Copper-Catalyzed Enantioselective Trifluoromethylthiolation of Secondary Propargyl Sulfonates

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 May 2021Copper-Catalyzed Enantioselective Trifluoromethylthiolation of Secondary Propargyl Sulfonates Xing Gao, Yu-Lan Xiao, Shu Zhang, Jian Wu and Xingang Zhang Xing Gao Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author , Yu-Lan Xiao Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author , Shu Zhang School of Materials and Energy, University of Electronic Science and Technology of China, Sichuan 611731 Google Scholar More articles by this author , Jian Wu Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author and Xingang Zhang *Corresponding author: E-mail Address: [email protected] Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 College of Chemistry, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.020.202000353 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Although trifluoromethylthiolated compounds have privileged applications in pharmaceuticals and agrochemicals, efficient strategies for the asymmetric construction of Csp3–SCF3 bonds are limited. Specifically, the catalytic asymmetric nucleophilic trifluoromethylthiolation remains challenging. Here, we report a copper-catalyzed enantioselective nucleophilic trifluoromethylthiolation of secondary propargyl sulfonates with trifluoromethylthio silver. The reaction exhibits high efficiency, good enantioselectivity, high functional group tolerance, and broad substrate scope, paving a new way for the asymmetric synthesis of trifluoromethylthiolated compounds. Download figure Download PowerPoint Introduction The trifluoromethylthio (CF3S) group has privileged applications in pharmaceuticals and agrochemicals due to its high lipophilicity (CF3S, π = 1.44; CF3, π = 0.88) and metabolic stability. Its substitution in biologically active molecules often leads to profound changes in physicochemical and pharmacokinetic properties.1–5 Over the past decade, various methods have emerged in the site-selective introduction of CF3S into organic molecules,6–10 most of which are focused on the construction of Csp2–SCF3 bonds.6–16 In contrast, the asymmetric construction of Csp3–SCF3 bonds at the stereogenic center has received less attention and remains underdeveloped,17–23 although these chiral compounds would have substantial impacts on research and development of new drugs. To date, asymmetric electrophilic trifluoromethylations have been developed, in which organocatalysts17–21,24,25 or Lewis acids26 are used to enantioselectively catalyze the formation of the Csp3–SCF3 bond at the stereogenic center (Schemes 1a and 1b). Despite the importance of these asymmetric trifluoromethylthiolation methods, their substrates are restricted to carbonyl compounds17–20,24–26 or alkenes,21,27–29 limiting their widespread applications in discovering new chiral bioactive molecules. Thus, the development of new strategies to stereoselectively synthesize diversified chiral trifluoromethylthiolated compounds is highly desirable. Scheme 1 | (a–c) Strategies for the catalytic enantioselective trifluoromethylthiolation. *Optically pure Download figure Download PowerPoint In this context, we envisioned that the transition-metal-catalyzed enantioselective nucleophilic trifluoromethylthiolation would provide opportunities to synthesize new bioactive molecules that are difficult to access through electrophilic strategies. The reaction enables us to employ a variety of readily available electrophiles, such as secondary alkyl electrophiles, for asymmetric trifluoromethylthiolation (Scheme 1c). To date, however, this strategy has not been reported and remains a challenging topic because of the lack of efficient catalytic system.30–33 We sought to explore the enantioselective substitution reaction of propargyl electrophiles by nucleophilic trifluoromethylthiolation via copper catalysis34–38 (Scheme 1c), which would lead to chiral trifluoromethylthiolated compounds with diversified structure after transformations of alkynes. For this copper-catalyzed process, we hypothesized that the CF3S anion, a soft nucleophile, may facilitate the enantioselective attack on the in situ generated chiral soft γ-electrophilic copper–allenylidene intermediate, thus rendering the catalytic nucleophilic trifluoromethylthiolation feasible. Herein, we report a copper-catalyzed enantioselective trifluoromethylthiolation of secondary propargyl sulfonates, representing the first example of catalytic nucleophilic asymmetric trifluoromethylthiolation. This method exhibits high efficiency, good enantioselectivity, high functional group tolerance, and broad substrate scope, including substrates bearing multichiral centers, and represents a new route for applications in organic synthesis and related chemistry. Experimental Methods To a 25 mL of Schlenk tube were added L5 (15.3 mg, 0.036 mmol, 12 mol %), Cu(CH3CN)4PF6 (11.2 mg, 0.03 mmol, 10 mol %) and AgSCF3 2 (67 mg, 0.3 mmol, 1.0 equiv) (Note: The exact molecular formula of AgSCF3 is 3CF3SAg·CH3CN. The molecular weight of AgSCF3 was calculated based on CF3SAg·1/3(CH3CN)). After the mixture was evacuated and backfilled with argon for three times, CH3CN (2 mL) and CH3OH (0.5 mL) were added. The reaction mixture was stirred at room temperature for 20 min, the Schlenk tube was then cooled to –40 °C. Propargyl sulfonate 1 (0.6 mmol, 2.0 equiv) and DIPEA (0.36 mmol, 1.2 equiv) were added. After stirring at -40 °C for 48 h, the reaction mixture was quenched with saturated aqueous NH4Cl and worked up with ethyl acetate. The resulting mixture was filtered with a pad of celite. The filtrate was concentrated and the residue was purified with silica gel chromatography to give product 3. Results and Discussion Optimization studies To test our hypothesis, secondary propargyl sulfonate 1a was chosen as the model substrate, and readily available and stable CF3S silver (CF3SAg) was used as the fluorine source (Table 1). Good yield of racemic 3a (70%) was obtained when the reaction was carried out in the presence of CuOAc (10 mol %), iPr-PyBox L1 (12 mol %), and DIPEA (diisopropylethylamine, 15 mol %) in CH3CN at room temperature (Entry 1). Decreasing the reaction temperature benefited the enantioselectivity of 3a (Entries 2 and 3). At a reaction temperature as low as −30 °C, enantiomeric 3a with 67.5∶32.5 er (enantiomeric ratio) was obtained, at the expense of yield (32%) (Entry 3). A survey of a series of PyBox ligands showed that ligand L5 with a flexible side chain had a beneficial effect on the enantioselectivity, providing 3a with 82∶18 er value (Entry 7). Ligands L4 and L3 bearing one or no methylene group between the phenyl and oxzole ring could also improve the er value, but both showed less activity (Entries 5 and 6). This flexible side chain effect was also observed using iBu-PyBox L2 as the ligand (Entry 4). In contrast, increasing the rigidity of the ligands failed to improve the enantioselectivity ( Supporting Information Table S3). Further optimization of the reaction conditions by decreasing the reaction temperature to −40 °C with Cu(CH3CN)4PF6/ L5 as the catalyst could improve the er value to 87.5∶12.5 (Entry 8, for details see the Supporting Information). Encouraged by these results, a series of PyBox ligands bearing flexible side chains were examined (Entries 9–14). We found that L9 and L10 with a longer chain length than L5 still provided comparable enantioselectivities (Entries 9 and 10). But the modification of L5 with different aryl substituents did not improve the er values (Entries 11–14). Other CF3S reagents, such as CsSCF3 or Me4NSCF3, were also tested; however, no product or lower yield with poor enantioselectivity was obtained (see Supporting Information Table S6), suggesting the critical role of CF3SAg for the reaction. Finally, the optimized reaction conditions were identified by increasing the loading amount of DIPEA to 1.2 equiv with propargyl sulfonate 1f as the substrate, L5 as the ligand, and methanol39 as the cosolvent, providing 3a in 72% yield (upon isolation) and 86∶14 er (Entry 15). The absence of MeOH led to decreased enantioselectivity with a higher yield (Entry 16). Table 1 | Representative Results for the Optimization of Copper-Catalyzed Enantioselective Trifluoromethylthiolation of Secondary Propargyl Sulfonates 1 with AgSCF3a Entry L Temperature (°C) DIPEA (x) 3a, yieldb (%)/erc 1 L1 25 15 70/50∶50 2 L1 −20 15 45/61∶39 3 L1 −30 15 32/67.5∶32.5 4 L2 −30 15 34/75∶25 5 L3 −30 15 32/65∶35 6 L4 −30 15 29/70∶30 7 L5 −30 15 36/82∶18 8d L5 −40 60 30/87.5∶12.5 9d L9 −40 60 33/87.5∶12.5 10d L10 −40 60 33/87∶13 11d L11 −40 60 31/26∶74 12d L12 −40 60 27/14∶86 13d L13 −40 60 24/16∶84 14d L14 −40 60 23/17.5∶82.5 15d–f L5 −40 120 73 (72)/86∶14 16d,e L5 −40 120 84/80∶20 aReaction conditions (unless otherwise specified): 1 (0.6 mmol, 2.0 equiv), 2 (0.3 mmol, 1.0 equiv), CH3CN (2.0 mL), 24–48 h. bDetermined by 19F NMR using fluorobenzene as an internal standard; the number given in parentheses is the isolated yield. cDetermined by chiral HPLC analysis. dCu(CH3CN)4PF6 (10 mol %) was used. ePropargyl sulfonate 1f (0.6 mmol, 2.0 equiv) was used. fMeOH (0.5 mL) was used. Scope of the reaction With the viable reaction conditions in hand, a series of secondary propargyl sulfonates 1 were examined (Scheme 2). Generally, high yields and enantioselectivities were obtained. Compared with 1a, higher er values (95∶5 to 97.5∶2.5) were obtained when the chain spacer between the aryl group and the substitution site was shortened to one methylene ( 3b– 3e). An attempt to install a CF3S group on the aryl-substituted propargyl sulfonates failed due to their instability. However, the following results showed that the more steric sulfonates benefited the enantioselectivities. For example, substrates bearing a more sterically hindered aryl group, such as 1-naphthyl ( 3e) or a branched substituent ( 3f), were applicable to the reaction and provided comparable er values. In addition, propargyl sulfonates with a long linear chain were competent coupling partners with good enantioselectivities obtained ( 3g– 3p); even a heptyl-substituted propargyl sulfonate underwent the enantioselective trifluoromethylthiolation smoothly ( 3p). High enantioselectivities were also observed using cyclic chain-substituted propargyl sulfonates ( 3s, 3t, and 3v), in which the ring size ranging from six to four members did not interfere with the stereoselectivity. Slightly decreased er values were obtained by increasing the chain length between six-membered rings (piperidine and tetrahydropyran) and the propargyl position ( 3q and 3r vs 3s; 3u vs 3v), suggesting that more steric sulfonates lead to higher enantioselectivity. Scheme 2 | Reaction scope of copper-catalyzed enantioselective trifluoromethylthiolation of propargyl sulfonates 1 with AgSCF3.aaReaction conditions (unless otherwise specified): 1 (0.6 mmol, 2.0 equiv), AgSCF3 (0.3 mmol, 1.0 equiv), CH3CN (2 mL), MeOH (0.5 mL). All reported yields are isolated yields. bGram-scale synthesis. Download figure Download PowerPoint The reaction exhibited high functional group tolerance. Versatile functional groups, such as ester, nitro, base-sensitive acetyl group, alkyl sulfonate, silyl ether, and carbamate moiety, were compatible with the reaction conditions ( 3i, 3j, 3l, 3n, 3o, and 3q– 3t); even pyridine- and amino acid-containing substrates furnished the corresponding products smoothly ( 3k and 3m). In particular, proline derivative provided the trifluoromethylthiolated product 3m in a high dr (diastereomeric ratio) value (94∶6). A series of (hetero)aryl halides ( 3b, 3c, and 3j), including aryl chloride, bromide, and iodide as well as α-chloropyridine ( 3k), were applicable to the reaction, and the side reaction between (hetero)aryl halides and CF3SAg did not occur, which could be benefical for the downstream transformations. Furthermore, substrates bearing a chiral center adjacent to the reaction site were also amenable to the reaction, producing the corresponding products with high dr values ( 3w and 3x). In light of the versatility of these resulting structural motifs, the present transformations provide potential applications in the synthesis of interesting new bioactive compounds. Most importantly, the production of these compounds can be readily scalable, as demonstrated by the gram-scale synthesis of complex molecule 3x with high efficiency (69% yield) and high stereoselectivity (94∶6 dr). The absolute configuration of the resulting enantioenriched product 3 was assigned to be S-configured by crystallographic characterization of compound 4c, which was derived from compound 3c through a [3 + 2] cyclization with azide. In the case of 3w and 3x, the absolution configuration is R-configured. Furthermore, the crystallographic analysis of 4c showed a weak hydrogen bond between the fluoride and the benzylic hydride.40–42 This unique property of the CF3S group may have a beneficial effect on the design of new bioactive molecules.43,44 To further probe whether the chiral center adjacent to the propargyl position has an influence on the stereoselectivity, propargyl sulfonate bearing a bulky chiral moiety 1zd was examined (Scheme 3). We found that the trifluoromethythiolation stereoselectivity of 1zd was sensitive to the configuration of the chiral ligand. The use of (S,S)-phenethyl-PyBox L5 provided the protected aminoalcohol 5a in 40% yield and 60∶40 dr value. This finding is in contrast to the trifluoromethyltholation stereoselectivity of propargyl sulfonates 1zb and 1zc, in which good yields and high dr values were obtained (Scheme 2, 3w and 3x). However, a higher yield (65%) and excellent dr value (99∶1) of 5b with opposite configuration at propargyl position was obtained using (R,R)-phenethyl-PyBox L5′ as the ligand. The absolute configuration of 5b was assigned to be S-configured by NMR analysis of compound 5b.45–47 In addition, ligand L5′ showed similar stereoselectivity as that for trifluoromethythiolation of 1zb or 1zc with L5 as the ligand ( Supporting Information). These results demonstrate that the chiral center with a sterically hindered substituent adjacent to the reaction site can affect the stereoselectivity, but the chiral ligand remains a key factor. The chiral ligand with proper configuration matching with the existing chiral center would provide high stereoselectivity. This deduction was further supported using a racemic phenethyl-PyBox ligand, where a lower 76∶24 dr value of 5b was obtained. Scheme 3 | The ligand effect on the synthesis of chiral trifluoromethylthiolated compounds 5. Download figure Download PowerPoint Synthetic utility The importance and utility of this protocol have also been highlighted by the efficient synthesis of an array of trifluoromethylthiolated amino acids. As depicted in Scheme 4a, treatment of propargyl sulfonate 1ze, which was drived from L-aspartic amino acid, with CF3SAg provided the trifluoromethylthiolated amino acid 7 with high diastereoselectivity (94∶6 dr) and good yield. The dr value of 7 could be increased to 99∶1 after purification with silica gel chromatography. Compound 7 could serve as a versatile building block for the diversity-oriented synthesis. For instance, the Sonogashira reaction of 7 with 2-iodothiophene as well as cycloaddition of 7 with in situ generated nitrile oxide48 proceeded smoothly, providing the corresponding heteroaryl-substituted amino acids 8a and 8b in good yields (Scheme 4b). Compound 7 could also be used to synthesize biologically relevant glycopeptide through simple transformations. Deprotection of 7 with trifluoroacetic acid (TFA), followed by condensation with dipeptide 9, provided tripeptide 10 in good yield (Scheme 4c). Subsequently, treament of 10 with the carbohydrate-derived azide 11 through click chemistry efficiently furnished glycopeptide 12.49 In light of the importance of fluorinated amino acids in the modification of peptide-based biologically active molecules and protein engineering,50–52 these transformations offer potential opportunities to discover interesting new bioactive molecules. Furthermore, the transformation of compound 3x could also lead to complex molecules. As shown in Scheme 4d, cyclization of 3x with TFA provided the chiral lactone 13 efficiently. Although the asymmetric electrophilic trifluoromethylthiolation is an efficient strategy to access chiral trifluoromethylthiolated compounds,17–21,24–29 it is still challenging to achieve these complex molecules through developed electrophilic methods, thus demonstrating the advantages of the current copper-catalyzed enantioselective nucleophilic trifluoromethythiolation process. Scheme 4 | (a–d) Transformations of chiral trifluoromethylthiolated propargyl compounds. Download figure Download PowerPoint The origin of the configuration of the reaction is explained using Maarseveen’s model.53 On the basis of previous reports,33,53–58 a cooperative copper catalysis may be involved in the reaction. As shown in Figure 1, one copper binds to the trifluoromethythio, while the other copper reacts with propargyl sulfonate 1 to produce the copper–allenylidene intermediate. The resulting trifluoromethylthiocopper subsequently attacks copper–allenylidene from the Si-face to provide the corresponding configuration. Figure 1 | Proposed reaction mode for the copper-catalyzed enantioselective trifluoromethylthiolation of secondary propargyl sulfonates. Download figure Download PowerPoint Conclusion We have developed the first example of an enantioselective nucleophilic trifluoromethylthiolation reaction via copper catalysis. The reaction allows trifluoromethylthiolation of a variety of secondary propargyl sulfonates with high efficiency and enantioselectivity. The steric effect of propargyl sulfonates and the flexibility of side chain on the chiral PyBox are the key factors for the reaction enantioselectivity. Given the versatile synthetic utility of carbon–carbon triple bond and high functional group tolerance of this method, the resulting chiral trifluoromethylthiolated propargyl compounds can serve as useful building blocks for the diversified synthesis of chiral trifluoromethylthiolated compounds, including glycopeptide, providing potential opportunities for applications in medicinal chemistry and chemical biology. Thus, this novel asymmetric nucleophilic trifluoromethylthiolation strategy paves a new way for the asymmetric synthesis of trifluoromethylthiolated molecules. Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Funding Information Financial support for this work was provided by the National Natural Science Foundation of China (nos. 21931013, 21702225, 21672238, and 21421002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB20000000). Acknowledgments The authors wish to acknowledge Xiao-Long Wan for conducting chiral HPLC analysis.