Synlett 2012; 23(6): 855-858
DOI: 10.1055/s-0031-1290508
letter
© Georg Thieme Verlag Stuttgart · New York

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

Hui Min Geng
a  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
,
Jack Li-Yang Chen
a  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
,
Daniel P. Furkert
a  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
,
Shende Jiang
b  School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P. R. of China, Fax: +64(9)3737422   Email: m.brimble@auckland.ac.nz
,
Margaret A. Brimble*
a  School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
› Author Affiliations
Further Information

Publication History

Received: 27 January 2012

Accepted after revision: 09 February 2012

Publication Date:
16 March 2012 (eFirst)

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.

 
  • References and Notes

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  • 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