Bioactive Phytochemicals: Efficient Synthesis of Optically Active Substituted Flav-3-enes and Flav-3-en-3-o-R Derivatives

The structural core of flavene (2-phenyl-2H-chromene) is commonly found in plant flavonoids, which exhibit a wide range of biological activities and diverse pharmacological profiles (e.g., antioxidant and anticancer activities). Flavonoids have attracted significant interest inmedicinal and synthetic chemistry. Substituted flav-3-ene 13was exclusively synthesized by the stereoselective elimination of the O-mesyl moiety on C-3 of 5,7,3,4-tetramethoxyflavan-3-mesylate 12 with 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction of 5,7,3,4-tetramethoxyflavan-3-one 15 with ytterbium trifluoromethanesulfonate in methanol afforded a novel 3-Osubstituted flav-3-ene derivative (3,5,7,3,4-pentamethoxyflav-3-ene) 17. The reduction of 4-(1,3,5-trihydroxybenzene)-5,7,3,4tetra-O-benzylflavan-3-one 19b with hydrogen afforded a new compound: 3-hydroxy-4-(1,3,5-trihydroxybenzene)-5,7,3,4tetrahydroxyflavan-3-en-3-ol 21 in good yield (95%), while the acetylation of 19a and 21 afforded the expected novel flav-3-en3-acetoxy derivatives 20 (92%) and 22 (90%), respectively.

Because of the medicinal importance of the core structural unit of flavenes, there has been significant interest in the development of methods for scaffold construction [3][4][5][6][7][8][9].However, previous studies have revealed that the synthesis of a functionalized flavene skeleton is a challenging task [5]; hence, few methods have reported the efficient stereoselective synthesis of flavenes [14][15][16][17][18][19][20][21].Clark-Lewis and Jemison [14] have reported the first synthesis of racemic 1 based on chalcone starting materials.Zaveri [15], Pelter and Stainton [16], Nay et al. [17], and Deodhar et al. [18] have independently utilized similar cyclization routes to synthesize 1.The reactions involve the reduction of the C-4 carbonyl group to a 4-hydroxyl group, followed by the elimination of water to yield racemic 1. Casiraghi and Casnati [19] have used cinnamaldehyde and alkyl phenoxymagnesium bromides as the starting material to obtain racemic 1.When 1 is heated under reflux in benzene in the presence of the corresponding phenoxymagnesium bromide, it isomerizes to 2. Cardillo et al. [20] have reported a biogenetic-like synthesis of racemic 1 from o-cinnamylphenols via the dehydrogenation of DDQ, while Subramanian and Balasubramanian [21] have synthesized racemic 1 from 1-arylprop-2-ynyl aryl ether in good yield by a facile Claisen rearrangement.Studies available on flavene synthesis have revealed that known reaction protocols afford racemic flavene products.Syntheses occurred via a cyclizable moiety, for example, chalcones and o-cinnamylphenol, or via the reduction of the C-4 carbonyl group and subsequent elimination of water, or the reduction of flavylium salts.To the best of our knowledge, no study has reported the elimination of the C-3 moiety flavan-3-ol to form 1. With this background, the substitution of the C-3-OH of (2R,3S) 5,7,3  ,4  -tetramethoxyflavan-3-ol (catechin) 8 and (2R,3R) 5,7,3  ,4  -tetramethoxyflavan-3-ol (epicatechin) 9 with a good leaving group, such as a tosyl or mesyl group, has been hypothesized to synthesize a range of flavonoids and optically active substituted flav-3-enes.In addition, the use of substituted flavan-3-one for synthesizing substituted flav-3-en-3-o-R substituted derivatives was considered.In this study, 5,7,3  ,4  -tetramethoxyflav-3-ene 13 was synthesized in a facile, efficient manner by E2 elimination using a nonnucleophilic strong Lewis base, as well as 3-substituted flav-3-ene derivatives using a strong Lewis acid.Workup.Unless specified and appropriate for reaction workup, water was added to the reaction mixture, and the aqueous phase was extracted with diethyl ether or ethyl acetate.The organic extract was washed with water and dried with Na 2 SO 4 or MgSO 4 , followed by the removal of solvent under reduced pressure at approximately 40 ∘ C. Products were purified by TLC or flash column chromatography.Compounds 8, 9, and 5,7,3  ,4  -tetra-methoxyflavan-3-one 15 were prepared according to previously reported procedures [22].
Synthesis of 5,7,3  ,4  -Tetramethoxyflavan-3-tosylates (10,11).The target product C-3-tosylated catechin 10 or C-3 tosylated epicatechin 11 is prepared in three steps.The first step involves the synthesis of 1-(p-toluenesulfonyl) imidazole: An anhydrous THF solution (10 mL) of imidazole (3.6 g, 52.9 mmol) was stirred under nitrogen, followed by the dropwise addition of a THF (8 mL) solution of p-toluenesulfonyl chloride (5 g, 26.2 mmol) over 10 min.After 1 h, the mixture was filtered and washed with THF, and the solvent was concentrated under reduced pressure to afford 1-(p-toluenesulfonyl) imidazole as white needle-like crystals.The crystals were washed with hexane and used in the next reaction step without further purification or characterization.The second step involves the preparation of the sulfonating agent.First, methyl triflate (180 mg, 1.10 mmol) was added dropwise to a 10 mL THF solution of 1-(p-toluenesulfonyl) imidazole (266 mg, 1.20 mmol), which was cooled to −5 ∘ C under nitrogen.Second, the reaction mixture was stirred at −5 ∘ C for another hour to obtain the "sulfonating agent" for the third step of tosylation.For tosylation, methylated catechin 8 or methylated epicatechin 9 (346 mg, 1.0 mmol) was dissolved in dry THF (10 mL) under nitrogen, and N-methylimidazole (82 mg, 0.8 mL, 1.00 mmol) was added.The mixture was added to the off-white sulfonating reagent.After another 10 min, the cooling system was removed, and the reaction continued at room temperature for 24 h.The mixture was chromatographed on silica gel with 1 : 1 toluene-ethyl acetate as the solvent mixture for development, affording 10 or 11 as a white amorphous solid in 82% yield (Scheme 2).Physical data were in agreement with those reported previously [24].

Results and Discussion
Efforts to eliminate or replace the secondary hydroxyl group at the C-3 of flavan-3-ol with a carbon-carbon bond were seemingly elusive, and attempts resulted in the decomposition of substrates after several hours of reaction.The nonsubstitution or effective elimination of the carbon-3 moiety possibly occurred via the pathway of an antibonding orbital, which is "hidden" inside the heterocyclic C-ring (most likely in a chair conformation) rather than the S N 2 reaction pathway; thus, it is not accessible to the approaching electronrich nucleophile [5] or by the nonnucleophilic strong base to abstract the OH proton by E2-type elimination.
By a simple method, a mixture of 8 and a mole equivalent of DMAP in THF under inert gas with methanesulfonyl chloride and excess triethylamine at subzero temperatures afforded 12 in excellent yield.After workup, the compound required no further purification before use in the elimination step.On the other hand, C-3-tosylated catechin 10 and C-3 tosylated epicatechin 11 were synthesized in three steps: (i) synthesis of 1-(p-toluenesulfonyl)imidazole, (ii) preparation of a sulfonating agent, and (iii) tosylation (Scheme 2).
The stereoselective elimination of the tosyl or the mesyl group at the C-3 of methylated catechin in anhydrous THF with a strong base at low temperature exclusively afforded flav-3-ene in low yields of 5% and 15%, respectively.By refluxing an anhydrous acetonitrile solution of catechin tosylate 10 or catechin mesylate 12 in the presence of DBU exclusively afforded 13 in good yields of 82% and 99%, respectively (Scheme 3).The reaction with 11 was repeated by substituting acetonitrile with dry THF, followed by refluxing the mixture for 24 h to afford 13 in a very low yield of 7.5%.This low yield is possibly caused by a radical inhibitor present in THF, which could retard the DBU activity.By refluxing the acetonitrile solution of 11 in the presence of DBU, a mixture of 13 and 14 (80% combined yield) in a ratio of approximately 1 : 1 was obtained, while the addition of 11 to an anhydrous THF solution of lithium diisopropylamide (LDA) at approximately −5 ∘ C also afforded 13 and 14 (44% combined yield) as an orange paste (Scheme 3).The product mixture of flavenes from the elimination of 11 can be explained by the basecatalysed trans elimination to a flav-2-ene of a hydrogen at C-2 trans to the tosyl group at C-3.This was in contrast to (2R,3S) tetra-O-methyl-3-O-tosyl-catechin 10, where the hydrogen at position 2 was cis to the tosyl group at C-3, and the only available trans hydrogen was at C-4, resulting in the exclusive formation of flav-3-ene and the retention of configuration at C-2.Typically, it was difficult to synthesize 2 and 1 because of their facile oxidation anthocyanidins.
The 1 H NMR spectra of the 3-O-derivatives 9, 10, and 11 clearly indicated the presence of an aromatic ABX system (dd,  = 2.0, 8.0 Hz; d,  = 2.0 Hz) and an AB resonance system ( = 2.0 Hz), representing the catechol and phloroglucinol character of the B and A rings, respectively.From the CD spectra of 9 and 11, the optical activities at C-2 and C-3 were maintained.As expected, 13 exhibited three oneproton resonances for the C-ring, a complex ABX system.The olefinic protons on C-3 and C-4 (H-3 and H-4) were coupled by cis-coupling ( 3,4 = 10 Hz), and the proton on C-2 (H-2) was coupled to both H-3 and H-4 ( 2,3 = 3 Hz, and  2,4 = 2 Hz).The benzylic proton H-2 was adjacent to an ether oxygen, which was observed at  5.76 as a doublet of doublets ( = 2.0, 3.0 Hz).Flav-3-enes contained a chiral carbon on C-2.The HMBC correlation between C-2/C-5 and H-4 in HMBC permitted distinction between H-4 and H-3.The (i)

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(ii) The efficient production of protected 3-oxocatechin analogue 15 (Scheme 4) with the retention of configuration at C-2 by Dess-Martin periodinane oxidation provided a novel approach towards nucleophilic attack at C-3.In contrast to tetrahedral sp 3 -functionalized C-3 of flavan-3-ol, the sp 2 -functionalized 3-oxo-group of 15 was planar, which decreased steric effects and permitted nucleophilic attack on the carbonyl carbon from either the or the -face.Under this premise, the C-C coupling of a nucleophile to the C-3 of 15 with various Lewis acids (e.g., AgBF 4 , TiCl 4 , InCl 3 , and Yb(OTf) 3 ) and solvents (CH 2 Cl 2 , THF, DMSO, ethanol, and methanol) was attempted, which failed to yield the expected C-3 coupling products.However, by the treatment of 15 with Yb(OTf) 3 in methanol and reflux of the reaction mixture for 6 h, 17 (17% yield) and 18 (32% yield) were obtained, via a hemiacetal intermediate (3-hydroxy-3,5,7,3  ,4  -pentamethoxyflavane) 16 (Scheme 4).Both 17 and 18 exhibited a Cotton effect at wavelengths ranging from 260 to 284 nm, indicating no change in the configuration at C-2.This observation is in contrast with the racemic products synthesized by Clark-Lewis and Jemison [14].
Enol ether 17 was characterized by the disappearance of the carbonyl resonance in the 13 C NMR spectrum of 15 at  206.1 ppm and the appearance of an additional methoxy resonance at  3.73 ppm in the 1 H NMR spectrum.The two enol carbons C-2 and C-3 were observed at 77.2 and 150.7, respectively.The two benzylic protons at C-4 of 15 disappeared and were replaced by an olefinic resonance at  5.60 ppm.Structural elucidation is further supported by mass spectrometry (M + ion at / 358), corresponding to the addition of a methyl group and the loss of a hydrogen.A negative Cotton effect in the  = 216 nm range was observed in the CD spectrum suggesting that optical activity at C-2 (2R-configuration) of the commercial catechin was maintained.This observation was supported by proton NMR coupling constants and the NOESY correction of the H-2 with H-2  and H-6  .The H-4 demonstrated NOESY correlations with the methoxy group on C-3 (Scheme 5).
Ketal 18 was characterized by the disappearance of the carbonyl resonance of 15 at approximately  206.1 ppm and the appearance of two additional methoxy resonances at  3.34 and 3.31, respectively.Ketal carbon (C-3) was observed at  101.2 ppm.This result was further supported by the M + ion at / 391, corresponding to the addition of two methoxy groups (and the loss of an OH group).NOESY demonstrated correlations between the two benzylic C-4 protons (4 and 4) and the A ring and C-2-proton.NOESY correlations       Notably, self-condensation products were not observed probably because of the deactivation of the nucleophilic properties of the A ring via the enolic C-ring tautomer (Scheme 7) [22].

Conclusion
Few synthetic methods have been published to efficiently synthesize flavenes, although none are stereoselective.
Substituted flav-3-enes were exclusively synthesized efficiently by the stereoselective elimination of the 3-Osubstituent on protected catechin using DBU.3-Substituted flav-3-ene derivatives were prepared by treating flavan-3one with a strong Lewis acid in the presence of a suitable nucleophile.Solvent choice was critical to the success of reactions and yields of corresponding products.Optical activities of the compounds were confirmed by CD data and NMR spectroscopy analysis.

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in dry THF afforded C-4 coupled product 19a,b (Scheme 6).The carbonyl signals for 19a,b were absent at the expected  204-206 ppm, probably because of a formation of hydrogen bonding between the D-ring neighbouring hydroxyl proton and the carbonyl oxygen.The debenzylation of 19b by hydrogenation afforded 21 with a free phenolic group in good yield.Flav-3-en-3-ols are versatile precursors for flavonoids[26], which play vital roles in the biogenesis pathway of tannins[27].The acetylation of 19a and 21 afforded 20 and 22, respectively, in good yield.Compound 20 was characterized by the absence of the carbonyl resonance at  206.3 ppm in the13 C NMR spectrum of the precursor 19a and the presence of four acetoxy resonances at  1.70, 1.95, 2.06, and 2.30 ppm, respectively, in the 1 H NMR spectrum of 20.The C-4 proton of 19a at 5.10 ppm disappeared, and the olefinic group at C-3, stabilized 20, was observed.The structure of 20 conformed to the M + ion at / 636.Octa-acetoxy 22 was characterized by eight acetate groups with proton resonances at  1.61, 1.66, 1.82, 1.99, 2.18, 2.20, 2.21, and 2.22 ppm, respectively, and the 13 C NMR resonances were observed at  20.0-21.1 ppm, with the expected M + ion at / 748.NOESY correction of H-2 with H-2  and H-6  was observed.The H-3 and H-4 protons signals were not observed on the NMR spectra for 20, 21, and 22 compounds.The 2R-configuration of the compounds was assessed via coupling constants from their respective spectral data and NMR NOESY proton correlations (Supp.

Figure 1 in
Supplementary Material available online at https:// doi.org/10.1155/2017/3971253).Scheme 7 shows the proposed mechanism of the reaction pathway to the oxidative formation of 19a,b.The exclusive formation of 19a,b was primarily attributed to absolute configuration on C-2 (2R), which predominantly directed the approaching nucleophile to the anti-face (4S).

Scheme 7 :
Scheme 7: Proposed mechanism for the formation of 19.