Organocatalytic Enantioselective Construction of Axially Chiral

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Cite This: J. Am. Chem. Soc. 2018, 140, 7056−7060

Organocatalytic Enantioselective Construction of Axially Chiral Sulfone-Containing Styrenes Shiqi 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, Chongqing University, Chongqing 401331, P. R. China S Supporting Information *

asymmetric method for the enantioselective preparation of axially 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 the application of VQM in asymmetric synthesis, we presumed that if an activated nucleophile could attack the highly electrophilic VQM intermediate, a formal nucleophilic addition13 of the VQM intermediate and subsequent aromatization would occur, affording axially chiral styrenes (Scheme 1). Since we were interested in the research field of sulfone chemistry, we decided to use sulfone-type nucleophilic reagents to verify our conception.

ABSTRACT: We describe herein an organocatalytic enantioselective approach for the construction of axially chiral sulfone-containing styrenes. Various axially chiral sulfone-containing styrene compounds were prepared with excellent enantioselectivities (up to >99% ee) and almost complete E/Z selectivities (>99% E/Z). Furthermore, the axially chiral sulfone-containing styrenes could be easily converted into phosphonic acid and S/P ligands, which could be potentially used as organocatalysts or ligands in asymmetric catalysis.

A

s a member of the axially chiral family, axially chiral styrene1 was first proposed to demonstrate a new concept of the memory of chirality by Kawabata et al.2 in 1991. Their enantiomers exist due to the restricted rotation around a single bond between a substituted alkene and an aromatic ring. The use of chiral olefins3 as ligands in metal-mediated catalysis has revolutionized the fields of organometallic chemistry and asymmetric synthesis. Axially chiral styrenes can be used as potential chiral catalysts, ligands, or substrates to induce selectivity in chemical transformations. Consequently, the development of methods for the enantioselective synthesis of these axially chiral styrenes is an important task in organic chemistry. Unlike well-established synthetic approaches for the construction of biaryl atropisomers,4 the enantioselective construction of axially chiral styrenes remains a daunting challenge in modern organic synthesis. To date, only a few examples of the enantioselective construction of axially chiral styrenes have been reported by the research groups of Baker,5 Miyano,6 Gu,7 and Smith.8 Recently, the seminal work on organocatalytic atroposelective synthesis of axially chiral styrenes via a direct enantioselective nucleophilic addition to alkynal was published by Tan.9 Despite these progresses, a practical enantioselective synthetic route allowing various substitution patterns is still highly desirable. Sulfones10 are an important class of pharmaceutically relevant compounds because of their wide spectrum of biological activities, such as cancer agents, secretase inhibitors for the treatment of Alzheimer’s disease, and antibacterial agents. The synthesis of hybrid molecules with more than one pharmacological property has gained momentum recently.11 In this regard, integrating the features of axially chiral styrenes and sulfones into a single scaffold is expected to increase the diversity of pharmaceuticals with new pharmacological activities. However, to the best of our knowledge, an © 2018 American Chemical Society

Scheme 1. Background and Project Synopsis

We initially evaluated the reaction between 1(phenylethynyl)naphthalen-2-ol (1a) and sodium benzenesulfinate14 (2a) in CHCl3 in the presence of quinine-derived thiourea A15 at room temperature. Unfortunately, the reaction did not provide any of the desired product, possibly because of the poor solubility of sodium benzenesulfinate in CHCl3. After optimization of the reaction conditions, the desired product was obtained in low yields and enantioselectivities when a polar solvent such as 1,4-dioxane or acetonitrile was used (Scheme 2). This preliminary progress encouraged us to search for a more efficient catalytic system for this transformation. Received: March 23, 2018 Published: May 21, 2018 7056

DOI: 10.1021/jacs.8b03211 J. Am. Chem. Soc. 2018, 140, 7056−7060

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Journal of the American Chemical Society

inferior results (Table 1, entries 2−4). We then evaluated the effect of additives on the enantioselectivity and yield of this reaction. To our delight, when 1.0 equiv of boric acid was added, the product was obtained in 75% yield with up to 99% ee (Table 1, entry 5), and other acids such as malonic acid and benzoic acid could deliver the product with good enantioselectivities but lower yields (Table 1, entries 6 and 7). The enantioselectivity and yield of this reaction dropped sharply when more acidic hydrogen chloride was used (Table 1, entry 8). With the best catalyst system in hand, the effect of the solvent on this reaction was evaluated, and various solvents including dichloromethane, toluene, THF, and acetonitrile were examined. However, all of these solvents proved to be worse in terms of chemical yields and stereoselectivities (Table 1, entries 9−12). Furthermore, increasing the amount of boric acid provided a small benefit to the chemical yield (Table 1, entries 13 and 14). Finally, when the reaction time was prolonged to 48 h, the yield of the reaction increased to 85% (Table 1, entry 15). Under the optimized reaction conditions, the use of Dproline also gave the same enantioselectivity as L-proline. This result indicated that the chirality of proline is not responsible for the induction of high enantioselectivity and that the bifunctional thiourea catalyst A dominates the enantioselectivity. Moreover, the structure and absolute configuration of the product were further confirmed by X-ray crystallography. Studies of thermal racemization demonstrated that the half-life of enantiopure 3a was about 1733 h at 90 °C in toluene (see the Supporting Information for details). This exciting result aroused our interest in the study of the reaction mechanism. To gain insights into the mechanism of this methodology, particularly whether the key VQM intermediate is involved and the influence of the sulfone source on the reaction, several control experiments were carried out (Scheme 3). First, we synthesized the MOM-protected

Scheme 2. Initial Attempt

Various chiral amino acids were first tested as additives (see the Supporting Information for details). To our delight, when the 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% yield with 66% ee (Table 1, entry 1). Next, various organocatalysts with different chiral skeletons and functional groups were screened. However, the screened catalysts B, C, and D provided Table 1. Optimization of the Reaction Conditionsa

Scheme 3. Preliminary Mechanistic Studies

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

a

Reaction 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. c Determined by HPLC analysis on a chiral stationary phase. dThe reaction was carried out for 48 h. 7057

DOI: 10.1021/jacs.8b03211 J. Am. Chem. Soc. 2018, 140, 7056−7060

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Journal of the American Chemical Society Table 2. Scope of Sulfinatesa

Even under the optimal reaction conditions, the reaction still proceeded sluggishly (Scheme 3, eq c). On the basis of the above results and our recent achievements with the VQM intermediate, a plausible catalytic cycle is depicted in Scheme 4. First, the VQM intermediate is Scheme 4. Plausible Catalytic Cycle

a

Reaction 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.

generated initially from 1a through a prototropic rearrangement that is synergistically promoted by the quinuclidine base and hydrogen bonding of the thiourea catalyst.16 At this stage, the absolute configuration of the allene moiety was confirmed to be R (see the Supporting Information for calculation details). Meanwhile, proline reacts with the sulfinate salt to generate a quaternary ammonium salt, which increases the solubility and reactivity of the sulfinate salt. Subsequently, nucleophilic addition of the activated sulfinate anion to the highly active VQM intermediate occurs, furnishing the product 3a. The boric acid here possibly plays the role of reactivating proline due to the 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 the addition partner (Table 2). The para-substituted groups on the aromatic ring of sodium benzenesulfinates were first investigated. Both electron-donating groups including methyl and acetylamino and electron-withdrawing groups including fluoro, chloro, and bromo were perfectly compatible with the reaction conditions, and the corresponding products were obtained in 67−91% yield with 96−99% ee (Table 2, 3a−f). Notably, sodium alkylsulfinates could give good yields (63−72%) with excellent enantioselectivities (98−99% ee) (Table 2, 3g−i). The entire process was readily extended to reactions utilizing o-alkynylnaphthols as substrates (Table 3). First, different substituent groups on the phenyl ring of 1-(phenylethynyl)naphthalen-2-ol were investigated. The positions and electronic properties of the substituents on the phenyl ring did not dramatically affect the chemical yield and stereoselectivity of the reaction (Table 3, 4a−j). Next, we evaluated disubstitutions on the phenyl ring, and all of them gave good yields with excellent ee values (Table 3, 4k−n). It is worth noting that with interesting fluoro substituents on the phenyl ring, the p-fluoro-, m-fluoro-, 2,5-difluoro-, and pentafluoro-substituted substrates produced 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 also compatible with the 2-methyl,5-fluoro-substituted substrate, which afforded 4l with excellent enantioselectivity (99%) in good yield (83%). Furthermore, the dinaphthyl product (Table 3, 4p) was also successfully formed with excellent results (78% yield, 99% ee). Next, a series of heterocycle-substituted products (Table 3, 4q−s) were obtained from corresponding substrates with good results (64−85% yield, 89−94% ee). Remarkably, a substrate with a substituent on the naphthalene ring was also well-tolerated by the catalytic system and gave excellent results in terms of chemical yield (85%) and enantioselectivity (98%) (Table 3, 4t). To explore the potential utility of axially chiral sulfonecontaining styrenes, a series of transformations were conducted (Scheme 5). First, the axially chiral sulfone-containing styrenes could be easily converted into the corresponding triflates 5. Then coupling reactions between the triflate and aniline, diethyl phosphonate, or diphenylphosphine oxide were catalyzed by palladium to give the corresponding products with good stereochemical integrity. Reduction of the sulfonyl groups to sulfide proceeded smoothly, afforded the potential S/P ligand 8. Moreover, phosphonic acid monoethyl ester 9, which could potentially be applied as an organocatalyst in asymmetric catalysis, was obtained after removal of the ethyl group. Finally, cross-coupling of sulfone groups and Grignard reagents is a useful tool for the construction of carbon−carbon bonds. For example, under the catalysis of PdCl2(PPh3)2, the coupling reaction between 5 and PhMgBr afforded (E)-7 in reasonable yield and enantioselectivity. In summary, we have developed a highly enantioselective synthesis of axially chiral sulfone-containing styrene derivatives 7058

DOI: 10.1021/jacs.8b03211 J. Am. Chem. Soc. 2018, 140, 7056−7060

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Journal of the American Chemical Society Table 3. Scope of o-Alkynylnaphtholsa

Scheme 5. Transformation of Axially Chiral SulfoneContaining Styrene 5a

a

Reagents 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.

were investigated to demonstrate their synthetic applications. On the basis of these remarkable results, we believe that our new VQM intermediate constitutes a significant step in asymmetric synthesis. Further investigation of the detailed mechanism and utilization of the VQM intermediate in the preparation of natural products and bioactive compounds is underway.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b03211. Experimental procedures and characterization data for all of the products (PDF) Crystallographic data for 3a (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Jun Deng: 0000-0002-6547-0244 Hailong Yan: 0000-0003-3378-0237

a

Reaction 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) at 25 °C for 48 h.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the Fundamental Research Funds for the Central Universities in China (Grant CQDXWL-2014Z003) and the Scientific Research Foundation of China (Grant 21402016).

by means of asymmetric organocatalysis. A broad range of valuable axially chiral sulfone-containing styrenes were synthesized in good yields with excellent enantioselectivities by means of this newly developed method. In addition, several further transformations of the enantioenriched chiral styrenes 7059

DOI: 10.1021/jacs.8b03211 J. Am. Chem. Soc. 2018, 140, 7056−7060

Communication

Journal of the American Chemical Society

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(15) For selected book and reviews, see: (a) Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis; Song, C. E., Ed.; Wiley-VCH: Weinheim, Germany, 2009. (b) Tian, S.K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621. (c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (d) MacMillan, D. W. C. Nature 2008, 455, 304. For selected examples, see: (e) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (f) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967. (g) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. J. Am. Chem. Soc. 2007, 129, 1878. (h) Bae, H. Y.; Sim, J. H.; Lee, J.-W.; List, B.; Song, C. E. Angew. Chem., Int. Ed. 2013, 52, 12143. (i) Bae, H. Y.; Kim, M. J.; Sim, J. H.; Song, C. E. Angew. Chem., Int. Ed. 2016, 55, 10825. (j) Sim, J. H.; Song, C. E. Angew. Chem., Int. Ed. 2017, 56, 1835. (16) (a) Inokuma, T.; Furukawa, M.; Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.; Matsuzaki, K.; Takemoto, Y. Chem. - Eur. J. 2011, 17, 10470. (b) Inokuma, T.; Furukawa, M.; Suzuki, Y.; Kimachi, T.; Kobayashi, Y.; Takemoto, Y. ChemCatChem 2012, 4, 983. (17) At this stage, we prefer that the boric acid play the role in regenerating proline by regulating the pH of the reaction. More detailed studies are ongoing in our group.

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DOI: 10.1021/jacs.8b03211 J. Am. Chem. Soc. 2018, 140, 7056−7060