Recent Advances on Asymmetric Synthesis of Dihydroflavones

Abstract

Dihydroflavones, as an important part of flavonoid compounds, possess a wide range of physiological activities and significant medicinal values. The importance of these compounds has driven the research on the preparation of dihydroflavonoid compounds, and many chiral dihydroflavonoid compounds can be obtained with potential activity, excellent yields, and stereoselectivity using various effective synthetic strategies. This paper reviews the biological activities of single-configuration chiral flavanones and provides a comprehensive overview of the research progress in the asymmetric synthesis of this group of flavonoids from 2002 to 2024, including (1) synthesis from ortho-hydroxy chalcones, (2) synthesis from chromones, (3) asymmetric reduction, (4) intramolecular Mitsunobu and carbene insertion. These methods provide some efficient and economical synthetic strategies for the asymmetric synthesis of flavanones, especially in enantioenriched aspects.

Keywords

enantiomeric activity - chiral dihydroflavone - asymmetric catalysis

Publication History

Received: 23 December 2023

Accepted: 06 January 2025

Article published online:
28 February 2025

• References

• 1 Tao H, Zhao Y, Li L. et al. Comparative metabolomics of flavonoids in twenty vegetables reveal their nutritional diversity and potential health benefits. Food Res Int 2023; 164: 112384
• 2 Khan MK, Dangles O. A comprehensive review on flavanones, the major citrus polyphenols. J Food Compos Anal 2014; 33 (01) 85-104
• 3 Shi S, Li J, Zhao X, Liu Q, Song SJ. A comprehensive review: biological activity, modification and synthetic methodologies of prenylated flavonoids. Phytochemistry 2021; 191: 112895
• 4 Yao L, Li J, Li L. et al. Coreopsis tinctoria Nutt ameliorates high glucose-induced renal fibrosis and inflammation via the TGF-β1/SMADS/AMPK/NF-κB pathways. BMC Complement Altern Med 2019; 19 (01) 14
• 5 El-Desoky AH, Abdel-Rahman RF, Ahmed OK, El-Beltagi HS, Hattori M. Anti-inflammatory and antioxidant activities of naringin isolated from Carissa carandas L.: in vitro and in vivo evidence. Phytomedicine 2018; 42: 126-134
• 6 Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res Int 2018; 25 (21) 20968-20984
• 7 Zhou Z, Fu C. A new flavanone and other constituents from the rhizomes of cyperus rotundus and their antioxidant activities. Chem Nat Compd 2013; 48: 963-965
• 8 Ramalingam M, Kim H, Lee Y, Lee YI. Phytochemical and pharmacological role of liquiritigenin and isoliquiritigenin from radix glycyrrhizae in human health and disease models. Front Aging Neurosci 2018; 10: 348
• 9 Gaur R, Yadav KS, Verma RK, Yadav NP, Bhakuni RS. In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin. Phytomedicine 2014; 21 (04) 415-422
• 10 Caleffi GS, Demidoff FC, Nájera C, Costa PRR. Asymmetric hydrogenation and transfer hydrogenation in the enantioselective synthesis of flavonoids. Org Chem Front 2022; 9 (04) 1165-1194
• 11 Ashatkina MA, Reznikov AN, Klimochkin YN. Intramolecular cyclization of ortho-substituted chalcones in the presence of palladium complexes with chiral bisphosphine ligands. Russ J Org Chem 2022; 58 (05) 710-719
• 12 Gutam M, Mokenapelli S, Yerrabelli JR, Banerjee S, Roy P, Chitneni PR. Synthesis and cytotoxicity of novel (E)-2-phenylchroman-4-one-O-((1-substituted-1H-1,2,3-triazol-4-yl) methyl) oxime derivatives. Synth Commun 2020; 50 (12) 1883-1891
• 13 Mondal R, Gupta AD, Mallik AK. Synthesis of flavanones by use of anhydrous potassium carbonate as an inexpensive, safe, and efficient basic catalyst. Tetrahedron Lett 2011; 52 (39) 5020-5024
• 14 Kumar KH, Perumal PT. A simple and facile solventless procedure for the cyclization of 2′-amino-and 2′-hydroxy-chalcones using silica-supported sodium hydrogen sulphate as heterogenous catalyst. Can J Chem 2006; 84 (08) 1079-1083
• 15 Bera SK, Maharana RR, Samanta K, Mal P. CBr₄ catalyzed activation of α,β-unsaturated ketones. Org Biomol Chem 2022; 20 (35) 7085-7091
• 16 Curti V, Di Lorenzo A, Rossi D. et al. Enantioselective modulatory effects of naringenin enantiomers on the expression levels of miR-17–3p involved in endogenous antioxidant defenses. Nutrients 2017; 9 (03) 215
• 17 Zhang W, Zhang Y, Zhang J, Deng C, Zhang C. Naringenin ameliorates collagen-induced arthritis through activating AMPK-mediated autophagy in macrophages. Immun Inflamm Dis 2023; 11 (10) e983
• 18 Arul D, Subramanian P. Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Pathol Oncol Res 2013; 19 (04) 763-770
• 19 Choi J, Lee DH, Jang H, Park SY, Seol JW. Naringenin exerts anticancer effects by inducing tumor cell death and inhibiting angiogenesis in malignant melanoma. Int J Med Sci 2020; 17 (18) 3049-3057
• 20 Bao L, Liu F, Guo HB. et al. Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway. Tumour Biol 2016; 37 (08) 11365-11374
• 21 Chang HL, Chang YM, Lai SC. et al. Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9. Exp Ther Med 2017; 13 (02) 739-744
• 22 Lu WJ, Ferlito V, Xu C, Flockhart DA, Caccamese S. Enantiomers of naringenin as pleiotropic, stereoselective inhibitors of cytochrome P450 isoforms. Chirality 2011; 23 (10) 891-896
• 23 Gaggeri R, Rossi D, Daglia M. et al. An eco-friendly enantioselective access to (R)-naringenin as inhibitor of proinflammatory cytokine release. Chem Biodivers 2013; 10 (08) 1531-1538
• 24 Liu L, Li XH, Ma XX. et al. ( ± )-Involucrasins A and B, two pairs of flavanone enantiomers from Shuteria involucrata and their inhibitory effects on the proliferation of various cancer cell lines. J Asian Nat Prod Res 2022; 24 (07) 641-647
• 25 Yang J, Lai J, Kong W, Li S. Asymmetric synthesis of sakuranetin-relevant flavanones for the identification of new chiral antifungal leads. J Agric Food Chem 2022; 70 (11) 3409-3419
• 26 Lovering F, Bikker J, Humblet C. Escape from flatland: increasing saturation as an approach to improving clinical success. J Med Chem 2009; 52 (21) 6752-6756
• 27 Demidoff FC, Caleffi GS, Figueiredo M, Costa PRR. Ru (II)-catalyzed asymmetric transfer hydrogenation of chalcones in water: Application to the enantioselective synthesis of flavans bw683c and tephrowatsin E. J Org Chem 2022; 87 (21) 14208-14222
• 28 Nibbs AE, Scheidt KA. Asymmetric methods for the synthesis of flavanones, chromanones, and azaflavanones. Eur J Org Chem 2012; 2012 (03) 449-462
• 29 Yang Q, Guo R, Wang J. Catalytic asymmetric syntheses of 2-aryl chromenes. Asian J Org Chem 2019; 8 (10) 1742-1765
• 30 Chinnabattigalla S, Dakoju RK, Gedu S. Recent advances on the synthesis of flavans, isoflavans, and neoflavans. J Heterocycl Chem 2021; 58 (02) 415-441
• 31 Zhang C, Liu Y, Liu X, Chen X, Chen R. Comprehensive review of recent advances in chiral a-ring flavonoid containing compounds: structure, bioactivities, and synthesis. Molecules 2023; 28 (01) 365
• 32 Meng L, Wang J. Recent progress on the asymmetric synthesis of chiral flavanones. Synlett 2016; 27 (05) 656-663
• 33 de Matos IL, Birolli WG, Santos DdA, Nitschke M, Porto ALM. Stereoselective reduction of flavanones by marine-derived fungi. Mol Catal 2021; 513: 111734
• 34 Cao H, Chen X, Jassbi AR, Xiao J. Microbial biotransformation of bioactive flavonoids. Biotechnol Adv 2015; 33 (01) 214-223
• 35 Bartmańska A, Tronina T, Popłoński J, Huszcza E. Biotransformations of prenylated hop flavonoids for drug discovery and production. Curr Drug Metab 2013; 14 (10) 1083-1097
• 36 Zhou K, Yang S, Li SM. Naturally occurring prenylated chalcones from plants: structural diversity, distribution, activities and biosynthesis. Nat Prod Rep 2021; 38 (12) 2236-2260
• 37 Lee JH, Jeong DY, Jung SY, Lee S, Park KW, Ku JM. Cu (II)-mediated chalcone synthesis via α-bromocarbonyl intermediate: a one-step synthesis of echinatin. Curr Org Chem 2017; 21 (07) 652-658
• 38 Nayak YN, Gaonkar SL, Sabu M. Chalcones: versatile intermediates in heterocyclic synthesis. J Heterocycl Chem 2023; 60 (08) 1301-1325
• 39 Biddle MM, Lin M, Scheidt KA. Catalytic enantioselective synthesis of flavanones and chromanones. J Am Chem Soc 2007; 129 (13) 3830-3831
• 40 Liu XB, Huang Y. Recent advances in organic synthesis via synergistic nickel/copper catalysis. Coord Chem Rev 2023; 489: 215173
• 41 Goldfogel MJ, Guo X, Meléndez Matos JL. et al. Advancing base-metal catalysis: development of a screening method for nickel-catalyzed Suzuki–Miyaura reactions of pharmaceutically relevant heterocycles. Org Process Res Dev 2021; 26 (03) 785-794
• 42 Pellissier H. Recent developments in enantioselective nickel-catalysed cycloadditions. Tetrahedron 2024; 153: 133840
• 43 Chen M, Gu YW, Deng W, Xu ZY. Mechanism and origins of regio-and stereoselective alkylboration of endocyclic olefins enabled by nickel catalysis. J Org Chem 2023; 88 (19) 14115-14130
• 44 Wang L, Liu X, Dong Z, Fu X, Feng X. Asymmetric intramolecular oxa-Michael addition of activated α,β-unsaturated ketones catalyzed by a chiral N,N′-dioxide nickel(II) complex: highly enantioselective synthesis of flavanones. Angew Chem Int Ed Engl 2008; 47 (45) 8670-8673
• 45 Wang HF, Xiao H, Wang XW, Zhao G. Tandem intramolecular oxa-Michael addition/decarboxylation reaction catalyzed by bifunctional cinchona alkaloids: facile synthesis of chiral flavanone derivatives. Tetrahedron 2011; 67 (30) 5389-5394
• 46 Hintermann L, Dittmer C. Asymmetric ion-pairing catalysis of the reversible cyclization of 2′-hydroxychalcone to flavanone: asymmetric catalysis of an equilibrating reaction. Eur J Org Chem 2012; 2012 (28) 5573-5584
• 47 Zhang YL, Wang YQ. Enantioselective biomimetic cyclization of 2′-hydroxychalcones to flavanones. Tetrahedron Lett 2014; 55 (21) 3255-3258
• 48 Korenaga T, Hayashi K, Akaki Y, Maenishi R, Sakai T. Highly enantioselective and efficient synthesis of flavanones including pinostrobin through the rhodium-catalyzed asymmetric 1,4-addition. Org Lett 2011; 13 (08) 2022-2025
• 49 Han F, Chen G, Zhang X, Liao J. Chiral heterodisulfoxide ligands in rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to chromenones. Eur J Org Chem 2011; 2011 (16) 2928-2931
• 50 He Q, So CM, Bian Z, Hayashi T, Wang J. Rhodium/chiral diene-catalyzed asymmetric 1,4-addition of arylboronic acids to chromones: a highly enantioselective pathway for accessing chiral flavanones. Chem Asian J 2015; 10 (03) 540-543
• 51 Yang Z, Yu JT, Pan C. Recent advances in rhodium-catalyzed C(sp²)-H (hetero)arylation. Org Biomol Chem 2021; 19 (39) 8442-8465
• 52 Ge R, Herington F, Mangawang A, Maiti D, Ge H. Palladium (II)-catalyzed cascade reactions initiated with directed activation of unactivated sp3 C–H bonds. Tetrahedron Chem 2023; 7: 100046
• 53 Yuen OY, Ng SS, Pang WH, So CM. Palladium-catalyzed chemoselective Suzuki–Miyaura cross-coupling reaction of poly (pseudo) halogenated arenes. J Organomet Chem 2024; 1005: 122983
• 54 Ramos ITL, Silva RJM, Silva TMS, Camara CA. Palladium-catalyzed coupling reactions in flavonoids: a retrospective of recent synthetic approaches. Synth Commun 2021; 51 (23) 3520-3545
• 55 Holder JC, Marziale AN, Gatti M, Mao B, Stoltz BM. Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to heterocyclic acceptors. Chemistry 2013; 19 (01) 74-77
• 56 Tamura M, Ogata H, Ishida Y, Takahashi Y. Design and synthesis of chiral 1,10-phenanthroline ligand, and application in palladium catalyzed asymmetric 1,4-addition reactions. Tetrahedron Lett 2017; 58 (40) 3808-3813
• 57 O'Reilly S, Guiry PJ. Recent applications of C1-symmetric bis (oxazoline)-containing ligands in asymmetric catalysis. Synth 2014; 46 (06) 722-739
• 58 Patterson JP, Cotanda P, Kelley EG. et al. Catalytic Y-tailed amphiphilic homopolymers - aqueous nanoreactors for high activity, low loading SCS pincer catalysts. Polym Chem 2013; 4 (06) 2033-2039
• 59 Lestini E, Blackman LD, Zammit CM. et al. Palladium-polymer nanoreactors for the aqueous asymmetric synthesis of therapeutic flavonoids. Polym Chem 2018; 9 (07) 820-823
• 60 Zhou L, Qiu J, Wang M, Xu Z, Wang J, Chen T. Fabrication of nanoreactors based on end-functionalized polymethacrylate and their catalysis application. J Inorg Organomet Polym Mater 2020; 30: 4569-4577
• 61 Zhang Z, Butt NA, Zhang W. Asymmetric hydrogenation of nonaromatic cyclic substrates. Chem Rev 2016; 116 (23) 14769-14827
• 62 Koy M, Bellotti P, Das M, Glorius F. N-Heterocyclic carbenes as tunable ligands for catalytic metal surfaces. Nat Catal 2021; 4 (05) 352-363
• 63 Margarita C, Andersson PG. Evolution and prospects of the asymmetric hydrogenation of unfunctionalized olefins. J Am Chem Soc 2017; 139 (04) 1346-1356
• 64 Zhao D, Beiring B, Glorius F. Ruthenium-NHC-catalyzed asymmetric hydrogenation of flavones and chromones: general access to enantiomerically enriched flavanones, flavanols, chromanones, and chromanols. Angew Chem Int Ed Engl 2013; 52 (32) 8454-8458
• 65 Zhao D, Candish L, Paul D, Glorius F. N-heterocyclic carbenes in asymmetric hydrogenation. ACS Catal 2016; 6 (09) 5978-5988
• 66 Lemke MK, Schwab P, Fischer P. et al. A practical access to highly enantiomerically pure flavanones by catalytic asymmetric transfer hydrogenation. Angew Chem Int Ed Engl 2013; 52 (44) 11651-11655
• 67 Ashley ER, Sherer EC, Pio B, Orr RK, Ruck RT. Ruthenium-catalyzed dynamic kinetic resolution asymmetric transfer hydrogenation of β-chromanones by an elimination-induced racemization mechanism. ACS Catal 2017; 7 (02) 1446-1451
• 68 Ma Y, Li J, Ye J, Liu D, Zhang W. Synthesis of chiral chromanols via a RuPHOX-Ru catalyzed asymmetric hydrogenation of chromones. Chem Commun (Camb) 2018; 54 (96) 13571-13574
• 69 Ren X, Han C, Feng X, Du H. A borane-catalyzed metal-free hydrosilylation of chromones and flavones. Synlett 2017; 28 (18) 2421-2424
• 70 Noda Y, Watanabe M. Synthesis of both enantiomers of flavanone and 2-methylchromanone. Helv Chim Acta 2002; 85 (10) 3473-3477
• 71 Han F, Choi PH, Ye CX. et al. Cyclometalated chiral-at-ruthenium catalyst for enantioselective ring-closing C (sp3)–H carbene insertion to access chiral flavanones. ACS Catal 2022; 12 (16) 10304-10312