Total synthesis, biosynthesis and biological profiles of clavine alkaloids

Abstract

This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson's disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids.

Figure 1

Early biosynthetic pathway steps and diverted ‘shunt’ products

Figure 2

Late biosynthetic pathway steps and diverted ‘shunt’ pathways

Figure 3

Classification of tricyclic, tetracyclic and rearranged clavine alkaloids

Figure 4

Retrosynthetic analysis of Stoltz’s approach to (−)-aurantioclavine (2)

Figure 5

Retrosynthetic analysis of Ishikura’s approach to (±)-aurantioclavine (2)

Figure 6

Retrosynthetic analysis of Ellman’s approach to (−)-aurantioclavine (2).

Figure 7

Retrosynthetic analysis of Takemoto’s approach to (−)-aurantioclavine (2).

Figure 8

Retrosynthetic analysis of Yang’s approach to (−)-aurantioclavine (2).

Figure 9

Retrosynthetic analysis of Murakami’s approach to (−)-cis and (−)-trans clavicipitic acid (1).

Figure 10

Retrosynthetic analysis of Shibata’s approach to (−)-cis-clavicipitic acid (1b).

Figure 11

Mannich mechanism for interconversion of rugulovasines A (11a) and B (11b)

Figure 12

Retrosynthetic analysis of Martin’s approach to rugulovasines A (11a) and B (11b) based on an intermolecular Mannich strategy

Figure 13

Second retrosynthetic analysis of Martin’s approach to rugulovasines A (11a) and B (11b) based on an intramolecular Mannich strategy

Figure 14

Retrosynthetic analysis of Jia’s approach to rugulovasine A (11a)

Figure 15

Retrosynthetic analysis of Szántay’s approach to cycloclavine (26)

Figure 16

Retrosynthetic analysis of Wipf’s approach to cycloclavine (26)

Figure 17

Retrosynthesis of Brewer’s approach to cycloclavine (26)

Figure 18

Retrosynthetic analysis of Cao’s formal synthesis of cycloclavine (26)

Figure 19

Retrosynthetic analysis of Opatz’s formal synthesis of cycloclavine (26)

Figure 20

Biologically active clavine alkaloids

Scheme 1

(−)-Aurantioclavine (2). Reagents and conditions: (a) isobutylene oxide, lithium 4,4'-ditert-butylbiphenylide (LiDBB), THF, −78 °C, 69%; (b) [Pd((−)-sparteine)Cl₂] (31) (10 mol%), O₂ (1 atm), (−)-sparteine (40 mol%), 3Å MS, t-BuOH, 40 °C to 70 °C, 98 h, 32, 51%, and 33, 37% (96% ee); (c) LiAlH₄, THF, −78 °C, 95%; (d) HN₃, PBu₃, DIAD, PhMe, −78 °C to −20 °C, 80%; (e) H₂, cat. Pd/C, HCl, MeOH, 23 °C; (f) o-NsCl, Et₃N, CH₂Cl₂, 0 °C to 23 °C, 92% (2 steps); (g) PyHBr₃, CH₂Cl₂, 0 °C to 23 °C, 72%; (h) tributylvinyltin, Pd(PPh₃)₄ (20 mol%), PhMe, 100 °C, 75%; (i) POCl₃, pyridine, 0 °C to 23 °C, 95%, 35:36 (68:32); (j) 9-BBN, THF, 23 °C (k) NaOH, H₂O₂, THF/EtOH/H₂O, 0 °C to 23 °C, 48% (2 steps); (l) DIAD, PPh₃, PhMe, 0 °C, 95%; (m) PhSH, K₂CO₃, DMF, 23 °C, 53%; (n) TBAF, THF, 70 °C, 68%.

Scheme 2

(±)-Aurantioclavine. Reagents and conditions: (a) NEt₃, MeOH (1:1), room temperature, 10 h; (b) Tf₂O, NEt₃, CH₂Cl₂, 0 °C, 0.5 h, 60% (2 steps); (c) 10% Pd/C, HCO₂NH₄ (4 equiv.), MeOH, room temperature, 0.5 h, 35% 2, 18% 39, 28% 44; (d) PdCl₂(PPh₃)₂, dppp, NEt₃, HCO₂H, DMF, 100 °C, 2 h, 43%.

Scheme 3

(−)-Aurantioclavine (2). Reagents and conditions: (a) TMSCl, Pd(OAc)₂ (0.5 mol%), Pd(Ad)₂Bu (1.5 mol%), H₂/CO (2: 1), TMEDA, 100 °C, PhMe; (b) N-t-Butylsulfinamide 50, Ti(OEt)₄, THF, 53% (2 steps); (c) TsCl, NEt₃, DMAP, −20 °C, CH₂Cl₂, 78%; (d) MIDA boronate 52 (2 equiv.), [Rh(OH)(cod)]₂ (2.5 mol%), dppbenz (5.0 mol%), K₃PO₄ (2 equiv.), H₂O/ dioxane (3:2), 60 °C, 78%, dr 97:3; (e) NaH, THF, 85%; (f) HCl, MeOH; (g) Mg, MeOH, 99% (2 steps)

Scheme 4

(−)-Aurantioclavine (2). Reagents and conditions: (a) SEMCl, Cs₂CO₃, CH₃CN, 96%; (b) Pd(OAc)₂, SPhos, Na₂CO₃, DMF, 100 °C, vinylborane 60; (c) DDQ, CH₂Cl₂/H₂O, 82% (2 steps); (d) BocNHTs, DIAD, PPh₃, THF, 88%; (e) conc. HCl, MeOH, CH₂Cl₂, 70%; (f) PhNTf₂, Et₃N, CH₂Cl₂, 87%; (g) vinylborane 59, Pd(PPh₃)₄, Na₂CO₃, EtOH/PhMe/H₂O, 100 °C; (h) DDQ, CH₂Cl₂/H₂O, 84% (2 steps); (i) ClCO₂Me, pyridine, CHCl₃, reflux; (j) TFA, CHCl₃, reflux, 87% (2 steps); (k) tBu-PHOX 66 (45 mol%), Pd₂(dba)₃ (15 mol%), Bu₄NCl (0.30 equiv.), 0 °C, CH₂Cl₂, 72 h, 77% (95% ee); (l) 2-methyl-2-butene, Grubbs 2^nd generation catalyst., 40 °C; (m) P(OEt)₃, 170 °C, 78% (2 steps); (n) NaOH (aq), THF/MeOH, reflux; (o) Cu, quinoline, 190 °C, 68% (2 steps); (p) Na/ naphthalene, DME, −78 °C, 90%

Scheme 5

(−)-Aurantioclavine (2). Reagents and conditions: (a) n-BuLi, DMF, THF, −78°C, 70%; (b) vinyl magnesium bromide, THF, −78°C, 5 min, 85%; (c) 73 (21 mol%), [{Ir(cod)Cl}₂] (4 mol%), Sc(OTf)₃ (20 mol%), DCE, 86% yield (93% ee); (d) AD-mix-α, t-BuOH/ H₂O, room temperature, 5 d (e) NaIO₄, MeOH/ H₂O, 0 °C, 5 min; (f) LiHMDS, tetrazole 75, THF, −78 °C, 70% BRSM (3 steps); (g) TMSOTf, lutidine, CH₂Cl₂, 90%; (h) K₂CO₃, MeOH/ H₂O, 100 °C, 90%.

Scheme 6

(−)-trans-(1a) and (−)-cis-clavicipitic acid (1b). Reagents and conditions: (a) DL-serine, AcOH, Ac₂O, 80 °C, 71%; (b) Aspergillus acylase, CoCl₂•6H₂O, NaH₂PO₄ buffer, 37 °C, 2 days, 49% (>99% ee); (c) 2-methyl-3-buten-2-ol, Pd(OAc)₂ (0.1 equiv.), TPPTS (0.2 equiv.), K₂CO₃, H₂O, 130 °C, 8 h then 60% AcOH (aq), 60 °C, 2 h, 61%.

Scheme 7

(−)-cis Clavicipitic acid. Reagents and conditions: (a) 82 (3 equiv.), K₂CO₃ (2 equiv.), DMF, room temperature, 3.5 h, 83%; (b) [Ir(cod)₂]BARF (10 mol%), rac-BINAP (10 mol%), PhCl, 135 °C, 15 h, 79%; (c) HBr/ AcOH (10 equiv.), room temperature, overnight; (d) NaBH(OAc)₃, (4.2 equiv.), Et₃N, CH₂Cl₂, room temperature, 24 h, 53% (2 steps); (d) KOH, MeOH/H₂O (2:1), room temperature, 15 min (ref [46])

Scheme 8

Rugulovasine A (11a) and B (11b). Reagents and conditions: (a) HNMe₂, CH₂O; (b) KCN, aq. DMF (1: 1), 71% (2 steps); (c) (Boc)₂O, DMAP, Et₃N, 94%; (d) DIBAL-H, CH₂Cl₂, −78 °C, 45 min then room temperature, 5 h; (e) benzylmethylamine, CH₂Cl₂, room temperature, 8 h; (f) silyloxyfuran 89, benzene, CSA, reflux, 1 h, 45% (3 steps); (g) KOtBu, NH₃ (liq.), hν, 51%; (h) HCl, H₂ (1 atm), 20% Pd(OH)₂, EtOH, room temperature, 11a:11b (1:2), 74%.

Scheme 9

Rugulovasines A (11a) and B (11b). Reagents and conditions: (a) furanyl stannane 97, Pd(PPh₃)₄, PhMe, K₂CO₃, reflux, 1 h then (Boc)₂O, DMAP, Et₃N, 94%; (b) DIBAL-H, −78 °C to room temperature, then SiO₂, 71%; (c) CBz-OSuc, Et₃N, DMF, room temperature, 26 h; (d) NaH, MeI, DMF, 85% (2 steps); (e) Cs₂CO₃, MeOH; (f) H₂, Pd/C, MeOH-THF, 11a:11b (2:1), 74% (2 steps).

Scheme 10

Rugulovasine A (11a). Reagents and conditions: (a) t-BuLi, THF, −78 °C, 80%; (b) propargylbromide, CrCl₃, LiAlH₄, THF/HMPA, room temperature, 66% (brsm); (c) Ru₃(CO)₁₂, 2,4,6-collidine, CO (1 atm), 100 °C, 58%; (d) Cs₂CO₃, MeOH/THF, 75%; (e) TMSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C, 87%

Scheme 11

Alternative route to intermediate 105. Reagents and conditions: (a) methyl 2-(bromomethyl)acrylate, Zn, I₂, THF, 50 °C, 90%; (b) Ru₃(CO)₁₂, Et₃N, dioxane, 100 °C, 2 h, 95%

Scheme 12

Cycloclavine (26). Reagents and conditions: (a) ethyl 3-(methylamino)propanoate (110), THF, 48%; (b) LiHMDS, THF, −70 °C, 50%; (c) POCl₃, pyridine, 120 °C; (d) HCl, EtOH, 25%; (e) LiAlH₄, Et₂O, 90 %; (f) SO₃•Py, THF; (g) LiAlH₄, Et₂O, 62% (2 steps); (h) CH₂N₂, Pd(OAc)₂ (i) HCl in dioxane, CH₂Cl₂/ Et₂O, 32% (brsm).

Scheme 13

Cycloclavine (26). Reagents and conditions: (a) DHP, HCl (cat.), 90%; (b) CHBr₃, Et₃N, cetrimide, NaOH (aq), CH₂Cl₂, 95%; (c) n-BuLi, THF, −95 °C then MeI, −95 °C to room temperature, 82%; (d) KOt-Bu, DMSO, room temperature, 69%; (e) p-TsOH, MeOH, room temperature, 79%; (f) MsCl, Et₃N, CH₂Cl₂, 0 °C, 1 h; (g) amide 117, NaH, DMF, room temperature, 12 h, 67% (2 steps); (h) NaHMDS, THF, −78 °C then TBSCl; (i) 195 °C, PhCF₃, µw, 1 h 52%, (72% brsm) (2 steps); (j) TBAF, THF, room temperature, 85%; (k) MeOC(O)Cl, 70 °C, 3 h, 71%; (l) LDA, THF, −78 °C, 1 h then TMSCl (1.3 equiv.), CH₃CN, 12 h, 67%; (m) 123, n-BuLi, THF, −78 °C, 51%; (n) 180 °C, PhCF₃, µW, 30 min, 44% (56% brsm); (o) LiAlH₄, THF, 66 °C, 30 min, quantitative.

Scheme 14

Cycloclavine (26). Reagents and conditions: (a) TBSOTf, Et₃N, CH₂Cl₂, 0 °C to room temperature, 45 min; (b) mCPBA, K₂CO₃, CH₂Cl₂, 0 °C, 2 h; (c) TBSCl, DMAP, imidazole, CH₂Cl₂, 6 h, 70% (3 steps); (d) ethyl diazoacetate, LDA, THF, −78 °C, 2 h, 79%; (e) SnCl₄, CH₂Cl₂, 0 °C, 10 min, 80%; (f) trimethylsilyl methylglycinate (133), PhMe, 0 °C, 30 min then 120 °C, 30 min, 65%; (g) DBU, H₂O, THF, reflux, 19 h; (h) TsCl, Bu₄NHSO₄, KOH, PhMe, 78% (2 steps); (i) DIBAL-H, PhMe, 0 °C to room temperature, 30 min; (j) Et₂Zn, I₂, CH₃I, CH₂Cl₂, 0 °C to room temperature, 24% (2 steps); (k) MsCl, NEt₃, 0 °C, 1 h; (l) LiBHEt₃, THF, 0 °C, 45 min; (m) NaOH, MeOH, reflux, 21% (3 steps)

Scheme 15

Cycloclavine (26). Reagents and conditions: (a) 2-hydroxy homopropargyl tosylamine (138), FeCl₃, CH₂Cl₂, reflux, 0.2 h, 83%; (b) NaBH₄, CeCl₃•7H₂O, MeOH, 0 °C; (c) PhSSPh, n-Bu₃P, benzene, 81% (2 steps); (d) n-Bu₃SnH, AIBN, benzene, reflux, 91%; (e) p-TsOH•H₂O, benzene, reflux, 63%; (f) sodium naphthalenide, THF, −78 °C; (g) formalin, AcOH, NaBH₃CN, THF, 71% (2 steps).

Scheme 16

Cycloclavine (26). Reagents and conditions: (a) EtOCHO, 93%; (b) LiAlH₄, Et₂O; (c) methacryloyl chloride 150, NaOH (aq), 79% (2 steps); (d) 152 (1 mol%), PhMe, reflux, 73%; (e) POCl₃, DMF, 91%; (f) (Boc)₂O, DMAP, MeCN, quant.; (g) NaBH₄, MeOH, 0 °C to room temperature, 92%; (h) Br₂, PPh₃, cyclohexane, 93%; (i) pyrrolinone 146, NaH, DMF, 0 °C to room temperature, 52%; (j) Pd(OAc)₂ (10 mol%), PPh₃ (60 mol%), Ag₂CO₃ (2 equiv.), NEt₃, PhMe, 110 °C, 74%; (k) LiAlH₄, THF, reflux, 56%