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(+)-Catechin Dimer, by Intramolecular Condensation

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(+)-Catechin Dimer, by Intramolecular Condensation molecules Article Regioselective Synthesis of Procyanidin B6, A 4-6-Condensed (+)-Catechin Dimer, by Intramolecular Condensation Yusuke Higashino 1, Taisuke Okamoto 1, Kazuki Mori 1, Takashi Kawasaki 2, Masahiro Hamada 3, Noriyuki Nakajima 3 and Akiko Saito 1,* 1 Graduate School of Engineering, Osaka Electro-Communication University (OECU), 18-8 Hatsu-cho, Neyagawa-shi, Osaka 572-8530, Japan; [email protected] (Y.H.); [email protected] (T.O.); [email protected] (K.M.) 2 College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan; [email protected] 3 Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University (TPU), 5180, Kurokawa, Imizu, Toyama 939-0398, Japan; [email protected] (M.H.); [email protected] (N.N.) * Correspondence: [email protected]; Tel.: +81-72-824-1131 Received: 9 January 2018; Accepted: 16 January 2018; Published: 18 January 2018 Abstract: Proanthocyanidins, also known as condensed tannins or oligomeric flavonoids, are found in many edible plants and exhibit interesting biological activities. Herein, we report a new, simple method for the stereoselective synthesis of procyanidin B6, a (+)-catechin-(4-6)-(+)-catechin dimer, by Lewis acid-catalyzed intramolecular condensation. The 5-O-t-butyldimethylsilyl (TBDMS) group of 5,7,3040-tetra-O-TBDMS-(+)-catechin was regioselectively removed using trifluoroacetic acid, leading to the “regio-controlled” synthesis of procyanidin B6. The 5-hydroxyl group of the 7,30,40-tri-O-TBDMS-(+)-catechin nucleophile and the 3-hydroxyl group of 5,7,30,40-tetra-O-benzylated-(+)-catechin electrophile were connected with an azelaic acid. The subsequent SnCl4-catalyzed intramolecular condensation proceeded smoothly to give the 4-6-condensed catechin dimer. This is the first report on the complete regioselective synthesis of a 4-6-connected oligomer without modifying the 8-position. Keywords: condensed tannin; proanthocyanidins; intramolecular condensation; procyanidin B6 1. Introduction Proanthocyanidins are a class of polyphenols and are generally referred to as condensed tannins or oligomeric flavonoids. They have attracted a great deal of attention because of their strong antioxidant activity and wide range of interesting biological functions [1,2]. However, proanthocyanidins are often obtained as a mixture of various analogues from plants. Thus, despite their simple structure as the derivatives of flavan-3-ols, the purification of each compound remains difficult. Flavan-3-ols such as catechin and epicatechin are one of the most well-known groups of biologically active polyphenols. The oligomers composed of these catechins and epicatechin are known as highly functional polyphenols contained in familiar foods such as cacao [3,4]. There are many reports related to other biological activities, such as antifungal [5,6], antiviral [5,7], anti-inflammatory [8], anticancer [3,9], and treating heart diseases [10], among others. Flavan-3-ol derivatives including proanthocyanidins are also converted to various structurally complex secondary polyphenols through chemical reactions that occur during food processing such as drying [11], frozen storage [12], and acidic treatment [13]. These complex and diverse forms make the isolation, structural determination, and evaluation of the biological activities of each compound much more difficult. Therefore, securing Molecules 2018, 23, 205; doi:10.3390/molecules23010205 www.mdpi.com/journal/molecules Molecules 2018, 23, 205 2 of 11 Molecules 2018, 23, 205 2 of 11 sufficientsufficient amount of proanthocyanidinproanthocyanidin as a pure compound for experimentexperiment is also important for elucidating thethe function function of proanthocyanidin.of proanthocyanidin. A synthetic A synthetic route to route oligomeric to oligomeric catechin and catechin epicatechin and derivativesepicatechin derivatives has been developed has been developed by Kozikowski by Kozikowski et al. [14– 16et] al. and [14–16] subsequently and subsequently by other researchby other groupsresearch [groups17–24]. [17–24]. Additionally, Additionally, our group our group has developedhas developed and and reported reported simple simple and and stereoselectivestereoselective methods to synthesize 4-8 condensed procyanidin oligomersoligomers (constituted by flavan-3-ols flavan-3-ols having two hydroxyl groupsgroups on on B andB and E rings) E rings) [25–38 ][25–38] and prodelphinidin and prodelphinidin oligomers oligomers (constituted (constituted by flavan-3-ols by having,flavan-3-ols three having, hydroxyl three groups hydroxyl on B and/or groups E rings)on B [and/or39] and E then rings) studied [39] theirand biologicalthen studied activities. their Thebiological key step activities. of the synthesis The key ofstep proanthocyanidins of the synthesis is of the proanthocyan coupling reactionidins betweenis the coupling the nucleophile reaction andbetween electrophile the nucleophile using a Lewisand electrophile acid such asusing TiCl a4 ,Lewis SnCl4 acid, or trimethylsilylsuch as TiCl4, triflateSnCl4, or (TMSOTf) trimethylsilyl as an activator.triflate (TMSOTf) As shown as an in activator. Figure1, theAs shown two dimers in Figu ofre (+)-catechin, 1, the two dimers 4-6-condensed of (+)-catechin, procyanidin 4-6-condensed B6 ( 1) andprocyanidin 4-8-condensed B6 (1) procyanidinand 4-8-condensed B3 (2), are procyanidin isomers with B3 different (2), are bonding isomers positions. with different The abundance bonding ofpositions. the 4-6-linked The abundance oligomer of isthe comparatively 4-6-linked oligomer low. Inis particular,comparatively the low. biological In particular, activities the of biological various 4-6-condensedactivities of various oligomers 4-6-condensed are yet to beoligomers studied are in detailyet todue be studied to the unavailability in detail due ofto thesethe unavailability compounds. Mostof these studies compounds. on the synthesis Most ofstudies proanthocyanidins on the synthesis focus onof 4-8-linkedproanthocyanid oligomersins asfocus target on compounds, 4-8-linked andoligomers only aas few target of themcompounds, address and the only stereoselective a few of them synthesis address of 4-6-linkedthe stereoselective oligomers. synthesis The cool of synthesis4-6-linked of oligomers. the 4-6 catechin The cool dimer, synthesis procyanidin of the B6 4-6 (1), catechin has been dimer, previously procyanidin achieved byB6 combining(1), has been the 8-halo-cappingpreviously achieved strategy by combining [24]. the 8-halo-capping strategy [24]. Figure 1. Structures of procyanidin B6 (1) and procyanidin B3 (2). Figure 1. Structures of procyanidin B6 (1) and procyanidin B3 (2). Due to increasing interest toward the structure-activity-relationship studies (SAR) of proanthocyanidins,Due to increasing developing interest new toward and simple the structure-activity-relationship methods for the synthesis of studiesvarious (SAR)types of proanthocyanidins,proanthocyanidins has developing become increasingly new and simpleimportan methodst. Therefore, for the we synthesisfocused on of developing various types a very of proanthocyanidinssimple approach to has the become selective increasingly synthesis important.of such compounds. Therefore, weHerein, focused we on report developing on an aeasy, very simpleapplicable, approach and toreliable the selective method synthesis for the of stereoselective such compounds. synthesis Herein, weof reportprocyanidin on an easy,B6 ( applicable,1) via an andintramolecular reliable method condensation for the reaction stereoselective without synthesis modifying of the procyanidin 8-position. B6 (1) via an intramolecular condensation reaction without modifying the 8-position. 2. Results and Discussion 2. Results and Discussion Previously, we developed a Lewis acid-catalyzed “intramolecular” one-to-one coupling approach Previously, we developed a Lewis acid-catalyzed “intramolecular” one-to-one coupling that allows for the stereoselective synthesis of 4-8-condensed (+)-catechin dimers (4, 6: Scheme 1) [28,31]. approach that allows for the stereoselective synthesis of 4-8-condensed (+)-catechin dimers (4, 6: The method includes the connection of flavan-3-ol-derived nucleophile and electrophile via a diester Scheme1)[28,31] . The method includes the connection of flavan-3-ol-derived nucleophile and linker and the subsequent condensation reaction by “intramolecular” coupling. Furthermore, the electrophile via a diester linker and the subsequent condensation reaction by “intramolecular” coupling. stereochemistry of the coupling product was found to depend on the length of the linker. Despite the Furthermore, the stereochemistry of the coupling product was found to depend on the length of the fact that the 3,4-cis structure is not preferentially obtained in intermolecular reactions, the linker. Despite the fact that the 3,4-cis structure is not preferentially obtained in intermolecular intramolecular TMSOTf-catalyzed coupling of azelaic acid (C9 dicarboxylic acid) diester (3) afforded reactions, the intramolecular TMSOTf-catalyzed coupling of azelaic acid (C9 dicarboxylic acid) diester 3,4-trans product 4, and the coupling of glutaryl (C3 dicarboxylic acid derivative) diester (5) gave (3) afforded 3,4-trans product 4, and the coupling of glutaryl (C3 dicarboxylic acid derivative) diester 3,4-cis product 6 [28] (Scheme 1). Therefore, this intramolecular coupling method could potentially solve the difficulties surrounding the stereoselective synthesis
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