Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Abstract

Open AccessCCS ChemistryCOMMUNICATIONS19 Aug 2022Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes Feng He, Liting Hou, Xianqing Wu, Haojie Ding, Jingping Qu and Yifeng Chen Feng He Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237 Google Scholar More articles by this author , Liting Hou Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237 Google Scholar More articles by this author , Xianqing Wu Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237 Google Scholar More articles by this author , Haojie Ding Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237 Google Scholar More articles by this author , Jingping Qu Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237 Google Scholar More articles by this author and Yifeng Chen *Corresponding author: E-mail Address: [email protected] Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, Frontiers Science Center for Materiobiology and Dynamic Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202010 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The facile construction of chiral quaternary α-alkenylated pyrrolidinones is a long-term challenge in organic synthesis. The asymmetric difunctionalization of 1,3-dienes represents the most compelling tool for assembling alkenylated compounds by regioselective 1,2- or 1,4-difunctionalization. Nevertheless, the manipulation of unactivated 1,3-dienes to forge the quarternary stereogenic center still remains largely underdeveloped. Herein, we disclose a nickel-catalyzed asymmetric 1,4-arylcarbamoylation of unactivated 1,3-dienes tethered on carbamoyl fluoride with readily available arylboronic acids, providing rapid access to the enantioenriched α-alkenylated pyrrolidinones bearing the quaternary stereogenic center in high yields with broad functional group tolerance. Moreover, this chiral ligand-controlled asymmetric transformation overcomes the intrinsic substrate control with a preexisting chiral center. Download figure Download PowerPoint Introduction 5-Membered lactams including oxindole1–3 and the pyrrolidinone scaffold4–6 represent key skeletons of many biologically active molecules. Among the variations on this motif, α−functionalized pyrrolidinone is the most ubiquitous substructure. The latest example is the core fragment of Paxlovid developed by Pfizer, which is the first oral antiviral for treatment of COVID-19 issued by the FDA in 2021.7 Therefore, the development of an efficient catalytic enantioselective synthesis of α-functionalized γ-lactams is of great significance but still remains challenging. The two main approaches for accessing the chiral pyrrolidinone are (1) the direct functionalization of simple lactam and (2) assembly from the easily accessible acyclic building block. Due to the scarcity of examples for direct functionalization of simple lactam,8,9 only limited catalytic enantioselective transformations of functionalized lactam such as decarboxylative allylation,10 hydrogenation,11,12 and cross-coupling13–15 have been developed. The representative later approach is the development of cyclization from acyclic precursors to stereoselectively forge the five-membered pyrrolidinone ring.16–20 Among various cyclization transformations, the functionalization of carbamoyl electrophiles is a particularly intriguing strategy due to the easy accessibility from the prevalent amine fragment by one more protective step and good stability toward the other acyl chloride derivatives.21 Very recently, the transition metal-catalyzed enantioselective cyclization of alkene-tethered carbamoyl electrophiles has emerged as a powerful synthetic toolbox to access the chiral 5-membered lactams, in which the stereodefined carbamoyl metalation is followed by interception of the resultant σ-alkyl metal species with either a nucleophile or an electrophile (Scheme 1a). This transformation has emerged as a valuable implement for the transition metal-catalyzed difunctionalization of alkenes from the aryl (pseudo)halides.22–28 With this strategy, a variety of functionalized chiral α-alkylated oxindoles from benzofused carbamoyl electrophiles were developed by the groups of Takemoto,29 Lautens,30,31 and Wang.32–34 Our group developed the Ni-catalyzed reductive alkylcarbamoylation of monosubstituted alkenes to form the tertiary α-alkylated pyrrolidinone.35–40 Later on, the quaternary α-alkylated pyrrolidinones synthesis from carbamoyl halides was achieved by Ye et al.,41 Lin et al.,42 and our group.36 Particularly, Ye and coworkers demonstrated the asymmetric arylcarbamoylation of alkenes to furnish the α-benzyl pyrrolidinone derivative with excellent yields and enantioselectivities. In sharp contrast, the enantioselective synthesis α-alkenyl pyrrolidinone derivatives from the cyclization is still a forbidding synthetic challenge.43–45 The incorporation of an alkenyl group at the adjacent position of lactam functionality is particularly appealing, which would pave a way for synthesis of various functionalized pyrrolidinones due to the versatile reactivity of the alkene group. Therefore, it is highly desirable to develop the expedient synthesis of this chiral motif due to the current scarcity of methods. Scheme 1 | Enantioselective synthesis of α-alkenyl pyrrolidinones with carbamoyl electrophiles. Download figure Download PowerPoint The regio- and enantioselective hydrofunctionalization and difunctionalization of 1,3-dienes, which enables the rapid access to a variety of functionalized alkenes, has recently been intensively investigated.46–56 Despite tremendous progress, the formation of a quaternary stereogenic center from analogous transformation is still largely underdeveloped.57–59 Specifically, the stereoselective construction of the quaternary stereocenter enabled by the asymmetric difunctionalization of 1,3-dienes is still an unmet challenge.60–65 During our continuing efforts towards the chiral lactam synthesis,35–37,66–68 we have been able to disclose the nickel-catalyzed intramolecular asymmetric arylcarbamoylation of unactivated 1,3-dienes tethered with carbamoyl fluoride. The interception of the η3-π-allyl nickel intermediate by readily available arylboronic acids allows the first 1,4-difunctionalization of 1,3-dienes to access a broad range of chiral α-alkenyl pyrrolidinones bearing an all-carbon quaternary center in up to 84% yield and 99% ee (Scheme 1b). Results and Discussion Initially, we selected carbamoyl fluoride 1a as the model substrate and PhB(OH)2 2a as the coupling component to evaluate various reaction parameters (Table 1). We were pleased to find that utilization of Ni(cod)2 as catalyst, (S)-BINAP (BINAP = 2,2′-bis(diphenylphosphaneyl)-1,1′-binaphthalene) as ligand, and Cs2CO3 as base in anhydrous toluene can afford the desired product 3a in 61% yield with 98% ee (entry 1). The utilization of o-xylene led to the lower yield (entry 2). Addition of the appropriate amount of H2O largely diminished the yield (entry 3). Changing the solvent toluene to dioxane completely shut down the reaction (entry 4) while utilization of K2CO3 instead of Cs2CO3 as a base gave 3a in low yield (entry 5). Next, we started to examine the effect of other types of chiral phosphine ligands. Use of bidentate phosphine ligands such as (S)-4-Tol-BINAP ( L2) and (S)-3,5-Xyl-BINAP ( L3) as well as (R)-H8-BINAP ( L4) all resulted in inferior yields, albeit with high ee values (entries 6–8). Intriguingly, other chiral phosphine ligands including (S)-OMe-BIPHEP ( L5), (R,R)-Me-DuPhos ( L6), (R,Rp)-iPr-FOXAP ( L7), and monodentate phosphoramidite ligand ( L8) were completely ineffective in this reaction, resulting in no detectable product formation at all (entries 9–12). Fortunately, elevating the temperature to 110 °C increased the yield to 77% without erosion of the enantiopurity (entry 13). Finally, increasing the amount of PhB(OH)2 to 3.0 equiv afforded product 3a in 84% isolated yield with 98% ee (entry 14). The leverage of moisture-sensitive base CsF provided slightly lower yield and ee (entry 15). Compared with carbamoyl fluoride, the corresponding carbamoyl chloride substrate gave a relatively inferior result, affording product 3a in 50% yield with 86% ee (entry 16). Table 1 | Reaction Condition Optimizationa Entry Ligand Solvent Base 3a (%)b ee (%)c 1 L1 Toluene Cs2CO3 61 98 2 L1 o-Xylene Cs2CO3 28 98 3 L1 Toluene:H2O = 10:1 Cs2CO3 29 98 4 L1 Dioxane Cs2CO3 0 — 5 L1 Toluene K2CO3 38 98 6 L2 Toluene Cs2CO3 43 97 7 L3 Toluene Cs2CO3 50 98 8 L4 Toluene Cs2CO3 26 −98 9 L5 Toluene Cs2CO3 0 — 10 L6 Toluene Cs2CO3 0 — 11 L7 Toluene Cs2CO3 0 — 12 L8 Toluene Cs2CO3 0 — 13d L1 Toluene Cs2CO3 77 98 14d,e L1 Toluene Cs2CO3 90 (84) 98 15d,e L1 Toluene CsF 76 97 16d,e,f L1 Toluene Cs2CO3 50 86 aReaction conditions: 1a (0.05 mmol), 2a (2.0 equiv, 0.10 mmol), Ni(cod)2 (10 mol %, 0.005 mmol), ligand (20 mol %, 0.01 mmol), Cs2CO3 (2.0 equiv, 0.1 mmol), and toluene (0.2 M, 0.25 mL) at 100 °C under N2 for 12 h. bCorrected gas chromatography yield. cDetermined by high-performance liquid chromatography analysis. dAt 110 °C. e3.0 equiv 2a was used, isolated yield on 0.2 mmol scale in parentheses. fThe carbamoyl chloride was used with isolated yield. Encouraged by the optimal results, we next turned our attention to evaluate the generality of this protocol with diverse arylboronic acids and different substituted 1,3-dienes (Scheme 2). Gratifyingly, a broad range of (hetero)aryl boronic acids bearing different functional groups were quite compatible, affording the corresponding products in moderate to high yields with excellent ees ( 3a– 3r). Particularly, ortho-substituted arylboronic acids provided products in 67%–71% yields and 95%–98% ees, indicating that the steric hindrance did not significantly affect the whole reaction efficiency and stereoselectivities ( 3b and 3m). Various functional groups such as ethers ( 3d, 3f, 3h, and 3j), TMS ( 3i), and F atom ( 3e) were tolerated well in this reaction, delivering the corresponding products in 49%–79% yields and 91%–99% ees. Notably, heteroaromatic boronic acids including furan ( 3o), thiophene ( 3p), dibenzofuran ( 3q), and carbazole ( 3r) were all suitable for this transformation, furnishing the desired products in good isolated yields and admirable enantioselectivities. The current protocol was incompatible with n-butyl and cyclohexenyl boronic acids, in which case the starting material completely decomposed. Scheme 2 | Substrate scope of nickel-catalyzed enantioselective carbocarbamoylation of unactivated 1,3-Dienes.aaReaction conditions: 1a (0.2 mmol), 2a (3.0 equiv, 0.6 mmol), Ni(cod)2 (10 mol %, 0.02 mmol), ligand (20 mol %, 0.04 mmol), Cs2CO3 (2.0 equiv, 0.4 mmol), and toluene (0.2 M, 1.0 mL) at 110 °C under N2 for 12 h. Download figure Download PowerPoint Next, the influence of the carbamoyl fluoride fragment on the catalytic dicarbofunctionalization of 1,3-dienes event was also investigated. It was found that various benzylic protecting groups on the nitrogen atom were competent, providing a broad array of functionalized α-alkenylated γ-lacams in good results ( 3s– 3v). Particularly, the electron-deficient fluorine substituent on the aromatic ring and steric 1-naphthyl did not interfere with the cyclization and provided the desired products in good yields ( 3u and 3v), albeit with lower ee for product 3v. Moreover, both the simple primary and secondary alkyl-substituted carbamoyl fluorides all proceeded well with excellent enantioselectivities ( 3w– 3z). It was noteworthy that substrates containing heterocycles including furan ( 3aa) and thiophene ( 3ab) were successful in this reaction, affording the chiral pyrrolidinones in good yields with high enantiopurity. The effect of substituents pendant from 1,3-dienes was then evaluated. Dienes bearing ethyl and bulky isopropyl all proved to be competent substrates under the standard conditions, giving products 3ac and 3ad in 70–76% yields and 90–92% ees. In addition, 6-membered ( 3ae) and 7-membered lactams ( 3af) were also investigated, and unfortunately, both substrates failed under the current conditions. We further examined the challenging 1,1,2- and 1,1,3-substituted dienes. However, no desired product was obtained, with most of the starting materials remaining ( 3ag and 3ah). The α-monoalkenylated pyrrolidinone 3ai was also not formed under the standard condition, which revealed that the existence of 1,2-disubstituted diene necessitated the carbamoylarylation.41 To gain more insight into this reaction, the enantioenriched carbamic fluoride 1n was exposed to the standard conditions. It was found that both 3aj and 3ak were obtained with comparably high yield and excellent diastereoselectivities (>25:1) by judicious choice of (S)-BINAP and (R)-BINAP as chiral ligands, respectively. However, with the utilization of racemic BINAP as the supporting ligand, lactams 3aj and 3ak were formed in 76% isolated yield with 1:1.1 dr value (Scheme 3). The results clearly illustrate that the newly formed stereocenter was completely governed by the chiral ligand that overcomes the stereogenic center preexisting in substrate. The absolute configuration of 3aj was assigned as S configuration, which has been unambiguously confirmed by X-ray diffraction. Scheme 3 | The influence of the chiral-directing groups. Download figure Download PowerPoint To further demonstrate the potential utility of this protocol, the gram-scale reaction of 1a was carried out, providing product 3a in 67% isolated yield and 98% ee (Scheme 4a). Subsequently, diverse transformations of the chiral pyrrolidinone 3a were then performed (Scheme 4b). Treatment of 3a with lithium aluminum hydride (LAH) furnished 3,3-alkyl, alkenyl pyrrolidine 4 in 97% yield with high enantioselectivity, while hydrogenation of the alkene moiety of 3a provided α,α-dialkyl-γ-lactam 5. Oxidative cleavage of the alkene enabled by ozonolysis delivered the α-acyl-γ-lactam 6 in 75% isolated yield. Furthermore, removing the p-methoxybenzyl group from 3a by handling it with ceric ammonium nitrate (CAN) afforded 7, which underwent a ring-opening process to deliver an unnatural γ-amino acid 9 bearing an all-carbon quaternary center. Scheme 4 | Reaction application. aReaction condition: (1) LAH (3.0 equiv), tetrahydrofuran (THF, 0.2 M), r.t., 12 h; (2) Pd/C (10 mol %), H2 (balloon), MeOH (0.1 M), r.t., 12 h; (3) O3, dichloromethane (DCM)/Pyridine = 99/1 (v/v, 0.05 M), −78 °C, PPh3 (2.0 equiv), r.t., 4 h; (4) CAN (3.0 equiv), MeCN (0.05 M), H2O (0.25 M), 0 °C to r.t., 2 h; (5) Boc2O (2.0 equiv), 4-dimethylaminopyridine (0.5 equiv), Et3N (2.0 equiv), DCM (0.05 M), 0 °C to r.t., 2 h; (6) LiOH (1 M, 2.0 equiv), THF (0.1 M), 50 °C for 3 h. Download figure Download PowerPoint Based on previous reports, we propose a plausible mechanism in Scheme 5. First, the carbamoyl fluoride 1 in which the C−F bond and the alkene moiety on the same side acts as the favored isomer to undergo oxidative addition with Ni(0) to generate intermediate A. Subsequently the isomer proceeds with intramolecular enantioselective cyclization to provide the π-allyl nickel complex B. Transmetallation of species B with arylboronic acids follow by reductive elimination of intermediate C, finally affording the desired product 3 with regenerating Ni(0) to finish the catalytic cycle. Scheme 5 | Plausible mechanism. Download figure Download PowerPoint Conclusion We have developed a highly regio- and enantioselective Ni-catalyzed 1,4-arylcarbamoylation of unactivated 1,3-dienes tethered to carbamoyl fluoride with readily available arylboronic acids. The reaction proceeded through a η3-π-allyl nickel intermediate and regioselectively furnished enantioenriched 1,4-dicarbofunctionalization products in high yields and excellent ees with broad substrate scope, providing an expedient and efficient approach for chiral α-alkenyl pyrrolidinones synthesis. Supporting Information Supporting Information is available and includes experimental procedures; characterization data; and 1H NMR, 13C NMR, and 19F NMR spectra for products. X-ray structural information about 3aj (CCDC-2153779) can be found through the Cambridge Crystallographic Data Centre (doi: 10.5517/ccdc.csd.cc2b95rl). Conflict of Interest There is no conflict of interest to report. Funding Information This work was supported by National Natural Science Foundation of China (grant no. 22171079), the Natural Science Foundation of Shanghai (grant no. 21ZR1480400), the Shanghai Rising-Star Program (grant no. 20QA1402300), the Shanghai Municipal Science and Technology Major Project (grant no. 2018SHZDZX03), the Program of Introducing Talents of Discipline to Universities (grant no. B16017), and the Fundamental Research Funds for the Central Universities and the China Postdoctoral Science Foundation (grant no. 2021M701197). The authors thank the Analysis and Testing Center of East China University of Science and Technology for help with NMR analysis.