Light-Driven Enantioselective Carbene-Catalyzed Radical-Radical Coupling

Abstract

An enantioselective carbene-catalyzed radical-radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an N-heterocyclic carbene-derived ketyl radical and a secondary sp³–carbon radical and allows access to chiral α-aryl aliphatic ketones in moderate-to-good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late-stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the N-heterocyclic carbene controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

Graphical Abstract

An enantioselective radical-radical coupling using combined photoredox/N-heterocyclic carbene (NHC) catalysis was developed. The coupling of a ketyl radical and an sp³–carbon radical allows access to α-chiral ketones in moderate-to-good yields and enantioselectivities. Computational investigations reveal the N-heterocyclic carbene controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

Bioactive ketones containing an α-stereogenic center are an important class of compounds in the pharmaceutical and agrochemical industries as well as in biologically relevant natural products (Figure 1A).^[1] Consequently, significant effort has been devoted to the development of catalytic approaches for the asymmetric synthesis of carbonyl compounds.^[2] Enantioenriched ketones bearing an α-stereogenic center can be accessed by a variety of methods, including transition metal-catalyzed cross coupling,^[3] copper-hydride catalyzed reductive coupling,^[4] borylative coupling,^[5] and α-functionalization.^[6] Even with these broad activities, the development of complementary synthetic strategies for preparing of α-chiral ketones remains in high demand (Figure 1B). Photoredox-catalyzed single-electron transfer reactions have emerged as a powerful approach for the construction of a wide range of carbon–carbon bonds.^[7] However, few enantioselective radical-radical coupling reactions to furnish valuable chiral building blocks have been disclosed to date. In particular, the conversion of various acylating and aryl/alkylating reagents into ketones has been accomplished using photo-induced nickel catalysis, but reports on the asymmetric synthesis of ketones via single-electron transfer remains limited to date.^[8] The approaches that have been developed to date often involve carbon–carbon bond formation proceeding via a reductive elimination step in a radical/transition-metal crossover reaction. In contrast to the coupling of a radical species and a transition metal, an alternative approach in which a radical-radical coupling occurs to directly access α-chiral ketones remains underdeveloped and an area of potential (Figure 1B).

Figure 1.

(A) Representative biologically active compounds containing α-chiral ketones. (B) Catalytic approaches for ketone synthesis. (C) Carbene-catalyzed radical-radical coupling. (D) Our strategy to build α-chiral ketones featuring enantioselective radical-radical coupling.

N-heterocyclic carbene (NHC) catalysis has proven to be a powerful strategy to exploit umpolung reactivity (i.e., polarity reversal) in a wide range of transformations.^[9] In traditional two-electron carbene catalysis, the addition of an NHC to a carbonyl-containing compound affords the corresponding acyl anion equivalent (Breslow intermediate) that can engage in nucleophilic attack on various electrophiles to access new carbon-carbon bonds (Figure 1B). While this traditional two-electron reactivity has undergone major development over the past two decades, there is a dearth of processes that engage sp³-electrophiles vs. sp² systems such as carbonyl and unsaturated compounds.

Single-electron NHC catalysis has recently received increasing attention for the construction of carbon–carbon bonds.^[10] In 2019, Ohmiya reported the NHC-catalyzed radical coupling of aldehydes with redox-active esters to afford ketones.^[11] We have disclosed light-driven NHC catalysis to construct racemic aryl and alkyl ketones via radical-radical coupling.^[12] This approach involved a single-electron reduction of an acyl azolium species to generate the NHC-bound ketyl radical.^[13] Ongoing work by our group,^[14] as well as the groups of Ohmiya,^[15] Studer,^[16] Chi^[17], and Ye^[18] has led to the development of successful methods to access different ketone classes. Despite the significant progress in this area, the products of these reactions are racemic and achieving moderate to high levels of enantioselectivity in these general process has remained elusive (Figure 1C).

Given the prevalence of α-stereogenic chiral ketone motifs in biologically relevant molecules, we sought to develop an asymmetric synthesis of α-aryl substituted aliphatic ketones.^[19] Although NHC-catalyzed radical-radical coupling has proven to be an alternative and efficient method for preparing versatile ketones,^{[10b, 10d, 10e]} to the best our knowledge, the single-electron carbene-catalyzed enantioselective synthesis of α-chiral ketones remains unreported. We hypothesized that a chiral NHC-derived acyl azolium could undergo single-electron reduction to afford the ketyl radical and subsequently react with a photocatalytically generated secondary sp³–carbon radical to produce the desired α-aryl substituted aliphatic ketone. Herein, we report the light-driven asymmetric NHC-catalyzed radical-radical coupling to directly access α-aryl substituted aliphatic ketones in high enantioselectivities (Figure 1D). We initiated our investigation of this reaction using acyl imidazole 1a and racemic Hantzsch ester 2a (Table 1). Notably, Hantzsch esters are mild radical precursors due to their ease of preparation and accessible redox potentials.^[20] We envisioned that the coupling strategy of a secondary sp³–carbon radical could proceed through an enantioconvergent pathway.^[12] To our delight, we found that triisopropylphenyl-substituted catalyst E^[21] and an iridium photocatalyst (PC, [Ir(dFCF₃ppy)₂(dtbbpy)]PF₆) provided the desired product in 51% isolated yield and 91:9 enantiomeric ratio (e.r.) at room temperature (entry 1, Table 1). Investigation of a series of chiral carbene catalysts delivered no improvement in yield and enantioselectivity (entries 2–5). Unfortunately, more sterically demanding 2,6-dibenzhydryl-substituted catalyst F afforded no desired product (entry 6). Examination of other bases revealed cesium carbonate to be the best base (entries 7–9). Interestingly, the use of Et₂O provided the product in 16% yield and 92:8 er, whereas other solvents led to no product formation (entries 10–12). It is worth noting that the racemic Hantzsch ester was efficiently converted into the highly enantioenriched product without any epimerization, indicating that the enantioconvergent radical-radical coupling was completely governed by combined photoredox and carbene catalysis.

Table 1.

Optimization of reaction conditions^[a]

^[a]Reactions performed with 1a (0.3 mmol), 2a (0.39 mmol), base (20 mol %), PC ([Ir(dFCF₃ppy)₂(dtbbpy)]PF₆, 0.003 mmol), triazolium (20 mol%), and CH₃CN (0.05 M) for 24 h. Absolute configuration of 3a determined based on X-ray crystal analysis of 3k.

^[b]1H NMR yield with 1,3,5-trimethoxybenzene as an internal standard.

^[c]E.r. determined by chiral-phase SFC analysis.

^[d]Yield of isolated product. ORP= oxidatively generated radical precursor.

With the optimized conditions, the carbene-catalyzed enantioselective radical-radical coupling of Hantzsch esters and acyl imidazoles was explored (Table 2). Gratifyingly, we found that a wide range of α-chiral ketones were furnished in good yields and high-to-excellent levels of enantioselectivities. The reaction of Hantzsch esters with para- and meta-substituted electron-donating and electron-withdrawing groups were tolerated, and the corresponding products (3b–g) were isolated in good yields and high enantiomeric ratio. Highly enantioenriched products (3h–i) with sterically large groups (i.e., naphthyl and dioxolane) also proceeded efficiently. An α-tertiary ketone featuring an ethyl group in place of the standard methyl group was also furnished, suggesting that further diversification at the α-position may be possible (3j).

Table 2.

Evaluation of substrate scope^[a]

^[a]Reactions performed at a 0.3 mmol scale. See the Supporting Information for details. Yields reported for isolated product. E.r. determined by chiral-phase SFC analysis.

^[b]Absolute configuration was determined by X-ray crystallography.^[22]

A broad range of acyl imidazoles were also successfully transformed to the corresponding chiral ketones. The reaction was compatible with acyl imidazoles featuring various functional group, such as N-Boc (3a), benzoyl (3k), allyl (3l), ether (3m), ester (3q), ketone (3r), difluoro (3s), and NH-Boc (3t) in good yields and high enantioselectivities. While the conversion of acyl imidazoles with varying ring sizes was accomplished in moderate yields and good-to-excellent enantiomeric ratio (3n,o), the reaction of a linear (non-branched) substrate afforded the product 3p in 68% and 65:35 er. The absolute configuration of (S)-3k was determined by X-ray crystallographic analysis.[22] Attempts to access an α-amino or α-hydroxy ketones provided the desired products with lower yields and selectivities, whereas the construction of a fully substituted α-quaternary center was unsuccessful under the standard conditions (Table 2, bottom and see SI).^[23]

To further demonstrate the synthetic utility of our strategy, we conducted the late-stage functionalization^[24] of pharmaceutically relevant compounds (Scheme 1A). By employing our standard reaction conditions with tranexamic acid, a drug used for the treatment of excessive blood loss,^[25] the desired ketone product 4a was afforded in 61% yield with 92:8 er.^[26] We then investigated the possibility of employing Hantzsch esters bearing bioactive moieties/drug fragments. Thus, racemic ibuprofen-functionalized Hantzsch ester provided the corresponding product 4b in 62% yield and 91:9 er, while racemic flurbiprofen afforded the product 4c with diminished yield and enantioselectivity. Finally, we successfully accessed a complex molecule containing two medicinal fragments.^[27] The desired product 4d was obtained in 55% yield and 93:7 enantiomeric ratio when the acyl imidazole of tranexamic acid and the Hantzsch ester of racemic ibuprofen were employed, thus highlighting the potential utility of this process in synthesis.

Scheme 1.

Functionalization of biologically active compounds and synthetic application. [a]Reactions performed under standard conditions. See the Supporting Information for details. [b]Conditions: (a) NaBH₄ (1.1 equiv), MeOH, rt, 2 h (b) ZnCl₂ (0.5 equiv), ClCH₂OMe, (c) BnNH₂ (1.1 equiv), TiCl₄ (1.0 equiv), Et₃N (3.0 equiv), THF (0.2 M), NaBH(OAc)₃ (10.0 equiv), AcOH (0.1 M), (d) CH₂O, HCl, CHCl₃, then Boc₂O, CH2Cl₂.

Furthermore, the α-aryl chiral ketone products of this transformation can be converted into a wide range of useful cyclic motifs (Scheme 1B). We found that the reduction of the ketone 3a with NaBH₄ and subsequent treatment of alcohol 5 with ClCH₂OMe delivered the corresponding isochroman 6 in moderate to good yield with excellent diastereoselectivity.^[28] Moreover, the reductive amination of 3a with BnNH₂ led to secondary amine 7, and a subsequent Pictet-Spengler reaction of the isolated major diastereomer allowed access to the corresponding tetrahydroisoquinoline product 8 in good yield.^[29]

To gain insight into the mechanism of this reaction, control experiments were conducted. While standard condition afforded the corresponding α-chiral ketone product, none of desired product was observed in the absence of either light, photocatalyst, or NHC (Scheme 2A). Additionally, we observed the dimer byproduct derived from the carbon radical intermediate of Hantzsch ester 2a, strongly supporting that the reaction system proceeds through a radical pathway (Scheme 2B). A further deuterium labeling experiment was carried out with deuterated acetonitrile. Analysis of the product revealed no deuterium incorporation into the product, suggesting that no intermolecular scrambling occurred by hydrogen atom abstraction or protonation from the solvent (Scheme 2C).

Scheme 2.

Mechanistic experiments

A plausible catalytic cycle for this asymmetric combined photoredox and carbene-catalyzed process can be proposed based on mechanistic experiments and our prior knowledge^[14a] in combination with density functional theory (DFT) (Figure 2). An acyl imidazole 1 can react with free chiral catalyst E′ to provide a chiral NHC-derived acyl azolium I. Single-electron reduction of the acyl azolium I affords the NHC-bound ketyl radical III. Secondary sp³–carbon radical II is generated by oxidation of the Hantzsch ester 2 by the photoexcited iridium catalyst followed by the homolytic cleavage of a cationic radical species. Finally, a stereodetermining radical-radical coupling between II and III and subsequent regeneration of catalyst E′, provides the desired α-chiral ketone. An examination of the potential structural aspects of III indicate the possibility of 3 of the four quadrants (in purple) of the ketyl radical being blocked. However, this cursory analysis does not address how the new formed stereocenter derived from achiral radical II is established.

Figure 2.

Proposed catalytic cycle.

To further investigate the origins of selectivity, we performed DFT computations at the PBE^[30]-D3BJ^[31]/6–31G*^[32] & LANL2DZ^[33] (for Cs) level of theory and with SMD solvation corrections^[34] for acetonitrile as implemented in Gaussian 16. PBE and D3BJ have both been successfully used in numerous studies of reaction mechanisms and selectivities by us^{[14a, 35]} and others.^[36] Single-point energy refinements were computed for key stereo-determining radical-radical coupling transition states at the DLPNO-CCSD(T)^[37]/def2-TZVPP^[38] level of theory with SMD solvation corrections for acetonitrile as implemented in ORCA 4.0.1. In addition, we have recomputed the salient portion of the reaction coordinate with wB97XD^[39]/def2-SVP^[38b]/SMD(acetonitrile) to verify the PBE-D3BJ results. All methods used (specifically, PBE, PBE-D3BJ, DLPNO-CCSD(T)//PBE-D3BJ, and wB97XD) gave results that were qualitatively consistent with each other.

The acyl imidazole featuring tetrahydropyran (1c) and racemic Hantzsch ester corresponding to chiral ketone 3m were chosen as model substrates. DFT (Figure 3A) revealed that the radical-radical coupling TS-IV between benzyl radical II and NHC-bound ketyl radical III is a stepwise process. The initial carbon–carbon bond forming radical-radical coupling is rate- and stereo-determining. This coupling leads directly to the tetrahedral intermediate V. Subsequent facile catalyst extrusion yields the α-chiral ketone product. In the key coupling TS-IV, benzyl radical II and NHC-bound ketyl radical III are both prochiral. As a result, there are four unique coupling patterns (Figure 3B). For the coupling process to be stereoselective, the carbene catalyst must provide a transient chiral environment that effectively discriminates and controls the approach of both prochiral centers. The benzyl radical II can approach the NHC-bound ketyl radical III either on the sterically congested face syn to the chiral indane of the NHC catalyst or the sterically accessible face anti to the chiral indane. Consequently, all syn transition states are strongly disfavored by roughly 10 kcal/mol compared to the anti (syn-si-TS-IV and syn-re-TS-IV, ΔG^‡ = 18.3 and 19.9, respectively vs anti-si-TS-IV and anti-re-TS-IV, ΔG^‡ = 8.8 and 11.5, respectively).

Figure 3.

(A) DFT-computed reaction coordinate diagram, computed at the PBE-D3BJ/6–31G* & LANL2DZ / SMD(CH₃CN) @ 298.15 level of theory (B) Radical-radical coupling transition structures, energies in kcal/mol, distances in Å. ΔG^‡_CCSD(T) energies computed at the DLPNO-CCSD(T)/def2-TZVPP//PBE-D3BJ/6–31G* & LANL2DZ / SMD(CH₃CN) @ 298.15 K level of theory.

Moreover, benzyl radical II can approach the favorable and accessible anti face of NHC-bound ketyl radical III either si or re (Figure 3B). Favorable 𝜋-𝜋 interactions between triazole NHC core and substrate-phenyl stabilize the si approach. The anti-si-TS-IV (ΔG^‡ = 8.8) is thus the most stable and leads to the formation of the experimentally observed major product (S)-3m. In the epimeric re-face approach (i.e., anti-re-TS-IV, ΔG^‡ = 11.5), this stabilizing interaction is lost, disfavoring this approach. This is borne out by the DLPNO-CCSD(T)/def2-TZVPP/SMD(CH₃CN) distortion-interaction analysis which reveals that the favored anti-si-TS which leads to the major product exhibiting ~1.9 kcal/mol greater stabilizing interactions and lesser distortions than the anti-re-TS (see SI). Rotating around the carbon–carbon bond to re-establish the stabilizing π-π interactions identified in the re-approach is prohibitive due to the steric repulsion between the substrate methyl and the N-aryl-isopropyl group. This computational observation is consistent with the reduced selectivity observed with the trimethylphenyl catalyst C compared to the optimal triisopropylphenyl catalyst E.

We have developed an efficient light-induced enantioselective carbene-catalyzed radical-radical coupling reaction. This process efficiently transfers an sp³-carbon radical intermediate derived from a Hantzsch ester to an azolium ketyl radical generated in situ, affording the highly enantioenriched product without epimerization of the α-stereogenic center. A wide range of α-chiral ketoneswere furnished in high-to-excellent levels of enantioselectivities (up to 93:7 er). The synthetic utility of this process was showcased by the functionalization of pharmaceutical compounds and the transformation of the products into privileged heterocyclic motifs. DFT investigations revealed that the radical-radical coupling is a stepwise process, with the initial carbon–carbon bond formation step being rate- and stereo-determining. Additional efforts on the development of single-electron NHC-catalyzed stereoselective reactions are currently underway in our laboratory.