Asymmetric Electrochemical Arylation in the Formal Synthesis of (+)-Amurensinine
At a Glance
Section titled “At a Glance”| Metadata | Details |
|---|---|
| Publication Date | 2021-01-09 |
| Journal | CCS Chemistry |
| Authors | Qinglin Zhang, Kang Liang, Chang Guo |
| Institutions | University of Science and Technology of China, Hefei National Center for Physical Sciences at Nanoscale |
| Citations | 41 |
Abstract
Section titled “Abstract”Open AccessCCS ChemistryCOMMUNICATION1 Dec 2021Asymmetric Electrochemical Arylation in the Formal Synthesis of (+)-Amurensinine Qinglin Zhang, Kang Liang and Chang Guo Qinglin Zhang Hefei National Laboratory for Physical Sciences at the Microscale, Department of Chemistry, University of Science and Technology of China, Hefei 230026 Google Scholar More articles by this author , Kang Liang Hefei National Laboratory for Physical Sciences at the Microscale, Department of Chemistry, University of Science and Technology of China, Hefei 230026 Google Scholar More articles by this author and Chang Guo *Corresponding author: E-mail Address: [email protected] Hefei National Laboratory for Physical Sciences at the Microscale, Department of Chemistry, University of Science and Technology of China, Hefei 230026 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202000720 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Asymmetric electrochemical synthesis has emerged as an attractive and sustainable alternative for the distinctive activation of bond connections in the preparation of diverse enantiomerically enriched targets, including natural products and pharmaceutical agents. Herein, we describe the chiral Lewis acid-catalyzed enantioselective electrochemical anodic coupling reaction as a key step in the presented formal synthesis of isopavine alkaloids. The direct functionalization of catechol derivatives with 2-acyl imidazoles was developed to provide a wide range of useful chiral α,α-diaryl carbonyl building blocks containing tertiary stereogenic centers with high reactivity and excellent stereoselectivity. The utility of this novel enantioselective electrochemical protocol is showcased by its implementation in the enantioselective formal synthesis of (+)-Amurensinine. Download figure Download PowerPoint Introduction The advances made in asymmetric catalytic synthesis to forge new carbon-carbon bonds with high levels of stereoselectivity have provided access to chiral molecular scaffolds that are ubiquitous in organic functional materials, pharmaceuticals, and natural products.1 Isopavine alkaloids2-5 represent a diverse family of alkaloids that commonly have been isolated from a widespread series of natural sources, exhibiting remarkable biological properties (Figure 1a).6 From a synthetic standpoint, the enantioselective enolate arylation would provide a simple and straightforward approach to generate key structural motifs I with α,α-diaryl tertiary chiral carbon centers in a stereoselective manner.7-10 However, the racemization via enolization process is associated with the stereoselective preparation of α,α-diaryl carbonyl architecture (Figure 1b).11,12 In this context, we sought to develop a complementary strategy that would allow the enantioselective catalytic construction of α,α-diaryl tertiary carbonyl architecture and provide direct access to the key functional and architectural elements found in (+)-Amurensinine.13-15 Figure 1 | Design of asymmetric electrochemical synthesis. (a) Representative chiral biologically relevant compounds. (b) Asymmetric catalytic synthesis of chiral α,α-diaryl carbonyls. (c) Enantioselective electrochemical synthesis leading to the formal total synthesis of isopavin alkaloid. Download figure Download PowerPoint Electrochemical synthesis has emerged as an enabling platform for mild and efficient bond-forming reactions without the requirement of stoichiometric quantities of chemical oxidants or reductants.16-31 The feasibility of electrochemical synthetic strategy has been demonstrated for providing rapid access to multiple natural product scaffolds selectively.32-35 However, enantioselective electrochemical transformation36-38 for the architectural assembly of the unique core in combination with the stereoselective installation of the requisite α,α-diaryl carbonyl-containing functional groups to pursue the total synthesis of bioactive molecules presents significant challenges.39-45 Given the pharmacological importance of isopavine alkaloids, direct asymmetric electrolysis46-57 to access enantiopure analogs in the context of total synthesis via a sustainable process is highly desirable. Recently, the Meggers group58 and our group59 established the enantioselective α-functionalization of carbonyl compounds enabled by Lewis acid catalysis in a range of unique asymmetric bond constructions. However, the discovery of electrochemical catalytic protocols for the asymmetric arylation remains a formidable challenge, thus offering a unique opportunity to develop targeted synthesis. Herein, we describe a Lewis acid-catalyzed asymmetric electrochemical arylation reaction that enables the catalytic assembly of tertiary stereocenter with high levels of stereocontrol and demonstrates the potential for the application of the formal synthesis of (+)-Amurensinine from achiral precursors (Figure 1c). Experimental Methods The Experimental Methods are available in the Supporting Information. Results and Discussion Optimization studies Our enantioselective electrochemical anodic coupling reaction was initially evaluated using 2-acyl imidazole 1a and tert -Butyldimethylsilyl (TBS)-protected catechol 2a as substrates along with chiral nickel catalysts for the analog synthesis of (+)-Amurensinine (Table 1). Indeed, the use of chiral diamine 4a as the ligand led to the desired adduct 3a in moderate yield, but with poor enantioselectivity in an undivided electrochemical cell under galvanostatic conditions (entry 1, 49% yield, 7% ee). Next, we evaluated different types of chiral diamine ligands to determine their influence on the reactivity and enantioselectivity of the transformation (entries 1-6). Gratifyingly, the desired product 3a could be forged in 83% yield with 93% ee when the diamine ligand 4d with the bulky 2,4,6-trichloro-phenyl group was employed (entry 4). No improvement was observed by varying the base and reaction temperature (entries 7-10). The use of copper as the Lewis acid allowed the synthesis of 3a in moderate yield, albeit with poor enantioselectivity (entry 11). Remarkably, a series of control experiments verified the necessity of each reaction component (entries 12-15). In the absence of Lewis acid or diamine ligand, no product was formed (entries 12-14). As expected, no reaction occurred in the absence of an externally applied electric current (entry 15). Notably, 3a was provided in only 12% yield and 93% ee with NaIO4 as chemical oxidant in the absence of electric current (entry 16). Further exploration revealed that the enantioselectivity was slightly decreased with Pt as electrodes (entry 17). Table 1 | Optimization of the Reaction Conditions Entry Lewis Acid 4 Base Yield (%) ee (%) 1 Ni(OAc)2 4a Quinuclidine 49 7 2 Ni(OAc)2 4b Quinuclidine 44 47 3 Ni(OAc)2 4c Quinuclidine 54 92 4 Ni(OAc)2 4d Quinuclidine 83 93 5 Ni(OAc)2 4e Quinuclidine 82 84 6 Ni(OAc)2 4f Quinuclidine 90 40 7 Ni(OAc)2 4d DIPEA 67 77 8a Ni(OAc)2 4d 2,6-Lutidine 31 93 9b Ni(OAc)2 4d Quinuclidine 51 82 10c Ni(OAc)2 4d Quinuclidine 36 91 11 Cu(OAc)2 4d Quinuclidine 52 13 12 — — Quinuclidine NR — 13 — 4d Quinuclidine NR — 14 Ni(OAc)2 — Quinuclidine NR — 15d Ni(OAc)2 4d Quinuclidine NR — 16e Ni(OAc)2 4d Quinuclidine 12 93 17f Ni(OAc)2 4d Quinuclidine 60 90 Note: Reactions were carried out using 2-acyl substrate 1a (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv), Lewis acid (10 mol %), 4 (20 mol %), nBu4NPF6 (0.3 mmol, 3.0 equiv), and base (0.1 mmol, 1.0 equiv) in Dichloromethane (DCM) (4 mL) at −40 °C for 24 h. DIPEA, N,N-diisopropylethylamine; NR, no reaction. aWith 10 mol % base. bAt 0 °C. cAt −78 °C, 48 h. dWithout the electric current. eNaIO4 (1.5 equiv) without electricity. fWith Pt as electrodes. Synthetic utility The utility of the present asymmetric electrochemical anodic coupling protocol was highlighted in the construction of the chiral α,α-diaryl carbonyl motifs by applying it to the catalytic enantioselective formal synthesis of (+)-Amurensinine according to the following sequence (Figure 2). The crucial asymmetric anodic coupling reaction of 2-acyl imidazoles bearing a disubstituted phenyl group 1b was accomplished with the use of chiral nickel catalyst under the electrochemical conditions, forming the corresponding adduct 3b in 92% yield and 85% ee. The dimethylation of 3b with (trimethylsilyl)diazomethane (TMSCHN2) furnished 5 in 86% yield without any loss in enantiomeric excess. Initial attempts to conduct the methylation utilizing the known methods of 2-acyl imidazole cleavage failed under various conditions. A detailed description of these experiments is provided in the Supporting Information. Gratifyingly, we found that the 2-acyl imidazole functionality was effectively transformed into corresponding ester 6 upon treatment with trimethyloxonium tetrafluoroborate (Me3O · BF4) as the methylation reagent followed by the addition of methanol and Diazabicyclo[5.4.0]undec Diazabicyclo[5.4.0]undec-7-ene (DBU) in a one-pot operation.60 Reduction of the ester group of 6 in the presence of LiAlH4, followed by O-triisopropylsilyl (O-TIPS) protection and further removal of the TBS moiety, finally afforded the corresponding alcohol 9. The subsequent oxidation and cyclization process furnished the carbocyclic core structure 11 in good yield. Carbonyl reduction of 11 with l-selectride generated the corresponding key alcohol 12, which can be converted into (+)-Amurensinine according to Stoltz’s procedures.13 Furthermore, the spectroscopy and the optical rotation of the key alcohol 12 were in agreement with the data previously reported in the literature.13 Figure 2 | Asymmetric formal synthesis of (+)-Amurensinine. Download figure Download PowerPoint Scope of the reaction Next, we evaluated a series of 2-acyl imidazoles 1 with TBS-protected catechol 2a in the asymmetric electrochemical anodic coupling reactions to probe the reaction scope using the optimal reaction conditions (Figure 3). The asymmetric anodic coupling reaction with a variety of 2-acyl imidazoles 1 was investigated under the optimized reaction conditions. Remarkably, the electronic nature of the substituents at the para positions of the benzene ring of 2-acyl imidazoles 1 seemed to have no obvious influence on the enantioselectivity of this arylation reaction ( 3c- 3j); however, the yields varied remarkably in some cases ( 3h- 3j). Furthermore, substituents at the meta or ortho positions on the aryl moiety of the 2-acyl imidazoles 1 had a negligible impact on the yield and enantioselectivity of the reaction ( 3k-3n). Generally, good enantioselectivities were attained with 2-acyl imidazoles bearing a disubstituted phenyl group, or a heterocyclic group ( 3o and 3p). N-phenyl-substituent (R2) at the imidazole moiety had a slight negative impact on the yield and enantioselectivity of the reaction ( 3q). Figure 3 | Substrate scope for 2-acyl imidazoles. aWith Ni(OAc)2 (20 mol %), 4d (40 mol %). Download figure Download PowerPoint The generality of the asymmetric anodic oxidation concerning the substituents on the catechol coupling partners 2 was also investigated (Figure 4a). Modified alkyl substrates, such as protected oxygen functionality and alkyl chloride, afforded the products in high yield and ee ( 3r and 3s). The catechol substrates bearing electron-deficient substituents at the meta position in the phenyl moiety underwent smooth electrochemical arylations in moderate yields and excellent ee ( 3t and 3u). In addition, 4-methylcatechol was also suitable for the reaction with target adduct 3v isolated in 81% yield and 94% ee. Pleasingly, a broad range of differently ortho-substituted catechol proved to be excellent coupling partners in this asymmetric anodic coupling reaction and afforded the desired products in high yield and good enantioselectivities ( 3w-3y). Remarkably, this method was compatible with pyrocatechol, giving the desired product 3z in moderate yield and great enantioselectivity. However, 2-aminophenol failed to undergo the reaction, indicating that the catechol backbone is crucial for the reaction to succeed. Following derivatization, the absolute stereochemistry of product 3v was determined by using X-ray crystallography following derivatization to 13 (Figure 4b). It was also consistent with the absolute configuration of 12 (Figure 2). Figure 4 | Substrate scope for catechols. (a) Scope of catechol component. (b) The absolute configuration of 13 was determined by X-ray crystallography. aWith 2 (0.3 mmol, 3.0 equiv).bWith constant current at 0.8 mA. cIn the absence of quinuclidine. Download figure Download PowerPoint Mechanistic studies To understand the mechanistic details of the anodic coupling reactions, we initiated the study by conducting the cyclic voltammetry (CV) experiments to study the redox potential of different reaction components. As shown in Figure 5a, two obvious oxidation peaks of catechol 2a were observed at 1.40 and 2.28 V versus saturated calomel electrode (SCE) in MeCN ( Supporting Information Figure S2). The first anode potential dropped from 1.40 V (vs SCE) along with the catechol derivative 2a to 0.34 V (vs SCE) upon addition of quinuclidine to facilitate proton-coupled electron transfer (PCET) at the electrode (Figure 5b and Supporting Information Figures S4 and S5), elucidating the pathways that originate from the generation of a para-phenoxyl radical intermediate61-67 under oxidative conditions. In addition, the oxidation potential of 1a and nickel catalyst [Ni( 4d)] was observed at 2.08 and 1.87 V (vs SCE in MeCN) ( Supporting Information Figure S1 and S3). Similarly, CV revealed that the oxidation potential of the nickel catalyst bound- 1a [Ni( 4d)- 1a] in the presence of quinuclidine was shifted to significantly lower potential (Figure 5c, E = 0.58 V vs SCE) ( Supporting Information Figure S6 and S7) and suggested the existence of [Ni( 4d)- 1a]· radical intermediate and diradical behavior of the catalytic electrochemical process. Furthermore, we found that the current response increased with increasing concentrations of nickel catalysts (Figure 5d and Supporting Information Figure S8). To confirm this assumption, controlled potential electrolysis (Figure 5e) at 0.50 V (vs SCE) gave the comparable results for the anodic coupling reaction of 1a and 2a instead of constant current electrolysis (Table 1, entry 9), suggesting that the direct anodic oxidation of para-phenoxyl radical to 1,2-benzoquinone (Ep/2 = 2.11 V vs SCE) contributed minimally to the observed reactivity. Besides, a standard electrolytic condition in the presence of 2,2,6,6-Tetramethylpiperidinooxy (TEMPO) provided the TEMPO-trapping product 14 in 6% yield (Figure 5f). The CV data along with control experiments led us to propose that a para-phenoxyl radical and [Ni( 4d)- 1a]· radical intermediate might be active species in the asymmetric electrochemical reaction (see Supporting Information for details). Figure 5 | Mechanistic investigation of the asymmetric electrochemical anodic coupling. (a) CV of related compounds in the corresponding solvent containing 0.1 M nBu4NPF6. (b) CV of 2a with and without quinuclidine. (c) CV of [Ni(4d)-1a] with and without quinuclidine. (d) The relationship of the current response with the concentrations of nickel catalyst in the presence of 1a and quinuclidine, (1) in the absence of nickel catalyst; (2) in the presence of 10 mol % [Ni(4d)]; (3) in the presence of 20 mol % [Ni(4d)]; (4) in the presence of 30 mol % [Ni(4d)]; and (5) in the presence of 40 mol % [Ni(4d)]. (e) Potential-controlled electrolysis between 1a and 2a. (f) Experiments to trap the Lewis-acid-bound radical species. Download figure Download PowerPoint Based on these experiments, a plausible mechanistic cycle is outlined in Figure 6. The key asymmetric anodic coupling is initiated by the coordination of the chiral nickel catalyst to the 2-acyl imidazoles 1,68-72 followed by the formation of a [Ni( 4d)- 1a]· radical intermediate III upon electrolysis-induced single electron transfer (SET) oxidation. In a parallel electrochemical cycle, anodic oxidation promotes the formation of the para-phenoxyl radical species IV from the catechol coupling partners 2. Subsequently, the radical-radical coupling reaction between III and IV was proposed to afford the final product 3. Figure 6 | Proposed mechanism. Download figure Download PowerPoint Conclusion We have developed an enantioselective electrochemical cross-coupling reaction of 2-acyl imidazoles with catechol derivatives, providing a unique method for the expeditious assembly of multifunctionalized α,α-diaryl carbonyl building blocks bearing the crucial tertiary chiral carbon stereocenter. This reaction features high enantioselectivity, good yields, and functional-group tolerance, making it applicable to structurally complex compounds, and drug discovery. Significantly, the unified enantioselective electrochemical methodology has been preliminarily explored for the asymmetric formal synthesis of (+)-Amurensinine. Supporting Information Supplemental Information is available and includes experimental procedures and compound characterization data. Conflict of Interest The authors declare no competing interests. Funding Information The authors acknowledge financial support from the National Natural Science Foundation of China (grant nos. 21702198 and 21971227), the Anhui Provincial Natural Science Foundation (grant no. 1808085MB30), and the Fundamental Research Funds for the Central Universities (no. WK2340000090). References 1. Jacobsen E. N.; Pfaltz A.; Yamamoto H.Comprehensive Asymmetric Catalysis: Vol. I-III, Suppl. I-II; Springer: New York, 1999. Google Scholar 2. Gözler B.; Lantz M. S.; Shamma M.The Pavine and Isopavine Alkaloids.J. Nat. Prod.1983, 46, 293−309. Google Scholar 3. Gottlieb L.; Meyers A. I.An Asymmetric Synthesis of Aporphine and Related Alkaloids via Chiral Formamidines. (+)-Glaucine, (+)-Homoglaucine, and (-)-8,9-Didemethoxythalisopavine.J. Org. Chem.1990, 55, 5659−5662. 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