Catalytic Asymmetric Domino Michael/Annulation Reaction of Bifunctional Chromone Synthons with β,γ-Unsaturated α-Keto Esters: Rapid Access to Polysubstituted Spirocyclic Hexahydroxanthones

Abstract

A thiourea-catalyzed asymmetric domino Michael/annulation process was devised employing bifunctional oxindole-chromones as C₄ synthons and β,γ-unsaturated α-keto esters as C₂ synthons. This reaction enables the highly diastereo- and enantioselective synthesis of a range of biologically relevant spirocyclic hexahydroxanthones with one quaternary and four tertiary stereogenic centers, also featuring an intriguing combination of two privileged motifs, including hexahydroxanthone and oxindole substructures, in good yields (up to 76%) and excellent stereoselectivities (up to >99% ee and >20:1 dr). Moreover, using β,γ-unsaturated α-keto esters as the C₂ building blocks, which are different from enone substrates such as chalcone and benzalacetone, with the reversible Michael reaction further expanded the scope of the method. In addition, scale-up also demonstrated the applicability of this protocol.

Key words

Michael addition - annulations - oxindoles - chromones - C₄ synthons - β,γ-unsaturated α-keto esters - spirocyclic hexahydroxanthones

• References

• 1a Masters KS, Bräse S. Chem. Rev. 2012; 112: 3717
• 1b Kharwar RN, Mishra A, Gond S, Stierle KA, Stierle D. Nat. Prod. Rep. 2011; 28: 1208
• 1c Sato S, Suga Y, Yoshimura T, Nakagawa R, Tsuji T, Umemura K, Andoh T. Bioorg. Med. Chem. Lett. 1999; 9: 2653
• 1d Shim SH, Baltrusaitis J, Gloer JB, Wicklow DT. J. Nat. Prod. 2011; 74: 395
• 1e Goel R, Sharma V, Budhiraja A, Ishar MP. S. Bioorg. Med. Chem. Lett. 2012; 22: 4665
• 1f Zhang F, Li L, Niu S, Si Y, Guo L, Jiang X, Che YA. J. Nat. Prod. 2012; 75: 230
• 2a Albrecht A, Bojanowski J. Adv. Synth. Catal. 2017; 359: 2907
• 2b Albrecht Ł, CruzAcosta F, Fraile A, Albrecht A, Christensen J, Jørgensen KA. Angew. Chem. Int. Ed. 2012; 51: 9088
• 2c Danda A, Kesava-Reddy N, Golz C, Strohmann C, Kumar K. Org. Lett. 2016; 18: 2632
• 2d Li J.-L, Zhou S.-L, Chen P.-Q, Dong L, Liu T.-Y, Chen Y.-C. Chem. Sci. 2012; 3: 1879
• 3a Wetzel S, Bon RS, Kumar K, Waldmann H. Angew. Chem. Int. Ed. 2011; 50: 10800
• 3b van Hattum H, Waldmann H. J. Am. Chem. Soc. 2014; 136: 11853
• 4a Zuo X, Liu XL, Wang JX, Yao YM, Zhou YY, Wei D, Gong Y, Zhou Y. J. Org. Chem. 2019; 84: 6679
• 4b Liu XL, Wei QD, Zuo X, Xu SW, Yao Z, Wang JX, Zhou Y. Adv. Synth. Catal. 2019; 361: 2836
• 4c Liu XL, Zhou G, Gong Y, Yao Z, Zuo X, Zhang WH, Zhou Y. Org. Lett. 2019; 21: 2528
• 4d Liu XL, Gong Y, Chen S, Zuo X, Yao Z, Zhou Y. Org. Chem. Front. 2019; 6: 1603
• 4e Xu SW, Liu XW, Zuo X, Zhou G, Gong Y, Liu XL, Zhou Y. Adv. Synth. Catal. 2019; 361: 5328
• 4f Chang SQ, Zou X, Gong Y, He XW, Liu XL, Zhou Y. Chem. Commun. 2019; 55: 14003
• 4g Liu XL, Zuo X, Wang JX, Chang SQ, Wei QD, Zhou Y. Org. Chem. Front. 2019; 6: 1485
• 4h Zhang WH, Zhou YY, He XW, Gong Y, Liu XL, Zhou Y. Org. Biomol. Chem. 2019; 17: 8369
• 5a Cheng D, Ishihara Y, Tan B, Barbas CF. III. ACS Catal. 2014; 14: 743
• 5b Singh GS, Desta ZY. Chem. Rev. 2012; 112: 6104
• 5c Hong LR, Wang R. Adv. Synth. Catal. 2013; 355: 1023
• 5d Han WY, Zhao JQ, Zuo J, Xu XY, Zhang XM, Yuan WC. Adv. Synth. Catal. 2015; 357: 3007
• 5e Ding M, Zhou F, Liu YL, Wang CH, Zhao XL, Zhou J. Chem. Sci. 2011; 2: 2035
• 5f Fan T, Zhang HH, Li C, Shen Y, Shi F. Adv. Synth. Catal. 2016; 358: 2017
• 5g Tan W, Li X, Gong YX, Ge MD, Shi F. Chem. Commun. 2014; 50: 15901
• 5h Cao ZY, Zhou F, Zhou J. Acc. Chem. Res. 2018; 51: 1443
• 5i Xu PW, Liu JK, Shen L, Cao ZY, Zhao XL, Yan J, Zhou J. Nat. Commun. 2017; 8: 1619
• 5j Zhu Y, Zhou J, Jin S, Dong H, Guo J, Bai X, Wang Q, Bu Z. Chem. Commun. 2017; 53: 11201
• 5k Zhang Y.-C, Jiang F, Shi F. Acc. Chem. Res. 2020; 53: 425
• 5l Guo JM, Bai XG, Wang QL, Bu ZW. J. Org. Chem. 2018; 83: 3679
• 5m Zhang K, Han HB, Wang LL, Zhang ZY, Wang QL, Zhang WJ, Bu ZW. Chem. Commun. 2019; 55: 13681
• 5n Zhang L.-L, Zhang J.-W, Xiang S.-H, Guo Z, Tan B. Chin. J. Chem. 2018; 36: 1182
• 6a Hussein AA, Meyer JJ. M, Jimeno ML, Rodríguez B. J. Nat. Prod. 2007; 70: 293
• 6b Ge HM, Zhu CH, Shi DH, Zhang LD, Xie DQ, Yang J, Ng SW, Tan RX. Chem. Eur. J. 2008; 14: 376
• 6c Pérez-Fons L, Garzón MT, Micol V. J. Agric. Food Chem. 2010; 58: 161
• 6d Pertino MW, Theoduloz C, Rodríguez JA, Lazo V. J. Nat. Prod. 2010; 73: 639
• 6e Nicolaou KC, Wu TR, Kang Q, Chen DY.-K. Angew. Chem. Int. Ed. 2009; 48: 3440
• 6f Nicolaou KC, Kang Q, Wu TR, Lim CS, Chen DY.-K. J. Am. Chem. Soc. 2010; 132: 7540
• 6g Sontag B, Ruth M, Spiteller P, Arnold N, Steglich W, Reichert M, Bringmann G. Eur. J. Org. Chem. 2006; 1023
• 6h Nakatani N, Inatani R. Agric. Biol. Chem. 1983; 47: 353
• 7a Wu S, Li Y, Xu G, Chen S, Zhang Y, Liu N, Dong G, Miao C, Su H, Zhang W, Sheng C. Eur. J. Med. Chem. 2016; 115: 141
• 7b Mondal S, Mukherjee S, Yetra SR, Gonnade RG, Biju AT. Org. Lett. 2017; 19: 4367
• 7c Leng H.-J, Li Q.-Z, Zeng R, Dai Q.-S, Zhu H.-P, Liu Y, Huang W, Han B, Li J.-L. Adv. Synth. Catal. 2018; 360: 229
• 7d Yetra SR, Mondal S, Mukherjee S, Gonnade RG, Biju AT. Angew. Chem. Int. Ed. 2016; 55: 268
• 8a Chen Y, Cui BD, Bai M, Han WY, Wan NW, Chen YZ. Tetrahedron 2019; 75: 2971
• 8b Bai M, Chen YZ, Cui BD, Xu XY, Yuan WC. Tetrahedron 2019; 75: 2155
• 8c Zhong X, Lv J, Luo S. Org. Lett. 2017; 19: 3331
• 9a Yao W, Dou X, Lu Y. J. Am. Chem. Soc. 2015; 137: 54
• 9b Lv J, Zhang L, Luo S, Cheng JP. Angew. Chem. Int. Ed. 2013; 52: 9786
• 9c Leckie SM, Brown TB, Pryde D, Lebl T, Slawin AM. Z, Smith AD. Org. Biomol. Chem. 2013; 11: 3230
• 9d Juhl K, Jorgensen KA. Angew. Chem. Int. Ed. 2003; 42: 1498
• 9e Belmessieri D, Morrill LC, Simal C, Slawin AM. Z, Smith AD. J. Am. Chem. Soc. 2011; 133: 2714
• 9f Albrecht L, Dickmeiss G, Weise CF, Rodríguez-Escrich C, Jorgensen KA. Angew. Chem. Int. Ed. 2012; 51: 13109
• 9g Wang L, Lv J, Zhang L, Luo S. Angew. Chem. Int. Ed. 2017; 56: 10867
• 9h Shen J, Liu D, An Q, Liu Y, Zhang W. Adv. Synth. Catal. 2012; 354: 3311
• 9i Matsumura Y, Suzuki T, Sakakura A, Ishihara K. Angew. Chem. Int. Ed. 2014; 53: 6131
• 9j Mal K, Das S, Maiti NC, Natarajan R, Das I. J. Org. Chem. 2015; 80: 2972
• 9k Lv J, Zhang L, Hu S, Cheng JP, Luo S. Chem. Eur. J. 2012; 18: 799
• 9l Li J, Lin L, Hu B, Lian X, Wang G, Liu X, Feng X. Angew. Chem. Int. Ed. 2016; 55: 6075
• 9m Wang L, Lv J, Li S, Luo S. Org. Lett. 2017; 19: 3366
• 9n Qi J, Xie X, Han R, Ma D, Yang J, She X. Chem. Eur. J. 2013; 19: 4146
• 9o Noël R, Gembus V, Levacher V, Brière J.-F. Org. Biomol. Chem. 2014; 12: 1245
• 9p Zhu Y, Xie M, Dong S, Zhao X, Lin L, Liu X, Feng X. Chem. Eur. J. 2011; 17: 8202
• 9q Huang H, Konda S, Zhao JC.-G. Angew. Chem. Int. Ed. 2016; 55: 2213
• 10a Mahatthananchai J, Dumas AM, Bode JW. Angew. Chem. Int. Ed. 2012; 51: 10954
• 10b Zhu YS, Yuan BB, Guo JM, Jin SJ, Dong HH, Wang QL, Bu ZW. J. Org. Chem. 2017; 82: 5669
• 10c Yang S.-Y, Han WY, He C, Cui BD, Wan NW, Chen YZ. Org. Lett. 2019; 21: 8857
• 10d Miao HJ, Wang LL, Han HB, Zhao YD, Wang QL, Bu ZW. Chem. Sci. 2020; 11: 1418
• 10e Li MZ, Tong Q, Han WY, Yang SY, Cui BD, Wan NW, Chen YZ. Org. Biomol. Chem. 2020; 18: 1112
• 10f Wang WB, Bai XG, Jin SJ, Guo JM, Zhao Y, Miao HJ, Zhu YS, Wang QL, Bu ZW. Org. Lett. 2018; 20: 3451
• 11 CCDC 1982865 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 12a Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672
• 12b Okino T, Hoashi Y, Furukawa T, Takemoto X, Xu Y. J. Am. Chem. Soc. 2005; 127: 119
• 12c Uchida N, Taketoshi A, Kuwabara J, Amamoto T, Inoue Y, Watanabe Y, Kanbara T. Org. Lett. 2010; 12: 5246