Catalytic enantioselective nitrone cycloadditions enabling collective syntheses of indole alkaloids

Abstract

Tetrahydro-β-carboline skeletons are prominent and ubiquitous in an extraordinary range of indole alkaloid natural products and pharmaceutical compounds. Powerful synthetic approaches for stereoselective synthesis of tetrahydro-β-carboline skeletons have immense impacts and have attracted enormous attention. Here, we outline a general chiral phosphoric acid catalyzed asymmetric 1,3-dipolar cycloaddition of 3,4-dihydro-β-carboline-2-oxide type nitrone that enables access to three types of chiral tetrahydro-β-carbolines bearing continuous multi-chiral centers and quaternary chiral centers. The method displays different endo/exo selectivity from traditional nitrone chemistry. The distinct power of this strategy has been illustrated by application to collective and enantiodivergent total syntheses of 40 tetrahydro-β-carboline-type indole alkaloid natural products with divergent stereochemistry and varied architectures.

Fig. 1. Relevance of THβCs and state of the art in catalytic asymmetric syntheses of THβCs.

a Representative THβC-type natural products and bioactive compounds. b Previous asymmetric approaches towards THβCs.

Fig. 2. Catalytic asymmetric synthesis of THβCs from nitrone.

a Development of the asymmetric conversion of 3,4-dihydro-β-carboline-2-oxides. b Our design of unified platform starting materials to construct various THβCs with varied architectures for collective total syntheses of natural products.

Fig. 3. Substrate scope of nitrones and vinyl ethers.

Reaction condition A: 1 (0.20 mmol), 2a or 2b (0.40 mmol), catalyst (0.02 mmol), and 3 Å MS (300 mg) in CHCl₃ (2.0 mL) at −60 °C. Reaction condition B: 6 (0.20 mmol), 2a (0.40 mmol), catalyst (0.02 mmol), and 3 Å MS (300 mg) in DCE (2.0 mL) at −60 °C. Isolated yield. d.r. >19:1. The ee values were determined by chiral HPLC analysis. ^a 6-ⁿOct-4a was used. ^b DCM was used. ^c DCE was used. ^d (R)-4b was used as catalyst. ^e Toluene as solvent at −20 °C.

Fig. 4. Investigation of the mechanism.

a The key transition states of 1,3-dipolar cycloaddition reactions. Gibbs free energy (in kcal/mol) obtained at the level of SMD(solvent)-B3LYP-D3/def2TZVP//B3LYP-D3/6-31G*. In accordance with experimental conditions, chloroform was utilized as the solvent for reactions involving 1a and 2a/2b with catalyst 4b. Dichloroethane was employed as the solvent for reactions of 6b and 2a with catalyst 4a. Additionally, toluene was the chosen solvent for reactions of 6b and 2b with catalyst 4a. b FMO diagram for the 1,3-dipolar cycloaddition reactions. HF/6-31G*//B3LYP-D3/6-31G*-computed orbital energies in eV are shown.

Fig. 5

Post-transformation.

Fig. 6. Total synthesis from product 3.

a (a) BnBr, MeCN, 25 °C, then DABCO, reflux, then (Boc)₂O, DMAP, Et₃N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) ClPh₃PCH₂OCH₃, ^tBuOK, THF, 0–25 °C, then HCO₂H, DCM, 25 °C; (d) Pd(OH)₂/C, H₂, MeOH, 25 °C; (e) TFA, DCM, 25 °C. b (a) Allyl bromide, MeCN, 25 °C, then DABCO, reflux, then (Boc)₂O, DMAP, Et₃N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) Ph₃PMe•Br, ^tBuOK, THF, 25 °C; (d) Grubbs II, Toluene, 80 °C; (e) Pd/C, H₂, EtOH, 25 °C; (f) TFA, DCM, 25 °C. c (a) (Z)-1-Bromo-2-iodo-2-butene, MeCN, 25 °C, then DABCO, reflux, then (Boc)₂O, DMAP, Et₃N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) MsCl, Et₃N, DCM, 0–25 °C, then TMSCN, TBAF, MeCN, 25 °C; (d) MeMgBr, Et₂O, 0–25 °C; (e) Pd(PPh₃)₄, ^tBuOK, THF, reflux, then silica gel, Toluene, reflux; (f) DIBAL-H, Toluene, −78 °C; (g) (MeO)₂P(O)CH₂CO₂Me, NaH, THF, 25 °C; (h) TFA, DCM, 0–25 °C; (i) Ni(COD)₂, Et₃N, Et₃SiH, MeCN, 25 °C; (j) Crabtree’s catalyst, H₂, DCM, 25 °C; (k) LiAlH₄, THF, 0–25 °C; (l) LDA, THF, −78 °C, then HCO₂Me, −78–25 °C; (m) TMSCHN₂, DIPEA, MeCN, MeOH, 25 °C; (n) PtO₂, H₂, MeOH, 25 °C. d (a) 2,3-Dibromopropene, MeCN, 25 °C, then DABCO, reflux, then (Boc)₂O, DMAP, Et₃N, 25 °C; (b) DIBAL-H, Toluene, −78 °C; (c) (MeO)₂P(O)CH₂CO₂Me, NaH, THF, 25 °C; (d) TFA, DCM, 25 °C; (e) AIBN, ⁿBu₃SnH, Toluene, reflux; (f) (Boc)₂O, DMAP, Et₃N, DCM, 25 °C; (g) DIBAL-H, Toluene, −78 °C; (h) Allylmagnesium bromide, THF, 0 °C; (i) Hoveyda–Grubbs II, DCM, reflux; (j) Pd/C, H₂, MeOH, 25 °C; (k) TFA, DCM, 25 °C; (l) DCC, DMSO, Cl₂CHCO₂H, 35 °C; (m) DCC, Cl₂CHCO₂H, DMSO, 35 °C, then TFA, DCM, 25 °C. e (a) MeI, MeCN, 25 °C, then DABCO, reflux, then (Boc)₂O, DMAP, Et₃N, reflux; (b) DIBAL-H, Toluene, −78 °C; (c) (MeO)₂POCH₂CO₂Me, NaH, THF, 25 °C; (d) PtO₂, H₂, MeOH, 25 °C; (e) DIBAL-H, Toluene, −78 °C, then TFA, DCM, 0–25 °C; (f) DIBAL-H, Toluene, −78 °C, then TFA, H₂O, THF, 0–25 °C.

Fig. 7. Total synthesis from product 5a and 7b.

a Total syntheses of eburnane-type indole alkaloids. Reagents and conditions: (a) (Boc)₂O, DMAP, Et₃N, DCM, 25 °C; (b) Comins’ Reagent, LiHMDS, THF, −78 °C; (c) LiCl, Pd(PPh₃)₄, ⁿBu₃SnH, THF, 25 °C; (d) Allyl bromide, MeCN, 25 °C, then DABCO, reflux; (e) Grubbs II, DCM, reflux, then TFA, DCM, 0–25 °C; (f) LDA, HMPA, −78 °C, then EtI, THF, −40 °C; (g) DIBAL-H, Toluene, 0 °C; (h) LiAlH₄, THF, 0–25 °C; (i) MsCl, Et₃N, DCM, 0–25 °C; (j) TMSCN, TBAF, MeCN, 25 °C; (k) DIBAL-H, Toluene, −78 °C; (l) PtO₂, H₂, EtOH, 25 °C; (m) TPAP, NMO, DCM, 0–25 °C; (n) TFA, DCM, 0–25 °C. b Total syntheses of eburnane-type indole alkaloids. Reagents and conditions: (a) DIBAL-H, Toluene, −78 °C then HCl in MeOH, 0–25 °C; (b) PtO₂, H₂, MeOH, 25 °C; (c) DIBAL-H, Toluene, −78 °C then HCl in EtOH, 0–25 °C; (d) PtO₂, H₂, EtOH, 25 °C; (e) SO₃•Py, DMSO, Et₃N, 0 °C-25 °C; (f) TMSCN, AlCl₃, CHCl₃, 0–25 °C; (g) conc. HCl, MeOH, 80 °C; (h) LiAlH₄, THF. 0–25 °C. c Total syntheses of (−)-arbornamine. Reagents and conditions: (a) LiAlH₄, THF, 0–25 °C; (b) TBDPSCl, Imidazole, DMF, 25 °C; (c) SmI₂, MeOH, THF, 25 °C; (d) (Z)-1-Bromo-2-iodo-2-butene, K₂CO₃, MeCN, 25 °C; (e) MsCl, Et₃N, DCM, 0–25 °C; (f) TMSCN, TBAF, MeCN, 25 °C; (g) DIBAL-H, Toluene, −78 °C; (h) PDC, DCM, 25 °C; (i) LiHMDS, THF, PhSeBr, −78 °C, then aq. NH₄Cl, H₂O₂, 0 °C; (j) Ni(COD)₂, Et₃N, Et₃SiH, MeCN, 25 °C; (k) TBAF, THF, 0–25 °C, then LiAlH₄, 0 °C.

Fig. 8. Enantiodivergent total syntheses of eburnane-type alkaloids.

Reaction conditions: (a) (Boc)₂O, DMAP, Et₃N, 25 °C; (b) Comins’ Reagent, LiHMDS, THF, −78 °C; (c) LiCl, Pd(PPh₃)₄, ⁿBu₃SnH, THF, 25 °C; (d) Allyl bromide, MeCN, 25 °C, then DABCO, reflux; (e) Grubbs II, DCM, reflux, then TFA, DCM, 0–25 °C; (f) LDA, HMPA, −78 °C, then EtI, THF, −40 °C; (g) DIBAL-H, Toluene, 0 °C; (h) MsCl, Et₃N, DCM, 0–25 °C; (i) TMSCN, TBAF, MeCN, 25 °C; (j) DIBAL-H, Toluene, −78 °C; (k) PtO₂, H₂, EtOH, 25 °C; (l) TFA, DCM, 0–25 °C; (m) TPAP, NMO, DCM, 0–25 °C; (n) DIBAL-H, Toluene, −78 °C then HCl in MeOH, 0–25 °C; (o) PtO₂, H₂, MeOH, 25 °C; (p) DIBAL-H, Toluene, −78 °C then HCl in EtOH, 0–25 °C.