The Nakanishi Symposium
on Natural Products & Bioorganic Chemistry

Nihon University
March 20, 2018

Sponsored by
The Chemical Society of Japan&
The American Chemical Society

Harada, Nobuyuki
Professor Emeritus, Tohoku University■EDUCATION
B. Sc. Chemistry, Faculty of Science, Tohoku University
Ph.D. Organic Chemistry, Tohoku University (Prof. K. Nakanishi)

1965
1970

■ACADEMIC CAREER Tohoku University
1970－2006
Chem. Res. Inst. of Nonaqueous Solutions, Inst. for Chem. Reaction
Science, and Inst. of Multidisciplinary Res. for Advanced Materials,
Research Associate, Associate Professor, and then Professor of Chemistry.
Columbia University, USA
Dept. of Chem., Postdoc (Prof. K. Nakanishi)
Institute for Molecular Science, Okazaki Nat. Res. Inst.
Adjunct Associate Professor.

－1－

1973－1975
1980－1982

Du Pont de Nemours & Company, USA
Experimental Station, Visiting Res. Scientist
Columbia University, USA
Dept. of Chem., Visiting Researcher/Scholar andSenior Research Scientist (Prof. K. Nakanishi)

1987
2006－2009■RESEARCH TOPICSa) Natural Products Chemistry and Structural Organic Chemistry.
b) Theory of Circular Dichroism, and Development of the CD Exciton
Chirality Method.
c) Enantioresolution, Absolute Configurational and Conformational Studies
of Chiral Compounds by CD, NMR, and X-Ray Methods Using Novel
Chiral Molecular Tools, CSDP and MNP Acids.
d) Molecular Machine: Light-Powered Chiral Molecular Motors.
■SELECTED PUBLICATIONS
1. A Method for Determining the Chiralities of Optically Active Glycols.
N. Harada and K. Nakanishi, J. Am. Chem. Soc., 91, 3989-3991 (1969).
2. The Exciton Chirality Method and its Application to Configurational andConformational Studies of Natural Products. N. Harada, and K. Nakanishi,
Acc. Chem. Res., 5, 257-263 (1972).
3. N. Harada and K. Nakanishi, "Circular Dichroic Spectroscopy – Exciton Couplingin Organic Stereochemistry –", University Science Books, Mill Valley, California,
and Oxford University Press, Oxford (1983).
4. The Absolute Stereochemistries of 6,l5-Dihydro-6,l5-ethanonaphtho[2,3-c]pentaphene and Related Homologues as Determined by both Exciton
Chirality and X-ray Bijvoet Methods. N. Harada, Y. Takuma, and H. Uda, J.
Am. Chem. Soc., 98, 5408-5409 (1976).
5. Light-driven Monodirectional Molecular Rotor. N. Koumura, R. W. J.
Zijlstra, R. A. van Delden, N. Harada, and B. L. Feringa, Nature, 401, 152155 (1999).
6. HPLC Separation of Diastereomers: Chiral Molecular Tools Useful for the
Preparation of Enantiopure Compounds and Simultaneous Determinationof Their Absolute Configurations. N. Harada, Molecules, 21, number 1328
(2016).
AWARDSa) Chemical Society of Japan Award for Creative Workb) Molecular Chirality Awardc) Molecular Chirality Distinguished Service Award

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1984
2000
2015

― Table of Contents ―Profile of Prof. Nobuyuki Harada;
Prize Winner of the Nakanishi Prize 2018……

1

Program of the Award Ceremonyof the Nakanishi Prize & Nakanishi Symposium……

4“Determining Molecular Configuration andConformation by Vibrational Circular Dichroism:
from Small Molecules to Macromolecules”
Prof. Tohru Taniguchi (Hokkaido University)……

5“Porphyrin-based Chiroptical Sensors of
Molecular and Supramolecular Chirality”
Prof. Nina Berova (Columbia University)……

7“In the Rising CD Era, How Can Mosher’s
Method Survive?”
Prof. Takenori Kusumi (Tokyo Institute ofTechnology）……

8“A Challenge of Organic Synthesis to Ciguatera
Fish Poisoning”
Prof. Masahiro Hirama (Tohoku University &AcroScale, Inc.)…… 10

Award Lecture“Chiral
Molecular
Science:fromtheDevelopment of CD Exciton Chirality Method
to the Invention of Light Powered Chiral
Molecular Motors”
Prof. Nobuyuki Harada(Professor Emeritus, Tohoku University)

…… 12

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Nakanishi Symposium 2018
Organized by：Nakanishi Symposium Organizing Committee
Co-organized by: Chemical Society of Japan,
Division of Natural Products Chemistry & Biological Science

Date
March 20th, 2018, 13:30–17:30
Venue Nihon University (S2; 2F 1326, 13th Bldg., Funabashi Campus)
Program■13:30-14:00
Award Ceremony of Nakanishi Prize 2018
Presider Prof. Michio Murata (Osaka University)
Prize Winner of the Nakanishi Prize 2018:
Prof. Nobuyuki Harada; Professor Emeritus, Tohoku University■14:00-17:00
Nakanishi Symposium
Presider Prof. Shigeru Nishiyama (Keio University)
14:00- “Determining Molecular Configuration and Conformation
by Vibrational Circular Dichroism: from Small Molecules
to Macromolecules”
Prof. Tohru Taniguchi: (Hokkaido University)
14:30- “Porphyrin-based Chiroptical Sensors of Molecular andSupramolecular Chirality”
Prof. Nina Berova (Columbia University)
Presider Prof. Keisuke Suzuki (Tokyo Institute of Technology)
15:00- “In the Rising CD Era, How Can Mosher’s Method Survive?”
Prof. Takenori Kusumi (Tokyo Institute of Technology）
15:30- “A Challenge of Organic Synthesis to Ciguatera Fish
Poisoning”
Prof. Masahiro Hirama (Tohoku Univ. & AcroScale, Inc.)
16:00-16:10 ---Break--Presider Prof. Michio Murata (Osaka University)
16:10- Award Lecture“Chiral Molecular Science: from the Development of CD
Exciton Chirality Method to the Invention of LightPowered Chiral Molecular Motors”
Prof. Nobuyuki Harada (Professor Emeritus, Tohoku Univ.)■17:10- Closing Remarks－4－Determining Molecular Configuration andConformation by Vibrational Circular Dichroism:
from Small Molecules to Macromolecules
Tohru Taniguchi
Faculty of Advanced Life Science, Hokkaido University
ttaniguchi@sci.hokudai.ac.jp“CD [circular dichroism] spectroscopy is still one of the least usedphysical tools and causes most organic chemists headaches,” wrote Prof.
Koji Nakanishi in his ACS autobiography in 1991.1 The current statusof CD is not significantly different; CD spectroscopies remain as muchless used methods for structural analysis than, for example, NMR
spectroscopy and mass spectrometry. However, the reliability andversatility of CD techniques have considerably improved owing to thedevelopment of vibrational circular dichroism (VCD) spectroscopy anddensity functional theory (DFT) calculations of ECD (electronic
circular dichroism) and VCD spectra. These developments establishedCD spectroscopy as a tool to elucidate the configuration andconformation of small organic molecules.2
Structural determination using VCD spectroscopy is normally carriedout by comparing experimental spectra and DFT-predicted ones.
Although this procedure is effective for small, rigid, hydrophobic
molecules, its applicability for medium-sized, flexible, and/orhydrophilic molecules is yet to be explored. Meanwhile, structural
analysis based on ECD spectroscopy has been performed without
theoretical calculations by using the ECD exciton chirality method
developed by Profs. Harada and Nakanishi.3 Inspired by the ECD
exciton chirality method, I invented a “VCD exciton chirality method”,
which enables structural determination just by observing a strong
bisignate VCD signal originating from interactions between two or
more carbonyl groups.4 The development of this method partially,
though not entirely, solved the drawback of the current DFT-based VCD－5－structural determination.
With VCD theoretical calculations and the VCD exciton chirality
method in hand, I have been studying the stereostructure of various
molecules including carbohydrates, lipids, peptides, nucleosides,
synthetic small molecules and macromolecules. Some of these topics
should demonstrate the advantages of VCD spectroscopy over othermethods, such as the capability of its picosecond shutter speed for
elucidating detailed molecular conformations.2,5This presentation will focus mostly on my recent VCD results on
flexible lipids, molecules containing five-membered rings, and axiallychiral molecules. VCD spectroscopy is not a panacea for all structuralproblems, but this presentation should address its usefulness for various
stereostructural studies.6
References:
1.

2.
3.
4.
5.
6.

K. Nakanishi, A Wandering Natural Products Chemists, ed. by J. I.
Seeman, American Chemical Society, Washington, D. C., 1991, p.
230 (Profiles, Pathways and Dreams Series). The quote is on page74, but I recommend reading through the entire book.
This paragraph is cited from the following article with somemodifications: Taniguchi, T. Bull. Chem. Soc. Jpn. 2017, 90, 1005.
Harada, N.; Nakanishi, K. J. Am. Chem. Soc. 1969, 91, 3989.
Taniguchi, T.; Monde, K. J. Am. Chem. Soc. 2012, 134, 3695.
Taniguchi, T.; Nakano, K. et al. Org. Lett. 2017, 19, 404.
I am grateful to Prof. Kenji Monde for his generous support andencouragement. I would like to express my sincere gratitude to Prof.
Koji Nakanishi (Columbia University), Prof. Nobuyuki Harada(Tohoku University), and Prof. Nina Berova (Columbia University)
for providing me an opportunity to learn the ECD exciton chirality
method.

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Porphyrin-based Chiroptical Sensors of
Molecular and Supramolecular Chirality
Nina Berova
Department of Chemistry, Columbia University, New York
ndb1@columbia.edu
In the past few decades porphyrins and metalloporphyrins (P) attracted
a great attention in response to the growing interest in development of
more versatile and efficient sensors for determination of chirality at
molecular and supramolecular level. The situation where two or more
porphyrins reside in chiral environment and interact through space
appears particularly beneficial for stereochemical analysis since thisinteraction leads to a very intense ECD response observable even on a
sub-microscale level.1,2 Discussion will include: i) determination of AC
of natural products by chemical/long-range P/P ECD exciton coupling
protocol1; ii) supramolecular analysis of AC of chiral bidentate guests
by stereodifferentiative complexation to achiral dimeric
metalloporphyrins receptors-hosts2; iii) complexation between chiraltweezers and achiral substrates3; iv) ECD analysis of covalentporphyrin conjugates of DNA4, PNA , as well as ICD analysis of noncovalent B /Z DNA-porphyrin complexes5.
References:
1.
2.
3.
4.

5.

Pescitelli, G.; Di Bari, L.; Berova, N. Chem. Soc. Rev. 2011, 4603;
2014, 5211.
Berova, N.; Pescitelliu, G.; Petrovic, A.; Proni, G., Chem. Commun.
2009, 5958.
Saha, B.; Ikabal, S.; Petrovic, A.; Berova, N.; Rath, S., Inorg. Chem.
2017, 3849.
Mammana, A.; Pescitelli, G.; Asakawa, T; Jockusch, S; Petrovic, A.;
Monaco, R.; Purrello, R.; Turro, N. J.; Nakanishi, K.; Ellestad, G.;
Balaz, M.; Berova. N., Chem.-Eur. J. 2009, 15,11853.
Gangemi, C.M.A; D’Urso, A.; Tomaselli, G.A.; Berova, N.; Purrello,R., Inorg. Biochem. 2017, 173, 141.

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In the Rising CD Era,
How Can Mosher’s Method Survive?
Takenori Kusumi
Department of Chemistry, Tokyo Institute of Technology
kusumi.t.ab@m.titech.ac.jp
Since Professor Harry S. Mosher reported the MTPA reagent for
determining the absolute configuration of secondary alcohols by NMR
spectroscopy in 1973,1 this ‘Mosher’s method’ has been widely used byorganic chemists, boosted by the rapid development of the NMR
techniques which made the assignment of proton signals quite easy.
The present speaker, together with several collaborators, has developed
other NMR chiral reagents similar to MTPA (and MPA) such as (1)1NMA, 2NMA, and 2ATMA applicable to secondary alcohols, (2)
PGME for carboxylic acids, and (3) sulfoximine for sulfoxides.2
These methods are empirical ones and have a minor disadvantage that
one must prepare two diastereomers using R- and S-reagents, although
the task may not be too troublesome for most of organic chemists.
On the other hand, CD is strictly based on theoretical physics, and more
‘white color’-ish (computer-works in an air-conditioned room)compared to the above mentioned rather ‘alchemistry’-ish methods(handworks with the sweat on the brow).
Obviously, usefulness of CD in elucidation of the absoluteconfiguration of natural products has been strenuously revealed byProfessor Koji Nakanishi followed by his renowned collaborators,
Professor Nobuyki Harada,3 the awardee of 2018 Nakanishi Prize, andProfessor Nina Berova of Columbia University, a co-editor of journal‘Chirality’.
Very recently, ECD (Electronical CD)4 and VCD (Vibrational CD)5
based on TDDFT (time dependent density functional theory) haveemerged as a strong tool for the absolute configuration assignment.

－8－

Owing to the impossible-to-catch-up-with advance of computer, one
can use these methods on the PC level these days. The results seem tobe reliable because the absolute configuration can be deduced bycomparing the experimental spectrum with the calculated one on adisplay.
For now, it can be said that the Mosher’s method could not be forgotten
when one deals with the very flexible molecules, for which even thecomputer cannot tell the stable conformations.
References:
1.
2.
3.

4.
5.

Dale, J. A.; Mosher, H. S., J. Am. Chem. Soc. 1973, 95, 512.
Kusumi, T.; Ooi, T.; Ohkubo, Y.; Yabuuchi, T. Bull. Chem. Soc. Jpn.
2006, 79, 965.
Harada, N.; Nakanishi K. “Circular Dichroism–Application to theStereochemistry of Organic Compounds” Tokyo Kagaku Dojin,
Tokyo, 1982.
Pescitelli, G.; Di Bari, L.; Berova, N., Chem. Soc. Rev. 2014, 5211.
Taniguchi, T.; Monde, K. J. Synth. Org. Chem. Jpn. 2017, 75, 522.

－9－

A Challenge of Organic Synthesis
to Ciguatera Fish Poisoning
Masahiro Hirama
Professor of Chemistry, Emeritus, Tohoku University& AcroScale, Inc.
hirama@m.tohoku.ac.jp

Ciguatera fish poisoning (CFP) caused by the consumption of fish thathave accumulated ciguatoxins (CTXs) affects more than 50,000 people
annually. The spread of CFP causes tremendous damage to public health,fishery resources, and the economies of tropical and subtropicalendemic regions. The difficulty in avoiding CFP arises from the lack ofsensitive and reliable analytical methods for detection andquantification of CTXs in ciguatoxic fish, along with the normal
appearance, smell, and taste of fish contaminated with the causative
toxins. Thus, an accurate, sensitive, routine, and portable detection
method for CTXs is urgently required.
Total synthesis of ciguatoxins (CTXs) is a formidable challenge, yet isthe sole realistic solution for obtaining sufficient quantities of CTXs forbiological, medical, and pharmacological studies. There was little
prospect for our success in the total synthesis of CTXs and furthermore,even the absolute stereochemistry of CTXs was unknown, when welaunched our synthetic endeavor in 1989.
We first implicated the absolute configuration of CTX using theHarada-Nakanishi Exciton chirality CD method with the synthetic
model compounds. Then, our 12-year effort culminated in the first total
synthesis of CTX3C in 2001.1 Our synthesis was appreciated as “TheArt of Total Synthesis” by Science (2001, 294, 1842), and “Organic
Chemistry Takes on Tropical Seafood Poisoning” by The Lancet (2001,
358, 1278). Our total synthesis unambiguously established theconfiguration of CTXs as implicated by the CD studies. Since then, ourhighly convergent and unified strategic approach featuring－10－

chemoselective RCM/radical cyclization reactions as key tactics has
been improved, and enabled the total synthesis of three other important
Pacific congeners, 51-hydroxyCTX3C, CTX1B, and 54-deoxyCTX1B,
as well as F-ring modified analogs.2 The synthesis of these compounds
has significantly impacted the biological and pharmacological studies
of CTXs.
The second aim of our research was developing anti-ciguatoxin
antibodies and antibody-based immunoassays. We therefore planned asynthesis-based approach using rationally designed synthetic haptens toaddress the problem of antibody development. Numerous immunization
studies in collaboration with Profs. Tsumuraya and Fujii using synthetic
hapten-keyhole limpet hemocyanin (KLH) conjugates showed that thepolyether fragments, which possess more than five ether rings and havea surface area larger than 400Å2, can be used as synthetic haptens toprovide highly sensitive and specific anti-CTX monoclonal antibodies(mAbs). These mAbs (10C9, 3D11, 8H4, and 3G8) have been used todevelop a direct sandwich enzyme-linked immunosorbent assay(ELISA) method for the reliable detection of CTXs, which shows nocross-reactivity with other related marine toxins. This ELISA protocolhas been recently improved to exhibit a detection limit (LOD) of lessthan 1 pg/mL using an alkaline phosphatase-fluorescent system. Thisdetection limit is sufficient to detect very small amount of CTX
contaminants in fish, as stipulated by FDA guidance (0.01 ppb=10
ng/kg).2 It should be noted that this ELISA method will be useful not
only for prevention of CFP but also for the epidemiological andphysiological studies.
References:1.

M. Hirama, T. Oishi, H. Uehara, M. Inoue, M. Maruyama, H.
Oguri, M. Satake, Science 2001, 294, 1904.

2.

M. Hirama, Proc. Jpn. Acad., Ser. B 2016, 92, 290, and citedtherein.

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Chiral Molecular Science: from the Development of
CD Exciton Chirality Method to the Invention ofLight Powered Chiral Molecular Motors
Nobuyuki Harada
Professor Emeritus, Tohoku University
n2harada@tagen.tohoku.ac.jp / n2harada8b@tohoku.ac.jp
The molecular chirality is a key concept in chemistry, bioscience, andmolecular technology like the invention of a light-powered chiral molecularmotor explained below. So, the primary subject is how to determine theabsolute configuration (AC) of chiral compounds in a reliable manner. There
are non-empirical methods for determining ACs of chiral compounds, e.g.,
the X-ray Bijvoet method and the CD exciton chirality method. In addition,
there are relative methods, where the internal reference of AC was used in Xray and 1H NMR methods. The author and coworkers have developed thesemethods and applied to various natural products and chiral synthetic
compounds. During these studies, we have also invented light powered chiralmolecular motors. These research results will be discussed in this lecture.
1. CD exciton chirality method.
In 1969, Harada and Nakanishi discovered the CD dibenzoate rule fordetermining the ACs of chiral glycols,1 as exemplified in Figure 1. This CD
method has successfully been applied to various natural products in a reliable
manner, because the observed CD showed intense bisignate Cotton effects,
and the CD mechanism was established by the exciton theory.2,3 The
equations for the exciton coupling system are formulated as follows.
-state:wave function: a = (1/√2)(iaj0 – i0ja)energy: E = Ea – Vijdipole strength: D = (1/)(μi0a – μj0a)2
rotational strength: R = +(1/)0 Rij • (μi0a  μj0a)

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
-state:wave function: a = (1/√2)(iaj0 + i0ja)energy: E = Ea + Vij
dipole strength: D = (1/)(μi0a + μj0a)2
rotational strength: R = –(1/)0 Rij • (μi0a  μj0a)
Interaction energy:
Vij = Rij–3 {μi0a • μj0a –3Rij–2 (μi0a • Rij)( μj0a • Rij)}

Figure 1. Exciton CD of steroidal dibenzoate 1 and AC determination.
We have also discovered that this CD method is applicable to compounds
already possessing a chromophore suitable for exciton coupling. For example,
the AC of chromomycin A3 derivative was determined4 as shown in Figure 2,
where the transitions of benzoate and naphthalene chromophores couple witheach other, making a left-handed helicity, and hence the negative first andpositive second Cotton effects were observed. Thus, the dibenzoate rule was
generalized as the CD exciton chirality method.
The history of AC determination was also the history of controversies. For
example, in the early 1970s, it was claimed that the ACs of compounds (–)-7
and (+)-8 shown in Figure 3 assigned by the exciton chirality method
disagreed with the ACs determined by the X-ray Bijvoet method applied totheir HBr salts, causing big controversies. Furthermore, it was also claimed
that the theory of the Bijvoet method was wrong, and hence the ACs
determined by the Bijvoet method should be reversed. If so, most textbooksof chemistry had to be revised.

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Figure 2. Application of the CD exciton chirality method to chromomycin
A3 derivatives.
To solve this problem, the author and coworkers synthesized the most ideal
cage compound (+)-5 for connecting the CD exciton chirality method and the
X-ray Bijvoet method5 as shown in Figure 3. The reasons why this compound
was selected are as follows: i) in the UV spectrum, an anthracene
chromophore exhibits a very intense and long-axis polarized 1Bb transition at
252 nm ( 204,000); ii) compound (+)-5 is of cage structure, and hence it has
no conformational flexibility; iii) the absolute sense of helicity between twolong axes of anthracene chromophores is clear in space; iv) compound (+)-5
would be synthesized starting from diester (+)-6, the AC of which was alreadyassigned by the X-ray Bijvoet method and chemical correlations.
In fact, the CD spectrum of compound (+)-5 showed very intense exciton split
Cotton effects (ext 268.0 nm,  +931.3 / ext 249.7 nm,  –720.8), from thesigns of which the AC of (+)-5 was determined as shown in Figure 3. ThisAC determination agreed with that by the X-ray Bijvoet method. Thesestudies thus put an end to the above controversies.

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Figure 3. CD and UV spectra of cage compound (+)-5, and consistency
between X-ray Bijvoet and CD exciton chirality methods.
2. -Electron SCF-CI-DV MO method.
The -electron SCF-CI-DV (Self Consistent Field-Configuration InteractionDipole Velocity) MO method is useful for determining the ACs of chiralcompounds containing a twisted -electron conjugated system. For example,
derivative (–)-9 of halenaquinol, a marine natural product, contains 1,3-diene
unit conjugated with naphthalene ring as shown in Figure 4, where the helicityof -conjugation system is governed by the chirality at the 12b position. The
CD spectrum of compound (–)-9 shows intense Cotton effects, e.g., ext 301
nm ( –23.3), 229 nm (+40.9), which reflect the helicity of the -conjugation
system.6
As the calculation model, compound (12bS)-10 was selected, where the AC
was selected at random, and its CD and UV curves were calculated by the
SCF-CI-DV MO method. As seen in Figure 4, the basic pattern of CD andUV spectra were well reproduced by the calculation, e.g., ext 322 nm (–22.4), 223 nm (+35.5), and therefore, the AC of derivative (–)-9 was
determined to be (12bS) as shown. The AC of halenaquinol was clearly
assigned.6－15－

Figure 4. CD and UV spectra of halenaquinol derivative (–)-9, and calculated
CD and UV curves of model compound 10.
It is important to prove the theoretically assigned ACs in an experimentalmanner. So, we attempted the synthesis of halenaquinol; starting from (8aR)(–)-Wieland-Miescher ketone, we have first succeeded in the total synthesisof (12bS)-(+)-halenaquinol of natural enantiomer via the reactions of 16
steps.7 The present results have thus established the reliability of the electron SCF-CI-DV MO method.
3. CSDP acid powerful for enantioresolution of alcohols andsimultaneous determination of their ACs.
To prepare enantiopure compounds and to determine their ACs
simultaneously, we have developed CSDP acid, Camphor-Sultam DichloroPhtahlic acid, (1S,2R,4R)-(–)-11 (Figure 5).8 For example, racemic alcohol(±)-12 was esterified with CSDP acid (–)-11 giving a mixture ofdiastereomeric esters, which was separated by HPLC on silica gel as shownin Figure 5: separation factor  = 1.18. The second-eluted ester (–)-13b was
obtained as single crystals. Therefore, its AC could be determined by X-ray
crystallography as shown in Figure 5, where the CSDP acid part was used as
the internal reference of AC. Hydrolysis of ester (3R,4R)-(+)-13a furnishedenantiopure alcohol (3R,4R)-(+)-12.9 Thus, the advantages of CSDP acid are
as follows:8 i) its diastereomeric esters are separable by HPLC on silica gel;ii) one of separated esters will be obtained as single crystals suitable for X-－16－

ray analysis in a high probability; iii) CSDP acid moiety can be used as theinternal reference of AC.

Figure 5. Enantioresolution of racemic alcohol and AC determination byusing CSDP acid (1S,2R,4R)-(–)-11.
4. Invention of light-powered chiral molecular motors.
Around 1985, the author was asked by Prof. H. Wynberg, Groningen
University, the Netherlands, to determine the ACs of chiral olefins 14 and 15(Figure 6).

Figure 6. The ACs of chiral olefins 14 and 15 determined by the -electron
SCF-CI-DV MO method.
In these compounds, two naphthalene chromophores conjugate with thecentral double bond, and the whole -electron conjugation systems are largely
twisted. Therefore, these compounds were ideal systems for the AC
determination by the -electron SCF-CI-DV MO method. By comparing the
calculated and observed CD curves, the ACs of chiral olefins 14 and 15 were
determined as shown in Figure 6.10

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To confirm the above ACs in an experimental manner, we attempted tosynthesize some derivatives containing heavy atoms suitable for the X-ray
Bijvoet method. For example, the synthesis of episulfide derivative wasattempted, but no desired product was obtained. Therefore, the authorchanged the strategy as shown in Figure 7, where the synthesis of dimethyl
derivatives 17a and 17c was planned, expecting that two methyl groups inchiral positions would be useful as the internal reference of AC.9

Figure 7. Synthesis of dimethyl derivatives (–)-17a and (+)-17c and AC
determination by X-ray internal reference method.
Starting from CSDP ester (3R,4R)-(+)-13a in Figure 5, the desired dimethyl
derivative (E)-(–)-17a could be synthesized, and its AC could be determinedby X-ray crystallography as shown in Figure 7, where two methyl groups
were used as the internal reference of AC. The shape and absolute intensityof CD spectrum of compound [CD(–)237.2]-(3R,3’R)-(P,P)-(E)-(–)-17a
were similar to those of olefin [CD(+)239.0]-(E)-14, but CD signs were
opposite to each other. Hence, the AC of olefin [CD(+)239.0]-(E)-14 wasestablished to be (M,M), which confirmed the above AC determination by the-electron SCF-CI-DV MO method.9
The photoreaction of trans-olefin (–)-17a furnished cis-olefin [CD(–)238.0](3R,3’R)-(P,P)-(Z)-(+)-17c, the AC of which was determined by X-ray
analysis of racemate (±)-17c as shown in Figure 7, because single crystals of
enantiomer (+)-17c could not be obtained. Thus, the X-ray analysis of－18－

racemate is also useful for determining AC by the internal reference method.
The CD spectra of olefins [CD(–)238.0]-(Z)-17c and [CD(+)238.1]-(Z)-15
were opposite in sign to each other, and hence the (M,M) AC of olefin[CD(+)238.1]-(Z)-15 was established.9
During these studies, we have invented a light powered chiral molecularmotor as follows.11 Namely, i) compound 17 isomerizes as shown in Figure
8 by photo and thermal reactions; ii) the reaction circulates in one direction,i.e., 17a 17b17c17d17a; iii) during one cycle of reactions, one
naphthalene ring rotates 360° in one direction against the other naphthalene
ring. Namely, a light powered chiral molecular motor was first synthesized,
where the motor mechanically rotates using the light energy, the rotational
direction is governed by the molecular chirality, and the motor motion can becontrolled by the on/off of light. The key point of the invention was theintroduction of two methyl groups.

Figure 8. The rotation mechanism of a light powered chiral molecular motor.
It is very interesting and also enjoyable that the basic research of AC
determination in an experimental manner created the breakthrough results,
which had never been expected at first even by researchers involved.

－19－

5. MNP acid powerful for enantioresolution of alcohols andsimultaneous determination of their ACs by 1H NMR method.
MNP acid, 2-methoxy-2-(1-naphthyl)propionic acid, (S)-(+)-18 is powerfulfor enantioresolution of racemic secondary alcohols and also for AC
determination by 1H NMR method as shown in Figure 9.8

Figure 9. The outline of MNP acid method.
Racemic secondary alcohol ()-19 is esterified with MNP acid (S)-(+)-18
yielding diastereomeric esters, which are easily separable by HPLC on silica
gel. The first-eluted ester is designated (S,X)-20a, where S indicates the ACof acid part, X does the AC of alcohol part to be determined. The secondeluted ester is designated (S,–X)-20b, where –X indicates the opposite AC of
X.

－20－

These two esters take the preferred conformations as shown in Figure 9 (b),where in the first-eluted ester (S,X)-20a, the substituent R2 is located over thenaphthalene ring, and hence the group R2 is high-field shifted in 1H NMR
chemical shift. On the other hand, in the second-eluted ester (S,–X)-20b, thesubstituent R1 is high-field shifted, because it is located over the naphthalene
group.
The parameter  is defined as shown in Figure 9 (c), and its value iscalculated for each proton from the observed 1H NMR data. The protons areplaced according to the sector rule, where protons with positive  values areplaced on the right side, while those with negative  values are placed on
the left side. The AC (X) of the alcohol part in the first-eluted ester can bethus determined.8
The following is a striking example of the MNP acid method.
Racemic
acetylene alcohol ()-21 was esterified with MNP acid (S)-(+)-18 yielding
diastereomeric esters 22a and 22b, which were largely separated by HPLCon silica gel as shown in Figure 10 (b): separation factor  = 1.78. From their
1H NMR data, the diamagnetic anisotropy parameter was calculated foreach proton as shown in Figure 10 (c), where the acetylene side chain shows
positive  values, while the saturated side chain shows negative values.
Therefore, the (19S) AC was assigned to the first-eluted MNP ester (–)22a.12
To verify the above ACs, we tried to crystallize the esters 22a and 22b fromvarious solvents, and finally obtained single crystals of ester (–)-22b whenrecrystallizing from iso-PrOH. The crystals were very thin plates with 5 m
thickness, and hence the strong X-ray of synchrotron radiation at SPring-8
was used. The structure of ester (–)-22b was determined as shown in Figure
10 (d): R = 0.0814. Although the crystalline state conformation is different
from that of the solution state, the AC was unambiguously determined byusing the MNP acid part as the internal reference of AC. The result was inagreement with the AC determined by the 1H NMR method using MNP acid.
Thus, the 1H NMR/MNP acid method was supported by X-ray
crystallography.

－21－

Figure 10. The application of the MNP acid method to acetylene alcohol 21.
The hydrolysis of ester (S;19S)-(–)-22a yielded enantiopure acetylene alcohol(S)-(–)-21, whose AC was unambiguously determined. The MNP acid
method is thus powerful for the preparation of enantiopure alcohols and also
for simultaneous determination of their ACs.

－22－

Conclusion.
As discussed above, there are several methods for determining the ACs ofchiral compounds. When applying these methods, it is important tounderstand the advantages and disadvantages of each method, and also toevaluate the reliability of the AC assignment carried out. Especially, when the
AC was assigned based on the theoretical CD calculation, it is necessary toconfirm the AC in an experimental manner.
Acknowledgements
The researches discussed in this lecture have been carried out in collaboration
with many coworkers, whose names are listed in references. The author
sincerely thanks them, especially the staffs and all the students of Haradagroup, for their efforts.

References:
1. A Method for Determining the Chiralities of Optically Active Glycols.
N. Harada, K. Nakanishi, J. Am. Chem. Soc. 1969, 91, 3989.
2. The Exciton Chirality Method and its Application to Configurationaland Conformational Studies of Natural Products. N. Harada, K.
Nakanishi, Acc. Chem. Res. 1972, 5, 257.
3. N. Harada, K. Nakanishi, "Circular Dichroic Spectroscopy – Exciton
Coupling in Organic Stereochemistry –", University Science Books,
Mill Valley, California, and Oxford University Press, Oxford (1983).
4. A Method for Determining the Chirality of Two Aromatic
Chromophores and the Absolute Configurations of Chromomycin A3
and Related Antibiotics. N. Harada, K. Nakanishi, S. Tatsuoka, J. Am.
Chem. Soc. 1969, 91, 5896.
5. The Absolute Stereochemistries of 6,l5-Dihydro-6,l5-ethanonaphtho[2,3-c]-pentaphene and Related Homologues as Determined by both
Exciton Chirality and X-ray Bijvoet Methods. N. Harada, Y. Takuma,
H. Uda, J. Am. Chem. Soc. 1976, 98, 5408.
6. Absolute Stereostructures of Halenaquinol and Halenaquinol Sulfate,
Pentacyclic Hydroquinones from the Okinawan Marine Sponge
Xestospongia Sapra, as Determined by Theoretical Calculation of CD
Spectra. M. Kobayashi, N. Shimizu, I. Kitagawa, Y. Kyogoku, N.
Harada, H. Uda, Tetrahedron Lett. 1985, 26, 3833.

－23－

7. Total Synthesis of (+)-Halenaquinol and (+)-Halenaquinone.
Experimental Proof of Their Absolute Stereostructures Theoretically
Determined. N. Harada, T. Sugioka, Y. Ando, H. Uda, T. Kuriki, J. Am.
Chem. Soc. 1988, 110, 8483.
8. HPLC Separation of Diastereomers: Chiral Molecular Tools Usefulfor the Preparation of Enantiopure Compounds and Simultaneous
Determination of Their Absolute Configurations. N. Harada,
Molecules 2016, 21, 1328.
9. Chemistry of Unique Chiral Olefins. 3. Synthesis and Absolute
Stereochemistry of trans- and cis-1,1',2,2',3,3',4,4'-Octahydro-3,3'dimethyl-4,4'-biphenanthrylidenes. N. Harada, N. Koumura, B. L.
Feringa, J. Am. Chem. Soc. 1997, 119, 7256.
10. Chemistry of Unique Chiral Olefins. 1. Synthesis, Enantioresolution,
Circular Dichroism, and Theoretical Determination of the Absolute
Stereochemistry of trans- and cis-1,1',2,2',3,3',4,4'-Octahydro- 4,4'biphenanthrylidenes. N. Harada, A. Saito, N. Koumura, H. Uda, B. de
Lange, W. F. Jager, H. Wynberg, B. L. Feringa, J. Am. Chem. Soc.
1997, 119, 7241.
11. Light-driven Monodirectional Molecular Rotor. N. Koumura, R. W.
J. Zijlstra, R. A. van Delden, N. Harada, B. L. Feringa, Nature 1999,
401, 152.
12. Synthesis of Enantiopure Aliphatic Acetylene Alcohols and1
Determination of Their Absolute Configurations by H NMR
Anisotropy and/or X-Ray Crystallography. S. Sekiguchi, M. Akagi, J.
Naito, Y. Yamamoto, H. Taji, S. Kuwahara, M. Watanabe, Y. Ozawa,
K. Toriumi, N. Harada, Eur. J. Org. Chem. 2008, 2313.

－24－

Tohru Taniguchi: born in 1980 in
Tobetsu, Ishikari, Hokkaido, and graduatedfrom Hokkaido University (B. 2002), andobtained his Ph.D. degree in Science from
Hokkaido University (2007). He was a
Visiting Scholar at Columbia University(2005-2006), JSPS Postdoctoral fellow atColumbia University (2007-2008, Prof. Koji
Nakanishi), and Postdoctoral fellow at
Harvard University (2008-2010, Prof.
Daniel Kahne). He has been an AssistantProfessor at Hokkaido University (2010-present). He has received several
awards including Young Scientist’s Research Award in Natural ProductChemistry (2012), CSJ Award for Young Chemists (2015), and Award for
Encouragement of Research in Polymer Science (2015).
Nina Berova: Born in Bulgaria andeducated at University of Sofia, Bulgariawith PhD (Prof. B. Kurtev) 1972. Appt.:
Asst. Prof. (1973-1981) and Assoc. Prof.
Univ. Sofia and Bulg. Acad, Sci. (19821988), Columbia University, Dept. Chem.
New York: Visiting Prof. (1988-1993),
Senior Res. Sci. & Full Prof. (1994-2008),
Research and Adjunct Prof. (2009-present).
Scholarships & Visiting Professorships: Moscow
Univ. & Russian Acad. Sci. (Prof. VM
Potapov) Visiting Scholar 1967-1968, Univ.
London and North East London Polytechnic (W. Klyne & M. Hargreaves)
1976, Research Fellow Deutsche Forschungsgemeinschaft, Bochum,
Germany (Prof. G. Snatzke) 1978-1979, JSPS Fellow 1996, Ecole Normale
Superieure Lyon, France 1994, Univ. Naples, Italy 1997, Univ. Santiago deCompostella, Spain 1999, Univ Louis Pasteur and ECPM, Strasbourg
France 2001, Sophia Univ. Tokyo (2011-2014), Nagoya Univ. (2010-2012),
National Taiwan Univ., 2015. Amongst Awards: Gold Medal “Piero Pino”(2003), Chirality Gold Medal (2007), Editor of Journal “Chirality” (1998present).

－25－

Takenori Kusumi: born in 1942 andgraduated from Tokyo University of
Education (B. 1966) PhD, Tokyo
University of Education (Prof. Hiroshi
Kakisawa) 1973, Postdoctoral fellow,
Columbia University (1979-1980, Prof.
Koji Nakanishi), Assistant Professor,
Department of Chemistry, Tokyo
University of Education (1973-1976),
Lecturer, Department of Chemistry,
Tsukuba
University(1976-1992),
Professor, Faculty of Pharmaceutical Sciences, Tokushima University(1992-2008), Special Professor, Department of Chemistry, Tokyo Instituteof Technology (2008- ). The Chemical Society of Japan Award for
Creative Work for 2004.
Masahiro Hirama: born in Tokyo, 1948
and graduated from Tohoku
University (B. 1970), Dr. of Science
Degree (1977, Tohoku Univ. Prof. ShoIto), Postdoctoral fellow (1977-1980,
Univ. of Pittsburg, Prof. S. J. Danishefsky& MIT, Prof. S. Masamune). Researcher,
the Suntory Institute for Bioorganic
Research, 1980-1983. Assistant professor(1983-1986), Associate professor (19861989),
Professor,
DepartmentofChemistry, Tohoku Univ. (1989-2012), Distinguished Professor (20082011), Professor, Emeritus, Tohoku Univ. (2012-). Board of Director,
AcroScale Inc. (2012-), Visiting Prof., Univ. Osaka Prefecture (2012-).
Awards including Chemical Society of Japan Award, Fujihara Award,
and the National Medal with Purple Ribbon..

－26－

The Recipients of the Prize hereto are:1996 Yoshimasa Hirata*
2008 Michel Rohmer*
1997 Frank H. Westheimer
2009 JoAnne Stubbe
1998 Albert J. Eschenmoser* 2010 Shosuke Yamamura*1999 Jeremy R. Knowles
2011 C. Dale Poulter2000 Satoshi Ōmura*2012 Daisuke Uemura*2001 John D. Roberts
2013 Arthur G. Palmer, III
2002 Sir Jack Baldwin*
2014 Jerrold Meinwald*
2003 A. Ian Scott2015 Fred McLafferty
2004 Isao Kitagawa*2016 Shoichi Kusumoto*2005 Stephen J. Benkovic
2017 Martin Gruebele
2006 Takeshi Yasumoto*2018 Nobuyuki Harada*
2007 Hung-wen Liu*Selection and presentation made by the Chemical Society of Japan.

Organizing Committee:◆Chairman
Michio Murata (Osaka University)◇Members
Ikuro Abe (The University of Tokyo)
Sigeru Nishiyama (Keio University)
Hiroyuki Osada (RIKEN)
Keisuke Suzuki (Tokyo Institute of Technology)
Daisuke Uemura (Kanagawa University)*The Organic Committee acknowledges the generous support from the Naito
Foundation.