S, Nihira T, Bayanmunkh B, Panbangred W, Igarashi Y. J. Antibiot. 2014; 67: 345
  • 3 Bérdy J. J. Antibiot. 2012; 65: 385
  • 4 Markworth CJ, Marron BE, Swain NA. WO 2010035166, 2010
  • 5 Dhimitruka I, SantaLucia J. Org. Lett. 2006; 8: 47
  • 6 Fráter G, Müller U, Günther W. Tetrahedron 1984; 40: 1269
    • 7a Radha Krishna P, Arun Kumar PV, Mallula VS, Ramakrishna KV. S. Tetrahedron 2013; 69: 2319
    • 7b Simmons B, Walji AM, MacMillan DW. C. Angew. Chem. Int. Ed. 2009; 48: 4349
  • 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]+.
  • 11 Zhao M, Li J, Song Z, Desmond R, Tschaen DM, Grabowski EJ. J, Reider PJ. Tetrahedron Lett. 1998; 39: 5323
    • 12a Micoine K, Fürstner A. J. Am. Chem. Soc. 2010; 132: 14064
    • 12b AnkiReddy S, AnkiReddy P, Sabitha G. Synthesis 2015; 47: 2860
    • 12c Gallenkamp D, Fürstner A. J. Am. Chem. Soc. 2011; 133: 9232
  • 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.