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Synthetic Studies on Flavan Derived Natural Polyphenols: a Complex Molecular Platform─ in Organic Synthesis Ken Ohmori ＊＊ Department of Chemistry, Tokyo Institute of Technology 2 ─ 12 ─ 1 O ─ okayama, Meguro ─ ku, Tokyo 152 ─ 8551, Japan (Received June 29, 2018; E ─ mail: [email protected]) Abstract: Flavan ─ derived polyphenols are widely distributed in the plant kingdom, and have long been known to possess remarkable biological activity and a positive effect on human health. However, the detailed biochemical functions of this class of molecules at a molecular level are still not well studied due to the limited availability of natural samples in sufcient quantity and quality. This account gives an overview of our synthetic efforts towards this class of molecules which exploit selective functionalization of the C(4) position of the avan skeleton. Various nucleophilic components could be introduced into this position via S N1 ─ type sub- stitution. As part of our synthetic studies on avan oligomers, an orthogonal activation method that employs two distinct avan units was developed. This enabled iterative coupling to give linear and/or doubly ─ linked a- van oligomers to be achieved. cic interactions of avan derivatives with biomolecules such 1． Introduction 3 as proteins, peptides, oligosaccharides and nucleotides, their Natural polyphenols constitute a large class of plant ─ biological modes of action are still not claried well at the derived natural products, and have long been known to possess molecular level due to the limited availability of natural and/or powerful antioxidant activity, which is potentially responsible synthetic samples in sufcient quantity and quality. Indeed, for their inuence on human health and/or diet. 1 their procurement largely relies on natural sources that gener- Of this compound class, the avan ─ derived polyphenols, ally produce a mixture of closely related compounds, which are i.e. monomeric or oligomeric proanthocyanidins, are of cur- hardly separable even by state ─ of ─ the ─ art chromatographic rent interest due to their signicant bioactivities, which include techniques. antioxidant, antiviral, antibacterial, and antitumor effects. 2 These difculties in obtaining pure samples, coupled with Although several biochemical studies have indicated spe- their promising biological activities, prompted us to initiate synthetic studies on this class of natural products. 2． C(4) ─ functionalization of the Flavan Skeleton based on the Flavonoid ─ glycoside Analogy Our studies began with functionalization of the C(4) position of the avan skeleton, which is pivotal for their oligomerization and/or conjugation with other molecular constituents. The basis for innovation was a “avonoid ─ glycoside analogy” inspired by the S N1 reactivity inherent in a glycoside (Figure 2). 4 Reactivity at the anomeric position is primarily governed by the pyran oxygen stabilizing the corresponding oxocarbenium species. In comparison, similar reactivity at the C(4) benzylic position of the avan skeleton is strongly pro- moted by the benzopyran oxygen and two additional oxy ─ functions present at the ortho and para positions on the ben- zene ring. This insight led us to come up with the idea that well ─ studied glycosidation methods could be applied as an efcient and reliable way to synthesize avan ─ related compounds. To conrm this hypothesis we looked at exploiting the S N1 Figure 1. Naturally occurring avan ─ derived polyphenols. Figure 2. Flavonoid ─ glycoside analogy. 1154 （ 18 ） J. Synth. Org. Chem., Jpn. reactivity at the C(4) position of the avan skeleton 4a (Figure 3). The C(4) ─ acetoxy derivatives 1a/b, were treated with various nucleophiles in the presence of a Lewis acid, e.g. BF 3·OEt 2, when smooth departure of the acetate followed by trapping of the resulting cationic species by a nucleophile proceeded to give the C(4) ─ substituted products 2a/2b. This reaction could be applied to various nucleophiles, not only carbon nucleophiles, e.g. ketene silyl acetal, allyltrimethylsilane, phloroglucinol derivatives, and indoles, but also heteroatom nucleophiles, e.g. Me 3SiN 3 and PhSH, giving the corresponding substituted products. Notably, 1,2 ─ cis substituted derivative 1b consistently gave the β ─ stereoisomer of 2b, while the Figure 4. B and A type avan oligomers. reaction of 1,2 ─ trans isomer 1a to give 2a as a mixture of ste- ─ ─ reoisomers favored the β ─ isomer. Only in the reaction of 1a with phloroglucinol derivative did the α stereoisomer which revealed remarkable antitumor effects correlated with 5 (α/β=88/12) dominate. The utility of this method was demon- the length of the oligomers. They prepared B ─ type oligomers strated in the total syntheses of natural products such as with various degrees of oligomerization through a non ─ selec- 4a dryopteric acid (a avan ─ acetic acid hybrid) and lotthanon- tive oligomerization of avan units followed by chromato- 4c gine (a avan ─ indole hybrid). graphic separation. These results were both remarkable, and promising as a method of searching for pharmaceutical candi- dates. However, further progress was hampered by the scarce availability of the larger oligomers. Therefore, further innovation leading to more reliable synthetic methods 6 is necessary in order to provide individual oligomers with rigorous control of their length as well as their stereo ─ and regiochemistry. The synthetic challenge posed by such avan oligomers can clearly be seen in the target structures (Figure 4). Although the B ─ type (linear ─ type) oligomers might be efciently accessed through a step ─ by ─ step coupling of mono- mer avan units, the simple Friedel ─ Crafts condensation employing a C(4) ─ substituted electrophilic avan unit and a nucleophilic counterpart is not suitable for this purpose. Scheme 1 illustrates the problem. Flavan derivative I bearing a leaving group at the C(4) position generates a highly stabilized cationic species A, a process facilitated by the strong electro ─ donative assistance from three oxygens. When A is trapped by a nucleophilic avan unit II, the desired cross ─ coupled product III would be formed. However, both the unreacted monomeric units I and II, as well as the resulting dimeric product III all have a nucleophilic site, resulting in formation of self ─ and/or higher ─ condensation products through multiple undesired Scheme 1. Potential reactivity for self ─ and/or cross ─ condensation of avan units. Figure 3. S N1 reactions of C(4) ─ acetates, 1a and 1b, and their applications to natural product syntheses. 3． Bromo ─ capping and Equimolar Coupling Next our attention turned to focus on the synthesis of a- van oligomers, which can be classied into two major groups (Figure 4). The B ─ type oligomers, e.g. procyanidin C1, consist of a linear oligomeric structure with adjacent avan units linked by a C ─ C single bond. In contrast, aesculitannin C rep- resents the A ─ type oligomers that contain a unique, bicyclic structure composed of two avan units. These compounds show a remarkably broad spectrum of signicant bioactivities, such as anti ─ viral, ─ bacterial, ─ tumor, ─ oxidant and enzyme ─ inhibiting properties. Kozikowski and Tückmantel undertook a systematic inves- tigation of the bioactivity of epicatechin homo ─ oligomers Vol.76 No.11 2018 （ 19 ） 1155 coupling reactions. A possible, but inelegant solution to this 2 h), the coupling smoothly proceeded to give the correspond- problem is use of nucleophilic partner II in excess for statisti- ing dimer 8 in excellent yield with high stereoselectivity. After cally avoiding self ─ and/or over ─ oligomerizations. saponication, hydrogenation of the aryl bromide and benzyl To overcome this issue we came up with the idea of sup- ethers under Sajiki’s conditions 9 led to procyanidin B6. 8 pressing unfavorable condensations by protecting the C(8) 4． Orthogonal Synthetic Strategy position of the nucleophilic avan unit of the electrophilic partner. We expected that a bromine atom would be ideally As equimolar coupling had become feasible, we next suited for this purpose, because its steric and electronic effects turned our attention to assemble higher oligomers via the would reduce C(8) ─ nucleophilicity, thereby suppressing self ─ step ─ by ─ step coupling method. In line with the avonoid ─ gly- 7 reactions. Pleasingly, the bromo ─ capped derivative 3 worked coside analogy, we were particularly interested in the orthogo- well as an electrophilic unit, resulting in clean formation of nal synthetic approach, 10 which is an efcient methodology in dimeric product (Scheme 2). Thus, upon treatment of 3 with a oligosaccharide synthesis [a) in Scheme 4]. This method real- slight excess of 4 (1.2 equiv) in the presence of BF 3·OEt 2 izes a selective and iterative activation of individual glycosyl (1.0 equiv, CH 2Cl 2, -78→-35 ℃, 1 h), the coupling smoothly donors in the presence of a glycosyl partner which is itself proceeded to give the corresponding dimer 5 in excellent yield inert to activation under the dened reaction conditions with high stereoselectivity. Notably, essentially an equimolar employed. set of the bromo ─ capped electrophile 3 and its nucleophilic partner 4 sufced for clean reaction to occur, in contrast to the Scheme 4. Concept of orthogonal synthetic strategy. reaction of the non ─ bromo derivative with nucleophilic partner 4. Scheme 2. Equimolar coupling of C(8) ─ capped avan unit 3 with nucleophilic avan unit 4. This bromo ─ capping methodology was further applied to 8 synthesize an unusual 4,6 ─ interavan linkage which is often found in rare avan oligomers, e.g. procyanidin B6. Thus, upon treatment of 6 with chloro ─ capped nucleophile 7 (1.5 equiv) in the presence of BF 3·OEt 2 (1.0 equiv, CH 2Cl 2, -78→-0 ℃, A typical combination of glycosyl donors enabling orthogonal glycosidation is thio ─ and uoroglycosides. A thioglyco- side can be selectively activated by a soft thiophilic promoter, Scheme 3. Synthesis of the 4,6 ─ linked avan derivative procyanidin B6. such as N ─ bromosuccinimide, without touching the glycosyl uoride. Conversely, the glyscosyl uoride is activated by a 11 hard Lewis acid, such as Cp 2HfCl 2─ AgClO 4.

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