CELEBRATING
E_cmyk

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Germany – Japan
Chemistry Symposium

SPEAKERS

on 20th June in Tokyo
J_cmyk

J_single color black

François Diederich

Hartmut Michel
Nobel Prize 1988

Alois Fürstner

Ryoji Noyori
Nobel Prize 2001

Hideo Hosono

THE CHEMICAL SOCIETY
OF JAPAN

Helmut Schwarz

Barry Sharpless
Nobel Prize 2001

Tohru Fukuyama

Akira Suzuki
Nobel Prize 2010

Terunori Fujita

Includingthe Nobel Lecturesof Professors
Michel, Noyori
Sharplessand Suzuki

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Program for the Symposium"Catalysis & Synthesis
Advanced Materials & Chemical Biology"
in Tokyo on 20th June 2011
Time

LengthLecture9h00

15 minYasuhiro Iwasawa / Michael Droescher /Kenichi Iga / Peter Gölitz
Welcome Remarks

9h15

45 minRyoji Noyori
Keisuke Suzuki
Asymmetric Hydrogenation: Our Three Decades with BINAP

10h00

40 minAlois Fuerstner
Catalysis for Total Synthesis

10h40

40 minHideo Hosono
Mikiko Sodeoka
Exploring New Superconductors and Other Supermaterials

11h20

15 min

Break

11h35

45 minHartmut Michel
Mikiko Sodeoka
25 Years of Membrane Protein Structures: Successes and Open Questions

12h20

40 minTerunori Fujita
Neville Compton
Olefin Polymerization: FI Catalysts for the Creation of Value-Added
Olefin-Based Materials

13h00

1 h 15 min

Break

14h15

40 minAkira Suzuki
Masakatsu Shibasaki
Cross-Coupling Reactions of Organoboranes: An Easy Way for C–C Bonding

14h55

40 minFrançois Diederich
Hideo Takezoe
Molecular Recognition in Chemical and Biological Systems

15h35

40 minTohru Fukuyama
Hideo Takezoe
Total Synthesis of Natural Products and Development of Synthetic
Methodologies

16h15

15 min

Break

16h30

40 minHelmut Schwarz
Wolfram Koch
Homolytic C–H Bond Activation: Experimental and Theoretical
Insights / Research in Germany

17h10

45 minBarry SharplessPeter Goelitz
Click Chemistry Keeps Evolving – Destinations Unknown

17h55

5 min

Ichiro Okura
Concluding Remarks

18h00

Reception “Beer and Pretzel”© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Moderator

Keisuke Suzuki

Eva Wille

Germany – Japan Chemistry Symposium
CELEBRATINGThe organizers gratefully
acknowledge the support of thefollowing institutions and companies:

SPONSORSANDSUPPORTERS

ドイツ研究振興協会日本代表部
Japan Office

The presentations are also video-recorded for internet broadcast with athree-hour delay and as an archive of the symposium‘s content so you canreview any of today‘s presentations on demand at chemistryviews.org
http://www.chemistryviews.org/view/0/asiaevent2011.html

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S P E A K ER S
Asymmetric Hydrogenation: Our Three
Decades with BINAP

Ryoji Noyori

noyori@chem3.chem.nagoya-u.ac.jp

Nagoya University and RIKEN(Saitama, Japan)

Noyori acquired bachelor's and master's degrees from Kobe University (Japan) andcompleted his PhD there in 1967, under the supervision of H. Nozaki, on the first example
of organometallic asymmetric catalysis. He was then appointed associate professor at
Nagoya University, and only later, in 1969, had the opportunity to carry out postdoctoral
research with E. J. Corey (Harvard University, USA). Back in Nagoya he was promoted toprofessor in 1972 and has remained faithful to this institution while serving as president of
RIKEN, since 2003. His work on asymmetric hydrogenation, for example with binap
complexes, earned him the Nobel Prize in 2001, together with W. S. Knowles and K. B.
Sharpless.

Catalysis for Total Synthesis

Alois Fürstner

fuerstner@mpi-muelheim.mpg.de

Max-Planck-Institut für Kohlenforschung(Mülheim/Ruhr, Germany)

Fürstner completed his PhD in 1987 at the Technical University of Graz with H. Weidmannand completed his habilitation there in 1992, following a postdoctoral fellowship with W.
Oppolzer (University of Geneva). He has been a group leader at the Max Planck Institute at
Mülheim since 1993 and has been a director there since 1998. He carries out pioneering
work at the interface between organometallic chemistry and organic synthesis, in particularalkene and alkyne metathesis and its application to the total synthesis of complex natural
products, such as carbohydrates and alkaloids.

Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S P E A K ER S
Exploring New Superconductors and Other
Supermaterials

Hideo Hosono

hosono@msl.titech.ac.jp

Tokyo Institute of Technology(Yokohama, Japan)

The research of H. Hosono is devoted to inorganic solid-state materials chemistry,
especially transparent oxide semiconductors, which are used in flat-panel displays, and newsuperconductors: He introduced iron into the family of oxide superconductor components.
Hosono earned a PhD from Tokyo Metropolitan University under the guidance of H.
Kawazoe in 1982 and joined the faculty of Nagoya Institute of Technology. In 1999, hebecame a professor at the Tokyo Institute of Technology.

25 Years of Membrane Protein Structures:
Successes and Open Questions

Hartmut Michel

hartmut.michel@mpibp-frankfurt.mpg.de

Max-Planck-Institut für Biophysik(Frankfurt/Main, Germany)

In 1988, Hartmut Michel received the Nobel Prize in Chemistry together with J. Deisenhofer
and R. Huber for the determination of the three-dimensional structure of a photosynthetic
reaction center. Michel studied biochemistry at the Universität Tübingen (Germany) and in1977 completed his PhD with D. Oesterhelt at the Universität Würzburg (Germany) on
proton gradients at the cell membranes of halobacteria. Shortly afterwards he began
attempts to crystallize membrane proteins, in which he succeeded in 1979. He moved with
Oesterhelt to the Max Planck Institute of Biochemistry (Martinsried, Germany) and in 1981
succeeded in crystallizing a photosynthetic reaction center. In 1987 he became director at
the MPI of Biophysics (Frankfurt/M.).

Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S P E A K ER S
Olefin Polymerization: FI Catalysts for theCreation of Value-Added Olefin-BasedMaterials
Terunori Fujita

terunori.fujita@mitsui-chem.co.jp

Mitsui Chemicals Inc. Research Center(Chiba, Japan)

T. Fujita graduated from Hokkaido University in 1982 and earned a PhD in 1988 insupramolecular chemistry from the Louis Pasteur University in Strasbourg under thesupervision of Jean-Marie Lehn. In 1982 he joined Mitsui Petrochemical Industries (nowMitsui Chemicals). In 2001 he was appointed a Mitsui research fellow for his contributions
to the development of new olefin polymerization catalysts, now known as FI catalysts. He iscurrently a board director and the Center Executive of the company’s research center.
Fujita’s research interests have focused on the synthesis of valuable organic materials bymeans of homogeneous and heterogeneous catalysis and, more recently, on thedevelopment of high-performance olefin polymerization catalysts for the creation of newvalue-added olefin-based materials.

Cross-Coupling Reactions of Organoboranes:
An Easy Way for C—C Bonding

Akira Suzuki

akikos@jimu.hokudai.ac.jp

Hokkaido University(Sapporo, Japan)

Suzuki received his doctorate in 1959 at Hokkaido University, Sapporo (Japan) and was,after a research stay with H. C. Brown (Purdue) in the late 1960s, a professor there from1965 until 1994. Towards the end of the 1970s he was able to show that organoboron
compounds can be coupled with vinyl and aryl halides under basic conditions and palladiumcatalysis. Together with Richard F. Heck and Ei-ichi Negishi, this discovery earned him theNobel Prize in Chemistry in 2010.

Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S P E A K ER S
Molecular Recognition in Chemical andBiological Systems

François Diederichdiederich@org.chem.ethz.ch

Eidgenössische Technische Hochschule(Zürich, Switzerland)

Diederich completed his PhD in 1979 at the University of Heidelberg (Germany) with H. A.
Staab. He carried out postdoctoral research at the University of California in Los Angeles(UCLA; USA) and at the Max Planck Institute for Medicinal Research in Heidelberg. Aftercompleting his habilitation in 1985 he returned to UCLA, and in 1992 he joined the ETH
Zürich. He has been the chairman of the editorial board of Angewandte Chemie since 2004.
Besides the areas of molecular recognition in chemistry and biology, supramolecular
nanochemistry, the chemistry of synthetic fullerenes, and novel materials from carbon-richacetylene derivatives, Diederich's research group is also interested in medicinal chemistryeg. of antimalarial drugs.

Total Synthesis of Natural Products andDevelopment of Synthetic Methodologies

Tohru Fukuyama

fukuyama@mol.f.u-tokyo.ac.jp

Graduate School of Pharmaceutical
Sciences (University of Tokyo, Japan)

After graduation from Nagoya University, Fukuyama obtained his PhD in 1977 under the
direction of Y. Kishi (Harvard University). After a postdoc time there, he joined the facultyof Rice University (Houston, TX) and became a professor of pharmaceutical sciences at the
University of Tokyo in 1995. His research is devoted to the total synthesis of complex
natural products.

Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S P E A K ER S
Homolytic C—H Bond Activation:
Experimental and Theoretical Insights/
Research in Germany

Helmut Schwarz

helmut.schwarz@mail.chem.tu-berlin.deTechnische Universität Berlin(Berlin, Germany)

After training as a chemical technician, Schwarz remained true to the Technical Universityof Berlin: He earned his doctorate and habilitation under the guidance of natural-products
chemist F. Bohlmann and is currently a professor of Organic Chemistry there. He held
numerous visiting appointments in Great Britain, Switzerland, Israel, France, Japan, andAustralia. His research is inextricably linked to mass spectrometry and gas-phase chemistry,
especially the activation of C-C and C-H bonds and the role of metals in catalysis. Since
2008, Helmut Schwarz has served as president of the Alexander von Humboldt Foundation,
which promotes academic cooperation between excellent scientists and scholars from
Germany and abroad.

Click Chemistry Keeps Evolving —Destinations Unknown

Barry Sharplesssharples@scripps.edu

The Scripps Research Institute(La Jolla, USA)The research of Barry Sharpless is focused on homogeneous oxidation catalysts, for which
he received the Nobel prize in chemistry in 2001. His group also works on asymmetric
processes and has developed the concept of click chemistry. Sharpless studied at
Dartmouth College and Stanford University where he earned a PhD under the guidance of
E. E. van Tamelen in 1968. He carried out post-doctoral research at Stanford (with J. P.
Collman) and Harvard University (with K. Bloch) before joining the faculty of the
Massachusetts Institute of Technology from 1970—90, interrupted by an appointment at
Stanford in the late 1970s. Since 1990, he is a Professor at The Scripps Research Institute.

Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Asymmetric Catalysis: Science and Opportunities (Nobel Lecture)**Ryoji Noyori*
Asymmetric catalysis, in its infancy inthe 1960s, has dramatically changed
the procedures of chemical synthesis,
and resulted in an impressive progression to a level that technically approximates or sometimes even exceeds thatof natural biological processes. The
recent exceptional advances in thisarea attest to a range of conceptual
breakthroughs in chemical sciences ingeneral, and to the practical benefits oforganic synthesis, not only in laborato-

ries but also in industry. The growth of
this core technology has given rise toenormous economic potential in the
manufacture of pharmaceuticals, animal health products, agrochemicals,fungicides, pheromones, flavors, andfragrances. Practical asymmetric catalysis is of growing importance to asustainable modern society, in which
environmental protection is of increasing concern. This subject is an essential
component of molecular science and

1. Prologue
Chirality (handedness; left or right) is an intrinsic universal
feature of various levels of matter.[1] Molecular chirality plays
a key role in science and technology. In particular, life
depends on molecular chirality, in that many biological
functions are inherently dissymmetric. Most physiologicalphenomena arise from highly precise molecular interactions,in which chiral host molecules recognize two enantiomericguest molecules in different ways. There are numerous
examples of enantiomer effects which are frequently dramatic. Enantiomers often smell and taste different. The structuraldifference between enanatiomers can be serious with respect
to the actions of synthetic drugs. Chiral receptor sites in thehuman body interact only with drug molecules having theproper absolute configuration, which results in marked differences in the pharmacological activities of enantiomers. A
compelling example of the relationship between pharmacological activity and molecular chirality was provided by the
tragic administration of thalidomide to pregnant women in
the 1960s. (R)-Thalidomide has desirable sedative properties,[*] Prof. Dr. R. Noyori
Department of Chemistry
Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
Fax: (# 81) 52-783-4177
E-mail: noyori@chem3.chem.nagoya-u.ac.jp[**] Copyright¹ The Nobel Foundation 2002. We thank the Nobel
Foundation, Stockholm, for permission to print this lecture.

2008

Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

technology in the 21st century. Most
importantly, recent progress has spurred various interdisciplinary research
efforts directed toward the creation ofmolecularly engineered novel functions. The origin and progress of myresearch in this field are discussed.
Keywords: asymmetric catalysis ¥asymmetric hydrogenation ¥ Nobel
lecture ¥ P ligands ¥ ruthenium

while its S enantiomer is teratogenic and induces fetal
malformations.[2, 3] Such problems arising from inappropriate
molecular recognition should be avoided at all costs. Nevertheless, even in the early 1990s, about 90 % of synthetic chiraldrugs were still racemic–that is, equimolar mixtures of bothenantiomers, which reflects the difficulty in the practicalsynthesis of single-enantiomeric compounds.[4] In 1992, theFood and Drug Administration in the U.S. introduced aguideline regarding ™racemic switches∫, in order to encourage
the commercialization of clinical drugs consisting of single
enantiomers.[5] Such marketing regulations for synthetic
drugs, coupled with recent progress in stereoselective organic
synthesis, resulted in a significant increase in the proportion of
single-enantiomer drugs. In 2000, the worldwide sales ofsingle-enantiomer compounds reached 123 billion U.S. dollars.[6] Thus, gaining access to enantiomerically pure compounds in the development of pharmaceuticals, agrochemicals, and flavors is a very significant endeavor.
Discovery of truly efficient methods to achieve this has
been a substantial challenge for chemists in both academia
and industry. Earlier, enantiomerically pure compounds wereobtained by the classical resolution of a racemate or transformation of readily accessible, naturally occurring chiralcompounds such as amino acids, tartaric and lactic acids,
carbohydrates, terpenes, or alkaloids. Even though stereoselective conversion of a prochiral compound to a chiralproduct, namely through an asymmetric reaction, is the most
attractive approach, practical access to pure enantiomers
relied largely on biochemical or biological methods. However,¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002

1433-7851/02/4112-2008 $ 20.00+.50/0

REVIEWS

Asymmetric Catalysis
the scope of such methods using enzymes, cell cultures, orwhole microorganisms is limited because of the inherent
single-handed, lock-and-key specificity of biocatalysts. On theother hand, a chemical approach allows for the flexible
synthesis of a wide array of enantiopure organic substancesfrom achiral precursors. The requirements for practicalasymmetric synthesis include high stereoselectivity, high rate
and productivity, atom economy, cost efficiency, operational
simplicity, environmental friendliness, and low-energy consumption. Traditional asymmetric synthesis using a stoichiometric amount of a chiral compound, though convenient forsmall to medium-scale reactions, is practical only if theexpensive chiral auxiliary deliberately attached to a substrateor reagent is readily recyclable; otherwise it is a wastefulprocedure.
Figure 1 illustrates a general principle of asymmetriccatalysis which provides an ideal way for multiplying molecular chirality.[7] A small amount of a well-designed chiralwith a high turnover number (TON) and a high turnover
frequency (TOF), while the enantioselectivity ranges from
50:50 (nonselective) to 100:0 (perfectly selective). The chiralligands that modify intrinsically achiral metal atoms mustpossess suitable three-dimensional structures and functionality, to generate sufficient reactivity and the desired stereoselectivity. Sometimes the properties of achiral ligands arealso important. The chiral catalyst can permit kinetically
precise discrimination among enantiotopic atoms, groups, or
faces in achiral molecules. Similarly, enantiomeric molecules
can also be discriminated. Certain well-designed chiral metal
catalysts not only accelerate the chemical reactions repeatedly but also differentiate between diastereomeric transition
states (TSs) with an accuracy of 10 kJ mol!1. In this way, suchcompact molecular catalysts with a molecular weight less than
1000, or " 20 ä in length or diameter, allow for an ideal
method for synthesizing enantiomeric compounds. The diverse catalytic activities of metallic species, as well as thevirtually unlimited structural variation of the organic ligand,provides enormous opportunities for asymmetric catalysis.

2. Discovery of Asymmetric Catalysis by Chiral
Organometallic Complexes

Figure 1. A general principle of asymmetric catalysis with chiral organometallic molecular catalysts. M " metal; A, B " reactant and substrate.

catalyst can combine A and B, which produces the chiral
AB compound stereoselectively in a large quantity. Of
various possibilities, the use of chiral organometallic molecular catalysts would be the most powerful strategy for thispurpose. Asymmetric catalysis is an integrated chemical
approach in which the maximum chiral efficiency can beobtained only by a combination of suitable molecular design
with proper reaction conditions. The reaction must proceed

In 1966, when I was in H. Nozaki×s (Figure 2) laboratory at
Kyoto, we discovered the first example of asymmetriccatalysis using a structurally well-defined chiral transitionmetal complex.[8] This finding resulted
from research done for an entirely
different purpose, which was to elucidate the mechanism of carbene reactions. As illustrated in Scheme 1, whena small amount (1 mol %) of a chiral
Schiff base ± CuII complex was used as amolecular catalyst in the reaction of
Figure 2. Professor
styrene and ethyl diazoacetate, the cisH. Nozaki (1985).
andtrans-cyclopropanecarboxylates
were obtained in 10 and 6 % enantiomeric excess (ee), respectively. We also observed asymmetricinduction in carbene insertion to a C!O bond of 2-phenyloxetane, which gave optically active 2,3-substituted tetrahydrofuran derivatives. At that time, the finding was syntheti-

Ryoji Noyori, born in Kobe in 1938, completed his master×s degree at Kyoto University andthereafter became an Instructor at the same university. He received his Ph.D. degree in 1967
under the supervision of H. Nozaki. He was appointed Associate Professor at Nagoya
University in 1968 and promoted to Professor in 1972. He spent a postdoctoral year in 1969 ±1970 at Harvard University with E. J. Corey. His research has focused on the fundamentals
and applications of molecular catalysis, based on organometallic chemistry, particularly
asymmetric catalysis. His scientific contributions have been recognized by numerous awards
including: the Tetrahedron Prize (1993), the Japan Academy Prize (1995), the Arthur CopeAward (1997), the King Faisal International Prize (1999), the Order of Culture (2000), theWolf Prize (2001), and the Roger Adams Award (2001). In 2001, he shared the Nobel Prize in
Chemistry with W. S. Knowles and K. B. Sharpless.

Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

2009

REVIEWS

R. Noyori

3. Asymmetric Hydrogenation in the Early Days
1 mol%
chiral Cu cat+

COOC2H5H

N2CHCOOC2H5
C6H5
N
O

Cu

+

COOC2H5H

H

H

10% ee

6% ee

O
N
C6H5

chiral Cu catalyst

Scheme 1. Discovery of asymmetric reaction by means of a chiral organometallic molecular catalyst.

cally primitive since the degree of enantioselection wasmeaningless practically. Later, T. Aratani, a Kyoto student,
went to Sumitomo Chemical Co., where he invented an
excellent chiral Cu catalyst for asymmetric cyclopropanation,
which achieved the industrial synthesis of chrysanthemates(efficient insecticides) and (S)-2,2-cyclopropanecarboxylic

R

R

COOR

H
O

chrysanthemates

S

S

COOH
NH2

NH
COONa
cilastatinacid. The latter compound is a building block of cilastatin, an
in vivo stabilizer of the carbapenem antibiotic, imipenem(Merck Co.; Figure 3).[9]Figure 3. Reaction apparatus for the Sumitomo asymmetric cyclopropanation.

2010

At present the asymmetric cyclopropanation is importantpractically, but in the late 1960s, it was just a special reaction inorganic synthesis. I decided to pursue hydrogenation, which isa core technology in chemistry. It is the simplest but mostpowerful way to produce a wide array of important compounds in large quantities using inexpensive, clean hydrogengas without forming any waste. Hydrogenation was initiatedat the end of the 19th century by P. Sabatier (1912 Nobel
laureate), who used fine metal particles as heterogeneous
catalysts. Some notable achievements that attracted me, before
doing research in this area, include: activation of H2 by atransition-metal complex in the late 1930s (M. Calvin, 1961
Nobel laureate),[10] homogeneous hydrogenation of olefinic
substrates with RuCl3 in 1961 (J. Halpern, J. Harrod, and B. R.
James),[11] and hydrogenation of olefinic compounds using[RhCl{P(C6H5)3}3] in 1965 (G. Wilkinson, 1973 Nobel laureate).[12] Most importantly, in 1956, S. Akabori at Osaka
reported that metallic Pd drawn on silk catalyzes asymmetric(heterogeneous) hydrogenation of oximes and oxazolones.[13]This pioneering work, though not effective synthetically, wasalready well known throughout Japan. In 1968, two years after
our asymmetric cyclopropanation in 1966, W. S. Knowles (fellow
Nobel laureate in 2001)[14] and L. Horner[15] independently
reported the first homogeneously catalyzed asymmetric hydrogenation of olefins with chiral monodentate tertiary phosphane ± Rh complexes, albeit in 3 ± 15 % optical yield.[16] H. B.
Kagan provided a major breakthrough in this area in 1971, when
he devised DIOP, a C2-chiral diphosphane ligand derived fromtartaric acid. He used its Rh complex for asymmetric hydrogenation of dehydro amino acids leading to phenylalanine in
about 80% ee, then recorded as 72 % ee.[17] The Knowles groupat Monsanto established a method for the industrial synthesis of!-DOPA, a drug for treating Parkinson×s disease, which used his
DIPAMP ± Rh catalyzed asymmetric hydrogenation as a key
step.[18] These achievements significantly stimulated the subsequent investigation of this important subject.
Shortly after moving from Kyoto to Nagoya in 1969 ± 70, I
spent a postdoctoral year at Harvard with E. J. Corey (1990
Nobel laureate). He asked me to hydrogenate selectively oneof the two C"C bonds in a prostaglandin F2& derivative to give
the F1& form having only one C"C bond.[19] This research was
helped by K. B. Sharpless (another fellow Nobel laureate in2001)[102] , who was then a postdoctoral fellow with K. Bloch(1964 Nobel laureate in Physiology or Medicine) and whosuggested a convenient TLC technique for analyzing thestructurally very similar olefinic compounds. In addition
to this background, my personal interaction with J. A. Osborn, a former Wilkinson student and co-inventor of[RhCl{P(C6H5)3}3][12] who was then an Assistant Professor at
Harvard, greatly enhanced my interest in asymmetric hydrogenation, which later became my life-long research interest.
My desire was to develop a truly efficient asymmetrichydrogenation which would have a wide scope of applications.
In the early 1970s, chiral phosphane ± Rh complexes couldhydrogenate satisfactorily only dehydro amino acids but not
many other olefins. Asymmetric hydrogenation of ketones
was totally unexplored.[20]Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

REVIEWS

Asymmetric Catalysis

4. BINAP, a Beautiful Chiral MoleculeH2 is the simplest molecule but it has enormous potentialfrom both a scientific and technical point of view. To discoverhigh-performance asymmetric catalysts, the development ofan excellent chiral ligand is crucial. Attracted by its molecular
beauty,[21] we initiated the synthesis of BINAP (2,2"-bis(diphenylphosphanyl)-1,1"-binaphthyl)[22] in 1974 at Nagoya withthe help of H. Takaya, my respected long-term collaborator.
BINAP was a new, fully aromatic, axially dissymmetric C2chiral diphosphane that would exert strong steric andelectronic influences on transition-metal complexes. Its properties could be fine-tuned by substitutions on the aromaticrings. However, synthesis of this optically pure C2-chiraldiphosphane was unexpectedly difficult. In 1976, for the firsttime, we managed to obtain optically active BINAP startingfrom optically pure 2,2"-diamino-1,1"-binaphthyl (Scheme 2 a).
However, this seemingly straightforward synthetic pathway
was not reproducible, because of the tendency of the chiralintermediates to cause racemization.[23] In 1978, we found a
reliable method for resolving racemic BINAP with an
optically active dimethyl(1-phenylethyl)aminopalladium(II)chloride complex,[22] while, later, optically pure BINAP
became available more conveniently by resolution of BINAP
dioxide with camphorsulfonic acid or 2,3-O-dibenzoyltartaricacid (Scheme 2 b).[24, 25]

Although the elusive BINAP was available, our goal was
still in the distance. Enantioselectivity of BINAP ± RhI
catalyzed asymmetric hydrogenation of &-(acylamino)acrylic
acids was highly variable and not satisfactory at that time,
ee values of the chiral products being at most about 80 %.
However, we remained patient. In 1980, six years after thestart, thanks to the unswerving efforts of my young associates,
we published our first work on asymmetric synthesis of aminoacids of high enantiomeric purity, up to 100 % ee, together
with the X-ray crystalline structure of a cationic BINAP ±Rh(norbornadiene) complex.[22, 26]
BINAP, a conformationally flexible atropisomeric C2 diphosphane, can accommodate a range of transition metals by
rotating about the binaphthyl C(1)-C(1") pivot and C(2 or 2")P bonds, without seriously increasing torsional strain, while
the resulting seven-membered chelate rings containing only
sp2 carbon atoms are in turn skeletally unambiguous. The
chirality of BINAP is transmitted to other metal-coordinationsites through the chelate structure.[22, 26] The # or % geometry ishighly skewed and determines the chiral disposition of the Pphenyl rings that play a key role in generating outstandingchirality-discriminating ability at the reactive coordinationsites. Thus BINAP-based metal complexes were expected to
exhibit high chiral-recognition ability in various catalytic
reactions, in addition to hydrogenation.

5. Asymmetric Synthesis of Menthola) Irreproducible stereospecific synthesis

NH2
NH2

NaNO2
CuBr

1. t-C4H9Li
2. (C6H5)2PCl

Br
Br

2
1
1'

P(C6H5)2P(C6H5)22'(R)-BINAPb) Optical resolution

(±)-

OH
OH

(±)-BINAP

1. [{(dimethyl(1-phenylethyl)amine)PdCl}2]
2. NaB(C6H5)4
3. fractional recrystallization
4. LiAlH4

P(C6H5)2P(C6H5)2(S)-BINAP(±)-

P(O)(C6H5)2
P(O)(C6H5)2

1. camphorsulfonic acid(or 2,3-O-dibenzoyltartaric acid)
2. fractional recrystallization
3. SiHCl3, (C2H5)3N

Scheme 2. Access to enantiomerically pure BINAP.
Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022+

P(C6H5)2P(C6H5)2(R)-BINAP

The cationic BINAP ± Rh complex was
best used in asymmetric isomerization ofallylic amines,[27] which realized an industrial synthesis of (!)-menthol from myrcene(Scheme 3).[28] This resulted from a fruitfulacademic/industrial collaboration between
groups at Osaka University (S. Otsuka and
H. Tani),[29] Nagoya University (R. Noyori),
Institute for Molecular Science (H. Takaya),Sizuoka University (J. Tanaka and K.
Takabe),[30] and Takasago International
Co. (Figure 4). The key step was the asymmetric isomerization of geranyldiethylamine, catalyzed by an (S)-BINAP ± Rh complex in THF and forming (R)-citronellal
enamine, which upon hydrolysis gives (R)citronellal in 96 ± 99 % ee. This is far superior to the 80 % ee of the naturally occurringproduct available from rose oil. Among
various Rh and other catalysts examined,
the BINAP-based cationic Rh complex was
the most reactive and the most stereoselective. The BINAP ± Rh catalyst clearly differentiates between the pro-S and pro-R hydrogen atoms on the flexible allylic amine
skeleton during the 1,3-suprafacial shift that
occurs by a nitrogen-triggered mechanism.[31] The asymmetric reaction is performed on a nine-ton scale. The full technical refinements of the position- and stereo2011

REVIEWS

R. Noyori

6. Asymmetric Hydrogenation of Olefinsby BINAP ± Ruthenium Complexes
Returning to the topic of asymmetric hydrogenation, our success resulted from the inventionof the BINAP ligand[32] and also from the use ofRu, which behaves differently from the conventional Rh.[33, 34] The cationic BINAP ± Rh complexes catalyze hydrogenation of &-(acylamino)acrylic acids or esters to give the corresponding
amino acid derivatives in high ee values(Scheme 4).[22, 23] However, the reaction is relatively slow, and high enantioselectivity is obtained
only under special conditions, probably becauseof the operation of the unsaturate/dihydridemechanism. J. Halpern[35] and J. M. Brown[36]showed that hydrogenation of enamides in thepresence of a C2-chiral diphosphane ± Rh complex proceeds by oxidative addition of H2 todiastereomeric Rh ± substrate chelate complexes,
followed by stepwise transfer of the two hydrides
to the coordinated olefin. Most significantly, theminor diastereomer of these complexes is themore reactive one.[37] Because of the excellent
chiral-recognition ability of BINAP, the reactive
species, which leads to the desired hydrogenation

Scheme 3. Takasago menthol synthesis. COD " 1,5-cyclooctadiene.

COOR1

R

NHCOR2+ H2

R = Ar oder H

R

COOR1
NHCOR2
R = Ar[Rh((S)-binap)]+

COOR1

R

NHCOR2
R[Rh((R)-binap)]++ H2[Rh((S)-binap)]+

R

COOR1
NHCOR2
S

Scheme 4. Asymmetric hydrogenation of &-(acylamino)acrylic acids catalyzed by BINAP ± Rh complexes.

Figure 4. At the Takasago plant for (!)-menthol synthesis (February,1984). From the left, K. Tani, H. Takaya, R. Noyori, S. Otsuka, S.
Akutagawa, and H. Kumobayashi.

selective addition of diethylamine to myrcene, which gives thestarting geranylamine, and the ZnBr2-catalyzed intramolecular ene reaction of (R)-citronellal, which forms isopulegol
with the three correct stereogenic centers, allowed for the
production of terpenic substrates totaling about 1500 tons per
year at Takasago International Co. Most of the (R)-citronellal
is converted to 1000 tons per year of (!)-menthol, one-thirdof the world demand. (R)-7-Hydroxydihydrocitronellal thus
prepared is a perfumery agent that smells like lily of thevalley. Its methyl ether is an intermediate in the synthesis ofmethoprene, a growth regulator of the yellow-fever mosquito.[28, 29]
2012

product, is present in a very small quantity and is even NMRinvisible in the equilibrium mixture.[23a] Therefore, conditions
such as hydrogen pressure, temperature, and concentrationmust be chosen carefully to obtain high enantioselectivity.
Furthermore, asymmetric hydrogenation was limited to thesynthesis of amino acids.
A major breakthrough occurred when we devised the
BINAP ± RuII dicarboxylate complexes in 1986 (Figure 5).[38, 39] The Ru complexes are excellent catalysts forasymmetric hydrogenation of various functionalized olefins,
as summarized in Scheme 5. The reaction proceeds via a Ru
monohydride intermediate formed by heterolysis of H2 by the
Ru complex. The Ru center remains in the #2 oxidation statethroughout the catalytic cycle,[40] in contrast to the Rh
complex, which involves a #1/#3 redox process. Heteroatoms
in the functional groups serve as a binding tether to thecatalytic Ru center. This hydrogenation has a very wide scope.
Hydrogenation of &,$- and $,"-unsaturated carboxylic acids
takes place in alcoholic media, where the sense and degree ofAngew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

REVIEWS

Asymmetric Catalysis

plexes effect highly enantioselective hydrogenation of (Z)-2acyl-1-benzylidene-1,2,3,4-tetrahydroisoquinolines.[38, 44] In asimilar manner, enantio-enriched &- and $-amino acids,[45] aswell as &-amino phosphonic acids,[46] are obtainable fromsuitably amido-substituted olefins. Notably, the RuII and RhI
complexes possessing the same BINAP chirality form antipodal amino acids as the predominant products.[47]Scheme 6 illustrates some chiral compounds that can beobtained by this asymmetric hydrogenation. An important
application is the synthesis of the anti-inflammatory drug,
naproxen, in 97 % ee from an &-aryl-acrylic acid.[41, 46] Natural

Figure 5. Structures of BINAP ± Ru diacetate complexes.

R3
R2

COOH
R

1

R3
R2

H2

R3

COOH

*

*

2

R
OH

R1

R1

R3

*

R2

OH

*

R1

NCOR

NCOR
(R'O)m(R'O)m(R'O)n(R'O)n

COOR1

COOR1

NHCOR2NHCOR2

R2COOR1

R3CONH

R2

NHCHO

COOR1

R3CONH

PO(OCH3)2
R

Scheme 6. Applications of BINAP ± Ru catalyzed hydrogenation of olefins.

PO(OCH3)2
R

NHCHO

Scheme 5. Asymmetric hydrogenation of functionalized olefins catalyzedby (S)-BINAP ± Ru dicarboxylates.

the enantioselection are highly dependent on the substitution
pattern and hydrogen pressure.[41] Allylic and homoallylic
alcohols are also hydrogenated with high enantioselection.[42]Certain racemic allylic alcohols can be resolved by the
BINAP ± Ru-catalyzed hydrogenation.[43] The chiral Ru comAngew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

and unnatural citronellol with up to 99 % ee are obtainablefrom geraniol or nerol without saturation of the C(6)!C(7)double bond, with a high substrate to catalyst (S:C) ratio. The
hydrogenation of (R,E)-6,7,10,11-tetrahydrofarnesol produces (3R,7R)-hexahydrofarnesol, a C15 side-chain of &-tocopherol (vitamin E) and a part of vitamin K1 . The hydrogenationof an allylic alcohol possessing a chiral azetidinone unit gives a
1$-methylcarbapenem synthetic intermediate diastereoselectively.[48] The discovery of this asymmetric hydrogenation
made possible the general asymmetric synthesis of isoquinoline alkaloids including morphine, benzomorphans, andmorphinans such as the antitussive dextomethorphan.[43, 49]
Importantly, the list of substrates can be extended toinclude various ketones, as generalized in Scheme 7 andFigure 6. The halogen-containing BINAP ± RuII complexes(oligomers),[50] but not the diacetate complexes, are efficient
catalysts for the asymmetric hydrogenation of a range offunctionalized ketones, wherein coordinative nitrogen, oxygen, and halogen atoms near C"O functions direct the2013

REVIEWS

R. NoyoriO

Ar2P
RuX2L2
P
Ar2

N
CH3N

H2

O

OH

OH

O
OH

O

O

R1

R1

R2 R2
Y = OR, SR, NR2
O
RO
P(OR3)2

Y

1

R

OH O
P(OR3)2
R2 R2

R2 R2
O

ONa
S O
O

OH ONa
S O
R
O

O

Br

OH Br

R

Scheme 8.
ketones.

R2 R2

O

O

OR2

1

R

O

O

R1

Scheme 7. Asymmetric hydrogenation of functionalized ketones catalyzedby (S)-BINAP ± Ru dihalide complexes (X " halogen).

Figure 6. H. Takaya, M. Kitamura, and T. Ohkuma (from the left) mademajor contributions to the asymmetric hydrogenation of functionalized
ketones catalyzed by (S)-BINAP ± Ru dihalide complexes.

reactivity and stereochemical outcome inan absolute sense.[51] A wide variety ofachiral ketones are hydrogenated enantioselectively to the corresponding chiralalcohols in 90 ± 100 % ee, in a predictablemanner. The reaction can normally be
performed in alcohols with up to 50 %substrate concentration under 4 ± 100 atm
at room temperature with an S:C ratio of
up to 10 000:1 on any scale, even using! 100 kg of the substrate. Scheme 8 showssome synthetic applications of this asymmetric hydrogenation. (R)-1,2-Propanediol thus obtained from hydroxyacetone
2014

O

O
OR3

(±)-R1CH3O
P(OCH3)2O–

R = CH3: carnitine
R = H: GABOBOH OOH OH O
OR

R

2

OH OH
OH

R

R

NH2
statine series

anti 1,3-diols

Applications of BINAP ± Ru-catalyzed hydrogenation ofis used for industrial synthesis of the antibacterial levofloxacin(Takasago Co./Daiichi Pharmaceutical Co.). In addition, "amino-$-hydroxybutyric acid (GABOB) and a compactin
intermediate can be prepared with high enantiomeric purity.[49, 52] Pre-existing stereogenic centers in the ketonic substrate significantly affect the steric course. Statines can beobtained with a high diastereo- and enantioselectivity.[53] The
double hydrogenation of 1,3-diones via chiral hydroxy ketones leads to the anti 1,3-diols in close to 100 % ee.[51a]Racemic $-keto esters with a configurationally labile &stereogenic center, by undergoing in situ stereoinversion, canbe transformed into a single stereoisomer out of the four
stereoisomers, with high stereoselectivity, as illustrated in
Scheme 9.[54] This dynamic kinetic resolution[55] has been used
for the synthesis of various biologically important compounds
such as threonine, (2S,3R)-3-(3,4-dihydroxyphenyl)serine (!DOPS),[52] phosphothreonine,[56] and fosfomycin.[57] Its utility
was highlighted by the industrial synthesis of carbapenem
antibiotics at Takasago International Co. (Scheme 10). The
requisite chiral 4-acetoxyazetidinone is prepared by the (R)BINAP ± Ru-catalyzed hydrogenation of racemic methyl &(benzamidomethyl)acetoacetate in dichloromethane, to givethe 2S,3R hydroxy ester with 94:6 erythro:threo diastereoselectivity[58] and 99.5:0.5 enantioselectivity.[54a] Quantitative
analysis[54] indicates that the 2S substrate is hydrogenated
15 times faster than the R enantiomer, and the slow-reacting
R isomer is inverted to the 2S enantiomer 92 times easier than
H2
[RuX2((R)-binap)]

NHCOR2
O

OH O

R3N+

OC2H5

compactinintermediate

OH O
Y

1

R1O

OH

R

N
O

OH O

Cl

levofloxacin
via (R)-1,2-propanediol

N(CH3)2

N(CH3)2

R

COOH

F

H2
[RuX2((R)-binap)]

NHCOCH3

OH O
R1

OR3
NHCOR2OH O
P(OCH3)2

L-threonine, L-DOPS etc.

OH O
P (OH)2NH2

NHCOCH3

phosphothreonine
O

O

P(OCH3)2
Br

H2[RuX2((S)-binap)]

OH O
P(OCH3)2
NHCOCH3

O
CH3
H

O

P (OH)2
H

fosfomycin

Scheme 9. Asymmetric hydrogenation by dynamic kinetic resolution. X " Cl, Br.
Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

REVIEWS

Asymmetric Catalysis

O
(±)-

H2
[RuII((R)-binap)]2+

O

OH O
OCH3

OCH3

NHCOC6H5NHCOC6H5

99% eeerythro:threo = 94:6
t-C4H9(CH3)2SiO

O

H H

HO
OCOCH3

NH

O

H H
SR

N

CO2H

carbapenems

Scheme 10. Stereoselective synthesis of carbapenem antibiotics.

it is hydrogenated. The extent of the BINAP catalyst-based
asymmetric induction is calculated to be 104:1 in favor of the
3R isomer, whereas the substrate-based asymmetric induction
is 9:1 in favor of the C(2)/C(3) erythro stereochemistry. The
volume of the hydrogenation reactor shown in Figure 7 is
13 m3.

Figure 8. Mechanism of (R)-BINAP ± Ru catalyzed hydrogenation of$-keto esters.

Figure 7. A large-scale BINAP ± Ru-catalyzed hydrogenation at Takasago
International Co.

$-Keto esters are the best substrates for the Ru catalyzed
asymmetric hydrogenation and lead to the $-hydroxy esters in! 98 % ee.[59] Figure 8 illustrates the mechanistic model. The
halide ligand in the Ru complex, which generates a strong acidand a RuHCl species by the action of H2 , is important tofacilitate the hydride transfer from the Ru center to thecarbonyl carbon.[55] In addition, the presence of the ester
Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

moiety interacting with the Ru center is crucial for both highreactivity and enantioselectivity. Because of the excellent
chiral recognition ability of BINAP, the two stereo-determining diastereomeric transition states (TSs) are well differentiated with the assistance of the oxygen ± Ru interaction.
The R-directing TS is highly favored over the S-generating
diastereomer, which suffers from substantial R/P-phenyl
repulsive interaction. The oxygen ± Ru dative bond (andrelated interaction in the reactions in Scheme 7) exerts apivotal function in the acceleration of hydrogenation as well.
Thus, $-keto esters are hydrogenated smoothly even in thesimplest ketone, acetone, containing a small amount of water.
Thus, although BINAP ± Ru dihalide catalysts have a very
wide scope, they are unable to hydrogenate simple, unfunctionalized ketones.

7. Asymmetric Hydrogenation of Simple Ketones by
BINAP/Diamine ± Ruthenium Complexes
For more than half a century, selective reduction of simple
ketones relied heavily on the metal-hydride chemistry devel2015

REVIEWS

R. Noyori

oped largely by H. C. Brown (1979 Nobel laureate). Chemoselective reduction of a C"O function in the presence of a
C"C group has been best effected by the stoichiometric
NaBH4 reagent.[60] Diastereoselective reduction of ketones
has frequently been achieved by Selectrides.[61] Enantioselective reduction of achiral ketones are effected by chiralstoichiometric reagents including BINAL-H,[62] DIP chloride,[63] and Alpine-borane[64] , or by the Corey ± Bakshi ± Shibata (CBS) method combining B2H6 or catecholborane and achiral oxazaborolidine catalyst.[65] Until very recently, thesetypes of selective C"O reductions were not generally achievable by catalytic hydrogenation.[49d, 66]
In 1995, when I was the director of the ERATO Molecular
Catalysis Project, we found that hydrogenation catalyzed by a
[RuCl2(phosphane)2(diamine)] complex and an alkaline baseprovided a general solution to this long-standing problem.[67]The use of appropriate chiral diphosphanes and chiraldiamines allows asymmetric hydrogenation of simple ketones
which lack any Lewis basic functionality capable of interacting with the metal center. The reactivity and stereoselectivity
are fine-tuned by changing the steric (bulkiness and chirality)and electronic properties of the auxiliaries. As generalized in
Scheme 11, the newly devised BINAP/diamine complex
O
R

Ar

H2
Ru catalyst
base

OH

OH

O
R

Het

R

Het
OH

O
Un

R

Ar

R

Un

Ar2 Cl
P
Ru
P
Ar2
Cl

H 2 R1
N
N
H2 R4

R

R2
R3

(S)-BINAP/(S)-diamine–RuII catalyst(S)-BINAP: Ar = C6H5(S)-TolBINAP: Ar = 4-CH3C6H4(S)-XylBINAP: Ar = 3,5-(CH3)2C6H3(S,S)-DPEN: R1 = R4 = C6H5;
R2 = R3 = H(S)-DAIPEN : R1 = R2 =4-CH3OC6H4;

R3 = H; R4 = (CH3)2CH

Scheme 11. General asymmetric hydrogenation of simple ketones. Ar "aryl, Het " heteroaryl, Un " alkenyl.

catalyzes rapid, productive, and highly enantioselective hydrogenation of a range of aromatic, heteroaromatic, andolefinic ketones in 2-propanol containing tBuOK or
KOH.[68±70] Among various complexes, [RuCl2(xylbinap)(daipen)][71] is particularly effective. For example, acetophenone and its derivatives are hydrogenated with S:C of up to
100 000:1, to give the secondary alcohols quantitatively in
99 % ee,[72] although the diamine-free BINAP ± Ru complexes
2016

are totally ineffective. Normally, C"C bonds are much morereactive than C"O in catalytic hydrogenation, but this systemallows for the preferential saturation of a C"O function over a
coexisting C"C linkage.[73, 74] Olefinic ketones, either conjugated or nonconjugated, can be converted to olefinic alcohols
selectively. The hydrogenation tolerates various functionalities including F, Cl, Br, I, CF3 , OCH3 , OCH2C6H5 ,COOCH(CH3)2 , NO2 , NH2 , and NRCOR. Both electronrich (furan, thiophene, thiazole, etc.) and -deficient rings(pyridine and pyrimidine) are left intact.[75] The simple[RuCl2(PAr3)2(NH2CH2CH2NH2)] complex hydrogenatesvarious substituted cyclic and acyclic ketones with highdiastereoselectivity, where the RuH intermediate acts as abulky hydride species.[76] Because of the basic and protic
nature of the reaction environment, hydrogenation of configurationally labile ketones allows for the dynamic kinetic
discrimination of diastereomers, epimers, and enantiomers,[76±78] which effects a new type of stereoselective reductionsof ketones which are not possible with stoichiometric hydride
reagents.
This asymmetric hydrogenation shows promise for thepractical synthesis of a wide variety of chiral alcohols. The
chiral diphosphane/diamine ± Ru complexes effect enantioselective hydrogenation of certain amino or amido ketones by anonchelate mechanism, without interaction between the Ru
center and nitrogen or oxygen atoms.[78] This method has been
applied to the asymmetric synthesis of various important
pharmaceuticals, which includes (R)-denopamine, a $1-receptor agonist, the antidepressant (R)-fluoxetine, the antipsychotic BMS 181100, and (S)-duloxetine, which is a potent
inhibitor of serotonin and norepinephrine uptake carriers(Scheme 12). Benzophenones can be hydrogenated to benzhydrols with an S:C ratio of up to 20 000:1 without overreduction.[79] Enantioselective hydrogenation of certain orthosubstituted benzophenones leads to the unsymmetrically
substituted benzhydrols with high ee values, which allows
convenient synthesis of the anticholinergic and antihistaminic(S)-orphenadrine. The antihistaminic (R)-neobenodine canbe synthesized by using asymmetric hydrogenation of obromo-p"-methylbenzophenone.
This approach is the first example of general and efficient
asymmetric hydrogenation of &,$-unsaturated ketones tochiral allylic alcohols of high enantiomeric purity.[72±74] The
selectivity profile is in sharp contrast to that observed with thediamine-free BINAP ± Ru complex, and efficiently catalyzes
asymmetric hydrogenation of allylic alcohols (Scheme 5). Itsutility has been demonstrated by the synthesis of intermediates of an &-tocopherol side-chain and anthracyclines, as wellas $-ionol (Scheme 12).[72, 73] The asymmetric hydrogenation
shown in Scheme 11 is generally achieved by the combined
use of an (S)-BINAP ligand and an (S)-1,2-diamine (or both
R enantiomers). This is also the case for the reaction ofs-cis exocyclic enones, such as (R)-pulegone. However, asymmetric hydrogenation of 2,4,4-trimethyl-2-cyclohexenone was
effected best with [RuCl2{(S)-tolbinap}{(R,R)-dpen}].[74, 80]
The cyclic allyl alcohol obtained in 96 % ee (Scheme 12) can
be converted into a series of carotenoid-derived odorants andbioactive terpenes, such as &-damascone. The R or S alcohols
with ee values as high as 95 % can be obtained, even with aAngew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

REVIEWS

Asymmetric Catalysis
a)
–

δ–
C

δ–
O

δ– H

H δ–

–

vs

N
δ–

Cl

H2
N

–

Ru
δ–

C

O

H

Ru

b)
R3P

Ru

R3P

Cl

N
H2

[H]
–2 HClC
H

X(R3P)2 Ru

O

O

H

H

H2
N

H
N
X(R3P)2 Ru

N
H2

H2
base

base
H

C

H H2
N
X(R3P)2 Ru
N
H2

+
H2

N
H2
H+
H2
N

X(R3P)2 Ru

+

N
H2

Figure 9. a) Nonclassical metal ± ligand bifunctional mechanism and conventional [2#2] mechanism. b) Catalytic cycle of hydrogenation of ketones
with a [RuCl2(PR3)2(NH2CH2CH2NH2)]/strong base combined system in
2-propanol. X " H, OR, etc.
Scheme 12. Application of asymmetric hydrogenation of simple ketones.

racemic TolBINAP ± RuCl2 complex in the presence of (R,R)or (S,S)-DPEN by asymmetric activation.[80±82] In this case, thehighly enantioselective hydrogenation catalyzed by the S diphosphane/R,R diamine complex (or R/S,S combination)
turns over 121 times faster than the less stereoselective
reaction promoted by the diastereomeric S/S,S (or R/R,R)
complex.[83]The reaction is rapid and highly productive. For example,
when a mixture of acetophenone (601 g), the (S)-TolBINAP/(S,S)-DPEN Ru complex (2.2 mg), and tBuOK (5.6 g) in
2-propanol (1.5 L; 30 % w/v substrate concentration) was
stirred under 45 atm H2 at 30 !C for 48 h, the R alcohol was
obtained with 80 % ee and 100 % yield.[71, 84] Under suchconditions, the turnover number was greater than 2 400 000,
while the turnover frequency at 30 % conversion was
228 000 h!1 or 63 s!1.
This high rate and chemoselectivity for the C " O function
are caused by the nonclassical metal ± ligand bifunctional
mechanism (Figure 9).[68, 70] The hydrogenation involves a
metal-hydride intermediate. Hydride transfer from the metal
center to the carbonyl carbon atom has been considered tooccur by a [2#2] mechanism. This reaction involves a Ru
hydride species possessing an NH2 ligand, whose hydridic
Ru!H and protic N!H are simultaneously transferred to the
C"O linkage via a six-membered pericyclic TS, thereby
forming an alcoholic product directly, without formation ofAngew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

a metal alkoxide (Figure 9 a). In this hydrogenation, the metal
and the ligand participate cooperatively in the bond-formingand -breaking processes. A more detailed mechanistic model
is given in Figure 9 b. The 18-electron-RuH species reduces
the ketone substrate by the pericyclic mechanism and theformal 16-electron Ru ± amide complex reacts directly with H2
in a [2#2] manner, or by a stepwise mechanism assisted by analcohol and a base, to give back the reducing RuH complex.[85]The reducing activity of the RuH species is generated by thehydrogen-bonding NH2 end in the diamine ligand, whichforms a fac relationship with the hydride ligand in theoctahedral geometry. Neither ketone substrate nor alcoholic
product interacts with the metallic center throughout thehydrogenation. The enantiofaces of prochiral ketones aredifferentiated on the molecular surface of the coordinatively
saturated RuH intermediate. This notion is in contrast to theconventional mechanism for hydrogenation of unsaturated
bonds that requires the metal ± substrate ! complexation.
This NH effect is common to the mechanism of Rucatalyzed asymmetric transfer hydrogenation.[86] Recently
we found that [RuCl{(S,S)-YCH(C6H5)CH(C6H5)NH2}(!6-arene)] (Y " O, NTs) complexes or their analogues
catalyze asymmetric transfer hydrogenation of aromatic andacetylenic carbonyl compounds, by using a 2-propanol/alkaline-base system to give the corresponding S chiral alcohols ofhigh enantiomeric purity, as generalized in Scheme 13.[87, 88] A
formic acid/triethylamine mixture often serves as a better
2017

REVIEWS

R. Noyori

O
R

X

OH

(S,S)-Ru cat.
baseX(CH3)2CHOH

R

R

R C H

D

X

H

X

H

O

OH
R2

O H

R'n

OH
D

2

Ru

R'n

Y

N

HN
Ph

H

Ph

(CH3)2C=O (CH3)2CHOH

Ph

18e complex

R

Ru

Y
Ph

16e complex

R1(S,S)-Ru cat.

CH3O

HCO2H/(C2H5)3N

CH3O

CH3O
N

CH3O

R C

R

H

H Ru
H

Rn

Cl

R

Ru
N
R'

Rn

O

Cl
Ph

or

Ru

H

Ph

N
H

N

O H N
Ph

H

Ph

Y
Ph
Ph

disfavored TS

Figure 10. Metal ± ligand bifunctional mechanism in asymmetric transferhydrogenation catalyzed by [RuH{(S,S)-YCH(C6H5)CH(C6H5)NH2}(!6arene)]. R " alkyl or D; Y " O or NTs.

Ts
Ph

Ph

(S,S)-Ru catalyst

Scheme 13. Asymmetric transfer hydrogenation of carbonyl compounds
and imines catalyzed by chiral Ru complexes. Ts " 4-toluenesulfonyl.

often insufficient and basic research through interdisciplinary
collaboration with scientists in other fields is needed. The
recent progress in asymmetric synthesis has, in fact, spurred
such endeavors which are directed toward the creation ofmolecularly engineered novel functions.
In the mid-1980s, we established the long-sought after
three-component coupling synthesis of prostaglandins (PGs)
illustrated in Scheme 14.[92] The five-membered unit could be
combined with the two C7 and C8 side-chain (& and ' side
chains) units by organometallic methodologies. Our asymmetric methods play a key role in controlling the C(11) andC(15) OH-bearing stereogenic centers. The requisite (R)-4hydroxy-2-cyclopentenone is conveniently prepared on amultikilogram scale by kinetic resolution of the racemate by

reducing agent. Certain imines are also reduced enantioselectively by this method. The detailed experimental[89] andtheoretical analyses[90] revealed that the transfer hydrogenation of carbonyl compounds with 2-propanol proceeds via acoordinatively saturated 18-electron complex, [RuH{(S,S)YCH(C6H5)CH(C6H5)NH2}(!6-arene)], as illustrated in Figure 10. The metal ± ligand bifunctional mechanism allows for
simultaneous delivery of the Ru!H and N!H to the C"Ofunction via a six-membered pericyclic TS, which gives an S alcohol andOH
COOH[Ru{(S,S)-YCH(C6H5)CH(C6H5)NH}(!6-arene)]. The latter 16-electron
Ru ± amide complex dehydrogenatesOOH
2-propanol to regenerate the Ru-hyPGD
1dride species.[86, 91]
O

The major goals of synthetic chemists and the chemical industry havebeen the efficient synthesis of known
valuable compounds. Another, andperhaps more important, pursuit is
the creation of new valuable substances and materials through chemical
synthesis. Toward this end, mere
chemical knowledge or technology is

C H Rufavored TS

R' = CH3 or H

8. Toward Cerebral Molecular
Science

Ar

Y

O H N

R = CH3, aryl

R'n

R'n

Ar

NH

R

2018

Ar

O

O

R1

C

Ar

OR

α chainω chain
COOH

O

O

OH

COOH

OH

OH

OH

OR

6

5

OH
PGF1α

PGE1
O

COOH

OH
COOCH3COOH
O

OR'
5,6-didehydro-PGE2

OH

OH
PGD2

O
COOH

COOH
OH

OH
PGI2

OH

OH

OH
PGF2α

Scheme 14. Three-component synthesis of prostaglandins.
' chain " (E,S)-LiCH"CHCH(OR")(CH2)4CH3 .

OH
PGE2

& chain " ICH2C$C(CH2)3COOCH3 ;Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

REVIEWS

Asymmetric Catalysis
BINAP ± Ru-catalyzed hydrogenation.[43] The BINAL-H reagent is useful for asymmetric synthesis of the lower sidechain block.[93, 94] This straightforward procedure is useful forthe synthesis of not only naturally occurring PGs but also theirartificial analogues.[95]To explore applications to the science of the human brain,
we collaborated with the research groups led by M. Suzuki(my long-term collaborator at Nagoya and now at Gifu
University), Y. Watanabe (Osaka City University), and B.
Langstrˆm (Uppsala University; Figure 11).[96, 97] After a long

Figure 11. The interdisciplinary collaborative team (from the left, M.
Suzuki, R. Noyori, Y. Watanabe, and B. Langstrˆm) that studied (15R)-TIC
and the methyl esters, labeled by radioactive nuclides.

methyl iodide and tributyl(aryl)stannane (excess) which isapplicable to the synthesis of (15R)-[11C]TIC methyl ester.[99]This technology was then transferred to the PET Center at
Uppsala. A very dedicated colleague in our team, M. Suzuki,
volunteered to test this new artificial compound on himself.
After being carefully examined, (15R)- [11C]TIC methyl ester
was injected into his right arm. The methyl ester was carriedthrough his blood stream, passed through the blood-brain
barrier, reached his brain, and was hydrolyzed to the freecarboxylic acid, which was bound to IP2 receptors in his
central nervous system. Figure 12 shows the PET images ofhorizontal slices of his brain, from the lower to the upper
portions. From this trial, a new receptor, IP2 , was found invarious important structures of the human brain. Thus, (15R)TIC and its analogues are expected to have effects on thebrain and, in fact, do show a unique neuroprotective effect,
which may be of clinical benefit. Primary cultured hippocampal neurons exposed to a high oxygen concentration
display the morphological features of apoptotic cell death and(15R)-TIC effectively protects them against such oxygen

investigation, (15R)-TIC, a PGI2-type carboxylic acid, wasfound to show strong, selective binding in the central nervous
system, which thereby identifies the novel IP2 receptor.
Interestingly, this compound has the unnatural 15R configuration, although most biologically active PG derivatives havethe natural 15S configuration. This discovery was made by anin vitro study using frozen sections of rat brain and frozen
sections of rat brain and (15R)-[3H]TIC as a probe.[98]However, this radioactive probe is not appropriate for studies
COOH

COOH

11

OH

HO 3

H

(15R)-[3H]TIC

OH

CH3

OH
(15R)-[11C]TIC

on living monkey or human brain, since $! particles emitted
from 3H can not penetrate tissues. Incorporation of 11C, a
positron emitter with a short half-life of about 20 min and ahigh specific radioactivity, as a radioactive nuclide is essential
for noninvasive studies using positron-emission tomography(PET). Positrons ($#) interact with free electrons in biologicalmaterials, and produce " rays that can penetrate tissues andare detectable outside the human body. However, thispresents a new chemical problem. The 11CH3 group must be
incorporated in the final step of the synthesis of (15R)-TIC
methyl ester, and the total time for synthesis, workup,
purification, and sterilization should be less than 40 min
because of the short half-life time of 11C. A student in mygroup at Nagoya made a concerted effort to achieve this and,eventually succeeded with a rapid Pd-mediated coupling ofAngew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

Figure 12. The uptake of (15R)-[11C]-TIC in the human brain. The PET
images of 18 horizontal slices from the lower to the upper portions of thebrain (volunteer: M. Suzuki; June 13, 2000. PET Center of Uppsala
University).

2019

REVIEWS
toxicity.[100] Similar neuroprotective effects were demonstrated in other in vitro experiments using serum deprivation andin in vivo studies of ischemic insults with gerbils, rats, andmonkeys. Thus, the IP2 receptor is a novel target for developing drugs which may be neuroprotective in brain disorders
and neutrodegenerative diseases.

9. Prospects for the futureStudies of molecular chirality have the promise to yieldsignificant clinical, scientific, and industrial benefits in the
future. A structurally diverse array of molecular substances
exists. All molecules possess common characteristics, namely,
fixed elemental composition, definite atomic connectivity, adefined relative and absolute stereochemistry, and someconformation. From such precise nanometer-scale structures,certain significant properties and functions emerge. Chemists
can design and synthesize molecules at will, based on
accumulated scientific knowledge. The practical synthesis ofenantiomers with a defined absolute stereochemistry is one of
the most significant areas of research. This endeavor is not
only an intellectual pursuit but is also a fertile area for thedevelopment of beneficial technologies.[101] Its utility is
obvious, and ranges from basic scientific research at a subfemtomole scale, as in the case of brain research describedabove, to the industrial production of high-value compounds
in multithousand tons per annum quantities. Louis Pasteur
stated in 1851 that ™Dissymmetry is the only and distinct
boundary between biological and nonbiological chemistry.
Symmetrical physical or chemical force cannot generate
molecular dissymmetry∫. This notion is no longer true. The
recent revolutionary development in asymmetric catalysis has
totally changed the approach to chemical synthesis. This field
is still growing rapidly and I am certain that it will play apivotal role in the development of the life sciences andnanotechnology in the 21st century.
The highest honor for me is to be recognized with theprestigious 2001 Nobel Prize in Chemistry. This honor must be
shared with my research family at Nagoya and with manycollaborators at other institutions. Asymmetric hydrogenation
has been the life-long focus of my research, and my studies
have relied largely on BINAP chemistry, which I initiated withthe late Professor Hidemasa Takaya. Subsequently, BINAP
chemistry was developed further in our laboratories at Nagoya,
where Professors Masato Kitamura and Takeshi Ohkuma
made major contributions. Other asymmetric hydrogenation
methods were discovered during my directorship of the
ERATO Molecular Catalysis Project (1991 ± 1996), which
was managed by Professor Takao Ikariya (now Tokyo Instituteof Technology) and Dr. Shohei Hashiguchi (Takeda Chemical
Industry). Our laboratory at Nagoya is small. To realize theutilization of our scientific achievements, it was important tocollaborate with other institutions. In this regard, I appreciate
the cooperation of the groups led by Professors Sei Otsuka andKazuhide Tani (Osaka University), and Professors Masaaki
Suzuki (Gifu University), Yasuyoshi Watanabe (Osaka City
University), and Bengt Langstrˆm (Uppsala University). These2020

R. Noyori
are just the names of the leaders of the research groups,
although many young associates and students also contributed
significantly. I had opportunities to have fruitful collaborations
with many other scientists whose names are cited in thereferences. We have been supported by many companies,
particularly Takasago International Corporation and Teijin
Company. The generous and consistent support from the
Ministry of Education, Culture, Sports, Science and Technology was essential for the success of my research. I am also
grateful to the Japan Science and Technology Corporation andmany private foundations for their support. Last, but not least,
I acknowledge Professor Hitosi Nozaki at Kyoto University,
my mentor who first introduced me to this fascinating andrewarding field of research.
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[19] E. J. Corey, R. Noyori, T. K. Schaaf, J. Am. Chem. Soc. 1970, 92, 2586.
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1973, 85, 1013; Angew. Chem. Int. Ed. Engl. 1973, 12, 954.
[21] R. Noyori, H. Takaya, Chem. Scr. 1985, 25, 83.
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Verhoeven, P. J. Reider, Org. Synth. 1998, 76, 6.
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[29] a) S. Otsuka, K. Tani in Asymmetric Synthesis Vol. 5 (Ed.: J. D.
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1968, 3143.
[34] Ru-catalyzed asymmetric hydrogenation of olefins was first achieved
using a DIOP ± Ru complex: B. R. James, D. K. W. Wang, R. F. Voigt,
J. Chem. Soc. Chem. Commun. 1975, 574.
[35] C. R. Landis, J. Halpern, J. Am. Chem. Soc. 1987, 109, 1746.
[36] J. M. Brown, P. A. Chaloner, J. Am. Chem. Soc. 1980, 102, 3040.
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[40] a) T. Ohta, H. Takaya, R. Noyori, Tetrahedron Lett. 1990, 31, 7189;b) M. T. Ashby, J. Halpern, J. Am. Chem. Soc. 1991, 113, 589.
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[42] H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S.
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Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S. Inoue,
I. Kasahara, R. Noyori, J. Am. Chem. Soc. 1987, 109, 4129.
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[44] a) M. Kitamura, Y. Hsiao, R. Noyori, H. Takaya, Tetrahedron Lett.
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Ohta, H. Takaya, R. Noyori, J. Org. Chem. 1994, 59, 297.
[45] W. D. Lubell, M. Kitamura, R. Noyori, Tetrahedron: Asymmetry
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[46] M. Kitamura, M. Yoshimura, M. Tsukamoto, R. Noyori, Enantiomer
1996, 1, 281.
Angew. Chem. Int. Ed. 2002, 41, 2008 ± 2022

REVIEWS[47] T. Ikariya, Y. Ishii, H. Kawano, T. Arai, M. Saburi, S. Yoshikawa, S.
Akutagawa, J. Chem. Soc. Chem. Commun. 1985, 922. This was thefirst use of BINAP in Ru-catalyzed asymmetric hydrogenation.
[48] M. Kitamura, K. Nagai, Y. Hsiao, R. Noyori, Tetrahedron Lett. 1990,
31, 549.
[49] For other synthetic applications, see reviews: a) G. M. Ramos Tombo, G. Bellusœ, Angew. Chem. 1991, 103, 1219; Angew. Chem. Int. Ed.
Engl. 1991, 30, 1193; b) A. Bˆrner, J. Holz in Transition Metals for
Organic Synthesis, Vol. 2 (Eds.: M. Beller, C. Bolm), Wiley-VCH,
Weinheim, 1998, p. 3; c) J. M. Brown in Comprehensive Asymmetric
Catalysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, p. 121; d) T. Ohkuma, M. Kitamura, R.
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Wiley-VCH, New York, 2000, p. 1.
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Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am. Chem. Soc. 1988,
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[53] T. Nishi, M. Kitamura, T. Ohkuma, R. Noyori, Tetrahedron Lett.
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[58] For the threo/erythro nomenclature, see: R. Noyori, I. Nishida, J.
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279, 23; e) X. Zhang, T. Taketomi, T. Yoshizumi, H. Kumobayashi, S.
Akutagawa, K. Mashima, H. Takaya, J. Am. Chem. Soc. 1993, 115,3318. See also: f) F. Robin, F. Mercier, L. Ricard, F. Mathey, M.
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REVIEWS
Naturforsch. B 1998, 53, 267; h) Q. Jiang, Y. Jiang, D. Xiao, P. Cao, X.
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Heterogeneous hydrogenation, see: j) T. Osawa, A. Tai, Y. Imachi,
S. Takasaki in Chiral Reactions in Heterogeneous Catalysis (Eds.: G.
Jannes, V. Dubois), Plenum, New York, 1995, p. 75; k) T. Harada, T.
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[67] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
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[68] R. Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 41; Angew. Chem.
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[69] R. Noyori, T. Ohkuma, Pure Appl. Chem. 1999, 71, 1493.
[70] R. Noyori, M. Koizumi, D. Ishii, T. Ohkuma, Pure Appl. Chem. 2001,
73, 227.
[71] Abbreviations: TolBINAP " 2,2"-Bis(di-4-tolylphosphano)-1,1"-binaphthyl. XylBINAP " 2,2"-Bis(di-3,5-xylylphosphano)-1,1"-binaphthyl. DPEN " 1,2-Diphenylethylenediamine. DAIPEN " 1,1-Di-4anisyl-2-isopropyl-1,2-ethylenediamine.
[72] T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K.
Murata, E. Katayama, T. Yokozawa, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1998, 120, 13 529.
[73] T. Ohkuma, H. Ooka, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995,
117, 10 417.
[74] T. Ohkuma, H. Ikehira, T. Ikariya, R. Noyori, Synlett 1997, 467.
[75] T. Ohkuma, M. Koizumi, M. Yoshida, R. Noyori, Org. Lett. 2000, 2,
1749.
[76] T. Ohkuma, H. Ooka, M. Yamakawa, T. Ikariya, R. Noyori, J. Org.
Chem. 1996, 61, 4872.
[77] T. Matsumoto, T. Murayama, S. Mitsuhashi, T. Miura, Tetrahedron
Lett. 1999, 40, 5043.
[78] T. Ohkuma, D. Ishii, H. Takeno, R. Noyori, J. Am. Chem. Soc. 2000,
122, 6510.
[79] T. Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R. Noyori, Org.
Lett. 2000, 2, 659.
[80] T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M.
Terada, R. Noyori, J. Am. Chem. Soc. 1998, 120, 1086.
[81] T. Ohkuma, H. Takeno, Y. Honda, R. Noyori, Adv. Synth. Catal.
2001, 343, 369.
[82] Review: K. Mikami, M. Terada, T. Korenaga, Y. Matsumoto, M.
Ueki, R. Angelaud, Angew. Chem. 2000, 112, 3676; Angew. Chem.
Int. Ed. 2000, 39, 3532. See also: K. Mikami, T. Korenaga, M. Terada,
T. Ohkuma, T. Pham, R. Noyori, Angew. Chem. 1999, 111, 517;
Angew. Chem. Int. Ed. 1999, 38, 495; K. Mikami, T. Korenaga, T.
Ohkuma, R. Noyori, Angew. Chem. 2000, 112, 3854; Angew. Chem.
Int. Ed. 2000, 39, 3707.
[83] Nonlinear effects in catalysis should be investigated carefully
because of the homochiral and heterochiral interaction of the chiralspecies present in the catalytic system. For reviews, see: a) R. Noyori,
S. Suga, H. Oka, M. Kitamura, Chem. Rec. 2001, 1, 85; b) C. Girard,
H. B. Kagan, Angew. Chem. 1998, 110, 3088; Angew. Chem. Int. Ed.
1998, 37, 2922; c) D. R. Fenwick, H. B. Kagan, Top. Stereochem. 1999,
22, 257.
[84] H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, E.
Katayama, A. F. England, T. Ikariya, R. Noyori, Angew. Chem. 1998,
110, 1792; Angew. Chem. Int. Ed. 1998, 37, 1703.

2022

R. Noyori[85] The ketone substrate reacts in an outer sphere of the coordinatively
saturated 18-electron complex without interaction with the metallic
center. Thus the general scheme given in Figure 1 is to be modified tosome extent. For other mechanistic investigations, see: a) K. AbdurRashid, M. Faatz, A. J. Lough, R. H. Morris, J. Am. Chem. Soc. 2001,
123, 7473; b) R. Hartmann, P. Chen, Angew. Chem. 2001, 113, 3693;
Angew. Chem. Int. Ed. 2001, 40, 3581.
[86] R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001, 66,
7931.
[87] R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97.
[88] a) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem.
Soc. 1997, 119, 8738; b) I. Yamada, R. Noyori, Org. Lett. 2000, 2,3425.
[89] K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew.
Chem. 1997, 109, 297; Angew. Chem. Int. Ed. Engl. 1997, 36, 285.
[90] a) M. Yamakawa, H. Ito, R. Noyori, J. Am. Chem. Soc. 2000, 122,
1466; b) D. A. Alonso, P. Brandt, S. J. M. Nordin, P. G. Andersson, J.
Am. Chem. Soc. 1999, 121, 9580.
[91] M. Yamakawa, I. Yamada, R. Noyori, Angew. Chem. 2001, 113, 2900;
Angew. Chem. Int. Ed. 2001, 40, 2818.
[92] a) M. Suzuki, A. Yanagisawa, R. Noyori, J. Am. Chem. Soc. 1985, 107,
3348; b) M. Suzuki, A. Yanagisawa, R. Noyori, J. Am. Chem. Soc.
1988, 110, 4718; c) M. Suzuki, Y. Morita, H. Koyano, M. Koga, R.
Noyori, Tetrahedron 1990, 46, 4809.
[93] M. Suzuki, H. Koyano, Y. Morita, R. Noyori, Synlett 1989, 22.
[94] This process has been used at Ono Pharmaceutical Co. for theindustrial synthesis of PGs using the Corey method.
[95] a) R. Noyori, M. Suzuki, Angew. Chem. 1984, 96, 854; Angew. Chem.
Int. Ed. Engl. 1984, 23, 847; b) R. Noyori, M. Suzuki, Chemtracts:
Org. Chem. 1990, 3, 173; c) R. Noyori, M. Suzuki, Science 1993, 259,44.
[96] a) M. Suzuki, K. Kato, R. Noyori, Yu. Watanabe, H. Takechi, K.
Matsumura, B. Langstrˆm, Y. Watanabe, Angew. Chem. 1996, 108,
366; Angew. Chem. Int. Ed. Engl. 1996, 35, 334; b) H. Takechi, K.
Matsumura, Yu. Watanabe, K. Kato, R. Noyori, M. Suzuki, Y.
Watanabe, J. Biol. Chem. 1996, 271, 5901.
[97] Account: M. Suzuki, R. Noyori, B. Langstrˆm, Y. Watanabe, Bull.
Chem. Soc. Jpn. 2000, 73, 1053.
[98] Yu. Watanabe, K. Matsumura, H. Takechi, K. Kato, H. Morii, M.
Bjˆrkman, B. Langstrˆm, R. Noyori, M. Suzuki, Y. Watanabe, J.
Neurochem. 1999, 72, 2583.
[99] a) M. Suzuki, H. Doi, M. Bjˆrkman, Y. Andersson, B. Langstrˆm, Y.
Watanabe, R. Noyori, Chem. Eur. J. 1997, 3, 2039; b) M. Suzuki, H.
Doi, K. Kato, M. Bjˆrkman, B. Langstrˆm, Y. Watanabe, R. Noyori,
Tetrahedron 2000, 56, 8263.
[100] T. Satoh, Y. Ishikawa, Y. Kataoka, Y. Cui, H. Yanase, K. Kato, Yu.
Watanabe, K. Nakadate, K. Matsumura, H. Hatanaka, K. Kataoka,
R. Noyori, M. Suzuki, Y. Watanabe, Eur. J. Neurosci. 1999, 11, 3115.
[101] R. Noyori, S. Hashiguchi, T. Yamano in Applied Homogeneous
Catalysis by Organometallic Complexes, 2nd ed. (Eds.: B. Cornils,
W. A. Hermann), VCH-Wiley, Weinheim, 557.
[102] Nobel lecture: K. B. Sharpless, Angew. Chem. 2002, 114, 2126;
Angew. Chem. Int. Ed. 2002, 41, 2024.

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REVIEWS

Searching for New Reactivity (Nobel Lecture)**K. Barry Sharpless*
The processes for the selective oxidation of olefins have long been among
the most useful tools for day-to-day
organic synthesis. Herein, the focus ison the asymmetric-epoxidation (AE)and asymmetric-dihydroxylation (AD)reactions developed by Sharpless andco-workers. The reactions have a wide
scope, are simple to run, and involve
readily available starting materials.

Ligand-accelerated catalysis is crucial
to these reactions and might be theagent for uncovering more catalytic
processes. In addition to the selectivity
benefits of catalysis, the phenomenonof turnover (amplification) raises its
potential impact. The author and his
co-workers developed small, highly
enantioselective catalysts that were
unfettered by the ™lock-and-key∫ se-

In 1938, three years before I was born, a live coelacanth wastaken from the waters off the eastern coast of South Africa.
Previously known only in the fossil record from some hundred
million years ago, the coelacanth and the implications of
its discovery remained big news for years, and fueled
an enthusiasm for ™creatures∫ that persisted for decades.
Those of us born in the 1940s grew up on photos ofeminent scientists setting off on expeditions, their sunburned
faces dwarfed by mountain explorers× garb, or making
thumbs-up signs as they entered the water in scuba gear. We
shared their confident expectation that the Loch Ness
Monster, Sasquatch, the Yeti–even a dinosaur–soon would
be taken alive.
I grew up loving the sea and loving fishing in particular,
but unlike most fishermen I cared less for the size or
quantity of the catch than for its rarity. Nothing could
be more exciting than pulling (if not this time, surely the
next!) a mysterious and hitherto unknown creature from thewater. As a kid, I passionately wanted to be one who caught[*] Prof. Dr. K. B. SharplessDepartment of Chemistry
The Scripps Research Institute10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)Fax: (! 1) 858-784-7562
E-mail: sharples@scripps.edu[**] Copyright¹ The Nobel Foundation 2002. We thank the Nobel
Foundation, Stockholm, for permission to print this lecture. Adaptedwith the permission of the editors from ™Coelacanths and Catalysis∫:
K. B. Sharpless, Tetrahedron 1994, 50, 4235.

2024

Angew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

lectivity of Natures enzymes, and tolerant of substrates throughout theentire range of olefin substitution patterns.
Keywords: asymmetric catalysis ¥ epoxidation ¥ hydroxylation ¥ N ligands ¥Nobel lecture

the next coelacanth, the first to see something that was
beyond reasoning, even beyond imagining.
Opening a Nobel Lecture with a fishing expedition may
seem frivolous, even indecorous, but I assure you nodisrespect is intended. These are the circumstances thatshaped my professional life: my first laboratory was New
Jersey×s Manasquan River, whose astonishingly rich variety
addicted me to discovery; a few years later, when I was ascomfortable at sea as I×d been on the river, my laboratory
became the Atlantic Ocean. Later, when I started doing
chemistry, I did it the way I fished–for the excitement, thediscovery, the adventure, for going after the most elusive catch
imaginable in uncharted seas.
Chemists usually write about their chemical careers interms of the different areas and the discrete projects in
those areas on which they have worked. Essentially all mychemical investigations, however, are in only one area,
and I tend to view my research not with respect to projects,
but with respect to where I×ve been driven by two
passions which I acquired in graduate school: I am passionate about the Periodic Table (and selenium, titanium, andosmium are absolutely thrilling), and I am passionate aboutcatalysis.
What the ocean was to the child, the Periodic Table is to thechemist; new catalytic reactivity is, of course, my personalcoelacanth.
Even though I grew up in Philadelphia, if someone asks me
where I×m from, I usually say ™the Jersey Shore∫, because
that×s where my family spent summers, as well as many
weekends and holidays, with my father joining us whenever he¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002

1433-7851/02/4112-2024 $ 20.00+.50/0

Asymmetric Oxidation
could. My father had a flourishing one-man general-surgery
practice, which meant he was perpetually on call. With him at
home so little and practically guaranteed to be called awaywhen he was, my mother liked being near family and friends at
the Shore, where her parents had settled and established afishery after emigrating from Norway. When I was a baby, myparents bought land on a bluff overlooking the ManasquanRiver, about four miles up from where the river enters the
Atlantic.
Like many scientists, I was a very shy child, happier andmore confident when on my own, and my interest was totallyabsorbed by the river. In those days, the incoming tidetransformed our part of the river, from a channel flanked bybroad mudflats to a quarter-mile basin that exploded with lifeof myriad variety–about a dozen kinds of fish big enough tomake it to the dinner table, plus blue crab, eel, and a bountyof fry and fingerlings that would graduate downstream to theocean. I was obsessed with finding and observing everythingthat lived in the river and knowing everyone who worked
on it.
My most delicious childhood memory is the excitement I
experienced at the instant of awakening on almost every
summer morning; the sound I associate with that feeling is the
distant whine of my first scientific mentor×s outboard motor.
That was my wake-up call, and within minutes I was at theriver×s edge, waiting in the predawn stillness for Elmer
Havens and his father Ollie to make their way across the riverfrom Herbertsville to pick me up to ™help∫ them seine forcrabs. Amused by my regularly walking along the bank towatch them haul their seine, Elmer eventually installed me in
the boat, which he used for transportation as well as forsteadying himself as he dragged the seine×s deep-water end.
Ollie walked one end of the seine along the shore, alarming
the crabs gathered at the river×s edge, and frightening them
toward deeper water, and so into the net×s pocket. Chest deepin water and mud, Elmer walked parallel to his father, with
one arm clasping the seine, the other hooked over the boat×s
gunwale. Elmer and I, our heads close together, would
speculate about the catch, taking into account all thevariables–the weather, the season, the tide. Every hundred

REVIEWS
yards or so, Elmer doubled ahead toward the shore to draw
the purse. I liked it best if a big eel or a snapping turtle
got caught up in the net, which made the water boil andthe net flop into the air. I always hoped we×d catch something
new.
I had a little dinghy, and my realm of exploration expanded
in direct proportion to my rowing ability. The same tide thatcreated this abundant estuary also was my nemesis, which
forever stranded me upriver in the narrows or perhaps at
Chapman×s Boat Yard, a mile downstream and on the
opposite bank. Since my parents couldn×t keep me off thewater, they opted for increasing the likelihood of my getting
home unaided by giving me a boat with an outboard. It wasn×t
long before I went down river all the way to the inlet(absolutely forbidden, of course), and, soon after, theprospect of new creatures to pull from the water lured meout through the rock jetty and into the ocean; at the time I wasonly seven or perhaps eight years old.
By the time I was ten, I ran crab and eel traps and supplied
everyone we knew with fish as well; at 14 I started working
during the summer as the first (and only) mate on a charterboat. My parents allowed me to go to sea when I was so young
and small even for my age because I was offered a job on arelative×s boat–little did my parents or I know that Uncle
Dink, a cousin actually, offered me the job so he wouldn×t
have to pay a ™full-sized∫ helper. I so wanted to keep working
on the boats that it was years before I dared tell my parents
what went on aboard the Teepee, like how the Coast Guard
refused assistance to Dink because his boat was in chronic
disrepair. (Consequently, some of our adventures at sea werememorable indeed–grappling hooks and guns have theirplace in the canon–and I mention this trove of Uncle Dink
stories because, for years, my MIT colleagues begged me totell them over and over again).
On a charter boat, the captain pilots the ship and finds thefish the customers reel in. Meanwhile, the mate is over theboat like a dervish, skillfully arraying the water with fishy
temptations–adjusting outriggers, finding the perfect combination of lure or bait and tackle, always mindful of the action
on nearby boats competing for the same fish[*] . Since my

K. Barry Sharpless and his co-workers have discovered and developed many widely used catalytic oxidation processes,
including the first general methods for stereoselective oxidation–the Sharpless reactions for asymmetric epoxidation,
dihydroxylation, and aminohydroxylation of olefins. His mentors at Dartmouth College (BA in1963), Stanford College (PhD in 1968 and postdoctoral research), and Harvard University(further postdoctoral research) were Prof. T. A. Spencer, Prof. E. E. van Tamelen, Prof. J. P.
Collman, and Prof. K. Bloch, respectively. Before 1990, when he became W. M. Keck Professorof Chemistry at the Scripps Research Institue, Prof. Sharpless was a member of Faculty at theMassachusetts Institute of Technology (1970 ± 77, 1980 ± 90) and Stanford University (1977 ±
80). Prof. Sharpless×s honours include the Chemical Sciences Award of the National Academyof Sciences (of which he is a member), the Roger Adams and Arthur C. Cope Awards from theAmerican Chemical Society, the Tetrahedron Award, the King Faisal Prize, the Prelog Medal,
the Wolf Prize, the Nobel Prize (2001), and honorary doctorates from five American andEuropean universities. The Sharpless research group continues to search for new homogeneousoxidation catalysts and for transition-metal-catalyzed asymmetric processes.

Angew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

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REVIEWS
friends were all mates, we naturally agreed that enticing fish tobite was the greatest challenge, but I alone felt that getting the
strike was the most fun, even more exciting than landing
the fish. I worked as a mate almost daily every summer, rightup until the day before I set out from New Jersey, headed
toward the biggest ocean and graduate school at Stanford
University.
That was in 1963. In the spring of that year, my inspiring
Dartmouth College chemistry professor and first research
director, Tom Spencer, talked me into delaying entering
medical school to try a year of graduate school. He sent me to
Stanford specifically to work for E. E. van Tamelen, Tom×s
own mentor at Wisconsin. The appeal of fishing was such that
Tom, to my later regret, never succeeded in getting me tospend any summers working in his lab. In fact, even in
graduate school, I expressed my ambivalence by continuing
to fantasize about finding a boat out of Manasquan toskipper and by failing–this did not please v.T.–to do thesimple paperwork required to renew my NSF predoctoral
fellowship.
However, toward the end of my first year at Stanford, aserendipitous misunderstanding catalyzed the complete transfer of my passion (some would say my monomania) from one
great science to another; from fishing to chemistry. Before
leaving for a lengthy European visiting professorship, v.T. sentme to the library to look for reactive inorganic species thatmight produce interesting transformations of organic compounds. My first projects with v.T. were selective oxidation ofpolyolefins and titanium-mediated deoxygenative coupling of
alcohols, and I was already primed to appreciate usefulchemistry employing ™strange∫ elements after selecting the
Wittig Reaction from a list of suggested topics for my student
seminar. The Wittig Reaction really engaged my enthusiasm,
and I ingenuously concluded that finding new reactions otherchemists could use looked like a lot of fun.
In any event, upon v.T.×s return, I discovered he had notintended for me to spend all those months immersed in theliterature. While I had no research results to report, I did havea notebook filled with ideas and an eagerness to drop my line
throughout the vastness of the Periodic Table. I don×t[*] This diversion into fishing as a metaphor for research could go on forpages; consider how, when a boat was hooking tuna–the catch of
choice–word spread by radio and the competition converged fromevery compass point. The hot boat×s captain greeted this acknowledgment of his success with some anxiety; while he liked setting the othercaptains× agendas and pleasurably speculating that the parties on theother boats were considering chartering him next time, the secrets of his
success nonetheless required protection, so trolling speeds werelowered to sink the lures and prevent rubberneckers from identifying
them, and red herrings (literally, on occasion!) were casually displayedon the fish box.
Isaak Walton and John Hersey devoted whole books to this metaphor,so indulge me for a few more sentences. The handy process versus
product dichotomy that applies so neatly to much of human endeavor
illuminates this fisherman ± chemist comparison, too. Conventional
wisdom places fly-fishing at the ™process∫ end of the scale, while a™product∫ fisherman uses sonar to find a school before he bothers to get
his line wet. Process person though I am, only the Manasquan River ran
through my fishing days; trolling for the unknown always had more
appeal than hooking a trout I already knew was there.

2026

K. B Sharpless
think I×ve gone fishing in the literal sense a dozen times
since then!
From van Tamelen, a Gilbert Stork prote¬ge¬, I inheritedenthusiastic disdain for ™safe∫ problems, deep admiration fortraditional multistep organic synthesis, and awe before
selective biological catalysis: studying the squalene oxide/
lanosterol cyclase enzyme left me impressed by enzymic
selectivity, but depressed by the difficulty of using enzymes forsynthetic transformations. After getting a double dose of him
in the classroom, Derek Barton became my model. At
Dartmouth, Tom Spencer taught a course on conformational
analysis, based on one he took at Wisconsin from William S.
Johnson (Tom×s uncle, in fact), then I experienced the originalat Stanford.[**] Being wet behind the ears, I took conformational analysis for granted; it was Sir Derek×s search
for new reactivity that electrified me. A postdoc with
Jim Collman (the only person, I concede, who gets more
excited about chemistry than I do) ignited my interest in
using simple metal complexes to develop catalysts (in the
Collman lab, incidentally, I had the privilege of many hours
at the blackboard with labmate Bob Grubbs). Then, before
taking up my job at MIT, a postdoc with Konrad Blochconfirmed my hunch that impatience rendered me incompetent around enzymes. Konrad graciously let me startworking on my own ideas when his were much too frustrating
for me.
One other part of my background seems to have contributed to my chemistry. The first American Sharpless (™Sharples∫ then) came to Pennsylvania in the 17th Century, notlong after William Penn. My father was a practicing Quaker
only as a child, but the values in our home were Quakervalues, and I was educated in a Quaker school. The Quakers
encourage modesty, thrift, initiative, and enterprise, but thegreatest good is being a responsible member of the community–being useful. ™Elegant∫ and ™clever∫ were the chemical
accolades of choice when I started doing research, just as™novel∫ is high praise now. Perhaps the Quakers are
responsible for me valuing ™useful∫ most.
So that is my background as a chemist. I×ve been accused ofgoing too far, when I speculate that chirality fascinates me
because I handled my umbilical cord in utero, but I×m quite
sincere in proposing that the extraordinary training I received
as a young chemist transformed an existing passion for
discovering the unknown into the search for new reactivity,
and that Quaker utilitarianism made the selective oxidation of
olefins so appealing.
With respect to chemical reactions, ™useful∫ implies wide
scope, simplicity to run, and an essential transformation ofreadily available starting materials. Clearly, if useful newreactivity is the goal, the obvious strategy is investigating the[**] When teaching MIT undergraduates, I always said ™The lights came onwith conformational analysis∫, without thinking where I picked up thephrase, but now I know: the previous Tetrahedron Prize article states™Just as chemists of the Robinson generation worked without concern
for stereochemical factors so we, in the early days, were working in
ignorance of conformational considerations until Derek Barton
showed us the light in 1950∫. The author is, of course, Bill Johnson(see reference [1]).
Angew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

Asymmetric Oxidation

REVIEWS

transformations chemists rely on. The processes forthe selective oxidation of olefins have long beenamong the most useful tools for day-to-day organic
synthesis because of these appealing characteristics ofolefins:
1) they are among the cheapest functionalized organic starting materials,2) they can be carried ™hidden∫ through conventional
acid/base-catalyzed transformations, then ™revealed∫ at will by adding heteroatoms throughselective oxidations,
Scheme 2. Asymmetric epoxidation and dihydroxylation reactions of geraniol.
3) most simple olefins are prochiral, and provide a
prominent portal to the chiral world.
The trisubstituted olefin geraniol, in addition to
being one of my favorite smells, provides an excellent
case study both for laying out the challenges of selective olefin
indirect solution to enantioselective epoxidation at the 6,7oxidation as well as for noting some benchmarks in meeting
position (Scheme 2).[5]those challenges.
In 1990 came the breakthrough introduction of enantioseAs shown in Scheme 1, geraniol (1) has two trisubstituted
lectivity into existing manganese ± salen ligand catalysts forolefinic units, one of which has a hydroxy group in the allylic
the epoxidation of isolated olefins.[6] Developed independposition. Four monoepoxides are possible: making either
ently by the groups of Jacobsen[6a, 10] and Katsuki,[6b] these
racemic 2 or racemic 3 requires regio- or chemoselectivity,
epoxidation catalysts work best on only a few of the six olefinsubstitution classes. Nonetheless, their very existence is tantalizing, and encourages the hope thata general, off-the-shelf solution will be found forthe direct asymmetric-epoxidation reaction acrossthe full range of isolated-olefin substitution patterns.
The greater generality of man-made catalysts,
such as these catalysts, compared with enzymes
was noted first by Knowles[7a,c] and Kagan.[7b]During the lean times in the first decade of mycareer, their pioneering development of man×s
Scheme 1. Regio- and enantioselective monoepoxidations of geraniol.
first highly enantioselective catalysts (the #DOPA synthesis that came out of Knowles×
Monsanto lab was the asymmetric hydrogenawhile making each of the individual enantiomers requires
tion×s first commercial application) sustained my faith that aenantioselectivity. When Henbest showed that the electronic
catalyst for asymmetric oxidation could be found. Jack
deactivation by the oxygen substituent at C-1 causes peracids
Halpern×s mechanistic studies[7d] on asymmetric-hydrogenato prefer the 6,7-double bond (especially on the estertion catalysis likewise inspired me. Several Japanese chemists,
derivatives), making racemic 3 became possible.[2] When I
chief among them Ryoji Noyori,[7e] hugely extended both thescope and application of the asymmetric hydrogenation
started doing research in the 1960s, neither racemic 2 nor any
process.[8]of the enantiomers could be synthesized directly. Solving theother half of the regioselectivity problem was an obvious
This focused search has frustrated but never bored me, evenchallenge, but enantioselectivity was considered well-nighafter so many years, and the geraniol paradigm illustrates why.
impossible.
My own investigations into the oxidation of olefins comIn 1973, Bob Michaelson cracked the other half of themenced at MIT in 1970, but, fittingly, I was back at Stanford
regioselectivity problem presented by geraniol.[3] Since earlyon January 18, 1980, for Tsutomu Katsuki×s dramatic discovery of the titanium-catalyzed asymmetric epoxidation.[4, 9a]transition-metal-catalyzed epoxidations with alkyl hydroperoxides were highly selective for the 2,3-position, racemic 2
Two years later, the most scientifically stimulating andcould be prepared as well.
professionally gratifying collaboration of my career, the total
In 1980, Tsutomu Katsuki discovered the titanium-catasyntheses of the eight #-hexoses with my MIT colleague Sat
lyzed asymmetric epoxidation (AE); the enantioselective
Masamune, capped the AE×s discovery.[11] Previous articles[12]oxidation of olefins bearing allylic hydroxy groups made it
in a vein similar to this one describe that chemistry; underpossible to make either 2 or ent-2, which thereby solved one
standing the AE×s significance and putting that understanding
side of the enantioselectivity problem.[4]to work are the purview here.
After the euphoria of completing the hexose syntheses,
The osmium-catalyzed asymmetric dihydroxylation (AD),three years were spent developing, refining, and finding morediscovered in 1987, subsequently was improved to the point
applications for the AE. During this time I returned to thethat either 3 or ent-3 could be made by way of the diol, an
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REVIEWS
search for new reactivity, but it was clear that my random,
scattershot attempts were going nowhere,[*] so I was gratefulfor the opportunity to spend the first three months of 1987 as a
Sherman Fairchild Scholar at Caltech.
Many universities and institutions have handsome Fairchildbuildings, but Caltech, ever the bastion of collegiality andcamaraderie, used its Fairchild grant to endow a program thatbrings scientists from many fields to be housed graciously inthe sunshine for as long as a year. Since my research group×s
investigation of the AE had reached the point of diminishingreturns, I left for Pasadena hoping to renew my mission.
I love reading journals, and I love mountains, so the Caltech
library with its panoramic view of Mount Wilson became mythinking place of choice. Every day Mount Wilson offered
new vistas, especially on those occasions when snow fellduring the night. One morning, the mountain was completely
cloaked (the first time a freezing temperature was recorded in
downtown LA, I recall), and the melting snow receded at sucha clip that I was sure I saw it happening. Mount Wilson was theperfect backdrop for bringing my own big picture back into
focus, and I returned to MIT eager to renew my search for new[*] I have enormous admiration for colleagues who can keep multiple
research projects alive and large groups humming, but the ™monomania∫ that prevents me from being able to do that is my long suit aswell, making it possible to concentrate–for years, actually–on a single
topic. I know some chemists call my approach ™intuitive,∫ a term I×ve
always thought underestimates the rigor that frames my method;perhaps ™unstructured∫ or ™contemplative∫ is more accurate. Many of
my cohorts are quick and facile and can jump on a few interesting bitsof data and start building tentative edifices that get taken apart andreassembled to suit new data. I, on the other hand, am ruminative: mytraining after all consisted of busily poking and perturbing theManasquan River, a curriculum both urgent and leisurely, one that
permitted exploration without assumptions and without the structure
imposed by deadlines or competition, or by knowing too little or too
much. Since I was compelled by shyness to learn to do much on myown, there was (and is) no right or wrong way, only many ways, somemore or less suited to a given endeavor. The discipline, nonetheless, isexacting; everything that can be observed should be observed, even if it
is only recalled as the bland background from which the intriguing bits
pop out like Venus in the evening sky. The goal is always finding
something new, hopefully unimagined and, better still, hitherto
unimaginable. When I became a bench- and desk-bound explorer, themethod stayed the same. I try to imagine away the packaging theinformation arrives in, then let bits and pieces move around lazily,
rather like objects tumbling slowly in zero gravity, but eventually, overtime, exploring every possible relationship with other information
that×s previously arrived. Since joining the faculty of The Scripps
Research Institute, I×ve discovered that ocean swimming and runningon the beach provide an excellent medium for this kind of activity.
However, in any climate, the best catalyst is generous, stimulating
conversation. This slow, but endlessly fascinating, method is like an
exotic ritual courtship, full of displays of bright feathers or offerings ofshiny metal or towers of sticks–what does it all, what does any of it
mean? Enormous concentration is required to remember it all in a waythat causes little sparks when certain conjunctions appear, making aconnection with something noted previously, perhaps decades ago.
Sadly, as I grow older, the connections become harder to summon up, so
the sparks, though they seem as bright as ever, are less frequent. I
describe this process at length because it×s not the way most scientists
approach their work, nor is it well suited to the demands of funding
agencies that are railroaded into answering questions posed forpolitical rather than scientific reasons, nor to the needs of graduate
students who require publications to compete for jobs. Academic
chemistry is much harder now, and I×m glad I was born when I was.

2028

K. B Sharpless
reactivity. Meditating on the AE yielded this lesson to guidethat search: Ligand-accelerated catalysis (the significance of
which is documented in M. G. Finn×s fine MIT thesis on themechanism of the AE[13] ), is crucial to the AE and not merely
a feature of it; despite its rarity, this phenomenon might be theagent for uncovering more catalytic processes.
Of course, the first and best-known example of ligand
acceleration is found in Criegee×s papers from the 1930s.[14] He
observed that pyridine accelerates the reaction in his classic
study of osmium tetroxide and olefins. Ironically, the lesson
from the AE was directing me back toward Criegee, whose
discoveries in olefin oxidation and osmylation were, in large
measure, the jumping-off point for my own research career.
I first looked into Criegee×s process shortly after becoming
an assistant professor at MIT. My attraction to the reaction of
OsO4 with olefins was inevitable. Osmium tetroxide not only
accomplishes an important synthetic transformation, but it
does so with a scope and reliability unique among reactions
used for organic synthesis. It reacts only with olefins and it
reacts with all olefins (slight poetic license here). Even R. B.
Woodward valued Criegee×s stoichiometric transformation somuch he was willing to use 100 g of OsO4 in one shot.
Osmium×s expense was not compatible with ™useful,∫ however
and, since the existing catalytic variants were not very
effective, I started searching for a reliable catalytic method.
In 1975, Kagayasu Akashi found a good process for us, basedon a hydroperoxide as an oxidant, tertiary-butyl hydroperoxide (TBHP),[15] but the brass ring was ultimately captured
that same year with the publication of the famous Upjohn
process based on N-methyl morpholine-N-oxide (NMO).[16]Throughout the rest of the 1970s, osmium remained ourprimary tool for looking for new reactivity. We discoveredthat imido osmium(!""") species effected stoichiometric cisoxyamination of olefins in direct analogy to the cis-dihydroxylation of olefins by osmium tetroxide; even more effective
catalytic versions of those transformations came shortly
thereafter.
In 1977 I left MIT, where I had been a contented member ofa wonderful chemistry faculty since 1970, for Stanford
University, where I previously spent six contented years as a
graduate student and postdoc, surrounded by a wonderfulchemistry faculty. I never made the transition back tocontentment at Stanford, probably because my research
wasn×t churning up much. This frustrated me and scared off
potential graduate students who wanted publications, not a
fishing expedition. In addition, at Stanford I remained awed
by a faculty I worshiped when a graduate student, and I lacked
the confidence to stand firm on issues, particularly faculty
appointments, that meant a lot to me. In 1979, at about thesame time I made the decision to return to MIT, Steve
Hentges, who worked in our well-developed osmium imido
area and already had the material for a good Ph.D. thesis in
hand, decided to take on one more project before writing up.
The notion of an asymmetric ligand for osmium tetroxide
had been knocking around the lab for years, and Steve first
approached the idea by making several pyridines with chiral
substituents at the 2-position; these gave diols with essentially
0 % ee![17] Pyridine is only a modest ligand for osmium
tetroxide, and, as we discovered, any ortho substituent is
Angew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

Asymmetric Oxidation
lethal to binding. But since William Griffith at Imperial
College had shown that quinuclidine binds much morestrongly to OsO4 , I suggested trying the cinchona alkaloids,
essentially substituted quinuclidines.[18] (Many chemists haveexpressed surprise at how quickly we arrived at what is now
the best ligand framework for the AD: anyone with a natural
products background and who is also a fan of Hans Wynberg×s
chemistry recognizes the cinchona alkaloids as the obvious
next step.) The results were spectacular, even without taking
into account a measurement error (discovered years later)that caused most of the ee values to be underreported by 5 ±15 %![17]Steve had a dramatic story to cap his thesis work, so hestarted writing; my attention was taken up by the decision to
return to MIT. Then, a couple of months later, Katsuki
discovered an asymmetric process with ingredients so cheap it
made working with osmium look like Rolls-Royce chemistry.
Although the AE was only weakly catalytic in the earlydays,[19] its uniformly high ee values and nontoxic, inexpensive
reagents were enough to completely divert our attention fromits promising but stoichiometric predecessor, the OsO4/
cinchona asymmetric dihydroxylation.
The preceding paragraph has no doubt failed to deflect yourattention from the obvious question: Why didn×t I try theHentges ligands in the Upjohn system in 1979? Indeed, why
did I propose the experiment in my NIH grant renewal in
January, 1984, but not follow up on it? ™As for the ligand,∫ I
wrote in the proposal, ™it is probably best to stay with thecinchona derivatives because the quinuclidine moiety is thebest ligand we know of for OsVIII complexes. The substrate will
be stilbene...the osmium catalyst will be recycled using anamine N-oxide. Ideally, both the osmium and the chiralalkaloid could be used in catalytic quantities. A successful
system of this type could be of great practical importance.∫
Instead of poking and perturbing, the Jersey Shore Schoolof Thinking×s cardinal rule, I stuck with the odds logic
suggested: ligands accelerate the reaction of OsO4 witholefins, but they also bind avidly to the resulting osmate
ester, and lethally affect catalyst turnover. This ability ofligands, such as pyridine and quinuclidine, to kill turnover incatalytic-osmylation systems had often been observed in
my laboratory. What I did not, nor could not, anticipate is
the perfect balance cinchona alkaloids achieve in ligating
ability; they bind well enough to accelerate the key step,
but weakly enough to slip off allowing the hydrolysis/reoxidation steps of the catalytic cycle to proceed. At thetime, however, the precedents seemed clear, so the AD
languished until 1987.
Unraveling the mechanism of the AE was largely the workof M. G. Finn.[13] His persistent exploration during the early to
mid-1980s of the AE×s titanium ± tartrate-catalyst system
exposed a complex mixture of species in dynamic equilibriumwith one another.[20] M. G. discovered the main species[Ti(dipt)(O-iPr)2]2 (DIPT " diisopropyl tartrate) is substantially more active than the many other species present(significantly, it is five to ten times more active than Ti(OR)4 ,a catalyst for the formation of racemic epoxy alcohol) and thisrate advantage funnels catalysis through the appropriate
tartrate-bearing species.
Angew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

REVIEWS
If the tartrate-induced acceleration of the titanium-catalyzed epoxidation reaction came as a surprise, investigatingthat phenomenon brought even more surprising results. We
ultimately found 24 metals other than Ti that catalyze theepoxidation of allylic alcohols by TBHP (Figure 1), but allthese systems were strongly inhibited or killed by adding
tartrate![21] Ligand-decelerated catalysis was clearly the rule,
while ligand acceleration was the extraordinarily valuable
exception.

Figure 1. Metals catalyzing the epoxidation of allylic alcohols by TBHP.
Adding tartrate ligand always affects reactivity: the titanium system isaccelerated.

Shortly before I left for Caltech, Chris Burns, encouraged
by Pui Tong Ho, presciently lobbied to resurrect the OsO4/
cinchona asymmetric dihydroxylation, and, without any
encouragement from me, I must admit, he embarked on thesynthesis of a stoichiometric C3-symmetric ligand for theAD.[22] A few months later, I too was again committed to
osmium, and when Bill Mungall and Georg Schrˆder reexamined the work from 1979, they uncovered ee values evenbetter than previously reported. Meanwhile, Eric Jacobsen
attacked the problem from the mechanistic side, and discovered that the ligand-dependent rate accelerations could beenormous.[23]With these very encouraging results on the stoichiometric
reaction just in, Istvan Marko¬ joined the project. I wastraveling at the time, and on his own initiative, unaware of the
NIH proposal, he combined Hentges× system[17] with thereliable Upjohn NMO-based catalytic-osmylation system,[16]immediately getting results indicating the reaction was
catalytic.[24] However, unlike the dramatic ™Eureka!∫ that
accompanied the discovery of the AE, cautious optimism was
the response to the catalytic AD and its initially modest
ee values. Now, however, after years of research since Marko¬×s
first experiments in October of 1987, the AD×s utility rivals
and often surpasses the AE×s.[9] Unlike the AE, for which
2029

REVIEWS
Katsuki×s initial tartrate-ester ligands have yet to be eclipsed,the ligands for the AD have evolved substantially ineffectiveness and scope, through substitution at the C-9hydroxy moiety.
The simple ester derivatives (e.g. the acetate and parachlorobenzoate esters) gave way in 1990 and 1991 to aryl
ether derivatives, first proposed by Yun Gao during a latenight group meeting to address the mechanistic question of a
possible ligating role of the ester carbonyl. Brent Blackburn
made the phenyl ether which, to our surprise, gave goodee values, but was too hard to make to be competitive with thethen dominant para-chlorobenzoate (CLB) ligand.
Almost a year later, Declan Gilheany correctly predictedthat aryl ethers should be better for aliphatic olefins than the
CLB ligand,[25] and these results laid the foundation for asteady expansion of this ligand class, which culminated in thephenanthryl ether ligand.[26] Another big jump in effectivenesscame with the dimeric alkaloid ligands having a phthalazinecore, first made by Jens Hartung in 1990.[27] Along with thepyrimidine ligands[28] whose development they inspired, theyremain the best general ligands for the AD reaction.
The search for better ligands was paralleled by advances incatalyst turnover efficiency:
1) John Wai found both the second-catalytic-cycle problem
and its partial remedy; slow addition of the olefin.[29]2) Since ferricyanide in tert-butanol/water provides an excellent two-phase system for catalytic osmylation,[30] HoiLun Kwong applied it to the AD, which solved the secondcycle problem and the need for slow addition.[31]3) Willi Amberg found that adding organic sulfonamides
greatly facilitates the rate of catalyst turnover for olefins
whose osmate esters resist hydrolysis.[27]As the practicality (it has been scaled up to run in 4000-liter
reactors with no ill effects on yield or ee value[32] ) and scope of
the AD process grew, so did the pressure to understand theorigin of its enantioselectivity. Mechanistic studies datingfrom the 1970s by Alan Teranishi and Jan B‰ckvall[33] were
rekindled by Eric Jacobsen in 1987 and continued into themid-1990s.[34]While a complete and general solution to the geraniol
paradigm×s final challenge is clearly within reach, comparing
selectivity at the bench with selectivity in living systems
remains striking. For example, the squalene monooxygenasein our livers unerringly deposits a single oxygen atom on thesqualene molecule and, in so doing, further chooses only thesi-enantioface of the terminal double bond (Scheme 3).[35] On
the other hand, the attempted AD of a single double bond ofsqualene does give the terminal diol in 96 % ee. The prefer-

Scheme 3. Enzymatic epoxidation of squalene.

2030

K. B Sharplessence for the terminal double bond is slight, however, andinternal diols as well as tetraols also can be isolated from thereaction.[36] Thus, while the AD catalyst cannot match theexquisite selectivity of the enzymic system, this very inability
to discriminate between the six trisubstituted double bonds ofsqualene allows the exhaustive AD of squalene (Scheme 4) inan overall yield of 79.8 % for the AD-! reaction.[37]Scheme 4. Exhaustive, stereoselective dihydroxylations of squalene.

Serial multistep reactions such as these are generally
stymied by Bob Ireland×s ™arithmetic demon∫–the geometricfall in yield in sequential chemical reactions. The AD of eachdouble bond is one step in a procession of six dihydroxylations, each with a chemical and an optical yield, twelve yields
in all. Thus the average yield of each step is (0.798)1/12 or 98 %,which translates to 98 % for each chemical yield, 96 % ee forthe single enantioselective reaction and 96 % de for each of
the five diastereoselective reactions. The high yield of a single
enantiomer from the multiple hydroxylation events requiredto oxidize squalene completely reflects the reliability andselectivity of the AD process. Joel Hawkins× Berkeley lab
kinetically resolved the chiral fullerene C76 , which resulted in
the first enantiomerically pure allotrope of carbon, the AD×s
most intriguing use to date.[38]My decision, nearly 25 years ago, to study the selective
oxidation of olefins produced an unexpected bonus, one thatgave me an opportunity to investigate uncharted territory on ascale that is more associated with the previous half-century
than with our own. Selenium, titanium/alkyl peroxides, andosmium, my three most successful olefin oxidation catalysts,
all had phobias associated with them, with the result thatmuch of their chemistry remained terra incognito. Selenium
and osmium were considered highly toxic, and the peroxide
oxidants used with titanium had a nasty reputation. Rarely did
I find myself in another chemist×s territory; likewise, few
wanted to cast a line in mine.
Tracking these elements offers a rather curious way to view
my research. Figure 2 a plots the time course of theirAngew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

Asymmetric Oxidation

REVIEWS

directing research (an oxymoron
perhaps?); indeed, some of you
flourished. Others were not wellserved, and to you I sincerely apologize. I×m exceedingly proud of the
MIT undergraduates who got theirfeet wet in my lab and now holdleading academic and industrial
positions: remember you got youropportunities because Tom Spencer
gave me mine, and I expect you to
Figure 2. a) Selenium, titanium, and osmium chemistry; note the osmium line×s bimodality. b) Growth ofdothe same. Mentioning Tom
catalysis in my laboratory. n " number of publications; P " percentage of publications.
brings me back, as so many things
do, to E. E. van Tamelen: the bright
flashes of his career remain of the first magnitude and still
dominance (as measured by publications, for want of a more
inspire me. And finally, my scientific career would have been
qualitative ruler) during the years 1970 ± 1993. Selenium cameunthinkable without the constant support and counsel of myfirst, flourished, then ended abruptly. Osmium research came
wife, best friend–and ghost writer–Jan.
next, coexisting with selenium until both were eclipsed by
I also thank the National Institute of General Medical Sciences,titanium, the descendant of molybdenum and vanadium.
National Institutes of Health (GM-28384) and the National
Osmium made a strong comeback, knocking off titanium.
Science Foundation for their continuous financial support overFigure 2 b, which charts my research with respect tothe past 25 years and, more recently, the W. M. Keckcatalytic transformations, looks quite unlike Figure 2 a, but
Foundation and the Skaggs Institute for Chemical Biology
relates directly to it. As my involvement with catalysis grew,for helping to make possible my present tenure at The Scripps
the largely stoichiometric selenium reagents lost their appeal;
Research Institute in La Jolla.
titanium fell because the effectiveness of the titanium catalyst
for the AE is modest, with about only 20 turnovers per
Received: March 12, 2002 [A 524]
titanium center before all activity is lost. Osmium, despite abimodal presentation, was never actually out of the picture,
merely quiescent until the discovery of the highly catalytic
AD (it has been run to completion with as little as 1/50,000 of[1] W. S. Johnson, Tetrahedron 1991, 47, XI.
osmium catalyst).
[2] H. B. Henbest, R. A. L. Wilson, J. Chem. Soc. 1957, 1958.
In Figure 2 b, the only real defection from the steady growth[3] K. B. Sharpless, R. C. Michaelson, J. Am. Chem. Soc. 1973, 95, 6136.
[4] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974.
of catalysis to dominion in my research was the 1982 trough[5] a) David Xu synthesized 4 and ent-4 in 1991 during his work on thecaused by the hexose synthesis collaboration with Sat
AD mechanism, from which synthesis of 3 and ent-3 was implicit; twoMasamune. Stepping out of the realm of catalysis is almost
other groups reported this reaction sequence: b) E. J. Corey, M. C.
unimaginable to me now.
Noe, W. C. Shieh, Tetrahedron Lett. 1993, 34, 5995; c) G. Vidari, A.
Dapiaggi, G. Zanoni, L. Garlaschelli, Tetrahedron Lett. 1993, 34, 6485;
Because of its unique potential for channeling a reactiond) G. Vidari, A. Giori, A. Dapiaggi, G. Lanfranchi, Tetrahedron Lett.
sequence along one of myriad possible pathways, selective
1993, 34, 6925. Gerry Crispino×s juvenile hormone III synthesis
catalysis lies at the heart of both pure and applied chemistry,
demonstrates the same conversion: e) G. A. Crispino, K. B. Sharpless,not to mention life chemistry. In addition to the selectivity
Synthesis 1993, 8, 777.
benefits of catalysis, the phenomenon of turnover (which[6] a) W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am.
Chem. Soc. 1990, 112, 2801; b) R. Irie, K. Noda, Y. Ito, N. Matsumoto,equals amplification), implicit in the definition, highly leverT. Katsuki, Tetrahedron Lett. 1990, 31, 7345.
ages its potential impact. For all these reasons, catalysis was[7] a) W. S. Knowles, M. J. Sabacky, J. Chem. Soc. Chem. Commun. 1968,
and continues to be the engine driving my research.
1445; b) T. P. Dang, H. B. Kagan, J. Chem. Soc. Chem. Commun. 1971,
Nature×s enzymes made it possible to imagine simpler
481; c) W. S. Knowles, M. J. Sabacky, B. D. Vineyard, D. J. Weinkauv,
J. Am. Chem. Soc. 1975, 97, 2567; d) See his excellent review: J.
asymmetric catalysts. What we found, however, was unimaHalpern, Science 1982, 217, 401; e) A. Miyashita, A. Yasuda, H.
ginable on two scores: small, highly enantioselective catalysts
Takaya, K. Toriumi, T. Ito, T. Souchi, R. Noyori, J. Am. Chem. Soc.
that were not only not fettered by nature×s ™lock-and-key∫
1980, 102, 7932.
modus operandi, but tolerant as well of substrates throughout[8] a) H. Takaya, T. Ohta in Catalytic Asymmetric Synthesis (Ed.: I.
the entire range of olefin substitution patterns. Now, going on
Ojima), VCH, Weinheim, 1993, p. 1; b) H. Kumobayashi, S. Akutagawa, S. Otsuka, J. Am. Chem. Soc. 1978, 100, 3949; c) S. Akutagawa,
four decades later, I am still plumbing the vastness of theK. Tani in Catalytic Asymmetric Synthesis (Ed.: I. Ojima,) VCH,
Periodic Table in search of new catalytic reactivity. The
Weinheim, 1993, p. 41. A history and review of the development of theunpredictability and rarity of what I seek are not deterrents
asymmetric hydrogen migration of allylamines can be found in: d) S.
since I am, after all, the product of optimistic times. There are
Otsuka, K. Tani, Synthesis 1991, 665.
[9] For review chapters on both the AE and AD, written largely by Royother coelacanths to be found!
Above all I thank and express my deep gratitude to my pastand present co-workers at MIT, Stanford and The Scripps
Research Institute. Many of you learned to tolerate my style ofAngew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

Johnson despite being coauthored by both of us, see: a) R. A.
Johnson, K. B. Sharpless, in Catalytic Asymmetric Synthesis (Ed.: I.
Ojima) VCH, Weinheim, 1993, p. 101; b) R. A. Johnson, K. B.
Sharpless in Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH,
Weinheim, 1993, p. 227.

2031

REVIEWS[10] E. N. Jacobsen in Catalytic Asymmetric Synthesis, (Ed.: I. Ojima),
VCH, Weinheim, 1993, p. 159.
[11] a) S. Y. Ko, A. W. M. Lee, S. Masamune, L. A. Reed, K. B. Sharpless,
F. J. Walker, Science 1983, 220, 949; b) S. Y. Ko, A. W. M. Lee, S.
Masamune, L. A. Reed, K. B. Sharpless, F. J. Walker, Tetrahedron
1990, 46, 245.
[12] a) K. B. Sharpless, CHEMTECH 1985, 692; b) K. B. Sharpless, Chem.
Br. 1986, 22, 1.
[13] M. G. Finn×s thesis work has appeared in two full papers: a) S. S.
Woodard, M. G. Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113,
106; b) M. G. Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113, 113.
[14] a) R. Criegee, Justus Liebigs Ann. Chem. 1936, 522, 75; b) R. Criegee,
Angew. Chem. 1937, 50, 153; c) R. Criegee, Angew. Chem. 1938, 51,
519; d) R. Criegee, B. Marchand, H. Wannowias, Justus Liebigs Ann.
Chem. 1942, 550, 99.
[15] K. B. Sharpless, K. Akashi, J. Am. Chem. Soc. 1976, 98, 1986.
[16] V. van Rheenen, R. C. Kelly, P. Y. Cha, Tetrahedron Lett. 1976, 1973.
[17] S. G. Hentges, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 4263.
[18] a) M. J. Cleare, P. C. Hydes, W. P. Griffith, M. J. Wright, J. Chem. Soc.
Dalton Trans. 1977, 941; b) W. P. Griffith, A. C. Skapski, K. A. Woode,M. J. Wright, Inorg. Chim. Acta 1978, 31, l413.
[19] Five years later, Bob Hanson made the simple but wonderful
discovery that adding molecular sieves to the reaction dramaticallyincreases catalyst turnover, so that the AE process became truly
catalytic: R. M. Hanson, K. B. Sharpless, J. Org. Chem. 1986, 51, 1922.
[20] Steve Pedersen provided invaluable structural results to aid M. G.
Finn×s studies during this period. Steve×s work gave us our first glimpse
into the dynamic world of complex mixtures in rapid equilibrium witheach other. His contributions are summarized in: K. B. Sharpless,
Chem. Scr. 1987, 27, 521. These studies led to no new catalysts, but theydrove home our appreciation for the absolute need for a ligandacceleration effect in catalyst systems where ligand exchange is rapid.
[21] K. S. Kirshenbaum, Ph. D. Thesis, Massachusetts Institute of Technology, 1985.
[22] C. J. Burns, Ph. D. Thesis, Massachusetts Institute of Technology, 1989.
[23] E. N. Jacobsen, E. I. Marko¬, M. B. France, J. S. Svendsen, K. B.
Sharpless, J. Am. Chem. Soc. 1989, 111, 737.
[24] E. N. Jacobsen, E. I. Marko¬, W. S. Mungall, G. Schrˆder, K. B.
Sharpless, J. Am. Chem. Soc. 1988, 110, 1968.

2032

K. B Sharpless[25] T. Shibata, D. G. Gilheany, B. K. Blackburn, K. B. Sharpless, Tetrahedron Lett. 1990, 31, 3817.
[26] K. B. Sharpless, W. Amberg, M. Beller, H. Chen, J. Hartung, Y.
Kawanami, D. L¸bben, E. Manoury, Y. Ogino, T. Shibata, T. Ukita, J.
Org. Chem. 1991, 56, 4585.
[27] K. B. Sharpless, W. Amberg, Y. Bennani, G. Crispino, J. Hartung, K.
Jeong, H. Kwong, K. Morikawa, Z. M. Wang, D. Xu, X. L. Zhang, J.
Org. Chem. 1992, 57, 2768.
[28] G. Crispino, K. S. Jeong, H. Kolb, Z. M. Wang, D. Xu, K. B. Sharpless,
J. Org. Chem. 1993, 58, 1958.
[29] J. S. M. Wai, I. Marko¬, J. S. Svendsen, M. G. Finn, E. N. Jacobsen, K. B.
Sharpless, J. Am. Chem. Soc. 1989, 111, 1123.
[30] M. Minato, K. Yamamoto, J. Tsuji, J. Org. Chem. 1990, 55, 766.
[31] H. Kwong, C. Sorato, Y. Ogino, H. Chen, K. B. Sharpless, Tetrahedron
Lett. 1990, 31, 2999.
[32] Private communication from Dr. Yun Gao of Sepracor, Inc., Marlborough, MA.
[33] K. B. Sharpless, A. Y. Teranishi, J. E. B‰ckvall, J. Am. Chem. Soc.
1977, 99, 3120.
[34] a) E. N. Jacobsen, E. I. Marko¬, M. B. France, J. S. Svendsen, K. B.
Sharpless, J. Am. Chem. Soc. 1989, 111, 737; b) T. Gˆbel, K. B.
Sharpless, Angew. Chem. 1993, 105, 1823; Angew. Chem. Int. Ed. Engl.
1993, 32, 1329; c) P. O. Norrby, H. Kolb, K. B. Sharpless, Organometallics 1994, 13, 44 ± 47; d) H. C. Kolb, P. G. Andersson, Y. L.
Bennani, G. A. Crispino, K. S. Jeong, H. L. Kwong, K. B. Sharpless, J.
Am. Chem. Soc. 1993, 115, 12 226 ± 12 227; e) H. C. Kolb, P. G.
Andersen, K. B. Sharpless, J. Am. Chem. Soc. 1994, 116, 1278 ± 1291;f) H. L. Kwong, Ph. D. Thesis, Massachusetts Institute of Technology,
1993.
[35] a) R. B. Boar, K. Damps, Tetrahedron Lett. 1974, 3731; b) D. H. R.
Barton, T. R. Jarman, K. G. Watson, D. A. Widdowson, R. B. Boar, K.
Damps, J. Chem. Soc. Chem. Commun. 1974, 861; c) D. H. R. Barton,
T. R. Jarman, K. G. Watson, D. A. Widdowson, R. B. Boar, K. Damps,
J. Chem. Soc. Perkin Trans. 1 1975, 1134.
[36] G. Crispino, K. B. Sharpless, Tetrahedron Lett. 1992, 33, 4273.
[37] G. A. Crispino, P. T. Ho, K. B. Sharpless, Science 1993, 259, 64.
[38] J. M. Hawkins, A. Meyer, Science 1993, 260, 1918.

Angew. Chem. Int. Ed. 2002, 41, 2024 ± 2032

Suzuki Coupling

DOI: 10.1002/anie.201101379

Nobel Review

Cross-Coupling Reactions Of Organoboranes: An Easy
Way To Construct C C Bonds (Nobel Lecture)**Akira Suzuki*
cross-coupling · organoboranes · palladium ·Suzuki coupling

Biography
I was born on September 12, 1930 in Mukawa, a small town in
Hokkaido, Japan. I attended the primary school there andentered secondary school at Tomakomai, where we had oneof the biggest paper companies in Japan. During my highschool, I was interested in mathematics. Consequently, when I
entered Hokkaido University in Sapporo, I was thinking ofstudying it. In the junior course, I became interested inorganic chemistry by reading the book “Textbook of Organic
Chemistry,” written by L. F. Fieser and M. Fieser. Finally, I
decided to major in organic chemistry.
The title of my doctoral thesis was “Synthesis of theModel Compounds of Diterpene Alkaloids”. In the study, I
used organometallic compounds, Grignard reagents, andorganozinc compounds as synthetic intermediates, and I
perceived that such organometallic compounds are interesting and versatile intermediates for organic synthesis. After I
completed the PhD program at the Graduate School of
Science, Hokkaido University, in 1959, I was employed as a
research assistant in the Chemistry Department. In October
1961, after two years and six months, I was invited to become
an assistant professor of the Synthetic Organic Chemistry
Laboratory at the newly founded Synthetic Chemical Engineering Department in the Faculty of Engineering. In April
1973, I succeeded Professor H. Otsuka at the Third Laboratory in the Applied Chemistry Department. In total, I havespent 35 years at Hokkaido University as a staff member—
two and a half years in the Faculty of Science, and anotherthirty-two and a half years in the Faculty of Engineering.
Other than about two years of study in America, and a few
months at other places overseas, most of my life has beenspent at the Faculty of Engineering. Including my nine years
as a student, the majority of my life has been at Hokkaido
University. After my retirement from Hokkaido University in
1994, I joined two private universities in Okayama prefecture—Okayama Science University and Kurashiki Universityof Science and Arts—and I retired from the universities in
2002. In the following I would like to describe a few memories
of my life in chemistry.

trying experiences tend to fade with time. I think now mainly
about the fun things, and I will describe a few memories that I
have from my work.
It was on a Saturday afternoon in 1962. I visited the
Maruzen bookstore in Sapporo. As I browsed the chemistry
books, I discovered a very unacademic looking volume, boundin red and black. This book was Hydroboration by H. C.
Brown, the 1979 Nobel Laureate in Chemistry. I took thebook in my hands, and began looking through its pages to findwords written in Professor Browns unique style. I purchased
the book and returned home. I can still remember clearly how
I picked it up after dinner that evening, and could not put it
down. It is not very long, but it remains as one of the few
scholarly books which I have stayed up all night to read. At
the time, I had just transferred to the Faculty of Engineeringfrom Science, and I wanted to begin research in a new area at
my new workplace. This is perhaps one reason why this book
had such an impact on me.
Inspired by this experience, I went to Purdue University inIndiana in the August of 1963 (Figure 1) and spent almost two
years at Professor Browns laboratory researching the newly
discovered hydroboration reaction as a postdoctoral research
associate (Figure 2). It was my first time in a foreign country,
and one of the things that left an impression on me was thestrength that America had at that time. For instance, one
American dollar was worth 360 yen. My monthly salary as adoctoral researcher was four times what I received even as an
assistant professor in Japan. There was little difference in thefood between the rich and the poor. There were many suchthings that I found that were unimaginable in Japan. Purdue
University has a strong relationship with Hokkaido University. In the past, the former president of the university,
Professor S. Ito, had studied at Purdue. Professor S. Nomachi
and Professor T. Sakuma were at Purdue at the same time as I
was.
From Professor Brown I learned many things, including
his philosophy towards research, but there is one thing he said
that I can recall with clarity: “Do research that will be in the
textbooks”. It is not easy to do this kind of work, but this hasremained my motto. Professor Brown was 51 years old, and heProfessor Herbert C. Brown and Purdue University[*] Prof. A. Suzuki
Hokkaido University
Sapporo, Hokkaido (Japan)

As I reflect on these long years, I see that there were manydifficult periods as well as joyful ones. Memories of the tough,[**] Copyright The Nobel Foundation 2010. We thank the Nobel
Foundation, Stockholm, for permission to print this lecture.

Angew. Chem. Int. Ed. 2011, 50

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Nobel Lectures

A. Suzuki

Figure 3. With Professor and Mrs. Brown at their home in IN (USA),
June 1995.

an advantage in some cases. For example, we could use thesecompounds in the presence of water without any special care.
I decided that there might be some way to use thesecompounds in organic reactions, and I created a new researchplan upon my return to Japan in April 1965 (Figure 4).
Figure 1. Leaving Tokyo/Haneda Airport for the US, August 1963.

Figure 4. My family, October 1969.
Figure 2. Working at Professor H. C. Brown’s Lab., Purdue Univ.,
August 1964.

was an extremely active researcher. He visited Hokkaido
University three times. I had the opportunity to meet him andMrs. Brown more than ten times (Figure 3), but we missed
them in 2004 and 2005, unfortunately.
Hydroboration is the reaction of alkenes with borane to
produce organic boron compounds. These boron compounds
differ from other organometallic compounds: they are chemically inactive, particularly in ionic reactions. For example,
organic boron compounds are stable in the presence of waterand alcohol, and do not undergo Grignard-type reactions.
Therefore, it was thought that such compounds would be
unsuitable as synthetic intermediates. Between 1963 and 1965,
when I was at Purdue, there were more than 30 doctoral
researchers and graduate students from all over the world in
the Brown Lab. Many of these friends shared the opinion thatthe boron compounds were inactive. In contrast, I thoughtthat the stable character of organoboron compounds could be
www.angewandte.org

Discovery of Alkyl Radical Formation from R3B
At the time, I focused on three characteristics of organoboron
compounds. First, compared to other organometallic compounds, the difference in the electronegativity of the C B
bond is small, meaning that it is an almost perfect covalentbond. Second, the boron atom has an open p-electron
structure, meaning that it might be susceptible to nucleophilic
reagents. This suggested that the compounds might undergo
reactions as shown in Equation (a). Third, studies of the C B

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Angew. Chem. Int. Ed. 2011, 50

Suzuki Couplingbonding distance showed that it was almost equal to the C C
bonding distance.
In consideration of these three points, I decided to study
the reaction of organic boron compounds with a,b-unsaturated ketones. In other words, I hypothesized that intermediate (I) in Equation (b) would be obtained through aquasihexagonal transition state, which would be hydrolyzed
to give a saturated ketone. When we examined methyl vinyl
ketone in the reaction, we found that the predicted corresponding saturated ketone was produced in a quantitative
yield [Eq. (b)]. We obtained these results in 1966, and I
notified Professor Brown of our findings in a letter, and he
was extremely interested. He told us that he wanted to
explore the results at Purdue as well. I supported his proposal,
and we continued to study a,b-unsaturated ketones at
Hokkaido, while a,b-unsaturated aldehydes would be investigated at Purdue. We analyzed the scope of the reaction, andtried several types of a,b-unsaturated ketone reactions andfound that each produced favorable amounts of the corresponding saturated ketones at room temperature. Although
we discovered that compounds with a substituent in theb position, such as compounds II, would not react at room
temperature, we found that the expected proportions of
products could be formed in THF (tetrahydrofuran) solution
at reflux temperature. I received a letter from G. Kabalka(now professor at the University of Tennessee), who was thena graduate student doing related research at Purdue. According to the letter, something similar was found for a,bunsaturated aldehydes. None of the corresponding saturated
aldehydes were produced by the reaction of compounds suchas III, which had a substitution group in the b position, eventhough many similar compounds such as acrolein reacted
easily at room temperature. I proposed that each laboratory
confirm the results of the other, and we began experiments on
III and found that the reaction proceeded in THF at reflux
temperature. However, subsequent experiments at the Brown
lab did not find that our reaction occurred. I remember asentence in the letter I received from Professor Brown
reporting their results. “Chemistry should be international.
Why do we have such a big difference between two places,
Sapporo, Japan, and West Lafayette, USA?”
When we looked more closely at these contradictory
results, we discovered something quite unexpected. A trace
amount of oxygen contaminating in the nitrogen gas we usedin our reaction system was catalyzing the reaction. At thetime, we knew that organoboron compounds reacted withoxygen, so both we and the Brown Lab conducted thereactions in nitrogen gas. In our laboratory, we used nitrogen
Angew. Chem. Int. Ed. 2011, 50

purchased from Hokkai Sanso (now called Air Water Inc.),
which we further purified. Nevertheless, trace amounts ofoxygen were still present in our nitrogen gas. The oxygen
acted as a catalyst and promoted the reaction. In the USA,
extremely pure nitrogen could easily be purchased in thosedays, and the nitrogen gas did not contain sufficient amountsof oxygen to cause the reaction.
From such unexpected results, we found that with small
amounts of oxygen catalyst, organoboron compounds would
produce alkyl radicals. Furthermore, the reaction followed
the radical chain mechanism as shown in Equation (c), rather
than the coordination mechanism that we had inferredpreviously [Eq. (b)].

Serendipity
One often hears lately of the idea of “serendipity” in research.
Serendipity refers to the capability to discover the crucial andessential components from unexpected phenomena. I believethat any researcher has the chance to exhibit serendipity.
However, in order to make the most of such opportunities, a
researcher must have the humility to see nature directly, an
attentiveness that does not let even the dimmest spark escape,and an insatiable appetite for research. Some amount of luck
also matters, but what can be said with certainty is that little
will come of a half-hearted effort.

Quick Publication
In 1970, we were performing experiments to directly produce
carboxylic acid from organoboron compounds. One possibility we explored was to use complexes derived from organoboron compounds and a cyanide ion which react with protonic
acids. We were not able to obtain our intended result, but we
discovered that these cyano complexes could produce symmetrical ketones in good yield when reacted with electrophilic
reagents like benzoyl chloride. Nonetheless, I was busy
preparing for a presentation at an international conference
to be held in Moscow in 1971, and we left for the conference
without finishing our paper on it. After I had successfully
given my invited lecture, I left the lecture hall to quench mythirst with a glass of water. At that time, a tall foreign man
introduced himself to me. That man was Professor A. Pelterof Manchester University in the UK. He later transferred to
the University of Wales, Swansea, and served as the chair of
the Department of Chemistry as well as the Vice-Chancellorof the university. At our first encounter in Moscow, I had no 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Nobel Lectures

A. Suzuki

idea that he was studying organoborane chemistry. We spoke
about many things that day and, to my surprise, I learned that
he had also performed the very research that we had justdone, and had already published his results the previous
month in Chemical Communications. As a result, our work
remains unpublished. Today, that reaction is sometimes called
the Pelter reaction. Knowing about our situation, Professor
Pelter sympathized with us and consoled us, but no one elseknew anything about it. We learned from it. When doing
research, we must keep three things in mind. First, we muststudy the existing literature carefully and comprehensively.
Second, we need to be aware that other researchers, near andfar, are thinking about the same things that we are. Third, wemust quickly publish papers on our results (not just oralpresentations).

Tragic Accident
Thinking back on that conference—the International Conference on Organo-Metallic Chemistry in Moscow 1971—I
cannot help but think of the tragic accident, in which an
ANA passenger jet collided with a Japan Self-Defense Forceaircraft in the skies above Shizuku-ishi in Iwate prefecture.
On that day, I had flown from Sapporo/Chitose to Tokyo/
Haneda to stay for one night before boarding an Aeroflot
plane to Moscow the next day. I flew on a Japan Airlines flightin the afternoon, with no idea that the plane that departed
only thirty minutes earlier would be involved in such a terrible
accident. Knowing nothing of the tragedy, I landed in Haneda,
and headed to the Haneda Tokyu Hotel near the Airport, andthen learned of the accident. All passengers and crew, 162
persons, were killed.

Haloboration Reaction
Thereafter, our group carried out research on the synthesis oforganic compounds through haloboration. I had one memory
from this that I will reflect upon. This research was based on
the discovery that a certain type of haloborane derivative
adds to terminal carbon–carbon triple bonds. This reaction
was discovered in 1981, but we first disclosed part of thisresearch in the United States in 1982. That fall, the American
Chemical Society hosted a symposium in Midland, Michigan,on organic synthesis involving organoboron compounds. I was
one of the special invited speakers, and was preparing totravel to the US when I received a letter from Professor
Brown. It was an invitation to visit Purdue to give a lecture
before the symposium. The topic of that lecture was
haloboration. Professor Brown listened to my presentation
intently, and raised his hand to comment the moment I
finished speaking. He said that his group had studied thepossibility and usefulness of the same reaction at almost thesame time as we had. They had looked at haloboration
reactions for acetylene compounds, but they had only looked
at reactions of the internal acetylenes as substrates. Theirwork was unsuccessful, and they ended the research. The
goddess of fortune is capricious, indeed.
www.angewandte.org

Over many long years, I have had many different
experiences. I have encountered many friends at the Facultyof Engineering, Hokkaido University, especially among manyof the people who continue to work at the Third Laboratoryof the Applied Chemistry Department, and the Organic
Synthetic Chemistry Laboratory in the Synthetic Chemical
Engineering Department. They have allowed me to enjoy along career in research. I conclude by expressing my sincere
gratitude to these students and colleagues in research.
I have won several awards for my work, listed below:* The Chemical Society of Japan Award, 1989.
* The Society of Synthetic Organic Chemistry Japan,
Special Award, 2004.
* Japan Academy Award, 2004.
* The Order of the Sacred Treasure, Gold Rays with
Neck Ribbon, 2005.
* P. Karrer Gold Medal, 2009.
* Nobel Prize in Chemistry, 2010.
* The Order of Culture of Japan, 2010.
* H. C. Brown Award of the American Chemical Society,2011.

Nobel Lecture
Introduction
Carbon–carbon bond-formation reactions are important
processes in chemistry, because they provide key steps in thebuilding of complex, bioactive molecules developed as
medicines and agrochemicals. They are also vital in developing the new generation of ingeniously designed organic
materials with novel electronic, optical, or mechanicalproperties, likely to play a significant role in the burgeoning
area of nanotechnology.
During the past 40 years, most important carbon–carbon
bong-forming methodologies have involved using transition
metals to mediate the reactions in a controlled and selective
manner. The palladium-catalyzed cross-coupling reaction
between different types of organoboron compounds andvarious organic electrophiles including halides or triflates in
the presence of base provides a powerful and general
methodology for the formation of carbon–carbon bonds.
The (sp2)C B compounds (such as aryl- and 1-alkenylboron
derivatives) and (sp3)C B compounds (alkylboron compounds) readily cross-couple with organic electrophiles togive coupled products selectively in high yields. Recently, the(sp)C B compounds (1-alkynylboron derivatives) have also
been observed to react with organic electrophiles to produce
the expected cross-coupled products.
Some of representative reactions between various organoboranes and a number of organic electrophiles are shown in
Scheme 1. The numbers in parentheses indicate the year they
were first reported by our group.
Such coupling reactions offer several advantages:(1) ready availability of reactants;(2) mild reaction conditions and high product yields;(3) water stability; 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2011, 50

Suzuki Coupling

tetracoordinate organoboron compounds,
instead of tricoordinate organoboron derivatives. According to the study by Gropen
and Haaland,[2] the methyl group in tetramethylborate was observed to be 5.5 times
more electronegative than the methyl groupin trimethylborane. Such behavior was also
expected for the reaction of triorganoboranes in the presence of base. Thus, we foundthat the reaction of vinylic boron compounds with vinylic halides proceedssmoothly in the presence of a base and acatalytic amount of a palladium complex toprovide the expected conjugated alkadienes
and alkenynes stereo- and regioselectively
in excellent yields (Table 1).
Scheme 1.

(4)easy use of the reaction both under aqueous andheterogeneous conditions;(5) toleration of a broad range of functional groups;(6) high regio- and stereoselectivity;(7) insignificant affect of steric hindrance(8) use of a small amount of catalyst;(9) application in one-pot synthesis;(10) nontoxic reaction;(11) easy separation of inorganic boron compound;(12) environmentally friendly process.

Table 1: Cross-coupling reaction of 1 with 2.

1[a] Cat.[b] (mol %) Base (equiv/2)
1b
1b
1a
1b

PdL4 (3)PdL4 (3)PdL4 (3)PdL4 (1)none
none
2 m NaoEt(2)-EtOH
2 m NaOEt(2)-EtOH

Solventt [h] Yield [%] of 3

THF
benzeneTHF
benzene

6
6
2
2

0
0
73
86

[a] 1 a, X2 = (Sia)2 (Sia = 1,2-dimethylpropyl); 1 b, X2 = catecholate. [b] L =PPh3.

As one of the defects of the reaction, one would point out
the use of bases. However, the difficulty can be overcome byusing suitable solvent systems and adequate bases. Consequently, these coupling reactions have been actively utilized
not only in academic laboratories but also in industrial
processes.

Coupling Reactions of (sp2)C B Compounds
Reactions of Vinylic Boron Compounds with Vinylic Halides
Synthesis of Conjugated Alkadienes
Cross-coupling reactions between vinylic boranes andvinylic halides were not reported to proceed smoothly in thepresence of only palladium catalysts. During the initial stageof our exploration, we postulated that a drawback of thecoupling is caused by the following aspects of the mechanism.
The common mechanism of transition-metal-catalyzed coupling reactions of organometallic compounds with organic
halides involves sequential a) oxidative addition, b) transmetalation, and c) reductive elimination.[1] It appeared that
one of the major reasons that 1-alkenylboranes cannot reactwith 1-alkenyl halides is step (b). The transmetalation process
between RMX (M = transition metal, X = halogen) andorganoboranes does not occur readily because of the weak
carbanion character of the organic groups in the organoboranes. To overcome this difficulty we anticipated the use ofAngew. Chem. Int. Ed. 2011, 50

Although the coupling reaction of (E)-1-alkenylboranes,
readily obtained by the hydroboration of appropriate alkynes
with disiamylborane or dicyclohexylborane, proceeds readily
with (E)- and (Z)-1-alkenyl bromides and iodides to give thecorresponding dienes (Table 2), (Z)-1-alkenylboranes, prepared by hydroboration of 1-haloalkynes followed by reaction
with tert-butyllithium, gave low product yields, near 50 %(Table 3).
Fortunately, it was found that high yields and highstereoselectivity could be achieved by coupling (Z)-1-alkenyl
halides with (Z)-1-alkenyldialkoxyboranes, instead of disiamyl- and dicyclohexylborane derivatives (Table 3).[3] Consequently, the cross-coupling reaction of 1-alkenylboranes
with 1-alkenyl halides can be achieved readily for the
Table 2: Cross-coupling reaction of (E)-1-vinyldisiamylboranes.[a]1-Alkenylborane

1-Alkenylbromide

Product

Yield [%]
(purity [%])
86 (98)88 (99)89 (98)[a] Reaction conditions: [Pd(PPh3)4], NaOEt, benzene, reflux, 2 h.

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Nobel Lectures

A. Suzuki

Table 3: Cross-coupling of (Z)-1-hexenyldisiamyl- or (Z)-1-hexenyldiisopropoxyborane.

BY2 in 4

Yield [%] of 5

Purity [%] of 5

B(Sia)2
B(OiPr)2

49
87

> 98
> 99

synthesis of all kinds of conjugated alkadienes. The reaction
has been applied to the synthesis of many natural andunnatural compounds which have conjugated alkadiene
structures.[4–7] Among the many synthetic applications of the
Suzuki coupling reaction for conjugated alkadienes, the total
synthesis of palytoxin (Scheme 2), a complex and toxic
natural product, is an epoch-making contribution.[8] As
another example, the total synthesis of lucilactaene is shownin Scheme 3.[9]Mechanism of the Vinylic-Vinylic Cross-Coupling
The principal features of the cross-coupling reaction are
as follows: a) Small catalytic amounts of the palladium
complexes (1–3 mol %) are required to obtain the coupled
products. b) The coupling reactions are highly regio- andstereoselective and take place while retaining the original
configurations of both the starting alkenylboranes and thehaloalkenes. The isomeric purity of the products generally
exceeds 98 %. c) A base is required to carry out a successful
coupling. In the initial stage of the study, as mentioned
previously, we considered that tetracoordinate organoboron
compounds facilitate the transfer of organic groups from theboron to the palladium complex in the transmetalation step.
In order to check this possibility, the reaction of lithium (1hexenyl)methyldisiamylborate was examined, as shown inEquation (1). The coupled product, however, was obtained
only in 9 % yield. On the other hand, it was found that(trichlorovinyl)palladium(II) complexes 6 and 9, both prepared as pure solids, reacted with vinylborane 7 to give diene
8 [Eqs. (2) and (3)]. In the case of 6, no reaction occurs
without a base, whereas the coupling reaction proceeds

Scheme 2. Synthesis of palytoxin.

smoothly in the presence of a base to give the coupled productin 89 % yield. The intermediate 9 readily reacts with 7 withouta base to provide the same product 8 in almost quantitative
yield after 1 h. Consequently, such evidence suggests thatvinylic alkoxypalladium(II) compounds such as 9 werenecessary intermediates in these cross-coupling reactions.
Accordingly, it is considered that the reaction proceeds
through the catalytic cycle shown in Scheme 4.[10]Reactions with Aryl Halides

Scheme 3. Synthesis of lucilactaene.

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As described in the previous section, it was discoveredthat vinylic boron compounds readily react with vinylic
halides to give coupled products—conjugated alkadienes.
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Angew. Chem. Int. Ed. 2011, 50

Suzuki Coupling

Table 5: Coupling of 1-alkenylboranes with various organic halides.
1-Alkenylborane

HalideProduct[a]Yield [%]

Phl

100

PhBr

98

PhCl

3
100

87

83
Scheme 4. Catalytic cycle for the coupling reaction of alkenylboranes
with haloalkenes.

We next attempted to examine the reaction of 1-alkenylboranes with haloarenes which also have sp2-hybridized carbon–
halogen bonds, and found that the reaction takes placesmoothly. Representative results are shown in Table 4.

Table 4: Cross-coupling reaction of 10 with iodobenzene.

Base

t [h]

Yield [%]

Ratio of 11/12

none
NaOEt
NaOMe
NaOH

6
2
2
2

0
100
100
100

100:0
100:0
100:0

This reaction has one more advantage that only one
product 11 (head-to-head coupled product) is formed. Additional coupling reactions of vinylic boranes are shown in
Table 5. Aromatic bromides and iodides easily react withvinylic boron compounds, but aromatic chlorides do notparticipate in the coupling, except reactive chlorides, such as
allylic and benzylic derivatives. Heteroaromatic halides canalso be used as coupling partners. Ortho substituents on thebenzene ring do not give difficulty. Thus, the cross-coupling
reaction can be used for the synthesis of benzo-fused
heteroaromatic compounds [Eq. (4)].[11]Angew. Chem. Int. Ed. 2011, 50

89
PhCH2Br

97

BrCCPh93

BrCCHex

95[a] Isomeric purity > 98 %.

Aromatic Boron Compounds
Reactions with Aromatic Halides
Synthesis of Biaryls
The coupling of aryl halides with copper at very hightemperature is called the Ullmann reaction, which is of broad
scope and has been used to prepare many symmetrical biaryls.
However, when a mixture of two different aryl halides is used,
there are three possible biaryl products. Consequently, thedevelopment of a selective and general synthesis of all kindsof biaryls has been desired.
The first method to prepare biaryls by the cross-couplingof aryl boranes with haloarenes was reported in 1981
[Eq. (5)].[12] The reaction proceeds even under heterogeneousconditions to give the corresponding coupled products
selectively in high yields. Since this discovery, various
modifications have been made to the reaction conditions.
As the bases, Na2CO3, NaHCO3, Tl2CO3, K3PO4, etc. are
employed. In some cases, CsF or Bu4NF can be used instead of
the usual bases [Eq. (6)].[13] Phosphine-based palladium 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Nobel Lectures

A. Suzuki

catalysts are generally employed since they are stable toprolonged heating; however, extremely high coupling reaction rates can sometimes be achieved by using palladiumcatalysts without a phosphine ligand, such as Pd(OAc)2, [{(h3C3H5)PdCl}2], and [Pd2(dba)3].
Carbon–carbon bond-forming reactions employing organoboron compounds and organic electrophiles have been
recently recognized as powerful tools for the construction of
new organic compounds. Among such reactions, aromatic–aromatic (or heteroaromatic) couplings between aromaticboronic acids or esters and aromatic electrophiles to provide
symmetrical and unsymmetrical biaryls selectively in highyields have been used most frequently. The importance ofbiaryl units as components in many kinds of compounds,
pharmaceuticals, herbicides, and natural products, as well as
engineering materials, such as conducting polymers, molecular wires, and liquid crystals, has attracted enormous interest
from the chemical community. Such aromatic–aromatic,aromatic–heteroaromatic, and heteroaromatic–heteroaromatic coupling reaction have been recently reviewed indetail.[14]Coupling of Aryl Boronic Acid Derivatives Having Highly StericallyHindered or Electron-Withdrawing Functionalities
Although steric hindrance of aryl halides is not a major
factor in the formation of substituted biaryls, low yields result
when ortho-disubstituted aryl boronic acids are used. For
example, the reaction with mesitylboronic acid proceeds only
slowly because of steric hindrance during the transmetalation
to the palladium(II) complex. The reaction of mesitylboronic
acids with iodobenzene at 80 8C in the present of [Pd(PPh3)4]
and various bases has been reported.[15] The results are
summarized in Table 6.

DME. On the other hand, the addition of stronger bases, e.g.,aqueous NaOH or Ba(OH)2, both in benzene and DME,
exerts a remarkable effect on the acceleration rate of thecoupling. By using aqueous Ba(OH)2 in DME at 80 8C,
mesitylboronic acid couples with iodobenzene within 4 h togive the corresponding biaryl in a quantitative yield. Somesuch coupling reactions are depicted in Equations (7) and (8).

An alternative procedure, using the esters of boronic acids
and anhydrous base, has been developed for stericallyhindered aryl boronic acids and provide high yields. The
coupling can be readily achieved by using the trimethylene
glycol ester of mesitylboronic acid and Cs2CO3 or K3PO4 in
DMF at 100 8C to give a quantitative yield of the coupled
products [Eq. (9)].[15]Table 6: Reaction of mesitylboronic acid with iodobenzene under
different conditions.

Base

Solvent

T [8C]
8h

Na2CO3
Na2CO3K3PO4NaOH
Ba(OH)2

benzene/H2O
DME/H2O
DME/H2O
DME/H2O
DME/H2O

80
80
80
80
80

25 (6)
50 (1)
70 (0)
95 (2)
99 (2)

Yield [%][a]
24 h

48 h

77 (12)66 (2)

84 (25)83 (7)[a] GLC yields of the coupling product based on iodobenzene; the yieldsof mesitylene are shown in parentheses.

Aqueous Na2CO3 in benzene or DME (dimethoxyethane)
is not effective as a base for the coupling of mesitylboronic
acid and the reaction is not completed even after two days.
Although the side reactions such as homocoupling are
negligibly small, the formation of mesitylene by hydrolytic
deboronation was observed, increasing with the reaction time.
It is noteworthy that such hydrolytic deboronation is faster inbenzene/H2O than in the modified conditions of aqueous
www.angewandte.org

Even without sterically hindered substrates, the reaction
under aqueous conditions is often undesirable because ofcompetitive hydrolytic deboronation. A kinetic study[16] into
the reaction of substituted aryl boronic acids showed thatelectron-withdrawing substituents accelerate the deboronation. Although there is no large difference between meta- andpara-substituted phenylboronic acids, substituents at theortho position may greatly increase the rate of deboronation.
For example, a 2-formyl group on aryl boronic acids is known
to accelerate the rate of hydrolytic deboronation.[16] Indeed,
the coupling of 2-formylphenylboronic acid with 2-iodotoluene at 80 8C using Na2CO3 in DME/H2O gives only a 54 %yield of the corresponding biaryl, with accompanying benzaldehyde (39 %). Aprotic conditions are desirable for suchboronic acids that are sensitive to aqueous base. Thus, thetrimethylene glycol ester of 2-formylphenylboronic acid 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2011, 50

Suzuki Coupling

readily couples with iodobenzene at 100 8C in DMF to givethe coupled product in a yield of 89 %, with less than 10 %benzaldehyde formed [Eq. (10)].[15]Table 8: Suzuki couplings of unactivated acryl chlorides.

Aryl chloride

Boronic acid

Product

T [8C] Yield
[%]
70

88

100

75

Recently, Buchwald et al. reported interesting catalysts
and ligands for the preparation of tetra-ortho-substituted
unsymmetrical biaryls.[17] Among the biphenyl-based ligands
tested, 14 gave excellent results, whereas significant amountsof aryl bromide reduction were observed when the ligands 13
were used (Table 7).

Table 7: Ligand effects in the coupling of hindered substrates.

LigandConv [%]

Biaryl [%]Biaryl/ArH

13 a
13 b
13 c
14

47
20
74
100

33
10
40
91

2.3
0.9
1.9
10

Coupling with Aromatic Chlorides
In aromatic–aromatic cross-coupling reactions, cheap andreadily accessible aryl chlorides are particularly importantfrom an industrial viewpoint as starting materials. Recently
some research groups, especially Fus group[18] and Buchwalds group[19] have reported very efficient methods for thereaction of aryl chlorides. For example, Fu and co-workers[18]have observed that the use of [Pd2(dba)3]/PtBu3 as the catalyst
and ligand result in a wide range of aryl and vinyl halides,
including chlorides, undergoing Suzuki cross-coupling witharyl boronic acids in very good yield, typically at room
temperature (Table 8). Furthermore, these catalysts display
novel reactivity patterns, such as the selective coupling in thepresence of [Pd2(dba)3]/PCy3/KF of a sterically hinderedaromatic chloride [Eq. (11)].
Despite the generally good yields in many Suzuki
reactions of chloroarenes, comparatively large amounts ofcatalyst are required. Beller et al. reported a new catalyst
Angew. Chem. Int. Ed. 2011, 50

system, with which they achieved the coupling of nonactivated and deactivated aryl chlorides highly efficiently ingood yields with generally only 0.005 mol % palladium, andthus under the industrially allowed level.[20] For instance, as a
new efficient catalyst system, they used diadamantyl-nbutylphosphane (BuPAd2) as a ligand and found that itproved to be extremely reactive. A typical example is shownin Equation (12).

Applications in the Synthesis of Biaryls
The anti-HIV alkaloids michellamine A (17) and B (18)have been synthesized. The tetraaryl skeleton of the michellamines was constructed by formation, first, of the inner(nonstereogenic) biaryl axis and subsequently of the twoother (stereogenic) axes by using a double Suzuki-type crosscoupling reaction between the dinaphthalene ditriflate 15 andisoquinolineboronic acid 16 [Eq. (13)].[21]The discovery and development of penicillin and otherantibacterial agents as drugs to fight infectious diseases weremilestone victories of humankind over bacteria. While theseagents saved millions of lives, they did not tame bacteria. On
the contrary, this war led to the emergence of newer andmore-dangerous bacterial strains that responded defiantly
against known antibacterial agents. Vancomycin is a memberof the polycyclic glycopeptide class of antibiotics and has
proved to be the last line of defense against drug-resistantbacteria. The daunting synthetic challenge posed by its
structure is largely due to the strained nature of the 12membered biaryl framework (AB ring system) and the two
16-membered biaryl ethers (COD and COE ring systems).

 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

Nobel Lectures

A. Suzuki

Nicolaou and his group reported a Suzuki coupling approachto the AB-COD bicyclic system of vancomycin.[22] Suzuki
coupling of iodide 19 with 20 was facilitated by a [Pd(Ph3)4]
catalyst and Na2CO3 to give a 1:1 mixture of the two
atropisomers 21 a and 21 b in 80 % combined yield[Eq. (14)]. The coupling of the parent boronic acid corresponding to 20 (without methyl groups) with iodide 19 led to asingle compound. Thereafter, the total synthesis of thevancomycin aglycon was reported by the same workers.[23]Solid-Phase Synthesis (Combinatorial Methodology)

The novel compound tetrakis(phenothiazinylphenyl)methane (23), showing remarkably large Stokes shift and areversible low oxidation potential, can be prepared in a goodyield by Suzuki coupling of tetrakis(p-bromophenyl)methane[22; Eq. (15)].[24]Oligothiophene-functionalized 9,9-spirobifluorene derivatives have been synthesized in high yields by Suzuki
coupling. The Negishi coupling reaction between oligothienylzinc chloride and various 9,9’-spirobifluorene bromides
with [Pd(PPh3)4] as the catalyst successfully produce thedesired compounds. However, the Negishi coupling provided
low yields, compared to the Suzuki coupling [Eq. (16)].[25]www.angewandte.org

Solid-phase reactions play an important role in parallel
synthesis and combinatorial chemistry, particularly in the areaof medicinal chemistry, where their potential has emerged asa result of the possibility of automation. A considerable
amount of attention has been focused on adapting andexploiting the advantage of solid-phase synthesis (SPS) forthe production of libraries of such organic compounds. In thiscontext, transition-metal-promoted reactions serve as efficient methods because they proceed under mild conditions
and are compatible with many functional groups. For instance,solid-phase Suzuki coupling has largely been developed by
the reaction of a resin-bound aryl halide with solution-phaseboronic acids.[14] Recently, the viability of solid-supported
boronic acids as reagents for Suzuki couplings was successfully demonstrated.[26]Applications in Polymer Chemistry
Aromatic, rigid-rod polymers play an important role in a
number of diverse technologies including high-performanceengineering materials, conducting polymers, and nonlinear
optical materials. The Suzuki polycondensation (SPC) reac- 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2011, 50

Suzuki Couplingtion of aryl diboronic acids and dihaloarenes for the synthesisof poly(p-phenylenes) was first reported by Schlter et al.[27]
SPC is a step-growth polymerization of bifunctional aromatic
monomers to poly(arene)s and related polymers(Scheme 5).[28] The required functional groups—boronic
acids or esters on one side, and bromide, iodide, and soforth on the other—may be present in different monomers(AA/BB approach) or combined in the same monomer (ABapproach).

synthetic utility of alkyl zinc compounds by the use of apalladium catalyst. Thereafter, alkyl lithium, tin, and aluminum reagents were also employed for such cross-coupling
reactions. The reaction of alkyl borane derivatives is particularly useful when one wishes to start from alkenes via
hydroboration. Consequently, we intended to examine thecoupling reactions between alkyl boron compounds andvarious organic halides in the presence of a base and apalladium complex, and found that no cross-coupling reactions of B-alkyl-9-borabicyclo[3.3.1]nonanes (B-R-9-BBN),
readily obtainable from alkenes by hydroboration, with 1halo-1-alkenes or haroarenes occurred under the standard
coupling conditions using [Pd(PPh3)4] as a catalyst, but the
coupling proceeds smoothly by using a catalytic amount of[PdCl2(dppf)] and bases, such as NaOH, K2CO3, and K3PO4 togive the corresponding substituted alkenes or arenes in
excellent yields [Eq. (18)].[30, 31] Because the reaction is

Scheme 5. Graphical representation of the Suzuki polycondensation

The method was extensively applied to monodisperse
aromatic dendrimers, water-soluble poly(p-phenylene),planar poly(p-phenylenes) with fixed ketoimine bonds, poly(phenylenes) fused with polycyclic aromatics, and nonlinear
optical materials.[14] One such application is shown inEquation (17).[29]tolerant of a variety of functionalities on either coupling
partner, stereochemically pure functionalized alkenes andarenes can be obtained under mild conditions [Eq. (19)]. The
utility of the reaction was demonstrated by the stereoselective
synthesis of 1,5-alkadienes (26) [Eq. (20)] and the extensionof a side chain in steroid 27 [Eq. (21)].[30, 31]

Coupling Reactions of (sp3)C B Compounds
Although organometallic reagents with 1-alkenyl, 1alkynyl, and aryl groups were successfully used for the
coupling reactions, those with alkyl groups having sp3 carbons
with b hydrogens were severely limited due to the competitiveside reactions. In 1971–1972 Kochi, Kumada, and Corriu
reported independently that the reaction of alkyl Grignard
reagents with alkenyl or aryl halides are markedly catalyzed
by FeIII or NiII complexes, and then Negishi demonstrated theAngew. Chem. Int. Ed. 2011, 50

Many chemists applied such a Suzuki coupling reaction byusing B-saturated alkylboron compounds. For instance,
Danishefsky et al. reported a total synthesis of the promising
anticancer agent ( )-epothilone B by using the coupling
method [Eq. (22)],[32, 33] and a sister compound, epothilone A,
was also synthesized by a similar procedure.[34] A full paper 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

Nobel Lectures

A. Suzuki

dium(0)-catalyzed Suzuki coupling reaction of alkyl boranes
with cyclic enol triflates has been developed by Tachibana
et al.[36] As shown in Equation (23), the cross-coupling
reaction is carried out in the presence of cesium carbonate
as a base and triphenylarsine as a co-ligand in DMF at room
temperature. Further reactions give the expected trans-fusedpolyether.
Base Problems
In cross-coupling reactions of organoboron compounds,
the presence of a base is essential; no reaction occurs withoutbase. On the other hand, there are many organic compounds
that are sensitive to bases. Consequently, the careful use ofbases is required in such cases. For example, Table 9 shows

Table 9: Solvent and base effects on the cross-coupling reaction.[a]Solvent

Base (equiv)

T [8C]t [h]Yield [%]

DMF
DMF
CH3CN
DMF

KOAc (4)
K2CO3 (2)K2CO3 (4)
K3PO4 (4)

50
50
50
50

18
18
18
20

18
64
46
92

[a] Catalyst: [PdCl2(dppf)].

describing the total synthesis of epothilones A and B has
appeared more recently.[35]Marine polyether toxins present challenging synthetic
targets because of their structural complexity and exceptionally potent biological activities. The most critical issue in thesynthesis of these large polyether compounds is the development of synthetic methods for the convergent coupling ofpolyether fragments. Despite recent advantages in the synthesis of medium-sized cyclic ethers, only a few methodologies for the convergent assembly of six-membered polyether structures were reported. A new strategy for thesynthesis of trans-fused polyethers based on the palla-

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that the selection of a base and solvent system provides
markedly different yields of the coupled products. By carefulselection of the reaction conditions (e.g., [PdCl2(dppf)]/
K2CO3/DMF), high yields of the desired coupled products
can be achieved [Eq. (24) and (25)].

 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2011, 50

Suzuki Coupling

Coupling Reactions of (sp)C B Compounds

Table 11: Pd-catalyzed arylation of alkynylmetal reagents mediated by 9MeO-9-BBN derivatives.

Alkynylboranes have long been known to be useful
synthetic intermediates. Compared to other organoboranes,
they are easily hydrolyzed by base. Because of this property,
alkynylboron compounds have not been employed in the
Suzuki coupling reaction, in which the presence of bases isessential. Recently, Soderquist et al. have found that theaddition of B-methoxy-9-borabicyclo[3.3.1]nonane to alkynyllithium reagents gives stable complexes 29, which undergo
efficient Suzuki coupling to produce a variety of alkynyl
derivatives 30 [Eq. (26), Table 10].[37]Substrate

RM

MeC
CNa
PhC
4-bromobenzaldehydeCNaethyl 4-bromobenMeC
zoate
CNa
PhC
4-bromobenzonitrileCNa

4-bromobenzophenone

9,10-dibromoanthracene

PhCCLi

Product

Yield [%]
89
77
86
93

84

Table 10: Coupled products from 29 [see Eq. (26)].
R

R’

Yield [%][a]

nBu
SiMe3
Ph
nBu
SiMe3
tBu
SiMe3

C6H5
C6H5
C6H5
p-MeOC6H4
CH2=CC6H5
cis-CH=CH-tBu
trans-CH=CH-nBu

60 (92)64
94
62 (68)88
56
55

initely, which will provide an advantage in their application tocombinatorial chemistry [Eq. (27)].[39][a] Yields of isolated analytically pure compounds (GC yields).

The Future

Almost at the same time, Frstner and Seidel reported thesame reaction.[38] The necessary alkynyl borates in thepalladium-catalyzed C C bond formation are preparedfrom 9-methoxy-9-BBN and a polar organometallic reagent
RM, such as 1-alkynylsodium, -potassium, and -lithiumcompounds, and not as usual from boranes and bases. Thisapproach allows cross-couplings of organic halides with, forexample, alkynyl, methyl, or TMSCH2 groups. The method ishighly chemoselective and turned out to be compatible withaldehyde, amide, ketone, ester, and cyano functions as well aswith basic nitrogen atoms in the substrates. Some of theresults are shown in Table 11. This reaction has been used toprepare compound 31, which is highly valuable for its
chemoluminescence properties.
Most recently the palladium-catalyzed cross-coupling
reaction of potassium alkynyltrifluoroborates with aryl halides or triflates has been reported to give readily coupled
products. The potassium alkynyltrifluoroborates are air- andmoisture-stable crystalline solids that can be stored indefAngew. Chem. Int. Ed. 2011, 50

Today, the Suzuki reaction continues to evolve, with many
new possibilities reported during the past decade. For
example, solid-phase Suzuki coupling has been developedby using either resin-bound aryl halides with solution-phaseboronic acids[14] or vice versa.[26] Such approaches, of course,play an important role in the combinatorial and parallel
methodologies now used to explore chemical reactivity, and is
especially well-suited to medicinal chemistry.
Increasingly, industry is seeking to use more environmentally friendly processes. These often require ingenious
solutions to which Suzuki coupling is well-suited. Researchgroups around the world are investigating modifications of
the reaction that work in aqueous media or with trace
amounts of catalysts. For example, Leadbeater and his teamcarry out Suzuki coupling using an ultralow (ppb) palladium
concentration in water,[40] while Kabalka and colleagues havecombined a solvent-free, solid-state approach with theapplication of microwave radiation to achieve coupling injust a few minutes.[41] Ionic liquids, which are excellent
solvents for transition-metal catalysts, are also being investigated.[42]We can expect to see many more interesting versions of
the Suzuki coupling in the future.

 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

Nobel Lectures

A. Suzuki

I would like to acknowledge the late Professor Herbert C.
Brown for his cordial encouragement and warm guidance tome, not only in chemistry but also my life. Thanks are also due
to many former co-workers, including graduate and undergraduate students at Hokkaido University.
Received: February 24, 2011[1] Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich,
P. J. Stang), Wiley-VCH, Weinheim, 1998.
[2] “Approximate Self Consistent Field Molecular Orbital Calculations on the Complexes of Trimethylboron, Boron Trichloride,
Trimethylaluminium, Alane and Aluminium Trichloride with
Trimethylamine”: O. Gropen, A. Haaland, Acta Chem. Scand.
1973, 27, 521 – 527.
[3] “Stereo- and Regiospecific Syntheses to Provide Conjugated(E,Z)- and (Z,Z)-Alkadienes, and Arylated (Z)-Alkenes in
Excellent Yields via the Palladium-Catalyzed Cross-Coupling
reactions of (Z)-1-alkenylboronates with 1-Bromoalkenes andAryl iodides”: N. Miyaura, M. Satoh, A. Suzuki, Tetrahedron
Lett. 1986, 27, 3745 – 3748.
[4] “Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds”: N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95,
2457 – 2483.
[5] “Cross-coupling reactions of organoboron compounds withorganic halides”: A. Suzuki in Metal-Catalyzed Cross-Coupling
Reactions (Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998, pp. 49 – 98.
[6] “Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998”: A.
Suzuki, J. Organomet. Chem. 1999, 576, 147 – 168.
[7] “The Suzuki Reaction with Arylboron Compounds in Arene
Chemistry”: A. Suzuki in Modern Arene Chemistry (Ed.: D.
Astruc), Wiley-VCH, Weinheim, 2002, pp. 53 – 106.
[8] “Total Synthesis of a Fully Protected Palytoxin Carboxylic
Acid”: Y. Kishi, R. W. Armstrong, J. M. Beau, S. H. Cheon, H.
Fujioka, W. H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, M. J.
Martinelli, W. W. McWhorter, Jr., M. Mizuno, M. Nakata, A. E.
Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-i.
Uenishi, J. B. White, M. Yonaga, J. Am. Chem. Soc. 1989, 111,
7525 – 7530; “Total Synthesis of Palytoxin Carboxylic Acid and
Palytoxin Amide”: R. W. Armstrong, J.-M. Beau, S. H. Cheon,
W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. J. Sung,
S. H. Kang, Y. Kishi, M. J. Martinelli, W. W. MacWhorter, Jr., M.
Mizuno, J. A. Tino, K. Ueda, J.-i. Uenishi, J. B. White, M.
Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 – 7533.
[9] “Total Synthesis of Lucilactaene, A Cell Cycle Inhibitor Activein p53-Inactive Cells”: R. S. Coleman, M. C. Walczak, E. L.
Campbell, J. Am. Chem. Soc. 2005, 127, 16038 – 16039.
[10] “Novel and Convenient Method for the Stereo- and Regiospecific Synthesis of Conjugated Alkadienes and Alkenynes via the
Palladium-Catalyzed Cross-Coupling Reaction of 1-Alkenylboranes with Bromoalkenes and Bromoalkynes”: N. Miyaura, K.
Yamada, H. Suginome, A. Suzuki, J. Am. Chem. Soc. 1985, 107,
972 – 980.
[11] “Palladium-Catalyzed Cross-Coupling Reaction of (1-Ethoxy-1alken-2-yl)boranes With ortho-Functionalized Iodoarenes. A
Novel and Convenient Synthesis of Benzo-Fused Heteroaromatic Compounds”: M. Satoh, N. Miyaura, A. Suzuki, Synthesis
1987, 373 – 377.
[12] “The Palladium-Catalyzed Cross-Coupling Reaction of Phenylboronic Acid with Haloarenes in the Presence of Bases”: N.
Miyaura, T. Yanagi, A. Suzuki, Synth. Commun. 1981, 11, 513 –
519.

www.angewandte.org[13] “Fluoride-Mediated Boronic Acid Coupling Reactions”: S. W.
Wright, D. L. Hageman, L. D. McClure, J. Org. Chem. 1994, 59,
6095 – 6097.
[14] “Suzuki Coupling”: A. Suzuki, Organic Syntheses via Boranes,
Vol. 3, Aldrich, USA, 2003.
[15] “Synthesis of Sterically Hindered Biaryls via the PalladiumCatalyzed Cross-Coupling Reaction of Arylboronic Acids ortheir Esters with Haloarenes”: T. Watanabe, N. Miyaura, A.
Suzuki, Synlett 1992, 207 – 210.
[16] “Heterolytic Cleavage of Main Group Metal-Carbon Bonds”:
M. H. Abraham, P. L. Grellier in The Chemistry of the MetalCarbon Bond, Vol. 2 (Eds.: F. R. Hartley, S. Patai), Wiley, New
York, 1985, pp. 25 – 150.
[17] “A Highly Active Suzuki Catalyst for the Synthesis of StericallyHindered Biaryls: Novel Ligand Coordination”: J. Yin, S. L.
Buchwald, J. Am. Chem. Soc. 2002, 124, 1162 – 1163.
[18] “Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild
Conditions”: A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc.
2000, 122, 4020 – 4028.
[19] “Highly Active Palladium Catalysts for Suzuki Coupling Reactions”: J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald, J.
Am. Chem. Soc. 1999, 121, 9550 – 9561.
[20] “A New Highly Efficient Catalyst System for the Coupling of
Nonactivated and Deactivated Aryl Chlorides with Arylboronic
Acids”: A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. 2000,
112, 4315 – 4317; Angew. Chem. Int. Ed. 2000, 39, 4153 – 4155.
[21] “A Convergent Total Synthesis of the Michellamines”: G.
Bringmann, R. Gtz, P. A. Keller, R. Walter, M. R. Boyd, F.
Lang, A. Garcia, J. J. Walsh, L. Tellitu, K. V. Bhaskar, T. R.
Kelly, J. Org. Chem. 1998, 63, 1090 – 1097.
[22] “A Suzuki Coupling-Macrolactamization Approach to the ABCOD Bicyclic System of Vancomycin”: K. C. Nicolaou, J. M.
Ramanjulu, S. Natarajan, S. Brse, H. Li, C. N. C. Boddy, F.
Rbsam, Chem. Commun. 1997, 1899 – 1990.
[23] “Total Synthesis of Vancomycin-Part 3: Synthesis of theAglycon”: K. C. Nicolaou, A. E. Koumbis, M. Takayanagi, S.
Natarajan, N. F. Jain, T. Bando, H. Li, R. Hughes, Chem. Eur. J.
1999, 5, 2622 – 2647.
[24] “Syntheses of Phenothiazinylboronic Acid Derivatives—Suitable Starting Points for the Construction of Redox Active
Materials”: C. S. Krmer, T. J. Zimmermann, M. Sailer, J. J.
Mller, Synthesis 2002, 1163 – 1170.
[25] “Head-to-Tail Regioregular Oligothiophene-Functionalized
9,9’-Spirobifluorene Derivatives. 1. Synthesis”: J. Pei, J. Ni, X.H. Zhou, X.-Y. Cao, Y.-H. Lai, J. Org. Chem. 2002, 67, 4924 –
4936.
[26] “Boronic Ester as a Linker System for Solid Phase Synthesis”: B.
Carboni, C. Pourbaix, F. Carreaux, H. Deleuze, B. Maillard,
Tetrahedron Lett. 1999, 40, 7979 – 7983.
[27] “Soluble poly(para-phenylene)s. 1. Extension of the Yamamoto
synthesis to dibromobenzenes substituted with flexible side
chains”: M. Rehahn, A. D. Schlter, G. Wegner, W. Feast,
Polymer 1989, 30, 1054 – 1059.
[28] “The Tenth Anniversary of Suzuki Polycondensation (SPC)”:
A. D. Schlter, J. Polym. Sci. Part A 2001, 39, 1533 – 1556.
[29] “Polymeric Alkoxy PBD [2-(4-Biphenylyl)-5-Phenyl-1,3,4-Oxadiazole] for Light-Emitting Diodes”: C. Wang, M. Kilitzirak, L.O. Palsson, M. R. Bryce, A. P. Monkman, D. W. Samuel I, Adv.
Funct. Mater. 2001, 11, 47 – 50.
[30] “Palladium-Catalyzed Cross-Coupling Reactions of B-alkyl-9BBN or Trialkylboranes with Aryl and 1-Alkenyl halides”: N.
Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki, Tetrahedron Lett.
1986, 27, 6369 – 6372.
[31] “Palladium-Catalyzed Inter- and Intramolecular Cross-Coupling
Reactions of B-alkyl-9-borabicyclo[3.3.1]nonane Derivatives
with 1-Halo-1-alkenes or Haloarenes. Syntheses of functional- 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2011, 50

Suzuki Couplingized alkenes, arenes, and cycloalkenes via a HydroborationCoupling Sequence”: N. Miyaura, T. Ishiyama, H. Sasaki, M.
Ishikawa, M. Satoh, A. Suzuki, J. Am. Chem. Soc. 1989, 111,
314 – 321.
[32] “Total Synthesis of ( )-Epothilone B: An Extension of the
Suzuki Coupling Method and Insights into Structure-Activity
Relationships of the Epothilones”: D.-S. Su, D. Meng, P.
Bertinato, A. Balog, E. J. Sorensen, S. J. Danishefsky, Y.-H.
Zheng, T.-C. Chou, L. He, S. B. Horwitz, Angew. Chem. 1997,
109, 775 – 777; Angew. Chem. Int. Ed. Engl. 1997, 36, 757 – 759.
[33] “A Novel Aldol Condensation with 2-Methyl-4-pentenal and Its
Application to an Improved Total Synthesis of Epothilone B”:
A. Balog, C. Harris, K. Savin, X.-G. Zhang, T. C. Chao, S. J.
Danishefsky, Angew. Chem. 1998, 110, 2821 – 2824; Angew.
Chem. Int. Ed. 1998, 37, 2675 – 2678.
[34] “Total Synthesis of ( )-Epothilone A”: A. Balog, D. Meng, T.
Kamenecka, P. Bertinato, D. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976 – 2978; Angew. Chem. Int. Ed.
Engl. 1996, 35, 2801 – 2803.
[35] “Total Syntheses of Epothilones A and B”: D. Meng, P.
Bertinato, A. Balog, D.-S. Su, T. Kamenecka, E. J. Sorensen,
S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073 – 10092.
[36] “New strategy for convergent synthesis of trans-fused polyether
frameworks based on palladium-catalyzed suzuki cross-coupling

Angew. Chem. Int. Ed. 2011, 50

reaction”: M. Sasaki, H. Fuwa, M. Inoue, K. Tachibana,
Tetrahedron Lett. 1998, 39, 9027 – 9030.
[37] “Alkynylboranes in the Suzuki–Miyaura coupling”: J. A. Soderquist, K. Matos, A. Rane, J. Ramos, Tetrahedron Lett. 1995, 36,2401 – 2402.
[38] “Palladium-Catalyzed Arylation of Polar Organometallics
Mediated by 9-Methoxy-9-borabicyclo[3.3.1]nonane: Suzuki
Reactions of Extended Scope”: A. Frstner, G. Seidel, Tetrahedron 1995, 51, 11 165 – 11 178.
[39] “Development of the Suzuki–Miyaura Cross-Coupling Reaction: Use of Air-Stable Potassium Alkynyltrifluoroborates in
Aryl Alkynylations”: G. A. Molander, B. W. Katona, F. Machrouhi, J. Org. Chem. 2002, 67, 8416 – 8423.
[40] “A Reassessment of the Transition-Metal Free Suzuki-Type
Coupling Methodology”: R. K. Arvela, N. E. Leadbeater, M. S.
Sangi, V. A. Williams, P. Granados, R. D. Singer, J. Org. Chem.
2005, 70, 161 – 168.
[41] “Solventless Suzuki Coupling Reactions on Palladium-Doped
KF/Al2O3”: G. W. Kabalka, R. M. Pagni, C. M. Hair, Org. Lett.
1999, 1, 1423 – 1425.
[42] “Palladium Catalysed Suzuki Cross-Coupling Reactions inAmbient Temperature Ionic Liquids”: C. J. Mathews, P. J.
Smith, T. Welton, Chem. Commun. 2000, 1249 – 1250.

 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

Confocal

Raman Imaging
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www.witec.de2011

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