Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Enantioselective Organocatalytic 1,6-Addition of Azlactones to paraQuinone Methides: An Access to α,α-Disubstituted and β,β-Diaryl-αamino acid Esters Wenjun Li,*,† Xianhong Xu,† Yang Liu,† Hua Gao,† Yuyu Cheng,‡ and Pengfei Li*,‡ †
Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao, 266021, China Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Blvd., Nanshan District, Shenzhen, Guangdong 518055, China
‡
S Supporting Information *
ABSTRACT: This work describes the first enantioselective 1,6-additions of azlactones to para-quinone methides. In the presence of a chiral phosphoric acid, 1,6-adducts were obtained in high yields (up to 96%) with excellent diastereoselectivities and enantioselectivities (all >20:1 diastereoselectivity ratio (dr), up to 99% enantiomeric excess (ee)). Importantly, the method offers a facile synthetic approach, not only to enantiopure α,α-disubstituted α-amino acid esters, but also to unnatural enantioenriched β,β-diaryl-αamino acid esters bearing adjacent tertiary and quaternary stereogenic centers.
U
synthesis of α,α-disubstituted α-amino acids.4 The versatility of the azlactone scaffold arises from the numerous reactive sites, allowing its application in a diversity of transformations to different α-amino acids. In sharp contrast, the asymmetric synthesis of β,β-disubstituted α-amino acids have mostly focused on the β,β-diarylalanines bearing identical β-aryl substituents.5 The catalytic enantioselective construction of the unsymmetrical β,β-diarylalanines (containing a β-stereogenic center) still remains challenging.6 Molinaro et al. reported the synthesis of the unsymmetrical β,β-diarylalanines via asymmetric catalytic hydrogenation of dehydro-β,β-diarylalanine derivatives (Scheme 1A).7 However, this method required one step of the expensive metal (rhodium)-mediated Suzuki− Miyura coupling for the preparation of the tetrasubstituted olefins. Recently, para-quinone methides (p-QMs) have been proved to be excellent electron-deficient alkenes involved in asymmetric reactions by Fan,8 Jørgensen,9 Liao,10 Li,11 Tortosa,12 Yao,13 Zhao,14 Enders,15 Wu,16 and Zhang.17 Especially, p-QMs are proposed as intermediates in the chiral phosphoric acid (CPA)-catalyzed asymmetric 1,6-addition by Sun.18 Notably, Deng et al. reported an asymmetric 1,6-addition between pQMs and glycine Schiff base mediated by copper for the synthesis of the unsymmetrical β,β-diaryl-α-amino acid esters (Scheme 1B).19 Several months later, Fan et al. independently reported a similar transformation via phase transfer catalysis (PTC, Scheme 1B).20 Despite their elegant work, more efficient and practical methods for the enantioselective construction of
nnatural chiral α-amino acids, such as α,α-disubstituted (Figure 1A) and β,β-diaryl-α-amino acids (Figure 1B),
Figure 1. Representative molecules containing α-amino acid motifs.
are prevalent substructures found in a large number of peptides, proteins, and natural products possessing a wide range of biological activities.1 Moreover, the incorporation of either α,αdisubstituted or β,β-diaryl-α-amino acids into peptides results in conformational restrictions and increased rigidity, leading to enhanced activity and resistance toward chemical and enzymatic degradation.2 Accordingly, much attention has been paid to the synthesis of enantiopure α,α-disubstituted and β,β-diaryl-α-amino acids.3 Despite the existence of many powerful methods for the construction of these complex skeletons, the challenge to asymmetrically construct their fully substituted stereogenic carbon center therefore continues to inspire many synthetic chemists. As a precursor of α-amino acids, azlactones (also known as oxazolones) are usually employed in the stereoselective © XXXX American Chemical Society
Received: January 8, 2018
A
DOI: 10.1021/acs.orglett.8b00072 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
Scheme 1. Related Synthetic Strategies for β,β-Diaryl-αamino acid Motifs
asymmetric β,β-diaryl-α-amino acids and their derivatives remain highly desirable. As mentioned above, two aryl groups of the asymmetric β,βdiaryl-α-amino acid esters could be introduced from p-QMs. In addition, azlactones could serve as a precursor of α-amino acids. Accordingly, the incorporation of p-QM and azlactone into one molecule might offer a straightforward approach to asymmetric β,β-diaryl-α-amino acid esters (Scheme 1C). Based on our work in asymmetric conjugate addition,21 and as a part of our research interests in developing the reaction of p-QMs,22 the asymmetric 1,6-addition between p-QM and azlactone was surveyed. At the outset, the reaction of p-QM 1a with azlactone 2a was utilized as a model reaction to verify the possibility of our design in the presence of CPA in CHCl3 at room temperature for 48 h (Table 1). After screening of the catalysts, the results confirmed that the 1,6-addition of azlactone 2a to p-QM 1a could be catalyzed by CPA. Especially, the 1,6-adduct 3aa was obtained in 59% yield with 74% ee and 18:1 dr from IIIcatalytic transformation (entry 3 in Table 1). Then, in order to improve the asymmetric induction and the yield, various solvents were screened, which showed that carbon tetrachloride was the most suitable reaction medium to furnish 3aa in 59% yield with 99% enantiomeric excess (ee) and >20:1 diastereoselectivity ratio (dr) (entry 7 in Table 1). In addition, increasing the temperature led to the formation of 3aa in 67% yield without compromising the asymmetric induction (entry 11 in Table 1). Gratifyingly, further improvement of yield was achieved after modulating the molar ratio of 1a and 2a from 1:2 to 1:3. Finally, the 1,6-addition under the optimal conditions could afford the product 3aa in a high yield of 85% with an excellent enantioselectivity of 99% and a high diastereoselectivity of >20:1. Under the optimal reaction conditions, the substrate scope of p-QMs 1 was examined (Table 2). The III-mediated 1,6addition was found to be applicable to a wide range of p-QMs 1, affording the desired 1,6-adducts in good yield with more than 90% ee and more than 20:1 dr. Notably, both the electrondonating group (MeO, Me) and electron-withdrawing group (F, Cl, Br) could be introduced into the aromatic ring of paraquinone methide with only a minor effect on the yield and
entry
catalyst
solvent
yieldb (%)
eec (%)
drd
1 2 3 4 5 6 7 8 9 10 11e 12f
I II III IV V III III III III III III III
CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 CCl4 toluene THF ClCH2CH2Cl CCl4 CCl4
78 52 59 52 56 37 59 15 20:1 >20:1 >20:1
70 98 99
>20:1 >20:1 >20:1
a Unless noted, a mixture of 1a (0.05 mmol), 2a (0.10 mmol), and catalyst (5 mol %) in the solvent (0.3 mL) was stirred at room temperature for 48 h. bIsolated yield. cEnantiomeric excess (ee), determined by HPLC analysis using a chiral stationary phase. d Diastereoselectivity ratio (dr), determined by 1H NMR. eAt 50 °C for 48 h. f2a (0.15 mol), at 50 °C for 48 h.
Table 2. Scope of para-Quinone Methides 1a
entry
Ar
product
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8
4-MeOC6H4 4-MeC6H4 4-FC6H4 4-ClC6H4 4-BrC6H4 3,4-(MeO)2C6H3 2-thienyl Me
3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha
85 70 79 74 74 68 73 20:1, determined by 1H NMR. b Isolated yield. cEnantiomeric excess (ee), determined by HPLC analysis using a chiral stationary phase.
asymmetric induction. It was found that 4-(3,4-dimethoxybenzylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone reacted with azlactone 2a to afford the desired 1,6-adduct in 68% yield with 88% ee and >20:1 dr (entry 6). Notably, heteroaromatic group-substituted p-QM was also compatible and the desired 1,6-adduct 3ga was obtained in 73% yield with 92% ee and B
DOI: 10.1021/acs.orglett.8b00072 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
addition has the potential for a large-scale production (Scheme 2A). Furthermore, the ring-opening reaction of 3aa (99% ee)
>20:1 dr from the III-mediated 1,6-addition between 2,6-ditert-butyl-4-((thiophen-2-yl)methylene)cyclohexa-2,5-dienone and azlactone 2a (entry 7 in Table 1). However, if we utilized the substrate containing the methyl group, almost no desired product was obtained (entry 8 in Table 1). Next, we carried out an investigation of the scope of azlactones 2 (see Table 3). A series of azlactones 2 bearing
Scheme 2. Synthetic Potential
Table 3. Scope of Azlactones 2a
entry
R1/R2
product
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9d 10 11
n-Pr/4-MeOC6H4 i-Bu/4-MeOC6H4 Ph/4-MeOC6H4 Et/4-FC6H4 Et/4-ClC6H4 Et/4-MeC6H4 Et/3-BrC6H4 Et/3-MeC6H4 Et/2-BrC6H4 Et/2-naphthyl Et/2-thienyl
3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak 3al
82 93 86 68 67 77 76 73 61 96 73
96 99 50 97 90 98 96 98 99 96 98
with potassium carbonate was investigated to give an amino acid derivative 4aa in 93% yield with 98% ee (Scheme 2B). Note that not only the enantiopure α,α-disubstituted α-amino acid esters but also the unnatural enantio-enriched β,β-diaryl-αamino acid ester bearing adjacent tertiary and quaternary stereogenic centers could be facilely prepared via the synthetic strategy. In the presence of AlCl3, the elimination of t-Bu group from aromatic ring of 4aa (98% ee) was also achieved to furnish 5aa in 95% yield with 96% ee (Scheme 2B). In summary, we have established the first chiral phosphoric acid-mediated enantioselective 1,6-addition of azlactones to pQMs. In the presence of a chiral phosphoric acid, asymmetric 1,6-addition between azlactones to p-QMs proceeded smoothly to furnish the corresponding 1,6-adducts in high yields with excellent asymmetric induction. In particular, the ring-opening reaction of 1,6-adduct was easily achieved with excellent yield and ee value, which offers a facile synthetic approach to unnatural enantio-enriched α,α-disubstituted and β,β-diaryl-αamino acid esters bearing adjacent tertiary and quaternary stereogenic centers.
a
Unless noted, a mixture of 1a (0.05 mmol), 2 (0.15 mmol), and III (5 mol %) in CCl4 (0.3 mL) was stirred at 50 °C for 48 h. bIsolated yields are given. cThe ee values were determined by HPLC analysis using a chiral stationary phase. In all cases, dr >20:1, determined by 1H NMR. dRoom temperature, 72 h.
different R1/R2 substituents could be accommodated to the IIImediated 1,6-addition, which gave the desired products 3 in good yields (61%−96%) with excellent enantioselectivities (up to 99%) and diastereoselectivities (>20:1). Generally, the R1 substituent in azlactone seemingly had little effect on the reaction, because products 3ab and 3ac were obtained in similar yields and asymmetric inductions (82%−93% yield, 96%−99% ee, >20:1 dr). As an exception, the reaction of 2-(4methoxyphenyl)-4-phenyloxazol-5(4H)-one (R1 = Ph) was found to furnish the 1,6-adduct 3ad in 86% yield with 50% ee and >20:1 dr. Different substitution patterns on the phenyl ring (R2) in azlactones were all tolerated (3ae−3aj). Regardless of the position (ortho, meta, or para) and the electronic nature (electron-donating or electron-withdrawing) of the substituents on the aromatic ring (R2), the corresponding 1,6-adducts 3ae− 3aj were obtained in 61%−77% yields with 90%−99% ee and >20:1 dr. Besides, 2-naphthyl- and 2-thienyl-substituted azlactones 2k and 2l could smoothly participate in the IIImediated 1,6-addition to give the corresponding products 3ak and 3al in considerable yields with excellent enantioselectivities and diastereoselectivities (96%−98% ee, >20:1 dr). The absolute configuration of 3aj was unambiguously determined by single-crystal X-ray crystallography (for a plausible mechanism, see the Supporting Information).23 To demonstrate the utility of this III-mediated 1,6-addition, the scaleup of the reaction was carried out. The reaction of pQM 1a at 1.5 mmol proceeded well under the standard conditions to generate the corresponding product 3aa in 88% yield with 99% ee and >20:1 dr, suggesting that this 1,6-
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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.8b00072. Experimental procedures and full characterization for all compounds (PDF) Accession Codes
CCDC 1586490 contains the supplementary crystallographic data for 3aj in 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, U.K.; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail address:
[email protected] (W. Li). *E-mail addresses:
[email protected], fl
[email protected] (P. Li). ORCID
Wenjun Li: 0000-0001-9045-7845 Notes
The authors declare no competing financial interest. C
DOI: 10.1021/acs.orglett.8b00072 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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(14) (a) Ma, C.; Huang, Y.; Zhao, Y. ACS Catal. 2016, 6, 6408. (b) Liao, J.-Y.; Ni, Q.; Zhao, Y. Org. Lett. 2017, 19, 4074. (15) (a) Zhao, K.; Zhi, Y.; Wang, A.; Enders, D. ACS Catal. 2016, 6, 657. (b) Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2016, 55, 12104. (16) Kang, T.-C.; Wu, L.-P.; Yu, Q.-W.; Wu, X.-Y. Chem.Eur. J. 2017, 23, 6509. (17) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. ACS Catal. 2017, 7, 2805. (18) (a) Wang, Z.; Wong, Y. F.; Sun, J. Angew. Chem., Int. Ed. 2015, 54, 13711. (b) Wong, Y. F.; Wang, Z.; Sun, J. Org. Biomol. Chem. 2016, 14, 5751. (19) He, F.-S.; Jin, J.-H.; Yang, Z.-T.; Yu, X.; Fossey, J. S.; Deng, W.P. ACS Catal. 2016, 6, 652. (20) Zhang, X.-Z.; Deng, Y.-H.; Yan, X.; Yu, K.-Y.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. J. Org. Chem. 2016, 81, 5655. (21) (a) Wang, Y.; Li, P.; Liang, X.; Zhang, T. Y.; Ye, J. Chem. Commun. 2008, 1232. (b) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008, 3302. (c) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J. Org. Lett. 2009, 11, 753. (d) Wen, S.; Li, P.; Wu, H.; Yu, F.; Liang, X.; Ye, J. Chem. Commun. 2010, 46, 4806. (e) Duan, J.; Cheng, J.; Li, P. Org. Chem. Front. 2015, 2, 1048. (f) Cheng, Y.; Han, Y.; Li, P. Org. Lett. 2017, 19, 4774. (22) (a) Zhang, L.; Zhou, X.; Li, P.; Liu, Z.; Liu, Y.; Sun, Y.; Li, W. RSC Adv. 2017, 7, 39216. (b) Han, Y.; Zhu, Y.; Zhang, P.; Li, W.; Li, P. ChemistrySelect 2017, 2, 11380. (c) Zhang, L.; Liu, Y.; Liu, K.; Liu, Z.; He, N.; Li, W. Org. Biomol. Chem. 2017, 15, 8743. (23) CCDC 1586490 (3aj) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
ACKNOWLEDGMENTS The authors acknowledge the financial support from National Natural Science Foundation of China (No. 21502043), the Natural Science Foundation of Shandong Province (No. ZR2017JL011), Special Funds for the Development of Strategic Emerging Industries in Shenzhen (No. VJCYJ20160429191918729), and the start-up grant from Qingdao University.
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REFERENCES
(1) (a) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Mini-Rev. Med. Chem. 2006, 6, 293. (b) Grauer, A.; König, B. Eur. J. Org. Chem. 2009, 2009, 5099. (2) (a) Almond, H. R.; Manning, D. T.; Niemann, C. Biochemistry 1962, 1, 243. (b) Khosla, M. C.; Stachowiak, K.; Smeby, R. R.; Bumpus, F. M.; Piriou, F.; Lintner, K.; Fermandjian, S. Proc. Natl. Acad. Sci. U. S. A. 1981, 78, 757. (c) Polinelli, S.; Broxterman, Q. B.; Schoemaker, H. E.; Boesten, W. H. J.; Crisma, M.; Valle, G.; Toniolo, C.; Kamphuis, J. Bioorg. Med. Chem. Lett. 1992, 2, 453. (3) (a) Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584. (b) Vogt, H.; Bräse, S. Org. Biomol. Chem. 2007, 5, 406. (c) Michaux, J.; Niel, G.; Campagne, J.-M. Chem. Soc. Rev. 2009, 38, 2093. (d) Noisier, A. F.; Brimble, M. A. Chem. Rev. 2014, 114, 8775. (4) (a) de Castro, P. P.; Carpanez, A. G.; Amarante, G. W. Chem. Eur. J. 2016, 22, 10294. (b) Mosey, R. A.; Fisk, J. S.; Tepe, J. J. Tetrahedron: Asymmetry 2008, 19, 2755. (c) Alba, A. R.; Rios, R. Chem.Asian J. 2011, 6, 720. (5) For selected examples, see: (a) Josien, H.; Martin, A.; Chassaing, G. Tetrahedron Lett. 1991, 32, 6547. (b) Chen, H. G.; Beylin, V. G.; Marlatt, M.; Leja, B.; Goel, O. P. Tetrahedron Lett. 1992, 33, 3293. (c) Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J.; Christensen, J. W. Tetrahedron Lett. 1995, 36, 8961. (d) Royo, S.; Jiménez, A. I.; Cativiela, C. Tetrahedron: Asymmetry 2006, 17, 2393. (e) Patterson, D. E.; Xie, S.; Jones, L. A.; Osterhout, M. H.; Henry, C. G.; Roper, T. D. Org. Process Res. Dev. 2007, 11, 624. (f) Metrano, A. J.; Miller, S. J. J. Org. Chem. 2014, 79, 1542. (6) For selected examples, see: (a) Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67, 1399. (b) Sui, Y.; Liu, L.; Zhao, J.L.; Wang, D.; Chen, Y.-J. Tetrahedron 2007, 63, 5173. (c) Valdez, S. C.; Leighton, J. L. J. Am. Chem. Soc. 2009, 131, 14638. (d) Zheng, B.H.; Ding, C.-H.; Hou, X.-L.; Dai, L.-X. Org. Lett. 2010, 12, 1688. (e) Wang, J.; Zhou, S.; Lin, D.; Ding, X.; Jiang, H.; Liu, H. Chem. Commun. 2011, 47, 8355. (f) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed. 2012, 51, 5188. (g) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.; Homs, A.; Yu, J.-Q. Science 2014, 343, 1216. (h) Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.; Mapelli, C.; Miller, M. M.; Poss, M. A.; Scola, P. M.; Yeung, K.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 3338. (7) Molinaro, C.; Scott, J. P.; Shevlin, M.; Wise, C.; Ménard, A.; Gibb, A.; Junker, E. M.; Lieberman, D. J. Am. Chem. Soc. 2015, 137, 999. (8) (a) Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.; Zeng, C.; Du, J.-Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. Angew. Chem., Int. Ed. 2013, 52, 9229. (b) Deng, Y.-H.; Zhang, X.-Z.; Yu, K.-Y.; Yan, X.; Du, J.-Y.; Huang, H.; Fan, C.-A. Chem. Commun. 2016, 52, 4183. (c) Zhang, X.-Z.; Gan, K.-J.; Liu, X.-X.; Deng, Y.-H.; Wang, F.-X.; Yu, K.-Y.; Zhang, J.; Fan, C.-A. Org. Lett. 2017, 19, 3207. (9) Caruana, L.; Kniep, F.; Johansen, T. K.; Poulsen, P. H.; Jørgensen, K. A. J. Am. Chem. Soc. 2014, 136, 15929. (10) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem., Int. Ed. 2015, 54, 12134. (11) (a) Dong, N.; Zhang, Z.-P.; Xue, X.-S.; Li, X.; Cheng, J.-P. Angew. Chem., Int. Ed. 2016, 55, 1460. (b) Zhang, Z.; Xie, K.; Yang, C.; Li, M.; Li, X. J. Org. Chem. 2018, 83, 364. (12) Jarava-Barrera, C.; Parra, A.; López, A.; Cruz-Acosta, F.; Collado-Sanz, D.; Cárdenas, D. J.; Tortosa, M. ACS Catal. 2016, 6, 442. (13) Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 428. D
DOI: 10.1021/acs.orglett.8b00072 Org. Lett. XXXX, XXX, XXX−XXX
