The Nakanishi Symposium
on Natural Products & Bioorganic ChemistryTokyo University of Science
March 19, 2021

Sponsored by
The Chemical Society of Japan&
The American Chemical SocietyYoshito Kishi
Professor Emeritus, Harvard University■EDUCATION
Bachelor of Science, Nagoya University
1961
Doctor of Philosophy (Chemistry), Nagoya University(Professors Yoshimasa Hirata and Toshio Goto)
1966
Postdoctoral Research Fellow (Chemistry), Harvard University(Professor R. B. Woodward)
1966-1968■ACADEMIC APPOINTMENT
Instructor of Chemistry, Nagoya University
1966-1970
Associate Professor of Agricultural Chemistry, Nagoya University
1970-1974
Visiting Professor of Chemistry, Harvard University
1972-1973
Professor of Chemistry, Harvard University
1974-1982
Morris Loeb Professor of Chemistry, Harvard University 1982-2002
Morris Loeb Professor of Chemistry, Emeritus, Harvard University
2002-

■RESEARCH TOPICS (chronological order)
1. Chemical studies of bioluminescence: The luminescent substance
named luciferin is an unstable compound, making its structural
determination extremely difficult. Dr. Kishi, however, determined thestructures of luciferins, such as those in Cypridina, Genji fireflies, krill,
dinoflagellates, and the luminous shellfish of Latia (1960s–1980s).
2. Total synthesis of complex natural products: The pufferfish toxin
tetrodotoxin, the structure of which was determined in 1964, is still
known as one of the most difficult natural products to synthesize due
to its highly functionalized structural complexity. Dr. Kishi achieved
the world’s first total synthesis of this compound in 1972. Later, heachieved total synthesis of the paralytic shellfish toxin saxitoxin, theanticancer drug mitomycin C, the fungus toxin sporidesmin, and theβ-lactam antibiotics (1970s–1980s).
3. Development of acyclic stereocontrol in total synthesis of natural
products: Until the early 1970s, total synthesis of polyether
antibiotics was almost impossible due to the presence of numerous
asymmetric centers. However, Dr. Kishi developed a versatilestereoselective reaction based on a completely new concept of acyclicstereocontrol and achieved total synthesis of several complex natural
products, such as the antibiotics lasalocid, monensin, narasin, andrifamycin. He showed the generality and usefulness of the acyclicstereocontrol methods, leading to explosive development in synthetic
chemistry (late 1970s–1990s).
4. Complete stereochemistry and total synthesis of palytoxin: The
highly toxic palytoxin is one of the largest and most complex natural
marine products in the world, with a molecular weight of 2,681 Da.
Dr. Kishi determined the fifty-one configurations of this molecule bymaking full use of organic synthesis, eventually completing its total
synthesis. Except for biological macromolecules such as proteins andnucleic acids, palytoxin is the largest natural product ever synthesizedby humankind, and its total synthesis is said to be a milestone in thehistory of chemistry (1980s–1990s).
5. Development of a universal NMR database: Dr. Kishi developed auniversal NMR database which allowed a non-destructive
determination of the configuration of acyclic compounds. With thisdatabase, he determined the stereochemistry of maitotoxin, a large
natural polyether marine product with a molecular weight of 3,422 Da,
as well as the stereochemistry of mycolactone, the causative toxin of
Buruli ulcer (1980s–present).
6.

Total synthesis of halichondrin and the development of theantitumor agents eribulin and C52-halichondrin-B amine: The
total synthesis of halichondrin B, a potent natural marine antitumor
product, was completed using the NHK reaction developed during thesynthesis of palytoxin. It was found that only the right side moiety ofhalichondrin B showed a similar antitumor activity as halichondrin.
After more than ten years of the collaborative research with Eisai Co.,a revolutionary antitumor agent, eribulin (trade name: Halaven), wasdeveloped. Eribulin has a complex structure, containing eighteen
asymmetric centers, and is the most complex organic compound
produced on a commercial basis. Most recently, this synthetic research
led to the large-scale synthesis of C52-halichondrin-B amine, a newantitumor drug candidate currently in clinical trials (1990s–present).

■HONORS The Chemical Society of Japan Award For Young Chemists(1967)
 ACS Award for Creative Work in Synthetic Organic Chemistry(1980)
 Harrison Howe Award (1981) The 24th Naito Memorial Award (1992)
 Nagoya Gold Medal (1995)
 Prelog Medal (1994)
 Havinga Medal (1996)
 Imperial Prize of the Japan Academy 学士院賞恩賜賞 (1999)
 ACS Ernest Guenther Award in the Chemistry of Natural
Products (2001)
 Tetrahedron Prize for Creativity in Organic Chemistry &BioMedicinal Chemistry (2001)
 Person of Cultural Merit 文化功労者 (2001)
 Special Award in Synthetic Organic Chemistry, Japan (2010)
 The Order of the Sacred Treasure, Gold and Silver Star 瑞宝中綬章 (2013)
 Ryoji Noyori Prize (2018)

― Table of Contents ―Profile of Prof. Yoshito Kishi
Prize Winner of the Nakanishi Prize 2020
Program of the Award Ceremonyof the Nakanishi Prize & Nakanishi Symposium

…… 2
…… 6

“Synthetic Studies on Biologically Active Natural
Products toward Practical Application”…… 7

Prof. Kosuke Namba (Tokushima University)“Synthesis of Polycyclic Alkaloids Based on
Dearomative Oxidative Cyclization”
Prof. Kazuo Nagasawa (Tokyo University of…… 8Agriculture and Technology）“Lessons from Total Synthesis of Carthamin,
A Red Pigment from Safflower (Benibana)”
Prof. Keisuke Suzuki…… 9(Tokyo Institute of Technology）“Studies on the Total Synthesis of Tetrodotoxin”
Prof. Tohru Fukuyama…… 10(The University of Tokyo)
Award Lecture“Beyond Total Synthesis of Complex Natural
Products”
Prof. Yoshito Kishi(Professor Emeritus, Harvard University)…… 11Nakanishi Symposium 2020
Organized by：Nakanishi Symposium Organizing Committee
Co-organized by: Chemical Society of Japan,
Division of Natural Products Chemistry & Biological Science

Date
March 19th, 2021, 13:30–17:00 Zoom Webinar
Program■13:30-13:50 Award Ceremony of Nakanishi Prize 2020
Congratulatory Address: Dr. Hiromitsu Kobayashi,
President, The Chemical Society of Japan
Prize Winner of the Nakanishi Prize 2020:
Dr. Yoshito Kishi; Professor Emeritus of Harvard University■13:50- Award Lecture
Presider Prof. Michio Murata; Osaka University“Chemistry and Biological Functions of Beyond Total
Synthesis of Complex Natural Products”
Prof. Yoshito Kishi■15:00-17:00
Nakanishi Symposium
Presider Prof. Hirokazu Arimoto (Tohoku University)
15:00- “Synthetic Studies on Biologically Active Natural
Products toward Practical Application”
Prof. Kosuke Namba (Tokushima University)
15:30- “Synthesis of Polycyclic Alkaloids Based on Dearomative
Oxidative Cyclization”
Prof. Kazuo Nagasawa (Tokyo University of Agriculture
and Technology)
15:30-15:40 ---Break--Presider Prof. Hideaki Oikawa (Hokkaido University)
15:40- “Lessons from Total Synthesis of Carthamin,
A Red Pigment from Safflower (Benibana)”
Prof. Keisuke Suzuki (Tokyo Institute of Technology)
16:10- “Studies on the Total Synthesis of Tetrodotoxin”
Prof. Tohru Fukuyama (The University of Tokyo)
16:40- Closing Remarks

Synthetic Studies on Biologically Active Natural
Products toward Practical Application
Kosuke Namba
Graduate School of Pharmaceutical Science, Tokushima University
namba@tokushima-u.ac.jp

Despite advances in organic synthetic chemistry have beenremarkable, total synthesis of biologically active natural products
having complex carbon framework and many functional groups isstill a difficult task. Therefore, although there are many usefulnatural products that are expected to contribute to the medical careand elucidation of life phenomena, the limited supply from natural
sources is a major barrier to their practical application in many cases.
In response to this problem, Prof. Kishi and collaborators havesucceed in the practical application of a very complex natural
product, halichondrin B, by supplying large quantities throughchemical synthesis. The author worked on the part of this practicalresearch and obtained valuable experience in Prof. Kishi’s group.
Now, the author believe that the solid supply of biologically active
natural products is a significant issue for the future total synthesis.
Based on this concept, in this presentation, I will discuss about ourrecent synthetic studies on mugineic acid1 (1) and palau’amine2 (2)in the view of the practical application of agrichemicals andpharmaceuticals.
Referecnes:
1. S. Takagi, Soil Sci.
Plant Nutr. 1976, 22,423.
2. R. B. Kinnel, H-P.
Gehrken,
P.
J.
Scheuer, J Am. Chem. Soc. 1993, 115, 3376.

Synthesis of Polycyclic Alkaloids Based on
Dearomative Oxidative Cyclization
Kazuo Nagasawa
Tokyo University of Agriculture and Technology
knaga@cc.tuat.ac.jp

Some biologically active alkaloids have characteristic polycyclicring systems with variety of functional groups including all-carbon
quaternary center. To access the structures efficiently, number ofapproaches have been reported. In our group, we have examined
the strategy for constructing the polycyclic ring system in thealkaloids with the following three steps; (i) connection of two
aromatic rings one of which is a phenol, (ii) dearomative oxidative
cyclization of phenol, and (iii) Michael type cyclization to theresulting dienones. In the process, it has an advantage that variety
of functional groups can be installed in aromatic groups before
constructing the polycyclic ring systems.
Based upon the strategy, we have demonstrated to construct 6-5-6,
and 6-6-6 ring systems including heterocycles with multi-functionalgroups. Furthermore, an additional fused type ring is constructedby the Michael type cyclization reaction. In this presentation,
synthesis of indole alkaloids of (+)-glacilamine1 and hasubanan typealkaloids are discussed.
Referecne:
1. M. Odagi, Y. Yamamoto, K.
Nagasawa, Angew. Chem., Int. Ed.
2018, 57, 2229.

Lessons from Total Synthesis of Carthamin,
A Red Pigment from Safflower (Benibana)
Keisuke Suzuki
Department of Chemistry, Tokyo Institute of Technology
ksuzuki@chem.titech.ac.jp

Carthamin is a traditional red pigment isolated from the petals ofsafflower, Carthamus tinctorius L (Benibana). The interest in the
structural identity of the pigment traces back to 19101 or even earlier.
From our interest in the natural products derived from type-II
polyketide biogenesis,2 we targeted this compound, having recently
succeeded in the total synthesis.3 In this talk, our lessons learned
from the struggle will be discussed.

References:
1. Kametaka, T.; Perkin, A. G. J. Chem. Soc. Trans. 1910, 97, 1415.
2. Suzuki, K. Chem. Rec. 2010, 10, 291.
3. Azami, K.; Hayashi, T.; Kusumi, T.; Ohmori, K.; Suzuki, K. Angew.
Chem. Int. Ed. 2019, 58, 5321.

Studies on the Total Synthesis of Tetrodotoxin
Tohru Fukuyama
Professor Emeritus, The University of Tokyo
tohru.fukuyama@post.harvard.edu

Tetrodotoxin (TTX) is one of the most famous natural products andis primarily known as a toxic principle of puffer fish. The potent
toxicity of TTX is attributed to the inhibition of voltage-gatedsodium channels (Navs). Remarkable biological activities as well as
unique structural features have made TTX a popular target for total
synthesis. Several successful total syntheses and a number ofsynthetic approaches to TTX have been covered in a recent review.1
As a young member of the TTX synthesis team of Prof. Kishi at
Nagoya University, I was involved in the first total synthesis of
racemic tetrodotoxin.2 More recently, we focused our attention on an
efficient asymmetric total synthesis of TTX which could be applied
to design a probe to capture mammalian Navs for structural studies.
Brief accounts of our first3 and second total syntheses of TTX as wellas the most recent approach will be discussed in the lecture.

References:
1.
2.

3.
4.

Makarova, M.; Rycek, L.; Hajicek, J.; Baidilov, D.; Hudlicky, T.
Angew. Chem. Int. Ed. 2019, 58, 18338.
Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.;
Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972,
94, 9219.
Maehara, T.; Motoyama, K.; Toma, T.; Yokoshima, S.; Fukuyama,
T. Angew. Chem. Int. Ed. 2017, 56, 1549.
I am deeply indebted to Prof. Satoshi Yokoshima, Graduate Schoolof Pharmaceutical Sciences, Nagoya University, for his continued
support and participation in the TTX project after my retirement.

Beyond Total Synthesis of Complex Natural Products
Yoshito Kishi
Department of Chemistry, Harvard University
kishi@chemistry.harvard.edu

With the halichondrin class of natural products as a case study, we
have been searching for the coupling-reactions effective at a latestage in a convergent synthesis of a complex molecule. In order tocarry out a given convergent synthesis effectively, these couplingreactions must meet with several demanding criteria, including thecoupling efficiency with a ~1:1 ratio of the coupling partners, thefunctional group compatibility, the coupling rates, thestereoselectivity, and others. Thus far, we have focused on thedevelopment of Ni/Cr-mediated aldehyde/vinyl-iodide couplings1
and Ni/Zr-mediated ketone synthesis,2 leading us to the developmentof unified, efficient, and scalable total synthesis of the halichondrinclass natural products.3
We will continue the research along these lines. At the same time,
we realize that the current synthesis allows us to address the nextlevel of our research-curiosity. In this presentation, we shall discuss
three of these attempts. First, with collaboration with Eisai Tsukuba
scientists, we have successfully demonstrated the scalability of thecurrent synthesis, thereby showing that the drug-supply issue can besolved by a total synthesis even for complex natural products suchas halichondrins.4 Second, we have been creating a library of in-vivo
active compounds on the basis of the halichondrin class of natural
products. Using Xenograft models with 11 cancer-cell lines, we haveshowed that: (1) each member in the library exhibits a unique profile
against the cancer models and (2) many compounds in the library
exhibit an outstanding in-vivo efficacy for these cancer models.
Third, in order to gain further mechanistic in-sights on theiranticancer effectiveness at a molecular level, we have synthetizedand tested the in-vitro and in-vivo activity of complete- and halfantipode of halihondrin-B and homohalichondrin-B, thereby giving
totally unexpected discoveries. In our view, these discoveries
immediately suggest exciting new research-directions for both basic
and applied research.

References
1. (a) H. Guo, C. Dong, D. Kim, D. Urabe, J. Wang, J. T. Kim, X. Liu,
T. Sasaki, and Y. Kishi, J. Am. Chem. Soc. 2009, 131, 15387. (b) K.
Yahata, N. Ye, K. Iso, S. R. Naini, S. Yamashita, Y. Ai, and Y. Kishi,
J. Org. Chem., 2017, 82, 8792 and references cited therein.
2. (a) V. P. Kumar, V. S. Babu, K. Yahata, and Y. Kishi, Org. Lett. 2017,19, 2766. (b) Y. Ai, N. Ye, Q. Wang, K. Yahata, and Y. Kishi, Angew.
Chem. Int. Ed. 2017, 56, 10791. (c) A. Umehara and Y. Kishi, Chem.
Lett. 2019, 48, 947 and references cited therein.
3. K. Yahata, N. Ye, Y. Ai, K. Iso, and Y. Kishi, Angew. Chem. Int. Ed.
2017, 56, 10796 and references cited therein.
4. S. Kawano, K. Ito, K. Yahata, K. Kira, T. Abe, T. Akagi, M. Asano, K.
Iso, Y. Sato, F. Matsuura, I. Ohashi, Y. Matsumoto, M. Isomura, T.
Sasaki, T. Fukuyama, Y. Miyashita, Y. Kaburagi, A. Yokoi, O. Asano,
T. Owa, and Y. Kishi, Sci. Rep. 2019, 9, 8656 and references citedtherein.

Kosuke Namba: born in Osaka in 1972 andgraduated from Osaka City University (B.
1996), PhD, Osaka City University (Prof. Y.
Ohfune) 2001, Postdoctoral fellow, Colorado
State University (2001-2003, prof. R. M.
Williams) and Harvard University (20032005, Prof. Y. Kishi), Researcher, the Suntory
Institute for Bioorganic Research (20052006), Assistant Professor, Tokushima Bunri
University (2006-2008, Prof. M. Nishizawa),
Lecturer and Associate Professor, Hokkaido
University (2008-2013, Prof. K. Tanino), Professor, Pharmaceutical
Science, Tokushima University (2013-). Incentive Award in Synthetic
Organic Chemistry, Japan in 2009.

Kazuo Nagasawa: born in 1965 and graduatedfrom Waseda University (B. 1988), PhD fromWaseda University (1993, Prof. Isao Shimizu),
Postdoctoral fellow, Harvard University (19971999, Prof. Yoshito Kishi), Researcher,
RIKEN, (1993-2000, Prof. Tadashi Nakata),
Associate Professor, Institute of Molecular andCellular Biosciences, University of Tokyo(2001-2004), Associate Professor, Departmentof Technology,
Tokyo University ofAgriculture and Technology (2004-2009),
Professor, Department of Technology, Tokyo University of Agriculture
and Technology (2009- ). Research Award in the Society of Synthetic
Organic Chemistry, Japan (2000), The Pharmaceutical Society of Japan
Award for Young Scientists (2003), Shionogi Award in the Society ofSynthetic Organic Chemistry, Japan (2018). position.

Keisuke Suzuki: born in Chigasaki in 1954
and graduated from University of Tokyo (B.
1978), Dr. Sci., University of Tokyo (Prof.
Teruaki Mukaiyama) 1983, Research
Associate, Keio University (1983–1987),
Lecturer (1987–1989), Associate Professor(1989–1994), Professor, Keio University(1994–1996), Professor, Tokyo Institute ofTechnology (1996–), Visiting Professor,
ETH (1990–1991, Prof. Seebach), Memberof Japan Academy (2018–). Chemical
Society of Japan Award for Young Chemists (1986), Japan IBM Award(1994), Nagoya Silver Medal (1999), Synthetic Organic ChemistryAward, Japan (2003), Prizes for Science and Technology, MEXT Japan(2006), Chemical Society of Japan Award (2008), Humboldt ResearchPrize (2009), Purple Ribbon Medal (2010), Japan Academy Prize(2015).
Tohru Fukuyama: born in 1948 in Anjo,
Japan. Nagoya University (B.A., 1971),
Harvard University (Ph.D., 1977, Prof.
Yoshito Kishi), Postdoctoral Fellow,
Harvard University (1977-1978, Prof.
Kishi), Assistant Professor (1978-1982),
Associate
Professor(1982-1988),
Professor (1988-1995), Department ofChemistry, Rice University, Professor(1995-2012),
Graduate
SchoolofPharmaceutical Sciences, University ofTokyo, Professor (2012-2013), Designated Professor (2013-2018),
Graduate School of Pharmaceutical Sciences, Nagoya University. A
number of awards including ACS Award for Creative Work in Synthetic
Organic Chemistry (2004) and Medal with Purple Ribbon.

The Recipients of the Prize hereto are:1996 Yoshimasa Hirata*
1997 Frank H. Westheimer
1998 Albert J. Eschenmoser*
1999 Jeremy R. Knowles
2000 Satoshi Ōmura*2001 John D. Roberts
2002 Sir Jack Baldwin*
2003 A. Ian Scott2004 Isao Kitagawa*2005 Stephen J. Benkovic
2006 Takeshi Yasumoto*2007 Hung-wen Liu

2008 Michel Rohmer*
2009 JoAnne Stubbe2010 Shosuke Yamamura*2011 C. Dale Poulter2012 Daisuke Uemura*2013 Arthur G. Palmer, III
2014 Jerrold Meinwald*2015 Fred McLafferty
2016 Shoichi Kusumoto*2017 Martin Gruebele
2018 Nobuyuki Harada*
2019 Lewis E. Kay2020 Yoshito Kishi**Selection and presentation made by the Chemical Society of Japan.

Organizing Committee:◆Chairman
Hideaki Oikawa (Hokkaido University)◇Members
Ikuro Abe (The University of Tokyo)
Hirokazu Arimoto (Tohoku University)
Hirokazu Kawagishi (Shizuoka University)
Michio Murata (Osaka University)
Minoru Ueda (Tohoku University)
Keisuke Suzuki (Tokyo Institute of Technology)*The Organic Committee acknowledges the generous support from the Naito Foundation.