Total Synthesis of (+)-Eburnamonine

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

• References and Notes

• 1a Zenk MH, Juenger M. Phytochemistry 2007; 68: 2757
• 1b Leonard J. Nat. Prod. Rep. 1999; 16: 319
• 1c Saxton JE. Nat. Prod. Rep. 1997; 14: 559

For synthesis of (±)-eburnamonine, see:
• 2a Kalaus G, Malkieh M, Katona I, Peredy M, Koritsanszky T, Kalaman A, Szantay C. J. Org. Chem. 1986; 50: 3760
• 2b Magnus P, Pappalardo P, Southwell I. Tetrahedron 1986; 42: 3215
• 2c Shono T, Matsumura Y, Ogaki M, Onomura O. Chem. Lett. 1987; 1447
• 2d Wenkert E, Hudlicky T. J. Org. Chem. 1988; 53: 1953
• 2e Wasserman H, Kuo G. Tetrahedron Lett. 1989; 30: 873
• 2f Meyers AI, Romine J, Robichaud AJ. Heterocycles 1990; 30: 339
• 2g Greiner P, Feldman PL, Chu-Moyer MY, Rapoport H. J. Org. Chem. 1990; 55: 3068
• 2h Ihara M, Takahashi M, Taniguchi N, Yasui K, Niitsuma H, Fukumoto J. J. Chem. Soc., Perkin Trans. 1 1991; 25
• 2i Karvinen E, Lounasmaa M. Heterocycles 1992; 34: 1773
• 2j Ghosh AK, Kawahama R. J. Org. Chem. 2000; 65: 5433
• 3a Takano S, Yonaga M, Morimsto M, Ogasawara K. J. Chem. Soc., Perkin Trans. 1 1985; 305
• 3b Hakam K, Thielmann M, Thielmann T, Winterfeldt E. Tetrahedron 1987; 43: 2035
• 3c Node M, Nagasawa H, Fuji K. J. Am. Chem. Soc. 1987; 109: 7901
• 3d Node M, Nagasawa H, Fuji K. J. Org. Chem. 1990; 55: 517
• 3e Schultz AG, Pettus L. J. Org. Chem. 1997; 62: 6855
• 3f Wee AG. H, Yu Q. Tetrahedron Lett. 2000; 41: 587
• 3g Wee AG. H, Yu Q. J. Org. Chem. 2001; 66: 8935
• 3h Jones SB, Simmons B, Mastracchio A, MacMillan DW. C. Nature (London) 2011; 475: 183
• 3i For an enzymatic approach, see: Palmisano G, D’Anniballe P, Santagostino M. Tetrahedron 1994; 50: 9487
• 4a Prasad KR, Kumar SM. Synlett 2011; 1602
• 4b Prasad KR, Penchalaiah K. J. Org. Chem. 2011; 76: 6889
• 4c Prasad KR, Gandi VR. Tetrahedron: Asymmetry 2011; 22: 499
• 4d Prasad KR, Penchalaiah K. Tetrahedron: Asymmetry 2011; 22: 1400
• 4e Prasad KR, Swain B. J. Org. Chem. 2011; 76: 2029
• 4f Prasad KR, Pawar AB. Synlett 2010; 1093
• 4g Prasad KR, Pawar AB. ARKIVOC 2010; (vi): 39
• 4h Prasad KR, Gandi VR. Synlett 2009; 2593
• 4i Prasad KR, Gholap SL. J. Org. Chem. 2008; 73: 2
• 4j Prasad KR, Gholap SL. J. Org. Chem. 2008; 73: 2916
• 4k Prasad KR, Swain B. Tetrahedron: Asymmetry 2008; 19: 1134
• 4l Prasad KR, Chandrakumar A. J. Org. Chem. 2007; 72: 6312
• 4m Prasad KR, Gholap SL. J. Org. Chem. 2006; 71: 3643
• 5 Dieters A, Martin SF. Chem. Rev. 2004; 104: 2199
• 6 For a recent application of lactic acid in the synthesis of chiral quaternary isocyanide, see: Ichikawa Y, Matsuda Y, Okumura K, Nakamura M, Masuda T, Kotsuki H, Nakano K. Org. Lett. 2011; 13: 2520
• 7 Baldwin JE, Moloney MG, Parsons AF. Tetrahedron 1992; 48: 9373
• 8 Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
• 9 The minor diastereomer was isolated in 38% yield
• 10a Schrodi Y, Pederson RL. Aldrichimica Acta 2007; 40: 45
• 10b Grubbs RH. Angew. Chem. Int. Ed. 2006; 45: 3760
• 10c Grubbs RH. Tetrahedron 2004; 60: 7117
• 10d Marco JA, Carda M, Murga J, Falomir E. Tetrahedron 2007; 63: 2929
• 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): ν_max = 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): ν_max = 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) {lit^3c [α]_D –88 (c 0.09, CHCl₃) for the enantiomer}; mp (171–172 °C) {lit.^3e mp 173–176 °C)}. IR (KBr): ν_max = 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