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. 2023 May 12;25(18):3222-3227.
doi: 10.1021/acs.orglett.3c00903. Epub 2023 May 1.

Enantioselective Synthesis of Fluorinated Indolizidinone Derivatives

Marcos Escolano  1 , Daniel Gaviña  1 , Santiago Díaz-Oltra  1 , María Sánchez-Roselló  1 , Carlos Del Pozo  1
Affiliations

Enantioselective Synthesis of Fluorinated Indolizidinone Derivatives

Marcos Escolano et al. Org Lett. .

Abstract

The enantioselective synthesis of fluorinated indolizidinone derivatives has been developed. The process involved an enantioselective intramolecular aza-Michael reaction of conjugated amides bearing a pendant α,β-unsaturated ketone moiety, catalyzed by the (S)-TRIP-derived phosphoric acid, followed by dimethyltitanocene methylenation and ring closing metathesis (RCM). Final indolizidine-derived products comprise a fluorine-containing tetrasubstituted double bond generated by the RCM reaction, which is a challenging task. The whole synthetic sequence took place in acceptable overall yields with excellent enantioselectivities.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Strategy Devised for the Enantioselective Synthesis of Fluorinated Indolizidines
Scheme 2
Scheme 2. Synthesis of Fluorinated Conjugated Amides 2
Scheme 3
Scheme 3. Scope of the Enantioselective Intramolecular Aza-Michael Reaction–
Unless otherwise noted, reactions were carried out with 2 (0.2–0.5 mmol) and catalyst IV (10 mol %) in chloroform (2 mL) at room temperature for 36 h. Isolated yields after flash column chromatography. Enantiomeric ratios were determined by HPLC analysis on a chiral stationary phase (see the Supporting Information for details).
Scheme 4
Scheme 4. Methylenation/RCM Sequence on Fluorinated Pyrrolidine 3a
Scheme 5
Scheme 5. Synthesis of Fluorinated Indolizidine Derivatives 5 by the Methylenation/RCM Sequence–
Reactions were carried out with 3 (0.1–0.3 mmol) and Cp2TiMe2 (2.5 equiv) in toluene (0.1 M) at 95 °C for 4 h. RCM was performed with HG-II (10 mol %) in toluene (0.005 M) at 105 °C for 48 h. Isolated yields after flash column chromatography. Enantiomeric ratios were determined by HPLC analysis on a chiral stationary phase (see the Supporting Information for details).
Scheme 6
Scheme 6. Hydrogenation of Compound (±)-5a
See this image and copyright information in PMC

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