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

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.


General Information
All reactions were performed in 10 ml oven-dried glassware under atmosphere of argon.
Analytical thin-layer chromatography was performed using glass plates pre-coated with 200-300 mesh silica gel impregnated with a fluorescent indicator (254 nm). Flash column chromatography was performed using silica gel (300-400 mesh). 1 H NMR and 13C NMR spectra were recorded in CDCl3 or DMSO-6d on a 400 MHz spectrometer; chemical shifts are reported in ppm with the solvent signals as reference, and coupling constants (J) are given in Hertz. The peak information is described as: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, comp = composite. Enantioselectivity was determined on HPLC using Chiralpak IA-3 and IB-3 column.
Synthesis of S-6 6 : To a 50-mL oven-dried flask containing a magnetic stirring bar and compound S-5 (2.0 mmol) in THF (5.0 ml), was added 15% NaOH (10 ml). The solution was stirred at room temperature for 5 h. After consumption of the material (monitored by TLC), the mixture was acidified with 1N HCl solution (to PH~3.0), The mixture was extracted with DCM (10 mL X 2) and the combined organic extracts was dried over Na2SO4, and solvent was evaporated in vacuo after filtration to give a pale yellow solid, this solid was directly used for the next step without purification.
To a 50-mL oven-dried flask containing a magnetic stirring bar, the above obtained acid, propargyl alcohol (2.4 mmol), and DMAP (4-dimethylaminopyridine, 24.4 mg, 0.2 mmol) in DCM (10 mL), was added DCC (dicyclohexylcarbodiimide, 0.63 g, 2.4 mmol) in batches at 0 o C, and the reaction mixture was stirred at room temperature overnight. After that, the reaction mixture was filtered through Celtie and rinsed with EtOAc (10 mL), and the filtrates were combined. After evaporating the solvents, the residue was purified by column chromatography on silica gel (Hexanes:EtOAc = 20:1) to provide the corresponding esters S-6 as white solid (> 90% yield).

General Procedure for the Asymmetric C-H Functionalization
give the desired polycyclic products 4.           All DFT calculations were performed with the Gaussian 09 software package. 10 For racemic reaction, geometry optimizations of all the minima and transition states involved were carried out using the pure functional PBE. 11,12 The SDD basis set 13

f) Reactivity discussion of substrate 3h:
For the substrate 3h, a higher temperature is need for C-H insertion reaction due to the steric repulsion between the methyl group and lactone ring in the C-H insertion transition state, as suggested by DFT calculations shown below. The C-H insertion step has activation barrier about 5 kcal/mol than that for substrate 3a when we used model catalyst (we speculated that, if real catalyst was used, this energy difference should become lower about 2 to 3 kcal/mol). We hypothesized that the reaction of 3h initially gave higher ee, because this was set up in the first step of the catalytic cycle and there was no difference from substrate 3a. But the product could then undergo racemization at 60 °C. One support for this hypothesis is that product 4c heating at 80 °C for 12 hours underwent racemization from 90% ee to 30% ee.

g) Estimation of the rotation barrier of axial chiral intermediate c-INT3
Considering that the C-H insertion step is the rate-determine step in this tandem reaction, we In the rotation transition state structure for intermediate c-INT3, remarkable distortion of chiral dirhodium catalyst and substrate part can be observed due to the strong repulsion of two aryl rings, which is shown below.