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Organocatalytic Enantioselective Construction of Axially Chiral Sulfone-Containing Styrenes Shiqi Jia, Zhili Chen, Nan Zhang, Yu Tan, Yidong Liu, Jun Deng, and Hailong Yan J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03211 • Publication Date (Web): 21 May 2018 Downloaded from http://pubs.acs.org on May 21, 2018
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Journal of the American Chemical Society
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. Supporting Information Placeholder ABSTRACT: We describe herein an organocatalytic enantiose-
Scheme 1. Background and Project Synopsis
lective approach for the construction of axially chiral sulfonecontaining styrenes. Various axially chiral sulfone-containing styrenes 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, S/P ligand, which could be potentially used as organocatalysts or ligands in asymmetric catalysis.
As a member of the axially chiral family, axially chiral styrene1 was firstly 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 a potential chiral catalyst, ligand or substrate to induce the selectivity in chemical transformations. Consequently, the development of methods for enantioselective synthesis of these axially chiral styrenes is an important task in organic chemistry. Unlike well-established synthetic approaches for the construction of biaryl atropisomers4, 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 Robert W. Baker5, Sotaro Miyano6, Gu7 and Smith8. Recently, the seminal work on organocatalytic atroposelective synthesis of axially chiral styrenes via a direct enantioselective reaction of the 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 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 molecule is expected to increase the diversity of pharmaceuticals with new pharmacological activities. However, to the best of our knowledge, the asymmetric method for the enantioselective preparation of axially chiral sulfone-containing styrenes has not been reported.
Recently we reported the first asymmetric intramolecular [4+2] cycloaddition of vinylidene ortho-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 vinylidene ortho-quinone methide (VQM) in asymmetric synthesis, we presumed that if an activated nucleophile could attack the highly electrophilic VQM intermediate, a formal nucleophilic addition13 of VQM intermediate and subsequent aromatization would occur and afford axially chiral styrenes (Scheme 1). Since we were interested in the research field of sulfone chemistry, we decided to use the sulfone-type nucleophilic reagents to verify our conception. We initially evaluated the reaction between 1(phenylethynyl)naphthalen-2-ol 1a and sodium benzene sulfinate14 2a in CHCl3 in the presence of quinine-derived thiourea A15 at room temperature. Unfortunately, the reaction did not provide any desired product, this possibly attributed to the poor solubility of sodium benzenesulfinate in CHCl3. After optimizing the
Scheme 2. Initial Attempt
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reaction conditions, the desired product was obtained with low yields and enantioselectivities when the polar solvent such as 1,4dioxane and acetonitrile were used (Scheme 2). This preliminary progress encouraged us to search for a more efficient catalytic system for this transformation.
Table 1. Optimization of the Reaction Conditionsa
lower yields (Table 1, entries 6-7). The enantioselectivity and yield of this reaction dropped sharply when more acidic hydrochloride was used (Table 1, entry 8). With the best catalyst system in hand, the solvent effect 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 equivalent of the boric acid provided a small benefit to the chemical yields (Table 1, entries 13-14). Finally, by prolonging the reaction time to 48 h, the yield of the reaction could be increased to 85% (Table 1, entry 15). Under the optimized reaction conditions, the use of D-proline can 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 the bifunctional thiourea catalyst A dominated the enantioselectivity. Moreover, the structure and absolute configuration of the product were further confirmed by X-ray crystallographic study. Studies on thermal racemization demonstrated that the half-life of enantiopure 3a was about 1733 h at 90 oC in toluene (see Supporting Information for details).
Scheme 3. Preliminary Mechanistic Studies entry
cat.
additive (equiv.)
solvent
yield (%)b
ee (%)c
1
A
-
CHCl3
49
66
2
B
-
CHCl3
15
72
3
C
-
CHCl3
62
32
4
D
-
CHCl3
27
40
5
A
H3BO3 (1.0)
CHCl3
75
99
6
A
malonic acid (1.0)
CHCl3
8
75
7
A
benzoic acid (1.0)
CHCl3
30
96
8
A
HCl (6.0 M) (1.0)
CHCl3
5
54
9
A
H3BO3 (1.0)
CH2Cl2
45
98
10
A
H3BO3 (1.0)
toluene
70
99
A
H3BO3 (1.0)
THF
