Transient-axial-chirality controlled asymmetric rhodium-carbene C(sp2)-H functionalization for the synthesis of chiral fluorenes

Kuiyong Dong,Xing Fan,Ju Cai,Sailan Chang,Lihua Qiu,Xinfang Xu,Yang Zheng,Chao Pei,Zhi-Xiang Yu

doi:10.1038/s41467-020-16098-8

Abstract

In catalytic asymmetric reactions, the formation of chiral molecules generally relies on a direct chirality transfer (point or axial chirality) from a chiral catalyst to products in the stereo-determining step. Herein, we disclose a transient-axial-chirality transfer strategy to achieve asymmetric reaction. This method relies on transferring point chirality from the catalyst to a dirhodium carbene intermediate with axial chirality, namely a transient-axial-chirality since this species is an intermediate of the reaction. The transient chirality is then transferred to the final product by C(sp2)-H functionalization reaction with exceptionally high enantioselectivity. We also generalize this strategy for the asymmetric cascade reaction involving dual carbene/alkyne metathesis (CAM), a transition-metal-catalyzed method to access chiral 9-aryl fluorene frameworks in high yields with up to 99% ee. Detailed DFT calculations shed light on the mode of the transient-axial-chirality transfer and the detailed mechanism of the CAM reaction.

Highlights

In catalytic asymmetric reactions, the formation of chiral molecules generally relies on a direct chirality transfer from a chiral catalyst to products in the stereo-determining step
We generalize this strategy for asymmetric cascade reaction, in which the donor/donor carbene is generated in situ via a dual carbene/alkyne metathesis (CAM) process[46,47,48,49,50,51,52,53,54], and directly construction of polycyclic 9-aryl fluorenes with high enantioselectivity (Fig. 1c, reaction 2)[55,56]
Rh2(S-TCPTTL)[4] was used as the catalyst, and solvents were initially evaluated, from which we found that reaction in tert-butyl methyl ether (TBME) afforded 2a with the highest selectivity

Summary

Introduction

The formation of chiral molecules generally relies on a direct chirality transfer (point or axial chirality) from a chiral catalyst to products in the stereo-determining step. The transient chirality is transferred to the final product by C(sp2)-H functionalization reaction with exceptionally high enantioselectivity We generalize this strategy for the asymmetric cascade reaction involving dual carbene/alkyne metathesis (CAM), a transition-metal-catalyzed method to access chiral 9-aryl fluorene frameworks in high yields with up to 99% ee. In most cases, partially leaving or even dissociation of the metal catalyst could occur to form the free zwitterionic intermediate (Fig. 1a, path b, FZI), especially in the case with the neutral dirhodium(II) complex[31], so the subsequent transformation will not secure the high stereoselectivity It is highly challenging and desirable for the development of stereoselective carbene transformations with efficient and practical strategies. We report our recent results by applying this asymmetric transfer strategy, the asymmetric formal C(sp2)-H bond insertion reaction of donor/donor carbene through a transient axialchirality-induced point chirality strategy, which provides a straightforward access to chiral 9-aryl fluorene frameworks with exceptionally high enantioselectivity (Fig. 1c, reaction 1). Considering the chiral fluorenes have found broad applications in various fields, including in pharmaceuticals[57], photoelectrical materials[58], and theoretical studies[59]; the present asymmetric reaction could add complementary values in this respect

Methods

Results

Conclusion