SPEAKERS on 20Th June in Tokyo

Home , Akira Suzuki (chemist), Hartmut Michel, Japan Academy, Order of Culture

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E_single color black Germany – Japan Chemistry Symposium SPEAKERS on 20th June in Tokyo

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François Diederich Alois Fürstner Helmut Schwarz

Hartmut Michel Ryoji Noyori Barry Sharpless Akira Suzuki Nobel Prize 1988 Nobel Prize 2001 Nobel Prize 2001 Nobel Prize 2010

Hideo Hosono Tohru Fukuyama Terunori Fujita Including the Nobel Lectures of Professors Michel, Noyori Sharpless and Suzuki

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All participants are also invited to join a Wiley-VCH reception right after the conference at 6 pm and take the chance to meet the speakers and colleagues. 306811_gu We look forward to seeing you. Program for the Symposium "Catalysis & Synthesis Advanced Materials & Chemical Biology" in Tokyo on 20th June 2011

Time Length Lecture Moderator 9h00 15 min Yasuhiro Iwasawa / Michael Droescher / Kenichi Iga / Peter Gölitz Welcome Remarks 9h15 45 min Ryoji Noyori Keisuke Suzuki Asymmetric Hydrogenation: Our Three Decades with BINAP 10h00 40 min Alois Fuerstner Keisuke Suzuki Catalysis for Total Synthesis 10h40 40 min Hideo Hosono Mikiko Sodeoka Exploring New Superconductors and Other Supermaterials

11h20 15 min Break 11h35 45 min Hartmut Michel Mikiko Sodeoka 25 Years of Membrane Protein Structures: Successes and Open Questions 12h20 40 min Terunori Fujita Neville Compton Olefin Polymerization: FI Catalysts for the Creation of Value-Added Olefin-Based Materials

13h00 1 h 15 min Break 14h15 40 min Akira Suzuki Masakatsu Shibasaki Cross-Coupling Reactions of Organoboranes: An Easy Way for C–C Bonding 14h55 40 min François Diederich Hideo Takezoe Molecular Recognition in Chemical and Biological Systems 15h35 40 min Tohru Fukuyama Hideo Takezoe Total Synthesis of Natural Products and Development of Synthetic Methodologies

16h15 15 min Break 16h30 40 min Helmut Schwarz Wolfram Koch Homolytic C–H Bond Activation: Experimental and Theoretical Insights / Research in Germany 17h10 45 min Barry Sharpless Peter Goelitz Click Chemistry Keeps Evolving – Destinations Unknown 17h55 5 min Ichiro Okura Concluding Remarks

18h00 Reception “Beer and Pretzel” Eva Wille

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Institut Kimia “ I consider Chemistry – An Malaysia Asian Journal to be one of the ﬁ nest journals of Chemistry. New Zealand Institute It has surpassed all expecta- of Chemistry tions. In a very short time, it Chairman of the Editorial Board has attained the quality and Ryoji Noyori Chemical Society of Vietnam impact equivalent to the very Nagoya University and RIKEN, best journals that we have. It Saitama, Japan Supported by has also given a special place for Asian chemistry because through this journal chemistry in Asia can shine in the world of chemistry. I am proud to be associated with this journal and I am sure that it will reach even greater heights in the years to come.

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Asymmetric Hydrogenation:Our Three Decades with BINAP

RyojiNoyori Nagoya University and RIKEN [email protected] (Saitama, Japan)

Noyori acquired bachelor's and master'sdegrees from Kobe University (Japan) and completed his PhD there in 1967, under the supervisionofH.Nozaki, on the first example of organometallicasymmetric catalysis. He was then appointed associate professor at Nagoya University, and onlylater, in 1969, had the opportunity to carry out postdoctoral research with E. J. Corey (Harvard University, USA). Back in Nagoya he was promoted to professor in 1972 and has remained faithful to this institution whileserving 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 TotalSynthesis

AloisFürstner Max-Planck-Institut für Kohlenforschung [email protected] (Mülheim/Ruhr, Germany)

Fürstner completed his PhD in 1987 at the Technical University of Graz with H. Weidmann and completed his habilitation there in 1992, following apostdoctoral fellowship with W. Oppolzer (University of Geneva). He has been agroup leader at the Max Planck Institute at Mülheim since 1993 and has been adirector there since 1998. He carries out pioneering work at the interface betweenorganometallicchemistry and organic synthesis, in particular alkene and alkyne metathesis and its applicationtothe total synthesis of complex natural products, such as carbohydrates and alkaloids.

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

Exploring New Superconductors andOther Supermaterials

Hideo Hosono Tokyo Institute of Technology [email protected] (Yokohama, Japan)

The research of H. Hosonoisdevoted to inorganic solid-state materialschemistry, especiallytransparent oxide semiconductors, which are used in flat-panel displays, and new superconductors: He introduced iron into the familyofoxide superconductor components. Hosonoearned aPhD from Tokyo Metropolitan University under the guidance of H. Kawazoe in 1982 and joined the faculty of Nagoya Institute of Technology. In 1999, he became aprofessor at the Tokyo Institute of Technology.

25 Years of MembraneProtein Structures: Successesand Open Questions

Hartmut Michel Max-Planck-Institut für Biophysik hartmut.michel@mpibp-frankfurt.mpg.de (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 aphotosynthetic reaction center.Michel studied biochemistry at the Universität Tübingen (Germany) and in 1977 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 aphotosynthetic reaction center.In1987 he became director at the MPI of Biophysics (Frankfurt/M.).

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

Olefin Polymerization: FI Catalysts for the Creation of Value-Added Olefin-Based Materials

Terunori Fujita Mitsui Chemicals Inc. Research Center [email protected] (Chiba, Japan)

T. Fujita graduated from Hokkaido University in 1982 and earned aPhD in 1988 in supramolecular chemistry from the Louis Pasteur University in Strasbourg under the supervision of Jean-Marie Lehn. In 1982 he joined Mitsui Petrochemical Industries (now Mitsui Chemicals). In 2001 he was appointed aMitsui research fellow for his contributions to the development of new olefin polymerization catalysts, now known as FI catalysts. He is currently aboard director and the Center Executive of the company’s research center. Fujita’s research interests have focused on the synthesis of valuable organic materials by means of homogeneous and heterogeneous catalysis and, more recently, on the development of high-performance olefin polymerization catalysts for the creation of new value-added olefin-based materials.

Cross-Coupling Reactions of Organoboranes: An EasyWay for C—CBonding

Akira Suzuki Hokkaido University [email protected] (Sapporo, Japan)

Suzuki received his doctorate in 1959 at Hokkaido University, Sapporo (Japan) and was, after aresearch stay with H. C. Brown (Purdue) in the late 1960s, aprofessor there from 1965 until1994. Towards the end of the 1970s he was able to show that organoboron compounds can be coupled with vinyl and aryl halides under basic conditionsand palladium catalysis. Together with Richard F. Heck and Ei-ichi Negishi,this discoveryearned him the Nobel Prize in Chemistry in 2010.

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

Molecular RecognitioninChemical and Biological Systems

François Diederich Eidgenössische Technische Hochschule [email protected] (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 CaliforniainLos Angeles (UCLA; USA) and at the Max Planck Institute for Medicinal Research in Heidelberg.After completing his habilitation in 1985 he returned to UCLA, and in 1992 he joined the ETH Zürich.Hehas 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 materialsfrom carbon-rich acetylene derivatives, Diederich's research group is also interested in medicinal chemistry eg. of antimalarial drugs.

TotalSynthesis of Natural Products and Development of SyntheticMethodologies

Tohru Fukuyama Graduate School of Pharmaceutical [email protected] Sciences (University of Tokyo, Japan)

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

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

Homolytic C—HBondActivation: Experimental andTheoretical Insights/ ResearchinGermany

HelmutSchwarz Technische Universität Berlin [email protected] (Berlin, Germany)

After training as achemical technician, Schwarz remained true to the Technical University of Berlin: He earned his doctorate and habilitation under the guidance of natural-products chemist F. Bohlmann and is currently aprofessor of Organic Chemistry there. He held numerous visiting appointments in Great Britain,Switzerland,Israel, France, Japan, and Australia. His research is inextricablylinked to mass spectrometryand gas-phase chemistry, especiallythe 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 betweenexcellent scientists and scholars from Germany and abroad.

Click Chemistry Keeps Evolving — DestinationsUnknown

Barry Sharpless The Scripps Research Institute [email protected] (La Jolla, USA)

The research of Barry Sharpless is focused on homogeneous oxidationcatalysts, 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 aPhD under the guidance of E. E. van Tamelen in 1968. He carried out post-doctoral research at Stanford (with J. P. Collman) and HarvardUniversity (with K. Bloch)before joiningthe faculty of the Massachusetts Institute of Technology from 1970—90, interrupted by an appointment at Stanford in the late 1970s. Since 1990, he is aProfessor at The ScrippsResearch Institute.

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REVIEWS

Asymmetric Catalysis:Science and Opportunities (Nobel Lecture)**

Ryoji Noyori*

Asymmetric catalysis,inits infancy in ries but also in industry.The growth of technology in the 21st century.Most the 1960s,has dramatically changed this core technology has given rise to importantly, recent progress has spur- the procedures of chemical synthesis, enormous economic potential in the red various interdisciplinary research and resulted in an impressive progres- manufacture of pharmaceuticals,ani- efforts directedtoward the creation of sion to alevel that technically approx- mal health products,agrochemicals, molecularly engineerednovel func- imates or sometimes even exceeds that fungicides,pheromones,flavors,and tions.The origin and progress of my of natural biological processes.The fragrances.Practical asymmetric catal- research in this field are discussed. recent exceptional advances in this ysis is of growingimportance to a area attest to arange of conceptual sustainable modern society,inwhich Keywords: asymmetric catalysis ¥ breakthroughs in chemical sciences in environmental protection is of increas- asymmetric hydrogenation ¥ Nobel general, and to the practical benefits of ing concern. This subject is an essential lecture ¥ Pligands ¥ ruthenium organicsynthesis,not only in laborato- component of molecular scienceand

1. Prologue while its S enantiomeristeratogenic and induces fetal malformations.[2, 3] Such problems arising from inappropriate Chirality(handedness;left or right) is an intrinsic universal molecular recognition should be avoided at all costs.Never- feature of various levels of matter.[1] Molecular chirality plays theless, even in the early 1990s,about 90%ofsynthetic chiral akey role in scienceand technology.Inparticular, life drugs were still racemic–that is,equimolar mixtures of both dependsonmolecular chirality,inthat many biological enantiomers,which reflects the difficulty in the practical functions are inherently dissymmetric.Most physiological synthesis of single-enantiomeric compounds.[4] In 1992, the phenomena arise from highly precisemolecular interactions, Food and Drug Administration in the U.S. introduced a in which chiral host molecules recognize two enantiomeric guideline regarding ™racemic switches∫, in order to encourage guest molecules in different ways.There are numerous the commercialization of clinical drugs consisting of single examples of enantiomer effects which are frequently dramat- enantiomers.[5] Such marketing regulations for synthetic ic. Enantiomers often smell and taste different. Thestructural drugs,coupled with recent progress in stereoselective organic difference between enanatiomers can be serious with respect synthesis,resulted in asignificant increase in the proportion of to the actions of synthetic drugs.Chiral receptorsites in the single-enantiomerdrugs.In2000, the worldwide sales of human body interact only with drug molecules having the single-enantiomercompounds reached 123billion U.S. dol- proper absoluteconfiguration, which results in marked differ- lars.[6] Thus,gaining access to enantiomerically pure com- ences in the pharmacological activities of enantiomers.A pounds in the development of pharmaceuticals,agrochem- compelling example of the relationship between pharmaco- icals,and flavors is avery significant endeavor. logical activity and molecular chiralitywas provided by the Discovery of truly efficient methods to achieve this has tragic administration of thalidomide to pregnant women in been asubstantial challenge for chemists in both academia the 1960s.(R)-Thalidomide has desirable sedative properties, and industry.Earlier, enantiomerically pure compounds were obtained by the classical resolution of aracemateortrans- [*] Prof.Dr. R. Noyori formationofreadily accessible,naturally occurring chiral Department of Chemistry compounds such as amino acids,tartaric and lactic acids, Nagoya University carbohydrates,terpenes,oralkaloids.Even thoughstereo- Chikusa, Nagoya464-8602 (Japan) selective conversion of aprochiral compound to achiral Fax: (81) 52-783-4177 E-mail:[email protected] product, namely through an asymmetric reaction, is the most [**] Copyright¹The Nobel Foundation 2002. We thank the Nobel attractive approach, practical access to pure enantiomers Foundation,Stockholm, for permission to print this lecture. relied largely on biochemical or biological methods.However,

2008 Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 ¹WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany,2002 1433-7851/02/4112-2008 $20.00+.50/0 Asymmetric Catalysis REVIEWS the scope of such methods using enzymes,cell cultures,or with ahigh turnover number (TON) and ahigh turnover whole microorganismsislimited because of the inherent frequency (TOF), while the enantioselectivity ranges from single-handed, lock-and-key specificity of biocatalysts.Onthe 50:50 (nonselective) to 100:0 (perfectly selective).The chiral other hand, achemical approachallows for the flexible ligands that modify intrinsically achiral metal atoms must synthesis of awide array of enantiopure organic substances possess suitable three-dimensional structures and functional- from achiral precursors.The requirements for practical ity,togenerate sufficient reactivity and the desired stereo- asymmetric synthesis include high stereoselectivity,high rate selectivity.Sometimes the properties of achiral ligands are and productivity, atom economy,cost efficiency,operational also important. Thechiral catalyst can permit kinetically simplicity,environmental friendliness, and low-energy con- precise discrimination among enantiotopic atoms,groups,or sumption. Traditional asymmetric synthesis using astoichio- faces in achiral molecules.Similarly,enantiomeric molecules metric amount of achiral compound, though convenient for can also be discriminated.Certain well-designed chiral metal small to medium-scale reactions,ispractical only if the catalysts not only accelerate the chemical reactions repeat- expensive chiral auxiliary deliberatelyattached to asubstrate edly but also differentiatebetween diastereomeric transition or reagent is readily recyclable;otherwise it is awasteful states (TSs) with an accuracy of 10 kJmolÀ1.Inthis way,such procedure. compactmolecular catalysts with amolecular weight less than Figure1 illustrates ageneral principle of asymmetric 1000, or < 20 äinlength or diameter, allow for an ideal catalysis which provides an ideal way for multiplying molec- methodfor synthesizing enantiomeric compounds.The di- ular chirality.[7] Asmall amount of awell-designed chiral verse catalytic activities of metallic species,aswell as the virtually unlimited structural variationofthe organic ligand, provides enormous opportunities for asymmetric catalysis.

2. Discovery of Asymmetric Catalysis by Chiral Organometallic Complexes

In 1966, when Iwas in H. Nozaki×s (Figure 2) laboratory at Kyoto,wediscovered the first example of asymmetric catalysis using astructurally well-defined chiral transition- metal complex.[8] This finding resulted from research done for an entirely different purpose,which was to eluci- date the mechanismofcarbene reac- Figure 1. Ageneral principle of asymmetric catalysis with chiral organo- tions.Asillustrated in Scheme 1, when metallic molecular catalysts. M metal;A,Breactantand substrate. asmall amount (1 mol%) of achiral Schiff base ±CuII complex was used as a catalyst can combine Aand B, which produces the chiral molecular catalyst in the reaction of AB compound stereoselectively in alarge quantity.Of styrene and ethyl diazoacetate,the cis- Figure 2. Professor variouspossibilities,the use of chiral organometallic molec- and trans-cyclopropanecarboxylates H. Nozaki(1985). ular catalysts would be the most powerful strategy for this were obtained in 10 and 6% enantio- purpose.Asymmetric catalysis is an integrated chemical meric excess (ee), respectively.Wealso observed asymmetric approachinwhich the maximum chiral efficiency can be inductionincarbene insertion to aCÀObond of 2-phenyl- obtained only by acombination of suitable molecular design oxetane,which gave optically active 2,3-substituted tetrahy- with proper reaction conditions.The reaction must proceed drofuran derivatives.Atthat time,the finding wassyntheti-

Ryoji Noyori, born in Kobe in 1938, completed his master×s degreeatKyoto University and thereafter became an Instructor at the sameuniversity.Hereceived his Ph.D.degreein1967 under the supervision of H. Nozaki. He was appointed Associate Professor at Nagoya University in 1968 and promoted to Professor in 1972. He spent apostdoctoralyear 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 AcademyPrize(1995),the Arthur Cope Award (1997),the King Faisal International Prize (1999), the Order of Culture (2000), the Wolf Prize (2001), and the Roger Adams Award (2001). In 2001,heshared the NobelPrizein Chemistry with W. S. Knowles and K. B. Sharpless.

Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 2009 REVIEWS R. Noyori

3. Asymmetric Hydrogenationinthe Early Days

At presentthe asymmetric cyclopropanation is important 1 mol% practically,but in the late 1960s,itwas just aspecial reaction in chiral Cu cat COOC H HCOOC H ++2 5 2 5 organicsynthesis.Idecided to pursuehydrogenation, which is HH H acore technology in chemistry.Itisthe simplest but most N CHCOOC H 2 2 5 powerful way to produce awide array of importantcompounds in large quantities using inexpensive,clean hydrogen 10% ee 6% ee C6H5 gas withoutforming any waste.Hydrogenation was initiated

N O at the end of the 19th century by P. Sabatier (1912 Nobel Cu laureate), who used fine metal particles as heterogeneous O N catalysts.Some notableachievements thatattracted me,before

doingresearch in this area, include:activation of H2 by a C6H5 transition-metalcomplexinthe late 1930s(M. Calvin, 1961 chiral Cu catalyst Nobel laureate),[10] homogeneous hydrogenation of olefinic

Scheme1.Discovery of asymmetric reactionbymeans of achiral organo- substrates with RuCl3 in 1961 (J.Halpern, J. Harrod, and B. R. metallic molecular catalyst. James),[11] and hydrogenation of olefinic compounds using

[RhCl{P(C6H5)3}3]in1965 (G.Wilkinson, 1973 Nobel laureate).[12] Most importantly,in1956, S. Akabori at Osaka cally primitive since the degree of enantioselection was reported that metallic Pd drawn on silk catalyzes asymmetric meaninglesspractically.Later, T. Aratani, aKyoto student, (heterogeneous) hydrogenation of oximes and oxazolones.[13] went to Sumitomo Chemical Co., where he invented an This pioneering work, though not effective synthetically,was excellent chiral Cu catalyst for asymmetric cyclopropanation, alreadywell known throughout Japan.In1968, two yearsafter which achieved the industrial synthesis of chrysanthemates our asymmetriccyclopropanation in 1966, W. S. Knowles (fellow (efficientinsecticides) and (S)-2,2-cyclopropanecarboxylic Nobel laureatein2001)[14] andL.Horner[15] independently reported the first homogeneously catalyzed asymmetric hydro- H genation of olefins with chiral monodentate tertiaryphos- COOR COOH RR S S phane±Rh complexes, albeit in 3±15 %opticalyield.[16] H. B. NH NH2 Kagan provided amajor breakthroughinthis area in 1971,when O COONa he devisedDIOP,aC2-chiraldiphosphane ligandderived from tartaricacid. He used its Rh complexfor asymmetric hydro- chrysanthemates cilastatin genation of dehydro amino acidsleading to phenylalaninein about 80% ee,then recorded as 72 % ee.[17] TheKnowlesgroup at Monsanto established amethod forthe industrial synthesisof acid. Thelatter compound is abuilding block of cilastatin, an l-DOPA, adrug fortreating Parkinson×s disease,which used his in vivo stabilizer of the carbapenem antibiotic, imipenem DIPAMP±Rh catalyzedasymmetric hydrogenation as akey (Merck Co.; Figure 3).[9] step.[18] These achievementssignificantly stimulated thesubse- quentinvestigation of this importantsubject. Shortly after moving from Kyoto to Nagoya in 1969 ±70, I spent apostdoctoral year at Harvard with E. J. Corey (1990 Nobel laureate). He asked me to hydrogenateselectively one

of the two CCbonds in aprostaglandin F2a derivative to give [19] the F1a form having only one CCbond. This research was helped by K. B. Sharpless (another fellow Nobel laureate in 2001)[102] ,who was then apostdoctoral fellow with K. Bloch (1964 Nobel laureateinPhysiology or Medicine) and who suggested aconvenient TLC technique for analyzing the structurally very similar olefinic compounds.Inaddition to this background, my personal interaction with J. A. Os- born, aformer Wilkinson student and co-inventorof [12] [RhCl{P(C6H5)3}3] who was then an Assistant Professor at Harvard, greatly enhanced my interest in asymmetric hydrogenation,which later becamemylife-long research interest. My desire was to develop atruly efficient asymmetric hydrogenation which would have awide scope of applications. In the early 1970s,chiral phosphane ±Rhcomplexes could hydrogenatesatisfactorily only dehydro amino acids but not Figure 3. Reaction apparatus for the Sumitomo asymmetric cyclopropa- many other olefins.Asymmetric hydrogenation of ketones nation. was totally unexplored.[20]

2010 Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 Asymmetric Catalysis REVIEWS

4. BINAP,aBeautiful Chiral Molecule Although the elusive BINAP was available,our goal was still in the distance. Enantioselectivity of BINAP ±RhI

H2 is the simplest molecule but it has enormous potential catalyzed asymmetric hydrogenation of a-(acylamino)acrylic from both ascientific and technical point of view.Todiscover acids washighly variable and not satisfactory at that time, high-performance asymmetric catalysts,the development of ee valuesofthe chiral products being at most about 80%. an excellentchiral ligand is crucial. Attracted by its molecular However, we remained patient. In 1980, six years after the beauty,[21] we initiated the synthesis of BINAP (2,2'-bis(di- start, thanks to the unswervingefforts of my young associates, phenylphosphanyl)-1,1'-binaphthyl)[22] in 1974 at Nagoya with we published our first work on asymmetric synthesis of amino the help of H. Takaya, my respected long-term collaborator. acids of high enantiomeric purity,upto100% ee,together

BINAP was anew,fully aromatic, axially dissymmetric C2- with the X-ray crystalline structure of acationic BINAP ± chiral diphosphane that would exert strong steric and Rh(norbornadiene) complex.[22, 26]

electronic influences on transition-metal complexes.Its prop- BINAP,aconformationally flexible atropisomeric C2 di- erties could be fine-tuned by substitutions on the aromatic phosphane,can accommodatearangeoftransition metals by

rings.However, synthesis of this optically pure C2-chiral rotating about the binaphthyl C(1)-C(1')pivot and C(2 or 2')- diphosphane was unexpectedly difficult.In1976, for the first Pbonds,without seriously increasing torsional strain, while time,wemanaged to obtain optically active BINAP starting the resulting seven-membered chelateringscontaining only from optically pure 2,2'-diamino-1,1'-binaphthyl (Scheme 2a). sp2 carbon atoms are in turn skeletally unambiguous.The However, this seemingly straightforward synthetic pathway chirality of BINAP is transmitted to other metal-coordination was not reproducible,because of the tendency of the chiral sites through the chelate structure.[22, 26] The d or l geometry is intermediates to cause racemization.[23] In 1978, we found a highly skewed and determines the chiral disposition of the P- reliable method for resolving racemic BINAP with an phenyl rings that play akey role in generating outstanding optically active dimethyl(1-phenylethyl)aminopalladium(II) chirality-discriminatingability at the reactive coordination chloridecomplex,[22] while,later, optically pure BINAP sites.Thus BINAP-based metal complexes were expected to becameavailable more conveniently by resolution of BINAP exhibit high chiral-recognition ability in various catalytic dioxide with camphorsulfonic acid or 2,3-O-dibenzoyltartaric reactions, in additiontohydrogenation. acid (Scheme2b).[24, 25]

5. Asymmetric Synthesis of Menthol a) Irreproducible stereospecific synthesis Thecationic BINAP ±Rhcomplex was best used in asymmetric isomerization of allylic amines,[27] which realized an industri- 2 NaNO2 1. t-C4H9Li NH2 CuBr Br 2. (C6H5)2PCl 1 P(C6H5)2 al synthesis of (À)-menthol from myrcene 1' [28] NH2 Br P(C6H5)2 (Scheme3). This resulted from afruitful 2' academic/industrial collaboration between groups at Osaka University (S.Otsuka and (R)-BINAP H. Tani),[29] Nagoya University (R. Noyori), Institute for Molecular Science (H. Takaya), b) Optical resolution Sizuoka University (J.Tanaka and K. Takabe),[30] and Takasago International Co.(Figure 4).The key step was the asym-

1. [{(dimethyl(1-phenylethyl)amine)PdCl}2] metricisomerization of geranyldiethyl- OH 2. NaB(C6H5)4 (±)- (±)-BINAP amine,catalyzed by an (S)-BINAP±Rh com- OH 3. fractional recrystallization plex in THF and forming (R)-citronellal 4. LiAlH4 enamine,which uponhydrolysis gives (R)- citronellal in 96 ±99%ee.This is far supe- rior to the 80% ee of the naturally occurring P(C H ) P(C H ) product available from rose oil. Among 6 5 2 + 6 5 2 P(C6H5)2 P(C6H5)2 variousRhand other catalysts examined, the BINAP-based cationic Rh complex was the most reactive and the most stereoselec- (S)-BINAP (R)-BINAP tive.The BINAP ±Rhcatalyst clearly differ- entiates between the pro-S and pro-R hy- drogenatoms on the flexible allylic amine 1. camphorsulfonic acid skeleton during the 1,3-suprafacial shift that P(O)(C6H5)2 (or 2,3-O-dibenzoyltartaric acid) (±)- occurs by anitrogen-triggered mecha- P(O)(C6H5)2 2. fractional recrystallization 3. SiHCl3, (C2H5)3N nism.[31] Theasymmetric reaction is performed on anine-ton scale.The full techni- Scheme2.Access to enantiomerically pure BINAP. cal refinements of the position-and stereo-

Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 2011 REVIEWS R. Noyori

6. Asymmetric HydrogenationofOlefins by BINAP ±Ruthenium Complexes

Returning to the topic of asymmetric hydrogenation, our success resultedfrom the invention of the BINAP ligand[32] and also from the use of Ru, which behaves differently from the conventional Rh.[33, 34] Thecationic BINAP ±Rhcom- plexes catalyze hydrogenation of a-(acylamino)- acrylic acids or esters to give the corresponding amino acid derivatives in high ee values (Scheme 4).[22, 23] However, the reaction is rela- tively slow,and high enantioselectivity is obtained only under special conditions,probably because of the operation of the unsaturate/dihydride mechanism.J.Halpern[35] and J. M. Brown[36] showed that hydrogenation of enamides in the

presence of a C2-chiral diphosphane ±Rhcom-

plex proceeds by oxidative additionofH2to diastereomeric Rh ±substratechelate complexes, followed by stepwise transfer of the two hydrides to the coordinated olefin. Most significantly, the minor diastereomer of these complexes is the more reactive one.[37] Because of the excellent Scheme3.Takasago menthol synthesis.COD 1,5-cyclooctadiene. chiral-recognition ability of BINAP,the reactive species,which leads to the desired hydrogenation

COOR1 [Rh((S)-binap)]+ COOR1 R + H2 R NHCOR2 NHCOR2 R = Ar oder H R [Rh((R)-binap)]+

R R COOR1 [Rh((S)-binap)]+ COOR1 + H2 NHCOR2 NHCOR2 R = Ar S Scheme4.Asymmetric hydrogenation of a-(acylamino)acrylic acids catalyzed by BINAP ±Rhcomplexes.

product, is present in avery small quantity and is even NMR- invisible in the equilibrium mixture.[23a] Therefore, conditions such as hydrogen pressure,temperature,and concentration Figure 4. At the Takasago plant for (À)-menthol synthesis (February, 1984). From the left, K. Tani, H. Takaya,R.Noyori, S. Otsuka, S. must be chosen carefully to obtain high enantioselectivity. Akutagawa, and H. Kumobayashi. Furthermore,asymmetric hydrogenationwas limited to the synthesis of amino acids. Amajor breakthrough occurred when we devised the selective addition of diethylamine to myrcene,which gives the BINAP ±RuII dicarboxylate complexes in 1986 (Fig- [38, 39] startinggeranylamine,and the ZnBr2-catalyzed intramolecu- ure 5). TheRucomplexes are excellent catalysts for lar ene reaction of (R)-citronellal, which forms isopulegol asymmetric hydrogenationofvarious functionalized olefins, with the three correct stereogenic centers,allowed for the as summarized in Scheme 5. Thereaction proceeds via aRu productionofterpenic substrates totaling about1500 tons per monohydride intermediate formed by heterolysis of H2 by the year at Takasago International Co.Most of the (R)-citronellal Ru complex. TheRucenter remains in the 2oxidationstate is converted to 1000 tons per year of (À)-menthol, one-third throughout the catalytic cycle,[40] in contrast to the Rh of the world demand.(R)-7-Hydroxydihydrocitronellal thus complex, which involves a 1/3redox process.Heteroatoms prepared is aperfumery agent that smellslike lily of the in the functional groups serve as abinding tether to the valley.Its methyl ether is an intermediate in the synthesis of catalytic Ru center. This hydrogenationhas avery wide scope. methoprene,agrowth regulator of the yellow-fever mosqui- Hydrogenation of a,b-and b,g-unsaturated carboxylic acids to.[28, 29] takes placeinalcoholic media, where the sense and degree of

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

Figure 5. Structures of BINAP ±Rudiacetatecomplexes.

3 3 R COOH H2 R COOH ** R2 R1 R2 R1

R3 OH R3 OH ** R2 R1 R2 R1

NCOR NCOR

(R'O)m (R'O)m Scheme6.Applications of BINAP ±Rucatalyzed hydrogenation of olefins.

(R'O)n (R'O)n

COOR1 COOR1 and unnatural citronellol with up to 99% ee are obtainable NHCOR2 NHCOR2 from geraniol or nerol without saturation of the C(6)ÀC(7) double bond, with ahigh substratetocatalyst (S:C) ratio.The hydrogenation of (R,E)-6,7,10,11-tetrahydrofarnesol produ- 1 1 R2 COOR R2 COOR ces (3R,7R)-hexahydrofarnesol, aC15 side-chain of a-tocoph-

erol (vitamin E) and apart of vitamin K1.The hydrogenation R3CONH R3CONH of an allylic alcohol possessing achiral azetidinoneunit gives a 1b-methylcarbapenem synthetic intermediate diastereoselec- [48] PO(OCH3)2 PO(OCH3)2 tively. Thediscovery of this asymmetric hydrogenation made possible the general asymmetric synthesis of isoquino- RNHCHO RNHCHO line alkaloidsincludingmorphine,benzomorphans,and Scheme5.Asymmetric hydrogenation of functionalized olefins catalyzed morphinans such as the antitussive dextomethorphan.[43, 49] by (S)-BINAP ±Rudicarboxylates. Importantly,the list of substratescan be extended to include various ketones,asgeneralized in Scheme 7and the enantioselection are highly dependent on the substitution Figure 6. Thehalogen-containing BINAP ±RuII complexes pattern andhydrogen pressure.[41] Allylicand homoallylic (oligomers),[50] but not the diacetate complexes,are efficient alcohols are also hydrogenated with high enantioselection.[42] catalysts for the asymmetric hydrogenation of arange of Certain racemic allylic alcohols can be resolved by the functionalized ketones,wherein coordinative nitrogen, oxy- BINAP ±Ru-catalyzed hydrogenation.[43] Thechiral Ru com- gen, and halogen atoms near COfunctions direct the

Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 2013 REVIEWS R. Noyori

O Ar2 F COOH P OH O OH O RuX L Cl R N+ 2 2 N N OC H 3 O– P 2 5 Ar CH N O 2 3 CH 3 R = CH3: carnitine O H OH R = H: GABOB 2 levofloxacin N(CH3)2 N(CH3)2 via (R)-1,2-propanediol

OH OH O OH O OH OH O OH R1O R OH OH OR2 OH RR R R NH compactin 2 OO OH O intermediate statine series anti 1,3-diols R1 Y R1 Y Scheme8.Applications of BINAP ±Ru-catalyzed hydrogenation of R2 R2 R2 R2 ketones.

Y = OR, SR, NR2 O O OH O is used for industrial synthesis of the antibacterial levofloxacin P(OR3) P(OR3) R1 2 R1 2 (Takasago Co./Daiichi Pharmaceutical Co.). In addition, g- R2 R2 R2 R2 amino-b-hydroxybutyric acid (GABOB) and acompactin OONa OH ONa intermediatecan be prepared with high enantiomeric puri- S O S Oty.[49, 52] Pre-existingstereogenic centers in the ketonic sub- R OOR strate significantly affect the steric course.Statines can be O Br OH Br obtained with ahigh 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 b-keto esters with aconfigurationally labile a- O O stereogenic center, by undergoinginsitu stereoinversion, can OR2 O R1 be transformedinto asingle stereoisomer out of the four R1 O stereoisomers,with high stereoselectivity,asillustrated in Scheme7.Asymmetric hydrogenation of functionalized ketones catalyzed Scheme 9.[54] This dynamic kinetic resolution[55] has been used by (S)-BINAP ±Rudihalidecomplexes (X halogen). for the synthesis of various biologically importantcompounds such as threonine,(2S,3R)-3-(3,4-dihydroxyphenyl)serine (l- 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 requisitechiral 4-acetoxyazetidinone is prepared by the (R)- BINAP ±Ru-catalyzed hydrogenationofracemic methyl a- (benzamidomethyl)acetoacetate in dichloromethane,togive the 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 substrateishydrogenated Figure 6. H. Takaya,M.Kitamura, and T. Ohkuma (from the left) made 15 times faster than the R enantiomer, and the slow-reacting major contributions to the asymmetric hydrogenation of functionalized ketones catalyzed by (S)-BINAP±Ru dihalidecomplexes. R isomerisinverted to the 2S enantiomer92times easier than

OO H2 OH O reactivity and stereochemical outcome in [RuX2((R)-binap)] (±)-R1 OR3 R1 OR3 L-threonine, L-DOPS etc. an absolute sense.[51] Awide variety of NHCOR2 NHCOR2 achiral ketones are hydrogenated enan- tioselectively to the corresponding chiral O H O alcohols in 90 ±100% ee,inapredictable O 2 OH O OH P(OCH ) [RuX2((R)-binap)] P(OCH ) P(OH) manner. Thereaction can normally be 3 2 3 2 2 performed in alcohols with up to 50% NHCOCH3 NHCOCH3 NH2 substrateconcentration under 4±100 atm phosphothreonine at room temperature with an S:Cratio of O O H2 OH O O up to 10000:1 on any scale,even using [RuX ((S)-binap)] P(OCH3)2 2 P(OCH3)2 CH3 P(OH)2 >100 kg of the substrate. Scheme 8shows H H Br NHCOCH O some synthetic applications of this asym- 3 fosfomycin metric hydrogenation. (R)-1,2-Propane- diol thus obtained from hydroxyacetone Scheme9.Asymmetric hydrogenation by dynamic kinetic resolution.XCl, Br.

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H O O 2 OH O [RuII((R)-binap)]2+ (±)- OCH3 OCH3

NHCOC6H5 NHCOC6H5 99% ee erythro:threo = 94:6

t-C H (CH ) SiO HO 4 9 3 2 HH HH OCOCH3 SR NH N O O CO2H carbapenems Scheme10. Stereoselective synthesis of carbapenem antibiotics. it is hydrogenated. Theextent of the BINAP catalyst-based asymmetric inductioniscalculated to be 104:1 in favor of the 3R isomer, whereas the substrate-based asymmetric induction is 9:1infavor of the C(2)/C(3) erythro stereochemistry.The volume of the hydrogenationreactor shown in Figure7 is 13 m3.

Figure 8. Mechanism of (R)-BINAP ±Rucatalyzed hydrogenation of b-keto esters.

moiety interacting with the Ru center is crucialfor both high reactivity and enantioselectivity.Because of the excellent chiral recognition ability of BINAP,the two stereo-determin- ing diastereomeric transition states (TSs) are well differentiated with the assistance of the oxygen ±Ruinteraction. The R-directing TS is highly favored over the S-generating diastereomer, whichsuffersfrom substantial R/P-phenyl repulsive interaction. Theoxygen±Ru dative bond (and related interaction in the reactions in Scheme 7) exerts a pivotal function in the acceleration of hydrogenation as well. Thus, b-keto esters are hydrogenated smoothly even in the simplest ketone,acetone,containingasmall amountofwater. Figure 7. Alarge-scale BINAP ±Ru-catalyzed hydrogenation at Takasago Thus,although BINAP ±Rudihalide catalysts have avery International Co. wide scope, they are unable to hydrogenatesimple,unfunc- tionalized ketones. b-Keto esters arethe best substrates for the Ru catalyzed asymmetric hydrogenation and leadtothe b-hydroxy esters in >98% ee.[59] Figure 8illustrates the mechanisticmodel. The 7. Asymmetric Hydrogenation of Simple Ketones by halide ligand in the Ru complex, which generates astrong acid BINAP/Diamine±Ruthenium Complexes and aRuHCl species by the action of H2,isimportantto facilitate the hydride transfer from the Ru centertothe Formore than half acentury,selective reduction of simple carbonyl carbon.[55] In addition, the presence of the ester ketonesrelied heavily on the metal-hydridechemistry devel-

Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 2015 REVIEWS R. Noyori oped largely by H. C. Brown (1979 Nobel laureate). Chemo- are totally ineffective.Normally,CCbonds are much more selective reduction of aCOfunction in the presence of a reactive than COincatalytic hydrogenation, but this system CCgroup has been best effected by the stoichiometric allows for the preferentialsaturation of aCOfunctionover a [60] [73, 74] NaBH4 reagent. Diastereoselective reduction of ketones coexistingCClinkage. Olefinic ketones,either conju- has frequently been achieved by Selectrides.[61] Enantioselec- gated or nonconjugated, can be converted to olefinic alcohols tive reduction of achiral ketones are effected by chiral selectively.The hydrogenation tolerates variousfunctionali- [62] stoichiometric reagentsincluding BINAL-H, DIP chlor- ties including F, Cl, Br, I, CF3,OCH3,OCH2C6H5 , [63] [64] ide, and Alpine-borane ,orbythe Corey±Bakshi ±Shi- COOCH(CH3)2 ,NO2,NH2,and NRCOR. Both electron- bata (CBS) methodcombining B2H6 or catecholborane and a rich (furan, thiophene, thiazole,etc.) and -deficient rings chiral oxazaborolidine catalyst.[65] Until very recently,these (pyridineand pyrimidine) are left intact.[75] Thesimple types of selective COreductions were not generally achiev- [RuCl2(PAr3)2(NH2CH2CH2NH2)] complex hydrogenates able by catalytic hydrogenation.[49d, 66] varioussubstituted cyclic and acyclic ketoneswith high In 1995, when Iwas the director of the ERATO Molecular diastereoselectivity,where the RuH intermediate acts as a Catalysis Project, we found that hydrogenation catalyzed by a bulky hydride species.[76] Because of the basic and protic

[RuCl2(phosphane)2(diamine)]complex and an alkaline base nature of the reaction environment, hydrogenation of config- provided ageneral solution to this long-standing problem.[67] urationally labile ketones allowsfor the dynamic kinetic Theuse of appropriate chiral diphosphanes and chiral discrimination of diastereomers,epimers, and enantiom- diamines allowsasymmetric hydrogenationofsimpleketones ers,[76±78] which effects anew type of stereoselective reductions which lack any Lewis basic functionality capable of interact- of ketones which are not possible with stoichiometric hydride ing with the metal center. Thereactivity and stereoselectivity reagents. are fine-tuned by changing the steric (bulkiness andchirality) This asymmetric hydrogenationshows promise for the and electronic properties of the auxiliaries.Asgeneralized in practical synthesis of awide variety of chiral alcohols.The Scheme 11,the newly devised BINAP/diamine complex chiral diphosphane/diamine±Ru complexes effect enantioselective hydrogenation of certain amino or amido ketones by a nonchelatemechanism, without interaction between the Ru O H2 OH Ru catalyst center andnitrogen or oxygenatoms.[78] This method has been Ar R base Ar R applied to the asymmetric synthesis of various important

pharmaceuticals,which includes (R)-denopamine,ab1-recep- O OH tor agonist, the antidepressant (R)-fluoxetine,the antipsy- chotic BMS 181100, and (S)-duloxetine,whichisapotent R R Het Het inhibitor of serotonin and norepinephrine uptake carriers (Scheme12). Benzophenones can be hydrogenated to benz- O OH hydrols with an S:Cratio of up to 20000:1 without over- reduction.[79] Enantioselective hydrogenation of certain ortho- Un R Un R substituted benzophenones leads to the unsymmetrically substituted benzhydrols with high ee values,which allows convenient synthesis of the anticholinergic and antihistaminic Cl 1 Ar2 H2 R (S)-orphenadrine.The antihistaminic (R)-neobenodine can P N R2 Ru be synthesized by using asymmetric hydrogenation of o- R3 P N bromo-p'-methylbenzophenone. Ar H R4 2 Cl 2 This approachisthe first example of general and efficient asymmetric hydrogenationofa,b-unsaturated ketones to (S)-BINAP/(S)-diamine–RuII catalyst chiral allylic alcohols of high enantiomeric purity.[72±74] The 1 4 (S)-BINAP: Ar = C6H5 (S,S)-DPEN: R = R = C6H5; selectivity profile is in sharp contrast to that observed with the R2 = R3 = H (S)-TolBINAP: Ar = 4-CH3C6H4 diamine-free BINAP ±Rucomplex, and efficiently catalyzes (S)-DAIPEN : R1 = R2 = (S)-XylBINAP: Ar = 3,5-(CH3)2C6H3 asymmetric hydrogenation of allylic alcohols (Scheme 5). Its 4-CH3OC6H4; 3 4 utility has been demonstrated by the synthesis of intermedi- R = H; R = (CH3)2CH ates of an a-tocopherol side-chain and anthracyclines,aswell Scheme11. General asymmetric hydrogenation of simple ketones.Ar [72, 73] aryl, Het heteroaryl, Un alkenyl. as b-ionol (Scheme 12). Theasymmetric hydrogenation shown in Scheme 11 is generally achieved by the combined use of an (S)-BINAP ligand and an (S)-1,2-diamine (orboth catalyzes rapid, productive, and highly enantioselective hy- R enantiomers). This is also the case for the reactionof drogenationofarange of aromatic, heteroaromatic, and s-cis exocyclic enones,such as (R)-pulegone. However, asym- olefinic ketonesin2-propanol containing tBuOK or metric hydrogenation of 2,4,4-trimethyl-2-cyclohexenone was [68±70] [74, 80] KOH. Amongvariouscomplexes,[RuCl2(xylbinap)- effected best with [RuCl2{(S)-tolbinap}{(R,R)-dpen}]. (daipen)][71] is particularly effective.For example,acetophe- Thecyclic allyl alcohol obtained in 96% ee (Scheme12) can none and its derivatives are hydrogenated with S:Cofupto be converted into aseries of carotenoid-derived odorants and 100000:1,togive the secondary alcohols quantitatively in bioactive terpenes,such as a-damascone.The R or S alcohols 99% ee,[72] although the diamine-free BINAP ±Rucomplexes with ee values as high as 95%can be obtained, even with a

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δ – δ– C O C O

δ–H Hδ– vs H Ru Ru N δ– δ–

Cl H2 R3P N Ru

R3P N Cl H2 [H] –2 HCl C O C O H H

H H2 H N N

X(R3P)2Ru X(R3P)2Ru N N H2 H2 H2

base base H+

+ + HHH2 H2 N N H2 X(R3P)2Ru X(R3P)2Ru N N H2 H2 Figure 9. a) Nonclassical metal ±ligand bifunctionalmechanism and conventional [22] 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.

Scheme12. Application of asymmetric hydrogenation of simple ketones. ametal alkoxide(Figure 9a). In this hydrogenation, the metal racemic TolBINAP ±RuCl2 complex in the presence of (R,R)- and the ligand participate cooperatively in the bond-forming or (S,S)-DPEN by asymmetric activation.[80±82] In this case,the and -breaking processes.Amore detailed mechanistic model highly enantioselective hydrogenationcatalyzed by the S di- is given in Figure 9b.The 18-electron-RuH species reduces phosphane/R,R diamine complex (or R/S,S combination) the ketonesubstratebythe pericyclic mechanism and the turns over 121 times faster than the less stereoselective formal 16-electron Ru ±amide complex reacts directly with H2 reaction promoted by the diastereomeric S/S,S (or R/R,R) in a[22] manner, or by astepwise mechanism assistedbyan complex.[83] alcohol and abase, to give back the reducingRuH complex.[85] Thereaction is rapid and highly productive.For example, Thereducingactivity of the RuH species is generated by the when amixture of acetophenone (601 g), the (S)-TolBINAP/ hydrogen-bonding NH2 end in the diamineligand, which (S,S)-DPEN Ru complex (2.2 mg), and tBuOK (5.6 g) in forms a fac relationship with the hydride ligand in the 2-propanol (1.5 L; 30 %w/v substrate concentration) was octahedral geometry.Neither ketone substrate nor alcoholic stirred under 45 atm H2 at 308Cfor 48 h, the R alcohol was product interacts with the metallic center throughout the obtained with 80% ee and 100%yield.[71,84] Under such hydrogenation. Theenantiofaces of prochiral ketones are conditions,the turnover number was greater than 2400000, differentiated on the molecular surface of the coordinatively while the turnover frequency at 30%conversion was saturated RuH intermediate.This notion is in contrast to the 228000hÀ1 or 63 sÀ1. conventional mechanism for hydrogenation of unsaturated This high rate and chemoselectivity for the C Ofunction bonds that requires the metal ±substrate p complexation. are caused by the nonclassical metal ±ligand bifunctional This NH effect is commontothe mechanism of Ru- mechanism (Figure9).[68, 70] Thehydrogenation involves a catalyzed asymmetric transfer hydrogenation.[86] Recently metal-hydride intermediate. Hydride transfer from the metal we found that [RuCl{(S,S)-YCH(C6H5)CH(C6H5)NH2}- center to the carbonyl carbonatom has been considered to (h6-arene)] (Y O, NTs) complexes or their analogues occur by a[22] mechanism.This reaction involves aRu catalyze asymmetric transfer hydrogenation of aromatic and hydride species possessing an NH2 ligand, whose hydridic acetylenic carbonyl compounds,byusing a2-propanol/alka- RuÀHand protic NÀHare simultaneously transferred to the line-base system to give the corresponding S chiral alcohols of COlinkage via asix-membered pericyclic TS,thereby high enantiomeric purity,asgeneralized in Scheme 13.[87,88] A forming an alcoholic product directly,without formationof formic acid/triethylamine mixture often serves as abetter

Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 2017 REVIEWS R. Noyori

O (S,S)-Ru cat. OH Ar base R Ar R R X X C R C H (CH3)2CHOH O O H

R'n R'n O OH

D D Ru Ru H Y HN Y X N X H Ph H (CH3)2C=O (CH3)2CHOH O OH Ph Ph Ph R2 R2 18e complex 16e complex R1 R1

R'n R'n CH3O CH3O (S,S)-Ru cat. Ar R N NH HCO2H/(C2H5)3N CH3O CH3O RCH Ru Ar C H Ru R R Y Y O H N O H N R = CH3, aryl H Ph H Ph Ph Ph

Rn Rn favored TS disfavored TS Figure 10. Metal ±ligand bifunctional mechanism in asymmetric transfer Ru Ru Ts hydrogenation catalyzed by [RuH{(S,S)-YCH(C H )CH(C H )NH }(h6- Cl O Cl N 6 5 6 5 2 N N arene)].Ralkyl or D; YOorNTs. H H R' Ph or H Ph Ph Ph often insufficient and basic research through interdisciplinary R' = CH3 or H collaboration with scientists in other fields is needed.The (S,S)-Ru catalyst recent progress in asymmetric synthesis has,infact, spurred Scheme13. Asymmetric transfer hydrogenation of carbonyl compounds such endeavors which are directed towardthe creation of and imines catalyzed by chiral Ru complexes.Ts4-toluenesulfonyl. molecularly engineered novel functions. In the mid-1980s,weestablished the long-sought after reducing agent. Certain imines are also reduced enantiose- three-component coupling synthesis of prostaglandins (PGs) lectively by this method. Thedetailed experimental[89] and illustrated in Scheme 14.[92] Thefive-membered unit could be [90] theoretical analyses revealed that the transfer hydrogena- combined with the two C7 and C8 side-chain (a and w side tion of carbonyl compounds with 2-propanol proceeds via a chains) units by organometallic methodologies.Our asym- coordinatively saturated 18-electron complex, [RuH{(S,S)- metric methods play akey role in controlling the C(11) and 6 YCH(C6H5)CH(C6H5)NH2}(h -arene)], as illustrated in Fig- C(15) OH-bearing stereogenic centers.The requisite(R)-4- ure 10. Themetal ±ligand bifunctional mechanism allowsfor hydroxy-2-cyclopentenone is conveniently prepared on a simultaneous delivery of the RuÀHand NÀHtothe CO multikilogram scale by kinetic resolution of the racemate by functionvia asix-membered pericyclic TS,which gives an S alcohol and OH O OH [Ru{(S,S)-YCH(C6H5)CH(C6H5)NH}- COOH COOH COOH (h6-arene)]. Thelatter 16-electron Ru ±amide complex dehydrogenates O OH OH OH OH OH 2-propanol to regenerate the Ru-hy- PGD PGE PGF dride species.[86, 91] 1 1 1α

O α chain O OH 65 ω chain COOCH COOH 8. Toward Cerebral Molecular 3 Science COOH OR OR OR' O OH 5,6-didehydro-PGE PGD Themajor goals of synthetic chem- 2 2 ists and the chemical industry have been the efficient synthesis of known O OH O valuable compounds.Another, and COOH COOH perhaps more important, pursuit is the creation of new valuable substan- OH OH OH OH OH OH ces and materials through chemical PGI2 PGF2α PGE2 synthesis.Toward this end, mere Scheme14. Three-componentsynthesis of prostaglandins. a chain ICH2CC(CH2)3COOCH3 ; chemical knowledge or technology is w chain (E,S)-LiCHCHCH(OR')(CH2)4CH3 .

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BINAP ±Ru-catalyzed hydrogenation.[43] TheBINAL-H re- methyl iodide and tributyl(aryl)stannane (excess) which is agent is useful for asymmetric synthesis of the lower side- applicable to the synthesis of (15R)-[11C]TIC methyl ester.[99] chain block.[93, 94] This straightforward procedureisuseful for This technology was then transferred to the PET Center at the synthesis of not only naturally occurring PGs but also their Uppsala. Avery dedicated colleagueinour team, M. Suzuki, artificial analogues.[95] volunteered to test this new artificialcompound on himself. To exploreapplications to the science of the human brain, After being carefully examined, (15R)- [11C]TIC methyl ester we collaboratedwith the research groups led by M. Suzuki was injected into his right arm. Themethyl ester was carried (my long-term collaborator at Nagoya and now at Gifu through his blood stream, passed through the blood-brain University), Y. Watanabe(Osaka City University), and B. barrier, reached his brain, and was hydrolyzed to the free [96, 97] La ngstrˆm (UppsalaUniversity;Figure 11). After along carboxylic acid, which was bound to IP2 receptors in his central nervous system. Figure 12 shows the PET images of horizontal slices of his brain, from the lower to the upper

portions. From this trial, anew receptor, IP2,was found in variousimportantstructures of the human brain. Thus,(15R)- TIC and its analogues are expected to have effects on the brain and, in fact, do show aunique neuroprotective effect, which may be of clinical benefit. Primary cultured hippo- campalneurons exposed to ahigh oxygen concentration displaythe morphological features of apoptotic cell death and Figure 11.The interdisciplinary collaborative team (from the left, M. Suzuki,R.Noyori, Y. Watanabe,and B. La ngstrˆm) that studied (15R)-TIC (15R)-TIC effectively protects them against such oxygen and the methylesters,labeled by radioactive nuclides.

investigation,(15R)-TIC,aPGI2-type carboxylic acid, was found to show strong, selective bindinginthe central nervous system, which thereby identifies the novel IP2 receptor. Interestingly,this compound has the unnatural 15R configuration, although most biologically active PG derivatives have the natural 15S configuration.This discovery wasmade by an in vitrostudy using frozen sections of rat brain and frozen sectionsofrat brain and (15R)-[3H]TIC as aprobe.[98] However, this radioactiveprobe is not appropriatefor studies

COOH COOH

11 CH3 OH HO 3H OH OH

(15R)-[3H]TIC (15R)-[11C]TIC on living monkey or human brain, since bÀ particles emitted from 3Hcan not penetratetissues.Incorporation of 11C, a positron emitter with ashort half-life of about 20 min and a high specific radioactivity, as aradioactive nuclide is essential for noninvasive studies using positron-emission tomography (PET).Positrons (b)interact with free electrons in biological materials,and produce g rays that can penetrate tissues and are detectable outside the human body.However, this 11 presentsanew chemical problem. The CH3 group must be incorporated in the final step of the synthesisof(15R)-TIC methyl ester, and the total time for synthesis,workup, purification, and sterilization should be less than 40 min Figure 12. Theuptakeof(15R)-[11C]-TIC in the humanbrain. ThePET because of the short half-life time of 11C. Astudent in my images of 18 horizontal slices from the lower to the upper portions of the group at Nagoya made aconcerted effort to achieve this and, brain (volunteer:M.Suzuki;June 13, 2000. PET CenterofUppsala eventually succeeded with arapid Pd-mediated coupling of University).

Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 2019 REVIEWS R. Noyori toxicity.[100] Similar neuroprotective effects were demonstrat- are just the namesofthe leaders of the research groups, ed in otherinvitro experiments using serum deprivation and although many young associates and students also contributed in in vivo studies of ischemic insults with gerbils,rats,and significantly.Ihad opportunities to have fruitful collaborations monkeys.Thus,the IP2 receptor is anovel target for devel- with many other scientists whose namesare cited in the oping drugs which may be neuroprotective in brain disorders references. We have been supported by many companies, and neutrodegenerative diseases. particularly Takasago International Corporationand Teijin Company. The generous and consistent support from the MinistryofEducation, Culture, Sports,Science and Technol- 9. Prospects for the future ogy was essential for the success of my research. Iamalso grateful to the Japan Science and Technology Corporationand Studiesofmolecular chirality have the promise to yield many private foundationsfor their support. Last, but not least, significant clinical, scientific, and industrial benefitsinthe Iacknowledge Professor Hitosi Nozaki at Kyoto University, future.Astructurally diverse array of molecular substances my mentor who first introducedmetothis fascinatingand exists.All molecules possess commoncharacteristics,namely, rewarding field of research. fixed elemental composition, definiteatomic connectivity,a defined relative and absolutestereochemistry,and some Received:January 25, 2002 [A512] conformation. From such precisenanometer-scale structures, certain significant properties and functions emerge.Chemists [1] Forexample,a)M.Gardner, The NewAmbidextrousUniverse, 3rd can design and synthesize molecules at will, based on ed.,W.H.Freeman&Co., New York, 1990;b)E.Heilbronner, J. D. accumulated scientific knowledge.The practical synthesis of Dunitz, ReflectionsonSymmetry,VHCA, Basel, 1993;c)R.Hoff- enantiomers with adefined absolute stereochemistry is one of mann, The Same and Not the Same,Columbia University Press,New York, 1995;d)H.Brunner. Rechts oder links in der Natur und the most significant areas of research. This endeavor is not anderswo,Wiley-VCH,Weinheim, 1999. only an intellectual pursuit but is also afertile area for the [2] G. Blaschke,H.P.Kraft, K. Fickentscher, F. Kˆhler, Arzneim.- development of beneficial technologies.[101] Its utilityis Forsch. 1979, 29,1640. obvious, and ranges from basic scientific research at asub- [3] This interpretation must be considered carefully,because the R enantiomer racemizesinvivo. femtomole scale,asinthe case of brain research described [4] a) Chem. Eng. News 1990, 68(12), 26;b)S.Borman, Chem. Eng. above,tothe industrial production of high-value compounds News 1990, 68(28), 9. in multithousand tons per annum quantities.Louis Pasteur [5] S. C. Stinson, Chem.Eng. News 1992. 70(39), 46. stated in 1851 that ™Dissymmetry is the only and distinct [6] S. C. Stinson, Chem.Eng. News 2001, 79(20), 45. boundarybetween biological and nonbiological chemistry. [7] R. Noyori, Asymmetric Catalysis in Organic Synthesis,Wiley,New York, 1994. Symmetrical physical or chemical force cannot generate [8] a) H. Nozaki, S. Moriuti, H. Takaya,R.Noyori, Tetrahedron Lett. molecular dissymmetry∫. This notion is no longer true.The 1966,5239;b)H.Nozaki, H. Takaya,S.Moriuti, R. Noyori, recent revolutionary development in asymmetric catalysis has Tetrahedron 1968, 24,3655. totally changed the approachtochemical synthesis.This field [9] a) T. Aratani, Pure Appl. Chem. 1985, 57,1839;b)T.Aratani in Comprehensive Asymmetric Catalysis, Vol. 3 (Eds.: E. N. Jacobsen, is still growingrapidly and Iamcertain that it will play a A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999,p.1451. pivotal role in the development of the life sciences and [10] a) M. Calvin, Trans.Faraday Soc. 1938, 34,1181;b)M.Calvin, J. Am. nanotechnology in the 21st century. Chem.Soc. 1939, 61,2230. [11] J. Halpern, J. F. Harrod, B. R. James, J. Am. Chem. Soc. 1961, 83,753. The highest honor for me is to be recognized with the [12] J. F. Young, J. A. Osborn, F. H. Jardine,G.Wilkinson, Chem. Commun. 1965,131. prestigious 2001 NobelPrize in Chemistry.This honor must be [13] S. Akabori, S. Sakurai, Y. Izumi, Y. Fujii, Nature 1956, 178,323. shared with my research family at Nagoya and with many [14] a) W. S. Knowles,M.J.Sabacky, Chem.Commun. 1968,1445;Nobel collaborators at other institutions.Asymmetric hydrogenation Lecture: b) W. S. Knowles, Angew.Chem. 2002, 114,2096; Angew. has been the life-longfocus of my research, and my studies Chem.Int. Ed. 2002, 41,1998. [15] L. Horner, H. Siegel, H. B¸the, Angew.Chem. 1968, 80,1034; Angew. have reliedlargelyonBINAP chemistry,which Iinitiated with Chem.Int. Ed. Engl. 1968, 7,942. the late Professor HidemasaTakaya. Subsequently,BINAP [16] These achievements were based on the classic work of Mislow and chemistry was developed further in our laboratories at Nagoya, Horner on resolution of chiral tertiaryphosphanes:a)O.Korpiun, where Professors Masato Kitamura andTakeshi Ohkuma R. A. Lewis,J.Chickos,K.Mislow, J. Am. Chem.Soc. 1968, 90,4842; made major contributions.Other asymmetric hydrogenation b) L. Horner, Pure Appl. Chem. 1964, 9,225, [17] T. P. Dang, H. B. Kagan, J. Chem. Soc. Chem. Commun. 1971,481. methods were discovered during my directorship of the [18] a) W. S. Knowles,M.J.Sabacky,B.D.Vineyard, J. Chem.Soc. Chem. ERATO Molecular Catalysis Project (1991 ±1996), which Commun. 1972,10; b) B. D. Vineyard, W. S. Knowles,M.J.Sabacky, was managedbyProfessor Takao Ikariya (now Tokyo Institute G. L. Bachman, D. J. Weinkauff, J. Am. Chem.Soc. 1977, 99,5946; of Technology) and Dr.Shohei Hashiguchi (Takeda Chemical c) W. S. Knowles, Acc. Chem.Res. 1983, 16,106;d)J.Crosby in Chirality in Industry:The Commercial Manufacture and Applications Industry). Our laboratory at Nagoya is small. To realize the of OpticallyActive Compounds (Eds.: A. N. Collins,G.N.Sheldrake, utilization of our scientific achievements,itwas important to J. Crosby), Wiley,Chichester, 1992,chap.1. collaborate with other institutions.Inthis regard, Iappreciate [19] E. J. Corey, R. Noyori, T. K. Schaaf, J. Am. Chem. Soc. 1970, 92,2586. the cooperation of the groups led by Professors Sei Otsuka and [20] One of the early examples of successful asymmetric catalysis was the ¬ Kazuhide Tani (Osaka University), and Professors Masaaki Ni-catalyzedhydrovinylation of norbornene,see:B.Bogdanovic,B. Henc, A. Lˆsler, B. Meister, H. Pauling, G. Wilke, Angew.Chem. Suzuki(Gifu University), Yasuyoshi Watanabe (OsakaCity 1973, 85,1013; Angew.Chem.Int. Ed. Engl. 1973, 12,954. University), and Bengt La ngstrˆm (Uppsala University). These [21] R. Noyori, H. Takaya, Chem.Scr. 1985, 25,83.

2020 Angew.Chem. Int. Ed. 2002, 41,2008 ±2022 Asymmetric Catalysis REVIEWS

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Chem.Commun. 1982,600;b)K.Tani, T. Yamagata, S. Akutagawa, Noyori, Org. Synth. 1993, 71,1;c)K.Mashima, K. Kusano, N. Sato,Y. H. Kumobayashi, T. Taketomi, H. Takaya, A. Miyashita, R. Noyori, Matsumura, K. Nozaki, H. Kumobayashi, N. Sayo,Y.Hori, T. S. Otsuka, J. Am. Chem.Soc. 1984, 106,5208. Ishizaki, S. Akutagawa,H.Takaya, J. Org. Chem. 1994, 59,3064. The [28] a) S. Akutagawa in Organic Synthesis in Japan:Past, Present, and halogen-containingRucomplexes are also effective for asymmetric Future (Eds.: R. Noyori, T. Hiraoka, K. Mori, S. Murahashi, T. hydrogenation of various functionalized olefins. Onoda, K. Suzuki, O. Yonemitsu), Tokyo KagakuDozin, Tokyo, [51] a) M. Kitamura, T. Ohkuma, S. Inoue,N.Sayo,H.Kumobayashi,S. 1992,p.75; b) S. Akutagawa in Chirality in Industry:The Commer- Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am. Chem. Soc. 1988, cial Manufacture and Applications of Optically Active Compounds 110,629;b)K.Mashima, K. Kusano,T.Ohta, R. Noyori, H. Takaya, (Eds.: A. N. 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Tokunaga, R. Noyori, J. Org. Chem. 1992, 57,4053; Ramachandran, H. C. Brown, ACSSymp.Ser. 1996, 641,1. c) H. Takaya,T.Ohta, S. Inoue, M. Tokunaga, M. Kitamura, R. [61] a) H. C. Brown, S. Krishnamurthy, J. Am. Chem.Soc. 1972, 94,7159; Noyori, Org. Synth. 1993, 72,74. b) S. Krishnamurthy,H.C.Brown, J. Am. Chem. Soc. 1976, 98,3383. [40] a) T. Ohta, H. Takaya, R. Noyori, Tetrahedron Lett. 1990, 31,7189; [62] a) R. Noyori, I. Tomino,Y.Tanimoto,M.Nishizawa, J. Am. Chem. b) M. T. Ashby, J. Halpern, J. Am. Chem. Soc. 1991, 113,589. Soc. 1984, 106,6709;b)R.Noyori, I. Tomino,M.Yamada,M. [41] T. Ohta, H. Takaya, M. Kitamura, K. Nagai, R. Noyori, J. Org. Chem. Nishizawa, J. Am. Chem.Soc. 1984, 106,6717. 1987, 52,3174. [63] ™Reductions in Organic Synthesis:Recent Advances and Practical [42] H. Takaya, T. Ohta, N. Sayo,H.Kumobayashi, S. Akutagawa,S. Applications∫: P. V. Ramachandran, H. C. Brown, ACSSymp.Ser. Inoue,I.Kasahara, R. Noyori, J. Am. Chem.Soc. 1987, 109,1596;H. 1996, 641,84. Takaya, T. 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Naturforsch. B 1998, 53,267;h)Q.Jiang, Y. Jiang, D. Xiao,P.Cao,X. [85] Theketone substrate reacts in an outer sphere of the coordinatively Zhang, Angew.Chem. 1998, 110,1203; Angew.Chem.Int. Ed. 1998, saturated 18-electron complexwithout interaction with the metallic 37,1100;i)P.Cao,X.Zhang, J. Org. Chem. 1999, 64,2127. center. Thus the general schemegiven in Figure 1istobemodified to Heterogeneous hydrogenation, see:j)T.Osawa, A. Tai, Y. Imachi, some extent. Forother mechanistic investigations, see:a)K.Abdur- S. Takasaki in ChiralReactionsinHeterogeneous Catalysis (Eds.: G. Rashid,M.Faatz, A. J. Lough, R. H. Morris, J. Am. Chem.Soc. 2001, Jannes,V.Dubois), Plenum,New York, 1995,p.75; k) T. Harada, T. 123,7473;b)R.Hartmann, P. Chen, Angew.Chem. 2001, 113,3693; OsawainChiral Reactions in Heterogeneous Catalysis (Eds.: G. Angew.Chem.Int. Ed. 2001, 40,3581. Jannes,V.Dubois), Plenum,New York, 1995,p.83. [86] R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001, 66, [67] T. Ohkuma, H. 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Chem.Soc. 1999, 121,9580. anisyl-2-isopropyl-1,2-ethylenediamine. [91] M. Yamakawa, I. Yamada, R. Noyori, Angew.Chem. 2001, 113,2900; [72] T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Angew.Chem.Int. Ed. 2001, 40,2818. Murata, E. Katayama, T. Yokozawa, T. Ikariya, R. Noyori, J. Am. [92] a) M. Suzuki, A. Yanagisawa, R. Noyori, J. Am. Chem.Soc. 1985, 107, Chem.Soc. 1998, 120,13529. 3348;b)M.Suzuki,A.Yanagisawa, R. Noyori, J. Am. Chem. Soc. [73] T. Ohkuma, H. Ooka,T.Ikariya, R. Noyori, J. Am. Chem.Soc. 1995, 1988, 110,4718;c)M.Suzuki, Y. Morita,H.Koyano,M.Koga, R. 117,10417. Noyori, Tetrahedron 1990, 46,4809. [74] T. Ohkuma, H. Ikehira, T. Ikariya, R. Noyori, Synlett 1997,467. [93] M. Suzuki, H. Koyano,Y.Morita,R.Noyori, Synlett 1989,22. [75] T. Ohkuma, M. Koizumi, M. Yoshida, R. Noyori, Org. Lett. 2000, 2, [94] This process has been used at Ono PharmaceuticalCo. for the 1749. industrial synthesis of PGs using the Corey method. [76] T. Ohkuma, H. Ooka, M. Yamakawa, T. Ikariya, R. Noyori, J. Org. [95] a) R. Noyori, M. Suzuki, Angew.Chem. 1984, 96,854; Angew.Chem. Chem. 1996, 61,4872. Int. Ed. Engl. 1984, 23,847;b)R.Noyori, M. Suzuki, Chemtracts: [77] T. Matsumoto,T.Murayama, S. Mitsuhashi, T. Miura, Tetrahedron Org. Chem. 1990, 3,173;c)R.Noyori, M. Suzuki, Science 1993, 259, Lett. 1999, 40,5043. 44. [78] T. Ohkuma, D. Ishii, H. Takeno,R.Noyori, J. Am. Chem.Soc. 2000, [96] a) M. Suzuki,K.Kato,R.Noyori, Yu.Watanabe,H.Takechi, K. 122,6510. Matsumura, B. La ngstrˆm, Y. Watanabe, Angew.Chem. 1996, 108, [79] T. Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R. Noyori, Org. 366; Angew.Chem.Int. Ed. Engl. 1996, 35,334;b)H.Takechi, K. Lett. 2000, 2,659. Matsumura, Yu.Watanabe,K.Kato,R.Noyori, M. Suzuki, Y. [80] T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M. Watanabe, J. Biol. Chem. 1996, 271,5901. Terada,R.Noyori, J. Am. Chem.Soc. 1998, 120,1086. [97] Account:M.Suzuki, R. Noyori, B. La ngstrˆm, Y. Watanabe, Bull. [81] T. Ohkuma, H. Takeno,Y.Honda, R. Noyori, Adv.Synth. Catal. Chem.Soc. Jpn. 2000, 73,1053. 2001, 343,369. [98] Yu.Watanabe,K.Matsumura, H. Takechi, K. Kato,H.Morii, M. [82] Review:K.Mikami, M. Terada,T.Korenaga, Y. Matsumoto,M. Bjˆrkman,B.La ngstrˆm, R. Noyori, M. Suzuki, Y. Watanabe, J. Ueki, R. Angelaud, Angew.Chem. 2000, 112,3676; Angew.Chem. Neurochem. 1999, 72,2583. Int. Ed. 2000, 39,3532. See also:K.Mikami, T. Korenaga, M. Terada, [99] a) M. Suzuki, H. Doi, M. Bjˆrkman, Y. Andersson, B. La ngstrˆm, Y. T. Ohkuma, T. Pham, R. Noyori, Angew.Chem. 1999, 111,517; Watanabe, R. Noyori, Chem.Eur.J.1997, 3,2039;b)M.Suzuki, H. Angew.Chem. Int. Ed. 1999, 38,495;K.Mikami, T. Korenaga, T. Doi, K. Kato,M.Bjˆrkman,B.La ngstrˆm, Y. Watanabe,R.Noyori, Ohkuma, R. Noyori, Angew.Chem. 2000, 112,3854; Angew.Chem. Tetrahedron 2000, 56,8263. Int. Ed. 2000, 39,3707. [100] T. Satoh,Y.Ishikawa, Y. Kataoka, Y. Cui, H. Yanase,K.Kato,Yu. [83] Nonlinear effects in catalysis should be investigated carefully Watanabe, K. Nakadate,K.Matsumura, H. Hatanaka, K. Kataoka, because of the homochiraland heterochiralinteraction of the chiral R. Noyori, M. Suzuki, Y. Watanabe, Eur.J.Neurosci. 1999, 11,3115. species present in the catalyticsystem.For reviews, see:a)R.Noyori, [101] R. Noyori, S. Hashiguchi, T. Yamano in Applied Homogeneous S. Suga, H. Oka, M. Kitamura, Chem.Rec. 2001, 1,85; b) C. Girard, Catalysis by Organometallic Complexes, 2nd ed.(Eds.: B. Cornils, H. B. Kagan, Angew.Chem. 1998, 110,3088; Angew.Chem.Int. Ed. W. A. Hermann),VCH-Wiley,Weinheim,557. 1998, 37,2922;c)D.R.Fenwick,H.B.Kagan, Top. Stereochem. 1999, [102] Nobel lecture:K.B.Sharpless, Angew.Chem. 2002, 114,2126; 22,257. Angew.Chem.Int. Ed. 2002, 41,2024. [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 Angew.Chem. Int. Ed. 2002, 41,2008 ±2022

REVIEWS

Searching for NewReactivity (Nobel Lecture)**

K. BarrySharpless*

Theprocesses for the selective oxida- Ligand-acceleratedcatalysis is crucial lectivity of Natures enzymes,and tol- tion of olefins have long been among to these reactions and might be the erant of substrates throughout the the most useful tools for day-to-day agent for uncovering more catalytic entire range of olefin substitution pat- organicsynthesis.Herein, the focus is processes.Inaddition to the selectivity terns. on the asymmetric-epoxidation (AE) benefits of catalysis,the phenomenon and asymmetric-dihydroxylation(AD) of turnover(amplification) raises its Keywords: asymmetric catalysis ¥ ep- reactionsdeveloped by Sharpless and potential impact. Theauthor and his oxidation ¥ hydroxylation ¥ Nligands ¥ co-workers.The reactions have awide co-workers developed small, highly Nobel lecture scope,are simple to run, and involve enantioselective catalysts that were readily available starting materials. unfettered by the ™lock-and-key∫ se-

In 1938, three years before Iwas born, alive coelacanth was the next coelacanth,the first to see something that was taken from the waters off the eastern coast of South Africa. beyond reasoning, evenbeyond imagining. Previously known only in the fossil record from some hundred OpeningaNobel Lecture with afishing expeditionmay million years ago,the coelacanthand the implications of seem frivolous,even indecorous,but Iassure you no its discovery remained big news for years,and fueled disrespectisintended. These are the circumstances that an enthusiasm for ™creatures∫ that persisted for decades. shaped my professional life:myfirst laboratory was New Those of us born in the 1940s grew up on photos of Jersey×sManasquan River, whose astonishingly rich variety eminent scientists setting off on expeditions,their sunburned addicted me to discovery;afew years later, when Iwas as faces dwarfed by mountain explorers× garb,ormaking comfortable at sea as I×d been on the river, my laboratory thumbs-up signs as they enteredthe water in scuba gear. We becamethe Atlantic Ocean.Later, when Istarted doing shared their confident expectation that the Loch Ness chemistry,Idid it the way Ifished–for the excitement, the Monster, Sasquatch, the Yeti–even adinosaur–soon would discovery,the adventure,for going after the most elusive catch be taken alive. imaginable in uncharted seas. Igrew up loving the sea and loving fishing in particular, Chemists usuallywrite about their chemical careers in but unlike most fishermen Icared less for the size or terms of the different areas and the discrete projects in quantity of the catch than for its rarity.Nothingcould those areas on which they have worked. Essentially all my be more exciting than pulling (if not this time,surely the chemical investigations,however, are in only one area, next!) amysterious andhitherto unknown creature from the and Itend to view my research not with respect to projects, water. As akid, Ipassionatelywanted to be one who caught but with respect to where I×ve been driven by two passionswhich Iacquired in graduate school:Iam pas- sionate about the Periodic Table (and selenium, titanium, and osmium are absolutely thrilling), and Iampassionate about [*] Prof.Dr. K. B. Sharpless Department of Chemistry catalysis. TheScripps Research Institute What the ocean was to the child, the Periodic Table is to the 10550 North TorreyPines Road, La Jolla, CA 92037 (USA) chemist;new catalytic reactivityis, of course,mypersonal Fax: (1) 858-784-7562 coelacanth. E-mail:[email protected] Even thoughIgrew up in Philadelphia, if someone asks me [**] Copyright¹The Nobel Foundation 2002. We thank the Nobel where I×m from, Iusuallysay ™the Jersey Shore∫, because Foundation,Stockholm,for permission to print this lecture.Adapted with the permission of the editors from ™Coelacanthsand Catalysis∫: that×s where my family spent summers,aswellasmany K. B. Sharpless, Tetrahedron 1994, 50,4235. weekends and holidays,with my father joining us whenever he

2024 Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 ¹WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany,2002 1433-7851/02/4112-2024 $20.00+.50/0 Asymmetric Oxidation REVIEWS could. My father had aflourishing one-man general-surgery yards or so,Elmer doubled ahead toward the shore to draw practice,which meant he was perpetually on call. With him at the purse.Iliked it best if abig eel or asnapping turtle home so little andpractically guaranteed to be called away got caught up in the net, which made the water boil and when he was,mymother liked being near family and friends at the net flop into the air. Ialwayshoped we×d catch something the Shore,where her parents had settled and established a new. fishery after emigrating from Norway.When Iwas ababy,my Ihad alittle dinghy,and my realm of exploration expanded parents boughtland on abluff overlooking the Manasquan in direct proportion to my rowing ability.The same tide that River, about four miles up from where the river enters the created this abundant estuary also was my nemesis,which Atlantic. foreverstranded me upriverinthe narrows or perhaps at Like many scientists,Iwas avery shy child, happier and Chapman×s Boat Yard, amile downstream and on the more confident when on my own, and my interest was totally oppositebank. Since my parents couldn×t keep me off the absorbed by the river. In those days,the incoming tide water, they opted for increasing the likelihood of my getting transformed our part of the river, from achannel flankedby home unaided by giving me aboat with an outboard. It wasn×t broad mudflats to aquarter-mile basin that exploded with life long before Iwent down river all the way to the inlet of myriad variety–about adozen kinds of fish big enough to (absolutely forbidden, of course),and, soon after, the make it to the dinner table,plus blue crab,eel, and abounty prospect of new creatures to pull from the water lured me of fry and fingerlings that would graduate downstream to the out through the rock jetty andinto the ocean;atthe time Iwas ocean.Iwas obsessed with finding and observing everything only seven or perhaps eight years old. that lived in the river and knowing everyonewho worked By the time Iwas ten, Iran crab and eeltraps and supplied on it. everyoneweknew with fish as well;at14Istarted working My most delicious childhood memory is the excitement I during the summer as the first (and only) mate on acharter experienced at the instant of awakening on almostevery boat. My parents allowed me to go to sea when Iwas so young summer morning;the sound Iassociate with that feeling is the and small even for my age because Iwas offered ajob on a distant whine of my first scientific mentor×s outboard motor. relative×s boat–little did my parents or Iknow that Uncle That was my wake-up call, and within minutes Iwas at the Dink, acousin actually,offered me the job so he wouldn×t river×s edge,waiting in the predawnstillness for Elmer have to pay a™full-sized∫ helper. Isowanted to keep working Havens and his father Ollie to make their way across the river on the boatsthat it was years before Idared tell my parents from Herbertsville to pickmeupto™help∫ them seine for what went on aboard the Teepee,like how the Coast Guard crabs.Amused by my regularly walking along the bank to refused assistance to Dink because his boat was in chronic watch them haul their seine,Elmereventually installed me in disrepair. (Consequently,some of our adventures at sea were the boat, which he used for transportationaswell as for memorable indeed–grappling hooks and guns have their steadying himself as he draggedthe seine×s deep-water end. place in the canon–andImention this trove of Uncle Dink Ollie walked one end of the seinealong the shore,alarming stories because,for years,myMIT colleagues begged me to the crabs gathered at the river×sedge,and frighteningthem tell them over and over again). toward deeper water, and so into the net×s pocket. Chest deep On acharter boat, the captain pilots the ship and finds the in water and mud, Elmer walked parallel to his father, with fish the customers reel in. Meanwhile,the mate is over the one arm clasping the seine,the other hooked over the boat×s boat like adervish, skillfully arraying the water with fishy gunwale.Elmerand I, our heads close together, would temptations–adjustingoutriggers, finding the perfect combi- speculateabout the catch, taking into accountall the nation of lure or bait and tackle,always mindful of the action variables–the weather, the season, the tide.Every hundred on nearbyboats 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 generalmethodsfor stereoselective oxidation–the Sharpless reactions for asymmetric epoxidation, dihydroxylation, and aminohydroxylationofolefins.His mentors at Dartmouth College (BAin 1963), Stanford College (PhD in 1968 and postdoctoralresearch), and Harvard University (further postdoctoralresearch) 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 Professor of Chemistry at the ScrippsResearch Institue,Prof.Sharpless was amember of Faculty at the Massachusetts Institute of Technology (1970 ±77, 1980 ±90) and Stanford University (1977 ± 80). Prof.Sharpless×s honoursinclude the Chemical SciencesAward of the National Academy of Sciences (of which he is amember), the RogerAdams and ArthurC.Cope Awards from the American Chemical Society,the Tetrahedron Award, the King Faisal Prize,the Prelog Medal, the Wolf Prize,the NobelPrize(2001),and honorary doctorates from five American and European universities.The Sharpless research group continues to search for new homogeneous oxidation catalysts and for transition-metal-catalyzed asymmetric processes.

Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 2025 REVIEWS K. BSharpless friends were all mates,wenaturally agreed that enticing fish to think I×ve gone fishing in the literal sense adozen times bite was the greatest challenge,but Ialone felt that getting the since then! strike wasthe most fun, even more exciting than landing From van Tamelen, aGilbertStork prote¬ge¬,Iinherited the fish. Iworked as amate almost daily every summer, right enthusiastic disdainfor ™safe∫ problems,deep admiration for up until the day before Iset out from New Jersey,headed traditional multistep organic synthesis,and awe before toward the biggest ocean and graduate school at Stanford selective biological catalysis:studying the squalene oxide/ University. lanosterol cyclase enzyme left me impressed by enzymic That was in 1963. In the spring of that year, my inspiring selectivity,but depressed by the difficulty of using enzymes for Dartmouth College chemistry professor and first research synthetic transformations.After getting adoubledose of him director, TomSpencer, talked me into delaying entering in the classroom, Derek Barton becamemymodel. At medical school to try ayear of graduate school. He sent me to Dartmouth, TomSpencer taught acourse on conformational Stanfordspecifically to work for E. E. vanTamelen, Tom×s analysis,based on one he took at Wisconsin from WilliamS. own mentor at Wisconsin. Theappeal of fishing was such that Johnson (Tom×s uncle,infact), then Iexperienced the original Tom, to my later regret, never succeeded in getting me to at Stanford.[**] Being wet behind the ears,Itook confor- spend any summersworking in his lab.Infact, even in mational analysis for granted;itwas Sir Derek×s search graduate school, Iexpressed my ambivalencebycontinuing for new reactivitythat electrified me.Apostdocwith to fantasize about finding aboat out of Manasquan to Jim Collman (the only person, Iconcede,who gets more skipper andbyfailing–this did not please v.T.–to do the excited about chemistry than Ido) ignited my interest in simple paperwork required to renew my NSF predoctoral using simple metal complexes to develop catalysts (in the fellowship. Collman lab,incidentally,Ihad the privilege of many hours However, towardthe end of my first year at Stanford, a at the blackboard with labmate Bob Grubbs). Then, before serendipitous misunderstanding catalyzed the complete trans- taking up my job at MIT,apostdocwith Konrad Bloch fer of my passion (some would say my monomania) from one confirmed my hunch that impatience rendered me incom- great science to another;from fishing to chemistry.Before petent around enzymes.Konrad graciously let me start leavingfor alengthy European visiting professorship,v.T.sent working on my own ideas when his were much too frustrating me to the library to look for reactive inorganic species that for me. might produce interesting transformations of organic com- One other part of my background seemstohave contrib- pounds.Myfirst projects with v.T. were selective oxidation of uted to my chemistry.The first American Sharpless(™Shar- polyolefins and titanium-mediated deoxygenative coupling of ples∫ then) came to Pennsylvania in the 17th Century,not alcohols,and Iwas already primedtoappreciate useful long after William Penn. My father was apracticing Quaker chemistry employing ™strange∫ elements after selecting the only as achild, but the values in our home were Quaker Wittig Reaction from alist of suggested topics for my student values,and Iwas educated in aQuakerschool. TheQuakers seminar. TheWittig Reaction really engaged my enthusiasm, encourage modesty,thrift,initiative,and enterprise,but the and Iingenuously concluded that findingnew reactions other greatest good is being aresponsible member of the commun- chemists could use looked like alot of fun. ity–being useful. ™Elegant∫ and ™clever∫ were the chemical In anyevent, uponv.T.×s return, Idiscovered he had not accolades of choice when Istarted doing research, justas intended for me to spend all those months immersed in the ™novel∫ is high praise now.Perhaps the Quakers are literature.While Ihad no research results to report,Idid have responsible for me valuing ™useful∫ most. anotebook filled with ideas and an eagerness to drop my line So that is my background as achemist. I×ve been accusedof throughout the vastness of the Periodic Table.Idon×t going too far, when Ispeculate that chirality fascinates me because Ihandled my umbilical cord in utero,but I×m quite sincere in proposing that the extraordinary training Ireceived as ayoung chemist transformedanexisting passion for [*] This diversion into fishing as ametaphor for research could go on for pages;consider how,when aboat was hooking tuna–the catch of discovering the unknown into the search for new reactivity, choice–word spread by radio and the competition converged from and that Quakerutilitarianismmade the selective oxidation of every compass point.The hot boat×s captain greetedthis acknowledg- olefins so appealing. ment of his success with some anxiety;while he liked setting the other With respecttochemical reactions,™useful∫ implies wide captains× agendas and pleasurably speculating that the parties on the scope,simplicity to run, and an essential transformation of other boats were considering chartering him next time,the secrets of his successnonetheless required protection, so trolling speedswere readily available starting materials.Clearly,ifuseful new lowered to sink the lures and prevent rubberneckers from identifying reactivity is the goal, the obvious strategy is investigating the them, and red herrings (literally,onoccasion!) were casually displayed on the fish box. Isaak Walton and John Herseydevoted whole bookstothis metaphor, so indulge me for afew more sentences.The handy process versus [**] When teachingMITundergraduates, Ialways said ™The lights came on product dichotomy that applies so neatly to much of human endeavor with conformational analysis∫, without thinking where Ipicked up the illuminates this fisherman ±chemistcomparison, too.Conventional phrase,but now Iknow: the previous TetrahedronPrize article states wisdom places fly-fishing at the ™process∫ end of the scale,while a ™Just as chemists of the Robinson generation worked without concern ™product∫ fisherman uses sonar to find aschoolbeforehebothers to get for stereochemical factorssowe, in the early days,were working in his line wet. Processperson though Iam, only the Manasquan River ran ignorance of conformational considerations until Derek Barton through my fishing days;trolling for the unknown always had more showed us the light in 1950∫. Theauthoris, of course,Bill Johnson appeal than hooking atroutIalready knew was there. (see reference [1]).

2026 Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 Asymmetric Oxidation REVIEWS transformations chemists rely on. Theprocesses for the selective oxidation of olefins have long been among the most useful tools for day-to-day organic synthesis because of these appealing characteristics of olefins: 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 heteroatomsthrough selective oxidations, 3) most simple olefins are prochiral, and provide a Scheme2.Asymmetric epoxidation and dihydroxylation reactions of geraniol. prominent portal to the chiral world. Thetrisubstituted olefin geraniol, in additionto being one of my favorite smells,provides an excellent case study both for laying out the challengesofselective olefin indirect solution to enantioselective epoxidation at the 6,7- oxidationaswell as for noting some benchmarks in meeting position (Scheme 2).[5] those challenges. In 1990 came the breakthrough introduction of enantiose- As shown in Scheme 1, geraniol(1)has two trisubstituted lectivityinto existing manganese ±salen ligand catalystsfor olefinic units,one of which has ahydroxy group in the allylic the epoxidation of isolated olefins.[6] Developed independ- position.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 afew of the six olefin- substitution classes.Nonetheless,their very exis- tence is tantalizing, and encourages the hope that ageneral, off-the-shelf solution will be found for the direct asymmetric-epoxidation reaction across the full range of isolated-olefin substitution patterns. Thegreater generalityofman-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 decadeofmy career, their pioneering development of man×s Scheme1.Regio- and enantioselective monoepoxidations of geraniol. first highly enantioselective catalysts (the l- DOPAsynthesis that cameout of Knowles× Monsanto lab was the asymmetric hydrogena- while making each of the individual enantiomers requires tion×s first commercial application) sustained my faith that a enantioselectivity.WhenHenbest showed that the electronic catalyst for asymmetric oxidation could be found. Jack deactivation by the oxygensubstituent at C-1 causes peracids Halpern×s mechanisticstudies[7d] on asymmetric-hydrogena- to prefer the 6,7-double bond (especially on the ester tion catalysis likewise inspired me.Several Japanesechemists, derivatives), making racemic 3 became possible.[2] When I chief among them Ryoji Noyori,[7e] hugely extended both the started doing research in the 1960s,neither racemic 2 nor any scope and application of the asymmetrichydrogenation of the enantiomers could be synthesized directly.Solvingthe process.[8] other half of the regioselectivity problem was an obvious This focusedsearch has frustrated but never bored me,even challenge,but enantioselectivity was considered well-nigh after so many years,and the geraniol paradigm illustrates why. impossible. My own investigations into the oxidation of olefins com- In 1973, Bob Michaelson cracked the other half of the mencedatMIT in 1970, but, fittingly,Iwas back at Stanford regioselectivity problem presented by geraniol.[3] Since early- on January18, 1980, for Tsutomu Katsuki×s dramatic discov- transition-metal-catalyzed epoxidations with alkyl hydroper- ery of the titanium-catalyzed asymmetric epoxidation.[4,9a] oxides were highly selective for the 2,3-position, racemic 2 Twoyears later, the most scientifically stimulatingand could be prepared as well. professionally gratifying collaboration of my career, the total In 1980, Tsutomu Katsuki discovered the titanium-cata- syntheses of the eight l-hexoses with my MIT colleagueSat lyzed asymmetric epoxidation (AE);the enantioselective Masamune, capped the AE×s discovery.[11] Previous articles[12] oxidationofolefins bearing allylic hydroxy groups made it in avein similar to this one describe that chemistry;under- possible 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. Theosmium-catalyzed asymmetric dihydroxylation(AD), After the euphoria of completing the hexose syntheses, discovered in 1987,subsequently was improved to the point three years were spent developing, refining, and finding more that either 3 or ent-3 could be made by way of the diol, an applications for the AE. During this time Ireturned to the

Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 2027 REVIEWS K. BSharpless search for new reactivity, but it was clear that my random, reactivity.Meditating on the AE yielded this lesson to guide scattershot attempts were going nowhere,[*] so Iwas grateful that search:Ligand-acceleratedcatalysis (the significance of for the opportunity to spend the first three months of 1987 as a which is documented in M. G. Finn×s fine MIT thesis on the Sherman Fairchild Scholar at Caltech. mechanism of the AE[13]), is crucialtothe AE and not merely Many universities and institutions have handsome Fairchild afeature of it;despite its rarity,this phenomenon might be the buildings,but Caltech, ever the bastion of collegiality and agent for uncovering more catalytic processes. camaraderie,used its Fairchild grant to endow aprogram that Of course,the first and best-known example of ligand brings scientists from many fields to be housed graciously in acceleration is found in Criegee×s papersfrom the 1930s.[14] He the sunshine for as long as ayear. Since my research group×s observed that pyridine accelerates the reaction in his classic investigation of the AE had reached the point of diminishing study of osmium tetroxide and olefins. Ironically,the lesson returns, Ileftfor Pasadena hoping to renew my mission. from the AE was directing me backtowardCriegee,whose Ilove readingjournals,and Ilove mountains,sothe Caltech discoveries in olefin oxidationand osmylation were,inlarge library with its panoramic view of Mount Wilson became my measure,the jumping-off point for my own research career. thinking place of choice.Every day Mount Wilson offered Ifirst looked into Criegee×s process shortly after becoming new vistas,especially on those occasions when snow fell an assistant professor at MIT.Myattraction to the reaction of during the night. One morning, the mountain was completely OsO4 with olefins was inevitable.Osmium tetroxidenot only cloaked(the first time afreezing temperature was recorded in accomplishes an important synthetic transformation,but it downtown LA, Irecall), and the melting snow receded at such does so with ascope and reliabilityunique amongreactions aclip that Iwas sure Isaw it happening.Mount Wilson was the used for organic synthesis.Itreacts only with olefins and it perfect backdrop for bringing my own big pictureback into reacts with all olefins(slight poetic license here). Even R. B. focus,and Ireturned to MITeager to renew my search for new Woodward valued Criegee×s stoichiometric transformation so

much he was willing to use 100 gofOsO4 in one shot. Osmium×s expensewas not compatible with ™useful,∫however [*] Ihave enormousadmiration for colleagues who can keep multiple and, since the existing catalytic variants were not very research projects alive and large groups humming, but the ™mono- effective,Istarted searching for areliable catalytic method. mania∫ that prevents me from being able to do that is my long suit as well, making it possible to concentrate–for years,actually–on asingle In 1975, Kagayasu Akashi found agood process for us,based topic. Iknow some chemists call my approach ™intuitive,∫ aterm I×ve on ahydroperoxide as an oxidant, tertiary-butyl hydroper- always thought underestimates the rigor that framesmymethod; oxide (TBHP),[15] but the brass ring was ultimately captured perhaps ™unstructured∫ or ™contemplative∫ is more accurate.Many of that same year with the publication of the famous Upjohn my cohorts are quick and facile and canjump on afew interesting bits process based on N-methyl morpholine-N-oxide (NMO).[16] of data and start buildingtentative edifices that get taken apart and reassembledtosuit new data. I, on the other hand, am ruminative:my Throughout the rest of the 1970s,osmium remained our trainingafter all consisted of busily pokingand perturbingthe primary tool for looking for new reactivity. We discovered Manasquan River, acurriculum both urgent and leisurely, one that that imido osmium(viii)species effected stoichiometric cis- permitted exploration without assumptions and without the structure oxyamination of olefins in direct analogy to the cis-dihydrox- imposed by deadlines or competition, or by knowing too little or too much. Since Iwas compelled by shyness to learn to do much on my ylation of olefins by osmium tetroxide; even more effective own, there was (and is) no right or wrong way,only many ways,some catalytic versions of those transformations came shortly more or less suited to agiven endeavor. Thediscipline, nonetheless, is thereafter. exacting;everything that can be observed should be observed, even if it In 1977 Ileft MIT,where Ihad been acontented member of is only recalled as the bland background from which the intriguing bits awonderful chemistry faculty since 1970,for Stanford pop out like Venus in the eveningsky.The goal is always finding something new,hopefully unimagined and, better still,hitherto University,where Ipreviously spent six contented years as a unimaginable.When Ibecameabench- and desk-bound explorer, the graduate student and postdoc, surrounded by awonderful method stayed the same.Itry to imagine away the packaging the chemistry faculty.Inever made the transition back to information arrivesin, then let bits and pieces move around lazily, contentment at Stanford, probably because my research rather like objects tumbling slowly in zero gravity,but eventually,over time,exploring every possible relationship with other information wasn×t churning up much. This frustrated me and scared off that×s previously arrived. Since joining the faculty of TheScripps potential graduate students who wanted publications, not a Research Institute,I×ve discovered that ocean swimming and running fishing expedition. In addition, at Stanford Iremained awed on the beach provide an excellentmediumfor this kind of activity. by afaculty Iworshiped when agraduate student, and Ilacked However, in any climate,the best catalyst is generous,stimulating the confidence to stand firm on issues,particularly faculty conversation. This slow,but endlessly fascinating, methodislike an exotic ritual courtship,full of displays of brightfeathers or offerings of appointments,that meant alot to me.In1979, at about the shiny metal or towersofsticks–what does it all, what does any of it same time Imade the decision to return to MIT,Steve mean?Enormous concentration is required to remember it all in away Hentges,who worked in our well-developed osmium imido that causes little sparks when certain conjunctions appear, making a area and already had the material for agood Ph.D.thesis in connection with something noted previously,perhaps decades ago. Sadly,asIgrow older, the connections become harder to summon up,so hand, decided to take on one more project before writing up. the sparks,though they seem as bright as ever, are less frequent. I Thenotion of an asymmetric ligand for osmium tetroxide describe this process at length because it×s not the way most scientists had been knocking around the lab for years,and Steve first approach their work,nor is it well suited to the demands of funding approached the idea by makingseveral pyridines with chiral agenciesthat are railroaded into answering questions posed for substituents at the 2-position; these gave diols with essentially political ratherthan scientific reasons,nor to the needs of graduate [17] students who require publications to compete for jobs.Academic 0%ee! Pyridine is only amodest ligand for osmium chemistry is much harder now,and I×m glad Iwas born when Iwas. tetroxide,and, as we discovered, any ortho substituent is

2028 Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 Asymmetric Oxidation REVIEWS lethal to binding. But since William Griffith at Imperial If the tartrate-induced acceleration of the titanium-cata- Collegehad shown that quinuclidine binds much more lyzed epoxidation reaction came as asurprise, investigating strongly to OsO4 ,Isuggested trying the cinchona alkaloids, that phenomenon brought even more surprising results.We essentially substituted quinuclidines.[18] (Many chemists have ultimately found 24 metals other than Ti that catalyze the expressed surprise at how quickly we arrived at what is now epoxidation of allylic alcohols by TBHP (Figure 1), but all the bestligand framework for the AD:anyone with anatural these systems were strongly inhibited or killed by adding products background and who is also afan of Hans Wynberg×s tartrate![21] Ligand-decelerated catalysis was clearly the rule, chemistry recognizes the cinchona alkaloids as the obvious while ligand acceleration was the extraordinarily valuable next step.) Theresults were spectacular, even without taking exception. into account ameasurement error (discoveredyears later) that caused most of the ee values to be underreported by 5± 15%![17] Steve had adramatic story to cap his thesis work, so he started writing;myattention was taken up by the decision to return to MIT.Then, acouple 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 weaklycatalytic in the early days,[19] its uniformly high ee values and nontoxic, inexpensive reagentswere enough to completely divert our attention from its promising but stoichiometric predecessor, the OsO4/ cinchona asymmetricdihydroxylation. Figure 1. Metals catalyzing the epoxidation of allylic alcohols by TBHP. Thepreceding paragraphhas no doubt failed to deflectyour Addingtartrate ligand always affects reactivity: the titanium system is accelerated. attention from the obvious question: Why didn×t Itry the Hentges ligands in the Upjohn system in 1979?Indeed, why did Ipropose the experiment in my NIH grant renewal in Shortly before Ileft for Caltech,Chris Burns,encouraged

January, 1984, but not follow up on it?™As for the ligand,∫I by Pui Tong Ho,presciently lobbied to resurrect the OsO4/ wrote in the proposal, ™it is probably besttostaywith the cinchona asymmetric dihydroxylation, and, without any cinchona derivatives because the quinuclidine moietyisthe encouragement from me,Imust admit, he embarked on the VIII best ligand we know of for Os complexes.The substrate will synthesis of astoichiometric C3-symmetric ligand for the be stilbene...the osmium catalyst will be recycled using an AD.[22] Afew months later, Itoo was again committed to amine N-oxide.Ideally,both the osmium and the chiral osmium, and when Bill Mungall and Georg Schrˆder reex- alkaloid could be used in catalytic quantities.Asuccessful amined the work from 1979, they uncovered ee values even system of this type could be of great practical importance.∫ better than previously reported. Meanwhile,Eric Jacobsen Instead of poking and perturbing, the Jersey Shore School attacked the problem from the mechanistic side,and discov- of Thinking×s cardinal rule,Istuck with the odds logic ered that the ligand-dependent rate accelerations could be [23] suggested:ligands acceleratethe reaction of OsO4 with enormous. olefins,but they also bind avidly to the resulting osmate ester, and lethally affect catalyst turnover. This ability of ligands,such as pyridine and quinuclidine,tokill turnover in catalytic-osmylation systems had often been observed in my laboratory.What Idid 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 the time,however, the precedents seemed clear, so the AD languished until 1987. With these very encouragingresults on the stoichiometric Unraveling the mechanism of the AE was largely the work reaction just in, Istvan Marko¬ joined the project. Iwas of M. G. Finn.[13] His persistent exploration during the early to travelingatthe time,and on his own initiative,unawareofthe mid-1980s of the AE×s titanium ±tartrate-catalyst system NIH proposal, he combined Hentges× system[17] with the exposedacomplex mixture of species in dynamic equilibrium reliable UpjohnNMO-based catalytic-osmylation system,[16] with one another.[20] M. G. discovered the main species immediately getting resultsindicating the reaction was [24] [Ti(dipt)(O-iPr)2]2 (DIPT diisopropyl tartrate) is substan- catalytic. However, unlike the dramatic ™Eureka!∫ that tially more active than the many other species present accompanied the discovery of the AE, cautiousoptimism was

(significantly,itisfive to ten times more active than Ti(OR)4 , the response to the catalytic AD and its initially modest acatalyst for the formationofracemic epoxy alcohol) and this ee values. Now,however, after years of research since Marko¬ ×s rate advantage funnels catalysis through the appropriate first experiments in October of 1987,the AD×s utility rivals tartrate-bearing species. and often surpasses the AE×s.[9] Unlike the AE, for which

Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 2029 REVIEWS K. BSharpless

Katsuki×s initial tartrate-ester ligands have yet to be eclipsed, ence for the terminal doublebond is slight, however, and the ligands for the AD have evolved substantially in internal diols as well as tetraols also can be isolated from the effectivenessand scope,through substitution at the C-9 reaction.[36] Thus,while the AD catalyst cannot match the hydroxy moiety. exquisite selectivity of the enzymic system, this very inability Thesimple ester derivatives (e.g. the acetate and para- to discriminate between the six trisubstituted double bonds of chlorobenzoate esters) gave way in 1990 and 1991 to aryl squalene allowsthe exhaustive AD of squalene (Scheme4)in ether derivatives,first proposed by YunGao during alate- an overall yield of 79.8%for the AD-b reaction.[37] night group meeting to address the mechanisticquestion of a possible ligating role of the ester carbonyl. Brent Blackburn made the phenyl ether which,toour surprise,gave good ee values, but was too hardtomake to be competitive with the then dominant para-chlorobenzoate(CLB) ligand. Almost ayear later, Declan Gilheany correctly predicted that aryl ethers should be better for aliphatic olefins than the CLB ligand,[25] and these results laid the foundation for a steady expansion of this ligand class,which culminated in the phenanthryl ether ligand.[26] Another big jump in effectiveness came with the dimeric alkaloid ligands having aphthalazine core,first made by Jens Hartung in 1990.[27] Along with the pyrimidine ligands[28] whose development they inspired, they remain the best general ligands for the AD reaction. Thesearch for better ligands was paralleled by advances in catalyst turnover efficiency: 1) John Waifound both the second-catalytic-cycle problem and itspartial remedy; slow addition of the olefin.[29] 2) Since ferricyanide in tert-butanol/water provides an excellent two-phase system for catalytic osmylation,[30] Hoi- Lun Kwong applied it to the AD,which solved the second- Scheme4.Exhaustive,stereoselective dihydroxylations of squalene. cycle problem and the need for slow addition.[31] 3) Willi Amberg found that adding organic sulfonamides greatly facilitates the rateofcatalyst turnover for olefins Serial multistep reactions such as these are generally whose osmate esters resist hydrolysis.[27] stymiedbyBob Ireland×s ™arithmetic demon∫–the geometric As the practicality (it has been scaled up to run in 4000-liter fall in yield in sequential chemical reactions.The AD of each reactors with no ill effects on yield or ee value[32] )and scope of double bond is one step in aprocession of six dihydroxyla- the AD process grew,sodid the pressure to understand the tions,each with achemical and an optical yield, twelve yields origin of its enantioselectivity.Mechanistic studies dating in all. Thus the average yield of each step is (0.798)1/12 or 98%, from the 1970s by Alan Teranishi and JanB‰ckvall[33] were which translates to 98%for each chemical yield, 96% ee for rekindled by Eric Jacobsen in 1987 and continued into the the single enantioselective reaction and 96% de for each of mid-1990s.[34] the five diastereoselective reactions. Thehigh yield of asingle While acomplete and general solution to the geraniol enantiomer from the multiple hydroxylation events required paradigm×s final challengeisclearly within reach, comparing to oxidizesqualene completely reflects the reliabilityand selectivity at the bench with selectivity in living systems selectivity of the AD process.Joel Hawkins× Berkeleylab remainsstriking.For example,the squalene monooxygenase kinetically resolved the chiral fullerene C76 ,which resulted in in our livers unerringly depositsasingle oxygen atom on the the first enantiomerically pure allotrope of carbon, the AD×s squalene molecule and, in so doing, further chooses only the most intriguing use to date.[38] si-enantioface of the terminal double bond (Scheme 3).[35] On My decision,nearly 25 years ago,tostudy the selective the other hand, the attempted AD of asingle double bondof oxidationofolefins produced an unexpected bonus,one that squalene does givethe terminal diol in 96% ee.The prefer- gave me an opportunity to investigate uncharted territory on a scale that is more associated with the previous half-century than with our own. Selenium, titanium/alkyl peroxides,and osmium, my three most successfulolefin oxidationcatalysts, all had phobias associated with them, with the result that much of their chemistry remained terra incognito.Selenium and osmium were considered highly toxic, and the peroxide oxidantsused with titanium had anasty reputation. Rarely did Ifind myself in another chemist×s territory;likewise,few wanted to cast aline in mine. Tracking these elements offers arather curiousway to view Scheme3.Enzymatic epoxidation of squalene. my research. Figure 2a plots the time course of their

2030 Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 Asymmetric Oxidation REVIEWS

directing research (an oxymoron perhaps?);indeed, some of you flourished. Others were not well served, and to you Isincerely apol- ogize. I×m exceedingly proud of the MIT undergraduates who got their feet wetinmylab and now hold leading academic and industrial positions:remember you got your opportunities because TomSpencer gave me mine,and Iexpect you to Figure 2. a) Selenium, titanium, and osmiumchemistry;note the osmiumline×s bimodality.b)Growth of catalysis in my laboratory. n number of publications; P percentage of publications. do the same.Mentioning Tom brings me back, as so many things do,toE.E.van Tamelen:the bright dominance (as measured by publications, for want of amore flashes of his career remain of the first magnitudeand still qualitative ruler) during the years 1970 ±1993. Selenium came inspire me.And finally,myscientific career would have been first, flourished, then ended abruptly.Osmium research came unthinkable without the constantsupport and counsel of my next, coexistingwith seleniumuntil both were eclipsed by wife,best friend–and ghost writer–Jan. titanium, the descendant of molybdenum and vanadium. Ialso thank the National Institute of General MedicalSciences, Osmium made astrong comeback, knocking off titanium. National Institutes of Health (GM-28384) and the National Figure2b, which charts my research with respectto Science Foundation for their continuous financial support over catalytic transformations,looks quite unlike Figure 2a,but the past 25 years and, more recently,the W. M. Keck relates directly to it. As my involvementwith catalysis grew, Foundation and the Skaggs Institute for Chemical Biology the largely stoichiometric selenium reagents lost their appeal; for helping to make possible my present tenure at The Scripps titaniumfell because the effectivenessofthe titanium catalyst Research Institute in La Jolla. for the AE is modest, with about only 20 turnovers per titaniumcenterbefore all activity is lost. Osmium, despite a Received:March 12, 2002 [A524] bimodal presentation, was never actually out of the picture, merely quiescentuntil the discovery of the highly catalytic AD (it has been run to completionwith 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 2b,the only real defection from the steady growth [3] K. B. Sharpless,R.C.Michaelson, J. Am. Chem.Soc. 1973, 95,6136. of catalysis to dominion in my research was the 1982 trough [4] T. Katsuki, K. B. Sharpless, J. Am. Chem.Soc. 1980, 102,5974. caused by the hexose synthesis collaboration with Sat [5] a) David Xu synthesized 4 and ent-4 in 1991 duringhis work on the AD mechanism, from which synthesis of 3 and ent-3 was implicit;two Masamune. Stepping out of the realm of catalysis is almost other groups reported this reactionsequence:b)E.J.Corey,M.C. unimaginable to me now. Noe,W.C.Shieh, Tetrahedron Lett. 1993, 34,5995;c)G.Vidari, A. Because of its unique potential for channeling areaction Dapiaggi, G. Zanoni, L. Garlaschelli, Tetrahedron Lett. 1993, 34,6485; sequencealong one of myriad possible pathways,selective d) G. Vidari, A. Giori, A. Dapiaggi,G.Lanfranchi, Tetrahedron Lett. catalysis lies at the heart of both pure and applied chemistry, 1993, 34,6925. Gerry Crispino×s juvenile hormone III synthesis demonstrates the same conversion:e)G.A.Crispino,K.B.Sharpless, not to mention life chemistry.Inaddition to the selectivity Synthesis 1993, 8,777. benefitsofcatalysis,the phenomenonofturnover (which [6] a) W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am. equals amplification), implicit in the definition, highly lever- Chem.Soc. 1990, 112,2801;b)R.Irie,K.Noda, Y. Ito,N.Matsumoto, ages its potential impact. Forall these reasons,catalysis was T. Katsuki, Tetrahedron Lett. 1990, 31,7345. [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, asymmetric catalysts.What we found, however, was unima- J. Am.Chem. Soc. 1975, 97,2567;d)See his excellentreview:J. ginable on two scores:small, highly enantioselective catalysts Halpern, Science 1982, 217,401;e)A.Miyashita, A. Yasuda, H. that were not only not fettered by nature×s ™lock-and-key∫ Takaya, K. Toriumi, T. Ito,T.Souchi, R. Noyori, J. Am. Chem.Soc. 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. Akuta- four decades later, Iamstill plumbing the vastness of the gawa, S. Otsuka, J. Am. Chem. Soc. 1978,100, 3949;c)S.Akutagawa, Periodic Table in search of new catalytic reactivity. The K. Tani in CatalyticAsymmetric Synthesis (Ed.:I.Ojima,) VCH, Weinheim, 1993,p.41. Ahistoryand review of the development of the unpredictability and rarity of what Iseek are not deterrents asymmetric hydrogen migration of allylamines can be foundin: d) S. since Iam, after all, the product of optimistictimes.There are Otsuka, K. Tani, Synthesis 1991,665. other coelacanthstobefound! [9] Forreview chapters on both the AE and AD,written largely by Roy Johnson despite being coauthoredbyboth of us,see:a)R.A. Above all Ithank and express my deep gratitudetomypast Johnson, K. B. Sharpless,inCatalyticAsymmetric Synthesis (Ed.:I. Ojima) VCH, Weinheim, 1993,p.101;b)R.A.Johnson, K. B. and presentco-workers at MIT,Stanford and The Scripps Sharpless in Catalytic Asymmetric Synthesis (Ed.:I.Ojima), VCH, Research Institute.Many of you learnedtotolerate my style of Weinheim, 1993,p.227.

Angew.Chem. Int. Ed. 2002, 41,2024 ±2032 2031 REVIEWS K. BSharpless

[10] E. N. Jacobsen in CatalyticAsymmetric Synthesis,(Ed.:I.Ojima), [25] T. Shibata, D. G. Gilheany, B. K. Blackburn, K. B. Sharpless, Tetrahe- VCH, Weinheim, 1993,p.159. dron Lett. 1990, 31,3817. [11] a) S. Y. Ko,A.W.M.Lee,S.Masamune,L.A.Reed, K. B. Sharpless, [26] K. B. Sharpless,W.Amberg, M. Beller, H. Chen, J. Hartung, Y. F. J. Walker, Science 1983, 220,949;b)S.Y.Ko, A. W. M. Lee,S. Kawanami, D. L¸bben, E. Manoury,Y.Ogino,T.Shibata, T. Ukita, J. Masamune,L.A.Reed, K. B. Sharpless,F.J.Walker, Tetrahedron Org. Chem. 1991, 56,4585. 1990,46, 245. [27] K. B. Sharpless,W.Amberg, Y. Bennani, G. Crispino,J.Hartung, K. [12] a) K. B. Sharpless, CHEMTECH 1985,692;b)K.B.Sharpless, Chem. Jeong, H. Kwong, K. Morikawa, Z. M. Wang, D. Xu, X. L. Zhang, J. Br. 1986, 22,1. Org. Chem. 1992, 57,2768. [13] M. G. Finn×s thesis work has appeared in two full papers:a)S.S. [28] G. Crispino,K.S.Jeong, H. Kolb,Z.M.Wang, D. Xu, K. B. Sharpless, Woodard, M. G. Finn, K. B. Sharpless, J. Am.Chem. Soc. 1991, 113, J. Org. Chem. 1993, 58,1958. 106;b)M.G.Finn, K. B. Sharpless, J. Am. Chem. Soc. 1991, 113,113. [29] J. S. M. Wai, I. Marko¬,J.S.Svendsen, M. G. Finn, E. N. Jacobsen, K. B. [14] a) R. Criegee, Justus Liebigs Ann. Chem. 1936, 522,75; b) R. Criegee, Sharpless, J. Am. Chem.Soc. 1989, 111,1123. Angew.Chem. 1937, 50,153;c)R.Criegee, Angew.Chem. 1938, 51, [30] M. Minato,K.Yamamoto,J.Tsuji, J. Org. Chem. 1990, 55,766. 519;d)R.Criegee,B.Marchand, H. Wannowias, Justus Liebigs Ann. [31] H. Kwong, C. Sorato,Y.Ogino,H.Chen, K. B. Sharpless, Tetrahedron Chem. 1942, 550,99. Lett. 1990, 31,2999. [15] K. B. Sharpless,K.Akashi, J. Am. Chem.Soc. 1976, 98,1986. [32] Private communication from Dr. YunGao of Sepracor, Inc.,Marl- [16] V. van Rheenen, R. C. Kelly,P.Y.Cha, Tetrahedron Lett. 1976,1973. borough,MA. [17] S. G. Hentges,K.B.Sharpless, J. Am. Chem. Soc. 1980, 102,4263. [33] K. B. Sharpless,A.Y.Teranishi, J. E. B‰ckvall, J. Am. Chem.Soc. [18] a) M. J. Cleare,P.C.Hydes,W.P.Griffith, M. J. Wright, J. Chem.Soc. 1977, 99,3120. Dalton Trans. 1977,941;b)W.P.Griffith, A. C. Skapski, K. A. Woode, [34] a) E. N. Jacobsen, E. I. Marko¬,M.B.France,J.S.Svendsen,K.B. M. J. Wright, Inorg. Chim. Acta 1978,31, l413. Sharpless, J. Am. Chem.Soc. 1989, 111,737;b)T.Gˆbel, K. B. [19] Five years later, Bob Hanson made the simple but wonderful Sharpless, Angew.Chem. 1993, 105,1823; Angew.Chem.Int. Ed. Engl. discovery that addingmolecular sieves to the reactiondramatically 1993, 32,1329;c)P.O.Norrby, H. Kolb,K.B.Sharpless, Organo- increases catalyst turnover, so that the AE process becametruly metallics 1994, 13,44±47; d) H. C. Kolb,P.G.Andersson, Y. L. catalytic:R.M.Hanson, K. B. Sharpless, J. Org. Chem. 1986, 51,1922. Bennani, G. A. Crispino,K.S.Jeong, H. L. Kwong, K. B. Sharpless, J. [20] Steve Pedersen provided invaluable structural results to aid M. G. Am. Chem. Soc. 1993, 115,12226 ±12227;e)H.C.Kolb,P.G. Finn×s studies during this period. Steve×s work gave us our first glimpse Andersen, K. B. Sharpless, J. Am. Chem.Soc. 1994, 116,1278 ±1291; into the dynamic world of complexmixtures in rapid equilibrium with f) H. L. Kwong, Ph. D. Thesis,Massachusetts Institute of Technology, each other. His contributions are summarized in:K.B.Sharpless, 1993. Chem.Scr. 1987, 27,521.These studies led to no new catalysts, but they [35] a) R. B. Boar, K. Damps, Tetrahedron Lett. 1974,3731;b)D.H.R. drove home our appreciation for the absolute need for aligand- Barton, T. R. Jarman,K.G.Watson,D.A.Widdowson,R.B.Boar, K. acceleration effect in catalyst systemswhere ligand exchange is rapid. Damps, J. Chem.Soc. Chem.Commun. 1974,861;c)D.H.R.Barton, [21] K. S. Kirshenbaum, Ph. D. Thesis,Massachusetts Institute of Tech- T. R. Jarman, K. G. Watson,D.A.Widdowson, R. B. Boar, K. Damps, nology, 1985. J. Chem. Soc. Perkin Trans.11975,1134. [22] C. J. Burns,Ph. D. Thesis,Massachusetts Institute of Technology, 1989. [36] G. Crispino,K.B.Sharpless, Tetrahedron Lett. 1992, 33,4273. [23] E. N. Jacobsen, E. I. Marko¬,M.B.France,J.S.Svendsen,K.B. [37] G. A. Crispino,P.T.Ho, K. B. Sharpless, Science 1993, 259,64. Sharpless, J. Am. Chem.Soc. 1989, 111,737. [38] J. M. Hawkins,A.Meyer, Science 1993, 260,1918. [24] E. N. Jacobsen, E. I. Marko¬,W.S.Mungall,G.Schrˆder, K. B. Sharpless, J. Am. Chem.Soc. 1988, 110,1968.

2032 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 CÀC Bonds (Nobel Lecture)** Akira Suzuki* cross-coupling · organoboranes · palladium · Suzuki coupling

Biography trying experiences tend to fade with time. I think now mainly about the fun things, and I will describe a few memories that I I was born on September 12, 1930 in Mukawa, a small town in have from my work. Hokkaido, Japan. I attended the primary school there and It was on a Saturday afternoon in 1962. I visited the entered secondary school at Tomakomai, where we had one Maruzen bookstore in Sapporo. As I browsed the chemistry of the biggest paper companies in Japan. During my high books, I discovered a very unacademic looking volume, bound school, I was interested in mathematics. Consequently, when I in red and black. This book was Hydroboration by H. C. entered Hokkaido University in Sapporo, I was thinking of Brown, the 1979 Nobel Laureate in Chemistry. I took the studying it. In the junior course, I became interested in book in my hands, and began looking through its pages to find organic chemistry by reading the book “Textbook of Organic words written in Professor Browns unique style. I purchased Chemistry,” written by L. F. Fieser and M. Fieser. Finally, I the book and returned home. I can still remember clearly how decided to major in organic chemistry. I picked it up after dinner that evening, and could not put it The title of my doctoral thesis was “Synthesis of the down. It is not very long, but it remains as one of the few Model Compounds of Diterpene Alkaloids”. In the study, I scholarly books which I have stayed up all night to read. At used organometallic compounds, Grignard reagents, and the time, I had just transferred to the Faculty of Engineering organozinc compounds as synthetic intermediates, and I from Science, and I wanted to begin research in a new area at perceived that such organometallic compounds are interest- my new workplace. This is perhaps one reason why this book ing and versatile intermediates for organic synthesis. After I had such an impact on me. completed the PhD program at the Graduate School of Inspired by this experience, I went to Purdue University in Science, Hokkaido University, in 1959, I was employed as a Indiana in the August of 1963 (Figure 1) and spent almost two research assistant in the Chemistry Department. In October years at Professor Browns laboratory researching the newly 1961, after two years and six months, I was invited to become discovered hydroboration reaction as a postdoctoral research an assistant professor of the Synthetic Organic Chemistry associate (Figure 2). It was my first time in a foreign country, Laboratory at the newly founded Synthetic Chemical Engi- and one of the things that left an impression on me was the neering Department in the Faculty of Engineering. In April strength that America had at that time. For instance, one 1973, I succeeded Professor H. Otsuka at the Third Labo- American dollar was worth 360 yen. My monthly salary as a ratory in the Applied Chemistry Department. In total, I have doctoral researcher was four times what I received even as an spent 35 years at Hokkaido University as a staff member— assistant professor in Japan. There was little difference in the two and a half years in the Faculty of Science, and another food between the rich and the poor. There were many such thirty-two and a half years in the Faculty of Engineering. things that I found that were unimaginable in Japan. Purdue Other than about two years of study in America, and a few University has a strong relationship with Hokkaido Univer- months at other places overseas, most of my life has been sity. In the past, the former president of the university, spent at the Faculty of Engineering. Including my nine years Professor S. Ito, had studied at Purdue. Professor S. Nomachi as a student, the majority of my life has been at Hokkaido and Professor T. Sakuma were at Purdue at the same time as I University. After my retirement from Hokkaido University in was. 1994, I joined two private universities in Okayama prefec- From Professor Brown I learned many things, including ture—Okayama Science University and Kurashiki University his philosophy towards research, but there is one thing he said of Science and Arts—and I retired from the universities in that I can recall with clarity: “Do research that will be in the 2002. In the following I would like to describe a few memories textbooks”. It is not easy to do this kind of work, but this has of my life in chemistry. remained my motto. Professor Brown was 51 years old, and he

[*] Prof. A. Suzuki Professor Herbert C. Brown and Purdue University Hokkaido University Sapporo, Hokkaido (Japan) As I reflect on these long years, I see that there were many [**] Copyright The Nobel Foundation 2010. We thank the Nobel difficult periods as well as joyful ones. Memories of the tough, Foundation, Stockholm, for permission to print this lecture.

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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 these compounds in the presence of water without any special care. I decided that there might be some way to use these compounds in organic reactions, and I created a new research plan 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. Discovery of Alkyl Radical Formation from R3B

At the time, I focused on three characteristics of organoboron was an extremely active researcher. He visited Hokkaido compounds. First, compared to other organometallic com- University three times. I had the opportunity to meet him and pounds, the difference in the electronegativity of the CÀB Mrs. Brown more than ten times (Figure 3), but we missed bond is small, meaning that it is an almost perfect covalent them in 2004 and 2005, unfortunately. bond. Second, the boron atom has an open p-electron Hydroboration is the reaction of alkenes with borane to structure, meaning that it might be susceptible to nucleophilic produce organic boron compounds. These boron compounds reagents. This suggested that the compounds might undergo differ from other organometallic compounds: they are chemi- reactions as shown in Equation (a). Third, studies of the CÀB cally inactive, particularly in ionic reactions. For example, organic boron compounds are stable in the presence of water and 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 that the boron compounds were inactive. In contrast, I thought that the stable character of organoboron compounds could be

www.angewandte.org 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50 Suzuki Coupling bonding distance showed that it was almost equal to the CÀC purchased from Hokkai Sanso (now called Air Water Inc.), bonding distance. which we further purified. Nevertheless, trace amounts of In consideration of these three points, I decided to study oxygen were still present in our nitrogen gas. The oxygen the reaction of organic boron compounds with a,b-unsatu- acted as a catalyst and promoted the reaction. In the USA, rated ketones. In other words, I hypothesized that intermedi- extremely pure nitrogen could easily be purchased in those ate (I) in Equation (b) would be obtained through a days, and the nitrogen gas did not contain sufficient amounts of 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 inferred previously [Eq. (b)].

quasihexagonal 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 Serendipity Hokkaido, while a,b-unsaturated aldehydes would be investigated at Purdue. We analyzed the scope of the reaction, and One often hears lately of the idea of “serendipity” in research. tried several types of a,b-unsaturated ketone reactions and Serendipity refers to the capability to discover the crucial and found that each produced favorable amounts of the corre- essential components from unexpected phenomena. I believe sponding saturated ketones at room temperature. Although that any researcher has the chance to exhibit serendipity. we discovered that compounds with a substituent in the However, in order to make the most of such opportunities, a b position, such as compounds II, would not react at room researcher must have the humility to see nature directly, an temperature, we found that the expected proportions of attentiveness that does not let even the dimmest spark escape, products could be formed in THF (tetrahydrofuran) solution and an insatiable appetite for research. Some amount of luck at reflux temperature. I received a letter from G. Kabalka also matters, but what can be said with certainty is that little (now professor at the University of Tennessee), who was then will come of a half-hearted effort. a graduate student doing related research at Purdue. Accord- ing to the letter, something similar was found for a,b- unsaturated aldehydes. None of the corresponding saturated Quick Publication aldehydes were produced by the reaction of compounds such as III, which had a substitution group in the b position, even In 1970, we were performing experiments to directly produce though many similar compounds such as acrolein reacted carboxylic acid from organoboron compounds. One possibil- easily at room temperature. I proposed that each laboratory ity we explored was to use complexes derived from organo- confirm the results of the other, and we began experiments on boron compounds and a cyanide ion which react with protonic III and found that the reaction proceeded in THF at reflux acids. We were not able to obtain our intended result, but we temperature. However, subsequent experiments at the Brown discovered that these cyano complexes could produce sym- lab did not find that our reaction occurred. I remember a metrical ketones in good yield when reacted with electrophilic sentence in the letter I received from Professor Brown reagents like benzoyl chloride. Nonetheless, I was busy reporting their results. “Chemistry should be international. preparing for a presentation at an international conference Why do we have such a big difference between two places, to be held in Moscow in 1971, and we left for the conference Sapporo, Japan, and West Lafayette, USA?” without finishing our paper on it. After I had successfully When we looked more closely at these contradictory given my invited lecture, I left the lecture hall to quench my results, we discovered something quite unexpected. A trace thirst with a glass of water. At that time, a tall foreign man amount of oxygen contaminating in the nitrogen gas we used introduced himself to me. That man was Professor A. Pelter in our reaction system was catalyzing the reaction. At the of Manchester University in the UK. He later transferred to time, we knew that organoboron compounds reacted with the University of Wales, Swansea, and served as the chair of oxygen, so both we and the Brown Lab conducted the the Department of Chemistry as well as the Vice-Chancellor reactions in nitrogen gas. In our laboratory, we used nitrogen of the university. At our first encounter in Moscow, I had no

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idea that he was studying organoborane chemistry. We spoke Over many long years, I have had many different about many things that day and, to my surprise, I learned that experiences. I have encountered many friends at the Faculty he had also performed the very research that we had just of Engineering, Hokkaido University, especially among many done, and had already published his results the previous of the people who continue to work at the Third Laboratory month in Chemical Communications. As a result, our work of the Applied Chemistry Department, and the Organic remains unpublished. Today, that reaction is sometimes called Synthetic Chemistry Laboratory in the Synthetic Chemical the Pelter reaction. Knowing about our situation, Professor Engineering Department. They have allowed me to enjoy a Pelter sympathized with us and consoled us, but no one else long career in research. I conclude by expressing my sincere knew anything about it. We learned from it. When doing gratitude to these students and colleagues in research. research, we must keep three things in mind. First, we must I have won several awards for my work, listed below: study the existing literature carefully and comprehensively. * The Chemical Society of Japan Award, 1989. Second, we need to be aware that other researchers, near and * The Society of Synthetic Organic Chemistry Japan, far, are thinking about the same things that we are. Third, we Special Award, 2004. must quickly publish papers on our results (not just oral * Japan Academy Award, 2004. presentations). * The Order of the Sacred Treasure, Gold Rays with Neck Ribbon, 2005. * P. Karrer Gold Medal, 2009. Tragic Accident * Nobel Prize in Chemistry, 2010. * The Order of Culture of Japan, 2010. Thinking back on that conference—the International Confer- * H. C. Brown Award of the American Chemical Society, ence on Organo-Metallic Chemistry in Moscow 1971—I 2011. cannot help but think of the tragic accident, in which an ANA passenger jet collided with a Japan Self-Defense Force aircraft in the skies above Shizuku-ishi in Iwate prefecture. On that day, I had flown from Sapporo/Chitose to Tokyo/ Nobel Lecture Haneda to stay for one night before boarding an Aeroflot plane to Moscow the next day. I flew on a Japan Airlines flight Introduction in the afternoon, with no idea that the plane that departed only thirty minutes earlier would be involved in such a terrible Carbon–carbon bond-formation reactions are important accident. Knowing nothing of the tragedy, I landed in Haneda, processes in chemistry, because they provide key steps in the and headed to the Haneda Tokyu Hotel near the Airport, and building of complex, bioactive molecules developed as then learned of the accident. All passengers and crew, 162 medicines and agrochemicals. They are also vital in develop- persons, were killed. ing the new generation of ingeniously designed organic materials with novel electronic, optical, or mechanical properties, likely to play a significant role in the burgeoning Haloboration Reaction area of nanotechnology. During the past 40 years, most important carbon–carbon Thereafter, our group carried out research on the synthesis of bong-forming methodologies have involved using transition organic compounds through haloboration. I had one memory metals to mediate the reactions in a controlled and selective from this that I will reflect upon. This research was based on manner. The palladium-catalyzed cross-coupling reaction the discovery that a certain type of haloborane derivative between different types of organoboron compounds and adds to terminal carbon–carbon triple bonds. This reaction various organic electrophiles including halides or triflates in was discovered in 1981, but we first disclosed part of this the presence of base provides a powerful and general research in the United States in 1982. That fall, the American methodology for the formation of carbon–carbon bonds. Chemical Society hosted a symposium in Midland, Michigan, The (sp2)CÀB compounds (such as aryl- and 1-alkenylboron on organic synthesis involving organoboron compounds. I was derivatives) and (sp3)CÀB compounds (alkylboron com- one of the special invited speakers, and was preparing to pounds) readily cross-couple with organic electrophiles to travel to the US when I received a letter from Professor give coupled products selectively in high yields. Recently, the Brown. It was an invitation to visit Purdue to give a lecture (sp)CÀB compounds (1-alkynylboron derivatives) have also before the symposium. The topic of that lecture was been observed to react with organic electrophiles to produce haloboration. Professor Brown listened to my presentation the expected cross-coupled products. intently, and raised his hand to comment the moment I Some of representative reactions between various orga- finished speaking. He said that his group had studied the noboranes and a number of organic electrophiles are shown in possibility and usefulness of the same reaction at almost the Scheme 1. The numbers in parentheses indicate the year they same time as we had. They had looked at haloboration were first reported by our group. reactions for acetylene compounds, but they had only looked Such coupling reactions offer several advantages: at reactions of the internal acetylenes as substrates. Their (1) ready availability of reactants; work was unsuccessful, and they ended the research. The (2) mild reaction conditions and high product yields; goddess of fortune is capricious, indeed. (3) water stability;

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tetracoordinate organoboron compounds, instead of tricoordinate organoboron derivatives. According to the study by Gropen and Haaland,[2] the methyl group in tetra- methylborate was observed to be 5.5 times more electronegative than the methyl group in trimethylborane. Such behavior was also expected for the reaction of triorganobor- anes in the presence of base. Thus, we found that the reaction of vinylic boron compounds with vinylic halides proceeds smoothly in the presence of a base and a catalytic amount of a palladium complex to provide 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 and Table 1: Cross-coupling reaction of 1 with 2. heterogeneous conditions; (5) toleration of a broad range of functional groups; (6) high regio- and stereoselectivity; (7) insignificant affect of steric hindrance 1[a] Cat.[b] (mol%) Base (equiv/2) Solvent t [h] Yield [%] of 3 (8) use of a small amount of catalyst; (9) application in one-pot synthesis; 1b PdL4 (3) none THF 6 0 (10) nontoxic reaction; 1b PdL4 (3) none benzene 6 0 1a m (11) easy separation of inorganic boron compound; PdL4 (3) 2 NaoEt(2)-EtOH THF 2 73 1b PdL (1) 2m NaOEt(2)-EtOH benzene 2 86 (12) environmentally friendly process. 4 [a] 1a,X2 =(Sia)2 (Sia= 1,2-dimethylpropyl); 1b,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 by using suitable solvent systems and adequate bases. Conse- Although the coupling reaction of (E)-1-alkenylboranes, quently, these coupling reactions have been actively utilized readily obtained by the hydroboration of appropriate alkynes not only in academic laboratories but also in industrial with disiamylborane or dicyclohexylborane, proceeds readily processes. with (E)- and (Z)-1-alkenyl bromides and iodides to give the corresponding dienes (Table 2), (Z)-1-alkenylboranes, prepared by hydroboration of 1-haloalkynes followed by reaction Coupling Reactions of (sp2)CÀB Compounds with tert-butyllithium, gave low product yields, near 50% (Table 3). Reactions of Vinylic Boron Compounds with Vinylic Halides Fortunately, it was found that high yields and high Synthesis of Conjugated Alkadienes stereoselectivity could be achieved by coupling (Z)-1-alkenyl halides with (Z)-1-alkenyldialkoxyboranes, instead of dis- Cross-coupling reactions between vinylic boranes and iamyl- and dicyclohexylborane derivatives (Table 3).[3] Con- vinylic halides were not reported to proceed smoothly in the sequently, the cross-coupling reaction of 1-alkenylboranes presence of only palladium catalysts. During the initial stage with 1-alkenyl halides can be achieved readily for the of our exploration, we postulated that a drawback of the coupling is caused by the following aspects of the mechanism. Table 2: Cross-coupling reaction of (E)-1-vinyldisiamylboranes.[a] The common mechanism of transition-metal-catalyzed coupling reactions of organometallic compounds with organic 1-Alkenylbor- 1-Alkenylbro- Product Yield [%] ane mide (purity [%]) halides involves sequential a) oxidative addition, b) transmetalation, and c) reductive elimination.[1] It appeared that 86 (98) one of the major reasons that 1-alkenylboranes cannot react with 1-alkenyl halides is step (b). The transmetalation process 88 (99) between RMX (M = transition metal, X = halogen) and organoboranes does not occur readily because of the weak 89 (98) carbanion character of the organic groups in the organoboranes. To overcome this difficulty we anticipated the use of [a] Reaction conditions: [Pd(PPh3)4], NaOEt, benzene, reflux, 2 h.

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Table 3: Cross-coupling of (Z)-1-hexenyldisiamyl- or (Z)-1-hexenyldiiso- Mechanism of the Vinylic-Vinylic Cross-Coupling propoxyborane. 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- and stereoselective and take place while retaining the original BY2 in 4 Yield [%] of 5 Purity [%] of 5 configurations of both the starting alkenylboranes and the > B(Sia)2 49 98 haloalkenes. The isomeric purity of the products generally B(OiPr) 87 >99 2 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 synthesis of all kinds of conjugated alkadienes. The reaction compounds facilitate the transfer of organic groups from the has been applied to the synthesis of many natural and boron to the palladium complex in the transmetalation step. unnatural compounds which have conjugated alkadiene In order to check this possibility, the reaction of lithium (1- structures.[4–7] Among the many synthetic applications of the hexenyl)methyldisiamylborate was examined, as shown in Suzuki coupling reaction for conjugated alkadienes, the total Equation (1). The coupled product, however, was obtained synthesis of palytoxin (Scheme 2), a complex and toxic only in 9% yield. On the other hand, it was found that natural product, is an epoch-making contribution.[8] As (trichlorovinyl)palladium(II) complexes 6 and 9, both pre- another example, the total synthesis of lucilactaene is shown pared as pure solids, reacted with vinylborane 7 to give diene in Scheme 3.[9] 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 product in 89% yield. The intermediate 9 readily reacts with 7 without a base to provide the same product 8 in almost quantitative yield after 1 h. Consequently, such evidence suggests that vinylic alkoxypalladium(II) compounds such as 9 were necessary 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

As described in the previous section, it was discovered that vinylic boron compounds readily react with vinylic Scheme 3. Synthesis of lucilactaene. halides to give coupled products—conjugated alkadienes.

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Table 5: Coupling of 1-alkenylboranes with various organic halides. 1-Alkenylborane Halide Product[a] Yield [%]

Phl 100 PhBr 98 PhCl 3

100

83 Scheme 4. Catalytic cycle for the coupling reaction of alkenylboranes with haloalkenes. 89

PhCH2Br 97

We next attempted to examine the reaction of 1-alkenylbor- BrCCPh 93 2 anes with haloarenes which also have sp -hybridized carbon– BrCCHex 95 halogen bonds, and found that the reaction takes place smoothly. Representative results are shown in Table 4. [a] Isomeric purity > 98%.

Table 4: Cross-coupling reaction of 10 with iodobenzene. Aromatic Boron Compounds Reactions with Aromatic Halides Synthesis of Biaryls

The coupling of aryl halides with copper at very high temperature is called the Ullmann reaction, which is of broad scope and has been used to prepare many symmetrical biaryls. Base t [h] Yield [%] Ratio of 11/12 However, when a mixture of two different aryl halides is used, none 6 0 there are three possible biaryl products. Consequently, the NaOEt 2 100 100:0 development of a selective and general synthesis of all kinds NaOMe 2 100 100:0 NaOH 2 100 100:0 of biaryls has been desired. The first method to prepare biaryls by the cross-coupling of aryl boranes with haloarenes was reported in 1981 [Eq. (5)].[12] The reaction proceeds even under heterogeneous This reaction has one more advantage that only one product 11 (head-to-head coupled product) is formed. Addi- tional coupling reactions of vinylic boranes are shown in Table 5. Aromatic bromides and iodides easily react with vinylic boron compounds, but aromatic chlorides do not participate in the coupling, except reactive chlorides, such as allylic and benzylic derivatives. Heteroaromatic halides can also be used as coupling partners. Ortho substituents on the benzene ring do not give difficulty. Thus, the cross-coupling conditions to give the corresponding coupled products reaction can be used for the synthesis of benzo-fused selectively in high yields. Since this discovery, various heteroaromatic compounds [Eq. (4)].[11] 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

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catalysts are generally employed since they are stable to DME. On the other hand, the addition of stronger bases, e.g.,

prolonged heating; however, extremely high coupling reac- aqueous NaOH or Ba(OH)2, both in benzene and DME, tion rates can sometimes be achieved by using palladium exerts a remarkable effect on the acceleration rate of the 3 catalysts without a phosphine ligand, such as Pd(OAc)2, [{(h - coupling. By using aqueous Ba(OH)2 in DME at 808C,

C3H5)PdCl}2], and [Pd2(dba)3]. mesitylboronic acid couples with iodobenzene within 4 h to Carbon–carbon bond-forming reactions employing orga- give the corresponding biaryl in a quantitative yield. Some noboron compounds and organic electrophiles have been such coupling reactions are depicted in Equations (7) and (8). recently recognized as powerful tools for the construction of new organic compounds. Among such reactions, aromatic– aromatic (or heteroaromatic) couplings between aromatic boronic acids or esters and aromatic electrophiles to provide symmetrical and unsymmetrical biaryls selectively in high yields have been used most frequently. The importance of biaryl 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 in detail.[14]

Coupling of Aryl Boronic Acid Derivatives Having Highly Sterically Hindered or Electron-Withdrawing Functionalities An alternative procedure, using the esters of boronic acids and anhydrous base, has been developed for sterically Although steric hindrance of aryl halides is not a major hindered aryl boronic acids and provide high yields. The factor in the formation of substituted biaryls, low yields result coupling can be readily achieved by using the trimethylene

when ortho-disubstituted aryl boronic acids are used. For glycol ester of mesitylboronic acid and Cs2CO3 or K3PO4 in example, the reaction with mesitylboronic acid proceeds only DMF at 1008C to give a quantitative yield of the coupled slowly because of steric hindrance during the transmetalation products [Eq. (9)].[15] to the palladium(II) complex. The reaction of mesitylboronic

acids with iodobenzene at 808C in the present of [Pd(PPh3)4] and various bases has been reported.[15] The results are summarized in Table 6.

Table 6: Reaction of mesitylboronic acid with iodobenzene under different conditions.

Base Solvent T [8C] Yield [%][a] 8h 24h 48h

Na2CO3 benzene/H2O 80 25 (6) 77 (12) 84 (25) Even without sterically hindered substrates, the reaction Na2CO3 DME/H2O 80 50 (1) 66 (2) 83 (7) under aqueous conditions is often undesirable because of K3PO4 DME/H2O 80 70 (0) competitive hydrolytic deboronation. A kinetic study[16] into NaOH DME/H2O 80 95 (2) the reaction of substituted aryl boronic acids showed that Ba(OH) DME/H O 80 99 (2) 2 2 electron-withdrawing substituents accelerate the deborona- [a] GLC yields of the coupling product based on iodobenzene; the yields tion. Although there is no large difference between meta- and of mesitylene are shown in parentheses. para-substituted phenylboronic acids, substituents at the ortho position may greatly increase the rate of deboronation.

Aqueous Na2CO3 in benzene or DME (dimethoxyethane) For example, a 2-formyl group on aryl boronic acids is known is not effective as a base for the coupling of mesitylboronic to accelerate the rate of hydrolytic deboronation.[16] Indeed, acid and the reaction is not completed even after two days. the coupling of 2-formylphenylboronic acid with 2-iodoto-

Although the side reactions such as homocoupling are luene at 808C using Na2CO3 in DME/H2O gives only a 54% negligibly small, the formation of mesitylene by hydrolytic yield of the corresponding biaryl, with accompanying benzal- deboronation was observed, increasing with the reaction time. dehyde (39%). Aprotic conditions are desirable for such It is noteworthy that such hydrolytic deboronation is faster in boronic acids that are sensitive to aqueous base. Thus, the

benzene/H2O than in the modified conditions of aqueous trimethylene glycol ester of 2-formylphenylboronic acid

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readily couples with iodobenzene at 1008C in DMF to give Table 8: Suzuki couplings of unactivated acryl chlorides. the coupled product in a yield of 89%, with less than 10% benzaldehyde formed [Eq. (10)].[15]

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 amounts of aryl bromide reduction were observed when the ligands 13 were used (Table 7). system, with which they achieved the coupling of nonactivated and deactivated aryl chlorides highly efficiently in Table 7: Ligand effects in the coupling of hindered substrates. good yields with generally only 0.005 mol% palladium, and thus under the industrially allowed level.[20] For instance, as a new efficient catalyst system, they used diadamantyl-n-

butylphosphane (BuPAd2) as a ligand and found that it proved to be extremely reactive. A typical example is shown in Equation (12).

Ligand Conv [%] Biaryl [%] Biaryl/ArH 13a 47 33 2.3 13b 20 10 0.9 13c 74 40 1.9 14 100 91 10 Applications in the Synthesis of Biaryls

The anti-HIV alkaloids michellamine A (17) and B (18) Coupling with Aromatic Chlorides have been synthesized. The tetraaryl skeleton of the michellamines was constructed by formation, first, of the inner In aromatic–aromatic cross-coupling reactions, cheap and (nonstereogenic) biaryl axis and subsequently of the two readily accessible aryl chlorides are particularly important other (stereogenic) axes by using a double Suzuki-type cross- from an industrial viewpoint as starting materials. Recently coupling reaction between the dinaphthalene ditriflate 15 and some research groups, especially Fus group[18] and Buch- isoquinolineboronic acid 16 [Eq. (13)].[21] walds group[19] have reported very efficient methods for the The discovery and development of penicillin and other reaction of aryl chlorides. For example, Fu and co-workers[18] antibacterial agents as drugs to fight infectious diseases were have observed that the use of [Pd2(dba)3]/PtBu3 as the catalyst milestone victories of humankind over bacteria. While these and ligand result in a wide range of aryl and vinyl halides, agents saved millions of lives, they did not tame bacteria. On including chlorides, undergoing Suzuki cross-coupling with the contrary, this war led to the emergence of newer and aryl boronic acids in very good yield, typically at room more-dangerous bacterial strains that responded defiantly temperature (Table 8). Furthermore, these catalysts display against known antibacterial agents. Vancomycin is a member novel reactivity patterns, such as the selective coupling in the of the polycyclic glycopeptide class of antibiotics and has presence of [Pd2(dba)3]/PCy3/KF of a sterically hindered proved to be the last line of defense against drug-resistant aromatic chloride [Eq. (11)]. bacteria. The daunting synthetic challenge posed by its Despite the generally good yields in many Suzuki structure is largely due to the strained nature of the 12- reactions of chloroarenes, comparatively large amounts of membered biaryl framework (AB ring system) and the two catalyst are required. Beller et al. reported a new catalyst 16-membered biaryl ethers (COD and COE ring systems).

Angew. Chem. Int. Ed. 2011, 50 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Nobel Lectures A. Suzuki

Nicolaou and his group reported a Suzuki coupling approach to 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 21a and 21b in 80% combined yield [Eq. (14)]. The coupling of the parent boronic acid corresponding to 20 (without methyl groups) with iodide 19 led to a single compound. Thereafter, the total synthesis of the vancomycin aglycon was reported by the same workers.[23]

Solid-Phase Synthesis (Combinatorial Methodology)

Solid-phase reactions play an important role in parallel synthesis and combinatorial chemistry, particularly in the area of medicinal chemistry, where their potential has emerged as a result of the possibility of automation. A considerable amount of attention has been focused on adapting and exploiting the advantage of solid-phase synthesis (SPS) for the production of libraries of such organic compounds. In this context, transition-metal-promoted reactions serve as efficient methods because they proceed under mild conditions and are compatible with many functional groups. For instance, The novel compound tetrakis(phenothiazinylphenyl)me- solid-phase Suzuki coupling has largely been developed by thane (23), showing remarkably large Stokes shift and a the reaction of a resin-bound aryl halide with solution-phase reversible low oxidation potential, can be prepared in a good boronic acids.[14] Recently, the viability of solid-supported yield by Suzuki coupling of tetrakis(p-bromophenyl)methane boronic acids as reagents for Suzuki couplings was success- [22; Eq. (15)].[24] fully demonstrated.[26] Oligothiophene-functionalized 9,9-spirobifluorene derivatives have been synthesized in high yields by Suzuki Applications in Polymer Chemistry coupling. The Negishi coupling reaction between oligothie- nylzinc chloride and various 9,9’-spirobifluorene bromides Aromatic, rigid-rod polymers play an important role in a

with [Pd(PPh3)4] as the catalyst successfully produce the number of diverse technologies including high-performance desired compounds. However, the Negishi coupling provided engineering materials, conducting polymers, and nonlinear low yields, compared to the Suzuki coupling [Eq. (16)].[25] optical materials. The Suzuki polycondensation (SPC) reac-

www.angewandte.org 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50 Suzuki Coupling tion of aryl diboronic acids and dihaloarenes for the synthesis synthetic utility of alkyl zinc compounds by the use of a of poly(p-phenylenes) was first reported by Schlter et al.[27] palladium catalyst. Thereafter, alkyl lithium, tin, and alumi- SPC is a step-growth polymerization of bifunctional aromatic num reagents were also employed for such cross-coupling monomers to poly(arene)s and related polymers reactions. The reaction of alkyl borane derivatives is partic- (Scheme 5).[28] The required functional groups—boronic ularly useful when one wishes to start from alkenes via acids or esters on one side, and bromide, iodide, and so hydroboration. Consequently, we intended to examine the forth on the other—may be present in different monomers coupling reactions between alkyl boron compounds and (AA/BB approach) or combined in the same monomer (AB various organic halides in the presence of a base and a approach). palladium 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 1- halo-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 to give 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 tolerant of a variety of functionalities on either coupling The method was extensively applied to monodisperse partner, stereochemically pure functionalized alkenes and aromatic dendrimers, water-soluble poly(p-phenylene), arenes can be obtained under mild conditions [Eq. (19)]. The planar poly(p-phenylenes) with fixed ketoimine bonds, poly- utility of the reaction was demonstrated by the stereoselective (phenylenes) fused with polycyclic aromatics, and nonlinear synthesis of 1,5-alkadienes (26) [Eq. (20)] and the extension optical materials.[14] One such application is shown in of a side chain in steroid 27 [Eq. (21)].[30,31] Equation (17).[29]

Coupling Reactions of (sp3)CÀB Compounds

Although organometallic reagents with 1-alkenyl, 1- alkynyl, and aryl groups were successfully used for the coupling reactions, those with alkyl groups having sp3 carbons Many chemists applied such a Suzuki coupling reaction by with b hydrogens were severely limited due to the competitive using B-saturated alkylboron compounds. For instance, side reactions. In 1971–1972 Kochi, Kumada, and Corriu Danishefsky et al. reported a total synthesis of the promising reported independently that the reaction of alkyl Grignard anticancer agent (À)-epothilone B by using the coupling reagents with alkenyl or aryl halides are markedly catalyzed method [Eq. (22)],[32,33] and a sister compound, epothilone A, by FeIII or NiII complexes, and then Negishi demonstrated the was also synthesized by a similar procedure.[34] A full paper

Angew. Chem. Int. Ed. 2011, 50 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-fused polyether.

Base Problems

In cross-coupling reactions of organoboron compounds, the presence of a base is essential; no reaction occurs without base. On the other hand, there are many organic compounds that are sensitive to bases. Consequently, the careful use of bases 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 KOAc (4) 50 18 18

DMF K2CO3 (2) 50 18 64

CH3CN K2CO3 (4) 50 18 46

DMF K3PO4 (4) 50 20 92

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

describing the total synthesis of epothilones A and B has that the selection of a base and solvent system provides appeared more recently.[35] markedly different yields of the coupled products. By careful

Marine polyether toxins present challenging synthetic selection of the reaction conditions (e.g., [PdCl2(dppf)]/

targets because of their structural complexity and exception- K2CO3/DMF), high yields of the desired coupled products ally potent biological activities. The most critical issue in the can be achieved [Eq. (24) and (25)]. synthesis of these large polyether compounds is the development of synthetic methods for the convergent coupling of polyether 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 the synthesis of trans-fused polyethers based on the palla-

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Coupling Reactions of (sp)CÀB Compounds Table 11: Pd-catalyzed arylation of alkynylmetal reagents mediated by 9- MeO-9-BBN derivatives. Alkynylboranes have long been known to be useful Substrate RM Product Yield [%] synthetic intermediates. Compared to other organoboranes, 4-bromobenzo- MeC 89 they are easily hydrolyzed by base. Because of this property, phenone CNa alkynylboron compounds have not been employed in the PhC 4-bromobenzaldehyde 77 Suzuki coupling reaction, in which the presence of bases is CNa essential. Recently, Soderquist et al. have found that the ethyl 4-bromoben- MeC 86 addition of B-methoxy-9-borabicyclo[3.3.1]nonane to alky- zoate CNa PhC nyllithium reagents gives stable complexes 29, which undergo 4-bromobenzonitrile 93 CNa efficient Suzuki coupling to produce a variety of alkynyl derivatives 30 [Eq. (26), Table 10].[37] 9,10-dibromoanthra- PhCCLi 84 cene

Table 10: Coupled products from 29 [see Eq. (26)]. RR’ Yield [%][a] nBu C6H5 60 (92) initely, which will provide an advantage in their application to [39] SiMe3 C6H5 64 combinatorial chemistry [Eq. (27)].

Ph C6H5 94 nBu p-MeOC6H4 62 (68)

SiMe3 CH2=CC6H5 88 tBu cis-CH=CH-tBu 56

SiMe3 trans-CH=CH-nBu 55 [a] Yields of isolated analytically pure compounds (GC yields).

The Future

Today, the Suzuki reaction continues to evolve, with many new possibilities reported during the past decade. For example, solid-phase Suzuki coupling has been developed by using either resin-bound aryl halides with solution-phase Almost at the same time, Frstner and Seidel reported the boronic acids[14] or vice versa.[26] Such approaches, of course, same reaction.[38] The necessary alkynyl borates in the play an important role in the combinatorial and parallel palladium-catalyzed CÀC bond formation are prepared methodologies now used to explore chemical reactivity, and is from 9-methoxy-9-BBN and a polar organometallic reagent especially well-suited to medicinal chemistry. RM, such as 1-alkynylsodium, -potassium, and -lithium Increasingly, industry is seeking to use more environ- compounds, and not as usual from boranes and bases. This mentally friendly processes. These often require ingenious approach allows cross-couplings of organic halides with, for solutions to which Suzuki coupling is well-suited. Research example, alkynyl, methyl, or TMSCH2 groups. The method is groups around the world are investigating modifications of highly chemoselective and turned out to be compatible with the reaction that work in aqueous media or with trace aldehyde, amide, ketone, ester, and cyano functions as well as amounts of catalysts. For example, Leadbeater and his team with basic nitrogen atoms in the substrates. Some of the carry out Suzuki coupling using an ultralow (ppb) palladium results are shown in Table 11. This reaction has been used to concentration in water,[40] while Kabalka and colleagues have prepare compound 31, which is highly valuable for its combined a solvent-free, solid-state approach with the chemoluminescence properties. application of microwave radiation to achieve coupling in Most recently the palladium-catalyzed cross-coupling just a few minutes.[41] Ionic liquids, which are excellent reaction of potassium alkynyltrifluoroborates with aryl hal- solvents for transition-metal catalysts, are also being inves- ides or triflates has been reported to give readily coupled tigated.[42] products. The potassium alkynyltrifluoroborates are air- and We can expect to see many more interesting versions of moisture-stable crystalline solids that can be stored indef- the Suzuki coupling in the future.

Angew. Chem. Int. Ed. 2011, 50 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. [13] “Fluoride-Mediated Boronic Acid Coupling Reactions”: S. W. Brown for his cordial encouragement and warm guidance to Wright, D. L. Hageman, L. D. McClure, J. Org. Chem. 1994, 59, me, not only in chemistry but also my life. Thanks are also due 6095 – 6097. to many former co-workers, including graduate and under- [14] “Suzuki Coupling”: A. Suzuki, Organic Syntheses via Boranes, Vol. 3, Aldrich, USA, 2003. graduate students at Hokkaido University. [15] “Synthesis of Sterically Hindered Biaryls via the Palladium- Catalyzed Cross-Coupling Reaction of Arylboronic Acids or Received: February 24, 2011 their 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 Metal- Carbon Bond, Vol. 2 (Eds.: F. R. Hartley, S. Patai), Wiley, New [1] Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Diederich, York, 1985, pp. 25 – 150. P. J. Stang), Wiley-VCH, Weinheim, 1998. [17] “A Highly Active Suzuki Catalyst for the Synthesis of Sterically [2] “Approximate Self Consistent Field Molecular Orbital Calcu- Hindered Biaryls: Novel Ligand Coordination”: J. Yin, S. L. lations on the Complexes of Trimethylboron, Boron Trichloride, Buchwald, J. Am. Chem. Soc. 2002, 124, 1162 – 1163. Trimethylaluminium, Alane and Aluminium Trichloride with [18] “Versatile Catalysts for the Suzuki Cross-Coupling of Arylbor- Trimethylamine”: O. Gropen, A. Haaland, Acta Chem. Scand. onic Acids with Aryl and Vinyl Halides and Triflates under Mild 1973, 27, 521 – 527. Conditions”: A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. [3] “Stereo- and Regiospecific Syntheses to Provide Conjugated 2000, 122, 4020 – 4028. (E,Z)- and (Z,Z)-Alkadienes, and Arylated (Z)-Alkenes in [19] “Highly Active Palladium Catalysts for Suzuki Coupling Reac- Excellent Yields via the Palladium-Catalyzed Cross-Coupling tions”: J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald, J. reactions of (Z)-1-alkenylboronates with 1-Bromoalkenes and Am. Chem. Soc. 1999, 121, 9550 – 9561. Aryl iodides”: N. Miyaura, M. Satoh, A. Suzuki, Tetrahedron [20] “A New Highly Efficient Catalyst System for the Coupling of Lett. 1986, 27, 3745 – 3748. Nonactivated and Deactivated Aryl Chlorides with Arylboronic [4] “Palladium-Catalyzed Cross-Coupling Reactions of Organo- Acids”: A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. 2000, boron Compounds”: N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 112, 4315 – 4317; Angew. Chem. Int. Ed. 2000, 39, 4153 – 4155. 2457 – 2483. [21] “A Convergent Total Synthesis of the Michellamines”: G. [5] “Cross-coupling reactions of organoboron compounds with Bringmann, R. Gtz, P. A. Keller, R. Walter, M. R. Boyd, F. organic halides”: A. Suzuki in Metal-Catalyzed Cross-Coupling Lang, A. Garcia, J. J. Walsh, L. Tellitu, K. V. Bhaskar, T. R. Reactions (Eds.: F. Diederich, P. J. Stang), Wiley-VCH, Wein- Kelly, J. Org. Chem. 1998, 63, 1090 – 1097. heim, 1998, pp. 49 – 98. AB [6] “Recent advances in the cross-coupling reactions of organo- [22] “A Suzuki Coupling-Macrolactamization Approach to the - boron derivatives with organic electrophiles, 1995–1998”: A. COD Bicyclic System of Vancomycin”: K. C. Nicolaou, J. M. Suzuki, J. Organomet. Chem. 1999, 576, 147 – 168. Ramanjulu, S. Natarajan, S. Brse, H. Li, C. N. C. Boddy, F. [7] “The Suzuki Reaction with Arylboron Compounds in Arene Rbsam, Chem. Commun. 1997, 1899 – 1990. Chemistry”: A. Suzuki in Modern Arene Chemistry (Ed.: D. [23] “Total Synthesis of Vancomycin-Part 3: Synthesis of the Astruc), Wiley-VCH, Weinheim, 2002, pp. 53 – 106. Aglycon”: K. C. Nicolaou, A. E. Koumbis, M. Takayanagi, S. [8] “Total Synthesis of a Fully Protected Palytoxin Carboxylic Natarajan, N. F. Jain, T. Bando, H. Li, R. Hughes, Chem. Eur. J. Acid”: Y. Kishi, R. W. Armstrong, J. M. Beau, S. H. Cheon, H. 1999, 5, 2622 – 2647. Fujioka, W. H. Ham, L. D. Hawkins, H. Jin, S. H. Kang, M. J. [24] “Syntheses of Phenothiazinylboronic Acid Derivatives—Suita- Martinelli, W. W. McWhorter, Jr., M. Mizuno, M. Nakata, A. E. ble Starting Points for the Construction of Redox Active Stutz, F. X. Talamas, M. Taniguchi, J. A. Tino, K. Ueda, J.-i. Materials”: C. S. Krmer, T. J. Zimmermann, M. Sailer, J. J. Uenishi, J. B. White, M. Yonaga, J. Am. Chem. Soc. 1989, 111, Mller, Synthesis 2002, 1163 – 1170. 7525 – 7530; “Total Synthesis of Palytoxin Carboxylic Acid and [25] “Head-to-Tail Regioregular Oligothiophene-Functionalized Palytoxin Amide”: R. W. Armstrong, J.-M. Beau, S. H. Cheon, 9,9’-Spirobifluorene Derivatives. 1. Synthesis”: J. Pei, J. Ni, X.- W. J. Christ, H. Fujioka, W.-H. Ham, L. D. Hawkins, H. J. Sung, H. Zhou, X.-Y. Cao, Y.-H. Lai, J. Org. Chem. 2002, 67, 4924 – S. H. Kang, Y. Kishi, M. J. Martinelli, W. W. MacWhorter, Jr., M. 4936. Mizuno, J. A. Tino, K. Ueda, J.-i. Uenishi, J. B. White, M. [26] “Boronic Ester as a Linker System for Solid Phase Synthesis”: B. Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 – 7533. Carboni, C. Pourbaix, F. Carreaux, H. Deleuze, B. Maillard, [9] “Total Synthesis of Lucilactaene, A Cell Cycle Inhibitor Active Tetrahedron Lett. 1999, 40, 7979 – 7983. in p53-Inactive Cells”: R. S. Coleman, M. C. Walczak, E. L. [27] “Soluble poly(para-phenylene)s. 1. Extension of the Yamamoto Campbell, J. Am. Chem. Soc. 2005, 127, 16038 – 16039. synthesis to dibromobenzenes substituted with flexible side [10] “Novel and Convenient Method for the Stereo- and Regiospe- chains”: M. Rehahn, A. D. Schlter, G. Wegner, W. Feast, cific Synthesis of Conjugated Alkadienes and Alkenynes via the Polymer 1989, 30, 1054 – 1059. Palladium-Catalyzed Cross-Coupling Reaction of 1-Alkenylbor- [28] “The Tenth Anniversary of Suzuki Polycondensation (SPC)”: anes with Bromoalkenes and Bromoalkynes”: N. Miyaura, K. A. D. Schlter, J. Polym. Sci. Part A 2001, 39, 1533 – 1556. Yamada, H. Suginome, A. Suzuki, J. Am. Chem. Soc. 1985, 107, [29] “Polymeric Alkoxy PBD [2-(4-Biphenylyl)-5-Phenyl-1,3,4-Oxa- 972 – 980. diazole] for Light-Emitting Diodes”: C. Wang, M. Kilitzirak, L.- [11] “Palladium-Catalyzed Cross-Coupling Reaction of (1-Ethoxy-1- O. Palsson, M. R. Bryce, A. P. Monkman, D. W. Samuel I, Adv. alken-2-yl)boranes With ortho-Functionalized Iodoarenes. A Funct. Mater. 2001, 11, 47 – 50. Novel and Convenient Synthesis of Benzo-Fused Heteroaro- [30] “Palladium-Catalyzed Cross-Coupling Reactions of B-alkyl-9- matic Compounds”: M. Satoh, N. Miyaura, A. Suzuki, Synthesis BBN or Trialkylboranes with Aryl and 1-Alkenyl halides”: N. 1987, 373 – 377. Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki, Tetrahedron Lett. [12] “The Palladium-Catalyzed Cross-Coupling Reaction of Phenyl- 1986, 27, 6369 – 6372. boronic Acid with Haloarenes in the Presence of Bases”: N. [31] “Palladium-Catalyzed Inter- and Intramolecular Cross-Coupling Miyaura, T. Yanagi, A. Suzuki, Synth. Commun. 1981, 11, 513 – Reactions of B-alkyl-9-borabicyclo[3.3.1]nonane Derivatives 519. with 1-Halo-1-alkenes or Haloarenes. Syntheses of functional-

www.angewandte.org 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2011, 50 Suzuki Coupling

ized alkenes, arenes, and cycloalkenes via a Hydroboration- reaction”: M. Sasaki, H. Fuwa, M. Inoue, K. Tachibana, Coupling Sequence”: N. Miyaura, T. Ishiyama, H. Sasaki, M. Tetrahedron Lett. 1998, 39, 9027 – 9030. Ishikawa, M. Satoh, A. Suzuki, J. Am. Chem. Soc. 1989, 111, [37] “Alkynylboranes in the Suzuki–Miyaura coupling”: J. A. Soder- 314 – 321. quist, K. Matos, A. Rane, J. Ramos, Tetrahedron Lett. 1995, 36, [32] “Total Synthesis of (À)-Epothilone B: An Extension of the 2401 – 2402. Suzuki Coupling Method and Insights into Structure-Activity [38] “Palladium-Catalyzed Arylation of Polar Organometallics Relationships of the Epothilones”: D.-S. Su, D. Meng, P. Mediated by 9-Methoxy-9-borabicyclo[3.3.1]nonane: Suzuki Bertinato, A. Balog, E. J. Sorensen, S. J. Danishefsky, Y.-H. Reactions of Extended Scope”: A. Frstner, G. Seidel, Tetrahe- Zheng, T.-C. Chou, L. He, S. B. Horwitz, Angew. Chem. 1997, dron 1995, 51, 11165 – 11178. 109, 775 – 777; Angew. Chem. Int. Ed. Engl. 1997, 36, 757 – 759. [39] “Development of the Suzuki–Miyaura Cross-Coupling Reac- [33] “A Novel Aldol Condensation with 2-Methyl-4-pentenal and Its tion: Use of Air-Stable Potassium Alkynyltrifluoroborates in Application to an Improved Total Synthesis of Epothilone B”: Aryl Alkynylations”: G. A. Molander, B. W. Katona, F. Mach- A. Balog, C. Harris, K. Savin, X.-G. Zhang, T. C. Chao, S. J. rouhi, J. Org. Chem. 2002, 67, 8416 – 8423. Danishefsky, Angew. Chem. 1998, 110, 2821 – 2824; Angew. [40] “A Reassessment of the Transition-Metal Free Suzuki-Type Chem. Int. Ed. 37 1998, , 2675 – 2678. Coupling Methodology”: R. K. Arvela, N. E. Leadbeater, M. S. [34] “Total Synthesis of (À)-Epothilone A”: A. Balog, D. Meng, T. Sangi, V. A. Williams, P. Granados, R. D. Singer, J. Org. Chem. Kamenecka, P. Bertinato, D. Su, E. J. Sorensen, S. J. Danishef- 2005, 70, 161 – 168. sky, Angew. Chem. 1996, 108, 2976 – 2978; Angew. Chem. Int. Ed. [41] “Solventless Suzuki Coupling Reactions on Palladium-Doped Engl. 1996, 35, 2801 – 2803. KF/Al2O3”: G. W. Kabalka, R. M. Pagni, C. M. Hair, Org. Lett. [35] “Total Syntheses of Epothilones A and B”: D. Meng, P. 1999, 1, 1423 – 1425. Bertinato, A. Balog, D.-S. Su, T. Kamenecka, E. J. Sorensen, [42] “Palladium Catalysed Suzuki Cross-Coupling Reactions in S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073 – 10092. Ambient Temperature Ionic Liquids”: C. J. Mathews, P. J. [36] “New strategy for convergent synthesis of trans-fused polyether frameworks based on palladium-catalyzed suzuki cross-coupling Smith, T. Welton, Chem. Commun. 2000, 1249 – 1250.

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