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Selenide-Catalyzed Enantioselective Synthesis of Trifluoromethylthiolated

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Selenide-Catalyzed Enantioselective Synthesis of Trifluoromethylthiolated ARTICLE DOI: 10.1038/s41467-018-02955-0 OPEN Selenide-catalyzed enantioselective synthesis of trifluoromethylthiolated tetrahydronaphthalenes by merging desymmetrization and trifluoromethylthiolation Jie Luo1, Qingxiang Cao1, Xiaohui Cao1 & Xiaodan Zhao 1 1234567890():,; Trifluoromethylthiolated molecules are an important class of biologically active compounds and potential drug candidates. Because of the lack of efficient synthetic methods, catalytic enantioselective construction of these molecules is rare and remains a challenge. To expand this field, we herein disclose a bifunctional selenide-catalyzed approach for the synthesis of various chiral trifluoromethylthiolated tetrahydronaphthalenes bearing an all-carbon qua- ternary stereocenter with gem-diaryl-tethered alkenes and alkynes by merging desymme- trization and trifluoromethylthiolation strategy. The products are obtained in high yields with excellent enantio- and diastereo-selectivities. This method can be applied to the desymme- trization and sulfenylation of diols as well. Computational studies reveal that selenide can activate the electrophilic reagent better than sulfide, confirming the higher efficiency of selenide catalysis in these reactions. On the basis of the theoretical calculations, an acid- derived anion-binding interaction is suggested to exist in the whole pathway and accounts for the observed high selectivities. 1 Institute of Organic Chemistry and MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, PR China. Correspondence and requests for materials should be addressed to X.C. (email: [email protected]) or to X.Z. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:527 | DOI: 10.1038/s41467-018-02955-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02955-0 n recent years, many efforts have been devoted to the incor- the main difficulty in this transformation, a proper chiral catalyst poration of fluorine atoms or fluorine-containing groups such is essential that can control the attacking environment of the aryl I fl fl as tri uoromethyl (CF3), tri uoromethoxy (CF3O), and tri- group and thus induce the enantioselectivity of multiprochiral fluoromethanesulfenyl (CF S) ones into the parent molecules for centers. Herein, we report our effort that gem-diaryl-tethered 3 – various purposes because of the fluorine effect1 6. Among these alkenes can undergo enantioselective desymmetrization fi endeavors, strategic synthesis of CF3S molecules has been paid and difunctionalization to ef ciently afford CF3S- special attention owing to the strong electron-withdrawing effect tetrahydronaphthalene derivatives with bifunctional selenide π = 5– and extremely high lipophilicity value ( R 1.44) of CF3S group catalyst. The generated products contain one chiral quaternary 12. However, little success has been achieved on enantioselective carbon center and other two stereocenters. The developed fl tri uoromethylthiolation until now, although stereogenic CF3S method can be applied to enantioselective desymmetrization and molecules warrant further studies considering the importance of sulfenylation of diols as well. – chiral centers in medicine13 20. Thus, developing new methods to create versatile chiral CF3S molecules, especially those with an all- carbon quaternary stereocenter through a novel and enantiose- Results lective reaction mode, is highly desirable. Initial Attempts and Optimization of Reaction Conditions.We Catalytic enantioselective desymmetrization is an attractive began our study of the electrophilic desymmetrization with 2,2- strategy for the construction of chiral all-carbon quaternary ste- diphenyl olefinic benzamide 1a as the model substrate. It could be reocenters by the conversion of prochiral quaternary carbon – easily synthesized from diphenylacetonitrile, and possesses two centers21 23. Using this strategy, numerous valuable, potentially phenyl groups as a nucleophile and an extra benzamide group. To bioactive molecules having a chiral all-carbon quaternary center test the desymmetrization of 1a, highly reactive electrophilic can be quickly accessed from different functionlized starting – (PhSO2)2NSCF3 as the CF3S source and bifunctional catalyst C1 materials24 43. In particular, olefinic or alkynyl carboxylic – – based on indane scaffold were utilized (Table 1). Based on our acids33,34, alcohols35 39, and amines40 43 were frequently former observations20, selenide C1 with a triflic amide group was employed as the substrates to undergo enantioselective desym- quite efficient for the trifluoromethylthiolation with the aid of metrization and cyclization to generate heterocycles by metal- or acid. Pleasingly, at room temperature, the corresponding product organocatalysis (Fig. 1a). In these transformations, the tethered 2a was smoothly formed rather than amination product from nucleophile played an important role that it could bind a catalyst benzamide group in 94% nuclear magnetic resonance (NMR) to guarantee an effective attack toward the multiple bond, which yield with 89% ee and 5:1 dr using trimethylsilyl tri- led to the formation of chiral products with high enantioselec- fluoromethylsulfonate (TMSOTf) as the acid. Lowering the tivities. In contrast, enantioselective desymmetrization involving reaction temperature to −78 °C could quickly improve the the attack of aryl group toward a multiple bond that results in the enantioselectivity to 97% ee with unchanged diastereoselectivity formation of multisubstituted tetrahydronaphthalene derivatives, fi – (Table 1, entry 2). It is noted that sul de catalyst C2 was not an important class of bioactive compounds44 46, has been far less effective for this transformation at all under the similar condi- explored possibly because of the lack of the appropriate interac- – tions (Table 1, entry 3). To improve the diastereoselectivity of 2a, tion between the aryl moiety and catalyst47 49. Only a few rele- various aryl selenides based on C1 were tested for the reaction. vant examples have been reported by Chemler who utilized While para-substituted phenyl group and meta-substituted phe- amine- or hydroxy-tethered alkenes for carboamination and nyl group on the selenide had little influence, ortho-substituent etherification through a copper-catalyzed radical pathway – on the phenyl ring largely enhanced the selectivity (Table 1, (Fig. 1b) 50 53. – – entries 5 8). To our delight, catalyst C7 bearing both ortho- Continuing our interest in Lewis basic selenium54 62-catalyzed fi – methyl and methoxy groups was highly ef cient to afford 2a in trifluoromethylthiolation19,20,63 65, we intended to produce chiral 99% yield with 99% ee and 50:1 dr. Using the mixed solvents of CF3S molecules with an all-carbon quaternary stereocenter CH2Cl2 and (CH2Cl)2, the enantioselectivity of product 2a could through an enantioselective, electrophilic desymmetrization, and be improved to > 99% (Table 1, entry 9). In addition, other acids trifluoromethylthiolation mode. We envisioned that when gem- including both Lewis acid or BrØnsted acid gave slightly lower diaryl-tethered alkenes were employed as the substrates, the aryl enantioselectivity (Table 1, entries 10–12). It is noteworthy that group on substrate could act as a nucleophile to attack chiral the reaction could not go to completion and the corresponding selenide-captured trifluoromethylthiiranium moiety to directly product was formed in moderate selectivity under the optimal afford chiral CF3S tetrahydronaphthalenes (Fig. 1c). To cope with conditions when the substrate derived from 1a by further a A b Ar Ar R′ NuH [M]/organocat. R′ Nu-H: –COOH Nu-H: Ar [Cu] (20 mol%) Ar n n Nu X ″ * –OH ″ w/o ″E+″ R * Few examples: Radical pathway R ′ * R n′ ″ n –NH 2 R = A or B 82–97% ee Y B R ′ E YH n = 0,1, n = 0,1 YH=sulfonyl amide or OH Chemler et al. c Selenide catalyst Ar R′ Ar R′ Ar R′ R′ Me (Undeveloped) Ar (This work) Ar * Ar Se ″E+″ ″E+″= ″+SCF ″ Se E 3 SCF X R SCF3 Se X 3 OMe R R * R NHTf Fig. 1 Enantioselective construction of all-carbon quaternary center-containing molecules via desymmetrization. a Known strategies for enantioselective desymmetrization. b Desymmetrization through copper-catalyzed radical pathway. c Enantioselective desymmetrization and trifluoromethylthiolation using aryl group as a nucleophile 2 NATURE COMMUNICATIONS | (2018) 9:527 | DOI: 10.1038/s41467-018-02955-0 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-02955-0 ARTICLE Table 1 Screening of reaction conditions Bz C6H5CO, Tf CF3SO2, TMSOTf Me3SiOSO2CF3, HPLC high-performance liquid chromatography, NMR nuclear magnetic resonance. Conditions: 1a (0.05 mmol), (PhSO2)2NSCF3 (1.5 equiv), catalyst (20 mol%), TMSOTf (1.0 equiv), CH2Cl2 (2.0 ml), 12 h. Yield refers to NMR yield using trifluoromethylbenzene as the internal standard. The ee value was determined by HPLC analysis on a chiral stationary 19 † . ‡ § phase. The dr value was determined by crude F NMR. *Mixed solvents of 1 ml CH2Cl2 and 1 ml (CH2Cl)2 were used. BF3 OEt2 (1.0 equiv) as the acid. TfOH (1.0 equiv) as the acid. Tf2NH (1.0 equiv) as the acid protecting nitrogen with methyl group was used (63% ee, see Moreover, the developed method was also suitable for alkyne- Supplementary Table 3 for details). derived compounds. Olefinic products were obtained in good yields. When phenyl-substituted substrate was utilized in the reaction, product 2m was formed with excellent ee (95% ee). The Desymmetrization and
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