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 bio- chemical functions of this class of molecules at a molecular level are still not well studied due to the limited availability of natural samples in suf cient quantity and quality. This account gives an overview of our syn- thetic 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.
ci c 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 clari ed 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 suf cient quantity and quality. Indeed, for their in uence 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 signi cant bioactivities, which include techniques. antioxidant, antiviral, antibacterial, and antitumor effects. 2 These dif culties 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) posi- tion of the avan skeleton, which is pivotal for their oligomeri- zation 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 ef cient and reliable way to synthesize avan ─ related com- pounds.
To con rm 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 pro- ceeded to give the C(4) ─ substituted products 2a/2b. This reac- tion could be applied to various nucleophiles, not only carbon nucleophiles, e.g. ketene silyl acetal, allyltrimethylsilane, phlo- roglucinol derivatives, and indoles, but also heteroatom nucleophiles, e.g. Me 3SiN 3 and PhSH, giving the correspond- ing substituted products. Notably, 1,2 ─ cis substituted deriva- tive 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 innova- tion 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 ef ciently 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 classi ed 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 signi cant 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. saponi cation, 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 ef cient 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 de ned reaction conditions with high stereoselectivity. Notably, essentially an equimolar employed. set of the bromo ─ capped electrophile 3 and its nucleophilic partner 4 suf ced for clean reaction to occur, in contrast to the Scheme 4. Concept of orthogonal synthetic strategy. reaction of the non ─ bromo derivative with nucleophilic part- ner 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 ─ inter avan 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 orthog- onal 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. In contrast to a conventional glycosylation sequence, the rapid assembly of complex oligosaccharides becomes possible by conducting orthogonal activation that signi cantly reduces tedious protec- tion―deprotection steps. Attracted by these features, we decided to employ this strategy for a higher oligomer synthesis that would enable an ef cient and reiterative chain extension of catechin units [b) in Scheme 4]. While searching for an orthogonal set of leaving groups, we found that a combination of an oxy and a thio group was suitable for our purpose, 7 enabling orthogonal assembly to be achieved in a controlled manner (Scheme 5). Thus, upon acti- vation of the bromo ─ capped C(4) ─ phenylthio derivative 9 with N ─ iodosuccinimide (NIS) in the presence of acetate 10 (1.2 equiv), smooth coupling proceeded via selective activation of the phenylthio group, giving a high yield of the dimer 11. At the second coupling stage, the dimer 11 was treated with
1156 （ 20 ） J. Synth. Org. Chem., Jpn. BF 3·OEt 2 in the presence of the nucleophilic partner 12, pro- selectively activated by NIS in the presence of the nucleophilic ducing the corresponding trimer 13 in excellent yield. All pro- unit H ─ (EG) ─ OEE 15, giving dimer Br ─ (EZ) ─ (EG) ─ OEE 16 tecting groups were removed through debromination (LiAlH 4), in 91% yield. The dimer 16 bearing a C(4) ─ oxy leaving group and hydrolysis of any remaining acetyl group(s) (KOH aq.), was activated by BF 3·OEt 2 in the presence of the catechin unit followed by hydrogenolysis of the benzyl groups [H 2, 17, affording the corresponding targeted trimer (not shown) in
Pd(OH) 2/C]. Anaerobic ltration (glass ─ ber lter) under an 92% yield. The acetyl protecting groups were removed with inert atmosphere (argon), and partial concentration followed NaOMe. Hydrogenolysis of the product (H 2, Pd (OH) 2/C, by reverse phase column chromatography and lyophilization THF, MeOH, H 2O), followed by lyophilization then afforded gave a free form of a catechin trimer (procyanidin C2) as a trimer EZ ─ EG ─ CA (18). snow ─ white solid. 5． Block Synthesis of Higher Catechin Oligomers
Scheme 5. Synthesis of procyanidin C2. Having established an ef cient oligomerization protocol, we widened the scope of our study by aiming for the synthesis of higher oligomers. We examined the orthogonal assembly of oligomeric building blocks, and found that the equimolar cou- pling of oligomer units is effective and enables rapid access to 7b higher oligomers, ranging from 6 to 24 ─ mers (Scheme 7). Of particular note is the last coupling stage, where the equimolar coupling of the large oligomeric units, 21 and 25, proved feasible, producing the single coupling product 26 of unique molecular weight. This reaction clearly proved the great power of this coupling strategy for the preparation of pure samples of linear avan oligomers. 6． NMR Analyses of Linear Oligomers As the structural complexity of the synthesized oligomers rapidly increases with their chain length and with multiple oxy ─ functions, structure analysis becomes dif cult. Moreover, additional complications arise out of atropisomerism due to the hindered rotation around inter avan bonds, which is slow enough for distinct rotational isomers to be observed on the 1 In a similar way, a hetero ─ avan trimer 18, isolated from H NMR time ─ scale (500 MHz). Introduction of fully ─ deuter- 12 ＊ the bark of Ziziphus jujuba, was synthesized (Scheme 6). This ated benzyl protecting groups ( ─ CD 2C 6D 5: Bn ) simpli ed the compound comprises three different avan constituents, i.e. 1 H NMR analysis, so that basically only the catechin “Core“ (-) ─ epiafzelechin (EZ), (-) ─ epigallocatechin (EG), and (+) ─ was visible, although even so oligomers larger than the trimer catechin (CA). gradually exceeded the limits of 1 H NMR analysis (Figure 5). 7b In spite of this potentially increasing analytical dif culty Scheme 6. Synthesis of the natural hetero ─ avan trimer for higher oligomers, an interesting observation was made in 18 (EZ ─ EG ─ CA). that beyond a certain size (＞12 ─ mer) they showed rather sim- ple spectral patterns, suggesting they possess higher ─ order structures, presumably helical forms. This nding is not only aesthetically pleasing, but also has implications for fundamen- tal structural organic chemistry. 7． Synthesis of Doubly ─ linked Flavan Oligomers Next, we centered our attention on the A ─ type avan oligomers (vide supra), 13 which share an unusual bridged struc- ture, i.e. the dioxabicyclo[3.3.1]nonane skeleton composed of two avan units. Recent studies have revealed the potential bioactivities of this class of molecules, demonstrating for example, an insulin ─ enhancing activity relevant to diabetes treatment 14 and also strong sweetness. 15 However, further investigation of structure ─ activity relationships has been ham- pered by the limited availability of natural samples. In planning their synthesis, one of the key challenges is construction of the characteristic dioxabicyclo[3.3.1]nonane skeleton. The pioneering work in this context was reported by 16 Jurd and co ─ workers, who carried out the annulation of a- After preparation of the requisite monomeric units 14, 15 vylium ion I with nucleophilic catechin unit II to form III and 17, their orthogonal activation and step ─ by ─ step assembly (Scheme 7). This process involves the dual bond formation was conducted. The electrophilic unit Br ─ (EZ) ─ SXy 14 was between C(4) and C(8’) positions and C(2) ─ O(7’) positions,
Vol.76 No.11 2018 （ 21 ） 1157 Scheme 7. Block assembly of catechin tetracosamer.
enabling a direct access to the requisite bicyclic system. oxy source (Scheme 8). Thus, heating 27 with an excess amount Although the simple use of non ─ chiral I would run into prob- of DDQ (4.0 equiv) in the presence of ethylene glycol gave lems with regard to enantiocontrol of access to III, this con- 69% yield of 2,4 ─ ethylenedioxy derivative 28. The C(8) posi- cept has inspired us to come up with an idea which could be tion of 28 was then masked by a bromine atom, affording bro- termed “flavan annulation”. We envisioned that if the following mide 29 in excellent yield. two requirements are met, the requisite dioxabicyclo skeleton With the dication precursor in hand, a model study on the would be easily accessible; (1) design of a suitable precursor V’ annulation reaction was performed by using 29 and di ─ O ─ instead of I to generate the dicationic species V, and (2) regio- benzyl phloroglucinol (30) as nucleophilic partner (Scheme 9). 17 selective dual bond formation via mode A, and not the reverse A mixture of 29 and 30 in CH 2Cl 2 was exposed to BF 3·OEt 2 at (mode B). An additional hope was stereoselectivity. Thanks to -78 ℃, then the temperature was gradually raised to -40 ℃ the C(3) stereocenter in V, we expected that the annulation over 2 h. The starting material 29 was almost consumed, and would proceed in a stereoselective manner. two new products were produced (run 1, Table 1). However, The rst task was to design and synthesize a dication pre- the major product was single ─ linked 31 with the C(4) ─ C(2’) cursor V’. Assuming that oxy ─ groups act as the leaving groups bond formed, whereas the minor product 32 had the desired X in V’, the latter would be available by oxidation of avan dioxabicyclic structure. It was noted that these products, 31 derivatives. Thus, initial attempts were aimed at the oxidation and 32, were the respective single stereoisomers as shown. of epicatechin derivative 27 with DDQ in the presence of vari- Speculating an intermediacy of 31 in the formation of 32, 17 ous alcohols. However, most cases gave only the 4 ─ alkoxy re ─ exposure of 31 to the same reaction conditions was carried product along with trace amounts of the 2 ─ alkoxy and 2,4 ─ out, and smooth conversion of 31 into 32 was observed. These dialkoxy products. After considerable experimentation, a satis- results indicated that the annulation proceeded in a stepwise factory result was obtained by using ethylene glycol as the alk- manner, starting with formation of the C(4) ─ C(2’) bond from
1158 （ 22 ） J. Synth. Org. Chem., Jpn. 1 Figure 5. Stack plot of H NMR spectra for linear ─ type (B ─ type) avan oligomer derivatives.
Scheme 8. Preparation of the 2,4 ─ dioxy avan unit.
Figure 6. Partial conformation of the linear oligomeric structure.
Scheme 7. Annulation strategy. the β ─ side to form 31 followed by C(2) ─ O bond formation to give 32. Eventually we found the annulation of 29 and 30 could be completed in one pot by extending the reaction time (2→3 h) and raising the temperature (-40→-20 ℃), to give 32 in excellent yield (run 2). Figure 8 illustrates the mechanistic rationale for the initial activation stage with 29, where the C(4) ─ benzyl cation was preferably generated over its C(2) ─ counterpart. This can be attributed to a difference in their relative stability. The C(4) cation would be stabilized by three oxygen lone pairs via the benzene ring, while the C(2) cation would only be stabilized by two. The resulting highly stabilized C(4) cationic species was trapped with the carbon nucleophile 30, which is suf ciently reactive at its C(2’) position rather than C(4’) position. The second activation generated the C(2) ─ benzylic cation, then intramolecular attack of the phenolic oxygen followed to form
Vol.76 No.11 2018 （ 23 ） 1159 Scheme 9. Model study for avan annulation. hindered ortho position to the uorine atom. The resulting anionic species was captured with epoxide 35 in the presence
of BF 3·OEt 2, giving adduct 36 in 95% yield. MOM protection of alcohol 36 followed by removal of the silyl group gave alco- hol 38 (94% yield) poised for the key pyran cyclization. Treat- ment of 38 with KH (THF, r.t., 24 h) cleanly gave pyran 39 in excellent yield. Treatment of 39 with PPTS in EtOH cleanly detached the MOM and tert ─ butyl groups, giving 40 in 90% yield. At this stage, addition of phloroglucinol was essential to secure a clean reaction, as it scavenged the electrophilic C1 species generated during the MOM deprotection. 18 With the requisite coupling units 29 and 40 in hand, the key annulation was attempted (Scheme 11). Upon treatment of
a mixture of 29 and 40 with BF 3·OEt 2 (CH 2Cl 2, -78→-30 ℃, 4 h), the reaction smoothly proceeded to give the desired prod- uct 41 in excellent yield. Notably, no formation of other regio ─ and stereoisomers was observed. As the α ─ face of the electro- Table 1. Reaction conditions and results for annulation reaction. philic avan unit 29 is shielded by the C(3) ─ substituent, nucleophile 40 approached from the β ─ side to form the double linkages at the C(2) and C(4) positions. After careful deprotec-
tion [i) n ─ Bu 4NF, ii) H 2, Pd(OH) 2], procyanidin A2 (42) was obtained in excellent yield. 17
Scheme 11. Annulation of 2,4 ─ dialkoxyl avan unit 29 with nucleophilic unit 40, and synthesis of procyanidin A2 (42).
Figure 8. Benzyl cation stabilization by oxygen atoms.
32. With these successful model studies complete, our focus moved on to applying this concept to the synthesis of A ─ type oligocatechins. 17 The rst target was procyanidin A2 (42, vide infra) which comprises two epicatechin units. Scheme 10 illus- trates the preparation of the selectively protected avan unit 40. 1,3,5 ─ Tri uorobenzene (33) was treated with potassium tert ─ butoxide followed by sodium benzyloxide, giving mono ─ 17,18 uoride 34 in excellent yield. Upon treatment of 33 with n ─ BuLi (-78 ℃, 1 h), regioselective lithiation occurred at the less
Scheme 10. Preparation of nucleophilic avan unit 40. TBS= tert ─ butyldimethylsilyl, DMF=dimethylformamide, We further tackled the synthesis of a trimeric natural prod- MOM=methoxymethyl, PPTS=pyridinium p ─ tolu- uct, (+) ─ cinnamtannin B 1 (48), which is known as a rare sweet enesulfonate. 1b,3 polyphenol (Scheme 12). To realize the convergent assembly of the trimeric scaffold, the orthogonal coupling strategy was adapted. Thus, annula- tion of dioxy electrophilic unit 29 with sul de 43 was carried
out by using BF 3·OEt 2 to give the coupling product 44 in 91% yield, where the arylthio group remained intact under the hard Lewis acidic conditions. Soft activation of dimeric sul de 44
was achieved with I 2 and Ag 2O allowing reaction with nucleo- philic epicatechin unit 45, and giving trimer 46 in 96% yield. The regio ─ and stereochemistry of the annulation were veri ed by extensive NMR studies. In the endgame, the two silyl groups were detached by
employing a large excess of n ─ Bu 4NF under re ux conditions
1160 （ 24 ） J. Synth. Org. Chem., Jpn. Scheme 12. Synthesis of (+) ─ cinnamtannin B 1. suggestions and comments with many helpful discussions, and encouragement throughout the course of this research. This work was supported by JSPS KAKENHI Grant Nos. JP13740351, JP17685007, JP21350050, JP23000006, JP16H06351, JP16H01137, and JP16H04107. Contributions from the Shorai Foundation for Science and Technology, Kurata Memorial Hitachi Science and Technology Foundation are greatly appreciated.
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Commun. 2014, 50, 14371. higher ─ order oligomers, mediated by metal ─ coordination, for 9） (a) Sajiki, H.; Kume, A.; Hattori, K.; Hirota, K. Tetrahedron Lett. instance. Polymer synthesis will also be investigated via two ─ 2002, 43, 7247. (b) Monguchi, Y.; Kume, A.; Hattori, K.; Maegawa, or three ─ dimensional extension of oligomeric building blocks. T.; Sajiki, H. Tetrahedron 2006, 62, 7926. 10） Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073. 11） (a) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G. Tetrahe- Acknowledgements dron Lett. 1988, 29, 3567. (b) Suzuki, K.; Maeta, H.; Matsumoto, T.; The author would like to express his sincere appreciation to Tsuchihashi, G. Tetrahedron Lett. 1988, 29, 3571. (c) Matsumoto, T.; all of the past and present members of his research group at Hosoya, T.; Suzuki, K. Tetrahedron Lett. 1990, 31, 4629. Tokyo Institute of Technology for their vital contributions. 12） Yano, T.; Ohmori, K.; Takahashi, H.; Kusumi, T.; Suzuki, K. Org. Biol. Chem. 2012, 10, 7685. The author would particularly like to express his deep appreci- 13） (a) Lou, H.; Yamazaki, Y.; Sasaki, T.; Uchida, M.; Tanaka, H.; Oka, ation to Professor Keisuke Suzuki, who provided invaluable
Vol.76 No.11 2018 （ 25 ） 1161 S. Phytochemistry 1999, 51, 297. (b) Kamiya, K.; Watanabe, C.; PROFILE Endang, H.; Umar, M.; Satake, T. Chem. Pharm. Bull. 2001, 49, 551. 14） (a) Anderson, R. A.; Broadhurst, C. L.; Polansky, M. M.; Schmidt, W. Ken Ohmori received his B.S. (1991), M.S. F.; Khan, A.; Flanagan, V. P.; Schoene, N. W.; Graves, D. J. J. Agric. (1993), and Ph.D. (1996) degrees from Keio Food Chem. 2004, 52, 65. (b) Jarvill ─ Taylor, K. J.; Anderson, R. A.; University under the direction of Professor Graves, D. J. J. Am. Coll. Nutr. 2001, 20, 327. (c) Khan, A.; Safdar, Shosuke Yamamura. In 1996, he became an M.; Khan, M. M. A.; Khattak, K. N.; Anderson, R. A. Diabetes Care Assistant Professor at the Tokyo Institute of 2003, 26, 3215. Technology, joined Prof. Keisuke Suzuki’s 15） (a) Morimoto, S.; Nonaka, G.; Nishioka, I. Chem. Pharm. Bull. 1985, group, and was promoted to Associate Pro- 33, 4338. (b) Morimoto, S.; Nonaka, G.; Nishioka, I. Chem. Pharm. fessor at the university (2007). He received Bull. 1987, 35, 4717, and a related paper, see; (c) Baek, N. ─ I.; Chung, the Nakamura Prize (2001), the Japan M. ─ S.; Shamon, L.; Kardono, L. B. S.; Tsauri, S.; Padmawinata, K.; Chemical Society Award for Young Chemists Pezzuto, J. M.; Soejarto, D. D.; Kinghorn, A. D. J. Nat. Prod. 1993, (2002), Sankyo Kagaku Award in Synthetic 56, 1532. Organic Chemistry (2005), Tokyo Tech 16） (a) Jurd, L.; Waiss, Jr., A. C. Tetrahedron 1965, 21, 1471, and related Award for Challenging Research (2008), papers, see; (b) Selenski, C.; Pettus, T. R. R. Tetrahedron 2006, 62, Merck ─ Banyu Lectureship Award (2008), 5298. (c) Kraus, G. A.; Yuan, Y.; Kempema, A. Molecules 2009, 14, Tejima Research Award (2011), Asian Core 807. Program Lectureship Award (2013), Daiichi ─ 17） Ito, Y.; Ohmori, K.; Suzuki, K. Angew. Chem. Int. Ed. 2014, 53, Sankyo Award for Medicinal Chemistry 10129. (2016), and Nagase Foundation Award 18） Stadlbauer, S.; Ohmori, K.; Hattori, F.; Suzuki, K. Chem. Commun. (2018). His research interest centers on deve- 2012, 48, 8425. lopment of new synthetic methodology and total synthesis of natural products, in partic- ular focusing on polycyclic natural products and avan ─ derived polyphenols.
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