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Synlett 2012; 23(10): 1477-1480
DOI: 10.1055/s-0031-1291143
letter
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of (+)-Eburnamonine

Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India, Fax: +91(80)23600529   Email: prasad@orgchem.iisc.ernet.in
,
John E. Nidhiry
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India, Fax: +91(80)23600529   Email: prasad@orgchem.iisc.ernet.in
› Author Affiliations
Further Information

Publication History

Received: 10 February 2012

Accepted after revision: 03 May 2012

Publication Date:
14 May 2012 (online)

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Abstract

The enantiospecific total synthesis of vinca alkaloid (+)-eburnamonine is accomplished from l-ethyl lactate. Key feature of the synthesis is the construction of the chiral quaternary center involving a Johnson–Claisen rearrangement and assembly of the pentacyclic core by the Pictet–Spengler reaction and ring-closing metathesis.

Key words

eburnamonine - alkaloids - l-ethyl lactate

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

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  • 9 The minor diastereomer was isolated in 38% yield
  • 11 Preparation of 17 To a stirred solution of the diene 5 (24 mg, 0.06 mmol) in dry CH2Cl2 (6 mL) was added Grubbs II catalyst (2 mg, 5 mol%) under an argon atmosphere, and the reaction mixture was stirred at r.t. for 5 h. After completion of the reaction (TLC), most of the solvent was evaporated off, and the crude residue thus obtained was purified by silica gel column chroma-tography using PE–EtOAc (7:3) as eluent to afford 17 (18 mg, 83%) as a yellow foam. [α]D +179.2 (c 0.6, CHCl3). IR (neat): νmax = 3371, 2960, 2930, 1458, 1048 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.78 (br s, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.34–7.06 (m, 7 H), 5.87 (dd, J 1 = 10.1 Hz, J 2 = 4.6 Hz, 1 H), 5.44 (d, J = 10.1 Hz, 1 H), 4.36 (s, 2 H), 3.64 (s, 1 H), 3.58 (qd, J 1 = 6.0 Hz, J 2 = 2.9 Hz, 1 H), 3.52 (qd, J 1 = 6.0 Hz, J 2 = 3.0 Hz, 1 H), 3.33 (dd, J 1 = 16.4 Hz, J 2 = 4.7 Hz, 1 H), 3.09 (dd, J 1 = 10.9 Hz, J 2 = 4.8 Hz, 1 H), 3.01 (d, J = 16.4 Hz, 1 H), 2.98–2.80 (m, 1 H), 2.78 (d, J = 16.4 Hz, 1 H), 2.58 (td, J 1 = 8.4 Hz, J 2 = 3.0 Hz, 1 H), 2.02–1.92 (m, 1 H), 1.87 (q, J = 7.7 Hz, 2 H), 1.46–1.36 (m, 1 H), 1.10 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 138.7, 136.2, 133.6, 132.9, 128.2 (2 C), 127.5 (2 C), 127.2, 126.8, 126.1, 121.5, 119.3, 117.9, 111.9, 110.7, 72.7, 68.0, 61.2, 55.1, 52.4, 43.0, 37.4, 32.5, 21.6, 8.9. HRMS: m/z calcd for [C26H30N2O + H]: 387.2436; found: 387.2436. Preparation of 18 To a stirred solution of the alkene 17 (18 mg, 0.05 mmol) in dry EtOH (2 mL) was added preactivated palladium on charcoal (10% w/w, 20 mg) under a nitrogen atmosphere. The reaction mixture was then subjected to hydrogenation under a hydrogen balloon and stirred at r.t. for 24 h. After completion of the reaction (TLC), it was filtered through a short pad of Celite using CHCl3 (20 mL). The solvent was evaporated off, and the crude residue thus obtained was purified by silica gel column chromatography using EtOAc–MeOH (19:1) as eluent to afford 18 (10 mg, 78%) as a white solid. [α]D +85.8 (c 0.4, CHCl3); mp (165–168 °C). IR (KBr): νmax = 3649, 3252, 2922, 1462, 1096 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.84 (br s, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.15 (t, J = 7.3 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 3.75 (td, J 1 = 11.6 Hz, J 2 = 2.4 Hz, 1 H), 3.44 (dt, J 1 = 11.8 Hz, J 2 = 4.4 Hz, 1 H), 3.36 (s, 1 H), 3.09 (d, J = 4.7 Hz, 1 H), 3.08 (s, 1 H), 3.07–2.97 (m, 1 H), 2.72–2.62 (m, 1 H), 2.67 (s, 1 H), 2.45 (td, J 1 = 11.7 Hz, J 2 = 3.0 Hz, 1 H), 2.23–2.00 (m, 1 H), 1.89–1.54 (m, 6 H), 1.37 (d, J = 15.0 Hz, 1 H), 1.26 (s, 1 H), 1.12 (t, J = 7.5 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 136.0, 132.2, 126.7, 121.7, 119.4, 118.2, 111.9, 110.6, 67.1, 58.7, 56.3, 54.0, 40.9, 38.8, 35.7, 32.3, 23.0, 21.3, 8.5. HRMS: m/z calcd for [C19H26N2O + H]: 299.2123; found: 299.2120. Eburnamonine (+)-1To a stirred solution of the alcohol 18 (10 mg, 0.03 mmol) in CH2Cl2 (1 mL) were added a small amount of 4 Å MS and NMO (7 mg, 0.06 mmol) under a nitrogen atmosphere at r.t., followed by TPAP (1 mg, 10 mol%) after 10 min. The reaction mixture was stirred for 1 h at r.t. After completion of the reaction, it was filtered through a small pad of Celite, which was washed with CH2Cl2 (20 mL). The organic layer was washed with sat. Na2SO3 (8 mL), brine (5 mL), sat. CuSO4 (5 mL) and dried over anhyd Na2SO4. The crude residue obtained after evaporation of the solvent was purified by rapid column chromatography using EtOAc as eluent to afford (+)-1 (4 mg, 40%) as a white solid. [α]D + 87.5 (c 0.2, CHCl3) {lit3c [α]D –88 (c 0.09, CHCl3) for the enantiomer}; mp (171–172 °C) {lit.3e mp 173–176 °C)}. IR (KBr): νmax = 2926, 2854, 1696, 1452, 1370 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 7.8 Hz, 1 H), 7.43 (d, J = 7.2 Hz, 1 H), 7.39–7.23 (m, 2 H), 3.99 (s, 1 H), 3.34 (dd, J 1 = 14.0 Hz, J 2 = 6.7 Hz, 1 H), 3.31–3.21 (m, 1 H), 2.98–2.84 (m, 1 H), 2.63 (Abq, J 1 = J 2  = 16.7 Hz, 2 H), 2.57–2.45 (m, 1 H), 2.53–2.40 (m, 1 H), 2.40 (dd, J 1 = 11.2 Hz, J 2 = 3.0 Hz, 1 H), 2.13–1.97 (m, 1 H), 1.83–1.58 (m, 4 H), 1.44 (q, J = 13.7 Hz, 2 H), 1.03 (td, J 1 = 13.7 Hz, J 2 = 3.8 Hz, 1 H), 0.93 (t, J = 7.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 167.6, 134.2, 132.0, 130.1, 124.3, 123.8, 118.1, 116.3, 112.6, 57.7, 50.7, 44.4, 44.3, 38.5, 28.4, 27.0, 20.7, 16.6, 7.6. HRMS: m/z calcd for [C19H22N2O + H]: 295.1810; found: 295.1811