A Convergent Synthesis of the 2-Formylpyrrole Spiroketal Natural Product Acortatarin A

Abstract

A concise and flexible synthesis of the morpholine-spiroketal natural product acortatarin A, isolated from the traditional Chinese medicine Acorus tatarinowii, is reported. The key step involves a Maillard-type condensation of an amine derived from d-mannitol with a dihydropyranone. The approach also enables access to analogues of acortatarin A for biological evaluation and can be applied to the synthesis of related 2-formylpyrrole natural products.

Key words

acortatarin - Chinese medicine - natural product synthesis - spiroketal - 2-formylpyrrole - Maillard reaction

• References and Notes

• 1 Tong XG, Zhou LL, Wang YH, Xia C, Wang Y, Liang M, Hou FF, Cheng YX. Org. Lett. 2010; 12: 1844
• 2 Verheijen JC, Zask A. Drugs Future 2007; 32: 537
• 3 Levin JI, Chen JM, Laakso LM, Du M, Du X, Venkatesan AM, Sandanayaka V, Zask A, Xu J, Xu W, Zhang Y, Skotnicki JS. Bioorg. Med. Chem. Lett. 2005; 15: 4345
• 4 Almstead NG, Bradley RS, Pikul S, De B, Natchus MG, Taiwo YO, Gu F, Williams LE, Hynd BA, Janusz MJ, Dunaway CM, Mieling GE. J. Med. Chem. 1999; 42: 4547
• 5a Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L. Diabetes Metab. Res. Rev. 2001; 17: 189
• 5b Ha H, Lee HB. Kidney Int. 2000; 58: S19
• 5c Lee HB, Yu MR, Yang Y, Jiang Z, Ha H. J. Am. Soc. Nephrol. 2003; 14: 241
• 5d Shi XY, Hou FF, Niu HX, Wang GB, Xie D, Guo ZJ, Zhou ZM, Yang F, Tian JW, Zhang X. Endocrinology 2008; 149: 1829
• 6 Sudhakar G, Kadam VD, Bayya S, Pranitha G, Jagadeesh B. Org. Lett. 2011; 13: 5452
• 7 Le Z.-G, Chen Z.-C, Hu Y, Zheng Q.-G. Synthesis 2004; 1951
• 8 Ledl F, Schleicher E. Angew. Chem., Int. Ed. Engl. 1990; 29: 565
• 9 Maeba I, Takeuchi T, Iijima T, Furukawa H. J. Org. Chem. 1988; 53: 1401
• 10a Achmatowicz Jr O, Bukowski P, Szechner B, Zwierzchowska Z, Zamojski A. Tetrahedron 1971; 27: 1973
• 10b Jones R, Krische M. Org. Lett. 2009; 11: 1849
• 11a Yu HJ, Chen CC, Shieh BJ. J. Nat. Prod. 1998; 61: 1017
• 11b Tamura O, Iyama N, Ishibashi H. J. Org. Chem. 2004; 69: 1475
• 11c Hellwig M, Geissler S, Matthes R, Peto A, Silow C, Brandsch M, Henle T. ChemBioChem 2011; 12: 1270
• 12 Chattopadhyay A. J. Org. Chem. 1996; 61: 6104
• 13 Jackson DY. Synth. Commun. 1988; 18: 337
• 14 Celanire S, Marlin F, Baldwin JE, Adlington MR. Tetrahedron 2005; 61: 3025
• 15 Synthesis of Dihydropyranone 5 To a stirred solution of 7 (0.60 g, 2.5 mmol) in CH₂Cl₂ (50 mL) at 0 °C MCPBA was added in one portion (0.70 g, 3.2 mmol). The solution was stirred at 0 °C for 30 min then for a further 4 h at r.t. The reaction was quenched by addition of sat. aq Na₂SO₃ (30 mL) and neutralised to pH 7–8 with 1 M NaOH solution. The reaction mixture was extracted with CH₂Cl₂ (2 × 50 mL), and the combined organic phases were washed with brine and dried over Na₂SO₄. Concentration in vacuo and column chromatography (hexane–EtOAc = 7:1) afforded the title compound 5 as a white solid (0.63 g, 2.4 mmol, 92%); mp 54–55 °C. ¹H NMR (400 MHz, CDCl₃): δ = 0.07 (s, 6 H), 0.88 (s, 9 H), 3.65 (d, J = 10.4 Hz, 1 H), 3.73 (d, J = 10.4 Hz, 1 H), 3.97 (br s, 1 H), 4.11 (d, J = 16.8 Hz, 1 H), 4.54 (d, J = 16.8 Hz, 1 H), 6.08 (d, J = 10.0 Hz, 1 H), 6.80 (d, J = 10.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.3 (C), 146.3 (CH), 128.2 (CH), 92.6 (C), 67.9 (CH₂), 66.5 (CH₂), 25.7 (CH₃), 18.3 (C), –5.3 (CH₃). IR (film): 3242, 295, 2929, 2857, 1677, 1244, 1114, 1061, 830, 773 cm^–1. ESI-HRMS: m/z calcd for C₁₂H₂₃SiO₄ [M + H]⁺: 259.1360; found: 259.1365
• 16 Synthesis of Acortatarin (1) and 2-epi-Acortatarin (14) To a stirred solution of 13 (20 mg, 0.04 mmol) in THF (0.5 mL) was added TBAF (1 M in THF, 0.5 mL, 0.5 mmol) under N₂. The reaction mixture was stirred for 2.5 h at r.t. then concentrated in vacuo The residue was purified by preparative TLC (hexane–EtOAc = 1:5) to afford acortatarin (1, 4 mg, 0.016 mmol, 40%) as a white solid and 2-epi-acortatarin (14, 2.7 mg, 0.011 mmol, 27%) as a yellow oil. Compound 1 (major): [α]_D ²⁰ +194.8 (c 0.15, MeOH) {lit.⁶ [α]_D +191.4 (c 0.27, MeOH)}. ¹H NMR (400 MHz, CD₃OD): δ = 2.10 (dd, J = 14.0, 2.8 Hz, 1 H), 2.30 (dd, J = 14.0, 8.4 Hz, 1 H), 3.58 (dd, J = 12.0, 4.8 Hz, 1 H), 3.67 (dd, J = 12.4, 3.6 Hz, 1 H), 4.02 (ddd, J = 6.9, 3.9, 2.9 Hz, 1 H), 4.18 (d, J = 14.0 Hz, 1 H), 4.24 (ddd, J = 8.9, 6.9, 3.9 Hz, 1 H), 4.55 (d, J = 10.0 Hz, 1 H), 4.81 (d, J = 16.8 Hz, 1 H), 4.97 (d, J = 16.8 Hz, 1 H), 6.03 (d, J = 4.4 Hz, 1 H), 6.98 (d, J = 4.4 Hz, 1 H), 9.32 (s, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 180.2 (CH), 137.6 (C), 132.4 (CH), 125.9 (CH), 106.1 (C), 104.5 (C), 89.4 (CH), 72.2 (CH), 63.0 (CH₂), 58.7 (CH₂), 52.0 (CH₂), 45.9 (CH₂). IR (film): 3360, 2921, 2851, 1736, 1659, 1412, 1260, 1036, 796 cm^–1. ESI-HRMS: m/z calcd for C₁₂H₁₅NNaO₅ [M + Na]⁺: 276.0842; found: 276.0843.Compound 14 (minor): [α]_D ²⁰ –85.0 (c 0.2, MeOH) {lit.⁶ [α]_D –57.8 (c 0.04, MeOH)}. ¹H NMR (400 MHz, CD₃OD): δ = 2.10 (dd, J = 12.0, 6.8 Hz, 1 H), 2.45 (dd, J = 13.2, 6.8 Hz, 1 H), 3.55 (dd, J = 11.6, 2.8 Hz, 1 H), 3.65 [dd, J = 11.6, 4.4 (18) Hz, 1 H], 3.96 (ddd, J = 10.8, 8.8, 2.8 Hz, 1 H), 4.18 (d, J = 13.6 Hz, 1 H), 4.33 (ddd, J = 12.4, 5.6, 1.6 Hz, 1 H), 4.63 (d, J = 13.6 Hz, 1 H), 4.75 (d, J = 16.8 Hz, 1 H), 5.05 (d, J = 16.8 Hz, 1 H), 6.01 (d, J = 4.4 Hz, 1 H), 6.98 (d, J = 4.4 Hz, 1 H), 9.33 (s, 1 H). ¹³C NMR (100 MHz, CD₃OD): δ = 180.2 (CH), 137.5 (C), 132.4 (CH), 126.1 (CH), 106.1 (C), 104.2 (C), 89.6 (CH), 72.2 (CH), 64.3 (CH₂), 59.2 (CH₂), 52.6 (CH₂), 45.8 (CH₂). IR (film): 3351, 2910, 2837, 1733, 1645, 1412, 1260, 1038, 796 cm^–1. ESI-HRMS: m/z calcd for C₁₂H₁₅NNaO₅ [M + Na]⁺: 276.0842; found: 276.0850
• 17 It did not prove possible to invert the C4 stereochemistry of 16 via a Mitsunobu sequence to access ent-1, possibly due to the steric bulk of the TBDPS group