ARTICLE https://doi.org/10.1038/s41467-020-16098-8 OPEN Transient-axial-chirality controlled asymmetric rhodium-carbene C(sp2)-H functionalization for the synthesis of chiral fluorenes ✉ Kuiyong Dong1,2,4, Xing Fan3,4, Chao Pei2, Yang Zheng2, Sailan Chang2, Ju Cai2, Lihua Qiu2, Zhi-Xiang Yu3 & ✉ Xinfang Xu 1,2 1234567890():,; 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. 1 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. 2 College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China. 3 Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking ✉ University, Beijing 100871, China. 4These authors contributed equally: Kuiyong Dong, Xing Fan. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2020) 11:2363 | https://doi.org/10.1038/s41467-020-16098-8 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16098-8 etal carbene reaction is one of the most versatile metal-associated zwitterionic intermediate29 or Wheland-type methods for the assembly of valuable molecules with intermediate30 (Fig. 1a, path a, MZI, through a M–C single M 1–8 structural complexity and diversity . In this regard, bond). However, in most cases, partially leaving or even dis- the pursuit of practical and efficient catalytic approach has been sociation of the metal catalyst could occur to form the free of long-standing appealing, especially the catalytic asymmetric zwitterionic intermediate (Fig. 1a, path b, FZI), especially in the carbene transformations, such as cyclopropanation9,10,X–H case with the neutral dirhodium(II) complex31, so the subsequent insertion11,12,C–H insertion13–16, hydride migration17, transformation will not secure the high stereoselectivity. There- cycloaddition18,19, ylide formation followed by rearrangement20 fore, it is highly challenging and desirable for the development of or interception21, and others22–28. Generally, the asymmetry stereoselective carbene transformations with efficient and prac- induction in these metal-carbene reactions heavily relied on the tical strategies. chiral catalyst-associated species, and the asymmetric transfer On the other hand, the axial chirality has been found in a strategy is a point-to-point chirality transfer manner. For exam- variety of rotation-hindered molecules32–39, such as BINAP and ple, the enantioselectivity control in catalytic asymmetric elec- BINOL derivatives, which have been widely used as privileged trophilic aromatic substitution reaction, which happens at the H- ligands or catalysts in asymmetric catalysis40–45. Inspired by the shift step, is enabled by the point chirality of the catalyst via a unique structures of these chiral ligands with axial chirality, we a S R H Path a ∗ M High ee L R Ar MZI R Ar R R ML* Stereodetermining step at H-shift L ∗ M S point-to-point chirality transfer Ar N2 ∗ S R H R H ∗ M -ML* Lower Path b L R R or no ee FZI Fragile M–C bond b Tight M = C bond R* R* R* R* R* R* R* O O R* O R O R O O O O O O O O O Rh R' O Rh R' O Rh R' O Rh R' Rh O Rh O Rh O Rh O O O O O O O O O O O O O R* R* R* R* R* R* R* R* Without axial chirality With axial chirality stereoselectivity is controlled by stereoselectivity is dominated by the chiral catalyst transient-axial-chirality c This work: C–H 1 1 2 Ar Ar2 Rh L* Ar Ar functionalization 1 2 2 4 Ar Ar (1) ∗ Ar3 Ar3 Axial chirality 3 N2 Rh2L*4 Chiral catalyst Ar Asymmetry induction Transient-axial-chirality point & axial chirality dominated chirality transfer O Ar R O O O O N2 C–H Rh2L4* functionalization Ar (2) O Ar Dual carbene/alkyne ∗ metathesis (CAM) R Rh L* Chiral catalyst Axial chirality 2 4 R Fig. 1 Asymmetry induction in metal-carbene reactions. a Asymmetry induction in catalytic metal-carbene C(sp2)-H functionalization. b Chirality in transient carbene intermediate. c This work describes the transient axial-chirality-controlled asymmetric C(sp2)–H functionalization. The pink crescent = chiral ligand (L = large group, S = small group). M = metal catalyst. Rh2L4* = chiral dirhodium complex. 2 NATURE COMMUNICATIONS | (2020) 11:2363 | https://doi.org/10.1038/s41467-020-16098-8 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16098-8 ARTICLE hypothesized that, when the dirhodium complexes catalyze the construction of polycyclic 9-aryl fluorenes with high enantios- generation of metal-carbene species with steric bulky carbene electivity (Fig. 1c, reaction 2)55,56. Considering the chiral fluor- precursors, such as ortho-substituted aryl carbene, a transient enes have found broad applications in various fields, including in axial-chirality will be formed in the corresponding carbene pharmaceuticals57, photoelectrical materials58, and theoretical intermediate (Fig. 1b). The axial chirality in the intermediate is studies59; the present asymmetric reaction could add com- called transient axial chirality, considering this chirality will then plementary values in this respect. be transfer to the final product by the followed reaction. In other word, instead of heavily relying on the point chirality of the metal catalyst in the later stereo-determining step (e.g., Fig. 1a), the final Results chirality transfer from catalyst to product in this mode would be Reaction optimization. We began our investigation of the determined by the initially formed axial chirality between the asymmetric C–H functionalization reaction with diaryl diazo catalyst and the substrate, due to the restricted rotation of these compound 1a, which is a typical donor/donor-type carbene carbene intermediates in the followed transformations. Thus, precursor, as model substrate (Table 1). To optimize reaction high enantioselectivity could be envisioned in metal-carbene conditions, Rh2(S-TCPTTL)4 was used as the catalyst, and sol- reactions based on this transient axial-chirality transfer strategy. vents were initially evaluated (entries 1–5), from which we found Herein, we report our recent results by applying this asymmetric that reaction in tert-butyl methyl ether (TBME) afforded 2a with transfer strategy, the asymmetric formal C(sp2)-H bond insertion the highest selectivity (entry 5, 82% ee and 92% yield). Lowering reaction of donor/donor carbene through a transient axial- the reaction temperature did not improve the selectivity (entry 6). chirality-induced point chirality strategy, which provides a Further investigation of a variety of dirhodium complexes turned fl straightforward access to chiral 9-aryl uorene frameworks with out that the optimum enhancement was achieved by Rh2(S- fl exceptionally high enantioselectivity (Fig. 1c, reaction 1). More- TFPTTL)4 with four electron-withdrawing uoro substituents on over, we generalize this strategy for asymmetric cascade reaction, the phthalimide ring (entry 10, 90% yield, 99% ee). It should be in which the donor/donor carbene is generated in situ via a dual mentioned that slowly addition of the rhodium catalyst to the – carbene/alkyne metathesis (CAM) process46 54, and directly diazo compound is essential in all these reactions to ensure the Table 1 Condition optimization. Rh(II) F (1.0 mol%) F 4 Å MS, rt N2 Ph Ph 1a 2a Entrya Rh(II) Solvent Yield (%)b Ee (%)c 1Rh2(S-TCPTTL)4 DCM 91 60 2Rh2(S-TCPTTL)4 DCE 90 63 3Rh2(S-TCPTTL)4 Toluene 85 75 4Rh2(S-TCPTTL)4 Hexane 90 62 5Rh2(S-TCPTTL)4 TBME 92 82 d 6 Rh2(S-TCPTTL)4 TBME 80 81 d 7 Rh2(S-PTTL)4 TBME 82 15 8Rh2(S-NTTL)4 TBME 90 65 9Rh2(S-TBPTTL)4 TBME 92 70 10 Rh2(S-TFPTTL)4 TBME 90 99 11 Rh2(S-PTPA)4 TBME 75 5 12 Rh2(S-PTA)4 TBME 72 2 13 Rh2(S-DOSP)4 TBME 90 13 d 14 Rh2(S-PTAD)4 TBME 92 25 H H t-Bu O Rh R O Rh O H N O Rh t-Bu H O O Rh O Rh N O Rh X O O O N O Rh N O O Rh X X SO2Ar 4 4 4 X 4 R = Me Rh (S-PTA) 2 4 X = F, Rh2(S-TFPTTL)4 R = Bn Rh (S-PTPA) Rh2(S-DOSP)4 2 4 X = Cl, Rh2(S-TCPTTL)4 Rh (S-NTTL) R = t-Bu Rh (S-PTTL) 2 4 Ar = p-(n-C12H25)C6H4 2 4 X = Br, Rh2(S-TBPTTL)4 R = adamantyl Rh2(S-PTAD)4 DCM dichloromethane, DCE 1,2-dichloroethane, TBME tert-butyl methyl ether. aThe reaction was carried out on a 0.2 mmol scale: 1a (0.2 mmol), and 4 Å MS (100 mg) in 1.0 mL solvent, was added a solution the catalyst in 1.0 mL of the same solvent via syringe pump in 40 min under inert atmosphere.