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

Actinomycetes are a major source of structurally diverse secondary metabolites that exhibit antagonism to Gram-positive bacteria. Igarashi and co-workers recently reported the isolation and characterization of the modified amino acid derivative jomthonic acid A (1; Figure [1]) from the culture broth of a soil-derived actinomycete of the genus Streptomyces sp. BB47.[2] Compound 1 contains four stereocenters and several unusual structural features, such as the 4-methyl-(2E,4E)-hexa-2,4-dienoate and β-methylphenylalanine fragments. Jomthonic acid A exhibits antidiabetic and antiatherogenic activities against mouse ST-13 preadiopocytes and it also inhibits the differentiation of preadipocytes into mature adipocytes at 2–50 μM.

Figure 1

In continuation of our interest in the total synthesis of bioactive natural products,[3] we have developed a convergent synthesis of jomthonic acid A (1). Our retrosynthetic analysis of 1 (Scheme [1]) suggested that it might be derived from the amido ester 2 through deprotection followed by oxidation. Compound 2 might be prepared from 4-methylhexa-2,4-dienoic acid (3) and amino ester 4 through amide coupling.[4] Compound 4 might be assembled from azide 5 and alcohol 6 under Yamaguchi conditions.[5] Compound 5 might, in turn, be obtained from trans-cinnamyl alcohol (7) by epoxidation, regioselective ring opening of the epoxide with the Gilmann reagent, and Mitsunobu reaction followed by oxidation. Likewise, alcohol 6 might be obtained by Frater–Seebach alkylation of ethyl (3R)-3-hydroxybutanoate.[6]

Scheme 1 Retrosynthetic analysis of jomthonic acid A (1)

Our synthetic approach began with commercially available trans-cinnamyl alcohol (7; Scheme [2]). This was converted into the chiral epoxy alcohol 9 in 87% yield by Sharpless asymmetric epoxidation. Regioselective ring opening of epoxide 9 with the Gilmann reagent gave diol 10 in 68% yield.[7] Next, selective protection of the primary hydroxy group of 1,2-diol 10 by TBDMSCl/imidazole/Bu₂SnO in ­CH₂Cl₂ at 0 °C for two hours gave silyl ether 11 in 93% yield. Subsequently, 11 was converted into the corresponding azide 12 in 85% yield under Mitsunobu conditions by using diphenyl phosphorazidate (DPPA) and DIAD in anhydrous THF at 0 °C to room temperature.[8] [9] Subsequent deprotection of silyl ether 12 with TBAF in THF afforded alcohol 13 (95% yield).[10] The purity of compound 13 was determined by LC/MS analysis, and the diastereomeric excess was found to be 98% (see Supporting Information). Compound 13, on further oxidation with TEMPO and PhI(OAc)₂ in CH₂Cl₂–H₂O (4:1) gave acid 5 in 93% yield.[11]

Scheme 2 Synthesis of fragment 5

In parallel, compound 6, required for the Yamaguchi esterification, was prepared from commercially available ethyl (3R)-3-hydroxybutanoate (8; Scheme [3]). Frater–Seebach alkylation of 8 gave 1,3-diol 14.[6] [12] Selective protection of the primary hydroxy group of this 1,3-diol with TBDPSCl/imidazole/Bu₂SnO in CH₂Cl₂ at 0 °C to room temperature gave silyl ether 6 in 93% yield.

Scheme 3 Synthesis of fragment 6

Having both coupling partners in hand, we performed a Yamaguchi esterification of acid 5 with silyl ether 6 to give the azide derivative 15 in 68% yield (Scheme [4]).[5] [13] Reduction of azide 15 with H₂ (1 atm) over Pd/C gave amine 4 in 90% yield. Compound 2 was obtained in 68% yield by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)-mediated coupling of amine 4 with acid 3, prepared from tiglic aldehyde by a reported procedure.[4] [14] Subsequently, the silyl group was removed by treatment with HF·Py in CH₃CN at 0 °C to room temperature to afford the alcohol 16 in 85% yield.[15] Finally oxidation of 16 with TEMPO and PhI(OAc)₂ in CH₂Cl₂–H₂O (4:1) gave the target compound 1. Spectroscopic data for this product were consistent with the reported values.[2]

Scheme 4 Synthesis of jomthonic acid A (1)

In conclusion, the first stereoselective total synthesis of jomthonic acid A was achieved by a convergent approach with an 8.0% overall yield by employing a Sharpless asymmetric epoxidation, a Gilmann reaction, a Mitsunobu azidation, hydrogenation, a Yamaguchi esterification, and amide coupling as the key steps.

Acknowledgment

M.D. and B.S are grateful to the UGC, New Delhi for the financial support in the form of fellowships.

• 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
• 8a Shioiri T. Diphenyl Phosphorazide (DPPA): More Than Three Decades Later, TCI Mail No. 134. Tokyo: Tokyo Chemical Industry Co. Ltd; 2007 https://www.tcichemicals.com/en/kr/support-download/tcimail/backnumber/article/134drE.pdf (accessed Nov 19, 2019)
• 8b Thompson AS, Grabowski EJ. J. WO 1995001970, 1995
• 8c Pastó M, Moyano A, Pericàs MA, Riera A. J. Org. Chem. 1997; 62: 8425
• 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.