International Research Journal of Pure & Applied Chemistry 8(3): 112-146, 2015, Article no.IRJPAC.2015.079 ISSN: 2231-3443

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Flavans: Synthetic Strategies: A Review

Ofentse Mazimba1* and Ngonye Keroletswe1

1Department of Chemistry, University of Botswana, Private Bag 00704, Gaborone, Botswana.

Authors’ contributions

This work was carried out in collaboration between both authors. Author OM designed the study, wrote the Introduction and section 1 of the Discussion, Author NK wrote the Discussion, Conclusion and format of References. Both authors read and approved the final manuscript.

Article Information

DOI: 10.9734/IRJPAC/2015/17422 Editor(s): (1) Wolfgang Linert, Institute of Applied Synthetic Chemistry, Vienna University of Technology Getreidemarkt, Austria. Reviewers: (1) Ogunwande Isiaka Ajani, Department of Chemistry, Lagos State University, Ojo, Nigeria. (2) Anonymous, Merbah University, Algeria. Complete Peer review History: http://www.sciencedomain.org/review-history.php?iid=1051&id=7&aid=9382

Received 13th March 2015 rd Review Article Accepted 23 March 2015 Published 23rd May 2015

ABSTRACT

Flavans consist of the 2-phenylchroman structural unit found naturally in the plant kingdom. They are important compounds due to their various pharmacological properties, such as anticarcinogenic, anti-inflammatory, antioxidant, antimalarial, antiviral properties and chemopreventive potential for Helicobacter pylori peptic ulcers. Because the flavans are only minutely available from natural sources improved synthesis of flavans are desirable to obtain sufficient quantities for biological testing. Thus, this review article aims at describing the synthetic protocols which exist in the literature. From the surveyed literature 153 synthetic flavans, flavens, isoflavan, neoflavans and anthocyanins were reported.

Keywords: Flavans; flavens; anthocyanins; isoflavan; synthesis; chalcones.

ABBREVIATIONS

BF3.Et2O = Boron trifluoride diethyl etherate NaBH4 = Sodium borohydride AcOH = Acetic acid LiAlH4 = Lithium aluminium hydride

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*Corresponding author: E-mail: [email protected];

Mazimba and Keroletswe; IRJPAC, 8(3): 112-146, 2015; Article no.IRJPAC.2015.079

Co12 = Human colon carcinoma cell line P-388 cell line = Murine lymphocytic leukemia cell line SGC-7901 = Gastric carcinoma, BEL-7402 = Hepatic carcinoma cell line HL-60 = Acute promyelocytic leukemia cell line MTT = 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide Pd(OAc)2 = Palladium (II) acetate Et3N = Triethyl amine CuI = Copper (I) iodide KOtBu = Potassium tert-butoxide DMF = Dimethylformamide NaBH3CN = Sodium cyanoborohydide PhBr = Bromobenzene BrCH2CH2Br = 1,2-Dibromoethane n-Bu4NHSO4 = Tetrabutylammonium hydrogen sulfate Pd(OH)2 = Palladium (II) hydroxide n-BuLi = n-Butyllithium DEAD = Diethyl diazenedicarboxylate rt = Room temperature AD-mix α = Asymmetric dihydroxylation mixture of reagents where phthalazine adduct contains dihydroquinine MeSO2NH2 = Methyl sulfonamide TBAF = Tetra-n-butylammonium fluoride EtC(OEt)3 = 1,1,1-Triethoxypropane PPTS = Pyridinium p-toluenesulfonate TEA = Triethyl amine PTC = Phase transfer catalyst Bi(OTf) = Bismuth triflate or bismuth (III) trifluoromethanesulfonate TBDPSI = t-Butyldiphenylsilyl ether 9-BBN = 9-Borabicyclo[3.3.1]nonane

1. INTRODUCTION strategies towards catechins and related tea polyphenols were reviewed by Asakawa and co- Flavan are an omnipresent 2-phenylchroman workers [6]. The lesser known important natural structural unit of the C6-C3-C6 type, 2-phenyl-3,4- flavans are 7-hydroxy-3,4-methylenedioxyflavan dihydro-2H-chromene nucleus found in (6) from Zephyranthes flava which is traditionally flavonoids. They are natural products distributed used to cure diabetes, ear and chest disorders in the plant kingdom with >17 000 natural flavans and viral infections [7], 4,6-dichloroflavan (7) isolated [1]. The well-studied flavans are the hinders rhinovirus replication in vitro [8], flavan-3-ols of which their natural occurrences morusyunnansin E (8) exhibits potent inhibitory and biological activities were presented in a 2008 activity on mushroom tyrosinase [9], whereas review article [1]. Flavans are found in foods (S)-equol (9) is believed to be a dietary such as red wines, green teas, apples, pears, phytoestrogen through binding to the estrogen and cocoa products. They exhibit interesting receptor b (ERb) which is 13 times more potent biological and pharmacological activities [2a-h] than the unnatural (R)-isomer [10,11]. (S)-Equol and high degree of structural diversity depending is a metabolite of soy isoflavone, daidzein whose on the type of constitutive units. transformation was assisted by intestinal bacteria such as gut microflora [12,13], 3’-hydroxyequol The well-known flavans from green tea (Camellia has shown potential to prevent hormone-related sinensis) are (+)-catechin (1), (-)-epicatechin (2), cancer [14]. Vestitol (10) displays anti- (-)-epigallocatechin (3) which possess various inflammatory, antimicrobial activities and has biological properties such as anticarcinogenic, chemo-preventive potential for peptic ulcers in H- anti-inflammatory, antioxidant and Pylori infected individuals [15,16]. The fully immunomodulatory properties, inhibition of bone substituted sideroxylonal B (11) from Eucalyptus resorption [3,4]. The green tea potent sideroxylon exhibits antibacterial [17, 18] and antioxidants are (-)-epicatechin gallate (4) and antitumor properties [19]. 7-O-gallyltriceflavan (-)-epigallocatechin gallate (5) [5]. The synthetic (12) exhibits antiviral properties [20] while

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Griffinord E (13) shows antimalarial activity [21]. group reductions. Recently, we have The natural flavans 1-13 are shown in Figure 1. demonstrated the versatility of our methods by reducing 2-thienylchalcones (37) to alcohols (38), Flavans have attracted the attention of many which were cyclized to flavans [2-(thiophen-2- synthetic chemists and a number of synthetic yl)chroman] bearing an electron rich thiophene protocols have been developed for their ring (39, 40) [29] as depicted in Scheme 4. synthesis due to their pharmacological importance. Thus this review describes the The reduction of o-hydroxychalcones with synthetic strategies reported for the synthesis of LiAlH4/AlCl3 affords trans-cinnamylphenol flavan and their analogues. This would assist to chromophore [30]. The cinnamylphenols were identify the most biologically important flavans photocyclized to flavans via irraditions of the and their simpler and efficient synthetic methods. substrate in benzene inside a pyrex tube using a Hence, enabling the future targeted synthesis of 125W Hg lamp (Scheme 5) [31]. Alternatively, flavans. flavan 43 was synthesized in higher yields by the Clemmenson reduction of flavanone [30,31], 2. DISCUSSION Scheme 6.

2.1 Flavans Zang and co-workers accomplished the synthesis of natural flavan racemates (52-54), via Li and co-workers have described the synthesis the Pd-C catalyzed hydrogenation / of flavans (6 and 16) starting from a chalcone hydrogenolysis of flavones as described in (14). The reduction of the chalcone using Raney Scheme 7. The esterification of the phenol with nickel followed by the BF3.Et2O assisted benzoic chloride followed by the Baker- cyclization in protic media formed the Venkataraman rearrangement affords 1,3- benzopyran ring of natural flavans as depicted in diketones (49). To complete the synthesis the Scheme 1 [22]. Flavan (16) is an antifeedant 1,3-diketone forms the natural flavone (51) after chemical constituent of Stypandra grandis and treatment with acetic acid, and the subsequent Lycoris raliata [23]. Xue and co-workers have hydrogenation/hydrogenolysis catalyzed by Pd-C utilized a similar protocol to accomplish the yields the racemic flavans (52-54) [32]. The two synthesis of Dracaena cinnabari [24,25] isolated flavans, 2(S)-7,8,3,4,5-pentamethoxyflavan flavans (23-25) starting from salicylaldehyde (17) (52) and 2(S)-5-hydroxy-7,8,3,4- as shown in Scheme 2. The ,-unsaturated tertramethoxyflavan (53), had been isolated from ketone function of the chalcone was reduced by the roots of Muntingia calabura. These natural H /Pd, which usually reduces C=C double bonds 2 flavonoids exhibited cytotoxic activity against [25]. human colon carcinoma Co12 and murine

lymphocytic leukemia P-388 cell lines [33]. The Our group have also accomplished the synthesis synthetic analogues were assessed for anti- of an array of flavans (30-34) [26,27]. Contrary to proliferative activity against human cancer cell reduction methods using H /Pd and H /Raney 2 2 lines, SGC-7901 gastric carcinoma, BEL-7402 Nickel in Scheme 1 and 2, Our group used hepatic carcinoma, HeLa cervical carcinoma, and NaBH to reduce chalcones [26] to the 4 HL-60 acute promyelocytic leukemia, by MTT corresponding alcohols, which were cyclized into assay. The flavan (52) exhibited 1.6-5.7 more flavans (30-34) [27,28] as shown in Scheme 3. potency than cisplatin, while (53) showed NaBH here reduced the C=C double bond, it is a 4 moderate activities [32]. reagent which is normally used for carbonyl

R1 RO OMOM R1 RO OMOM R i 1 RO O ii and iii R2 R 93-98 % 2 R2 57-80% O OH

14 15 6 R= H, R1, R2 = OCH2O 16 R= Me, R1= OH, R2 = H

i) H2/Raney Ni (W-2), EtOH; ii) BF3.Et2O, 1,4-dioxane, 1.5h; iii) HCl, MeOH, reflux

Scheme 1: Li et al. synthesis of flavans

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OH O OH OH HO O O HO O OH R2 OH R1 OH MeO O 6 R OH Y = OH OH Cl O 8 O R R1 R2 HO O 1 H OH H 2 OH H H Cl 3 OH H OH 4 OY H H 7 OH 5 OY H OH OHC OH 9 OH HO O HO CHO CHO MeO O HO O OH OH HO OMe OMe O OH 10 11 12 OH OH OH OH HO O OH O O O HO OH O

OH

13 Figure 1: Some naturally occuring bioactive flavans O MOMO OMOM R1 MOMO OMOM i + R1 85-90 % R CHO 2 R1 O 21 17 18 R1 = OMe, R2= OMOM 19 R1 = OMOM R2= OMe 20 R1 = OMOM, R2= H 99% ii

iii R1 MOMO OMOM R1 RO O iv R2 deprotection R 80-93 % 2 OH

23 R1 = OMe, R2= OH 22 24 R1 = OH R2= OMe 25 R1 = OH, R2= H

Reagents and conditions: i) KOH, MeOH, rt; ii) H2/Pd-C (5%), EtOH, rt; iii) BF3.Et2O, 1,4-dioxane, rt; iv) HCl, MeOH. Scheme 2: Xue et al. synthesis of flavans.

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O OH OH + i R R CHO 56-87% O 26 27 28 62-90% ii R O iii OH 62-87 % R

OH 30 R = H 33 R = p-OMe 31 R = o-OMe 34 R= m,p-diOMe 29 32 R = m-OMe o Reagents and conditions: i) NaOH, EtOH, 2h, 60 C; ii) NaBH4, MeOH, rt, 0.5h; iii) AcOH, reflux. Scheme 3: Mazimba et al. synthesis of flavans.

Suchand and co-workers [34] reported a three formations were found to exclusively form flavans step protocol for the sysnthesis of flavans. Firstly, (59-67) in good yield (68-85%) as shown in the intermolecular [Pd] catalyzed C-C bond Scheme 8 [34]. formation between 2-bromoiodobenzene (55) and allylic alcohols (56) affords dihydrochalcones The Suchand and co-workers protocol was (57). The dyhydrochalcones (57) were reduced extended to the synthesis of flavans substituted to secondary alcohols (58) using NaBH4. The at C-2 (69-76) as described in Scheme 9. The third step was the intramolecular [Pd]-catalyzed strategy involved the reaction of C–O bond formation which cyclizes the 2º dihydrochalcones (57) and Grignard reagent [34]. alcohols (58) into the chroman ring (59-67). But, Ramulu and co-workers showed the versatility of the [Pd] catalysis was inferior in yields (0-62%) the [Pd] and [Cu]-catalysed construction of C-C [35,36] and formed back the ketone moiety of and C-O bonds in the synthesis of flavans by dihydrochalcones (57) as the minor product (9- preparing flavans (77-85) [37] shown in Fig. 2. 65%). Whereas, the [Cu]-catalyzed C-O bond

R R O OH OH S + S i CHO 87% O 35 36 37 90% ii R S R iii OH O S 65-70 %

OH 39 R = H 40 R = OMe 38

Reagents andconditions: i) NaOH, Grind; ii) NaBH4, MeOH, rt, 0.5h; iii) AcOH, reflux. Scheme 4: Mazimba's synthesis of 2-(thiophen-2-yl)chroman

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R OH R OH R O LiAlH4/AlCl3 hv THF Benzene 52-63% 40-64 % O 43 R= PH 41 42 44 R= Me 45 R= OMe Scheme 5: Photocyclization of cinnamylphenols to flavans

O Zn(Hg) O HCl 86 %

O 46 43 Scheme 6 Clemmensen reduction of flavanone to flavans

MeO OMe OMe COCl OMe MeO OH R MeO OH OMe ii + i MeO O MeO R 83% O 75% O OMe O O O 47 48 49 50

72% iii

OMe OMe OMe OMe OMe OMe MeO O iv MeO O R R 82 %

52 R= OMe O 53 R= OH 51 54 R= OCH2Ph o Reagents and conditions: i)dry pyridine, 110 C, 1h; ii) pyridine, NaOH, rt, 4h; iii) CH3COOH, 6h; iv) H2, Pd-C, CH3COOC2H5, rt, 12h; v) H2, Pd-C, CH3OH, rt, 24 h. Scheme 7: Zhang et al. synthesis of flavans.

A multi-component reactions between magnesium bromide, while reduction using phloroglucinol (86), styrene (87) and sodium borohydride or sodium cyanoborohydride formaldehyde (89) in the presence of a afforded flavens 105-109 [39]. Further reactions heterogeneous solid catalyst directly furnished of flavens with sodium cyanoborohydride flavans (89; Scheme 10) shown in Fig. 3. afforded the corresponding flavans 110-114 Besides silica-HClO4, other catalyst that shown in Scheme 11. These reactions were efficiently assisted the reaction were silica-FeCl3, successful only for flavens bearing electron HClO4 and Amberlyst-IR-50 [38]. donating groups in ring B at positions C-2’ and C- 4’ [39]. The ring B electron donating groups Flavens 102-104 were synthesized by the permit the resonance stabilization of the positive reduction of flavylium perchlorate (101) using charge placed at C-2 before being quenched by

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a hydride ion. The reaction of flav-2-ens of type K2CO3/acetone with subsequent base elimination 115 with alcohols in the presence of Lewis acid under phase transfer catalysis furnished diene yields 2-alkoxyflavans 118-120, which were (127). 4H-chromene ring (128) was obtained subsequently reduced to flavans (121-123) using from diene 127 through ring closure assisted by NaBH3CN in Scheme 12 [39]. the Grubbs-2 catalyst. Heck reaction of compound 128 with 2-MeOPh-N2BF4 followed by 5,7-Dihydroxy-4´-methoxyflavan (130) was ring closing metathesis furnished flav-3-en (129). synthesized in a total of seven steps from 3,5- Palladium-catalyzed hydrogenation- bis(benzyloxy)phenol (124) by Machado and hydrogenolysis afforded 5,7-dihydroxy-4´- coworkers [40]. O-allylation of phenol 124 using methoxyflavan (130) (Scheme 13) [40]. Flavan allyl bromide yields an allylic ether 125, which 130 has been isolated from Faramea guianensis under thermal conditions undergoes a Claisen and shows significant in vitro leishmanicidal rearrangement to furnish a phenol (126). activity [41]. Esterification of 126 using 1,2-dibromoethane in

O OH R R OH Br 3 Br 3 R2 Br R3 ii + i R4 R4 97-99 % R1 I 64-78 % R R R4 5 5 R1 R1 R5 R1 R1 55 56 57 58 R R R R R 1 2 3 4 5 iii 59 H H OMe H H 68-85 % 60 H H OMe OMe H R3 61 H H OMe OMe OMe R4 62 H H OCH2- OCH2- H R O 63 OMe H OMe H H 2 R 64 OMe H OMe OMe H 5 65 OMe H OMe OMe OMe R1 66 OMe H OCH2- OCH2- H 67 H OMe OMe H H o Reagents and conditions: i) 3 mol % Pd(OAc)2, Et3N, MeCN, 80 C; ii) NaBH4, MeOH, rt; iii) 20 mol% CuI, 2,2- bipyridyl (20 mol %), KOtBu, DMF, 120 oC

Scheme 8: [Pd] catalyzed C-C and [Cu]-catalysed C-O bond formations in the synthesisis of flavans

O R3 HO R6 R R R4 Br 3 Br 3 ii R2 O i R5 R4 R4 R 67-85 % 6 R 88-97 % R 5 5 R1 R2 R2 R R 1 1 R1 R2 R3 R4 R5 R6 57 68 69 H H OMe H H Me 70 H H OMe OMe H Me 71 H H OMe OMe OMe Me 72 H H OCH2- OCH2- H Me 73 OMe H OMe H H Me 74 OMe H OMe OMe OMe Me 75 OMe H OCH2- OCH2- H CH2CH2 76 H OMe OMe H H Me o t o Reagents and conditions: i) R6MgX, THF, -10 C-rt; ii) 20 mol% CuI, 2,2-bipyridyl (20 mol %), KO Bu, DMF, 120 C Scheme 9: Grignard reagents C-C and [Cu]-catalysed C-O bond formations in the synthesis of flavans

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MeO OMe OMe OMe OMe

OMe OMe OMe OMe O O O O

MeO 77 78 79 80 O OMe OMe

O OMe OMe O O O

MeO 81 82 83 MeO OMe O

OMe O O O

84 85 Figure 2: Flavans reported by Ramulu et al. (37)

R2 HO OH R2 R3 + R Silica-HClO4 HO O R 3 + H2CO R1 4 ACN, 80oC OH 35-94 % R1 R4 OH 86 87 88 89

Scheme 10: Bharate et al. MCR in the synthesis of flavans

Hodgetts and co-workers have reported a phenylchroman. Further addition of the synthetic strategy towards flavans in which the organolithium reagent forms a chromanyllithium intermolecular and intramolecular Mitsunobu by the second halogen-metal exchange. reactions were the keys steps. The Quenching of the electrophile accomplishes the intermolecular Mitsunobu reaction between 2- one pot synthesis of flavans (140-144) as bromophenol (131) and (R)-3-chloro-1-phenyl-1- described in Scheme 15 [42]. propanol (132) under standard inversion conditions afforded (S)-phenyl ether (133). The synthesis of enantiomerically pure 4’,6- Cyclization was accomplished in the presence of dichloroflavan (BW683C) (7) was achieved n-butyllithium [42] to furnish enantiomerically starting from the asymmetric reduction of suitable pure flavans as shown in Scheme 22. prochiral ketone, 3,4-dichloropropiophenone Tephrowatsin E (138) is a natural flavan isolated (145) with (R)-oxazaborolidine and borane [42, from Tephrosia watsoniana [43]. 44] as described in Scheme 16.

The one pot cyclization and in situ 2.2 C2, C3-substituted Flavan Derivatives functionalization of the Mitsunobou reaction ether product was probed. The first addition of n- Deodhar and co-workers [45] described the butylithium was selective towards the ortho- synthesis of 4-arylflavans (153) from flavanone bromo metal exchange which leads to the (151) which was derived via the condensation formation of the flavan ring affording 6-bromo-2- reaction of resacetophenone (148) and 4-

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hydroxybenzaldehyde (149). The acetylated 4-aryloxyflavans (155-161) [50,47] without flavanone (151) furnished 7,4-diacetoxyflavan-4- producing 4-arylflavans (Scheme 18). The ol (152) after the palladium-catalyzed disadvantage for these synthetic methods were hydrogenation. The OH-group was substituted concomitant formation of 4-aryloxyflavans and with an aryl group in the presence of BF3.OEt2 4-arylflavans, which needed separation, and yielding equal mixtures of cis and trans-flavans failure to work with 7-methoxy or 3-hydroxy (153) after KOH hydrolysis of the acetyl group substituted flavan-4-ols. [45]. Thus, a synthetic method based on the opening The condensation reaction of phenols and of flav-3-ene epoxides (166) with phenols and secondary alcohols in the presence of BF3.OEt2 phenolates ions was reported. The phenols ring to form ethers [46] was applied to the synthesis opening reaction affords 2,3-cis-3,4-cis- (167) of 4-aryloxyflavans. The synthesis of 4- and 2,3-trans-3,4-cis-(169) 4-aryloxyflavan-3-ols aryloxyflavans (155-161) was accomplished by while the phenolate ions yields 2,3-cis-3,4-trans- reactions of phenol with flavan-4-ols (154) (168) and 2,3-trans-3,4-trans-(171) 4- catalyzed by boron trifluoride in ether, Scheme aryloxyflavan-3-ols as shown in Scheme 19 [48]. 25 [47,48]. p-Cresol resulted in the highest yield The phenols cis-openning of the epoxide ring (70%) for 4-aryloxyflavans. Catalysis using occurs by the ion-pair mechanism [51] to alcoholic hydrogen chloride or toluene-p- exclusively give 3,4-cis-stereochemistry, while sulphonic acid yields 4-arylflavans (162-164) the phenolate reaction is an SN2 mechanism that [47,49]. The thermal decomposition of flavan-4- leads to 3,4-trans stereochemistry. yl phenyl carbonates (165) of flavan-4-ol yielded

R1 R1 ClO4 R6 O MgBr, PhBr R6 O R2 R2 ether, 70 % R7 R7 R3 R3 R5 R4 R5 R4 101 R1 R3 R4 102 H H Ph 103 OMe H Ph NaBH3CN 104 OMe Br H 54-90 % AcOH/Ac2O R2, R5 R6 = H NaBH CN 60-80 % 3 AcOH/Ac2O

R1 R1 NaBH3CN R O R O 6 AcOH/Ac2O 6 R2 R2 R7 62-79 % R7 R3 R3 R5 R4 R5 R4

R1 R2 R3 R4 R5 R6 R1 R2 R3 R4 R5 R6 105 H H H H H H 110 H H H H H H 106 NO2 H H H H H 111 OMe H H Ph H H 107 OMe H H H H H 112 OMe H H H H H 108 OMe OMe H H OMe OMe 113 OMe OMe H H OMe OMe 109 R1-6 = H, R7 = OMe 114 R1-6 = H, R7 = OMe Scheme 11: Synthesis of flavans via reduction of flavylium salts

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O H O O H O

HO O HO O HO O HO O

H H

O OH O OH O OH O OH 90 91 92 93 O O O O HO O O O HO O HO O HO O O OH O OH O OH O OH 94 95 96 97

O

HO O O O O O O O OH HO O

98 99 100 Figure 3: Flavans reported by Bharate and co-workers

R R 1 R1 1 NaBH3CN AcOH/Ac2O O R2-OH O O

AlCl3 OR2 80-99 % 79% 115 R1 R2 R1 118 H Me 121 H 119 H Et 122 H 120 OMe Me 123 OMe

Scheme 12: Flavan synthesis from flavens When Zhang and co-workers attempted to Scheme 20 [52]. Ten examples of compound reduce the orthogonally protected chalcones type (187) and (188) were reported, while flavan- (178) to the olefin, cinnamylphenol derivative 3-ol (187) is also a derivative of (-)-epicatechin (182) the formation of flavene (180) was (2). The racemic diol (181) was accomplished by observed [52]. Apparantly the flavene was the dihydroxylation of flavene (180) using a non- formed due to the pre-mature quenching of the asymmetric dihydroxylation protocol [52, 53]. reaction with acid, since the reduction of the carbonyl group with NaBH4/CeCl3 rapidly formed The tetramethyl ether of melacacidin was the alcohol intermediate (179), while the synthesized by the hydrogenation of 7,8,3,4- conversion to the olefin was a much slower step. tetramethylflavonol (189) over Raney nickel to The intermediate E-configuration of the double furnish tetra-O-methylmelacacidin (190) shown in bond favors the acid catalyzed intramolecular Scheme 21 [54]. (2R,3R,4R)-Melacacidin is a cyclization to form the flavene (180), while the natural flavan-3,4-diol obtained from Acacia olefin (182) was formed after prolonged stirring. species and has shown to have moderate The olefin (182) was transformed into flavan-3-ol allergenic properties [55]. (187) and flavan-3-one (188) as described in

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OBn BnO O BnO OH BnO O i ii iii iv v BnO OH 77 % 80 % 80 % OBn OBn OBn 124 125 126 127

OMe OMe

BnO O HO O BnO O vi vii 50 % 65 % OBn OBn OH 128 129 130

Reagents and conditions: i) Allyl bromide, K2CO3, acetone, 60 °C, 15 h; ii) 230 °C, 1 h; iii) BrCH2CH2Br, K2CO3, acetone, 60 °C, 38 h; iv) 50 % aq. NaOH, n-Bu4NHSO4, benzene, 1 h; v) Grubbs-2 Ru-catalyst, toluene , 60 °C, 10 min; vi) 2-MeOPh-N2BF4, Pd(OAc)2, 2,6-di-t-butyl-4-methylpyridine, EtOH, 55 °C, 20 min (over two steps); vii) H2, Pd(OH)2, THF/MeOH, 25 °C, 5 h. Scheme 13: Machado et al. synthesis of F. guianensis flavan

R Cl R R1 OH Cl 1 1 R Br R2 Br 2 R2 i ii + R O 74-83 % R3 OH 64-82 % 3 R3 O

131 132 133 R1 R2 R3 134 H H H 135 H Me H 136 H Cl H 137 -(CH)4- H 138 OMe H OMe o Reagents and conditions: i) PPh3, DEAD, THF, rt.; ii) n-BuLi, THF, -50 C to rt. Scheme 14: Mitsunobu reaction in the synthesis of flavans

Cl E R Br Br R 140 None Br i, ii, iii 141 DMF CHO 142 CO ) CO H O 57-84 % O 2(g 2 143 (CH2O)n CH2OH 144 MeI Me 139 Reagents and conditions: i) n-BuLi, THF, -50 oC to rt; ii) n-BuLi; iii) E (electrophile), -50 oC to rt.

Scheme 15: Mitsunobu reaction one pot cyclization and fuctionalization into flavans

O Cl OH Cl Cl Br i Cl 91 % OH ii, iii Cl O Cl 78 % Cl 145 146 147 7 o Reagents and conditions: i) BH3, (R)-oxazaborolidine, THF, 0 C; ii) PPh3, DEAD, THF, rt; iii) n- BuLi, THF, -50 oC to rt.

Scheme 16: Synthesis of 4',6-dichloroflavan

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HO OH OH OAc

HO OH AcO O O 148 i ii, iii + O 65 % O 90 % O H 150 151 iv OH 90 % 149 OAc R AcO O R O v, vi Ar-H + 83-100 % OH Ar 152 153 Ar= MeO MeO OMe OMe O O OMe Ph OMe Br Ph O HO HO MeO N H O MeO o Reagents and conditions: i) KOH, 100 C; ii) HCl, MeOH, reflux; iii) Ac2O, pyridine; iv) H2, Pd/C, EtOH v) BF3.OEt2, DCM, rt; vi) KOH, MeOH. Scheme 17: Deodhar and co-workers synthesis of 4-arylflavans

Phenol O R1 R2 R3 O BF3.OEt2 155 H H H R 156 Me H Me ether, 25-70 % 1 157 H H Me O R2 158 H NO H OH 2 159 H H NO2 154 R1 R3 160 H H Tolyl Phenol ArOCOCl 161 2-Naphthyloxy HCl-EtOH or p-TsOH, DCM Phenol, 4-72 % 7-32 %

O O

O OAr 162 R= p-Me R 163 R= H O 164 R=p-OH 165

Scheme 18: Synthesis of 4-arylflavans and 4-aryloxyflavans

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R R O O O i 77 % O OH O ii OAr 166 169 ii 170 i 100 % 95 % 73 % R

O O O O

OH OH OH OAr OAr OAr O 172 167 168 R= H or OMe iii 171 40 %

O O O v iv OH 100 % OH 90 % OH O O O

O O O

O PhO2S HO 175 174 173 Reagents and Conditions: i) ArOH; ii) ArO- Na+; iii) CHCl3; iv) NaBH4, MeOH-CHCI3; v) PhSO2H, HOAc, EtOH Scheme 19: Synthesis of 4-aryloxyflavans from 2,3-cis and 2,3-trans-flav-3-ene

The Clark-Lewis group reported the synthesis of NMR was used to assign the configurations and four sets of racemates (193, 197, 199-200) of the heterocyclic ring was found to adopt a half- flavan-3,4-diols in Scheme 22. The cis-cis chair conformation. The coupling constants were racemate (193) was obtained from flavanol 192 distinctive for 2H, 3H and 4H in flavan-3-diols as by Raney-Ni hydrogenation [56,57]. The cis [J2ax-3eq=0.9-1 Hz and J3eq-4ax=3.3-3.9 Hz] and reduction of 2,3-transflavandiols (198) with trans [J2ax-3ax=7.1-10 Hz, J3ax-4ax=5.8-7.5 Hz and LiAlH4 furnished 2,3-trans, 3,4-cis-racemate J3eq-4eq=0-1 Hz] [56,58]. (199) and 2,3-trans, 3,4-trans-racemate (200). The least accessible leucoanthocyanidins Machado and coworkers synthesized 4- racemic form was synthesized by the reduction methoxyflav-3-en (205) from phenol (201) in a of the 3-bromoflavanone (195) into 3- total of five steps [40,59]. Phenol (201) (R = H) bromoflavan-4-ol (196) with NaBH4. The was reacted with allyl bromide in the presence of treatment of 3-bromoflavan-4-ol (196) with K2CO3 and acetone followed by thermal Claisen potassium acetate in acetic anhydride afforded rearrangement to compound 202. O-allylation of the 2,3-cis-3,4-trans racemate (197) as compound (202) with tetravinyltin in acetonitrile, described in Scheme 22 [58]. The acetic catalyzed by copper (II) acetate furnished allyl anhydride was used for the acetylation of the ether (203). Ring closure metathesis using racemate obtained with KOAc-EtOH which was Grubbs-2 catalyst afforded chromene (204) and 1 an oil, while its diacetate was a solid. The H the Heck-Matsuda arylation with Ar-N2BF4 using

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palladium (II) acetate catalyst furnished 4- with phosphorous halide, Scheme 26. The 4- methoxyflav-3-en (205) as depicted in Scheme halogenoflavans were reported to have a 2,4- 1 23. Pd2(dba)3dba equally worked as a catalyst trans configuration based on H-NMR but at slightly elevated temperature of 65ºC to interpretations, J2,3 =13-14 Hz and J3,4 = 6-6.5 furnish 4-methoxyflav-3-en (205) in 54% [59,60]. Hz. An attempt to recrystallize the 4- chloroflavan (223) from methanol led to the Mewett and coworkers [61] synthesized flavan-3- substitution of the halide by the MeO- ion (229). ols, (211, 212), starting from the reaction of The action of arylphenols on 4-halogenoflavan acetophenone (206) and benzaldehyde (207) gave the desired product albeit at lower yields (Scheme 24). The first key step was the (20-30%) and inversion of configuration. reduction of the chalcone with NaBH4 to afford Improved yields 40-50% for the 4-arylflavans (E)-1,3-diarylpropene (209). The reported (230-235) were accomplished using + NaBH4-H2O/H reduction system was selective stoicheiometric amount of a phase transfer towards C=O reduction only, similar to catalyst, PTC (benzyltri-n-butylammonium LiAlH4/AlCl3-THF [30], but was in utter-contrast to bromide) as shown in Scheme 27. Flavan-4-yl reductions using H2/Pd-C [25] and NaBH4-MeOH sulphides (238, 239) were synthesized by the systems [26,29,34] which reduced both the C=C action of thiophenolate nucleophile on 4- and C=O bonds. After the MOM protection of chloroflavan (223) (Scheme 28), while 4- free OH, asymmetric dihydroxylation of the (E)- aminoflavans (240-244) were synthesized using 1,3-diarylpropene (209) double bond using AD- amino group nucleophiles [66-69] as described in mix-β afforded (1R,2R)-syn-diol (210) (AD-mix-α Scheme 29. equally works to give (1S,2S)- syn-diol. The deprotection and cyclisation [62] furnished a Flavylium salts were reduced to flavenes in mixture of cis- and trans-flavan-3-ols, (211-212), various ways. Lithium aluminium hydride is in a ratio of 1:3 respectively [61]. In chalcone generally used for the preparation of flav-2-ens reductive protocols the hydroxyl group is derived unsubstituted at C2’ and C3 (246), and flav-3-ens from the C=O reduction [29], and cyclization substituted at C3 and C2’ (247-248; Scheme 30) afford flavans while in this protocol the cyclization [70]. Mixture of flav-2-ens (249) and flav-3-enes step yields C-3 hydroxy substituted flavans (250) were obtained for flavylium ions bearing (flavan-3-ol), due to the presence of 1,2-diols electron donating groups at C-2’, which render moiety. LiAlH4 a less useful reducing agent [71].

The dimethyldioxirane (DMD), oxidation of The catalytic reduction of 3,5,7,2,4- flavan-4-ol and flavans (213) derivatives affords pentamethoxyflavylium chloride (251) with Pd- the corresponding C-2 hydroxy derivatives (213, BaSO4 furnished 3,5,7,2,4-pentamethoxyflavan 215) in good yields [63,64], Scheme 25. (252; Scheme 31) [72], which is a derivative of Treatment of compound (214) with silica gel cyanomaclurin (3,5,7,4-tetrahydoxyflavan) [73]. eliminates the acetic acid to give flavene (216). Cyanomaclurin (253) is a constituent of The flavane with the 4-equatorial acetoxy is more Atorcapus species and exhibit antibacterial and stable. On the other hand the dehydration of tyrosinase inhibitor activity [74,75]. flavan (215) requires POCl3 at 50ºC. The differences have been ascribed to the fact that An efficient bromination of flav-2-ens (254) with the presence of the axial acetoxy group in N-bromosuccinimide in methanol occurred more hydroxylated intermediate (218) weakens the rapidly than substitution into the aromatic moiety hydrogen bonding between the C-2 hydroxy to give 2,3-cis-2methoxy-3-bromoflavans (255). group and the benzyl ethereal oxygen, which The reduction of flavans (255) with tri-n-butylin favors dehydration [63,65]. The flavylium ion, hydride removed the bromine atom to afford 2- anthocyanin (217) was obtained after the methoxyflavans (257-259), while the removal of treatment of flavene (216) with HCl, whereas the methoxy group was achieved by using mild oxidants were required for transformations LiAlCl4 to yield 3-bromoflavane (256). The 3- of flavene (219 and 220) [63]. bromoflavanes (256) gave the corresponding 2- methoxyflavanes (257-259) after treatment with The reaction of nucleophiles (alcohols or amines) silver nitrate in methanol as shown in Scheme 32 with flavan-4-ols or flavan-4-halides affords the [39,76]. corresponding 4-substituted flavans. A series of 4-halogenoflavans (223-227) were obtained via Gharpute and co-workers [77] reported a mild SN2 substitution reaction of flavan-4-ol (222) protocol for the synthesis of flavans (263-266)

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using in situ generated quinone methide (o-QMs) the reaction required a 1:1 equivalent of styrene (262), which undergoes a [4+2] cycloaddition (261) for an efficient hetero Diels-Alder reaction reaction with styrene (261) and non-aryl [77-79]. The BPA catalyzed reaction had a vinylogous systems such as acrylates as shown diastereoselectivity (3:1) favouring the cis in Scheme 33 and Figure 4. The o-QMs were isomer, while Bi(OTf)3 catalyst produced a generated from o-hydroxy bisbenzylic alcohols racemic mixture (1:1) though at the same yields (260) using (±)-binolphosphoric acid (BPA) and [77]. OR1 RO OH RO OH OR1 i OMe OHC OMe 100% OR O 1 OR1 O 176 177 178

ii OR 1 OR1 RO OH ii, NaBH4 OMe RO OH 24 h stirring OMe 73% OR 1 OR1 OH 182 179

15 % H+ OR1 OBn iii RO O OMe MOMO O 57% OMe iv 88% OR1 OBn 180 181 OR TBS 1 OR RO O TBS 1 OR OMe v 1 RO O vi 93% OMe RO OH OH OMe 84% OH OR OH 1 OH OR1 OR1 183 184 185

100% vii

OR OR1 1 OR1 ix viii RO O RO O OMe RO O OMe 66 % 87% OMe

O OH O OR1 OR1 OR 1 O R= Bn or MOM 188 187 186

o Reagents and conditions: i) NaH, Heptane/DMF; ii) NaBH4, CeCl3.7H2O, THF/EtOH, 0 C; iii) K3Fe(CN)6, K2CO3, OsCl3.H2O, quinuclidine, methane sulfonamide, t-butanol/H2O/THF, rt, 18 h then NaBH3CN-HOAc, o o 50 C, 2h; iv) TBDMSCl, imidazole, DMF; v) AD-mix-a, MeSO2NH2/K2CO3, t-BuOH/water/THF, 0 C; vi) o o TBAF, AcOH, THF, 0 C; vii) EtC(OEt)3, PPTS, DCM, 65 C; viii) K2CO3, MeOH; ix) Dess–Martin periodinane, DCM, rt. Scheme 20: Zhang et al. chalcone reduction and synthesis of flavanes, flavan-3-one and flavan-3-ol

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OMe OMe OMe OMe MeO O MeO O OMe Raney-Ni OMe EtOH, 100-110 atm 40% OH O OH 189 190 Scheme 21: Synthesis of melacacidin tetramethyl ether

OMe OMe OMe

OH O O R i R ii R 57 % 16-36 % Me Me OH Me OH O O OH 191 192 193 R= H, OMe OMe OMe OMe

OAc O O R iii R vii R Br 44-52 % 43-65 % Me Br Me Br Me Br O O OH 194 195 196

40-50 % iv 54-64% viii OMe OMe OMe

O O O R vi R R 30-86 % Me OH Me OH Me OH O OH OH 198 199 197

58-68 % v R= H, OMe, OAc R= H, OMe, OAc OMe

O R

Me OH OH R= H, OMe 200 - o Reagents and Conditions: i) H2O2-OH ; ii) Raney-Ni, EtOH, 100 atm, 90 C, 14h; iii) HCl, EtOH-H2O, 4h o o iv) Br2, CCl4, COMe2, 15 min; v) LiAlH4, THF, 0 C, 1h; vi) LiAlH4, AlCl3, THF, 0 C, 1h; vii) NaBH4, MeOH, 2 o o days, 0 C or LiAlH4, THF, 1h, 0 C; viii) KOAc, AcOH, Ac2O. Scheme 22: Synthesis of flavan-3,4-diol racemates

Gharpure and co-workers applied the hetero are both potent DNA-damaging agent and DNA Diels-Alder reaction of o-quinone with styrene to polymerase  inhibitors [80-83]. The total the synthesis of Myristinins A and B/C [77]. synthesis of Myristinins A and B/C reported by Myristinins A (279) and B/C are natural Gharpure and co-workers in Scheme 34 [77] is neoflavans isolated from Myristica cinnamomea, shorter than the lengthy strategy reported by Knema elegans and Horsfieldia amygdaline Hecht and co-workers [80,81]. [80,81] showing anti-inflammatory, antifungal and

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OH R R iv O i, ii iii R 73% 91 % OH 81 % O R 2017 202 203 204 R = H R = H R = NO2 OMe R = NO2 v O 54-57 % R 205 R = H R = NO2 Reagents and conditions: i) K2CO3, allyl bromide, acetone, 60 C; ii)  (180-240 C), neat; iii) Cu(OAc)2, Sn(CH=CH2)4, O2, MeCN, 25 °C, 24 h; iv) Grubb’s second generation Ru-catalyst, toluene, 60 °C, 1 h; v) Ar-N2BF4, Pd(OAc)2, 2,6-di-t-butyl-4-methylpyridine, EtOH, 55 C, 2.5 h. Scheme 23: Machado et al. synthesis of 4'-methoxyflav-3-en

R1 R2 OH O O R1 1 5 R R OH 3 HO R R5 OMOM R2 i ii, iii + 4 R5 R2 R 80-84 % 88-97 % R4 R3 R4 R3 O 206 207 208 209

R1 OMOM iv R5 R2 OH 88-94 % R4 R3 OH 210

v 88-95 % 70-94 %

R1 R1 R2 R2

R5 O R5 O R3 R3

R4 OH R4 OH 211 212 R1 = R3 = R4 = R5 = H; R2 = OMe (2R,3R)- R3 = R4 = R5 = H; R1 = R2 = OMe (2S,3R)- R1 = R3 = R5 = H; R2 = R4 = OMe R3 = R5 = H; R1 = R2 = OMe; R4 = Me R4 = R5 = H; R2 = R3 = OMe; R1 = Br 3 4 5 1 2 R = R = R = H; R = R = OCH2O R1 = R3 = R4 = H; R2 = OMe; R5 = OBn R3 = R4 = H; R1 = R2 = OMe; R5 = OBn R1 = R3 = R4 = R5 = H; R2 = OBn + Reagents and conditions: i) KOHaq/ EtOH; ii) EtCO2Cl/TEA/THF, then NaBH4/H2O, then H ; iii) MOMCl/(i-Pr)2NEt/THF; iv) AD-mix- or AD-mix-/MeSO2NH2, H2O/BuOH, 0-4 C; v) HCl/MeOH-H2O. Scheme 24: Mewett and coworkers synthesis of flavan-3-ols

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R5 R5 R5 OH DMD DMD OH R2 O R2 O R2 O 63 % 57 %

R R4 R1 3 R4 R R4 R1 R3 R1 3 R1, R2, R3, R5 = H R3, R4 = H R4 = OAc R1, R2, R5 = OAc 214 213 215

36% Silica gel DMD POCl3 AcOH OAc 50oC OH OAc OH AcO O O AcO O

OAc OAc OAc 216 218 220 13% H+ OAc 62% PCC OAc O AcO O PCC AcO O 60%

OAc OAc OAc 217 219 221 Scheme 25: Hydroxylation and oxidation of flavans R1 R1 PX O O 3 R2 R2 ether 52-64 % R1 R2 X 223 H H Cl X OH 224 H H Br 225 OMe H Cl 222 226 OMe H Br 227 OMe OMe Cl Scheme 26: Synthesis of 2,4-trans-4- halogenoflavans

The strategy begun by deriving the o-QM [Cu]-catalyzed C–O bond formation from the precursor (272), iodoalcohol (271) from the precursor diphenylalcohols. The synthesis starts addition of diiodide to an aldehyde (270). The o- with the Lewis acid promoted Friedel-Crafts QM undergoes a [4+2] cycloaddition with styrene Michael addition of electron rich phenols (281) to furnish arylflavan in good diastereoselectivity onto the double bond of the cinnamate ester (cis:trans; 9:1). The arylflavan stabilized by (280) to furnish a -diaryl ester (282). styrene dienophile reacted with ethyl vinyl ether Preferential electrophilic aromatic bromination of (275) under Heck reaction conditions to afford the electron rich aromatic ring at the -diaryl ketone 276. Ketone 276 was reported to be ester, followed by reduction of the ester furnished difficult in forming an enolate ion due to steric the required precursor alcohols (284). The hindrance, but repeat generation of ketone 276 cyclization using intramolecular [Cu]-catalyzed enolate ions using t-BuOK and alkylation with n- C–O bond formation was successful and decyl iodide accomplished the synthesis of furnished neoflavans (285) shown in Scheme 35 Myristinin A (279) [79] as depicted in Scheme 34. and Fig. 5 in good yields [84].

Suchand and co-workers presented the neoflavan synthesis based on the intramolecular

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R1 R1 O O R2 PTC R2 DCM, 39-52 % X 228

MeOH R3 52 % recrystallization R1 R2 R3 230 H H H R1 231 H H Me 232 OMe H H O R2 233 OMe H Me 234 OMe H Ac 235 Ar-R3 = 4-methoxy(2-naphtyl) OMe 229 Scheme 27: Synthesis of 2,4-cis-4- arylflavans

R1 R1 O O PhSNa Dioxane, 43-49 % SPh X 236 238 R1= H 237 239 R1= OMe Scheme 28: Flavan-4-yl sulphides synthesis

O O R1NH2 Dioxane, 16-30 % R R HN 2 Cl 1 R1 R2 223 240 CH2Ph H 241 Ph H 242 H NHPh 243 CH2CO2Et H 244 H NHCH2CO2Et Scheme 29: Synthesis of 4-aminoflavans

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OMe

O

40 % OMe 246

R Cl 1 O O 22 and 53 % + O LiAlH 4 Me Me ether R2 247 248 R1 245 O O mixtures OMe OMe 46% 249 250 Scheme 30: Reduction of flavylium ions with LiAlH4

OMe OMe OH Cl MeO O MeO O HO O Pd-BaSO4 OMe EtOH, 46% OMe OH OMe OMe O OMe OMe OH 251 252 253 Scheme 31: Synthesis of pentamethoxyflavan

R1 R1 R O 4 N-bromosuccinimide R4 O R2 R2 MeOH, 74-100 % OMe Br

R3 R3 254 255 n-Bu3SnH C H 6 6 45-53 % 52-84 % LiAlH4-AlCl4 R1 ether R1 R4 O R2 OMe AgNO3 -MeOH R O 4 R 52-53 % 2 R3 Br R1 R2 R3 R4 R3 257 H H H H 258 OMe H H H 256 259 OMe OMe OMe OMe Scheme 32: Synthesisi of 2-methoxyflavan and 3-bromoflavans

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R4 R4 R4 R3 R3 R3

R5 R2 R5 R2 R5 R2 OH + BPA

R6 DCM, rt 61-94 % R1 OH R1 O R1 O

R6 260 261 262 R1 R2 R3 R4 R5 R6 263 H H H H H OBn 264 H H H OMe H H 265 H OMe H OMe OMe Me 266 OMe OMe I OMe OMe Me Scheme 33: Synthesis of flavans using [4+2] cycloaddition of o-QMs and styrene OMe OMe

MeO OMe O OMe O O O MeO O OMe MeO O OMe MeO O O 267 268 269

Figure 4: Flavane derivatives reported by Gharpure and co-workers

The synthesis of [3.3.1]-bicyclic ketals was were (S)-one selective. The (R)-flavanone was accomplished by the Pd(II)-catalyzed asymmetric ineffectively reduced by Saccharomyces 1,4-conjugate addition of organoboron reagent brasiliensis KCh 905 to afford (2S,4R)-trans- [85], 2-hydroxyphenylboronic acid (294) to flavan-4-ol (12%, 91% ee) and (2R,4R)-cis- chalcones (293). The 2-hydroxyphenyl palladium flavan-4-ol (7%, 22% ee) [87]. metal complex (295) was generated in situ via the transmetalation of 2-hydroxyphenylboronic 2.3 Isoflavans acid (294), with the chiral Pd(ii)-complex [generated from Pd(PhCN)2Cl2 and ligand (R)- Deodhar and co-workers [45] used the procedure 3,5-xyly-BINAP, L3]. The palladium complex 295 for the synthesis of flavans (152) (Scheme 17) to act as a bis(nucleophile) in the construction of the construction of isoflavans 325 from the chiral flavan heteroannular ketals shown in isoflavanol (323) [88,89] as described in Scheme Scheme 36 [86]. The products were reported in 38. Trans-4-aryl/heteroarylisoflavans were higher enantio-selectivities and the substituent synthesized in good to excellent yields and on the chalcones only affected the yields. bearing various substituents [45]. Besides the flavanone reductions utilizing inorganic catalyst reductions, the application of Takashima and co-workers outlined the biocatalysts has also been reported. Three day synthesis of natural flavans, (S)-equol, (R)- biotransformation of (S)-flavanone (317) with sativan and (R)-vestitol using allylic substitution yeast of the genus Candida wiswanathi KCh 120 [90]. The (S)-equol synthesis was offset by the enabled the enantioselective reduction of the Wittig reaction between the phosphonium salt ketone functional group to give (2S,4S)-cis- derived from arylaldehyde and the protected 2- flavan-4-ol (38%, 95%) (318) and (2R,4S)-trans- hydroxypropanal (326). The aldehyde was flavan-4-ol (51%, 92% ee) (319) as shown in synthesized from ethyl-(S)-lactate (329). The Scheme 37. The reductions by the yeast species Wittig product was the cis-olefin (332), which

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after deprotection and esterification afforded the Scheme 38. The synthetic protocol for (R)- key intermediate, picolinate (333) in 94% ee sativan differs with that of (S)-equol at the (cis:trans: 14:1). The allylic substitution of (S)- deprotection and cyclization steps. The picolinate with the copper reagent produced the protecting benyl group was removed by H2-Pd/C anti SN2 trans olefin product which when catalyst and cyclization with Mitsunobu reagent, subjected to OsO4-catalyzed dihydroxylation PPh3 and DEAD constructed the benzopyran ring gave a polar diol of 335. The cleavage of the diol of (R)-sativan (344) as shown in Scheme 41 by NaIO4 and in situ reduction of the resulting [90,96-98]. aldehyde with NaBH4 affords an alcohol, which was brominated to obtain compound 335. The The synthetic strategy towards (R)-vestitol (10) cyclization of 335 yields (S)-equol (9) in 91% ee was similar to that of (R)-sativan (344), but the after demethylations using BBr3 [90-92] as copper reagent utilized was derived from the depicted in Scheme 39. The synthesis of (S)- Grignard reagent 2-MOMO-4-MeOC6H3MgBr. equol was previously reported in a similar The final step was the deprotection of the MOM manner from (S)-picolinate with yields of 74% group with HCl in MeOH (Scheme 42) to furnish and 99% ee [93]. The first total synthesis of (S)- (R)-vestitol in 90% ee [90,92,99]. equol was reported by Heemstra and co-workers in an overall yield of 9.8%. Their six step protocol Gharpure and coworkers reported the synthesis key step was the Evans alkylation [94] to form of isoflavans using in situ generated o-quinone the stereocenter and an intramolecular methides (o-QM) as heterodiene in the [4+2] etherification to generate the benzopyran ring, Diels-Alder cycloaddition reaction shown in which was deprotected to furnish (S)-equol as Scheme 43. The required o- shown in Scheme 41 [95]. acetotoxymethylphenol (347) was prepared from the salicyladehyde derivative (348) reduction, For the synthesis of (R)-sativan, the intermediate while the arylenol ethers (348) were synthesized (R)-picolinate was synthesized from ethyl-(R)- via Wittig reaction on an arylaldehyde (347). lactate using similar reactions described in

OMe OMe

CHO OMe OH I I i OBn MeO OMe MeO OMe 2730 + 64 % ii 90% MeO OMe OH OBn BnO O BnO OH 270 271 272 274 OBn OEt 275 iii iv OH O OMe O OMe O

(CH2)10Me (CH ) Me 2 10 Me(CH ) CH I v 2 9 2 HO OH MeO OMe 277 MeO OMe v

HO O BnO O BnO O

OH OBn OBn 279 278 276 o o Reagents and conditions: i) n-BuLi, THF, -78 C; ii) BPA, DCM; iii) Pd(OAc)2, PPh3, Et3N, DMF, 110 C; iv) HCl; v) t-BuOK, THF, 0 oC-rt. Scheme 34: Synthesis of Myristinin A

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OMe O OMe O OMe O OMe

OMe OMe OMe

286 287 289 O OMe O OMe O OMe OMe OMe OMe Et

Cl 290 291 292 Figure 5 Neoflavans reported by Suchand and co-workers

COOEt COOEt COOEt

i ii + OR OR OR 62-87 % 90-97 % R 1 R1 R1 Br 280 281 282 283 iii 89-94 % O OR CH2OH

iv R OR 1 67-78 % R1 Br 285 284 o o Reagents and conditions: i) FeCl3, DCE, rt, 12h; ii) Br2, DCM, 0 C, 3h; iii) LAH, Et2O, 0 C, 1h; iv) CuI, 2,2'-bipy. t-BuKO, DMF, 120 oC, 24h. Scheme 35: [Cu]-catalyzed C-O bond formation in the synthesis of neoflavans

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O

R3 R4 R3 R OH toluene, rt. O 2 20-93% R1 90-98 %ee R2 O R4 293 R1 296-316 B(OH) Pd(PhCN)2Cl2 2 PdL* L3, AgBF4, toluene, rt. OH OH R1 R2 R3 R4 294 295 305 MeO H H 2-MePh 306 MeO H H 2-ClPh R R R R 1 2 3 4 307 MeO H H 2-BrPh 296 MeO H H Ph 308 MeO H H 3-ClPh 297 H MeO H Ph 309 MeO H H 4-ClPh 298 H H MeO Ph 310 MeO H H 4-FPh 299 H H OH Ph 311 MeO H H 4-CF Ph 300 H H Me Ph 4 312 MeO H H 4-MePh 301 H H F Ph 302 H H Cl Ph 313 MeO H H 4-MeOPh 314 MeO H H 3,4-diMePh 303 H H Br Ph 315 H H H Ph 304 H H NO2 Ph 316 H H H C4H4S Scheme 36: Synthesis of flavan heteroannular ketals

O OH OH Candida wiswanathi sterile culture + substrate in acetone O O O

cis trans- 38 %, 95 % 51 %, 92 % ee 317 318 319 Scheme 37: Biotransformations of flavanone to flavan-4-ols

The Diels Alder reaction of diene, o-quinone Versteeg and co-workers reported the synthesis methides (o-QM; 351) generated from o- of isoflavans using the Evans chiral auxilliary acetotoxymethylphenol and the dienophile, alkylation. The acylation of the trimethylsilyl arylenol ethers (348) afforded diastereomeric ethers of chiral auxiliary, (4S,5R)-(+)- and mixture of isoflavan acetals (352). Reductive (4R,5S)-(-)-imidazolidin-2-ones (365) with elimination of the methoxy group afforded phenylacetyl chlorides (367) affords N-acyl isoflavans (353) in poor to excellent yields as imidazolidinones (368). The LICA (lithium shown in Scheme 43 [100]. isopropylcyclohexylamide) generated enolate ion of N-acyl imidazolidinones were alkylated in good Natural isoflavans were prepared by de- yields giving only one diastereoisomer (369; de protecting compounds (353-364 in Scheme 43) 84-90%). The reduction of the alkylation products using H2/Pd-C in ethylacetate. Compound 363 into arylpropanols followed by the cyclization and 364 furnished equol (340) and vestitol (10) in afford isoflavans (371). The cyclization after the 83 and 87 % yield respectively. Compound 362 activation of the hydroxyl group gives lower methoxy groups were removed using pyridinium yields (46-60%) when NaH was used, but higher hydrochloride to give 3’-hydroxyequol (9) in 65% yields (73-95%) were observed when yield [100]. Mitsunobou conditions were employed [101,97]

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as shown in Scheme 44. The reports indicated antioxidative effect and also inhibit the that the alkylation step had preferential formation tyrosinase-dependent melanin biosynthesis of the Z-enolate. Thus, the alkylation was [102,103]. The synthetic strategy towards (±)- directed to the face of the enolate opposite the Glabridin was outlined by Yoo and Nahm [104] phenyl moiety on the chiral auxiliary and the as described in Scheme 45. configuration of the isoflavans were stated to be 3R or 3S [94,101]. The C-3 configuration of the The heartwood of Dalbergia nitidula contains the isoflavans were determined by that of chiral natural isoflavan oligomer, (3S,4S)-3,4-trans-4- auxiliary. (4S,5R)-(+)-imidazolidin-2-ones affords [(3S)-6',7-dihydroxy-4'-methoxyisoflavan-3'-yl]- the 3S-isoflavans while the (4R,5S)-(-)- 2',7-dihydroxy-4-methoxy-isoflavan (388). The imidazolidin-2-ones yields the 3R isomers synthesis of the [4,3’]-bi-isoflavan was [101,97]. accomplished by the condensation of (+)-vestitol (10) with (+)-medicarpin (387) as the elctrophile. Glabridin (386) is a natural isoflavan from the The pterocarpan (389) reacted with phenolic licorice of Glycyrrhiza glabra. Glabridin has been electrophiles (390-391) to furnish 4-arylisoflavan found to be responsible for the licorice and dimers shown in Scheme 46 and 47 [105].

HO OH

HO OH AcO O 320 i ii, iii + 90 % O 73 % O O OH OAc HO 322 323 OH iv 90 % 321 HO O AcO O v, vi Ar-H + 64-95 % Ar OH OH OAc Cis:trans 2:1 Ar= 325 324 O OMe OH O MeO OMe Br OMe Ph

HO Ph MeO O MeO O MeO O OH OMe OMe MeO OH

OMe MeO OH MeO OH o Reagents and conditions: i) BF3.OEt2, 110 C; ii) HC(OEt)3, pyridine, piperidine; iii) Ac2O, pyridine; iv) H2, Pd/C, EtOH; v) BF3.OEt2, DCM, rt.; vi) KOH, MeOH. Scheme 38: Deodhar and co-workers synthesis of 4-arylisoflavans

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MeO MeO i)9-BBN, THF, 0oC MeO [Ph3PCH3] Br, BuLi ii) H O , NaOH CHO 2 2 o THF, 0 C to rt. iii) CBr , PPh PPh3Br OMe OMe 4 3 91 % iv) PPh3, EtOH, OMe  326 327 328

CO2Et TBDPSl CO2Et DIBAL-H CHO i) NaN(TMS)2 o OH THF, 0 C Imidizole OTBDPS DCM, -78 oC to rt. OTBDPS o 100% 89 % ii) 178 C to rt. 329 330 331 97 % MeO MeO i) Bu4NF ii) PyCO2H, DCC, DMAP 94 % OMe OMe OTBDPS OCOPy 333 332

4-MeOC6H4MgBr CuBr•Me2S, –70 to –50 °C, not purified OMe OMe OH

i)OsO4, NMO, Acetone, H2O ii) NaIO4, MeOH, H2O Br i) BBr3, DCM ii) K2CO3, COMe2 iii) NaBH , 4 O iv) CBr4, PPh3 82 % 74 % OMe OMe HO OMe OMe 334 335 9 Scheme 39: Synthesis of (S)-equol

O O O MeO O O O N NaHMDS, THF LiAlH , THF O N O 4 o -5-10 C, 40 min. -5oC-rt, 1h. Br 48% 96% Ph Ph OH 336 O Br OMe + 338 339 Br

O Br Cs2CO3, Pd(OAc)2 337 P(tBu)2 PhMe, 50oC, 22h.

46% HO MeO Pyr-HCl O 150oC, 28h, 66% O

OH 9 e e > 9 9 . 9 % 340 OMe Scheme 40: Synthesis of (S)-equol via Evans alkylation

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i) 2,4-(MeO)2C6H3MgBr BnO BnO CuBr•Me2S –60 to –50 °C, OMe ii)OsO4, NMO, acetone, H O OBn OBn 2 OCOPy iii) NaIO4, MeOH, H2O OH OMe iv) NaBH4, 73 % 341 342 H , Pd/C HO 92% 2 MeOH HO OMe i) DEAD, PPh3, THF O ii) LiOH, MeOH, 80oC OMe 77 % OH OMe OH 344 343 OMe Scheme 41: Synthesis of (R)-sativan the (R)-picolinate

HO HO HO

i) DEAD, PPh , THF HCl, MeOH OMOM 3 OMOM OMOM OH ii) LiOH, MeOH, 80oC O reflux, 80 % O 87 % OH OMe OMe OMe 345 346 10 from 343 Scheme 42: Synthesis of (R)-vestitol the (R)-picolinate

CHO OMe i R4 O OMe R1 R3 63-83 % R1 R3 iii R2 R2 347 348 46-58 % 3 1 + R R R2 CHO OR5 ii 352 R4 OH R4 OH 85 % R4 O iv R5 = H, Ac 349 351 35-92 % 350 R1 R2 R3 R4 354 H H H H R4 O 355 Me H H H 356 OMe H H H 357 OMe H OMe H 358 H OMe OMe H R3 R1 359 OMe H H OMe R2 360 Me H H OMe 353 361 OMe H OMe OMe 362 OMe OMe H OMe 363 OBn H H OBn 364 OMe H OBn OBn Reagents and conditions: i) Ph3P CH2OMeCl, LiHMDS, THF, 0 ºC; ii) NaBH4, MeOH, rt.; then AcCl, Py, DCM, o o 0 C to rt.; iii) PhH, 80 ºC or PhMe, 115 ºC; iv)Et3SiH, BF3.OEt2, DCM, 0 C Scheme 43: Isoflavan synthesis using DA reaction between o-QM and arylenol ethers

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R 2 R2 O R R1 R3 R R 2 O O O O 1 3 R R 1 3 iii MeN NX O ii + MeN N MeN N 86-92 % Me Ph Cl 72-91 % Me Ph Me Ph 365 X= H i MOMO R4 366 X= SiMe3 367 368 369

76-90 % iv, v R1 R2 R3 R4 372 H H H H 373 H H MeO H R4 O OH OH R1 vi, vii R4 374 MeO H H H R1 R2 375 H MeO H MeO 73-92 % R2 376 MeO H MeO H ee 94-99 % 377 H H MeO MeO R3 R3 378 MeO H H MeO 371 370 379 MeO H MeO MeO

o Reagents and conditions: i) BuLi, Ph3CH, THF, 0 "C; then Me3SiCl, -78 C to rt; ii) tetrabutylammonium o O fluoride, MeCN, rt; iii) LICA, 2-O-methoxymethylbenzyl bromide, THF-DCM, -40 C; iv) LiAlH4, THF, -24 C to rt; v) HCI, MeOH, reflux; vi) BrsCl, pyridine, DCM, rt; vii) PPh3, DEAD, THF, rt.

Scheme 44: Synthesis of isoflavans using chiral auxilliary

OMOM HO OH O OH O OBz MeO2C + H i H ii H 97 % OMOM O 47 % O O 380 381 382 383 iii 87 % O O v, vi O OH OH O OH iv CO2Me OH 85 % 46 % HO OMOM OMOM MOMO MOMO 386 385 384 Reagents, conditions: i) (CH3)2C=CHCHO, MgSO4/py; ii) BzCl/CH2Cl2, TEA, 0 °C; iii) LDA, THF, -78 °C; iv) LiBH4, THF, reflux; v) PPh3, DEAD, THF; vi) TsOH, i-PrOH, reflux. Scheme 45: Synthesis of isoflavan: Glabridin

HO O OH HO O OH HO O OH + EtOH, HCl MeO OMe o OMe O 25 C, 12 h. OMe 20 % OH O OH 10 387 388 Scheme 46: Synthesis of [4,3]-bi-isoflavan

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MeO O OH MeO O OH MeO OMe HO OH OMe + HO OH HO OH O OH

OMe 392 73.6 % 393 26.4 %

HO OH EtOH, HCl 50 oC, 12 h. MeO O OH OH 390 HO O OH MeO O OH MeO OMe +

OMe O OMe OH O OH 391 389 394 23 % EtOH, HCl 40 oC, 21 h.

MeO O MeO O OH OH

OMe OMe OH OH

O O

MeO OH MeO OH MeO

OH O OMe 396 29 % 397 25 %

Scheme 47: Synthesis of isoflavan oligormers from reaction of a pterocarpan with phenolics

3. CONCLUSION antimicrobial properties. As such, numerous efforts have been directed towards their As mentioned earlier on, flavans are important syntheses. Among the many methods reported, compounds containing the 2-phenylchroman the common methods for their preparations moiety. They have been reported to possess include; (i). Reduction of flavanone and flavone anticancer, anti-inflammatory, antioxidants and with Raney-Ni, NaBH4 or H2/Pd (ii) cyclisation of

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2-(3-hydroxy-3-phenylpropyl)phenol derived from inhibition of Staphylococcus aureus chalcones via reduction using NaBH4 or H2/Pd biofilms. Int. J. Mol. Sci. 2013;14(10): (iii). Reduction of anthocyanins with NaBH3CN in 19434-19451. AcOH/Ac2O or with MgBr/PhBr followed by 2d. Bae UJ, Lee da Y, Song MY, Lee SM, Park NaBH3CN, (iv). Reactions of flav-2-enes with JW, Ryu JH, Park BH. A prenylated flavan alcohols in Lewis acid with subsequent reduction from Broussonetia kazinoki prevents with NaBH3CN, (v). Condensation of phenols cytokine-induced β-cell death through with secondary alcohols in BF3.OEt2 to 4α- suppression of nuclear factor-κB activity. aryloxyflavans and (vi). bromination of flav-2- Biol Pharm Bull. 2011;34(7):1026-1031. enes with N-bromosuccinimide. Neoflavans were 2e. Li LJ, Zhang Y, Zhang P, Pi HF, Ruan HL, synthesized by the intramolecular [Cu]-catalyzed Wu JZJ. Flavans from the leaf of Ilex cyclization of 3-(2-bromophenyl)-3-phenylpropan- centrochinensis. Asian Nat. Prod. Res. 1-ol. Isoflavans are isomers of flavans in which 2011;13(4):367-372. the 2-phenyl ring has shifted to position 3. 2f. Veitch NC, Grayer R. Flavonoids and their Hence, methods for their syntheses are similar to glycosides, including anthocyanins. J. Nat. those for flavans with with the addition of the Prod. Rep. 2011;28(10):1626-1695. intramolecular etherification of 3-bromo-2-(4- 2g. Cui Y M, Wang H, Liu QR, Han M, Lu Y, methoxyphenyl)propyl)-2,4-dimethoxybenzene Zhao CQ. Flavans from Iris tenuifolia and with good ee. Flavens, on the other hand have a their effects on β-amyloid aggregation and C=C double bond at either position 2 or 3. They neural stem cells proliferation in vitro. are mainly synthesized through (i). Reduction of Bioorg. Med. Chem. Lett. 2011;21(15): anthocyanins, (ii). Reduction of chalcones and 4400-4403. (iii) hydroxylation of flavans with BMD followed 2h. Amor NB, Bouaziz A, Romera-Castillo C, by oxidation with POCl3 to flav-2-enes. Salido S, Linares-Palomino PJ, Bartegi A, Anthocyanins are generally synthesized via Salido GM, Rosado JA. Characterization of hydroxylation of flavans with subsequent the intracellular mechanisms involved in oxidation. This report has presented the the antiaggregant properties of synthesis of flavans, isoflavans, neoflavans, cinnamtannin B-1 from bay wood in human flavens and anthocyanins. platelets. J. Med. Chem. 2007;50(16): 3937-3944. ACKNOWLEDGEMENTS 3. Crespy V, Williamson G. A review of the health effects of green tea catechins in in We thank the University Library for assistance vivo animal models. J. Nutr. 2004;134(12 during the Literature search. Suppl):3431-3440. 4. Moore RJ, Jackson KG, Minihane AM. COMPETING INTERESTS Green tea (Camellia sinensis) catechins and vascular function. Br. J. Nutr. 2009; 102(12):1790-1802. Authors have declared that no competing 5. Zaveri NT. Green tea and its polyphenolic interests exist. catechins: Medicinal uses in cancer and non-cancer applications. Life Sciences. REFERENCES 2006;78(18):2073-2080. 6. Asakawa T, Hamashima Y, Kan T. 1. Aron PM, Kennedy JA. Flavan-3-ols: Chemical synthesis of tea polyphenols and nature, occurrence and biological activity. related compounds. Curr. Pharm. Des. Mol. Nutr. Food Res. 2008;52(1):79-104. 2013;19(34):6207-6217. 2a. Saini KS, Ghosal S. Naturally occurring 7. Ghosal S, Singh SK, Srivastava RS. flavans unsubstituted in the heterocyclic Flavans from Zephyranthes flava. ring. 1984, Phytochemistry. 1984;23(11): Phytochemistry. 1985;24(1):151-153. 2415-2421. 8. Bauer DJ, Selway JWT, Batchelor,JF, 2b. Simard F, Legault J, Lavoie S, Pichette A. Tisdale M, Caldwell IC, Young DA. 4′,6- Balsacones D-I, dihydrocinnamoyl flavans Dichloroflavan (BW683C), a new anti- from Populus balsamifera buds. rhinovirus compound. Nature. 1981;292: Phytochemistry. 2014;100:141-149. 369-370. 2c. Manner S, Skogman M, Goeres D, Vuorela 9. Hu X, Wu JW, Wang M, Yu MH, Zhao QS, P, Fallarero A. Systematic exploration of Wang HY, Hou AJ. 2-Arylbenzofuran, natural and synthetic flavonoids for the flavonoid, and tyrosinase inhibitory

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