Ir-catalyzed enantioselective B−H alkenylation for asymmetric synthesis of chiral-at-cage o‑carboranes

The asymmetric synthesis of chiral-at-cage o-carboranes, whose chirality is associated with the substitution patterns on the polyhedron, is of great interest as the icosahedral carboranes have wide applications in medicinal and materials chemistry. Herein we report an intermolecular Ir-catalyzed enantioselective B−H alkenylation for efficient and facile synthesis of chiral-at-cage o-carboranes with new skeletons under mild reaction conditions. Generally very good to excellent yields with up to 99% ee can be achieved in this Ir-catalyzed B−H alkenylation. The enantiocontrol model is proposed based on Density Functional Theory calculations in which the use of chiral phosphoramidite ligand is essential for such asymmetric o-carborane B−H alkenylation.

S tereochemistry has been one of the most active research areas in modern chemistry. Asymmetric catalysis with chiral metal complexes, enzymes, and chiral organic molecules have emerged as successful and powerful tools in asymmetric synthesis to obtain enantiomerically enriched compounds [1][2][3][4][5] . Despite a great variety of chiral structures incorporating central, axial, planar, and helical chirality achieved by catalytic asymmetric synthesis, to obtain the inherent chirality of three-dimensional cage compounds such as carboranes is extremely challenging and the currently available methods to access such an enantioenriched skeleton are still rather limited [6][7][8][9] .
Herein, we report an intermolecular catalytic asymmetric B−H functionalization of o-carboranes with the assistance of a directing group and chiral phosphoramidite ligand. This protocol allows easy access to chiral-at-cage o-carborane derivatives in high yields and excellent enantioselectivities via Ir-catalyzed enantioselective B−H alkenylation under mild reaction conditions. It illustrates an important application of asymmetric synthesis beyond conventional organic chemistry into the chemistry of chiral boron cages.
The circular dichroism (CD) spectra of (R)-3ba and (S)-3ba exhibited unambiguously mirror images to each other, indicating a pair of enantiomers. The absolute configurations of (R)-3ba and (S)-3ba were determined via single-crystal X-ray analyses (Fig. 2). In addition, the single-crystal X-ray structure and CD spectrum of (S)-3bd (see the Supplementary Information for detail) further confirm the assignment of the absolute configurations for (R)-3ba and (S)-3ba.
Substrate scope. Under the optimized reaction conditions ( Table 2, entry 9), the alkyne substrate scope was then examined and the results were summarized in Fig. 3. Generally, diaryl acetylenes with electron-withdrawing groups such as -F, -Cl, -Br, -CF 3, and -CO 2 Me worked very well, affording (S)-3bb-3bf, 3bm, and 3bq in excellent yields with 89-99% ee. p-Acyl and pphenyl were also tolerated with low conversions and enantioselectivities (3bg, 3bh). For the electron-donating group containing substrates, a higher reaction temperature of 80°C was R R  required to promote the reaction, leading to slightly decreased enantioselectivity. It was found that the addition of 1.1 equiv of Cu(OAc) 2 to the above reactions could not only accelerate the reaction but also improve the enantioselectivity (3bi-3bk, 3bn-3bp, 3br, 3bs) with a lower reaction temperature probably due to the activation of alkynes via their complexation with Cu(II) salt. Steric factors also played a role as di-o-tolylacetylene was not compatible. Unsymmetrical alkyne MeC≡CPh gave two regioisomers of 3bt and 3bt′ in a 4:1 ratio with 58% and 60% ee, respectively. For the scope of o-carboranes (Fig. 4), cage C substituent R 1 does not have an obvious impact on the reactions except for R 1 = H (3ca), affording the corresponding (S)-B(5)-alkenylated compounds (3aa, 3ba, 3da-3ha) in high yields (94−99%) with excellent enantioselectivity (92−99% ee). For B(9,12)-dimethylated o-carborane, a lower alkenylation efficiency was observed, but the enantioselectivity remained unchanged (3ia; 60% yield, 99% ee). On the other hand, bulky substituent R 3 on the amide group resulted in slightly low yields and enantioselectivities (3na-3ra).
Compounds 3 and 4 were fully characterized by 1 H-, 13 C-and 11 B-NMR spectroscopy, as well as high-resolution mass spectrometry. The molecular structures of 3bd, 3bs, and 3ha were further confirmed by single-crystal X-ray analyses.

Mechanistic investigations.
To gain some insight into the reaction mechanism, several control experiments were conducted. Under standard reactions, using C 6 H 5 SO 3 D as the acid additive gave (S)-3ba-d 1 in 98% yield and 99% ee with 20% D-incorporation (Fig. 6a). On the other hand, treatment of 1b-d 8 with C 6 H 5 SO 3 H resulted in a 55% D-incorporation, suggesting some D-H exchange with the acid (Fig. 6b). In the absence of C 6 H 5 SO 3 H additive, (S)-3ba-d 8 with >95% D-incorporation was obtained, indicating that the deuterium was originated from B(5)-D, and no deuterium scrambling over carborane was observed (Fig. 6c). To gain additional information regarding the initial rate of the reaction, parallel reactions using substrate 1b and 1b-d 8 were conducted, leading to the kinetic isotope effect of k H /k D = 0.95 ( Fig. 6d; see Supplementary Figs. 11 and 12 for detail), which indicates that B−H activation is not involved in the ratedetermining step.
As the Ir(I) can be oxidized by Ag(I) to generate in-situ active catalyst Ir(III) 43 that performs even better than [Cp*IrCl 2 ] 2 ( Table 2), a plausible reaction mechanism is proposed in Fig. 7.   In the reaction, cage B(4/5) regioselectivity is dominated by the combination of the Ir(III) catalyst and the directing group 31,33 , whereas the enantioselectivity is controlled by the chiral phosphoramidite ligand 40 . (S)-or (R)-L8 leads to (S)-or (R)-enantiomer, respectively. To shed some light on the enantioselectivity in the current asymmetric B−H functionalization, the transition states TS-R and TS-S leading to the final alkenylation products in R and S configuration, respectively, were located by DFT calculations on the basis of concerted metalation-deprotonation (CMD) mechanism (Fig. 8). The B −Ir bond-forming step (from the intermediates B to C) was identified as the stereoselectivity-determining step, leading to the preferentially generated (S)-B(5)-alkenylation product. The transition state TS-S was calculated to be more stable than its enantiomer TS-R by 4.1 kcal/mol. Non-covalent interactions (NCI) analysis, which has been successful to identify electrostatic interactions, was performed using Multiwfn software 45,46 to gain further insight into the key factors that control stereoselectivity. The NCI pictures show that the π···π interactions exist in both isomers with nearly equal contributions (Fig. 8b). The C-H···π interactions only exist in TS-S. These additional interactions would be responsible for stabilizing the transition state TS-S.
In summary, the first intermolecular asymmetric B−H functionalization has been developed via Ir catalysis for the enantioselective synthesis of chiral-at-cage o-carboranes under NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-27441-y ARTICLE mild reaction conditions. Generally very good to excellent yields with up to 99% ee can be achieved in this Ir-catalyzed B−H alkenylation. The enantiocontrol model is proposed based on DFT calculations in which the use of chiral phosphoramidite ligand is essential for such asymmetric o-carborane B−H functionalization. This work sets a good example for exploring the potential of asymmetric synthesis beyond conventional organic chemistry into the chemistry of chiral-at-cage o-carboranes.

Methods
A representative procedure for the synthesis of 3. An oven-dried Schlenk flask equipped with a stir bar was charged with [Ir(cod)Cl] 2 (1.7 mg, 0. 0025 mmol) and (S)-L8 (2.6 mg, 0.005 mmol), followed by dry toluene (1 mL). The mixture was stirred at room temperature for 1 h, to which was successively added 1 (0.10 mmol), 2 (0.12 mmol), benzenesulfonic acid (24 mg, 0.15 mmol), AgNTf 2 (4.9 mg, 0.0125 mmol), and dry toluene (1 mL). The flask was closed under an atmosphere of nitrogen, then stirred at 50°C for 40 h. After hydrolysis with water (5 mL) and extraction with diethyl ether (10 mL × 3), the ether solutions were combined, dried over anhydrous Na 2 SO 4, and concentrated to dryness in vacuo. The residue was subjected to flash column chromatography on silica gel (230-400   Fig. 5 Large-scale synthesis of (S)-3ba and its transformation. a Largescale synthesis of (S)-3ba. b Deacylation of (S)-3ba.   Fig. 7 Proposed catalytic cycle. Possible reaction mechanism of the Ircatalyzed enantioselective B−H alkenylation. The chiral ligand on Ir has been marked as L* for clarity.