Enantioselective Synthesis of Chiral γ-Amino Acid Esters via Photoredox/Nickel-Catalyzed Aryl-Aminoalkylation of Alkenes

Enantioselective Synthesis of Chiral γ-Amino Acid Esters via Photoredox/Nickel-Catalyzed Aryl-Aminoalkylation of Alkenes | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Chinese Journal of Chemistry This is a preprint and has not been peer reviewed. Data may be preliminary. 25 February 2025 V1 Latest version Share on Enantioselective Synthesis of Chiral γ-Amino Acid Esters via Photoredox/Nickel-Catalyzed Aryl-Aminoalkylation of Alkenes Authors : Fu Ye , Youzhi Xu , Songlin Zheng , Genping Huang , and Weiming Yuan 0000-0002-0766-960X [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174045084.48655778/v1 Published Chinese Journal of Chemistry Version of record Peer review timeline 332 views 233 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Chiral γ-amino acids are among the most valuable and ubiquitous structural units in natural products, pharmaceuticals and many physiologically active compounds. Herein, we demonstrate a convenient synthetic approach to chiral γ-amino acid structures via an asymmetric aryl-aminoalkylation of alkenes enabled by a dual photoredox/nickel catalysis. Taking advantage of the mild and redox-neutral condition, high levels of enantiocontrol of α-carbonyl benzylic stereocenters are obtained. Experimental and computational mechanistic studies were performed to gain insights into the mechanism and origin of enantioselectivity. The results reveal that the reaction follows a Ni(0)/Ni(I)/Ni(III)/Ni(I) catalytic cycle and C‒X bond oxidative addition is the enantiodetermining step. Enantioselective Synthesis of Chiral γ-Amino Acid Esters via Photoredox/Nickel-Catalyzed Aryl-Aminoalkylation of Alkenes Fu Ye a , Youzhi Xu b , Songlin Zheng c , Genping Huang b *, and Weiming Yuan a * a Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, P. R. China b Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China c Hubei Three Gorges Laboratory, Yichang 443007, P. R. China ABSTRACT: Chiral γ-amino acids are among the most valuable and ubiquitous structural units in natural products, pharmaceuticals and many physiologically active compounds. Herein, we demonstrate a convenient synthetic approach to chiral γ-amino acid structures via an asymmetric aryl-aminoalkylation of alkenes enabled by a dual photoredox/nickel catalysis. Taking advantage of the mild and redox-neutral condition, high levels of enantiocontrol of α-carbonyl benzylic stereocenters are obtained. Experimental and computational mechanistic studies were performed to gain insights into the mechanism and origin of enantioselectivity. The results reveal that the reaction follows a Ni(0)/Ni(I)/Ni(III)/Ni(I) catalytic cycle and C‒X bond oxidative addition is the enantiodetermining step. Background and Originality Content Amino acids are among the most valuable and ubiquitous structural units in natural products, pharmaceutical agents, and many physiologically active compounds. 1 Among them, γ -Aminobutyric acid (GABA) has attracted remarkable attention as a well-known inhibitory neurotransmitter in the mammalian central nervous system (CNS) that displays a substantial role in brain disorders 2 There are many pharmaceutical compounds containing chiral GABA motif such as ( S )-pregabalin, ( R )-baclofen, and CCR2-receptor antagonist. 3 Due to their diverse bioactive interests and wide applications, significant efforts have been devoted to the synthesis of γ -amino acids and related derivatives. 4 However, enantioselective synthesis of chiral α -aryl substituted γ -amino acids and the derivatives remains a formidable challenge due to the high propensity for racemization of such α -carbonyl benzylic stereocenters under basic conditions or elevated temperatures. 5 Thus, further developing mild, efficient and modular synthesis of valuable chiral α -aryl γ -amino acid scaffolds is of highly interesting and desirable. Recently, nickel-catalyzed intermolecular 1,2-dicarbofunctionalization of readily available olefins has emerged as a powerful and versatile access to complex molecular architectures by simultaneously forging two adjacent sp 3 -hybridized carbon centers across the π-system in a single operation. 6 However, nickel-catalyzed three-component asymmetric variants have been largely underdeveloped, which remains an unmet challenge due to the difficulties of controlling chemo-, regio- and stereoselectivities. The Morken group reported a seminal work on nickel-catalyzed enantioselective intermolecular 1,2-dicarbofunctionalization of alkenes with alkyl iodides and organozinc reagents. 7 Later on, nickel-catalyzed reductive asymmetric three-component cross-couplings have been developed by Diao 8 , Chu 9 , Nevado 10 , among others 11 . Nevertheless, these synthetic approaches rely on the use of reactive organometallic reagents or metal-based reductants ( Scheme 1a ). A recent elegant work on nickel-catalyzed enantioselective electroreductive cross-coupling of alkenes was demonstrated by the Mei group. 12 Benefit from the development of metallaphotoredox chemistry, 13 the asymmetric alkene conjugate cross-coupling reactions have been recently developed via dual photoredox/chiral metal catalysis ( Scheme 1b ). 14 Various mild Csp 3 nucleophiles and electrophiles can be used as alkyl radical precursors, but the radical patterns are limited to tertiary and secondary alkyl radicals. Our group has previously reported a three-component conjugate cross-coupling of α -silylamines, alkenes, and aryl halides via a dual photoredox/nickel catalysis. 15 In line with the synthetic importance of chiral α -aryl γ -amino acid structures, we questioned whether it would be possible to furnish an enantioselective conjugate cross-coupling by introducing a chiral ligand to induce the enantioselectivity control. Here, we report our recent progress in dual photoredox/nickel-catalyzed asymmetric intermolecular aryl-aminoalkylation of alkenes by identifying a chiral bioxazoline ligand (BiOx) ( Scheme 1c ). This mild and redox-neutral reaction represents a highly enantioselective approach for rapid assembly of chiral α -aryl γ -amino acid structures from readily available starting materials. 16 Scheme 1. Nickel-catalyzed enantioselective intermolecular 1,2-dicarbofunctionalization of alkenes. Results and discussion The initial study began with the model reaction with methyl 4-iodobenzoate 1a , tert-butyl acrylate 2a and 4-((trimethylsilyl)methyl)morpholine 3a ( Table 1 ). After a systematic study of reaction conditions (for details, see the supporting information), we found that in the presence of Ir(dFppy) 2 (bpy)PF 6 (10 mmol%), NiBr 2 •DME (10 mmol%), L7 (15 mmol%), under blue LED irradiation at room temperature for 24 h, the reaction proceeded smoothly in a mixed solvent system (DMA: t BuOMe = 1:1, 0.1 M) to afford desired product γ -amino acid ester 4 with a α -carbonyl benzylic stereocenter in 65% yield and 95% enantiomeric excess (ee) (entry 1). BiOx ligands with different substituents and side arms were synthesized and investigated (see Table S1). Notably, the BiOx ligand bearing a large (3,5-di- tert -butyl)phenyl side arm group gave the best yield and enantioselectivity (entry 1). While decreasing the size of the side arm gradually decreased the enantioselectivity (entries 6-7). Chiral BiOx ligands without a middle linker such as L1 and L2 resulted in decreased ee and yield (entries 2-3). Ligand screening showed that chiral BiOx templates were generally more effective than chiral biimidazoline (BiIM) ligands such as L3 and L4 (entries 4-5). Other nickel catalysts such as NiCl 2 or Ni(cod) 2 gave slightly lower yield and ee (entries 8-9). Of note, organic photosensitizer 4-CzIPN could give a comparable reactivity and promising level of stereocontrol (entry 10), while Ir(ppy) 3 was not effective for this dual catalytic system (entry 11). The mixed DMA/ t BuOMe solvent system was essential for guaranteeing a high enantioselective control, as a substantial decrease in enantioselectivity was observed when NMP, DMF, or mixed solvents were used (entries 12-13, also see Table S2 for solvent screening). Control experiments indicated that photocatalyst, nickel, ligand, and visible light were all essential for the success of this asymmetric transformation (entry 14). Table 1. Optimization of reaction conditions a a All reactions were carried out on a 0.1 mmol scale, 1a:2a:3a = 1:2:2 (molar ratio), Ir(dFppy) 2 (bpy)PF 6 (1 mmol %), NiBr 2 • DME (10 mmol %), ( R,S )- L7 (15 mmol %), DMA/ t BuOMe (v/v) = 1:1, 0.1 M, 1.5 W blue LED, 25 °C, 24 h. GC yields were determined using n -tridecane as an internal standard. The ee values were determined by HPLC on a chiral stationary phase. Scheme 2. Substrate scope. a a Unless otherwise noted, all reactions were carried out on a 0.2 mmol scale with aryl iodides 1 (0.2 mmol, 1.0 equiv.), 2 (0.4 mmol, 2.0 equiv.), 3 (0.4 mmol, 2.0 equiv.), Ir(dFppy) 2 (bpy)PF 6 (1.7 mg, 2.0 µmol, 0.01 equiv.), NiBr 2 •DME (6.2 mg, 20 µmol, 0.10 equiv.), L7 (20 mg, 30 µmol, 0.15 equiv.), DMA/ t BuOMe =1:1 (2.0 mL) at room temperature for 24 h. Isolated yields after chromatography are shown. The ee values were determined by HPLC on a chiral stationary phase. b Aryl bromide was used. With the optimized reaction conditions in hand, the evaluation of substrate scope was performed in Scheme 2 . A variety of aryl iodides bearing both electron-donating and electron-withdrawing groups in the para or meta positions were amenable to the reaction system ( 4-21 ), affording structurally diverse enantioenriched γ -amino acid derivatives in moderate yields and excellent enantioselectivities (up to 96% ee). Functional groups including esters, halides, ketones, ethers, sulfonyl amides, and cyano groups were compatible with the mild and redox-neutral reaction conditions. β -Iodonaphthalene was also suitable substrate, furnishing the corresponding product with a high level of stereocontrol ( 15 ). Particularly, heteroaryl halides such as 2-fluoro-4-iodopyridine ( 20 ) and 2-iododibenzo[ b , d ]furan ( 21 ) were successfully applied in this synergistic protocol, affording desired products with high enantioselectivity. Next, the substituent effect of acrylates was investigated. In several previous reports, ter t-butyl substituent was found to be essential for achieving high enantioselectivity. However, in our case, not only tert -butyl acrylates but also primary and secondary alkyl-substituted acrylates were also viable substrates, delivering the corresponding products without obvious erosion in ee ( 22-26 ). Furthermore, aryl bromide participated smoothly as well with a similar level of stereocontrol ( 23 ). It should be noted that the absolute configuration of ( R )- 23 was unambiguously assigned by X-ray diffraction analysis. Moreover, complex alkenes derived from natural products such as estrone was well tolerated ( 27 ). Scheme 3. Mechanistic studies. We next turned our attention to examining the scope of α -silylamine component. Given the importance of heterocyclic amine architectures in pharmaceutical chemistry, facile introducing these moieties into target compounds is of great interest. Under the standard condition, we were delighted to find that a broad range of N -heterocycles, such as morpholine ( 28 ), piperazine ( 29 ), thiomorpholine ( 30 ) were proceeded smoothly to provide the desired coupled products in moderate yields and good ee values. Piperidines bearing functional groups such as ester ( 31 ), OBz ( 35 ) reacted smoothly. Piperazine ring including benzo[ b ]thiophene ( 32 ), 1,3-difluorobenzene ( 33 ) and benzonitrile ( 34 ) fragments could be introduced into target molecules smoothly with good enantioselectivity. This synthetic protocol provides a facile and modular assembly of enantioriched α -aryl γ -amino acid structures. Mechanistic studies To gain insight into mechanism of this reaction, a series of control experiments were conducted and the results are summarized in Scheme 3 . The reaction was completely inhibited by adding a free radical scavenger 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO). Instead, TEMPO-adducts were detected by high-resolution mass spectrometric (HRMS) analysis of the crude mixture, thus suggesting that an α -amino radical is likely involved in the catalytic system ( Scheme 3a ). Control experiments demonstrated that α -silylamine is essential for this transformation, as other α -amino radical precursors led to no conversion probably due to their relatively higher oxidative potentials that leading to a poor reactivity ( Scheme 3b ). In order to gain more insight into the active nickel species in the catalytic cycle, we synthesized the ligated aryl-Ni II I complex 36 and found that the reaction of aryl-Ni II I complex 36 with 2a and 3a failed to deliver the desired product 4’ , while the reaction proceeded smoothly in the presence of catalytic amount of aryl-Ni II I complex 36 ( Scheme 3c ). Furthermore, the use of the dtbbpy ligand afforded the corresponding racemic γ -amino acid derivative 4’ in 42% yield. This result highlighted that the observed 36 lack of reactivity in production of 4’ is not due to the use of the dtbbpy ligand. Taken together, these results indicated that the putative aryl-Ni II might not be a productive intermediate in the main catalytic cycle. In other word, the Ni 0 /Ni II /Ni III pathway is most unlikely to occur. In addition, Stern-Volmer fluorescence quenching experiments showed that α -silylamine rather than other reaction components was the most effective quencher for reductive quenching of the excited state of photocatalyst ( Scheme 3d ). Nonlinear effects studies showed that the e.e. of the product was linearly related to the e.e. of the ligand, suggesting that the step determining enantioselectivity may involve a single chiral bisoxazoline ligand and a nickel species ( Scheme 3e ). To gain a deeper understanding of the detailed reaction mechanism, density functional theory (DFT) calculations were performed at the level of (u)TPSS-D3BJ (SMD) /def2-TZVPP//(u)B3LYP-D3BJ/SDD&6-31G(d) (see SI for computational details). The experimentally used methyl 4-iodobenzoate 1a , ethyl acrylate 2’ and in-situ generated α -amino radical 3a’ were selected as the model substrates, with a simplified ligand L7* to reduce computational cost ( Figure 1a ). The calculations indicate that the reaction begins with a Giese addition, where the α -amino radical 3a’ reacts with ethyl acrylate 2’ to form α- carbonyl radical IM1 via transition state TS1 , with an energy barrier of only 7.3 kcal/mol. Alternative pathways, such as the C‒I oxidative addition of 1a , were also considered but had much higher energy barriers than the Giese addition (see SI for details). The α -carbonyl radical IM1 is then captured by the Ni(0) center of IM2 CSS through transition state TS2 doublet , leading to the Ni(I) intermediate IM3 doublet . Subsequently, C‒I oxidative addition of 1a occurs through transition state TS3 doublet , resulting in Ni(III) intermediate IM3 doublet . The catalytic cycle is completed by C‒C reductive elimination. The dissociation of the I anion from IM4 doublet to form the cationic intermediate IM5 doublet is thermodynamically favored by 9.8 kcal/mol. Finally, IM5 doublet undergoes C‒C reductive elimination via transition state TS4 doublet , delivering the product-coordinated intermediate IM6 doublet , from which ligand exchange with the I anion releases the final product 4 and regenerates the Ni(I) precatalyst IM7 doublet . After the detailed reaction mechanism established, the key enantioselectivity-determining step, C‒I oxidative addition, was examined using the experimentally employed tert -butyl acrylate 2a and chiral ligand L7 ( Figure 1b ). The computations show that the C‒I oxidative addition via transition state ( R )- TS5 doublet is lower in energy than that via ( S )- TS5 doublet by 1.9 kcal/mol, which is in good agreement with the experimentally observed enantioselectivity of 95% ee. Scrutiny of the optimized geometries reveals that two transition states adopt distinct configurations. In ( R )- TS5 doublet , the aryl group is oriented perpendicular to chiral ligand, while in ( S )- TS5 doublet the aryl group atom is positioned within the plane of the chiral ligand. As a consequence, the chiral ligand in ( S )- TS5 doublet has to undergo greater distortion to accommodate the aryl group. Moreover, the weak π-π interaction between the aryl group and the phenyl ring of the chiral ligand was observed in ( R )- TS5 doublet , which is absent in ( S )- TS5 doublet . The combination of the steric repulsion and π-π interaction may make ( S )- TS5 doublet higher in energy than ( R )- TS5 doublet , which accounts for the experimentally observed enantioselectivity. It is also noteworthy that the ( S )-configured transition state analogous to ( R )- TS5 doublet was considered but found to be significantly higher in energy than ( S )- TS5 doublet , which is mainly due to the steric repulsion between the ( S )-configured alkyl moiety and chiral ligand (Figure S8). Based on the experimental results and DFT calculations, we proposed a mechanism of this nickel/photoredox dual-catalyzed enantioselective cross-coupling reaction ( Scheme 3f ). As illustrated in cycle: Single electron reduction of α -silylamine (E 1/2 ox = +0.4 ∼0.8 V vs SCE) 17 by the excited state of photocatalyst (E 1/2 PC*/PC˙¯ = +1.12 V vs SCE) 18 generates an α -amino radical A , which undergoes Giese addition to alkene to get an α -carbonyl radical B , subsequently intercepted by Ni(0) to form Ni(I) intermediate C , followed by concerted oxidative addition with aryl halides D and reductive elimination to afford γ -amino acid derivatives. Final single-electron-transfer (SET) between Ni(I) [E red (Ni I /Ni 0 ) = −1.17 V vs SCE] 19 and the reduced state of photocatalyst (E 1/2 PC/PC˙¯ = −1.25 V vs SCE) 18 regenerates both catalysts. Figure 1. Computational studies. (a) Calculated energy profile of the Ni-catalyzed reaction with simplified ligand L7* . (b) Oxidative addition transition states with chiral ligand L7 . Bond distances and energies are given in Å and kcal/mol, respectively. Conclusion In conclusion, we have developed an asymmetric three-component cross-coupling of acrylates, aryl halides and α -silylamines via dual nickel/photoredox catalysis, producing highly valuable chiral α -aryl γ -amino acid derivatives with moderate to good yields and high enantioselectivities. A variety of (hetero)aryl halides and α -silylamines are nicely tolerated. The mild and redox-neutral conditions guarantee the high enantioselectivity. The results of computational and experimental studies indicate that the conjugate cross-coupling reaction proceeds via Giese addition with α -amino radical, radical addition to Ni 0 with α -carbonyl radical, concerted oxidative addition with aryl halides, and subsequent C–C reductive elimination. ASSOCIATED CONTENT The supporting information is available free of charge via the Internet at http://pubs.acs.org. Full experimental details, all characterization data, including 1 H NMR, 13 C NMR, HMRS for all new compounds, and copies of NMR spectra (PDF) AUTHOR INFORMATION Corresponding Author Genping Huang ─ Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China. Email: [email protected] Weiming Yuan ─ Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, P.R. China; orcid.org/0000-0002-0766-960X E-mail: [email protected] Author Fu Ye ─ Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology (HUST), 1037 Luoyu Road, Wuhan 430074, P. R. China; Youzhi Xu ─ Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. China. Songlin Zheng ─ Hubei Three Gorges Laboratory, Yichang 443007, P. R. China. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We acknowledge the financial supports from the National Key R&D Program of China (2024YFA1510500) and the National Natural Science Foundation of China (22201087, 22073066, 22471191). REFERENCES 1. Conti, P.; Tamborini, L.; Pinto, A.; Blondel, A.; Minoprio, P.; Mozzarelli, A.; Micheli, C. D. Drug Discovery Targeting Amino Acid Racemases. Chem. 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Collection Chinese Journal of Chemistry Keywords asymmetric synthesis chiral γ-amino acids nickel catalysis photoredox catalysis radical reaction Authors Affiliations Fu Ye Hubei Provincial Key Laboratory of Bioinorganic Chemistry and Materia Medica View all articles by this author Youzhi Xu Tianjin University School of Science View all articles by this author Songlin Zheng Hubei Three Gorges Laboratory View all articles by this author Genping Huang Tianjin University School of Science View all articles by this author Weiming Yuan 0000-0002-0766-960X [email protected] Hubei Provincial Key Laboratory of Bioinorganic Chemistry and Materia Medica View all articles by this author Metrics & Citations Metrics Article Usage 332 views 233 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Fu Ye, Youzhi Xu, Songlin Zheng, et al. Enantioselective Synthesis of Chiral γ-Amino Acid Esters via Photoredox/Nickel-Catalyzed Aryl-Aminoalkylation of Alkenes. 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