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

Introduction

Dihydroflavone ([Fig. 1]), also called flavanone, is the product of the 2,3-double bond hydrogenation reduction of flavone.[1] They are widely distributed in nature and possess a chiral center at position 2 of the B ring, making the compounds chiral molecules.[2] Flavonoids account for the largest proportion of plant secondary metabolites and exhibit diverse physiological and pharmacological activities, holding a significant position in both natural products and synthesis.[3] However, due to the generally low content of dihydroflavone compounds in plant tissues and the difficulty in isolating and purifying them, research related to dihydroflavones is relatively limited.

Fig. 1 Dihydroflavone or flavanone.

Dihydroflavone compounds possess various physiological activities including antitumor effects, immune activity, anti-inflammatory, antiapoptosis,[4] [5] [6] and antioxidative effects, and low toxic side effects, and therefore have a significant pharmaceutical value.[7] In isomer's study of dihydroflavonoids, isomer-specific pharmacological properties have been identified attributing to their different but highly similar intrinsic structures.[8] For example, in comparison to liquiritigenin, isoliquiritigenin isolated from the root of Glycyrrhiza uralensis Fisch, performed better in different pharmacological evaluations.[9] However, due to the low natural abundance of dihydroflavone compounds and the challenge of the purification process, the organic synthesis of dihydroflavone compounds has become increasingly important, especially in terms of enantiomerically enriched asymmetric synthesis.[10]

The classical synthesis methods of dihydroflavones involve the cyclization reaction of chalcones in the presence of hydrochloric acid or sodium hydroxide in alcoholic solutions.[11] [12] However, these methods usually suffer from a long cyclization time and low yield. Subsequent studies by Mondal, Kumar, Bera, and others significantly shortened the reaction time and improved the reaction yield through catalyst optimization and exploration of reaction conditions ([Scheme 1]).[13] [14] [15] Noticeably, these reactions resulted in racemic compounds and further exploration of the chiral aspect at the 2-position of dihydroflavone compounds has not been conducted.

Naringenin ([Fig. 1]) exists in aglycone forms in vegetables and fruits and as either of the two enantiomers (R and S), but in nature, it occurs primarily in the form of the S-enantiomer. However, both enantiomers exhibit biological activities in antioxidant and antitumor properties.[16] [17] In 2013, Arul and Subramanian discovered that naringenin inhibited the growth of human liver cancer cells and possesses the ability to interfere with the cell cycle.[18] With further research, the compound also inhibited the proliferation and migration of human gastric cancer cells (SGC-7901) and human melanoma cells (B16F10 and SK-MEL-28).[19] [20] A recent study also suggested that naringenin induces apoptosis of A549 lung cancer cells through the activation of the caspase-3 cascade.[21] The inhibitory effects of naringenin enantiomers on four subtypes of CYP450 were first investigated by Lu et al.[22] As inhibitors of CYP19 and CYP2C19, the (S)-enantiomer was approximately twice as potent as the (R)-enantiomer. In contrast, as inhibitors of CYP2C9 and CYP3A, the (R)-enantiomer is approximately twice as potent as the (S)-enantiomer. In each case, the IC₅₀ value of racemic naringenin was between those of the (R)- and (S)-enantiomers. The enantioselective evaluation of the anti-inflammatory effects of naringin was studied by Gaggeri et al,[23] and the biological results clearly showed that (R)-naringenin, as a eutomer, exerted a higher effect than the (S)-enantiomer at nontoxic doses.

Liu et al[24] isolated involucrasins ([Fig. 1]) from the extract of Shuteria involucrata and obtained two pairs of flavanone enantiomers (R = OMe and OH). They found that when R = OMe, different enantiomers showed different antiproliferative activities on HCT116, Caco-2, and MCF-7 cancer cell lines.

A preliminary screening of the antifungal activity of exocyclic racemic dihydroflavones was conducted by Yang et al.[25] The roles of substituents in A and C fragments and the chiral effects at the 2-position were also investigated, through the validation of EC₅₀ values. The results showed that dihydroflavone compounds with different configurations and racemates exhibited different antifungal activities under the same substituent conditions. The antifungal activities of different substituents were significantly different ([Table 1]). From the above examples, it is clear that the importance of the absolute stereostructure of flavanones is gradually being recognized and reported in biomedical literature. Therefore, it is important to study the configuration of the 2-position chiral center in terms of drug action.

Table 1 EC₅₀ values of different flavanones against Rhizoctonia solani [25]

Compd.	EC50	Compd.	EC50	Compd.	EC50
rac-1	>100	(S)-8	8.2	(R)-17	66.8
(R)-1	15.6	rac-9	37.9	rac-18	15.1
rac-2	36.8	(R)-9	52.8	(R)-18	40.8
(R)-2	46.3	rac-10	>100	rac-19	44.1
rac-3	18.6	(R)-10	56.9	(R)-19	>100
(R)-3	7.0	rac-11	17.6	rac-20	46.3
(S)-3	14.5	(R)-11	60.2	(R)-20	145.7
rac-4	6.5	(S)-11	>100	rac-21	5.1
(R)-4	15.8	rac-12	50.1	(R)-21	31.8
(S)-4	16.3	(R)-12	66.9	rac-22	63.0
rac-5	15.6	rac-13	>100	(R)-22	>100
(R)-5	16.8	(R)-13	11.4	rac-23	4.7
(S)-5	24.4	(S)-13	>100	(R)-23	18.5
rac-6	27.5	rac-14	>100	rac-24	1.9
(R)-6	16.3	(R)-14	30.9	(R)-24	0.8
(S)-6	16.3	rac-15	37.7	(S)-24	3.1
rac-7	72.5	(R)-15	69.2	rac-25	11.9
(R)-7	45.1	rac-16	>100	(R)-25	14.9
rac-8	28.9	(R)-16	31.7	rac-26	19.2
(R)-8	7.4	rac-17	>100	(R)-26	8.4

The “escape from flatland” proposed by Lovering et al[26] has influenced the concept of molecular design for medicinal chemists, demonstrating the importance of the chiral effects in pharmaceutical science. However, the chirality and biological activity of flavanones-type compounds have been less studied, mainly due to the difficulty of obtaining both enantiomeric forms, especially the non-natural configurations. Until the early 2000s, it was possible to prepare (R) and (S) flavonoid compounds by enzymatic resolution of racemic compounds or chemical cleavage. Another method is using substrates with chiral auxiliaries for inter- or intramolecular conjugate addition as well as asymmetric hydrogenation reactions to produce chalcones and their analogs with high enantiomeric excess (ee) values.[27] [28] [29] Furthermore, through the selection and application of transition metals and corresponding ligands, metal-catalyzed enantioselective arylation has become the most efficient and convenient method for the asymmetric synthesis of flavonoid compounds.[30] [31] [32] In recent years, with the development of synthetic biology, enzymes or microorganisms with high catalytic activity and selectivity have been discovered, making the specific synthesis of optically active flavonoid compounds possible.[33] [34] [35]

Currently, due to the limited research on the stereoisomeric configurations of dihydroflavones, asymmetric synthesis of dihydroflavones by biological methods is less reported. In this paper, we review the latest progress in the stereoselective synthesis of dihydroflavone compounds by chemical synthesis, aiming to provide a theoretical basis for the asymmetric synthesis of dihydroflavone compounds and structural design modification in subsequent studies.

The synthetic methods of flavanone-type compounds are mainly divided into the following categories: (1) synthesis from ortho-hydroxy chalcones, (2) synthesis from chromones, (3) asymmetric reduction, (4) intramolecular Mitsunobu rearrangement, and (5) intramolecular C–H insertion of carbene generated from α-diazo ketones.

Synthesized from ortho-Hydroxy Chalcones

Chalcones are a class of compounds characterized by aromatic rings and a ketone functional group. They are found in many natural plants, especially common in leguminous plants, and belong to the flavonoid class of compounds.[36] Their structure includes an α,β-unsaturated ketone group and therefore significant intermediates in the synthesis of organic compounds.[37] [38] Dihydroflavones are usually synthesized by an intramolecular Michael addition of a neighboring hydroxy group in the A ring and the α,β-unsaturated ketone, forming a C–O bond and introducing a chiral center. This often requires chiral catalysts for asymmetric induction. However, when the substrate contains an ester group, the products of the addition reaction need to be hydrolyzed and decarboxylated under acidic conditions and at high temperatures, and thus, the tolerance of the substrate is a great challenge for this method.

In 2007, Biddle et al[39] reported a method wherein a bifunctional quinine-derived thiourea L1 catalyzed the activation of the conjugate addition of phenolic hydroxyl groups to α-ketoester enolates (27) to produce the enantioenriched dihydroflavones (28). The target product is obtained through a two-step process involving an intramolecular O-Michael addition followed by decarboxylation under acidic conditions. The introduction of tert-butyl ester groups enhances the reactivity of the coupling receptor while minimizing the elimination of chalcones. The interaction between the quinoline ring nitrogen and the phenol promotes selective intramolecular conjugate addition. Importantly, the functional groups of tertiary amine and thiourea together provide high selectivity within a single catalyst. The addition reaction occurred at a lower temperature, reducing the occurrence of elimination reactions that produce flavonoid compounds. The reaction yield ranges from 65 to 94%, with a high ee value (80–94%) for the R configuration. This reaction demonstrated a certain degree of applicability to substrates ([Scheme 2]).

Scheme 1 Representative route for the synthesis of dihydroflavones.

Scheme 2 Quinine-derived thiourea-catalyzed intramolecular oxa-Michael addition.

Nickel complexes, especially chiral nickel complexes, have been widely used in catalyzing organic synthesis.[40] [41] [42] [43] In 2008, Wang et al[44] reported a method for the asymmetric synthesis of dihydroflavones using α-ester-substituted ortho-hydroxy chalcones as substrates ([Scheme 3]). Through screening of nickel ligands, a three-carbon linker L2 ligand derived from proline was screened, and under the conditions of this ligand, a series of products were obtained by screening a variety of common substituents on the C-ring, with yields of 90 to 99% and ee values of 80 to 98% for the R configuration. The method is characterized by a broad substrate scope, tolerance to air and moisture, low catalyst loading, and an enantioselectivity of up to 99%, making it an attractive approach for obtaining chiral dihydroflavones. However, the authors did not conduct further investigation into the mechanism of this catalytic system.

Scheme 3 Nickel(II)-catalyzed intramolecular oxa-Michael addition.

In 2011, Wang et al[45] catalyzed the intramolecular Michael addition of α-acetoxy chalcones 31 using cinchona alkaloid catalysts L3, followed by decarboxylation to prepare chiral dihydroflavones 32. The reaction conditions were mild, with good yields and excellent S enantiomeric ee values ([Scheme 4]). This method had good substrate suitability for the synthesis of a wide range of chiral dihydroflavone compounds. Further investigation revealed that the reaction time should be shortened when R is an electron-withdrawing group since prolonging the reaction time will decrease the ee value. Although this method facilitates the generation of chiral flavone derivatives, the practicality is still limited by the fact that the consumption of quinidine is over 20 mol% and reaction times exceed 16 hours. This paper also proposed the use of α-keto esters, instead of ortho-hydroxy chalcones, which will provide an indirect solution for the asymmetric synthesis of flavanones, whereas direct asymmetric cyclization has been attempted but not yet successful.

Scheme 4 Cinchona alkaloid-catalyzed intramolecular Michael addition and degreasing reactions.

In 2012, Hintermann and Dittmer[46] reported an asymmetric mechanism for the cyclization of 2-hydroxy chalcones 33 into dihydroflavones 34 using cinchona alkaloids L4 as a chiral agent ([Scheme 5]). The group constructed a model resembling dihydroflavone isomerase, showcasing the kinetics of the asymmetric catalytic reaction and revealing the challenges of asymmetric catalysis in near-equilibrium reversible reactions. The group obtained the dihydroflavone compounds with a yield of 71% and an ee value of 80% for the R configuration, thereby validating the model.

Scheme 5 Asymmetric synthesis of dihydroflavones.

In 2014, Zhang and Wang[47] reported the asymmetric synthesis of dihydroflavones 36 from chalcones 35 using L-proline-derived L5 as a chiral catalyst, demonstrating the potential of the catalyst in the cyclization of a-Michael addition ([Scheme 6]). The catalyst stereoselectively activates both the enone and phenol hydroxyl groups by simultaneously forming an iminium ion intermediate and hydrogen bonding, directing the oxygen nucleophile to attack the double bond's Si face, thereby forming the product. The enantioselectivity of the reaction can be enhanced by the addition of 4-chlorobenzoic acid. Under this reaction condition, the dihydroflavone compounds could be achieved from a series of substrates, with yields of 83 to 99%, and ee values of 55 to 82% for the S configuration. However, the catalytic efficiency of this reaction is not very high, as indicated by a reaction time of 72 hours and a catalyst use of 20 mol%.

Scheme 6 L-proline derivatives-catalyzed intramolecular oxa-Michael addition.

Synthesis from Chromone

C–C bond coupling via transition metal-catalyzed 1,4-addition of chalcones with arylboronic acid compounds is one of the most efficient and straightforward methods for the asymmetric synthesis of dihydroflavones. This method yields dihydroflavone with high enantiomeric purity and can be widely used for the preparation of the derivatives of dihydroflavones.

In 2011, Korenaga et al[48] developed a rhodium-catalyzed symmetric addition using chromone 37 as substrate, [RhOH(cod)]₂ in conjunction with a chiral ligand L6 as asymmetric reaction catalysis ([Scheme 7]). This method ensured enantioselectivity while avoiding ring-opening under basic conditions. Further solvent screening and catalyst loading optimization effectively suppressed the formation of 1,2-addition products, leading to 1,4-addition product 38 in good yields (>80%) and high ee values (≥99%) for the S configuration. Additionally, for the first time, the group demonstrated the practicality of this method by catalyzing the synthesis of both (S)- and (R)-pinostrobin. This method allows convenient preparation of biologically active chiral dihydroflavones using commercially available chalcones and arylboronic acids.

Scheme 7 Rh-catalyzed asymmetric addition of chromones.

In 2011, Han et al[49] developed a new chiral heterodithio ligand L7, which catalyzed the addition of arylboronic acids to chalcones 40, in the presence of rhodium to generate flavanones 41 ([Scheme 8]). The reaction is characterized by mild conditions and high optical activity (ee value of 92–95% for the R configuration), but the yields were low, typically in the range of 35 to 70%.

Scheme 8 Rh-catalyzed asymmetric addition of arylboronic acids to chromones.

He et al[50] demonstrated the feasibility of chiral diene ligands in Rh-catalyzed 1,4-addition of arylboronic acids to chalcones ([Scheme 9]). The group identified (R,R)-Ph-bod (L8) as the most suitable ligand and KOH (5 equiv.) as a base for the reaction. The group also investigated the types and positions of substituents on the aromatic rings of compounds 43 and 42, leading to a series of substrates, with yields of 70 to 80% and ee values exceeding 97% for the R configuration. This demonstrated the excellent enantioselectivity of the catalytic system and its wide applicability to substrates. Moreover, no competitive side reactions such as 1,2-addition or ring-opening induced by strong bases were observed in this catalytic system.

Scheme 9 Rhodium-catalyzed asymmetric 1,4-addition of ArB(OH)₂ to chromones.

Although rhodium-catalyzed nonenantioselective additions of arylboronic acids to chalcones have been repeatedly reported, these methods are often limited by the high cost of catalysts, relatively high catalyst dosage, or the challenging and inconvenient handling of chiral ligands.[51] Therefore, it is crucial to establish and utilize practical and convenient asymmetric palladium catalysts to provide modular synthetic pathways. Palladium catalysis plays a pivotal role in aromatic coupling reactions. Palladium, as a transition metal catalyst, facilitates the formation of carbon–carbon bonds in aromatic coupling reactions. Its outstanding catalytic performance, selectivity, and activity make it one of the ideal catalysts for numerous chemical reactions. It plays a crucial role in achieving efficient and environmentally friendly chemical synthesis processes. Therefore, it is important to establish and apply practical and convenient asymmetric palladium catalysts to provide modular synthesis pathways.[52] [53] [54]

In 2013, Holder et al[55] reported for the first time the enantioselective conjugate addition of arylboronic acids to heterocyclic conjugate acceptors derived from chromones and 4-quinolones ([Scheme 10]). The group utilized the (S)-t-BuPd/PyOX L9-catalyzed system to perform the asymmetric conjugate addition of chromone 45 and arylboronic acid 46, obtaining flavanones 47 with moderate to excellent yields (83–96%) and high enantioselectivity (60–98% ee). The reaction system has high functional group tolerance as compared with other systems. Additionally, the reaction is characterized by a single and easily prepared catalyst system, high substrate applicability, and good tolerance to moisture and air, enabling it an efficient method to synthesize flavanones 47 with free hydroxyl groups.

Scheme 10 Palladium-catalyzed asymmetric addition of arylboronic acids to chromones.

Tamura et al[56] described the synthesis of chiral 1,10-phenanthrolines, and its use as a ligand in the palladium-catalyzed asymmetric 1,4-addition of phenylboronic acid to enones ([Scheme 11]). The group designed and synthesized the chiral phenanthroline ligand L10, and screened the solvent, temperature, and reaction time to optimize the reaction conditions. Under these conditions, (R)-2-phenylchroman-4-one 50 was produced with a yield of 96% and ee value of 97% using 48 and 49 as substrates, demonstrating the high efficiency of the catalyst. Additionally, a plausible mechanism of the asymmetric catalytic addition after the binding of Pd with the ligand was also proposed by the group ([Scheme 11]).

Scheme 11 Palladium-catalyzed asymmetric addition of phenylboronic acid to 4H-chromen-4-one.

Yang et al[25] have developed a new palladium catalytic system with CarOx-type ligand L11 via modification of PyOx-type ligands. The system enabled the highly enantioselective addition of arylboronic acids 52 to chromone 51 ([Scheme 12]). They modified the substituents on both chalcones and aromatic boronic acids and conducted a series of addition reaction studies to obtain various dihydroflavonoid compounds 53. They found that the changes in the type and position of the substituents have an unpredictable effect on the reaction yields, fluctuating between 15 and 97%. However, for the R configuration, the ee values were almost always greater than 80%, indicating that the reaction is highly optically isomerizable.

Scheme 12 Palladium- and CarOx ligand-catalyzed asymmetric addition of arylboronic acids to chromones.

Catalysis in nanoreactors is usually more effective than traditional heterogeneous catalysis due to the increased local concentration of reagents within nanoreactors, enhanced catalytic stability, and the effects of confinement, leading to improved selectivity or specificity in molecular recognition and increased reaction rates. In some cases, it allows for the recycling of catalysts.[57] [58] Lestini et al[59] synthesized amphiphilic diblock copolymers of Pd-PyOx chiral catalysts and assembled them into nanoreactors L12 ([Fig. 2]) for asymmetric addition reactions of arylboronic acids in water. This method reduced the amount of Pd catalysts to 0.5 mol%, achieving a yield of around 95% yield and an ee value of approximately 80% for the R configuration.

Fig. 2 Pd-PyOx nanoreactor.

Zhou et al[60] synthesized the temperature-sensitive polymer POEGMA₃₆-PyOx with terminal chiral oxazoline ligands L13 ([Fig. 3]), which was coordinated with palladium trifluoroacetate. With a low loading of palladium at 0.5 mol%, the system achieved the dihydroflavonoid compounds with a yield of 98% and an ee value of 82% for the R configuration. Moreover, the catalyst's thermosensitive properties could be exploited for its recovery.

Fig. 3 POEGMA₃₆-PyOx-Pd(II).

Asymmetric Reduction of Flavonoids

Asymmetric hydrogenation has become an effective method for the preparation of chiral compounds.[61] [62] [63] Asymmetric hydrogenation of flavones is characterized by high atom economy and ease of operation and also facilitates the synthesis of dihydroflavones from flavonoid compounds extracted from natural products. Currently, both transition metal catalysis and nontransition metal catalysis have been reported in asymmetric hydrogenation synthesis of dihydroflavones.

In 2013, Zhao et al[64] synthesized dihydroflavonoid compounds 56 by asymmetric hydrogenation of flavonoid compounds 54 ([Scheme 13]). They conducted the reaction by stirring Ru(cod)(2-methylallyl)₂, NHC ligand L14, and t-BuKO in hexane for 16 hours, followed by the addition of substrate and toluene. Hydrogenation was performed at 5 to 25°C for 36 hours under 120 to 150 bar of H₂. Under these reaction conditions, flavonols 55 were formed. An additional oxidative procedure using pyridinium chlorochromate (PCC) as the oxidant was required to obtain the desired flavanones. This transformation provided the corresponding flavanones 56 without compromising the integrity of the newly formed stereocenter at C2. Through this procedure, (S)-configured dihydroflavones have been efficiently prepared with yields of 88 to 95% and ee values of 78 to 91%. This method offered a viable route for the conversion of flavonoid compounds into dihydroflavonoid compounds.

Scheme 13 Rubidium-catalyzed asymmetric hydrogenation of flavonoids.

Years later, these catalysts were widely used for asymmetric hydrogenation of various substrates.[65] The catalytic system based on ruthenium and chiral NHC ligands L14 can be used for the highly enantioselective hydrogenation of 10 different heterocycles. The catalytic system was proved to be equally effective by asymmetric hydrogenation of hexahydroxyflavonoid compounds. The dihydroflavone with different substituents on the C ring exhibits enantioselectivity (up to 98%) and a good diastereomeric ratio (5:1).

Also in 2013, Metz et al reported the enantioselective synthesis of natural flavanones 59 using asymmetric transfer hydrogenation (ATH) as a key step through a kinetic resolution of the corresponding racemates 57 ([Scheme 14]).[66] In the screening process, a mixture of formic acid and triethylamine was used to generate in situ the rhodium metal precursor and monophenylated diamine ligand. Following the conditions for conversion to catalytically active metal hydride species (R,R)CT-L15 under transfer hydrogenation conditions, the ATH reactions with various flavonol derivatives 58 were conducted at 2 mol% (R,R)CT-L15. This resulted in the reduction and cleavage of multiple flavanone derivatives, with the ketones and alcohols separating in good yields and high ee values. According to the different substrates, partial reactions could significantly reduce the catalyst loading to 0.2 mol%, yielding flavanone derivatives with a 99% ee value. Through ATH and dynamic resolution under this system, nearly enantiomerically pure flavanones could be obtained in high yield.

Scheme 14 Rhodium-catalyzed asymmetric transfer hydrogenation of flavanone.

In 2017, Ashley et al reported the dynamic kinetic resolution of β-substituted chromanones through rhodium-catalyzed ATH,[67] with flavonoids included in the scope of the reaction ([Scheme 15] ). Inspired by Metz's rhodium-catalyzed ATH–KR of flavanones, the group found that 8-diazabicyclo [5.4.0]-undec-7-ene instead of trimethylamine as a base allowed for reduction more efficiently at lower loadings and achieved higher enantioselectivity. Various Noyori-type rhodium catalysts performed well in combination with TsDENEB ligands. When racemic flavonoid 60 was used as a substrate, the reaction catalyzed by 0.5 mol% of the L16 catalyst gave the trans-alcohol (S,S) 61 in a yield of 82% with excellent diastereoselectivity and enantioselectivity (94:6 syn/anti, 99% ee). Further oxidation of these trans-alcohols yielded the corresponding flavonoid compounds with a single stereoisomer. Although exploration within the reaction scope mainly focused on β-alkyl substituted compounds rather than derivatives of flavonoid compounds, the method still holds great potential for the asymmetric synthesis of flavonoids.

Scheme 15 Rubidium-catalyzed asymmetric transfer hydrogenation of flavanones.

In 2018, Ma et al reported the asymmetric hydrogenation of chromanones for the synthesis of chiral chromanones using RuPHOX-Ru L17 as a catalysis system ([Scheme 16A]).[68] The optimal reaction condition was screened using methanol as the solvent, sodium carbonate as the base, and 20 bar of hydrogen pressure. Under these conditions, hydrogenation of flavonoid substrates 62 was conducted, yielding a series of chiral chromanones 63 and their derivatives with high yields (95–99%) and high stereoselectivity. Investigation of the reaction mechanism showed that the hydrogenation initially occurred at the C = C bond followed by the C = O double bond. Furthermore, it was demonstrated that the products could be quantitatively oxidized by PCC to optically active flavanones, as exemplified by the transformation of chromanol 63a to dihydroflavonoid 64 under conditions where the product is not racemic ([Scheme 16B]).

Scheme 16 (A) RuPHOX-Ru-catalyzed asymmetric hydrogenation. (B) Chromanol transformation.

Ren reported the preparation of dihydroflavones 66 by asymmetric hydrogenation of flavones 65,[69] achieving the Piers-type hydrosilylation of flavones for the first time ([Scheme 17]). This was achieved by in situ generation of dihydroborane through hydroboration of pentafluorostyrene and HB(C₆F₅)₂, delivering dihydroflavonoid compounds with high yields (94–99%). The reaction was poorly enantioselective, with ee values of 11 to 17% for the R configuration. This provided a new avenue of research for the reduction of dihydroflavonoid compounds with nonmetal catalysts.

Scheme 17 Metal-free catalyzed asymmetric hydrogenation of flavonoids.

Other Synthesis Methods

In 2002, Noda and colleagues reported the asymmetric synthesis of flavonoids using 2-hydroxybenzaldehyde 67 as a starting material ([Scheme 18]).[70] 67 was condensed with propane-1,3-dithiol to give the 1,3-dithiane derivative 68 followed by the ring-opening of optically active epoxides and Mitsunobu cyclization and desulfurization to yield the optically pure dihydroalkanone compounds 71. The reaction consisted of four steps, making it quite complex, with an overall yield of approximately 25%. This protocol relied on chiral epoxide compounds and could be considered at that time as a substrate adaptive method for the synthesis of dihydroflavonoid compounds.

Scheme 18 Enantioselective synthesis of enantiomers of flavanone.

In 2022, Han and colleagues prepared a novel cyclical chiral ruthenium catalyst, which was used for enantioselective ring-closing reactions ([Scheme 19A]).[71] The catalyst employs nonchiral ligands, deriving chirality solely from the stereocenter of Ru, and catalyzes the cyclization of diazoketones through C(sp3) − H carbene insertion, leading to the generation of R-configured flavanones with high yields (up to 99%) and high ee (up to 96% ee). The catalyst also avoided the formation of oxirane ylide intermediates in the reaction process, preventing [1,2]-shift and suppressing the generation of by-product benzo-furanone skeletal 74 ([Scheme 19B]).

Scheme 19 (A) Enantioselective ring-closing C (sp³) − H carbene insertion to access chiral flavanones. (B) [1,2]-shift from oxonium ylide intermediate.

Conclusion

Dihydroflavones are a class of organic compounds with broad biological activity, holding significant value in fields such as pharmaceuticals, natural product synthesis, and materials science. Research and development of asymmetric synthesis methods for dihydroflavones have been a focal point in the field of organic synthesis. Over the past two decades, significant progress has been made in improving and optimizing methods for the asymmetric synthesis of dihydroflavones. Researchers have employed various catalytic systems and chiral ligands, explored different reaction conditions, and assessed substrate compatibility to achieve control over enantioselectivity. For example, the Pd/PyOX system has been widely used for the asymmetric addition of highly substituted chalcones, where high stereoselectivity and yield were obtained under mild conditions.

In the future, the asymmetric synthesis of dihydroflavone compounds still holds tremendous potential for development. With the continuous improvements in organic synthesis methods and advances in catalytic chemistry, we can anticipate the emergence of more efficient and selective strategies. For instance, the realization of higher synthetic efficiency and product purity is foreseeable. In addition, with the development of chiral ligands and catalysts, it is expected that more substrates will be available, thereby enriching the structural diversity and biological activity of dihydroflavone compounds.

Conflict of Interest

None declared.

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Publication History

Received: 23 December 2023

Accepted: 06 January 2025

Article published online:
28 February 2025