Organocatalytic Enantioselective Construction of Axially ChiralSulfone-Containing StyrenesShiqi Jia, Zhili Chen, Nan Zhang, Yu Tan, Yidong Liu, Jun Deng, and Hailong Yan*

Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, ChongqingUniversity, Chongqing 401331, P. R. China

*S Supporting Information

ABSTRACT: We describe herein an organocatalyticenantioselective approach for the construction of axiallychiral sulfone-containing styrenes. Various axially chiralsulfone-containing styrene compounds were prepared withexcellent enantioselectivities (up to >99% ee) and almostcomplete E/Z selectivities (>99% E/Z). Furthermore, theaxially chiral sulfone-containing styrenes could be easilyconverted into phosphonic acid and S/P ligands, whichcould be potentially used as organocatalysts or ligands inasymmetric catalysis.

As a member of the axially chiral family, axially chiralstyrene1 was first proposed to demonstrate a new conceptof the memory of chirality by Kawabata et al.2 in 1991. Theirenantiomers exist due to the restricted rotation around a singlebond between a substituted alkene and an aromatic ring. Theuse of chiral olefins3 as ligands in metal-mediated catalysis hasrevolutionized the fields of organometallic chemistry andasymmetric synthesis. Axially chiral styrenes can be used aspotential chiral catalysts, ligands, or substrates to induceselectivity in chemical transformations. Consequently, thedevelopment of methods for the enantioselective synthesis ofthese axially chiral styrenes is an important task in organicchemistry. Unlike well-established synthetic approaches for theconstruction of biaryl atropisomers,4 the enantioselectiveconstruction of axially chiral styrenes remains a dauntingchallenge in modern organic synthesis. To date, only a fewexamples of the enantioselective construction of axially chiralstyrenes have been reported by the research groups of Baker,5

Miyano,6 Gu,7 and Smith.8 Recently, the seminal work onorganocatalytic atroposelective synthesis of axially chiralstyrenes via a direct enantioselective nucleophilic addition toalkynal was published by Tan.9 Despite these progresses, apractical enantioselective synthetic route allowing varioussubstitution patterns is still highly desirable.Sulfones10 are an important class of pharmaceutically

relevant compounds because of their wide spectrum ofbiological activities, such as cancer agents, secretase inhibitorsfor the treatment of Alzheimer’s disease, and antibacterialagents. The synthesis of hybrid molecules with more than onepharmacological property has gained momentum recently.11 Inthis regard, integrating the features of axially chiral styrenes andsulfones into a single scaffold is expected to increase thediversity of pharmaceuticals with new pharmacologicalactivities. However, to the best of our knowledge, an

asymmetric method for the enantioselective preparation ofaxially chiral sulfone-containing styrenes has not been reported.We recently reported the first asymmetric intramolecular [4

+ 2] cycloaddition of vinylidene o-quinone methide (VQM),derived from 2-ethynylphenol derivatives, with benzofuran.12

As part of an ongoing effort in our group to explore theapplication of VQM in asymmetric synthesis, we presumed thatif an activated nucleophile could attack the highly electrophilicVQM intermediate, a formal nucleophilic addition13 of theVQM intermediate and subsequent aromatization would occur,affording axially chiral styrenes (Scheme 1). Since we wereinterested in the research field of sulfone chemistry, we decidedto use sulfone-type nucleophilic reagents to verify ourconception.

We initial ly evaluated the reaction between 1-(phenylethynyl)naphthalen-2-ol (1a) and sodium benzenesulfi-nate14 (2a) in CHCl3 in the presence of quinine-derivedthiourea A15 at room temperature. Unfortunately, the reactiondid not provide any of the desired product, possibly because ofthe poor solubility of sodium benzenesulfinate in CHCl3. Afteroptimization of the reaction conditions, the desired productwas obtained in low yields and enantioselectivities when a polarsolvent such as 1,4-dioxane or acetonitrile was used (Scheme2). This preliminary progress encouraged us to search for amore efficient catalytic system for this transformation.

Received: March 23, 2018Published: May 21, 2018

Scheme 1. Background and Project Synopsis

Communication

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Various chiral amino acids were first tested as additives (seethe Supporting Information for details). To our delight, whenthe reaction was conducted with quinine-derived thiourea A(10 mol %) as the catalyst in CHCl3 in the presence of 10 mol% L-proline, the reaction generated the product in 49% yieldwith 66% ee (Table 1, entry 1). Next, various organocatalystswith different chiral skeletons and functional groups werescreened. However, the screened catalysts B, C, and D provided

inferior results (Table 1, entries 2−4). We then evaluated theeffect of additives on the enantioselectivity and yield of thisreaction. To our delight, when 1.0 equiv of boric acid wasadded, the product was obtained in 75% yield with up to 99%ee (Table 1, entry 5), and other acids such as malonic acid andbenzoic acid could deliver the product with good enantiose-lectivities but lower yields (Table 1, entries 6 and 7). Theenantioselectivity and yield of this reaction dropped sharplywhen more acidic hydrogen chloride was used (Table 1, entry8). With the best catalyst system in hand, the effect of thesolvent on this reaction was evaluated, and various solventsincluding dichloromethane, toluene, THF, and acetonitrile wereexamined. However, all of these solvents proved to be worse interms of chemical yields and stereoselectivities (Table 1, entries9−12). Furthermore, increasing the amount of boric acidprovided a small benefit to the chemical yield (Table 1, entries13 and 14). Finally, when the reaction time was prolonged to48 h, the yield of the reaction increased to 85% (Table 1, entry15). Under the optimized reaction conditions, the use of D-proline also gave the same enantioselectivity as L-proline. Thisresult indicated that the chirality of proline is not responsiblefor the induction of high enantioselectivity and that thebifunctional thiourea catalyst A dominates the enantioselectiv-ity. Moreover, the structure and absolute configuration of theproduct were further confirmed by X-ray crystallography.Studies of thermal racemization demonstrated that the half-lifeof enantiopure 3a was about 1733 h at 90 °C in toluene (seethe Supporting Information for details).This exciting result aroused our interest in the study of the

reaction mechanism. To gain insights into the mechanism ofthis methodology, particularly whether the key VQMintermediate is involved and the influence of the sulfonesource on the reaction, several control experiments were carriedout (Scheme 3). First, we synthesized the MOM-protected

substrate 1a′, which is not capable of generating the VQMintermediate. In fact, the reaction did not proceed at all when1a′ was used as the substrate (Scheme 3, eq a). This resultindicated that the formation of the VQM intermediate wascrucial for this transformation. When benzenesulfinic acid wasused as the sulfone source without proline and an additive, theproduct was obtained in less than 5% yield (Scheme 3, eq b).

Scheme 2. Initial Attempt

Table 1. Optimization of the Reaction Conditionsa

aReaction conditions: 1a (0.1 mmol), catalyst (10 mol %), L-proline(10 mol %), additive, and 2a (0.1 mmol) in chloroform (2 mL) at 25°C for 24 h. bDetermined after chromatographic purification.cDetermined by HPLC analysis on a chiral stationary phase. dThereaction was carried out for 48 h.

Scheme 3. Preliminary Mechanistic Studies

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Even under the optimal reaction conditions, the reaction stillproceeded sluggishly (Scheme 3, eq c).On the basis of the above results and our recent

achievements with the VQM intermediate, a plausible catalyticcycle is depicted in Scheme 4. First, the VQM intermediate is

generated initially from 1a through a prototropic rearrange-ment that is synergistically promoted by the quinuclidine baseand hydrogen bonding of the thiourea catalyst.16 At this stage,the absolute configuration of the allene moiety was confirmedto be R (see the Supporting Information for calculation details).Meanwhile, proline reacts with the sulfinate salt to generate aquaternary ammonium salt, which increases the solubility andreactivity of the sulfinate salt. Subsequently, nucleophilicaddition of the activated sulfinate anion to the highly activeVQM intermediate occurs, furnishing the product 3a. The boricacid here possibly plays the role of reactivating proline due tothe proton buffering property (Scheme 4).17

With the identified optimized conditions (Table 1, entry 15),the scope of sodium sulfinates was investigated with 1a as theaddition partner (Table 2). The para-substituted groups on thearomatic ring of sodium benzenesulfinates were first inves-tigated. Both electron-donating groups including methyl andacetylamino and electron-withdrawing groups including fluoro,chloro, and bromo were perfectly compatible with the reactionconditions, and the corresponding products were obtained in67−91% yield with 96−99% ee (Table 2, 3a−f). Notably,sodium alkylsulfinates could give good yields (63−72%) withexcellent enantioselectivities (98−99% ee) (Table 2, 3g−i).The entire process was readily extended to reactions utilizing

o-alkynylnaphthols as substrates (Table 3). First, differentsubstituent groups on the phenyl ring of 1-(phenylethynyl)-naphthalen-2-ol were investigated. The positions and electronicproperties of the substituents on the phenyl ring did notdramatically affect the chemical yield and stereoselectivity ofthe reaction (Table 3, 4a−j). Next, we evaluated disubstitutionson the phenyl ring, and all of them gave good yields withexcellent ee values (Table 3, 4k−n). It is worth noting that withinteresting fluoro substituents on the phenyl ring, the p-fluoro-,m-fluoro-, 2,5-difluoro-, and pentafluoro-substituted substratesproduced the desired axially chiral sulfone-containing styrenes

in good yields (75−82%) with excellent ee values (91−99%)(Table 3, 4e, 4j, 4m, 4o). The reaction conditions were alsocompatible with the 2-methyl,5-fluoro-substituted substrate,which afforded 4l with excellent enantioselectivity (99%) ingood yield (83%). Furthermore, the dinaphthyl product (Table3, 4p) was also successfully formed with excellent results (78%yield, 99% ee). Next, a series of heterocycle-substitutedproducts (Table 3, 4q−s) were obtained from correspondingsubstrates with good results (64−85% yield, 89−94% ee).Remarkably, a substrate with a substituent on the naphthalenering was also well-tolerated by the catalytic system and gaveexcellent results in terms of chemical yield (85%) andenantioselectivity (98%) (Table 3, 4t).To explore the potential utility of axially chiral sulfone-

containing styrenes, a series of transformations were conducted(Scheme 5). First, the axially chiral sulfone-containing styrenescould be easily converted into the corresponding triflates 5.Then coupling reactions between the triflate and aniline, diethylphosphonate, or diphenylphosphine oxide were catalyzed bypalladium to give the corresponding products with goodstereochemical integrity. Reduction of the sulfonyl groups tosulfide proceeded smoothly, afforded the potential S/P ligand8. Moreover, phosphonic acid monoethyl ester 9, which couldpotentially be applied as an organocatalyst in asymmetriccatalysis, was obtained after removal of the ethyl group. Finally,cross-coupling of sulfone groups and Grignard reagents is auseful tool for the construction of carbon−carbon bonds. Forexample, under the catalysis of PdCl2(PPh3)2, the couplingreaction between 5 and PhMgBr afforded (E)-7 in reasonableyield and enantioselectivity.In summary, we have developed a highly enantioselective

synthesis of axially chiral sulfone-containing styrene derivatives

Scheme 4. Plausible Catalytic Cycle

Table 2. Scope of Sulfinatesa

aReaction conditions: 1a (0.1 mmol), A (10 mol %), L-proline (10 mol%), H3BO3 (1.5 equiv), and 2 (0.1 mmol) in chloroform (2 mL) at 25°C for 48 h.

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by means of asymmetric organocatalysis. A broad range ofvaluable axially chiral sulfone-containing styrenes weresynthesized in good yields with excellent enantioselectivitiesby means of this newly developed method. In addition, severalfurther transformations of the enantioenriched chiral styrenes

were investigated to demonstrate their synthetic applications.On the basis of these remarkable results, we believe that ournew VQM intermediate constitutes a significant step inasymmetric synthesis. Further investigation of the detailedmechanism and utilization of the VQM intermediate in thepreparation of natural products and bioactive compounds isunderway.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/jacs.8b03211.

Experimental procedures and characterization data for allof the products (PDF)Crystallographic data for 3a (CIF)

■ AUTHOR INFORMATIONCorresponding Author*yhl198151@cqu.edu.cnORCIDJun Deng: 0000-0002-6547-0244Hailong Yan: 0000-0003-3378-0237NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis study was supported by the Fundamental Research Fundsfor the Central Universities in China (Grant CQDXWL-2014-Z003) and the Scientific Research Foundation of China (Grant21402016).

Table 3. Scope of o-Alkynylnaphtholsa

aReaction conditions: 1 (0.1 mmol), A (10 mol %), L-proline (10 mol%), H3BO3 (1.5 equiv), and 2a (0.1 mmol) in chloroform (2 mL) at25 °C for 48 h.

Scheme 5. Transformation of Axially Chiral Sulfone-Containing Styrene 5a

aReagents and conditions: (a) PhNH2, Cs2CO3, Pd(OAc)2, toluene,90 °C; (b) PhMgBr, PdCl2(PPh3)2, Et2O, 40 °C; (c) Ph2P(O)H,Pd(OAc)2, NEt3, dppb, DMSO, 120 °C; HSiCl3, NEt3, CH2Cl2, 40 °C;(d) HP(O)(OEt)2, Pd(OAc)2, NEt3, dppb, DMSO, 110 °C; Me3SiBr,CH2Cl2.

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