Catalytic asymmetric C–Si bond activation via torsional strain-promoted Rh-catalyzed aryl-Narasaka acylation

Atropisomers are important organic frameworks in bioactive natural products, drugs as well as chiral catalysts. Meanwhile, silanols display unique properties compared to their alcohol analogs, however, the catalytic synthesis of atropisomers bearing silanol groups is challenging. Here, we show a rhodium-catalyzed torsional strain-promoted asymmetric ring-opening reaction for the synthesis of α-silyl biaryl atropisomers. The reaction features a dynamic kinetic resolution of C(Ar)-Si bond cleavage, whose stereochemistry was controlled by a phosphoramidite ligand derived from (S)-3-methyl-1-((2,4,6-triisopropylphenyl)sulfonyl)piperazine. This work is a demonstration of an aryl-Narasaka acylation, where the C(Ar)-Si bond cleavage is promoted by the torsional strain of α, α’-disubstituted silafluorene.

A tropisomers are an important class of compounds, which showcased chirality due to the restricted rotation around the single C-C, C-N, or C-O bonds [1][2][3] . Among them axially chiral biaryls have caught extensive attentions due to their wide existence in bioactive natural products, drugs 4,5 ; furthermore it is one of prior skeletons for chiral ligands or catalysts in asymmetric catalysis.
In comparison with the classic asymmetric couplings, which proceed via a highly bulky metal intermediate (Fig. 1a), the ringopening strategy surcumvented this key intermediate and it provided an efficient protocol for construction of biaryl atropisomers. Bringmann pioneered the atropisomer synthesis via ringopening of lactones, with either stoichiometric or catalytic methods ( Fig. 1b) 41,42 . Recently, Zhang and co-workers realized Ir-catalyzed asymmetric hydrogenation of Bringmann's lactones 43 . Under the catalysis of nickel, copper, and palladium, the groups of Hayashi, Gu and others realized the ring-opening of dibenzo[b,d]thiophenes 44 , diaryliodoniums [45][46][47][48] , and 9H-fluoren-9-ols (Fig. 1b) 49 . This ring-opening reactions showed particular advantages in the preparation of sterically hindered ortho tetrasubstituted atropisomeric biaryls; furthermore, these ringopening reactions displayed excellent diversity: hydroxyl, hydroxymethyl, thiol, iodine, and keto groups were efficiently introduced to the position adjacent to the chiral axis.
Silanols display unique applications in pharmaceutical chemistry and organic chemistry 50,51 . For example, compound 1 displays nuclear receptor modulator activity and has better lipophilicity than the corresponding carbinol 52 . Silanols 2 and 3 were used as organocatalysts for asymmetric syntheses 53,54 . Considering the remarkable property of silanol groups, we wonder if ortho silanol substituted biaryl atropiosmers could be accessed via the carbon-silica bond cleavage of silafluorene in a stereoselective manner. Unfortunately, the silanes showed low reactivity in classic cross-couplings, i.e., Hiyama or Hiyama-Denmark Couplings 55,56 . Pleasingly, the Narasaka acylation 57,58 , which favored C-SiMe 3 bond breaking over the C-SiMe 2 (OH), provided a potential solution for C-Si bond cleavage of silafluorene (Fig. 2b). However, challenges still remain: (a) only vinyl silanes underwent Narasaka acylation; (b) it is necessary to differentiate up to four C(aryl)-Si bonds in our systems. The releasing of noncyclic aryl ring is the undesired pathway; (c) the classic Narasaka acylation is steric sensitive, and vinyltriphenylsilane displayed extremely low reactivity (Fig. 2c). It is forseeable, the reaction would be more challenging if tetra(arylsilanes) were used. In the previous studies on the ringopening reactions, we found that the two non-hydrogen groups adjacent to the axis increased the distortion of the molecule. The distorted molecule is the energetic compound, which had relative lower activation energy than the non-distorted one for the ringopening reaction. Different from the inherent high strain of threeor four-membered rings, we anticipated that the activity of ringopening reaction can be increased by the torsional strain of α, α′-disubstituted five-membered silafluorenes. Furthermore, the torsional strain also enabled to differentiate one of four C(aryl)-Si bonds to give desired products.
Substrate scope. Under the optimal conditions, a number of acid anhydrides were tested with 4b as the substrate (Fig. 3). The aliphatic anhydrides also smoothly coupled with 4b to produce the corresponding silonols. The longer alkyl chain slightly decreased the yields and selectivity (6c-6f). 2-Methoxyacetic anhydride steadily underwent this acylation reaction to give 6g in excellent yield and enantioselectivity. The reaction of cyclopropanecarboxylic anhydride afforded the product 6h in 81% yield with 85% ee. The acrylic anhydride derivatives also reacted with 4b uneventfully to furnish the products in excellent ee values (6i-6k). The aromatic anhydrides were also compatible substrates. The p-methylbenzoic anhydride gave a slightly decreased yield, while the electron-withdrawing substituents were advantageous for both yields and stereoselectivity (6l-6o). Subsequently, other substituted aromatic acid anhydrides, including 3,4,5-trimethoxybenzoic anhydride, were submitted to the standard conditions to produce the corresponding silanols 6p-6s with excellent ees. Lastly, the 2-naphthoic or heteroaromatic anhydride were checked, and both of the reactions proceeded smoothly with the ee values were marginally changed (6t and 6u).
Silafluorenes bearing different substituents were further investigated (Fig. 4). Ligand L1 was found more efficient for substrate 4a, which reacted with propionic anhydride and butyric anhydride to give 6v and 6w in 85% and 90% ee, respectively. The substituted benzene rings attached to the silicon atom have marginal effect on the selectivity, all the silanols were formed in excellent stereoselectivity (6x-6bb). The silafluorenes with biphenyl skeleton gave relatively lower stereoselectivity (6cc-6ee). The diastereochemistry of compound 6cc was determined to be R by single crystal X-ray diffraction analysis (CCDC 1968743). The starting material α,α′,β,β′-tetramethyl biphenylsilafluorene showed slight poor stability, as a result, the corresponding product 6ff was isolated in only 45% yield with 87% ee.
while the increased size of compound 4a makes the naphthyl rings no longer coplanar. It is a twisted molecule with a distortional angle being 31.8°of the binaphthyl skeleton (Fig. 6a). We calculated the rotational barrier [ΔG g (298.15 K, 1 atm) ] of 4a, which is around 20.4 kcal/mol. Thus, the calculated half-life of 4a is around 94 s at room temperature (Fig. 6b). In order to learn more about the torsional strain energy of 4a, we calculated the hydrogenation energies of 4a and 4c, respectively (Fig. 6c). Considering the structural differences between 4a and 4c, we further calculated the hydrogenation energy of noncyclic compounds 4a′ and 4c′ (for details see Supplementary Table 2). Thus, the torsional strain energy of 4a is calculated as below: ΔG gð298:15 K; 1 atmÞ ¼ ðΔG1 À ΔG2Þ À ðΔG1 0 À ΔG2 0 Þ ¼ 12:58 kcal mol À1 : Markedly, the treatment of [Rh(CO) 2 Cl] 2 with one molar ratio of phosphoramidite L7 in dichloromethane formed a yellowish dimer [Rh(CO)Cl(L7)] 2 by releasing two molecules of CO. Recrystallization of this complex in ethyl acetate/hexanes gave a reddish orange crystal that was suitable for X-ray crystallography analysis (CCDC 1969002) (Fig. 6d). In this crystal structure, the (2,4,6-triisopropylphenyl)sulfonylpiperazine moiety worked as a large group by shielding one face of the rhodium center.
Based on the above results and previous studies on Narasaka acylation 66 , a brief catalytic cycle was tentitatively proposed (Fig. 7). The coordination of L7 to the pre-catalyst formed monomer Rh(I) complex. The oxidative addition of Rh(I) with silafluorene 4b cleavaged C(Ar)-Si bond to form 10, which gave optically active biaryl intermediate 11 via reductive elimination forming a Si-O bond. Subsequently, the second oxidation between 11 with acid anhydride 5 delivered Rh(III) complex 12. Reductive elimination of 12 furnished acylation product 13, which would give the final product 6 after hydrolysis of tri(aryl) silyl benzoate moiety.

Discussion
In conclusion, we reported a Rh-catalyzed asymmetric ring-opening acylation reaction for the synthesis of α-silyl biaryl atropisomers, a class of chiral bulky silanols. The torsional strain of five-membered silafluorenes enabled the success of selective cleavage of C(Ar)-Si bond, thus accomplishing an aryl-Narasaka acylation variant. Additional notable merit of this work is the developed sulfonylpiperazine derived phosphoramidite ligands, which showed high stereo-induction in C(Ar)-Si cleavage/ring-opening reaction.

Data availability
Additional data supporting the findings described in this paper are available in the Supplementary Information. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC), under deposition numbers CCDC 1968747 (4a), CCDC 19689851 (4c), CCDC 1968743 (6cc), CCDC 2013379 (6gg), CCDC 1969002 (Rh-1), and CCDC 1987455 (9). These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.  Fig. 7 Possible mechanism. The oxidative addition of in situ formed Rh(I) catalyst with 4b gives 10. Subsequent reductive elimination forms optically active biaryl intermediate 11. The second oxidation addition of 11 with acid anhydride 5 gives 12, which regenerates Rh(I) catalyst and compound 6 via reductive elimination, followed by hydrolysis.