Stereoretentive cross-coupling of chiral amino acid chlorides and hydrocarbons through mechanistically controlled Ni/Ir photoredox catalysis

The direct modification of naturally occurring chiral amino acids to their amino ketone analogs is a significant synthetic challenge. Here, an efficient and robust cross-coupling reaction between chiral amino acid chlorides and unactivated C(sp3)–H hydrocarbons is achieved by a mechanistically designed Ni/Ir photoredox catalysis. This reaction, which proceeds under mild conditions, enables modular access to a wide variety of chiral amino ketones that retain the stereochemistry of the starting amino acids. In-depth mechanistic analysis reveals that the strategic generation of an N-acyllutidinium intermediate is critical for the success of this reaction. The barrierless reduction of the N-acyllutidinium intermediate facilitates the delivery of chiral amino ketones with retention of stereochemistry. This pathway avoids the formation of a detrimental nickel intermediate, which could be responsible for undesirable decarbonylation and transmetalation reactions that limit the utility of previously reported methods.

electrophiles for the atom-economical synthesis of ketones 24,25 by generating a halogen atom for C-H abstraction [26][27][28][29] . Thorough mechanistic investigations revealed that two different reaction pathways could operate depending on the redox nature of the Ni complex and acyl electrophile. These pathways differ in terms of the order in which oxidative addition of the acyl electrophile and C-H activation of the hydrocarbon occur, resulting in an oxidative-addition-initiated pathway involving an acylnickel(II) intermediate (i) 16,[30][31][32] and a C-Hactivation-initiated pathway involving an alkylnickel intermediate (ii) 33 (Fig. 1b). However, such nickel intermediates can participate in undesirable decarbonylation 11,[34][35][36][37] and/or transmetalation [38][39][40] reactions, leading to losses in optical purity and decreased reaction efficiencies (Table 2). Therefore, neither of these pathways effectively produces chiral α-amino acid derivatives. It has been established that the presence of an α-heteroatom substituent accelerates the decarbonylation of acyl radical intermediates 41 , which imposes a challenging mechanistic hurdle for the use of optically active α-amino acid derivatives in the streamlined synthesis of chiral α-amino ketones directly from hydrocarbons.
To address this challenge, a completely different reaction pathway was devised, in which the formation of both problematic species, acylnickel(II) and alkylnickel, could be bypassed. It was postulated that reducing the acyl electrophile prior to the redox reaction of the nickel species would furnish an acylnickel(III) intermediate directly (iii). The acylnickel(III) intermediate could then react further to form the product through photocatalytic C-H abstraction (Fig. 1b, blue trace). Beneficially, this pathway does not require modulation of the nickel oxidation state after acyl radical formation. Thus, the C-H activation and reductive elimination processes are accelerated, which kinetically inhibits the undesirable decarbonylation reaction. However, the reduction barriers of acid chlorides (e.g., benzoyl chloride 2z, E o = −1.53 V vs SCE) are too high for these compounds to be reduced by Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (E o red = −1.37 V vs SCE), the optimized photocatalyst for reported C-H acylation reactions 42,43 . To solve the problem, more electron-deficient N-acylpyridinium compounds 44,45 , which can be formed by reacting acid chlorides with pyridine derivatives, were applied 46 .
Herein, using the designed nickel redox modulation strategy with in situ generated N-acylpyridinium intermediates, we achieved the direct cross-coupling of chiral amino acid chlorides with unactivated C(sp 3 )-H hydrocarbons to produce chiral amino ketones (Fig. 1c).

Reaction optimization
N-Phthaloyl-L-phenylalanine (1a) and cyclohexane were chosen as model substrates to investigate the reaction conditions (Table 1).  Compound 1a was treated with an in situ generated Vilsmeier reagent 47,48 to furnish amino acid chloride 2a. After the simple evaporation of volatiles, 2a was used for the reaction without further purification. The reaction conditions were optimized to obtain target product 3a in 81% NMR yield (74% isolated yield) using 3 equiv of cyclohexane and 2 equiv of 2,6-lutidine (entry 1). Notably, no loss of stereochemical integrity occurred as the product was obtained in 99% ee (identical to that of 1a, Supplementary Table 1). A good yield was also obtained with only 1 equiv of cyclohexane (entry 2) and the yield became nearly quantitative with 5 equiv of cyclohexane (entry 3), indicating that the proportion of a C-H substrate can be flexibly tuned depending on its availability and cost. Reducing the amount of 2,6lutidine led to a slight decrease in the reaction efficiency (entry 4). To assess the reactivities of different pyridine derivatives, structurally diverse pyridines were tested. With pyridine itself, the reaction efficiency greatly decreased, likely due to undesired radical addition to pyridine (entry 5) 49 . When 2,4,6-collidine was introduced instead of 2,6-lutidine, a similar yet slightly diminished reactivity was observed (entry 6). The use of 2,6-di-tert-butylpyridine led to a huge loss of reaction efficiency, demonstrating that a sterically more hindered pyridine derivative lowers the reactivity (entry 7) 50 . 2,4,6-Triphenylpyridine, which may form an acyl analog of the Katritzky salt 51,52 , generated the targeted product in a moderate yield (entry 8). When 2,6-lutidine was replaced with common inorganic bases such as cesium carbonate, sodium bicarbonate, or potassium phosphate, the reaction efficiency decreased significantly (entries 9-11). In addition, under base-free conditions, only a low yield of the desired product was observed (entry 12), indicating the essential role of 2,6-lutidine. Control experiments without light, the nickel catalyst, or the photocatalyst failed to produce the desired product, implying that these components are necessary for the reaction to proceed (entry 13).

Substrate scope
With the optimized conditions in hand, the amino acid scope of the developed method was investigated (Fig. 2). The reaction was effective with a wide range of amino acids, demonstrating excellent functional group compatibility. Initially, several phenylalanine derivatives were tested (3a-3g). To our delight, even fluorineor chlorine-substituted derivatives (3b-3e) were well tolerated, providing opportunities for further functionalization. Electron-withdrawing trifluoromethyl and cyano groups on the phenyl ring of the phenylalanine did not affect the reaction efficiency (3f, 3g). Other amino acids also successfully delivered the corresponding chiral amino ketones. The simplest amino acid, glycine, exhibited a good yield (72%, 3h). Alkyl-chainbearing amino acids such as alanine, homoalanine, norvaline, leucine, and cyclohexylalanine, which possess high steric hindrance and hydrophobicity 53 , reacted smoothly under the standard reaction conditions (3i-3m). Homophenylalanine, an important bioactive non-natural chiral amino acid 54 , effectively produced 3n in moderate yield (51%). Notably, amino acids bearing polar side chains could also be employed after appropriate protection. O-Methylated tyrosine reacted smoothly (43%, 3o). Furthermore, benzyl-protected serine gave the desired ketone in moderate yield (50%, 3p). Aspartic acid and glutamic acid methyl esters furnished chiral amino ketones bearing ester side chains, albeit in lower yields (54%, 3q; 27%, 3r). The reactions of cyclic amino acids with different protecting groups also furnished the target products (40%, 3s; 78%, 3t). Due to their innate instability and high tendency to undergo racemization, peptidyl acid chlorides bearing more than two amino acid residues could not be employed 47,48 . In addition, α-amino acid homologues were tested, as they are known to exhibit significantly different biochemical properties 55 . Two β-amino acids (β-alanine and β-phenylalanine) delivered the target products in very good yields (77%, 3u; 82%, 3v). Moreover, γ-amino acids, such as γ-aminobutyric acid (GABA), baclofen, and gabapentin, all effectively gave the corresponding products in good yields (67-74%, 3w-3y).
The direct cross-coupling of amino acids and amino alkyl substrates produced unsymmetrical α,α′-diaminoketones in very good yields (79-89%, 24a-26a). Although some 1,3-diaminoketone compounds have been reported to exhibit bioactive properties 2 , synthetic access to this substrate class has been limited 13 . To the best of our knowledge, the developed reaction is unique in providing direct synthetic access to α′-oxyor α′-amino-substituted chiral amino ketones. Because α-heteroatom-substituted organometallic reagents cannot be readily prepared, transition-metal-catalyzed crosscoupling reactions (Fig. 1a) are not readily applicable for synthesizing such compounds 14  the desired products in moderate yields (52-70%, 27a-29a); however, benzylic functionalization required more equivalents (10 equiv) of the C-H substrate. Aryl chlorides were also tolerated as the C-H substrate, as in the case of amino acids (30a-32a). Complex bioactive C-H substrates were also tolerated producing the corresponding amino-acid-coupled complexes. Ambroxide (61%, 33a) and gemfibrozil (70%, 34a) reacted smoothly to provide the coupled products in a regioselective fashion, which demonstrates the streamlined latestage introduction of a chiral amino acid moiety, taking advantage of the excellent functional group compatibility of the developed protocol. Having observed that our reaction disfavors tertiary C-H bonds when adamantane was used, we attempted an intermolecular competition experiment using an equivalent amount of cyclohexane and 2,3-dimethylbutane ( Supplementary Fig. 40). The reaction exclusively furnished the secondary C-H functionalized product 3a, albeit in a lowered yield (63%, 99% ee). We presume this unusual secondary selectivity arises from steric hindrance lowering the reactivity at the tertiary position. Finally, the stereochemical integrity of selected products (3a, 3k, 3l, 3n, 3o, 3s, 16a, 17a, 26a, and 27a as chosen based on the limited availability of racemic compounds) was investigated. The stereochemistry was fully maintained during the reaction, except with benzylic substrates, which led to a small decrease in enantiopurity (from 99% to 98% ee, Supplementary

Mechanistic investigations
After demonstrating the wide applicability of the developed reaction conditions, the underlying reaction mechanism was investigated through comprehensive computational and experimental studies. First, control experiments were performed to compare the developed reaction conditions with the two previously reported protocols, which featured oxidative addition first 16,30-32 or C-H activation first 33 ( Table 2). The optimized reaction conditions (entry 1) afforded the desired product in high yields without any enantiomeric loss, whereas the previously reported reaction conditions exhibited low yields accompanied by a significant decrease in enantioselectivity (entries 2 31 and 3 33 ). Even when N-acylsuccinimide 35a was employed under the reported conditions 33 for the C-H-activation-initiated pathway, no product was generated (entry 4). It has been reported that such acyclic secondary-alkyloyl-derived N-acylsuccinimide substrates are incompatible, presumably due to their sensitivity to sterics 33 . Notably, a dimerization byproduct (2a-dimer) was detected in both entries 2 and 3, but no such product was generated under the developed reaction conditions, implying that undesirable decarbonylation or transmetalation processes were successfully suppressed by the proposed strategy.
It is well documented that N-acylpyridiniums can be generated from acyl chlorides and pyridines 58 . Some stabilized N-acylpyridiniums, such as N-acylpyridinium and N,N-dimethylaminopyridinium salts, have been isolated and fully characterized 44,59 . However, attempts to isolate the N-acyllutidinium intermediate 2z-lut were unsuccessful, presumably because its stability was decreased by the steric hindrance of the pyridine ring.
Instead, in situ NMR studies were conducted to investigate the formation of 2a-lut. The 1 H NMR spectrum of a 1:2 mixture of 2a and 2,6-lutidine is shown in Fig. 4a. Here, an upfield shift of the 2a resonances and a downfield shift of the 2,6-lutidine methyl peak was witnessed. This observation is in good agreement with the analogous lutidinium salt generated from ethyl chlorooxoacetate and 2,6-lutidine, reported by the Wu group 46 . In addition, pronounced peak broadening and even separation of the α-carbonyl proton resonance were detected, likely due to the steric bulkiness of the 2,6-lutidine moiety leading to the formation of rotameric species. An NOE study of this mixture indicated NOE signals between the carbonyl α-proton, benzylic proton and the lutidine methyl group, indicating their presence in the same molecule. Further studies were conducted by monitoring the IR carbonyl stretch of cyclohexane carbonyl chloride (2aa) with and without the addition of 2,6-lutidine (Fig. 4b). Here, 2aa was chosen as the phthalimide group present in 2a led to complex carbonyl absorptions. The characteristic carbonyl stretch of 2aa was observed at 1789 cm −1 . When 1 equiv of 2,6-lutidine was introduced, the IR spectrum clearly showed a new absorption band in the carbonyl region at 1741 cm −1 . This is indicative of the formation of a new carbonyl species, like the postulated N-acyllutidinium intermediate.
After confirming the generation of an N-acyllutidinium compound, the single-electron reduction of the N-acyllutidinium intermediate was investigated. When 2,2,6,6-tetramethylpiperidine-Noxide (TEMPO, 1 equiv) was introduced, acyl-TEMPO (2a-TEMPO) was formed in 51% yield, indirectly confirming the generation of acyl radicals during the reaction (Fig. 4c). Next, cyclic voltammetry experiments were conducted with 2aa as the model substrate (Fig. 4d). The measured reduction potential of 2aa was -2.45 V vs SCE, which indicates that the direct reduction of 2aa is not feasible with the iridium photocatalyst (Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 , E o red = −1.37 V vs SCE) 60,61 . After the addition of 2,6-lutidine, the reduction wave of 2aa was diminished, accompanied by the formation of a new irreversible reduction wave at E p = −0.95 V vs SCE. This new reduction likely originated from the lutidinium intermediate 2aa-lut. The observed value, which falls within the range suitable for reduction by Ir[dF(CF 3 ) ppy] 2 (dtbbpy)PF 6 , is in good agreement with the computed reduction potential of 2aa-lut (−1.05 V vs SCE). This change in the reduction potential suggests that the generation of acyl radicals is facilitated by the formation of an N-acyllutidinium intermediate, as initially postulated. Furthermore, the reduction potential of the lutidinium species when coordinated to nickel catalyst ( 3 IV-2aa) was computed to be less negative (-0.85 V vs SCE), indicating that the nickel catalyst may facilitate the reduction process. In addition, Stern-Volmer quenching experiments were conducted with 2a and 2,6-lutidine. 2a or 2,6-lutidine alone could not effectively quench the iridium photocatalyst. However, a 1:2 mixture of 2a and 2,6-lutidine showed highly efficient quenching of the excited photocatalyst (Fig. 4e). Overall, these mechanistic studies confirm that the proposed N-acyllutidinium intermediate is indeed generated and can be effectively reduced to furnish the postulated acylnickel species.
Furthermore, to obtain an improved understanding of the reaction mechanism, computational studies were performed using density functional theory (DFT) at the B3LYP-D3/6-311++G**/ SDD 62,63 level of theory (Supplementary Data 1). First, the redox barriers (ΔG ‡ ) of initial catalytic species (dtbbpy)Ni II Cl 2 3 I were investigated using Marcus theory 64,65 to clarify its behavior (Fig. 5). The barrier for reduction of 3 I to Ni(I) species 2 II, a key process in the oxidative-addition-initiated pathway, was computed to be 21.7 kcal/mol. Similarly, the barrier for the oxidation of 3 I to high- valent Ni(III) species 2 III in the C-H-activation-initiated pathway was determined to be 25.4 kcal/mol. In contrast, the proposed single-electron reduction of 2z-lut after binding to nickel species 3 IV was found to be practically barrierless, directly delivering acylnickel(III) intermediate 2 V. These results clearly indicate that the reduction of 2z-lut is favored over the redox processes of the relevant nickel species, and this serves as a thermodynamic sink to drive the reaction.  A full energy profile for the proposed pathway was constructed through extensive computational studies (Fig. 6). Initially, the N-acyllutidinium intermediate undergoes facile coordination to nickel precatalyst 3 I to give 3 IV. Initially, the N-acyllutidinium intermediate undergoes facile coordination to nickel precatalyst 3 I to give 3 IV, followed by an essentially barrierless reduction (0.7 kcal/mol) to form 2 V (-28.8 kcal/mol), which serves as a thermodynamic sink, rendering this process irreversible. The photolysis of 2 V may lead to its excited state V*, which undergoes chlorine-mediated hydrogen atom transfer to give alkylnickel species 2 VI (3.7 kcal/mol). Excited state V* and its C-H abstracting transition state could not be located in a straightforward manner using DFT. However, it is well documented that such processes are downstream transformations when assisted by light as an energy source 66,67 . This process has served as a fundamental step for the development of a variety of C(sp 3 )-H functionalization reactions through the implementation of photoirradiated Ni/Ir dual catalysis 68 . Kinetic isotope effect (KIE) experiments using 2a as a substrate resulted in k H /k D values of 1.08 (parallel reactions) and P H /P D values of 1.83 (intermolecular competition reactions) 69 (Supplementary Fig. 55-57). This indicates that the product-determining C-H activation ( 2 V to 2 VI) is not the turnoverlimiting step 33 . Reductive elimination through 2 VI-TS to produce the desired product was found to have an activation barrier of 8.7 kcal/ mol 70 . Finally, the oxidation of Ni(I) species 2 VII to initial precatalyst 3 I through VII-TS (-21.5 kcal/mol) completes the catalytic cycle. In this case, the overall reaction barrier (8.7 kcal/mol) is very low, which accounts for the kinetic inhibition of side reactions such as decarbonylation. These results indicate that modulation of the redox state of the nickel species is rather sluggish. Thus, the designed strategy, which bypasses the redox processes of the nickel species, is crucial for direct C(sp 3 )-H coupling between chiral α-amino acid chlorides and hydrocarbons.
Combining the experimental and computational findings, a plausible mechanism is proposed, as shown in Fig. 7. The N-acyllutidinium intermediate binds to the nickel(II) precatalyst, generating 3 IV. Subsequent single electron reduction of 3 IV furnishes acyl group-bound 2 V along with the liberation of 2,6-lutidine. This highvalent nickel species undergoes hydrogen atom transfer mediated by a  Fig. 7 | Proposed reaction mechanism. The iridium photocatalyst serves to reduce the N-acyllutidnium bound to the Ni(II) species ( 3 IV), furnishing Ni(III) species 2 V. 2 V undergoes light-assisted C-H activation and reduction elimination to deliver the ketone product and Ni(I) species 2 VII. Finally, 2 VII is oxidized back the the initial catalyst 3 I. chlorine radical liberated through direct photolysis to yield alkyl acyl nickel species 2 VI. This species then undergoes reductive elimination to deliver the desired ketone product, followed by reoxidation of the resulting Ni(I) species 2 VII to its initial state 3 I.
In conclusion, cross-coupling between chiral amino acid chlorides and unactivated C(sp 3 )-H substrates was realized using nickel/ photoredox dual catalysis under mild reaction conditions. Through strategic modulation of the reaction mechanism, a variety of chiral amino acids were transformed into the corresponding amino ketones without the loss of stereochemical integrity. This method overcomes the limitations associated with decarbonylative racemization in previously reported methodologies for Ni/photoredox catalysis. Comprehensive mechanistic studies revealed that the N-acyllutidinium intermediate, generated from the acid chloride and 2,6-lutidine, is crucial for driving the reaction to the successful reduction-initiated pathway. This pathway commences with the single-electron reduction of the N-acyllutidinium species, thus directly furnishing an acylnickel(III) intermediate and preventing undesirable side reactions. Computational analysis revealed that modulating the nickel oxidation state is a sluggish process that may lead to acyl radical decarbonylation. Thus, circumventing this process with the developed reduction-initiated strategy is key for maintaining the optical purity of the product. Various functionalized chiral amino ketones were efficiently synthesized using the developed reaction. The present findings demonstrate successful mechanistic control to realize a challenging coupling reaction in Ni/ photoredox catalysis, which can provide further insight into the development of new synthetic methods.

General procedure for the N-acyllutidinium-mediated acylation
To an 8 mL vial equipped with a PTFE-coated stirrer bar were added the corresponding N-protected amino acid (0.20 mmol, 1.0 equiv), oxalyl chloride (30.9 μL, 0.36 mmol, 1.8 equiv), a catalytic amount of DMF (0.2 μL), and CH 2 Cl 2 (2.0 mL). The resulting mixture was stirred for 2-16 h at room temperature before it was concentrated under reduced pressure and azeotropically dried with benzene (2 mL × 2) to afford the desired N-protected amino acid chloride which was used directly for the next step.

Data availability
Detailed experimental procedures, computational details, and characterization data for new compounds are available from the Supplementary Information. Cartesian coordinates of the calculated structures are available from the Supplementary Data 1. The authors declare that the data supporting the manuscript are included in the manuscript and supplementary materials.