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. 2026 Jan 5;148(2):2709–2718. doi: 10.1021/jacs.5c19070

Asymmetric C–H Functionalization of Bicyclo[2.1.1]hexanes and Their 2‑Oxa- and 2‑Aza Derivatives via Rhodium Carbene Intermediates

Ziyi Chen †, Duc Ly †, Yuzuru Kanda ‡, Vadym V Levterov §, Yaroslav Panasiuk §,∥, Pavel K Mykhailiuk §,∥, Djamaladdin G Musaev †,⊥,*, Huw M L Davies †,*
PMCID: PMC12833809  PMID: 41490573

Abstract

Bicyclo­[2.1.1]­hexanes have generated considerable interest in recent years as bioisosteres of benzene. In this article, a C–H functionalization approach is described to derivatize the bicyclo[2.1.1]­hexanes. The approach relies on dirhodium-catalyzed C–H insertion by donor/acceptor carbenes, which proceeds in a highly diastereoselective and enantioselective manner. By the appropriate choice of substrates, the reaction can also be highly site-selective. The bicyclo[2.1.1]­hexane is a difficult system for C–H functionalization via carbene intermediates because it is a strained molecule, which causes the C–H bonds to be stronger than in an unstrained system. The only catalyst that performed well in this transformation is the newly developed D4 symmetric catalyst, Rh2(S-megaBNP)4, which contains four (4,4′-dichloro-6,6′-di­(3,5-di-tert-butyl)­phenyl)­binaphthyl phosphate ligands. Computational studies revealed that the donor–acceptor carbene binds in a defined cleft within the bowl-shape of the dirhodium catalyst. Due to the high symmetry of the catalyst, only two orientations of the carbene are possible, and the most stable one has an open face for attack by the substrate. The substrate also needs to approach through a defined cleft causing the reaction to proceed with high levels of diastereoselectivity and enantioselectivity. These studies represent a further example of how the dirhodium catalysts can display many of the characteristics typically associated with enzymes with well-defined secondary interactions between the wall of the catalyst and the approaching substrate controlling the stereochemical outcome.

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Introduction

Bicyclic compounds have become of considerable interest in the pharmaceutical industry as bioisosteres for substituted benzene rings, commonly found in many drug candidates. − These bicyclic scaffolds have shown improved solubility, metabolic stability, and other physiochemical properties to assist with the development of new therapeutic agents. − Bicyclo[1.1.1]­pentanes have been extensively explored as bioisosteres for 1,4-disubstituted arenes (Scheme a). ,,− More recently, substituted bicyclo[2.1.1]­hexanes have been examined as bioisosteres for 1,2- or 1,3-disubstituted arenes or heteroarenes. ,,,,,− Consequently, a variety of drug candidates or analogues have been developed, as illustrated in the examples of heteroatom-substituted bicyclo[2.1.1]­hexanes 1a–d shown in Scheme b. −

1. Bicyclic Motifs as Bioisosteres for Benzene.

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Due to the increasing significance of bicyclo[2.1.1]­hexane derivatives in drug discovery programs, there has been considerable recent interest in developing new methods to access this ring system. ,− Some of the most significant methods are strain-release [2π + 2σ] cycloaddition with bicyclo[1.1.0]­butanes, ,,− photochemical [2 + 2] cycloaddition, ,,, and iodine mediated cyclization. , Recently, it has been demonstrated that monosubstituted bicyclo[2.1.1]­hexanes and their 2-aza and 2-oxo analogs can be readily accessed by intramolecular [2 + 2] photocycloaddition or iodocyclization (Scheme a). With ready availability of the monosubstituted substrates, an attractive approach for further diversification would be a catalyst-controlled post C–H functionalization of these bicyclic compounds.

2. Preparation of Mono-substituted BCH and C–H Functionalization of BCH.

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In order to achieve this, it is necessary to develop methods that distinguish between the C–H bonds in these substrates. The Hartwig group demonstrated that iridium catalyzed borylation proceeds cleanly at the tertiary C–H bond of bicyclo[2.1.1]­hexanes and the resulting borylated products are amenable for further diversification (Scheme b). The products from the borylation are achiral; thus, an asymmetric C–H functionalization of bicyclo[2.1.1]­hexanes derivatives has yet to be achieved. The Davies group has developed a range of chiral catalysts to achieve site selective C–H functionalization by means of carbene-induced C–H functionalization, − and this has been applied to various building blocks of pharmaceutical relevance. , In this article, we report the enantioselective and diastereoselective C–H functionalization of bicyclo[2.1.1]­hexane (BCH) and its oxa- and aza-derivatives (Scheme c). The bicyclic hydrocarbons are challenging because the C–H bonds are unactivated and a successful outcome requires control of site-selectivity, diastereoselectivity, and enantioselectivity. The heteroatom functionalized bicyclic compounds have activated sites adjacent to the heteroatom suitable for C–H functionalization; thus, the site selectivity is not as challenging, but the diastereoselectivity and enantioselectivity still need to be controlled.

Results and Discussion

C–H Functionalization of Bicyclo[2.1.1]­hexanes

The Davies group demonstrated that chiral dirhodium tetracarboxylates are very effective at enantioselective catalyst-controlled C–H functionalization with rhodium-stabilized donor/acceptor carbenes. , In addition to selective reactions at activated sites, such as alpha to oxygen or nitrogen, they are capable of selective C–H functionalization of acyclic hydrocarbons and various cycloalkane derivatives. Recently, we also reported that the binaphthyl phosphate catalyst, Rh2(S-megaBNP)4, is capable of selective C–H functionalization of unactivated tertiary C–H bonds and outperforms the dirhodium tetracarboxylate catalysts in this reaction. With a collection of chiral catalysts in hand, the current study began with a test reaction, the C–H functionalization of 1-(4-bromophenyl)­bicyclo[2.1.1]­hexane (4a, 2 equiv) with p-bromophenyldiazoacetate 3a as the carbene precursor and a catalyst loading of 1 mol % (Table ).

1. Catalyst Screening for C–H Functionalization of 1-Aryl Bicyclo[2.1.1]­hexane .

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Entry Catalysts X:Y Combined Yield (%) r.r. (5a + 6a:7a) d.r. (5a:6a) ee (%)
1 Rh2(S-DOSP)4 1:2 5      
2 Rh2(S-p-PhTPCP)4 1:2 5      
3 Rh2(S-TCPTAD)4 1:2 5      
4 Rh2(S-TPPTTL)4 1:2 5      
5 Rh2(S-NTTL)4 1:2 <5      
6 Rh2(S-2Cl5BrTPCP)4 1:2 30 15:1 3:1 –80 (ent-5a)
7 Rh2(S-BNP)4 1:2 5      
8 Rh2(S-Ph4-BNP)4 1:2 5      
9 Rh2(S-megaBNP)4 1:2 43(40) 3:1 >20:1 99(5a), 93(7a)
10 Rh2(S-megaBNP)4 1:1 47 2:1 >20:1 99(5a), 93(7a)
11 Rh2(S-megaBNP)4 1.5:1 78 2:1 >20:1 99(5a), 93(7a)
12 Rh2(S-megaBNP)4 2:1 92(89 ) 2:1 >20:1 99(5a), 93(7a)
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a

0.1 mmol of substrate and 1 mol % catalyst were dissolved with 1 mL of CH2Cl2 in a 4 mL vial. 0.2 mmol of diazo was dissolved in 1 mL of CH2Cl2, and the mixture was added to the reaction vial via a syringe pump over 3 h at 40 °C (0.05 M). d.r. and NMR yields were obtained from crude 1H NMR with trimethoxybenzene as internal standard.

b

NMR yield using 1,3,5-trimethoxybenzene as internal standard.

c

0.5 mol % catalyst was used.

d

Isolation yield.

We recognized that the all-carbon bicyclic system 4a might be difficult to functionalize because the C–H bonds are unactivated and sterically crowded. Disappointedly, a vast majority of our premier dirhodium tetracarboxylate catalysts (Scheme ) failed to give any of the desired products (Table , entries 1–5). Instead, carbene dimerization was the dominant reaction pathway. These catalysts range from being sterically accessible to sterically crowded; thus, the lack of reactivity is presumably because the C–H bonds in 4a are simply not sufficiently reactive, and carbene dimerization becomes the alternative outcome.

3. Catalysts Used in the Optimization Studies.

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Only one of our dirhodium tetracarboxylates, Rh2(S-2Cl-5Br-TPCP)4, gave a significant amount of the C–H functionalization products (entry 6, 30% NMR yield). The major product 5a is derived from C–H functionalization at the distal methylene site and was formed with site-selectivity of 16:1 r.r. over the tertiary C–H insertion product 7a. There was no evidence of any C–H functionalization occurring at the other three methylene sites in 4a, presumably because the C2-methylene site adjacent to the phenyl is too sterically crowded and the two methylene sites in the four-membered ring are less reactive. The major product ent-5a is obtained with relatively low diastereoselectivity (3:1 d.r.) but reasonably high enantioselectivity (80% ee, enantiomer of 5a). Rh2(S-2Cl-5Br-TPCP)4 is considered to be a sterically demanding catalyst, adopting a rigid, C4-symmetric bowl shape, which would help explain why the C–H functionalization preferentially occurs at the secondary site over the tertiary site. The reason the carbene is more effective at C–H functionalization but less prone to dimerization using this catalyst compared to the other dirhodium tetracarboxylate catalysts is less clear, but it is likely that the catalyst bowl shape influences how substrates can approach the carbene.

Considering the difficulties we observed in achieving an effective reaction with the dirhodium tetracarboxylate catalysts, we decided to apply our new binaphthyl phosphate catalyst, Rh2(S-megaBNP)4, because it is considered to generate more electrophilic carbene intermediates than the dirhodium tetracarboxylate catalysts. First, we examined the parent binaphthylphosphonate catalyst Rh2(S-BNP)4 and the tetraphenyl derivative Rh2(S-Ph4-BNP)4, but they both performed poorly in the reaction, resulting in only traces of the C–H functionalization products (entries 7 and 8). In contrast, when Rh2(S-megaBNP)4 was used as a catalyst, a great improvement in the efficiency of the desired reaction was observed and the C–H functionalization products were obtained in 43% NMR yield (entry 9). Rh2(S-megaBNP)4 is not as sterically demanding as Rh2(S-2Cl-5Br-TPCP)4, and consequently, the site selectivity for secondary 5a over tertiary 7a was less pronounced (3:1 r.r). The stereoselectivity, however, was greatly improved as 5a was formed in >20:1 d.r. and in 99% ee. The minor tertiary product 7a was also formed with a high enantioselectivity (93% ee). As there was still evidence of the carbene dimer being formed, the reaction was then examined with bicyclohexane 4a as the limiting agent, and under these conditions, the yield was greatly improved (92% NMR yield, 89% isolated yield), whereas the stereoselectivity remained about the same (entry 12). The relative stereochemistry of 5a was determined by 1H NMR in which the chemical shift of the bridgehead proton was similar to the starting material 4a, whereas diastereomer 6a showed strong shielding of the bridgehead proton (over 0.5 ppm upfield shift). These studies showed that Rh2(S-megaBNP)4 is uniquely suited for this reaction, capable of high yielding reactions and the formation of the secondary C–H functionalization product 5a with exceptionally high levels of enantioselectivity and diastereoselectivity.

Since Rh2(S-megaBNP)4 was identified as the optimum catalyst, the scope of the C–H functionalization was examined with a range of aryldiazoacetates (3a–h) and arylbicyclohexanes (4a–d) (Scheme ). In the benchmarking studies when Rh2(S-megaBNP)4 was originally disclosed, it was found that a para-substituent on the aryl ring was advantageous for high asymmetric induction, and so, para-substituted aryldiazoacetates were used in this study. A test reaction with the unsubstituted phenyldiazoacetate was also examined, but the C–H functionalization with this carbene source proceeded in low yield (∼20%; see Supporting Information, pages S58–S62). In general, the reactions followed the same trend observed in the optimization studies, forming about a 2:1 mixture of secondary (5a–l) and tertiary (7a–l) C–H functionalization products but with exceptionally high levels of enantioselectivity for both products and high levels of diastereoselectivity for the secondary C–H functionalization product (Scheme ). Aryldiazoacetates with trihaloethyl ester were used throughout because functionalization of unactivated C–H bonds is far more effective with these electron deficient esters. Indeed, a test reaction with the methyl ester of 4a gave no evidence of a C–H functionalization product (see, Supporting Information, pages S58–S62). Among the para-substituted aryldiazoacetates, the regioselectivity ranged from 1:1 to 2:1 r.r. and the diastereoselectivity for the secondary product varied from 9:1 to >20:1 d.r. The enantioselectivity was exceptionally high for the secondary products 5a–l (98–99% ee) and still very acceptable for tertiary products 7a–l (81–96% ee). A range of aryldiazoacetates (3a–h) can be used, and the reaction is compatible with halo, trifluoromethyl, and ester functionalities on the aryldiazoacetate, and even 2-chloropyridyl is tolerated. Para- and meta-substituted arylbicyclohexanes (4a–d) were also evaluated (4-tert-butyl, trifluoromethyl, and 3,4-dimethoxy), and they all afforded the C–H functionalization products with excellent diastereoselectivity and enantioselectivity (>20:1 d.r. and 90–99% ee), although with moderate regioselectivity (1.2–2.4:1). The 6-bromonaphthalen-2-yl substrate gave moderate diastereoselectivity (10:1 d.r. for 5l) but high enantioselectivity (99% ee for secondary 5l and 94% ee for tertiary 7l). The absolute configuration of compound 5l was confirmed by X-ray crystallography. The absolute configuration of the other products is assigned by analogy.

4. Scope of the C–H Functionalization of BCH.

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Only Rh2(S-megaBNP)4 is truly effective at achieving high levels of asymmetric induction in the binaphthyl phosphate series of catalysts. Consequently, alternative catalysts are not currently available to modify the overall site selectivity of the reaction as is typically the case in C–H functionalization reactions with dirhodium tetracarboxylates. Therefore, we decided to explore whether the use of ortho-substituted aryldiazoacetates would result in more steric encumbrance and drive the reaction toward C–H functionalization of secondary sites. The reaction with 2-chlorophenyldiazoacetate 3i resulted in enhanced secondary C–H functionalization (5:1 r.r.) but with a decrease in the diastereoselectivity (4:1 d.r) and enantioselectivity (90% ee, Scheme ). The absolute configuration of 8a was also confirmed by X-ray crystallography. As para-substitution tends to enhance the enantioselectivity with Rh2(S-megaBNP)4-catalyzed reactions, 2-chloro-4-bromo diazo 3j was also examined, and a much better result was obtained. The secondary product 8b was formed with improved site selectivity (11:1 r.r.), diastereoselectivity (12:1 d.r.), and enantioselectivity (98% ee). These results demonstrate that site selectivity can be controlled by increasing the steric features of the carbene, and this is a useful alternative strategy to catalyst control.

5. Enhancement of Site-Selectivity.

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C–H Functionalization of 2-Oxa- and 2-Azabicyclo[2.1.1]­hexanes

We also investigated the C–H functionalization of 2-oxa and 2-azabicyclo[2.1.1]­hexanes because this type of scaffold has been incorporated in potential drug candidates. ,,, The evaluation of the same series of catalysts was conducted using the 1-substituted 2-oxabicyclo[2.1.1]­hexane 10a as the test substrate (Table ). Due to the activating influence of the heteroatom, the reaction preferentially occurs at C-3 and all of the dirhodium tetracarboxylate catalysts are capable of achieving C–H functionalization (Table , entries 1–6). However, with most of the carboxylate catalysts, the yield of 11a is still low, and the diastereoselectivity is close to 1:1. The only carboxylate catalyst that gives a significant improvement is Rh2(S-TPPTTL)4, which gave a 59% yield of 11a with moderate diastereocontrol (4:1 d.r.) and enantiocontrol (79% ee) (entry 6). The parent binaphthylphosphonate catalyst Rh2(S-BNP)4 also gave poor results (entry 7). Once again, Rh2(S-megaBNP)4 gave exceptional results, generating 11a in >20:1 d.r. and 90% ee (entry 8). Ironically, in the Rh2(S-megaBNP)4 catalyzed reaction, the yield for the formation of the oxa product 11a (43%) is lower than what was obtained with the carbocyclic products 5a and 7a (92%). This follows the general trend observed in the benchmarking studies that the carbene derived from a Rh2(S-megaBNP)4-catalyzed reaction appears more electrophilic than the dirhodium tetracarboxylate carbene and is less tolerant to nucleophilic functional groups.

2. Catalyst Screening for C–H Functionalization of 1-Iodo-2-oxabicyclo[2.1.1]­hexane.

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Entry Catalysts NMR Yield of 11a (%) d.r. (11a:12a) ee (%)
1 Rh2(S-DOSP)4 20 1:1  
2 Rh2(S-PTAD)4 23 1:1  
3 Rh2(S-TCPTAD)4 11 1:1  
4 Rh2(S-2Cl5BrTPCP)4 15 1:2  
5 Rh2(S-NTTL)4 14 1:1  
6 Rh2(S-TPPTTL)4 59 4:1 –79
7 Rh2(S-BNP)4 24 3:1  
8 Rh 2 ( S -megaBNP) 4 43(40 ) >20:1 90
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The Rh2(S-megaBNP)4-catalyzed reaction can be applied to a variety of 1-substituted 2-oxabicyclohexane derivatives 10b–f as illustrated in Scheme . Halogen, ester, ether, and N-phthalimido groups were well tolerated, generating 11b–f with high diastereoselectivity (10:1 to >20:1 d.r.) and enantioselectivity (85%–92% ee). The disubstituted 2-oxabicyclohexane 10g was also examined, and it gave the desired product 11g with high diastereoselectivity (>20:1 d.r.) and enantioselectivity (84% ee). In general, however, the reaction with a 1,4-disubstituted 2-oxabicyclohexane is more challenging, and if the second substituent is sterically demanding or electron withdrawing, low yields of C–H functionalization products are obtained (see SI for details on unsuccessful reactions).

6. Reaction Scope of 2-Oxabicyclo[2.1.1]­hexane.

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Two 1-substituted 2-azabicyclo[2.1.1]­hexanes (2-azaBCH) were also examined as substrates. The reaction catalyzed by Rh2(S-megaBNP)4 was generally effective, favoring secondary C–H functionalization at the site adjacent to the nitrogen (Scheme ). The reaction with the trifluoromethyl derivative 13a gave 14a in 32% yield with exceptionally high stereoselectivity (>20:1 d.r. 98% ee). A good reaction was also obtained with ester derivative 13b forming product 14b in 48% yield and 94% ee. In this case, the diastereoselectivity is conservatively estimated as >10:1 because the N-Boc hindered rotation makes analyzing the product ratio challenging.

7. Reaction Scope of 2-Azabicyclo[2.1.1]­hexane.

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In general, the bicyclo[2.1.1]­hexane scaffold is a challenging system for rhodium carbene induced C–H functionalization. The dirhodium tetracarboxylate catalysts, which have performed well in a wide variety of C–H functionalization reactions, failed in this system, and only the binaphthyl phosphate catalyst Rh2(S-megaBNP)4 performed well. The remarkable behavior of Rh2(S-megaBNP)4 in this reaction deserves further analysis. X-ray crystallographic and solution NMR studies have previously revealed that the catalyst adopts a D4 symmetric structure and the 1,3-di-tert-butylphenyl functionality plays a crucial role in rigidifying this structure (Figure A, Top). To shed light on the above-reported selectivity of the Rh2(S-megaBNP)4-catalyzed C–H functionalization, we turned to computational analyses of the rhodium carbene intermediate and how it reacts with the bicyclo[2.1.1]­hexane scaffold. The large size of the catalysts (>400 atoms) makes the use of high-level DFT approaches impractical. Therefore, we applied a 2-layer ONIOM method − where 16 tert-butyl groups of Rh2(S-megaBNP)4 were treated at the molecular mechanics (UFF) level but the rest of the system including carbene, substrate, and catalyst were described at the density functional (we used the M06 functional) level (see Supporting Information for a discussion for the selection of this approach and comparison with other density functional methods). Confirmation that the ONIOM­(M06/UFF) level of calculation was appropriate for analyzing Rh2(S-megaBNP)4 is seen by a comparison of the calculated D4 symmetrical structure versus the X-ray crystallographic structure (with RMSD = 0.406 Å). The overlay of the crystal structure (blue) of Rh2(S-megaBNP)4 and the computationally optimized structure (green) is shown in Figure A, Bottom. During the computational studies, we utilized noncovalent interaction (NCI) map analyses to determine further the key interligand interactions that are involved in maintaining the high symmetric structure of the catalyst. These studies showed that inner C–H/O and outer C–H/π interactions are important contributors to the D4 symmetric orientation of the catalyst (see Figure S3, SI Section 7.2). ,

1.

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Computational study. (A) Top: DFT optimized structure of Rh2(S-megaBNP)4 (RMSD = 0.4 Å compared to X-ray structure); Bottom: an overlay of DFT optimized structure (green) and X-ray structure (blue). (B) Top: Two carbene isomers, reported energies are free Gibbs energy in kcal/mol. The highlighted tert-butyl groups in green, pink, and yellow are important for interaction with carbene and substrate; Bottom: Steric plots of carbene isomers I and II by the SambVca 2.1 program with the carbene’s carbon as the center of the map and the radius of 7 bohr. (C) Transition states of C–H insertion into 2 °C–H bond leading to 5a from TS1 and 6a from TS2. (D) Activation-strain model analysis; the reported energies are the differences of TS2 and TS1. ΔΔE d,sub and ΔΔE d,Rh distortion energy of substrate and rhodium-carbene fragments. ΔΔE Int interaction energy. (E) Energy decomposition analysis via the sobEDA method using the Multiwfn program. All figures were rendered by the VMD program.

Empirical observations during the benchmark studies on Rh2(S-megaBNP)4 revealed that a para-substituent on the aryldiazoacetate is beneficial for high asymmetric induction. This observation led to the hypothesis that a para-substituent contributes to locking the carbene in a defined orientation between adjacent ligands. To validate this hypothesis, we turned to examine the structure of the rhodium-carbene complex generated by Rh2(S-megaBNP)4 at the ONIOM­(M06/UFF) level with the aim to identify orientations of the carbene in the reactive pocket of the catalyst. The study was conducted by using the carbene generated from 3a with a para-bromophenyl substituent. The calculations revealed that there were only two favored orientations of the carbene in the complex (I and II) because of the high symmetry of the catalyst (Figure C). Generally, the aryl group of the carbene resides in the same plane as the rhodium carbene bond, and these two identified structures are differentiated by the orientation of the ester group which is aligned perpendicular to the rhodium carbene bond. − The p-bromophenyl substituent on the carbene in both complexes I and II resides between two tert-butyl groups of adjacent ligands (colored green and purple in Figure B, Top). Furthermore, the p-bromophenyl group is tilted significantly out-of-plane toward the green tert-butyl group, presumably due to a favorable interaction with the naphthyl and tert-butyl moiety of the ligand. This tilting effect also sets the carbene into a pretransition state position opening up one face of the carbene for attack. The tilting effect could possibly explain the unique reactivity of Rh2(S-megaBNP)4 toward C–H functionalization of very difficult substrates such as the bicyclic substrates used in this study. Of the two possible orientations, carbene (I) with the trichloroethoxy group pointed toward the green tert-butyl side is more stable than carbene (II) by 2.2 kcal/mol. Furthermore, in carbene (I), the face of the carbene away from the green tert-butyl group is especially open for attack. This finding is further supported by the steric plot presented in Figure B, Bottom. This figure cleanly shows that the (Si)-face of the carbene complex (I) is fairly open while the (Re)-face is almost completely blocked. The distinction between the two faces is far more significant for the carbene complex (I) than the carbene complex (II). The observed asymmetric induction is consistent with the experimentally observed selective reaction at the (Si) face of the carbene

In order to validate the model generated thus far, we decided to challenge it to see if it would predict the high diastereoselectivity exhibited in the secondary C–H functionalization of the bicyclic substrates. It is well established that the C–H functionalization step proceeds in a concerted, asynchronous manner. In the case of the reaction with carbene complex (I), the substrate must approach between two adjacent tert-butyl groups colored purple and yellow (Figure C). Two transition states TS1 and TS2 leading to two possible diastereomers of the C–H functionalization products were located. The transition state TS1 is 3.0 kcal/mol more stable than TS2 and leads to the experimentally observed major diastereomer. A closer analysis of the two transition states reveals that the preference for TS1 over TS2 is because of the better orbital interaction (Figure D,E). , It is well established that approach of the substrate toward the carbene has a well-defined trajectory and presumably the two tert-butyl groups influence the approach on the substrate. Rh2(S-megaBNP)4 is considered to be a relatively rigid catalyst, and so, it does not alter its shape in a significant way to accommodate the approaching substrate. Consequently, the energy difference between the two transition states depends how well aligned the substrate can be in the presence of the ligands to maximize favorable orbital overlap in the transition state during the C–H functionalization (Figure S6, SI Section 7.4). ,

Conclusion

This study illustrates that highly diastereoselective and enantioselective functionalization of secondary C–H bonds in BCHs and hetero-BCHs can be achieved by using the recently developed catalyst Rh2(S-megaBNP)4. The C–H functionalization is achieved by a carbene-induced C–H functionalization and demonstrates the effectiveness of rhodium-stabilized donor/acceptor carbenes in these reactions. Compared with traditional chiral dirhodium tetracarboxylate catalysts, the Rh2(S-megaBNP)4-catalyzed carbene reaction is far superior in this reaction to any of the dirhodium tetracarboxylates and other BNP derivatives that were tested. It can achieve the transformation in high yield and with exceptional control of the diastereoselectivity and enantioselectivity. Computational studies revealed the likely cause of its remarkable behavior. The catalyst exists in a D4 symmetric arrangement, and when the carbene is bound to the dirhodium, it adopts distinct orientations. Interactions between the aryl group of the bound carbene and the naphthyl and a tert-butyl group on the ligand causes the (Re) face of the carbene to tilt toward the catalyst wall opening the (Si) face to attack. When the bicyclic derivatives approach the carbene, they must do so with a defined orientation, resulting in a highly diastereoselective reaction. These studies illustrate the highly significant role that secondary noncovalent interactions of the catalyst wall can have on the outcome of the carbene-induced C–H functionalization. They also explain why donor/acceptor carbenes with aryl as the donor group are capable of such highly selective reactions, because the interaction of the aryl group with the catalyst is a critical element for defined orientation to the rhodium-carbene complex.

Supplementary Material

ja5c19070_si_001.pdf (18.3MB, pdf)

Acknowledgments

The computational work was conducted using the facilities of the Emerson Computing Center. Constructive discussions within the Catalysis Innovation Consortium facilitated this study. At Emory University, we thank Dr. Bing Wang for NMR measurements, Dr. Fred Strobel for MS measurements, and Dr. John Bacsa for X-ray measurements.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c19070.

  • Complete experimental procedures, materials, computational details, compound characterizations, and crystal structure forms of compounds 5l and 8a (PDF)

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This work was supported by the National Institute of Health (R35GM158221).

The authors declare the following competing financial interest(s): H.M.L.D. and Z.C. are named inventors on a patent application entitled "New Class of Dirhodium Tetrakisbinaptholphosphates as Chiral Catalysts".

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