Asymmetric One-Pot Construction of Three Stereogenic Elements

Letter Cite This: Org. Lett. 2019, 21, 95−99

pubs.acs.org/OrgLett

Asymmetric One-Pot Construction of Three Stereogenic Elements: Chiral Carbon Center, Stereoisomeric Alkenes, and Chirality of Axial Styrenes Anqi Huang,†,§ Lili Zhang,†,§ Dongmei Li,‡ Yidong Liu,*,‡ Hailong Yan,*,‡ and Wenjun Li*,† †

Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, Shandong 266021, P. R. China Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China

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‡

S Supporting Information *

ABSTRACT: An organocatalytic enantioselective method for the synthesis of multiple stereoisomers bearing E, Z configurations, stereogenic carbon centers, and axially chiral styrenes is reported. The method enabled the rapid construction of a series of stereochemical complexity products with excellent E, Z selectivity, diastereoselectivity (>20:1 dr), and enantioselectivity (up to 96% ee). This method provides an efficient and concise synthesis route of multiple stereoisomers with a wide range of potential applications in organic synthesis.

T

he synthesis of multiple stereoisomers1 in optically active forms is a central challenge in chemistry. A common feature of such compounds is the presence of multiple stereogenic elements, and the match/mismatch of each stereogenic element gives rise to the possibility of a large number of stereoisomers.2 The control of the relationship between stereogenic elements is therefore an essential element to the synthesis of many complex targets of interest. To date, several ways to generate stereochemical complexity in a selective manner have been developed.3 However, most of them focused on the preparation of scaffolds bearing the same type of stereogenic elements.4,5 Catalytic reactions that address both stereogenic carbon centers and an element of axial chirality are rarely explored.6 Further, to the best of our knowledge, a reaction which can generate three types of stereogenic elements (E, Z configurations, stereogenic carbon centers, and an element of axial chirality) has not reported. Due to their distinct properties of chirality and topology, these stereochemically complex molecules are important in the development of chiral catalyst backbone and bioactive substances.7 Therefore, it is necessary to develop an ideal approach to construct skeletons containing three types of stereogenic elements in a single step. To advance this underdeveloped area, and in coordination with our interest in expanding the scope of vinylidene orthoquinone methide (VQM)8 chemistry, herein, we described an organocatalytic enantioconvergent methodology toward three types of stereogenic elements in a single molecule starting from racemic 5H-oxazol-4-ones with in situ generated vinylidene ortho-quinone (Figure 1). This reaction allows the formation of three types of stereogenic elements including E, Z configurations, stereogenic carbon centers, and an element of axially © 2018 American Chemical Society

Figure 1. Design of novel scaffolds bearing three stereogenic elements.

chiral styrenes9 in one step with excellent selectivity, thus expanding the repertoire of strategies available to the synthesis of stereochemically complex molecules. A suitable nucleophile, which can smoothly attack the in situ generated VQM intermediate thus producing stereochemical complex, is the cornerstone of success in achieving this goal. 5H-Oxazol-4-ones,10 which have been commonly employed as nucleophile precursor for the synthesis of various α-alkyl-αhydroxy carboxylic acid derivatives, was selected as a strategic synthon in this study. Then we started our research with racemic 5H-oxazol-4-ones 2a and 2-(phenyl acetylene) naphthol 1a as the model substrates to optimize the reaction conditions. First, we evaluated the performance of various hydrogen-bond donor catalysts.11 The product 3aa was obtained in good yields with low ee and >20:1 dr in the presence of chiral squaramides in CH2Cl2 at 25 °C (Table 1, entries 1−4). To our delight, the enantioselectivity was Received: November 4, 2018 Published: December 19, 2018 95

DOI: 10.1021/acs.orglett.8b03492 Org. Lett. 2019, 21, 95−99

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Organic Letters Table 1. Optimization of the Reaction Conditionsa

entry

cat.

solvent

time (h)

1 2 3 4 5 6 7 8 9 10 11 12 13e 14f 15g 16h 17i 18h,j

4a 4b 4c 4d 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 CCl4 toluene PhCF3 PhCl THF CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

24 24 24 24 24 24 24 24 24 24 24 48 48 48 48 48 48 48

yield (%)b 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa, 3aa,

41 38 83 81 70 51 72 52 28 21 20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 − >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

a

Unless noted, 1a (0.06 mmol), 2 (0.05 mmol), 4e (10 mol %) in CHCl3 (0.3 mL) at 25 °C for 48 h. Isolated yields were given. The ee values were determined by HPLC analysis using a chiral stationary phase. In all cases, dr >20:1, determined by 1H NMR. bThe reaction was stirred for 96 h.

a

Unless noted, 1a (0.05 mmol), 2a (0.06 mmol), 4 (10 mol %) in the solvent (0.3 mL) at 25 °C for the time given. bIsolated yield. c Enantiomeric excess (ee) of the major enantiomer, determined by HPLC analysis using a chiral stationary phase. ddr = diastereoselectivity ratio, determined by 1H NMR. eAt 0 °C. fAt 35 °C. g1a:2a = 1.0:1.5. h1a:2a = 1.2:1.0. i1a:2a = 1.5:1.0. j4e (5 mol %).

ones 2a−n bearing different R/Ar substituents. For instance, the R group could be alkyl (Me, Et, nPr, iBu) and benzyl groups to afford the products 3aa−ae in 75−90% yields with 84−92% ee and >20:1 dr. Specifically, the Ar group of 5Hoxazol-ones 2 could be various substituted phenyl groups with either electron-donating (Me, OMe) or electron-withdrawing groups (F, Cl, Br) in different positions to afford the corresponding adducts 3af−am in high yields (79−86%) with excellent enantioselectivities (88−94%) and diastereoselectivities (all >20:1). No significant electronic effect on the aromatic moiety was observed. Furthermore, if we replaced the Ar group of 5H-oxazol-ones 2 with a furyl group, the desired product 3an could be obtained in 73% yield with 88% ee. To further explore the scope of this transformation, we turned our attention to the asymmetric reactions between oalkynylnaphthols 1 and 5H-oxazol-ones 2b. To our delight, the electronic nature of the Ar substituents of o-alkynylnaphthols 1b−m had little effect on the efficiency and stereoselectivity. As shown in Scheme 2, the desired products 3bb−mb could be obtained in 78−90% yields with 88−96% ee and >20:1 dr. Importantly, various substituents, including electron-withdrawing (F, Cl, Br) and electron-donating groups (Me, OMe), were tolerated on the aromatic ring of o-alkynylnaphthols 1 with only minor effects on the yields and asymmetric induction (3bb−kb). The naphthalene and thiophene rings also exhibited high reactivity to afford the corresponding product 3lb and 3mb in 82−83% yields with 90−92% ee.

enhanced when 4e was employed as the catalyst (Table 1, entry 5). After identifying 4e as the best catalyst, we found that the reaction media also played an important role in this reaction. The screening of reaction media revealed that chloroform (CHCl3) was more suitable for the asymmetric transformation (Table 1, entries 6−11). When chloroform was utilized as the solvent, we obtained a 51% yield with 90% ee and >20:1 dr. To further increase the yield, we prolonged the reaction time to 48 h and realized a 75% yield with 86% ee and >20:1 dr (Table 1, entry 12). A low yield was observed when we conducted the reaction at 0 °C (Table 1, entry 13). If we raised the reaction temperature to 35 °C, 84% ee with >20:1 dr was still obtained (Table 1, entry 14). Similar results were obtained after the survey of reactant ratio (Table 1, entries 15−17). When the catalyst load was decreased to 5 mol %, a 68% yield with 80% ee and >20:1 dr could be obtained after 48 h (Table 1, entry 18). Finally, based on the optimization of reaction parameters, 4e and CHCl3 were respectively selected as the catalyst and the ideal medium with 1a:2a = 1.2:1.0 for this transformation to furnish 3aa in 75% yield with 88% ee and >20:1 dr. With the determined optimal reaction conditions, we then investigated the substrate scope of 5H-oxazol-ones (Scheme 1). This catalytic strategy was applicable to various 5H-oxazol96

DOI: 10.1021/acs.orglett.8b03492 Org. Lett. 2019, 21, 95−99

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Organic Letters Scheme 2. Scope of o-Alkynylnaphtholsa

Scheme 3. A Possible Mode of Activation

undergoes Michael addition from the Re face to afford final products with excellent E, Z selectivity, diastereoselectivity, and enantioselectivity. To demonstrate the utility of this catalytic asymmetric transformation, the reaction was scaled up to 2.0 mmol and the desired product 3ab was obtained in 77% yield with 92% ee and >20:1 dr (Scheme 4). The encouraging results imply that the catalytic asymmetric reactions have the potential for a large-scale production. Scheme 4. Synthetic Potential

We further aimed to diversify the 5H-oxazol-4-ones group and demonstrate the versatility of the multiple stereoisomers scaffold. As shown in Scheme 5, 3ab was treated with a strong Scheme 5. Synthetic Transformations a

Unless noted, 1 (0.06 mmol), 2b (0.05 mmol), 4e (10 mol %) in CHCl3 (0.3 mL) at 25 °C for 48 h. Isolated yields were given. The ee values were determined by HPLC analysis using a chiral stationary phase. In all cases, dr >20:1, determined by 1H NMR. bThe reaction was stirred for 72 h.

Besides, a substrate with a bromo substituent on the naphthalene ring was also tolerated by the catalytic system and the desired product 3nb was obtained in 80% yield with 90% ee. The absolute configuration of the enantioenriched 3 was unambiguously determined based on the X-ray crystal structure of 3jb (CCDC 1866295). To interpret the observed stereochemical outcome, a possible mode of activation has been proposed based on the basis of experimental results of this study and previous reports (Scheme 3).8,10,11 This transition model was considered based on the principle of hydrogen bonding interaction between the chiral organocatalyst and substrates. The chirality of the in situ formed VQM intermediate was believed to play a significant role in the regulation of the E, Z selectivity and enantioselectivity of axially chiral styrenes, presumably via a hydrogen bond with the squaramide group. The tertiary amine of the less sterically hindered cinchona alkaloid activates the racemic 5H-oxazol-4-ones through the deprotonation thus giving the nucleophilic enolate. The nucleophilic enolate

base (NaOH) to activate a ring opening and afforded the desired α-hydroxycarboxylic amide 5 in 98% yield with the same diastereo- and enantioselectivity. With a weak base (NaHCO3), we obtained the corresponding amide 6 with a benzoyl-protected α-tertiary alcohol without any loss of enantiopurity. In addition, 3ab underwent diastereoselective reduction in the presence of NaBH3CN to provide oxazolidin4-one product 7 in 94% yield.10g In summary, we have developed a highly enantioselective approach to multiple stereoisomers bearing E, Z config97

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Organic Letters

Acc. Chem. Res. 2015, 48, 1832−1844. (c) Chu, W.-D.; Zhang, Y.; Wang, J. Recent Advances in Catalytic Asymmetric Synthesis of Allenes. Catal. Sci. Technol. 2017, 7, 4570−4579. (d) Desimoni, G.; Faita, G.; Quadrelli, P. Forty Years after “Heterodiene Syntheses with α,β-Unsaturated Carbonyl Compounds”: Enantioselective Syntheses of 3,4-Dihydropyran Derivatives. Chem. Rev. 2018, 118, 2080−2248. (4) For selected examples on contiguous stereocenters, see: (a) Sparr, C.; Gilmour, R. Cyclopropyl Iminium Activation: Reactivity Umpolung in Enantioselective Organocatalytic Reaction Design. Angew. Chem., Int. Ed. 2011, 50, 8391−8395. (b) Tan, Y.; Luo, S.; Li, D.; Zhang, N.; Jia, S.; Liu, Y.; Qin, W.; Song, C. E.; Yan, H. Enantioselective Synthesis of anti−syn-Trihalides and anti−syn−antiTetrahalides via Asymmetric β-Elimination. J. Am. Chem. Soc. 2017, 139, 6431−6436. (c) Zhou, Z.; Wang, Z.-X.; Zhou, Y.-C.; Xiao, W.; Ouyang, Q.; Du, W.; Chen, Y.-C. Switchable Regioselectivity in Amine-Catalysed Asymmetric Cycloadditions. Nat. Chem. 2017, 9, 590−594. (d) Xie, Y.; List, B. Catalytic Asymmetric Intramolecular [4 + 2] Cycloaddition of In Situ Generated ortho-Quinone Methides. Angew. Chem., Int. Ed. 2017, 56, 4936−4940. (5) For selected examples on compounds with two or more stereogenic axes, see: (a) Shibata, T.; Fujimoto, T.; Yokota, K.; Takagi, K. Iridium Complex-Catalyzed Highly Enantio- and Diastereoselective [2 + 2+2] Cycloaddition for the Synthesis of Axially Chiral Teraryl Compounds. J. Am. Chem. Soc. 2004, 126, 8382−8383. (b) Ogaki, S.; Shibata, Y.; Noguchi, K.; Tanaka, K. Enantioselective Synthesis of Axially Chiral Hydroxy Carboxylic Acid Derivatives by Rhodium-Catalyzed [2 + 2+2] Cycloaddition. J. Org. Chem. 2011, 76, 1926−1929. (c) Lotter, D.; Neuburger, M.; Rickhaus, M.; Häussinger, D.; Sparr, C. Stereoselective AreneForming Aldol Condensation: Synthesis of Configurationally Stable Oligo-1,2-Naphthylenes. Angew. Chem., Int. Ed. 2016, 55, 2920−2923. (6) For selected examples, see: (a) Di Iorio, N.; Righi, P.; Mazzanti, A.; Mancinelli, M.; Ciogli, A.; Bencivenni, G. Remote Control of Axial Chirality: Aminocatalytic Desymmetrization of N-Arylmaleimides via Vinylogous Michael Addition. J. Am. Chem. Soc. 2014, 136, 10250− 10253. (b) Min, C.; Lin, Y.; Seidel, D. Catalytic Enantioselective Synthesis of Mariline A and Related Isoindolinones through a Biomimetic Approach. Angew. Chem., Int. Ed. 2017, 56, 15353− 15357. (c) Liu, Y.; Tse, Y.-L. S.; Kwong, F. Y.; Yeung, Y.-Y. Accessing Axially Chiral Biaryls via Organocatalytic Enantioselective DynamicKinetic Resolution-Semipinacol Rearrangement. ACS Catal. 2017, 7, 4435−4440. (d) Kwon, Y.; Chinn, A. J.; Kim, B.; Miller, S. J. Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond-Forming Cross-Coupling and CatalystControlled Atroposelective Cyclodehydration. Angew. Chem., Int. Ed. 2018, 57, 6251−6255. (e) Carmona, J. A.; Hornillos, V.; RamírezLópez, P.; Ros, A.; Iglesias-Siguënza, J.; Gómez-Bengoa, E.; Fernández, R.; Lassaletta, J. M. Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous Generation of Central and Axial Chirality. J. Am. Chem. Soc. 2018, 140, 11067−11075. (7) Drug Stereochemistry: Analytical Methods and Pharmacology; Jozwiak, K., Lough, W. J., Wainer, I. W., Eds.; CRC: Boca Raton, FL, 2012. (8) For selected examples, see: (a) Doria, F.; Percivalle, C.; Freccero, M. Vinylidene-Quinone Methides, Photochemical Generation and β-Silicon Effect on Reactivity. J. Org. Chem. 2012, 77, 3615−3619. (b) Wu, X.; Xue, L.; Li, D.; Jia, S.; Ao, J.; Deng, J.; Yan, H. Organocatalytic Intramolecular [4 + 2] Cycloaddition between In Situ Generated Vinylidene ortho-Quinone Methides and Benzofurans. Angew. Chem., Int. Ed. 2017, 56, 13722−13726. (c) Liu, Y.; Wu, X.; Li, S.; Xue, L.; Shan, C.; Zhao, Z.; Yan, H. Organocatalytic Atroposelective Intramolecular [4 + 2] Cycloaddition: Synthesis of Axially Chiral Heterobiaryls. Angew. Chem., Int. Ed. 2018, 57, 6491− 6495. (d) Jia, S.; Chen, Z.; Zhang, N.; Tan, Y.; Liu, Y.; Deng, J.; Yan, H. Organocatalytic Enantioselective Construction of Axially Chiral Sulfone-Containing Styrenes. J. Am. Chem. Soc. 2018, 140, 7056− 7060. (e) Arae, S.; Beppu, S.; Kawatsu, T.; Igawa, K.; Tomooka, K.; Irie, R. Asymmetric Synthesis of Axially Chiral Benzocarbazole Derivatives Based on Catalytic Enantioselective Hydroarylation of

urations, stereogenic carbon centers, and an element of axially chiral styrenes via organocatalysis. The reaction proceeds under mild reaction conditions, tolerates a range of functional groups, and is applicable to gram-scale synthesis. The obtained products can be easily converted into useful synthetic intermediates. Further expansions of this new work, mechanistic investigations, and applications toward complex molecules synthesis are currently ongoing in our laboratory.

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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/acs.orglett.8b03492. Experimental details and spectral data for all compounds (PDF) Accession Codes

CCDC 1866295 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hailong Yan: 0000-0003-3378-0237 Wenjun Li: 0000-0001-9045-7845 Author Contributions §

A.H. and L.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the financial support from National Natural Science Foundation of China (21772018, 21502043), Chongqing Science and Technology Commission (cstc2017jcyjAX0389), the Natural Science Foundation of Shandong Province (ZR2017JL011), and the start-up grant from Qingdao University.

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REFERENCES

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Organic Letters Alkynes. Org. Lett. 2018, 20, 4796−4800. (f) Li, D.; Tan, Y.; Peng, L.; Li, S.; Zhang, N.; Liu, Y.; Yan, H. Asymmetric Mannich Reaction and Construction of Axially Chiral Sulfone-Containing Styrenes in One Pot from α-Amido Sulfones Based on the Waste-Reuse Strategy. Org. Lett. 2018, 20, 4959−4963. (9) (a) Kawabata, T.; Yahiro, K.; Fuji, K. Memory of Chirality: Enantioselective Alkylation Reactions at an Asymmetric Carbon Adjacent to a Carbonyl Group. J. Am. Chem. Soc. 1991, 113, 9694− 9696. (b) Feng, J.; Li, B.; He, Y.; Gu, Z. Enantioselective Synthesis of Atropisomeric Vinyl Arene Compounds by Palladium Catalysis: A Carbene Strategy. Angew. Chem., Int. Ed. 2016, 55, 2186−2190. (c) Zheng, S.-C.; Wu, S.; Zhou, Q.; Chung, L. W.; Ye, L.; Tan, B. Organocatalytic Atroposelective Synthesis of Axially Chiral Styrenes. Nat. Commun. 2017, 8, 15238. (d) Jolliffe, J. D.; Armstrong, R. J.; Smith, M. D. Catalytic Enantioselective Synthesis of Atropisomeric Biaryls by a Cation-Directed O-Alkylation. Nat. Chem. 2017, 9, 558− 562. (10) For selected examples, see: (a) Trost, B. M.; Dogra, K.; Franzini, M. 5H-Oxazol-4-ones as Building Blocks for Asymmetric Synthesis of α-Hydroxycarboxylic Acid Derivatives. J. Am. Chem. Soc. 2004, 126, 1944−1945. (b) Misaki, T.; Takimoto, G.; Sugimura, T. Direct Asymmetric Aldol Reaction of 5H-Oxazol-4-ones with Aldehydes Catalyzed by Chiral Guanidines. J. Am. Chem. Soc. 2010, 132, 6286−6287. (c) Misaki, T.; Kawano, K.; Sugimura, T. Highly ZSelective Asymmetric 1,4-Addition Reaction of 5H-Oxazol-4-ones with Alkynyl Carbonyl Compounds Catalyzed by Chiral Guanidines. J. Am. Chem. Soc. 2011, 133, 5695−5697. (d) Trost, B. M.; Hirano, K. Highly Stereoselective Synthesis of α-Alkyl-α-Hydroxycarboxylic Acid Derivatives Catalyzed by a Dinuclear Zinc Complex. Angew. Chem., Int. Ed. 2012, 51, 6480−6483. (e) Zhao, D.; Wang, L.; Yang, D.; Zhang, Y.; Wang, R. Highly Diastereo- and Enantioselective Synthesis of α-Alkyl Norstatine Derivatives: Catalytic Asymmetric Mannich Reactions of 5H-Oxazol-4-ones. Angew. Chem., Int. Ed. 2012, 51, 7523−7527. (f) Zhu, B.; Lee, R.; Li, J.; Ye, X.; Hong, S.-N.; Qiu, S.; Coote, M. L.; Jiang, Z. Chemoselective Switch in the Asymmetric Organocatalysis of 5H-Oxazol-4-ones and N-Itaconimides: AdditionProtonation or [4 + 2] Cycloaddition. Angew. Chem., Int. Ed. 2016, 55, 1299−1303. (g) Li, J.; Qiu, S.; Ye, X.; Zhu, B.; Liu, H.; Jiang, Z. Dipeptide-Based Chiral Tertiary Amine-Catalyzed Asymmetric Conjugate Addition Reactions of 5H-Thiazol/Oxazol-4-Ones. J. Org. Chem. 2016, 81, 11916−11923. (11) For selected book and reviews, see: (a) Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis; Song, C. E., Ed.; Wiley-VCH: Weinheim, 2009. (b) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Squaramides: Bridging from Molecular Recognition to Bifunctional Organocatalysis. Chem. - Eur. J. 2011, 17, 6890−6899. (c) Ian Storer, R.; Aciro, C.; Jones, L. H. Squaramides: Physical Properties, Synthesis and Applications. Chem. Soc. Rev. 2011, 40, 2330−2346. (d) Ni, X.; Li, X.; Wang, Z.; Cheng, J.-P. Squaramide Equilibrium Acidities in DMSO. Org. Lett. 2014, 16, 1786−1789.

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