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. 2020 Feb 21;23(2):100840.
doi: 10.1016/j.isci.2020.100840. Epub 2020 Jan 17.

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

Haiyang Wang  1 , Qingdong Hu  1 , Mingxu Wang  1 , Chang Guo  2
Affiliations

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

Haiyang Wang et al. iScience. .

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.

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Conflict of interest statement

Declaration of Interests The authors declare no conflict of interest.

Figures

None
Graphical abstract
Scheme 1
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
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
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
Scheme 4
Enantioselective Synthesis of Analgesic Agent 9
Figure 1
Figure 1
Proposed Mechanism
See this image and copyright information in PMC

References

    1. Andrews I.P., Kwon O. Enantioselective total synthesis of (+)-ibophyllidine via an asymmetric phosphine-catalyzed [3 + 2] annulation. Chem. Sci. 2012;3:2510–2514. - PMC - PubMed
    1. Awata A., Arai T. Pybidine/Copper catalyst: asymmetric exo’-selective [3+2] cycloaddition using imino ester and electrophilic indole. Angew. Chem. Int. Ed. 2014;53:10462–10465. - PubMed
    1. Baskar B., Dakas P.-Y., Kumar K. Natural product biosynthesis inspired concise and stereoselective synthesis of benzopyrones and related scaffolds. Org. Lett. 2011;13:1988–1991. - PubMed
    1. Cai L., Zhang K., Kwon O. Catalytic asymmetric total synthesis of (−)-actinophyllic acid. J. Am. Chem. Soc. 2016;138:3298–3301. - PMC - PubMed
    1. Carmosin, R.J., Carson, J.R., and Pitis, P.M.. (2000). Octahydropyrrolo-[3,4-C]-carbazoles useful as analgesic agents. US Patent No. 6063803.

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