Synthesis and Epoxidation of Flav-3-enes as Methodology for the Biomimetic Preparation of Flavan-3,4-diols

Abstract

Since flavonoids exhibit a remarkable number of pharmacological properties like antioxidant, anti-inflammatory, and antimicrobial activities, a great deal of work has been done on the medicinal and therapeutical application of these compounds. Despite the central role of flavan-3,4-diols in the synthesis of many other classes of flavonoids, only a few methods for the preparation of these compounds have been reported. In this paper, the results on the preparation of methoxy-substituted flavan-3,4-diols, displaying natural substitution patterns, from readily available starting materials through a 3-step process is disclosed. It is also indicated that the 4-aryl-substituted analogues can become available from the corresponding flav-3-enes if an aromatic nucleophile is added during the dimethyldioxirane (DMDO) epoxidation process.

Key words

aldol condensation - reductive cyclization - epoxidation - dimethyldioxirane - flav-3-ene - flavan-3,4-diol

Publication History

Received: 14 February 2023

Accepted after revision: 27 April 2023

Article published online:
25 May 2023

• References

• 1 Sharma R. In Polyphenols in Human Health and Disease . Watson RR, Preedy VR, Zibadi S. Academic Press; San Diego: 2014: 757-778
• 2 Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Am. J. Clin. Nutr. 2001; 74: 418
• 3 Kang SR, Park KI, Park HS, Lee DH, Kim JA, Nagappan A, Kim EH, Lee WS, Shin SC, Park MK, Han DY, Kim GS. Food Chem. 2011; 129: 1721
• 4 Xie Y, Yang W, Tang F, Chen X, Ren L. Curr. Med. Chem. 2015; 22: 132
• 5 Smith ML, Murphy K, Doucette CD, Greenshields AL, Hoskin DW. J. Cell. Biochem. 2016; 117: 1913
• 6 Luo H, Daddysman MK, Rankin GO, Jiang B.-H, Chen YC. Cancer Cell Inter. 2010; 10: 16
• 7 Egert S, Rimbach G. Adv. Nutr. 2011; 2: 8
• 8 Panche AN, Diwan AD, Chandra SR. J. Nutr. Sci. 2016; 5: 1
• 9 Yao LH, Jiang YM, Shi J, Tomás-Barberán FA, Datta N, Singanusong R, Chen SS. Plant Foods Hum. Nutr. 2004; 59: 113
• 10 Mouton CH. L, Steenkamp JA, Young DA, Bezuidenhoudt BC. B, Ferreira D. Tetrahedron 1990; 46: 6885
• 11 Fabre S, Gueroux M, Nunes E, Szlosek-Pinaud M, Pianet I, Fouquet E. Tetrahedron 2015; 71: 3045
• 12a Steenkamp JA, Mouton CH. L, Ferreira D. Tetrahedron 1991; 47: 7605
• 12b Yano T, Ohmori K, Takahashi H, Kusumi T, Suzuki K. Org. Biomol. Chem. 2012; 10: 7685
• 12c Krohn K, Ahmed I, John M, Letzel M, Kuck D. Eur. J. Org. Chem. 2010; 2544
• 12d Alharthy RD, Hayes CJ. Tetrahedron Lett. 2010; 51: 1193
• 12e Maloney DJ, Chen S, Hecht SM. Org. Lett. 2006; 8: 1925
• 12f Fujii W, Toda K, Kawaguchi K, Kawahara S, Katoh M. Tetrahedron 2013; 69: 3543
• 13 Steenkamp JA, Malan JC. S, Ferreira D. J. Chem.Soc., Perkin Trans. 1 1988; 2179
• 14a Takahashi H, Kubota Y, Miyazaki H, Onda M. Chem. Pharm. Bull. 1984; 32: 4852
• 14b Takahashi H, Li S, Harigaya Y, Onda M. Chem. Pharm. Bull. 1988; 36: 1877
• 14c Onda M, Li S, Li X, Harigaya Y, Takahashi H, Kawase H, Kagawa H. J. Nat. Prod. 1989; 52: 1100
• 14d Agusta A, Maehara S, Ohashi K, Simanjuntak P, Shibuya H. Chem. Pharm. Bull. 2005; 53: 1565
• 14e Yenjai C, Wanich S. Bioorg. Med. Chem. Lett. 2010; 20: 2821
• 14f Kozilowski AP, Tückmantel W, Hu Y. J. Org. Chem. 2001; 66: 1287
• 14g Bernini R, Crisante F, Gentili P, Morana F, Pierini M, Piras M. J. Org. Chem. 2011; 76: 820
• 15a Augustyn JA. N, Bezuidenhoudt BC. B, Ferraira D. Tetrahedron 1990; 46: 2651
• 15b Burke AJ, O’Sullivan WI. Tetrahedron 1997; 53: 8491
• 15c Litkei G, Gulácsi K, Antus S, Blaskó G. Eur. J. Org. Chem. 1995; 1711
• 15d Hu C, Zhou Z, Xiang Y, Song X, Wang H, Tao K, Ye X. Med. Chem. Res. 2018; 27: 194
• 16a Kholer EP, Chadwell HM. Org. Synth. 1922; 2: 1
• 16b Montes-Avila J, Díaz-Camacho SP, Sicairos-Félix J, Delgado-Vargas F, Rivero IA. Bioorg. Med. Chem. 2009; 17: 6780
• 17a Zhang M, Jagdmann GE. Jr, Van Zandt M, Beckett P, Schroeter H. Tetrahedron: Asymmetry 2013; 24: 362
• 17b Han Z, Achilonu MC, Kendrekar PS, Joubert E, Ferreira D, Bonnet SL, Van der Westhuizen JH. J. Nat. Prod. 2014; 77: 583
• 17c Hofmann E, Webster J, Do T, Kline R, Snider L, Hauser Q, Higginbottom G, Campbell A, Ma L, Paula S. Bioorg. Med. Chem. 2016; 24: 578
• 18 Smith MB. Organic Synthesis, 3rd ed. Smith MB. Academic Press; Oxford: 2010: 347-490
• 19a Clark-Lewis JW, Skingle DC. Aust. J. Chem. 1967; 20: 2169
• 19b Clark-Lewis JW, Jemison RW. Aust. J. Chem. 1968; 21: 2247
• 20a Zaveri NT. Org. Lett. 2001; 3: 843
• 20b Devakaram R, Black DStC, Andrews KT, Fisher GM, Davis RA, Kumar N. Bioorg. Med. Chem. 2011; 19: 5199
• 21a Lyttle DA, Jensen EH, Struck WA. Anal. Chem. 1952; 24: 1843
• 21b Brown HC, Mead EJ, Subba Rao BC. J. Am. Chem. Soc. 1955; 77: 6209
• 22 Pasumansky L, Goralski CT, Singaram B. Org. Process Res. Dev. 2006; 10: 959
• 23 Yuan H, Bi K.-J, Li B, Yue R.-C, Ye J, Shen Y.-H, Shan L, Jin H.-Z, Sun Q.-Y, Zhang W.-D. Org. Lett. 2013; 15: 4742
• 24 Bulman Page PC, Appleby LF, Chan Y, Day DP, Buckley BR, Slawin AM. Z, Allin SM, McKenzie MJ. J. Org. Chem. 2013; 78: 8074
• 25a Pieterse T. New ring closing metathesis based methodology for the synthesis of monomeric flavonoids, Ph. D. Thesis. University of the Free State; South Africa: 2017: 156-158
• 25b Pieterse T. New ring closing metathesis based methodology for the synthesis of monomeric flavonoids, Ph. D. Thesis. University of the Free State; South Africa: 2017: 180-181
• 26a Adam W, Saha-Möller CR, Zhao C.-G. Organic Reactions, Vol. 61. Wiley; Hoboken: 2002: 219-516
• 26b Waddington VL. Applications and mechanisms of dioxirane oxidations, Ph.D. Thesis. Loughborough University; UK: 1998: 1-45
• 26c Waddington VL. Applications and mechanisms of dioxirane oxidations, Ph.D. Thesis. Loughborough University; UK: 1998: 115-142
• 26d Murray RW, Singh M, Jeyaraman R. J. Am. Chem. Soc. 1992; 114: 1346
• 26e Wang Z.-X, Tu Y, Frohn M, Zhang J.-R, Shi Y. J. Am. Chem. Soc. 1997; 119: 11224
• 27a Adam W, Fell RT, Saha-Möller CR, Zhao C.-G. Tetrahedron: Asymmetry 1998; 9: 397
• 27b Klein S, Roberts SM. J. Chem. Soc., Perkin Trans. 1 2002; 2686
• 28a Adam W, Jekő J, Lévai A, Nemes C, Patonay T, Sebők P. Tetrahedron Lett. 1995; 36: 3669
• 28b Adam W, Fell RT, Lévai A, Patonay T, Peters K, Simon A, Tóth G. Tetrahedron: Asymmetry 1998; 9: 1121
• 28c Lévai A, Adam W, Fell RT, Gessner R, Patonay T, Simon A, Tóth G. Tetrahedron 1998; 54: 13105
• 29a Du Preez IC, Roux DG. J. Chem. Soc. C 1970; 1800
• 29b Benavides A, Bassarello C, Montoro P, Vilegas W, Piacente S, Pizza C. Phytochemistry 2007; 68: 1277
• 29c Van Jaarsveldt J. New methodology for the biomimetic synthesis of flavan-3,4-diols and derivatives, M. Sc. Thesis. University of the Free State; South Africa: 2019: 78-91
• 30a He F, Pan Q.-H, Shi Y, Duan C.-Q. Molecules 2008; 13: 2674
• 30b Robertson AV. Can. J. Chem. 1959; 37: 1946
• 30c Freitas AA, Shimizu K, Dias LG, Quina FH. J. Braz. Chem. Soc. 2007; 18: 1537
• 31 Arterburn JB. Tetrahedron 2001; 57: 9765
• 32 Angelis YS, Hatzakis NS, Smonou I, Orfanopoulos M. Tetrahedron Lett. 2001; 42: 3753
• 33 D’Accolti L, Fusco C, Annese C, Rella MR, Turteltaub JS, Williard PG, Curci R. J. Org. Chem. 2004; 69: 8510
• 34 Adam W, Saha-Möller CR, Zhao C.-G. J. Org. Chem. 1999; 64: 7492
• 35a Clayden J, Greeves N, Warren SG. Organic Chemistry, 2nd ed. Oxford University Press; Oxford: 2012: 439
• 35b Clayden J, Greeves N, Warren SG. Organic Chemistry, 2nd ed. Oxford University Press; Oxford: 2012: 574-575
• 35c Clayden J, Greeves N, Warren SG. Organic Chemistry, 2nd ed. Oxford University Press; Oxford: 2012: 854
• 36 Van Tonder JH. Studies directed at the stereoselective synthesis of flavonoids through the hydrogenation of prochiral precursors, M. Sc. Thesis. University of the Free State; South Africa: 2008: 91-101
• 37 Hayes BL. Microwave Synthesis: Chemistry at the Speed of Light. CEM Pub; Matthews/ NC: 2002: 8-138
• 38 Brown BR, Cummings W, Newbould J. J. Chem. Soc. 1961; 3677
• 39 Gan L, Brook MA. Can. J. Chem. 2006; 84: 1416
• 40 Quiroz-Florentino Hs, Hernández-Benitez RI, Aviña JA, Burgueño-Tapia E, Tamariz J. Synthesis 2011; 1106
• 41 Kohari Y, Hoshino Y, Matsuyama H, Nakano H. Heterocycles 2010; 82: 843
• 42 Pouget C, Fagnere C, Basly J, Leveque H, Chulia A. Tetrahedron 2000; 56: 6047
• 43 Machado AH. L, de Sousa MA, Patto DC. S, Azevedo LF. S, Bombonato FI, Correia CR. D. Tetrahedron Lett. 2009; 50: 1222
• 44 Krohn K, Ahmed I, John M. Synthesis 2009; 779
• 45 Stokes S, Mustain R, Pickle L, Mead KT. Tetrahedron Lett. 2012; 53: 3890
• 46 Ashihara Y, Nagata Y, Kurosawa K. Bull. Chem. Soc. Jpn. 1977; 50: 3298
• 47 Adam W, Chan YY, Cremer D, Gauss J, Scheutzow D, Schindler M. J. Org. Chem. 1987; 52: 2800
• 48 Fujise S, Hishida S, Onuma T, Adachi K, Fujise Y, Munekata T. Bull. Chem. Soc. Jpn. 1962; 35: 1245
• 49 Fujise S, Munekata T, Ishikawa E, Kobayashi T, Sakai I, Ueno M, Yuki T, Hishida S. Nippon Kagaku Zasshi 1963; 84: 81
• 50 Takahashi H, Li S, Harigaya Y, Onda M. J. Nat. Prod. 1988; 51: 730
• 51 Clark-Lewis JW, Jackman LM, Spotswood TM. Aust. J. Chem. 1964; 17: 632
• 52 Clark-Lewis JW. Aust. J. Chem. 1968; 21: 2059
• 53 Jurd L, Lundin R. Tetrahedron 1968; 24: 2653