Download PDF
CC BY 4.0 · Pharmaceutical Fronts 2025; 07(01): e9-e21
DOI: 10.1055/a-2510-4827
Review Article

Recent Advances on Asymmetric Synthesis of Dihydroflavones

Zhihao Du
1   Incubation Center For Science and Technology Achievements, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Guojing Li
1   Incubation Center For Science and Technology Achievements, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Wenhao Dai
1   Incubation Center For Science and Technology Achievements, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Yu Liu
1   Incubation Center For Science and Technology Achievements, China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
› Author Affiliations Funding None.
› Further Information
Also available at
   Permissions and Reprints


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

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • 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
    CrossrefPubMedSearch in Google Scholar
  • 2 Khan MK, Dangles O. A comprehensive review on flavanones, the major citrus polyphenols. J Food Compos Anal 2014; 33 (01) 85-104
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 28 Nibbs AE, Scheidt KA. Asymmetric methods for the synthesis of flavanones, chromanones, and azaflavanones. Eur J Org Chem 2012; 2012 (03) 449-462
    CrossrefPubMedSearch in Google Scholar
  • 29 Yang Q, Guo R, Wang J. Catalytic asymmetric syntheses of 2-aryl chromenes. Asian J Org Chem 2019; 8 (10) 1742-1765
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 32 Meng L, Wang J. Recent progress on the asymmetric synthesis of chiral flavanones. Synlett 2016; 27 (05) 656-663
    Search in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 34 Cao H, Chen X, Jassbi AR, Xiao J. Microbial biotransformation of bioactive flavonoids. Biotechnol Adv 2015; 33 (01) 214-223
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 38 Nayak YN, Gaonkar SL, Sabu M. Chalcones: versatile intermediates in heterocyclic synthesis. J Heterocycl Chem 2023; 60 (08) 1301-1325
    CrossrefSearch in Google Scholar
  • 39 Biddle MM, Lin M, Scheidt KA. Catalytic enantioselective synthesis of flavanones and chromanones. J Am Chem Soc 2007; 129 (13) 3830-3831
    CrossrefPubMedSearch in Google Scholar
  • 40 Liu XB, Huang Y. Recent advances in organic synthesis via synergistic nickel/copper catalysis. Coord Chem Rev 2023; 489: 215173
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 42 Pellissier H. Recent developments in enantioselective nickel-catalysed cycloadditions. Tetrahedron 2024; 153: 133840
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 47 Zhang YL, Wang YQ. Enantioselective biomimetic cyclization of 2′-hydroxychalcones to flavanones. Tetrahedron Lett 2014; 55 (21) 3255-3258
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 57 O'Reilly S, Guiry PJ. Recent applications of C1-symmetric bis (oxazoline)-containing ligands in asymmetric catalysis. Synth 2014; 46 (06) 722-739
    Thieme ConnectSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 61 Zhang Z, Butt NA, Zhang W. Asymmetric hydrogenation of nonaromatic cyclic substrates. Chem Rev 2016; 116 (23) 14769-14827
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 63 Margarita C, Andersson PG. Evolution and prospects of the asymmetric hydrogenation of unfunctionalized olefins. J Am Chem Soc 2017; 139 (04) 1346-1356
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 65 Zhao D, Candish L, Paul D, Glorius F. N-heterocyclic carbenes in asymmetric hydrogenation. ACS Catal 2016; 6 (09) 5978-5988
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    Thieme ConnectSearch in Google Scholar
  • 70 Noda Y, Watanabe M. Synthesis of both enantiomers of flavanone and 2-methylchromanone. Helv Chim Acta 2002; 85 (10) 3473-3477
    CrossrefSearch in Google Scholar
  • 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
    CrossrefSearch in Google Scholar