Desymmetrization of Cyclic 1,3-Diketones under N-Heterocyclic Carbene Organocatalysis: Access to Organofluorines with Multiple Stereogenic Centers.

Guanjie Wang,Min Zhang,Yezhi Guan,Zhenqian Fu,Chenlong Wei,Pengcheng Zheng,Yonggui Robin Chi,Wei Huang,Donghui Wei,Xianfang Hong,Ye Zhang

doi:10.34133/2021/9867915

Abstract

Symmetric 1,3-diketones with fluorine or fluorinated substituents on the prochiral carbon remain to be established. Herein, we have developed a novel prochiral fluorinated oxindanyl 1,3-diketone and successfully applied these substrates in carbene-catalyzed asymmetric desymmetrization. Accordingly, a versatile strategy for asymmetric generation of organofluorines with fluorine or fluorinated methyl groups has been developed. Multiple stereogenic centers were selectively constructed with satisfactory outcomes. Structurally diverse enantioenriched organofluorines were generated with excellent results in terms of yields, diastereoselectivities, and enantioselectivities. Notably, exchanging fluorinated methyl groups to fluorine for this prochiral 1,3-diketones leads to switchable stereoselectivity. Mechanistic aspects and origin of stereoselectivity were studied by DFT calculations. Notably, some of the prepared organofluorines demonstrated competitive antibacterial activities.

Highlights

Asymmetric desymmetrization represents one of the most facile and efficient methods for the generation of enantioenriched organic compounds, especially with multiple stereogenic centers, from meso or prochiral raw materials [1–4]
This desymmetric strategy as the key step has shown wide application in diverse natural product synthesis associated with diverse promising biological activities [22, 23]
Given the significant success of asymmetric N-heterocyclic carbene (NHC) catalysis [43–52] and privileged structural characters of prochiral 1,3-diketones, based on our ongoing interest in organocatalysis [53–57], we envisioned that a versatile method for the synthesis of enantioenriched organofluorines with multiple stereogenic centers might be established based on NHC-catalyzed asymmetric desymmetrization of novel prochiral fluorinated or fluoromethylated oxindolyl 1,3-ketones

Summary

Introduction

Asymmetric desymmetrization represents one of the most facile and efficient methods for the generation of enantioenriched organic compounds, especially with multiple stereogenic centers, from meso or prochiral raw materials [1–4]. Given the significant success of asymmetric N-heterocyclic carbene (NHC) catalysis [43–52] and privileged structural characters of prochiral 1,3-diketones, based on our ongoing interest in organocatalysis [53–57], we envisioned that a versatile method for the synthesis of enantioenriched organofluorines with multiple stereogenic centers might be established based on NHC-catalyzed asymmetric desymmetrization of novel prochiral fluorinated or fluoromethylated oxindolyl 1,3-ketones. Spiro compounds containing oxindole moieties are proven among the important scaffolds in natural products and bioactive molecules exemplified by those in Figure 1(d) [61, 62] These available prochiral 1,3-diketones could react with unsaturated acyl triazolium intermediates [63–65] obtained from bromoenals with NHC to construct spiropolycyclic organofluorines with five stereogenic centers, including three quaternary stereocenters. It may be mentioned that enantioselective synthesis of tricyclic β-lactones by NHC-catalyzed desymmetrization of cyclic 1,3-diketones has been demonstrated recently by Shee and coworkers [66]

Results

Discussion

Materials and Methods

Conflicts of Interest