Goniomitine: an overview on the chemistry of this indole alkaloid

Abstract

This paper reports an overview on the chemistry of the indole alkaloid goniomitine focusing, mainly, on the methods of synthesis related to this natural product and analogs.

Figure 1

Natural (−)- and unnatural (+)-goniomitine (1).

Scheme 1

Biogenetic hypothesis of transformation of vincadifformine (2) into goniomitine (1): (a) oxidative fission of the C-5, N-4 bond; (b) decarboxylation; (c) retro-Mannich reaction; (d) nucleophilic attack of the indole nitrogen on the iminium moiety.

Scheme 2

Chemical transformations of goniomitine (1) into the acetyl derivatives 5 and 6.

Scheme 3

Reagents and conditions: (a) (i) n-BuLi (2.2 equiv), hexane (reflux, 6 h) and (ii) methyl 3-(3-pyridyl)propanoate, THF (−78 to 15°C); (b) MeMgI (10 equiv), ethylene oxide (10 equiv), Et₂O (1 h), reflux (2 h); (c) MeI, CH₂Cl₂ (reflux, 2 h); (d) H₂, PtO₂, MeOH (3 h); (e) H₂, PtO₂, NaOMe, MeOH (3 h).

Scheme 4

Reagents and conditions: (a) Zn (5.0 equiv), AcOH-EtOH (1 : 3), reflux (4 h); (b) EtI (2.0 equiv), t-BuOK (1.2 equiv), THF (−70 to −30°C, 15 min); (c) allyl bromide (2.0 equiv), t-BuOK (1.2 equiv), THF (−30°C, 5 min); (d) o-dichlorobenzene (reflux, 24 h); (e) LiAlH₄ (1.0 equiv), CuI (0.5 equiv), HMPA-THF (1 : 4), −75°C (15 min); (f) propane-1,3-diyldithiotosylate (1.5 equiv), t-BuOK (3.0 equiv), t-BuOH-THF (1 : 4), 0°C; (g) KOH (5.0 equiv), t-BuOH (70°C, 12 h); (h) CH₂N₂, Et₂O; (i) MeI (1.0 equiv), CaCO₃ (5.0 equiv), 10% aq. MeCN (reflux, 1 h); (j) Ph₃P (4.0 equiv), CBr₄ (2.0 equiv), Et₃N (3.0 equiv), CH₂Cl₂ (0°C, 5 min); (k) LDA (3.0 equiv), THF (−78°C, 10 min); (l) compound 20 (1.1 equiv), PdCl₂(PPh₃)₂ (2%), CuI (5%), Et₃N (reflux, 30 min); (m) NaOEt (10 equiv), Et₃N (5%), EtOH (reflux, 3 h); (n) (i) dicyclohexylborane (1.5 equiv), THF (0°C, 30 min), (ii) 10% NaOH (1.0 equiv), 30% H₂O₂ (3.0 equiv), 0°C (30 min); (o) phthalimide (1.3 equiv), Ph₃P (1.3 equiv), (i-PrO₂CN)₂ (1.3 equiv), THF (0°C, 10 min); (p) NH₂NH₂·H₂O (4.0 equiv), EtOH (reflux, 2 h); (q) [Me₂N=CH₂]Cl (1.5 equiv), CH₂Cl₂ (r.t., 30 min); (r) MeI, MeOH (r.t., 10 min); (s) NaCN (1.3 equiv), DMF (100°C, 10 min); (t) POCl₃ (6.0 equiv), toluene (reflux, 2 h); (u) NaBH₄, MeOH, 0°C; (v) DIBAL (1.5 equiv), CH₂Cl₂ (−75°C, 10 min); (x) dil. H₂SO₄; (y) NaBH₄; (z) 30% HCl-MeOH (1 : 10), reflux (30 min).

Scheme 5

Reagents and conditions: (a) m-CPBA (1.1 equiv), CH₂Cl₂ (r.t., 3 h); (b) 0.2 mol L⁻¹ NaOH-MeOH (r.t., 5 min); (c) NaI (3.0 equiv), AcOH (r.t., 1.5 h); (d) 11 mol L⁻¹ HCl (105°C, 10 min); (e) TFA (16 equiv), CH₂Cl₂ (r.t., 20 min); (f) TFA (r.t., 4 h); (g) TFA (16 equiv), CH₂Cl₂ (r.t., 15 h); (h) TFA (12.5 equiv), CH₂Cl₂ (r.t., 45 h).

Scheme 6

Scheme 7

Reagents and conditions: (a) NaBH₃CN, AcOH (r.t., 1.5 h); (b) NaOH-MeOH (120°C, 1 h); (c) LiAlH₄ (excess), THF (reflux, 3 h); (d) H₂ (1 atm), 10% Pd-C, MeOH (r.t., 5 h); (e) TiCl₃-H₂O, MeOH (r.t., 20 h); (f) 30% HCl-MeOH (120°C, 1.5 h).

Scheme 8

Reagents and conditions: (a) vinylindole 47 (1.0 equiv), enamine 49 (2.37 equiv), CH₃CN, LiClO₄ (0.1 mol L⁻¹), electrolysis (480 mV versus Ag/AgNO₃, current (20 to 2 mA), 200 min); (b) vinylindole 48 (1.0 equiv), enamine 49 (6.17 equiv), CH₃CN, LiClO₄ (0.1 mol L⁻¹), electrolysis (480 mV versus Ag/AgNO₃, current (20 to 2 mA), 200 min); (c) vinylindole 47 (1.0 equiv), enamine 50 (1.4 equiv), CH₃CN, LiClO₄ (0.1 mol L⁻¹), electrolysis (480 mV versus Ag/AgNO₃, current (20 to 2 mA), 40 min); (d) vinylindole 47 (1.0 equiv), enamine 51 (2.1 equiv), CH₃CN, LiClO₄ (0.1 mol L⁻¹), electrolysis (480 mV versus Ag/AgNO₃, current (20 to 2 mA), 200 min).

Scheme 9

Reagents and conditions: (a) compound 56 (5.0 equiv), NaBH₃CN (immediate addition), MeOH (r.t., 16 h); (b) compound 56 (5.0 equiv), NaBH₃CN (delayed addition, 20 min), MeOH (r.t., 16 h); (c) TiCl₃-H₂O (6.0 equiv), MeOH (r.t., 20 h); (d) Ac₂O, Py (r.t., 48 h); (e) Ac₂O, Py (r.t., 3 h); (f) CH₂O, NaBH₃CN, AcOH (r.t., 2 h); (g) LiAlH₄, THF (reflux, 3 h).

Scheme 10

Reagents and conditions: (a) (i) n-BuLi (2.0 equiv), THF (−78°C), (ii) EtI (1.0 equiv), −78°C (1 h), (iii) BnBr (1.0 equiv), r.t. (overnight); (b) (i) LDA (1.0 equiv), THF (−78°C, 15 min), (ii) BrCH₂CH₂OTHP (1.1 equiv), r.t. (overnight); (c) TsOH (0.1 equiv), MeOH (ice-brine bath, 4 h); (d) Et₃N (2.1 equiv), MsCl (1.0 equiv), CH₂Cl₂ (0°C to r.t., 3 h); (e) NaCN (2.0 equiv), MeCN, 120°C (μw, 8 h, 900 rpm stirring); (f) Nitrile 68 (1.0 equiv), cyclopropane 69 (2.9 equiv), TMSOTf (1.0 equiv), EtNO₂ (−30°C, 24 h); (g) 5% Pd-C (0.03 equiv), mesitylene (reflux, 24 h); (h) NaOH (10 equiv), EtOH-H₂O (1 : 1), 150°C (μw, 3 h, 900 rpm stirring); (i) Na (5.0 equiv), liq. NH₃ (0.042 mol L⁻¹), THF (−78°C, 10 min); (j) (i) [Me₂N=CH₂]Cl (1.5 equiv), CH₂Cl₂ (r.t., 15 min), (ii) MeI (40 equiv), MeOH (r.t., 10 min), (iii) NaCN (1.3 equiv), DMF (100°C, 10 min); (k) (i) POCl₃ (6.0 equiv), toluene (reflux, 2 h), (ii) NaBH₄ (2.0 equiv), MeOH (0°C, 30 min); (l) (i) DIBAL (1.5 equiv), CH₂Cl₂ (−78°C, 10 min), (ii) 0.75 mol L⁻¹ H₂SO₄, (iii) NaBH₄ (2.2 equiv), EtOH (0°C, 30 min); (m) TsOH (cat.), Et₃N-MeOH (3 : 5, v/v), reflux (30 min).

Scheme 11

Reagents and conditions: (a) (i) n-BuLi (2.2 equiv), THF (0°C, 30 min), (ii) EtI (1.5 equiv), 0°C (20 min), (iii) benzyl chloroformate (1.05 equiv), 0°C (20 min); (b) (i) NaBH₄ (1.05 equiv), MeOH (0°C, 15 min), (ii) conc. H₂SO₄, Et₂O (r.t., 1 h); (c) N₂CH₂COOEt (4.0 equiv), (CuOTf)₂·C₇H₈ (0.02 equiv), CH₂Cl₂ (18 h); (d) (i) BF₃·OEt₂ (0.15 equiv), CH₂Cl₂ (−20 to 0°C), (ii) NaOH (9.0 equiv), H₂O-THF-EtOH (1 : 1 : 3), 0°C to 60°C (2 h); (e) (i) DMTMM (1.5 equiv), THF (r.t., 60 min), (ii) MeNHOMe.HCl (1.0 equiv), NMM (2.0 equiv), r.t. (36 h); (f) TIPSCl (1.05 equiv), imidazole (2.1 equiv), DMF (r.t., 1 h); (g) (i) n-BuLi (1.2 equiv), Et₂O (0°C then reflux, 2 h), (ii) CO₂ (0°C, 30 min), (iii) H₃O⁺ (pH 2); (h) (i) t-BuLi (3.0 equiv), compound 82 (1.5 equiv), TMEDA (2.0 equiv), THF (−78°C, 3 h), (ii) amide 79 (1.0 equiv), THF (0°C, 20 min); (i) TsOH (0.2 equiv), CH₂Cl₂ (r.t., 10 min); (j) (i) NaBH₄, MeOH (0°C to r.t., 3 h), (ii) Ac₂O, Py (r.t., overnight), (iii) H₂, Pd-C (0.1 equiv), EtOH, (iv) TBAF (4.4 equiv), THF (r.t., 30 min).

Scheme 12

Reagents and conditions: (a) (i) compound 85 (1.3 equiv), n-BuLi (1.2 equiv), THF (−78°C, 1.5 h), (ii) compound 86 (1.0 equiv), THF (r.t., 22 h); (b) MsCl (1.6 equiv), Et₃N (2.0 equiv), CH₂Cl₂ (0°C to r.t., 20 min); (c) (i) LDA (2.4 equiv), n-Bu₃SnH (2.4 equiv), THF (−78°C, 1 h), (ii) CuBr·SMe₂ (2.7 equiv), −78°C (40 min), (iii) mesylate 88 (1.0 equiv), THF (−78°C, 1 h); (d) (i) 2-I-PhNHBoc (1.28 equiv), compound 89 (1.0 equiv), TBAC (3.29 equiv), TFP (0.25 equiv), Pd₂(dba)₃ (0.03 equiv), CuI (0.11 equiv), DMF (r.t., 2 h); (e) (i) o-NO₂PhSeCN (1.54 equiv), n-Bu₃P (1.55 equiv), THF (r.t., 5 h), (ii) 30% aq. H₂O₂ (1.48 mol L⁻¹), THF (0°C (20 min), r.t. (17 h)); (f) compound 90 (1.0 equiv), lactam 91 (9.44 equiv), Hoveyda-Grubbs-II cat. (0.3 equiv), neat (140°C, 3 h); (g) H₂, 5% Pd-C (0.1 equiv), AcOEt (r.t., 23 h); (h) DIBAL (3.4 equiv), THF (−78°C to r.t.); (i) H₂, 20% Pd (OH)₂, AcOH-EtOH (5 : 2), r.t. (2 h); (j) TBAF (3.3 equiv), THF (r.t., 14 h).

Scheme 13

Reagents and conditions: (a) (i) O₃, MeOH (−78°C, 15 min) and (ii) NaBH₄ (1.5 equiv), −78°C to r.t. (2 h); (b) (i) o-NO₂PhSeCN (3.9 equiv), n-Bu₃P (6.0 equiv), THF (r.t., 3 h) and (ii) 30% aq. H₂O₂, THF (0°C to r.t., 9 h); (c) indole 90 (1.0 equiv), lactam 97 (3.5 equiv), Hoveyda-Grubbs-II cat. (0.31 equiv), xylene (140°C, 3 h); (d) H₂, 5% Pd-C (0.1 equiv), AcOEt (r.t., 27 h); (e) (i) NaH (17.8 equiv), Et₂O (0°C, 30 min) and (ii) DIBAL (1.07 equiv), 0°C to r.t. (10 min), repeat three-times; (f) H₂, 20% Pd (OH)₂, n-PrOH/1,4-dioxane (1 : 1), r.t. (11 h); (g) TBAF (3.3 equiv), THF (r.t., 14 h).

Scheme 14

Reagents and conditions: (a) (i) NaI (1.5 equiv), TMSCl (1.5 equiv), MeCN (r.t., 30 min), (ii) lactone 101 (1.0 equiv), MeCN (r.t., 16 h), (iii) TMSCl (0.5 equiv), EtOH (r.t., 71 h); (b) compound 102 (1.0 equiv), norbornene (2.01 equiv), K₂CO₃ (4.01 equiv), iodide 103 (4.01 equiv), PdCl₂ (0.1 equiv), DMF-DMSO (9 : 1), H₂O (0.5 mol L⁻¹), air (60°C, 26 h); (c) (i) indole 104 (1.0 equiv), LiHMDS (3.0 equiv), THF (−78°C to r.t.), (ii) CH₂=CHCH₂Br (3.0 equiv) (−78°C (40 min), r.t. (30 min)); (d) (i) lactam 105 (1.0 equiv), 9-BBN (1.39 equiv), (0°C (15 min), r.t. (1 h)), (ii) aq. NaOH (1 mol L⁻¹), 35% aq. H₂O₂ (0.18 mol L⁻¹), 0°C (30 min); (e) alcohol 106 (1.0 equiv), PPh₃ (2.08 equiv), DPPA (2.94 equiv), DIAD (2.8 equiv), 0°C to r.t. (3.5 h); (f) azide 107 (1.0 equiv), LiAlH₄ (4.01 equiv), THF (0°C to r.t., 2 h); (g) AcOH-THF-H₂O (3 : 1 : 1, v/v), 40°C (24 h).

Scheme 15

Reagents and conditions: (a) compound 40 (1.0 equiv), NaBH₃CN (5.73 equiv), AcOH (r.t., 2.5 h); (b) TiCl₃ (3.1 equiv), MeOH (r.t., 20 h); (c) compound 109 (1.0 equiv), HCO₂NH₄ (5.71 equiv), 10% Pd-C (0.33 equiv), MeOH (reflux, 45 min); (d) 4 mol L⁻¹ HCl (100°C, 1 h).

Scheme 16

Reagents and conditions: (a) (i) compound 113 (2.0 equiv), CH₃MgCl (2.0 equiv), THF (−78°C to r.t.), (ii) Mg (2.2 equiv), reflux (3 h), (iii) compound 112 (1.0 equiv), THF (reflux, 2 h), (iv) 2 mol L⁻¹ HCl (0°C, 3 h); (b) TBSCl (1.1 equiv), imidazole (1.5 equiv), DMF (r.t, 3 h); (c) (i) CuBr·Me₂S (2.0 equiv), EtMgBr (4.0 equiv), THF (−78 to −40°C, 40 min), (ii) compound 114 (1.0 equiv), THF (−40°C, 3 h), (iii) Comins' reagent (2.0 equiv), THF (r.t., 24 h); (d) compound 116 (1.0 equiv), ICH₂CH₂OBn (1.2 equiv), Cs₂CO₃ (1.3 equiv), DMF (60°C, overnight); (e) compound 117 (1.0 equiv), 10% aq. KOH, MeOH-THF (5 : 1), r.t. (5-6 h); (f) t-BuOK (1.0 equiv), EtOH (r.t., 1 h); (g) (i) compound 118 (1.2 equiv), [PdCl(allyl)]₂ (5 mol%), X-Phos (15 mol%), triflate 115 (1.0 equiv), diglyme (100°C, 2 h), (ii) TBAF (4.0 equiv), THF (r.t., 4 h); (h) compound 119 (1.0 equiv), Ph₃P (2.1 equiv), DPPA (2.9 equiv), DIAD (2.8 equiv), THF (0°C to r.t., 3.5 h); (i) (i) compound 120 (1.0 equiv), NaHCO₃ (5.0 equiv), MeOH, O₃ (−78°C, 20–30 seg), (ii) Me₂S (50 equiv), −78°C to r.t. (24 h), (iii) Zn (70 equiv), CaCl₂ (20 equiv), MeOH (reflux, 2 h); (j) compound 121 (1.0 equiv), sodium naphthalenide (6.0 equiv), THF (−20°C, 15 min).