Annulation of O-silyl N,O-ketene acetals with alkynes for the synthesis of dihydropyridinones and its application in concise total synthesis of phenanthroindolizidine alkaloids

The formation of N-heterocycles with multiple substituents is important in organic synthesis. Herein, we report a novel method for the construction of functionalized dihydropyridinone rings through the annulation of an amide α-carbon with a tethered alkyne moiety. The reaction of the amide with the alkyne was achieved via O-silyl N,O-ketene acetal formation and silver-mediated addition. Furthermore, the developed method was applied for the total synthesis of phenanthroindolizidine and phenanthroquinolizidine alkaloids. By varying the coupling partners, a concise and collective total synthesis of these alkaloids was achieved.


General Information
All chemicals were of reagent grade and were used as purchased. All reactions were performed under an inert atmosphere of dry nitrogen using distilled dry solvents. The reactions were monitored by thin-layer chromatography (TLC) using silica gel 60 F-254 thin-layer plates. Compounds on the TLC plates were visualized under UV light and sprayed with either potassium permanganate or anisaldehyde solutions. Flash column chromatography was conducted on silica gel 60 (230-400 mesh). The melting points were measured using a Buchi B-540 melting point apparatus without correction. 1 H and 13 C NMR spectra were recorded on a JEOLJNM-ECZ400S/L1 (400 MHz) instrument at 298 K unless otherwise noted. Chemical shifts are reported in ppm (δ) units relative to the undeuterated solvent as a reference peak (CDCl3-d1: 7.26 ppm/ 1 H NMR, 77.16 ppm/ 13 C NMR).
The following abbreviations are used to represent the NMR peak multiplicities: s (singlet), d

Screening for the formation of 2
General procedure for the optimization of the reaction conditions (Table S1): Metal (0.010 mmol, 0.10 equiv) and base (0.40 mmol, 4.0 equiv) were added to a solution of compound 1 (29 mg, 0.10 mmol, 1.0 equiv) in solvent (2 mL, 0.05 M), as given in Table S1. The mixture was stirred under the conditions provided in Table S1 and quenched with saturated NaHCO3 aqueous solution (5 mL) at 0 °C. The mixture was extracted three times with CH2Cl2 (3 × 10 mL), and the combined organic fraction was dried over MgSO4 and concentrated under reduced pressure. The chemical yield was estimated by 1 H NMR analysis of the crude reaction mixture using tetrachloroethane (C2H2Cl4) as the internal standard. General procedure for the optimization of the reaction conditions (Table 1): Metal (0.010 mmol, 0.10 equiv) and base (0.40 mmol, 4.0 equiv) were added to a solution of compound 1 (29 mg, 0.10 mmol, 1.0 eq.) in DCE (2 mL, 0.05 M), as given in Table 1. The mixture was stirred under the   conditions given in Table 1 and quenched with saturated NaHCO3 aqueous solution (5 mL) at 0 °C.
The mixture was extracted three times with CH2Cl2 (3 × 10 mL), and the combined organic fraction was dried over MgSO4 and concentrated under reduced pressure. The chemical yield was estimated by 1 H NMR analysis of the crude reaction mixture using tetrachloroethane (C2H2Cl4) as the internal standard. The crude mixture was purified by flash chromatography on silica gel (hexane:EtOAc = 5:1, v/v) to obtain compound 2 as a colorless oil.  (Table S2): AgNTf2 (0.010 mmol, 0.10 equiv), Silyl reagent (0.40 mmol, 4.0 equiv) and DIPEA (0.40 mmol, 4.0 equiv) were added to a solution of compound 1 (29 mg, 0.10 mmol, 1.0 equiv) in DCE (2 mL, 0.05 M), as given in Table S2. The mixture was stirred under the conditions provided in Table S2 and quenched with saturated NaHCO3 aqueous solution (5 mL) at 0 °C. The mixture was extracted three times with CH2Cl2 (3 × 10 mL), and then the combined organic fraction was dried over MgSO4 and concentrated under reduced pressure. The chemical yield was estimated by 1 H NMR analysis of the crude reaction mixture using tetrachloroethane (C2H2Cl4) as the internal standard. General procedure for the optimization of the reaction conditions (Table S3): AgNTf2 (0.010 mmol, 0.10 equiv), TMSOTf (0.40 mmol, 4.0 equiv) and DIPEA (0.40 mmol, 4.0 equiv) were added to a solution of compound 1 (29 mg, 0.10 mmol, 1.0 equiv) in solvent (2 mL, 0.05 M), as given in Table S3. The mixture was stirred at room temperature under the conditions provided in Table S3 and quenched with saturated NaHCO3 aqueous solution (5 mL) at 0 °C. The mixture was extracted three times with CH2Cl2 (3 × 10 mL), and then the combined organic fraction was dried over MgSO4

General procedure for the optimization of the reaction conditions
and concentrated under reduced pressure. The chemical yield was estimated by 1 H NMR analysis of the crude reaction mixture using tetrachloroethane (C2H2Cl4) as the internal standard.

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Computational Studies

General procedure for molecular energy calculations
Computational energy minimization was performed for systems 9a and 10a using the DMol3 program 10 in Material Studio 2022 (Accelrys Software Inc., San Diego, CA, USA). A generalized gradient approximation (GGA) for the Perdew, Burke, and Ernzerhof (PBE) 11 exchange-correlation function was applied with double-numerical plus d-function polarization (DNP), as implemented in DMol3. All the molecules were modeled in the solvent phase (1,2-dichloroethane, COSMOS).

Geometry optimization and energy minimization of the compounds
The energy levels of the compounds were calculated as described above. This computational energy minimization demonstrated that 10a is thermodynamically more stable than 9a. The energy differences was 3.95 kcal/mol.