Enantioselective [4+2] Annulation to the Concise Synthesis of Chiral Dihydrocarbazoles

Abstract

A highly efficient phosphine-catalyzed enantioselective [4 + 2] annulation of allenoates with 3-nitroindoles or 3-nitrobenzothiophenes has been developed. The protocol represents a unique dearomatization-aromatization process to access functionalized dihydrocarbazoles or dihydrodibenzothiophenes with high optical purity (up to 97% ee) under mild reaction conditions. The synthetic utility of the highly enantioselective [4 + 2] annulation enables a concise synthesis of analgesic agent.

Keywords: Catalysis; Organic Reaction; Organic Synthesis.

Graphical abstract

Scheme 1

Phosphine-catalyzed [4 + 2] Dearomatization/Aromatization Reactions for the Formation of Enantioenriched Heterocycles (A) Representative examples of chiral hydrocarbazole derivatives. (B) Formal [4 + 2] annulation for the preparation of hydrocarbazole. (C) Concise approach to the enantioselective synthesis of analgesic agent.

Scheme 2

Substrate Scope of Enantioselective [4 + 2] Annulation Unless indicated otherwise, the reactions were conducted with 1 (0.1 mmol), 2 (0.15 mmol), and catalyst 4d (0.01 mmol) in toluene at room temperature for 12–48 h. Then silica gel was added to the reaction mixture to complete elimination of HNO₂. ^aYield of the isolated product after purification by chromatography on silica gel. ^bEnantiomeric excess determined by HPLC analysis. ^cAromatization process was performed at 50°C. ^d20 mol% of 4d. ^eThe reaction was performed on 1 mmol scale.

Scheme 3

Enantioselective [4 + 2] Annulation of 3-Nitrobenzothiophene 5 Unless indicated otherwise, the reactions was conducted with 5 (0.1 mmol), 2 (0.15 mmol), and catalyst 4d (0.01 mmol) in toluene (1.0 mL) at 0°C for 48–60 h. Then silica gel was added to the reaction mixture to complete elimination of HNO₂. Yield of the isolated product after purification by chromatography on silica gel. Enantiomeric excess determined by HPLC analysis. ^a0.02 mmol of 4d was used.

Scheme 4

Enantioselective Synthesis of Analgesic Agent 9

Figure 1

Proposed Mechanism