design, synthesis, mechanistic rationalization and application of
TRANSCRIPT
List of Papers
This thesis is based on the following papers and appendix, referred to in the text by their Roman numerals:
I. A Theoretical and Experimental Study of the Asymmetric Addition of Dial-kylzinc to N-(diphenylphosphinoyl)benzalimine. Brandt, Peter; Hedberg, Chris-tian; Lawonn, Klaus; Pinho, Pedro; Andersson, Pher G. Chemistry-A European Journal 1999, 5(6), 1692-1699.
II. Diels-Alder Reaction of Heterocyclic Imine Dienophiles. Hedberg, Christian; Pinho, Pedro; Roth, Peter; Andersson, Pher G. Journal of Organic Chemistry2000, 65(9), 2810-2812.
III. Catalytic Asymmetric Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine. Hedberg, Christian; Andersson, Pher G. Advanced Synthesis and Catalysis 2005, In Press.
IV. New Mechanistic Insights into the Iridium-Phosphanooxazoline Catalyzed Hydrogenation of Unfunctionalized Olefins: A DFT and Kinetic Study.Brandt, Peter; Hedberg, Christian; Andersson, Pher G. Chemistry-A European Journal 2003, 9(1), 339-347.
V. Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogena-tion of Olefins. Källström, Klas; Hedberg, Christian; Brandt, Peter; Bayer, An-nette; Andersson, Pher G. Journal of the American Chemical Society 2004,126(44), 14308-14309.
VI. Origin of Enantioselectivity in Ir-Catalyzed Asymmetric Hydrogenation of Tri-Substituted Olefins. Hedberg, Christian; Källström, Klas; Brandt, Peter; Bayer, Annette; Andersson, Pher G. Manuscript.
VII. Mechanistic Insights into the Phosphine free RuCp*-Diamine Catalyzed Hy-drogenation of Arylketones: An Experimental and Theoretical Study. Hed-berg, Christian; Källström, Klas; Arvidsson, Per I.; Andersson, Pher G.; Brandt, Peter. Journal of the American Chemical Society, Submitted.
VIII. Appendix: Supplementary Material. Hedberg, Christian.
Contribution report
The author wishes to clarify his contributions to the papers I-VII in the thesis:
I. Performed a significant part of the experimental work; contributed partly to the formulation of the research problem; contributed to some extent with the interpre-tation of the results and writing of the paper. Dr. Peter Brandt performed the DFT-calculations.
II. Contributed with the original idea; formulated the research problem; performed a significant part of the experimental work; contributed significantly to the interpre-tation of the results and to the writing of the paper.
III. Contributed partly to the formulation of the research problem; performed all ex-perimental work and wrote the paper.
IV. Contributed partly to the formulation of the experimental research problem; per-formed all experimental work; contributed partly to the interpretation of the re-sults and writing of the paper. Dr. Peter Brandt performed the DFT-calculations.
V. Contributed with the original idea; formulated the research problem; performed a significant part of the experimental work; contributed significantly to the interpre-tation of the results and to the writing of the paper. Dr. Peter Brandt performed the DFT-calculations. Dr. Annette Bayer and Prof. Lars Kristian Hansen performed the X-ray crystallographic diffraction experiments.
VI. Contributed with the original idea; formulated the research problem; performed a significant part of the experimental work; contributed significantly to the interpre-tation of the results and to the writing of the paper. Dr. Annette Bayer and Prof. Lars Kristian Hansen performed the X-ray crystallographic experiments.
VII. Contributed with the original idea concerning the experimental system; performed a minor part of the experimental work; contributed significantly to the interpreta-tion of the experimental results and to some extent in the writing of the paper. Dr. Peter Brandt and Prof. Pher Andersson performed the DFT-calculations.
Contents
1 Introduction ............................................................................................121.1 History of Chirality .........................................................................131.2 Enantiomerically Pure Compounds ................................................141.3 Different Approaches to the Preparation of Chiral Compounds .....15
2 Synthesis of 2-Azanorbornyl-3-methanols as Catalysts for the Addition of Organometallics to Activated Imines .................................................17
2.1 The Glyoxalimine Aza-Diels-Alder Reaction.................................172.2 Ligand Synthesis and Application ..................................................19
2.2.1 Introduction .............................................................................192.2.2 Synthesis and Mechanistic Evaluation ....................................20
3 Aza-Diels-Alder Reaction of Heterocyclic Imine Dienophiles ..............273.1 Introduction.....................................................................................273.2 Synthesis and Evaluation ................................................................28
4 Catalytic Asymmetric Total Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine.....................................................................32
4.1 Introduction.....................................................................................324.2 Retrosynthetic Analysis ..................................................................334.3 Synthesis and Evaluation ................................................................34
5 Iridium-Catalysed Asymmetric Hydrogenation of Olefins ....................375.1 Introduction.....................................................................................375.2 Mechanistic Studies ........................................................................38
5.2.1 Introduction .............................................................................385.2.2 Derivation of Rate Expression and Experimental Kinetics .....395.2.3 Reaction Mechanism ...............................................................425.2.4 Rationalization of Enantioselectivity ......................................44
5.3 Application of Selectivity Model in Ligand Design .......................455.3.1 General Guidelines from Mechanism Study ...........................455.3.2 Design of First Generation Ligands ........................................46
5.4 Synthesis and Evaluation of Designed Ligands ..............................485.4.1 Synthesis and Evaluation of First Generation Ligands ...........485.4.2 Design Modifications Leading to Second Generation Ligands ....................................................................................56
5.4.3 Synthesis and Evaluation of Second Generation Ligands .......575.5 Conclusions.....................................................................................65
6 Catalytic Asymmetric Hydrogenation of Ketones by Phosphine Free Ruthenium Catalysts...............................................................................66
6.1 Introduction.....................................................................................666.2 Results and Discussion ...................................................................68
6.2.1 Hydrogenation of Aryl alkyl ketones; Results ........................686.2.2 Rationalizing Mechanism and Enantioselectivity ...................69
6.3 Conclusions.....................................................................................74
7 Acknowledgements ................................................................................75
8 References ..............................................................................................76
Abbreviations
Å Ångström Abs. Config. Absolute Configuration Atm Atmosphere(s) BArF tetrakis 3,5-(trifluoromethyl)-phenyl borateBn Benzyl COD 1,5-Cyclooctadiene Cp* Pentamethylcyclopentadienyl CpH Cyclopentadiene DABCO 1,4-Diazabicyclo 2.2.2 octaneDBTA 2,3-Dibenzoyl tartaric acid DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL Diisobutylaluminium hydride DIPA Diisopropylamine DMAP 4-Dimethylaminopyridine DoE Design of Experiments equiv. Equivalent(s) Et Ethyl h Hour(s) HPLC High Performance Liquid Chromatography i-Pr iso-Propyl m-CPBA meta-Chloroperbenzoic acid Me Methyl Me-CBS Methyl- oxazaborolidine catalyst MeCN Acetonitrile Ms Molecular sieves n-Bu n-Butyl NMR Nuclear Magnetic Resonance NOE Nuclear Overhauser Effect Ns p-Nitrosulphonylbenzene o.n. Over night Ph Phenyl rt Room temperature (23°C) t-Bu tert-Butyl TFA Trifluoroacetic acid THF Tetrahydrofuran Ts p-toulenesulphonyl
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Populärvetenskaplig Sammanfattning på Svenska
Man kan med fog säga att organisk kemi är en av de mest fundamentala av vetenskaperna. Den behandlar det som kan anses vara livsvetenskapernas fundament: De organiska molekylernas kemi och interaktioner med var-andra. Oavsett vilket biologiskt system som betraktas, så kan det på mole-kylnivå sägas vara frågan om organisk kemi. Den organiska kemin, såsom eget ämne, har under det senaste seklet och framförallt under de senaste de-cennierna genomgått en häpnadsväckande utveckling. I gränsytorna till andra ämnen, exempelvis fysik och biovetenskaper har tekniska och farma-ceutiska applikationer uppstått. Vad som är viktigt att komma ihåg är det faktum att de flesta av våra dagliga konsumtionsvaror på ett eller annat sätt är relaterade till organisk bulk,- finkemikalie- eller läkemedelsindustri. Det handlar om så diversa områden som material härrörande från petrokemisk industri, exempelvis plast och drivmedel; läkemedel av allehanda slag; agro-kemikalier såsom pesticider, herbicider och djurfarmaprodukter, vilka idag är av essensiell betydelse för jordbrukssektorn; det område som idag kallas “performance chemicals” dvs. tillsatser och färgämnen för polymer-, materi-al-, elektronik- och pappersindustri; tillsatser för livsmedelsindustrin; doft-ämnen för parfymindustrin, mfl. Kort sagt så är, i princip, all konsumtions-varuindustri idag beroende av syntetisk organisk kemi.
En intressant egenskap hos vissa kemiska föreningar, i synnerhet de kol-föreningar som brukar benämnas organiska, är att de uppvisar spegelbild-isomeri, fenomenet benämns kiralitet inom ämnet. En kiral molekyl har pre-cis samma fysikaliska egenskaper som en racemisk blandning av två motsat-ta spegelbilder, bortsett från att smältpunkten kan variera emellanåt, förutom att de kirala molekylerna har egenskapen att de vrider planpolariserat ljus av varierande våglängder ur dess plan. Därför brukar dessa föreningar benäm-nas optiskt aktiva. Den benämningen är av åldrigt ursprung och kan härledas till det tidiga 1800-talet, då fenomenet först uppmärksammades av den mångsysslande franske vetenskapsmannen J. B. Biot. De kirala molekylernas mest intressanta egenskaper är när de interagerar med varandra, dvs. olika kirala former av en och samma molekyl känner igen en annan kiral molekyl på olika sätt. Detta fenomen kallas av den organiske kemisten för diastereo-mera interaktioner och kan sägas vara själva livets mest grundläggande för-utsättning. Eftersom allt levande är uppbyggt av celler, till största delen kon-struerade av proteiner, även benämnda som äggviteämnen, vilka i sin tur består av kirala aminosyror, så är själva livet också kiralt. De molekylära igenkänningsmekanismerna som styr de biologiska processerna bygger till stor del på energiskillnaderna i de diastereomera interaktionerna mellan olika kirala molekyler. Eftersom vår kropp och dess receptorer, byggda av ovan nämda aminosyror, är kirala, så förefaller det rätt så naturligt att antaga att de molekyler som förväntas ha biologisk aktivitet, exempelvis läkemedel, bör
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vara kirala. Arbetet som presenteras här i avhandlingen syftar till att etablera metoder för syntes, och i förlängningen även produktion, av kirala förening-ar med hjälp av katalytiska metoder. Fördelen med att inducera kiralitet med hjälp av en katalysator, jämfört med ett stökiometriskt reagens, är att en yt-terst liten mängd kiralt material (katalysatorn) behövs för att åstadkomma en kiral produkt, förutsatt att katalysatorn är effektiv. För att kunna designa katalysatorer med såväl hög selektivitet som aktivitet, behövs en grund-läggande förståelse hur dessa system fungerar, vilket har varit det andra hu-vudmålet i denna avhandling.
Första delarbetet (Paper I) avhandlar syntes av kirala aminer med hjälp av en stökiometrisk/katalytisk metod, mekanismen för den aktuella reaktionen studerades också. Vi kom slutgiltigt fram till att möjligheterna att etablera en katalytisk process var rätt så små. Kirala aminer är viktiga produker i ett brett spektrum av applikationer, främst med biologiska tillämpningar.
Andra delarbetet (Paper II) behandlar en s.k. aza-Diels-Alder reaktion, en sorts cykloaddition, där ett kolskelett innehållande en kväveatom konstrue-ras. Syftet med detta arbete var ursprungligen att etablera en metod för syn-tes av en grupp föreningar som kunde vara intressanta som kirala ligander för exempelvis iridium-katalyserad hydrogenering av prokirala kol-kol dub-belbindningar. Nu blev inte utfallet av arbetet det önskade, men den etable-rade metoden har stort preparativt värde och är flitigt citerad i literaturen.
Tredje delarbetet (Paper III) redogör för utvecklandet av en katalytisk me-tod för syntes av en kiral läkemedelsubstans, vars trivialnamn är tolterodin, handelsnamn Detrol . Detta preparat är en potent hämmare av den så kallade muskarinreceptorgruppen och används i kiral form. Den terapeutiska indika-tionen för utskrivning av Detrol är överaktiv urinblåsa och inkontinens. Dessa problem drabbar främst medelålders och äldre kinnor och har tidigare varit svårmedicinerade. De preparat som har använts för samma indikation innan Detrol lanserades på marknaden medförde biverkningar i form av muntorrhet, med dålig tandhälsa som följd, samt andra slemhinnerelaterade problem. Arbetet i tredje delarbetet avsåg att etablera en katalytisk syntes av kiralt tolterodin, istället för att som idag tillverka den racemiska blandningen av de två spegelbildsisomererna och separera dem efter sista syntessteget.
Fjärde delarbetet (Paper IV) behandlar en mekanistisk studie av iridium-katalyserad asymmetrisk hydrogenering av prokirala kol-kol dubbelbind-ningar. Asymmetrisk hydrogenering kan sägas vara föredragen teknologi för produktion av kirala föreningar, såväl inom finkemikalie- som läkemedels-industri. Tekniken bygger på att man med hjälp av en kiral katalysator adde-rar vätgas över en omättad kol-kol eller kol-heteroatom dubbelbindning. Beroende på från vilket håll reaktionen sker, erhåller man olika spegelbilds-isomerer. En högselektiv katalysator klarar av att nästintill fullständigt skilja på de två prokirala sidorna av dubbelbindningen. Tekniken kan också sägas vara mycket miljövänlig. Anledningen till detta är att några egentliga rest-produkter inte bildas vid reaktionen som använder lättillgänglig vätgas och
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vanligen mycket små katalysatormängder. Katalysatorerna använda i dessa reaktioner består vanligen av en kiral ligand koordinerad till den katalytiskt aktiva metallatomen, exempelvis rodium, rutenium, eller som i detta fallet, iridium. I den mekanistiska studien presenterad i det fjärde delarbetet etable-rade vi ett förslag för reaktionsmekanismen avseende en viss typ av hydro-generingsreaktion. Detta förslag har vållat stora diskussioner i litteraturen, som vanligt är mer konservativt lagda experimentalister skeptiska till teore-tiska beräkningar, troligen endast på grund av att de själva inte behärskar tekniken. Vi kom fram till att det är troligt att den katalytiska cykeln går mellan oxidationstalen (III) och (V) för iridium, jämfört med oxidationstalen (I) och (III) för samma reaktion med rhodium. Vidare etablerade vi en mo-dell för att beskriva upphovet till enantioselektiviteten hos katalysatorn, det vill säga den kirala induktionen från katalysatorn till produkten. Detta papper ligger till grund för de två följande delarbetena (Paper V-VI)
I det femte delarbetet (Paper V) används resultaten från det tidigare arbe-tet (Paper IV) för att etablera en modell för rationell design av kirala iridium-katalysatorer för asymmetrisk hydrogenering av kol-kol dubbelbindningar. Dessa nya iridiumkatalysatorer bygger på en ny typ av heterocykliska ligan-der vars syntes beskrivs i detalj. Arbetet kan sägas ha varit mycket fram-gångsrikt och resultaten är de bästa rapporterade hitintills i litteraturen.
Det sjätte delarbetet, som fortfarande föreligger i manuskriptform, kan sägas vara en fortsättning på föregående arbete. Iridium-katalyserad hydro-genering av kol-kol dubbelbindningar studeras vidare, och en ny typ av kira-la ligander syntetiseras, där de tidigare etablerade strukturerna (Paper V) förbättras. Arbetets syfte är att i ett längre perspektiv systematiskt undersöka de faktorer som styr aktivitet och selektivitet hos de katalytiska system vi har studerat. Resultaten är mycket intressanta och för första gången har vi visat att det är möjligt att hydrogenera substrat som tidigare har ansetts som “omöjliga”.
I det sjunde och sista delarbetet (Paper VII) studeras den katalytiska hyd-rogeneringen av prokirala ketoner med en ruteniumkatalysator baserad på en lättillgänglig och billig kiral ligand. Syftet med detta arbete var att etablera ett protokoll för katalytisk syntes av kirala alkoholer från lättillgängliga startmaterial i form av ketoner. Vidare så är inte särskilt mycket känt om reaktionsmekanismen, vilket också var ett mål att etablera mer kunskap om. Arbetet har varit framgångsrikt och såväl hög selektivitet som mekanistisk förståelse har etablerats. Denna kunskap kommer vidare att användas för konstruerandet av nästa generation kirala katalysatorer för ketonhydrogene-ring.
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1 Introduction
During the 20th century, synthetic organic chemistry has grown to a level of importance unimaginable even one hundred years ago. Many of our daily used pharmacy products are the fruits of one and a half centuries of chemical research. However, the application of modern organic chemistry is not re-stricted to the production of pharmaceuticals. The majority of our consum-able products rely heavily on bulk organic and speciality chemicals, includ-ing: polymer, food, textile, agriculture and the electronics industries. So great have the advances been in the last decades that the majority of pharma-ceutical compounds are prepared by transformations that require the ad-vanced knowledge only recently obtained. Synthetic methods used for the preparation of such molecules have evolved slowly from mere academic curiosity, into widely accepted and applied production technologies. With the demand for speciality chemicals still growing, and moving even more toward the direction of complexity, the area of synthetic organic chemistry remains a fundamental field of academic research.
During the second part of the 20th century a high degree of fundamental understanding has been established within the subject. Unveiling the rules guiding pericyclic reactions and, the introduction of the concept of retrosyn-thetic analysis have been milestones in the development of organic synthesis. During the same time, important analytical methods like NMR spectroscopy and mass spectrometry has developed into highly sensitive routine methods, supporting chemical research with structural and mechanistic information.
Today, organic chemistry is a more diverse subject than ever, the rise of new scientific domains like material science and chemical biology has pro-vided new entries into the field. Synthetic organic chemistry is not longer a subject merely for the researchers of its own field, but rather an important toolbox for a variety of scientific disciplines. Due to the development of biotechnology, organic synthesis is entering into a new age, with the possi-bility of preparing compounds that are even more complex and refined. In-deed, many complex pharmaceuticals like macrolides and other antibiotics are already prepared in a semi-synthetic approach. With the development of more refined and sensitive biomolecules comes the need for milder and more selective synthetic transformations.
Today’s chemists are also challenged by the necessity to reduce the quan-tity of chemical waste and pollution generated during synthesis, to this effect the job of chemists has only just started. Whilst we can produce a broad
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range of synthetic compounds, to perform this in an environmentally friendly manner, as done by biotransformations, is a major challenge. Therefore, the method development and understanding of organic chemistry is more impor-tant today than ever.
1.1 History of Chirality Optically active compounds have been known since the early 19th century. As early as 1801, the French mineralogist Haüy noticed that quartz crystals of different natural origins exhibited hemihederal phenomena, with certain facets of the crystals being non-superimposable mirror images of each other. A few years later, another French scientist, Biot, found that plates of quartz crystals, cut of right angles to its symmetry axis, rotated plane polarised light in opposite directions, depending on the original symmetry. Biot extended his investigations to solutions of organic compounds and found that many compounds of natural origin behaved in a similar manner.[1] Scientifically oriented people at that time were fascinated by the fact that simple organic molecules could interact with polarized light, turning it in either direction. At the time, the phenomenon was explained by the fact that the compounds were of natural origin, produced by living organisms. In 1849, Pasteur was able to separate the two enantiomorphous crystal forms of racemic sodium ammonium tartrate manually with a pair of tweezers by a simple assignment of the crystal shape through a lens.[2] He then found that a solution of the enantimorphous crystals rotated the polarized light in opposite directions. Pasteur then made the tremendously important statement that the rotation of polarized light caused by the different tartaric acid salt crystals was the property of chiral molecules. The two forms of optically active tartaric acid were related to each other as three-dimensional mirror images. Later during the 19th century, Emil Fisher established that enantiomers of a given com-pound have a specific rotation with the same magnitude, but in opposite directions. The first catalytic asymmetric synthesis reported in the literature was a decarboxylation of a prochiral , -disubstituted malonic acids in the presence of the naturally occurring alkaloid brucine, reported by Marckwald in 1904.[3] Since that time the phenomenon of chirality has been intensely explored, and has maybe turned into one of the most important fields of or-ganic chemistry. The major breakthrough on synthesis of chiral compounds was made in the late 1960’s, when the synthetic tools of organic chemistry became more sophisticated. Many chemists today are still asking each other, what is an asymmetric synthesis? Marckwald answered the question in 1904.
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”Asymmetrische Synthesen sind solche, welche aus symmetrisch consti-tuiren Verbindnungen unter intermediärer Benutzung optisch-activer Stoffe, aber unter Vermeidung jedes analytischen Vorganges, optisch-activ Substan-zen erzeugen”
Advances in chiral methodologies have allowed these techniques to be ex-tended for use on production scale. Several asymmetric processes are operat-ing in chemical plants around the world today. The first large-scale proc-esses were based on enzymatic systems, but during the 1990’s, several metal catalysed asymmetric reactions were setup for pharmaceutical- and special-ity-chemical production.[4] The use and demand for optically active sub-stances is greater today than ever, even so much that Pasteur, Fisher and Marckwald probably never realized the importance of their discoveries.
1.2 Enantiomerically Pure Compounds Today we know that chiral compounds are fundamental for the existence of life. A majority of biological processes are consequences of the fact that different enantiomers react with receptors in different ways, depending on their absolute configuration. Life itself is in many ways chiral. For example, the mechanism of smell is based on stereogenic interactions between the sensor, our nose, and a volatile compound. Enantiomeric compounds often have different odors or tastes, the enantiomers of limonene smell and taste like lemons or oranges, and the enantiomers of phenylalanine taste bitter or sweet, depending on the absolute configuration. In order to develop safe and efficient pharmaceuticals we must have in mind that the biological receptor is chiral. Several major disasters with racemic pharmaceuticals have been reported, the best-known example in Sweden is the vide spectra psychoac-tive thalidomide (Neurocedyn ), having one active enantiomer and the other one being a severe teratogen. This is a common example when discussing the importance of chirality in pharmaceutical products. It is however impor-tant to highlight the positive aspects that single enantiomer drugs have, com-pared to racemates. It is obvious that a change to single enantiomer pharma-ceutical and agricultural chemicals will change the market and increase pa-tient safety and decrease environmental impact. Indeed, the market of single enantiomer compounds is growing fast. Out of the 60% of all drugs that con-tain a chiral center, a percentage that has remained relatively unchanged over the last 20 years, racemates dominated in 1983 (60%) and the drug com-
”Asymmetric synthesies are those which produce optically active compounds from symmet-rically constituted compounds with the intermediate use of optically active materials, but with the avoidance of any separations"
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pounds that were marketed as single enantiomers at that time were mainly of natural origin. In 2002 only a fraction (10%) of the drugs that contained a chiral compound were racemates, with the rest sold as single enantiomers. Since 1992, new chemical pharma compounds possessing chirality must have each enantiomer individually screened and evaluated as different chemical entities during the drug approval process.[5]
1.3 Different Approaches to the Preparation of Chiral Compounds
There are a number of ways to prepare enantiomerically pure compounds, of these the most common is still optical resolution of a racemic mixture. This method is often used to resolve racemic amines or acids, possessing the pos-sibility of forming diastereomeric salts with a resolving agent. The resolving agent is often a naturally occurring compound; some well-known examples are tartaric acid, brucine, quinine and its related alkaloids.[6] Enzymatic methods, like lipase catalysed reactions are also popular for preparative scale work.[7] Further resolution approaches include; direct crystallization of race-mates induced by seeding;[8, 9] separation of enantiomers by chromatography on chiral stationary phases, a method that has gained tremendously in impor-tance during the last decade.[10, 11] Whilst, the maximum yield of a resolution is 50%, and often lower due to losses in recrystallization or chemical modifi-cation steps, recovery and racemization of the unwanted isomer can some-times overcome this drawback. A good and innovative example of in siturecycling is the dynamic kinetic resolution approach.[12]
In 1974 Eliel et al. proposed the following criteria for judging the perform-ance of an asymmetric synthesis:[13] (a) The synthesis must be highly stereo-selective. (b) If the chiral auxiliary is an integral part of the molecule, the chiral center generated in the reaction must be easily removed from the aux-iliary without racemization. (c) The chiral auxiliary or reagent must be re-coverable in high yield and without racemization. (d) The chiral auxiliary or catalyst should be readily available from inexpensive materials in enanti-omerically pure form.
Today, we define the two main methods as ”Chiral pool” and “Asymmet-ric synthesis”. In the case of a chiral pool, the product is derived from an available enantiomerically pure compound, which is transformed into the desired product. Whilst in an asymmetric synthesis, chirality is induced by the action of a chiral reagent or auxiliary. The chiral reagent and auxiliary methods use at least one equivalent of the chiral starting material, making it an expensive synthetic route which requires recycling in process applica-tions.
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A more practical form of asymmetric synthesis is asymmetric catalysis.Most catalytic asymmetric processes are metal catalysed, although several organocatalysed systems have appeared during the last five years.[14, 15] Most of the organocatalysts cannot be regarded as catalysts, rather substoichiomet-ric reagents. Employing just a mole-fraction of the metal catalyst, often less than one mole percent is enough for inducing chirality in the prochiral sub-strate. The first successful process to employ asymmetric catalysis on pro-duction scale was Monsanto's L-dopa process, involving asymmetric hydro-genation of an acyl enamine with a modified Wilkinson catalyst.[16, 17] After the introduction of a large number of ligands suitable for asymmetric hydro-genation reactions, enantioselective hydrogenation has become an estab-lished reaction. The academic focus of catalytic asymmetric transformations then turned to oxidations. Reactions such as epoxidations, dihydroxylations, and aminohydroxylations have been reported, Sharpless and Katsuki intro-duced the first practical useful asymmetric oxidation in 1980. It involves epoxidation of allylic alcohols and is still one of the most popular oxidative asymmetric processes. Today, we have a wide spectrum of asymmetric re-ductions, oxidations, addition reactions, and other miscellaneous methods in our hands, some of them highly useful, others not so. At the present time, asymmetric hydrogenation is still the most widely used catalytic asymmetric transformation,[18, 19] with several companies offering asymmetric hydro-genation technology on a license basis.[20]
This thesis contains two papers dealing with synthesis of organic com-pounds from a chiral pool starting material (papers I-II) with the aim of ap-plying the products as ligands within catalytic asymmetric synthesis. One paper containing a catalytic asymmetric total synthesis of a pharma-compound (paper III). The four other papers concerns mechanistic studies and synthetic development of ligands for catalytic asymmetric hydrogena-tion reactions of olefins and ketones (papers IV-VII).
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2 Synthesis of 2-Azanorbornyl-3-methanols as Catalysts for the Addition of Organometallics to Activated Imines
2.1 The Glyoxalimine Aza-Diels-Alder Reaction
Since the discovery of the 4+2 cycloaddition by Otto Diels and Kurt Alder in 1928,[21] the Diels-Alder reaction has been utilized by generations of or-ganic chemists for constructing complex stereogenic carbon skeletons.[22]
The first example of an imine acting as a dienophile was reported by Alder in 1943.[23] Reactions of various enaminoesters with dienes did not produce the carbocyclic adducts, but instead gave the tetrahydropyridines, via reac-tion of the imine tautomer of the enamine. Although this observation was made 60 years ago, little research was performed in this area until the 1990’s. Nowadays, aza-Diels-Alder methodology is considered as textbook chemistry, with a wide variety of complex natural products prepared by em-ploying this methodology.[24] In general, electron deficient imines are the most reactive dienophiles; particularly those possessing a N-sulfonyl, N-acyl, or iminium salt functionalities. The imino Diels-Alder reactions studied in this thesis is catalyzed by acid and can be regarded as an iminium type reac-tions. The work presented in the first two papers of this thesis (paper I-II) is based on the synthesis of chiral compounds possessing the 2-aza-norbornyl skeleton, prepared by an aza-Diels-Alder reaction, and it is therefore appro-priate to give some background to the reaction.[25]
For the cases described in paper I, highly activated glyoxal aldehyde is pre-pared by cleavage of dimethyl tartrate (DMT) or diethyl tartrate (DET) in ether solution by action of periodic acid. Simple filtration and evaporation of the ethereal filtrate gives the corresponding ethyl or methylglyoxylate, pure enough for imine formation.[26] The imine that will act as dienophile in the aza-Diels-Alder reaction is formed by mixing freshly prepared alkylglyox-alate and optically pure -phenylethylamine in the presence of 4Å molecular sieves in anhydrous dichloromethane. One equivalent of Brønstedt acid is needed to protonate the formed imine. A strong non-aqueous acid possessing a non-nucleophilic counter ion is preferred, like methanesulfonic acid or trifluoroacetic acid together with borontrifluoride etherate (Scheme 1).
18
RO
O
O
RO
O
N Ph
Me
RO
O
N Ph
Me
N PhCO2R
Me
1a (major) and diastereomers 1b-1d (minor), R = Me
Hi ii iii
Reagents and Conditions: i) (S)- -phenylethylamine, CH2Cl2, 0°C; ii) TFA, BF3•Et2O, -78°C; iii) CpH, -78°C to rt.
Scheme 1. Formation and reaction of activated imine dienophile.
The 4+2 cycloaddition between the imine dienophile and cyclopentadiene is highly diastereoselective. The selectivity was previously reported by Stella et al. to be 96:2:2 (1a:1b:1c+1d).[27] However, during this work, the ob-served diastereoselectivities have not been that high, rather 88:10:2 (1a:1b:1c+1d) The commonly accepted selectivity model is based on differ-ent sterical discrimination of the Si- and Re-faces of the protonated trans-imine. The exo-Re face is the less hindered side, giving 1a as the major product (Figure 1). In order to obtain high diastereoselectivity it is important to perform the reaction at low temperature, e.g. starting at -78°C and slowly raise it to room temperature. The actual cycloaddition reaction was found to take place at approximately -40 °C.[28]
N
O
MeO
Me
PhHH
Si face
Re face
N PhCO2Me
Me
1c (S)
exo endo
N Ph
CO2Me
Me
1a (R)
NPh
CO2Me
Me
NPhMeO2C
Me
endoexo
1b
(R)
(S)
1d
Figure 1. Selectivity model for aza-Diels-Alder reaction.
It is possible that the slightly lower selectivity observed could be a conse-quence of carrying out the reaction on large scale, and therefore having less control of the temperature. In the optimized procedure using methylglyoxy-late it is possible to obtain 1a as a crystalline compound without chromatog-
19
raphy in 60% yield, calculated from (S)- -phenylethylamine at 1 mol scale.[29] A recent report from a Japanese pharmaceutical company describes the same synthesis on 200-kilogram scale; the product was then isolated in 31% yield without chromatography.[30]
2.2 Ligand Synthesis and Application
2.2.1 IntroductionMuch work has been done on asymmetric dialkylzinc additions to carbon-yls.[31] A less well-investigated area is the addition to imines. This is perhaps due to the lower electrophilicity of the N,C double bond and the fact that imines exist as cis-trans mixtures, giving raise to two different sets of facialselectivity, and in addition, the tendency of enolizing imines to undergo de-protonation instead of 1,2-addition. Some examples can be found in the lit-erature of asymmetric additions of organometallic reagents to imines. The first of these was the addition of organolithiums to N-aryl imines by Tomi-oka et al. in 1990.[32] This initial publication was soon followed by the cata-lytic reaction.[33] Further studies with different chiral 1,2-amino alcohols as promoters were performed by Itsuno et al.[34] Interestingly, the addition of dialkylzinc reagents to N-silyl and N-aryl imine substrates failed to afford any of the desired products. Activation of the imine with electron withdraw-ing substituents like N-acyl, N-tosyl or N-phosphinoyl group was crucial to success in the reaction. Katritzky et al. reported the first dialkylzinc addition to an imine in 1992.[35] The substrate in the first report was a benzotriazol masked N-acyl imine. Shortly after Katritzkys first publication on the sub-ject, Soai et al. reported that dialkylzincs undergo asymmetric additions to N-(diphenyphosphinoyl) benzalimines in the presence of chiral 1,2-amino alcohols.[36] The reaction was reported both with stochiometric and catalytic amounts of the chiral additive. Previous work by Tanner and Andersson have described the use of rigid chiral aziridino-methanols as promoters for the addition of organozinc reagents to N-(diphenyphosphinoyl) benzalimi-nes.[37, 38] Later, Pinho and Andersson prepared a series of rigid 2-aza no-rbornyl methanols (Table 1) and used them in the addition reaction with promising results.[39]
Short path silica gel filtration were used to remove polar impurities from the crude reaction mixture.
20
Table 1. Previous results employing ligands 24a-g.
NR1
R2
R2
OHPh N
PPh
Ph
O 3 equiv. Et2Zn,toulene
1-0.1 equiv. ligand type 24
R1 R2 ee (%)Entry
123456789
BnMeEti-PrBnBnBnBnBn
HHHHMei-PrPhHH
917592858843168568
635043596552334638
yielda(%)
24a-g22 23
a Isolated yield of 23
Ligand24a24b24c24d24e24f24g24a24a
equiv. ligand1.01.01.01.01.01.01.00.30.1
Ph NH
PPh
Ph
OH Et
Considering the results listed in Table 1, ligands 24a and 24c (entry 1 and 3) proved to be superior. Unfortunately, enantioselectivity and isolated yield of 23 dropped when a catalytic amount of ligand was employed. Disubstitution
to the alcohol (entries 5-7) proved to lower the enantioselectivity and iso-lated yield of addition product. In order to improve the enantioselectivity and enable a catalytic process, the introduction of a stereogenic center at the -position to the alcohol was envisioned.
2.2.2 Synthesis and Mechanistic Evaluation The second generation ligands were compounds that contain a secondary alcohol functionality. These ligands were developed as a consequence of the theoretical study of the reaction mechanism, which suggested that a second stereogenic center outside the bicyclic skeleton, possessing the right absolute configuration, would further improve the selectivity. The preparation of both diastereomers of these compounds were considered as straight-forward through a Grignard addition to aldehyde 4. Addition of Grignard reagents to 4 proceeded with good diastereoselectivity, but in moderate yield (55%). Further synthetic manipulations, removal of the chiral auxiliary and alkyla-tion of the resulting secondary amine, proceeded as expected in good yield (Scheme 2).
21
N PhCO2Et
Me
N Ph
Me
N PhCO2Et
Me
N PhCHO
Me
OH
N Ph
MeR
HOH
NHR
H
OH N PhR
HOH
1a 2 3 4
5a, R = Ph (95%)6a, R = Me (95%)7a, R = i-Pr (78%)
8a, R = Ph (96%) 9a, R = Me (93%)10a, R = i-Pr (95%)
11a, R = Ph (61%)12a, R = Me (65%)13a, R = i-Pr (64%)
i ii iii
iv v vi
Reagents and Conditions: i) H2 (1 atm.) Pd(C) (10wt%), EtOH, K2CO3, rt, 2h, quantitative; ii) LiAlH4, THF 0°C to rt, 5h, 96%; iii) Swern oxidation, 92%; iv) RMgX•CeCl3, THF, -78°C to rt, o.n.; v) H2 (1 atm.) Pd(OH)2(C) (20wt%), EtOH, reflux, o.n.; vi) BnBr, K2CO3, MeCN, rt, 32h.
Scheme 2. Synthesis of ligands 11a-13a.
To overcome the initial problem of moderate yield in the addition of Grig-nards to 4, additives such as CeCl3 and Ti(IV) compounds were investigated; surprisingly, this not only had a positive effect on the yield, but also on the diastereoselectivity (Table 2). Organocerium additions to aminoaldehydes has not been reported in the literature until this work, and the high selectivity can be explained by the formation of an oxophilic, sterically demanding organocerium species.[40] Attack on the carbaldehyde can only take place from the least hindered side and without chelating control of the nearby ni-trogen. The final yield of the Grignard addition step could be raised from 55% to 90% diastereomerically pure material (Table 2).
Table 2. Study of additives for the addition of organometallics to aldehyde 4.
123456789
1011
PhMgBrPhLiPhMgBrPhMgBrPhMgBrPhLiMeMgClMeMgClMeLiMeLiMeLi
nonenoneCeCl3CeCl3TiCl4CeCl3noneCeCl3CeCl3TiCl4Ti(i-OPr)4
-78°-78°-78°-10°-78°-78°-78°-78°-78°-78°-78°
5a5a5a5a5a5a6a6a6a6a6a
5530956545886295858590
6555958570686296909591
Entry RM Additive Temp.°C Product Yield (%)a de(%)b
a Isolated yield, b Determined by 1H NMR in crude product
N PhCHO
Me
4
N Ph
MeR
OHH
N Ph
MeR
HOH
5a-6a Major diastereomer
5b-6b Minor diastereomer
Entry1-11
22
To access the epimers of 5a, 6a and 7a, and thus allow experimental verifi-cation of the computational study, it was planned to use the Mitsunobu reac-tion for inverting the absolute configuration at the newly formed stereogenic centers.[41] However, compounds 5a-7a were completely inert to inversion under Mitsunobu conditions, probably due to the severe sterical hindrance induced by the 1-phenylethylamine moieties. Instead, another route to the desired diastereomers had to be developed. The idea followed that, if one diastereomer was available by the addition of an organometallic reagent to the aldehyde, then the other diastereomer should be accessible by hydride reduction of the corresponding ketone. This approach called for development of new aza-Diels-Alder chemistry starting with an imine derived from alkyl- and aryl-glyoxals instead of alkylglyoxalate. In case of 15, (R = Me) the reaction was performed in aqueous HCl instead of organic solvent. Employ-ing phenylglyoxal monohydrate as starting material (14, R=Ph), reaction conditions previous described for 1a gave an acceptable yield of 16. This approach proved to be effective and the synthetic route to these new ligands is described in Scheme 3.
N PhCOR
MeO
O
RN Ph
COR
Me
N Ph
MeR
OHH
NHR
OH
H N PhR
OHH
ia, iia, respective ib, iib iii iv
v vi
Reagents and Conditions: ia) (S)- -phenylethylamine, CH2Cl2, 0°C; iia) TFA, BF3•Et2O,CpH, -78°C to rt; ib) (S) -phenylethylamine, 2 M HCl, H2O, 2h, 0°C; iib) CpH, 48h, 0°C; iii) H2, 1 atm., Pd(C) (10 wt%), EtOH, K2CO3 (trace), rt, 1h, quantitative ; iv) LiAlH4, THF,-78°C to rt; v) H2,1 atm., Pd(OH)2(C), EtOH, reflux, o.n.; vi) BnCl, K2CO3, MeCN, rt.
14, R = Ph (a)15, R = Me (b)
16, R = Ph (42%) 17, R = Me (31%)
18, R = Ph (95%)19, R = Me (95%)
5b, R = Ph (71%)6b, R = Me (65%)
8b, R = Ph (96%) 9b, R = Me (91%)
11b, R = Ph (65%)
Scheme 3. Synthesis of ligand 11b.
In order to improve the diastereoselectivity of the ketone reduction, a study of different reducing agents was performed. Sodium borohydride (NaBH4)has been claimed to be the reagent of choice in diastereoselective reductions of aminoketones to 1,2-amino alcohols.[42] However, whilst this method gave fairly good diastereoselectivity, the isolated yields of the major di-astereomers were low. The best compromise between diastereoselectivity and isolated yield proved to be LiAlH4 at low temperature (Table 3). Later on, this protocol was revised for a similar class of compounds; employing one equivalent of tetrabutylammoniumborohydride (n-Bu4NBH4) in CH2Cl2at
23
-20°C proved to be a superior combination in terms of yield and diastereose-lectivity.[43]
24
Table 3. Study of diastereoselectivity in the reduction of ketones 18-19.
123456
181818181919
NaBH4LiAlH4DIBALLiEt3BHNaBH4LiAlH4
0°-78°-78°-78°0°
-78°
5b5b5b5b6b6b
457160654065
806050548565
Entry Ketone Reductant Temp.°C Product Yield (%)a de(%)b
a Isolated yield of pure major diastereomer, b Determined by 1H NMR in crude product.
N Ph
MeR
OHH
N Ph
MeR
HOH
5b-6b Major diastereomer
5a-6a Minor diastereomer
N PhCOR
Me
18-19
Entry 1-6
PhPhPhPhMeMe
R
In order to establish the relative stereochemistry of the two series of di-astereomers 5a-6a originating from Grignard addition to aldehyde 4 and 5b-6b, from the reduction of ketones 18 and 19; after debenzylation treated with phosgene, and the resulting carbamates 20a-b and 21a-b relative stereo-chemistry were assigned by NOE difference spectroscopy (Figure 2). The absolute configuration of aza-Diels-Alder adduct 1a have been established by X-ray crystallographic investigations of a derivative.[44, 45]
NHR1
R2
OH N
R2R1
O
Oi
20a, R1 = Ph, R2 = H (60%)21a, R1 = Me,R2 = H (45%)20b, R1 = H, R2 = Ph (65%)21b, R1 = H, R2 = Me (30%)
8a, R1 = Ph, R2 = H9a, R1 = Me, R2 = H8b, R1 = H, R2 = Ph9b, R1 = H, R2 = Me
Reagents and Conditions: i) Et3N, phosgene, CH2Cl2, 0°C.
N
HPhO
O
N
HMeO
O
N
PhHO
O
N
MeHO
O
H H
H H
10.8% 3.1%
1.4% 0.4%21b20b
21a20a
Irr.Irr.
Irr. Irr.
Figure 2. Establishment of relative stereochemistry by NOE measurments.
In order to prove the absolute configuration of aza-Diels-Alder adducts 16and 17, Swern oxidation of 5a gave a compound identical to 18. Since all spectroscopic data were in complete agreement with that observed for 18, it could be concluded that the two compounds must have the same absolute configuration (Scheme 4).
25
N PhCOPh
Me
N Ph
MePh
HOH
i
Reagents and Conditions: i) Swern oxidation.
5a 18 (85%)
Scheme 4. Establishing absolute stereochemistry for aza-Diels-Alder adducts 16-17.
The two sets of diastereomeric compounds 11a-13a and 11b were investi-gated as ligands for addition of diethyl zinc to N-(diphenylphosphinoyl) ben-zalimine and the presence of an additional stereogenic center turned out to be an important factor for increasing the selectivity. The right choice of the absolute stereochemistry improved the enantioselectivity in the reaction from 91% enantiomeric excess (ligand 24a) to 97% enantiomeric excess (ligand 11a, entry 1, Table 4). Unfortunately, enantioselectivity and isolated yield of 23 dropped when employing a catalytic amount of ligand (Table 4, entry 5-6), similar to previous reported results by Pinho and Andersson.[39]
Table 4. Results obtained with second generation ligands.
Ph NPPh
Ph
O
Ph NH
PPh
Ph
OH Et
22 23
123456
PhMei-PrHPhPh
HHHPhHH
979379716954
706859524535
aDetermined by chiral HPLC (ChiralCel OD-H) bIsolated yield of pure 23 after flash chromatography.
NBn
R2
R1
OH
11a12a13a11b11a11a
11-13
R1 R2 ee (%)Entry yielda(%)Ligand equiv. ligand
1.01.01.01.00.300.10
3 equiv. Et2Zn,toulene
1-0.1 equiv. ligand 11-13
The introduction of an -substituent in the ligand structure turned out to be important and the right choice of the configuration at the new stereogenic center allowed us to improve enantioselectivity from 91% enantiomeric ex-cess in the first generation of ligands by Andersson and Pinho, to 97% enan-tiomeric excess in the second generation presented here. This gave us inter-esting insights about the mechanism and origin of enantioselectivity. The mechanism of the reaction was investigated by DFT-calculations and the observed enantioselectivity was rationalized (Paper I). Calculated and experimental data agreed on the formation of the (S)-product. The difference in energy between the lowest (S)- and the lowest (R)-transition state arises from the orientation of the four-member ring (Zn2-C-C-N) where an exoorientation is preferred (Figure 3).
26
Zn
P
O
N
C
1.981 2.191 2.374
1.370
2.1902.036
2.0272.212
1.984
1.985
2.033
2.018
2.1981.368
2.399
2.204
Entry 5
Entry 91.986
Figure 3. The two lowest (S)- (top, entry 5, favored), (R)- (bottom, entry 9, unfa-vored) transition states found (entries 5 and 9 in Table 1, Paper I).
This last parameter was evaluated for ligands 24a and 11a, showing that ligand 11a should lead to an improved enantioselectivity for the reaction, seen as energy differences in Table 5. These theoretical results were verified experimentally in Table 4, showing a difference in enantioselectivity, which correlates to the relative energies of the two diastereomeric transition states.
Table 5. Relative energies of (R)- and (S)-transition states for ligand 24a compared with 11a. Relative transition state energies given in kcal mol-1.
24a11a24a11a
ChiralLigand
Productenantiomer
SSRR
B3PW91/a//HF/3-21G
Out-of-plane angle(Zn1-O-Zn2-( -C))
Dihedral angle(C-Zn2-N-C)
0.00.01.82.8
140°168°
-153°-155°
8°4°
-9°-12°
aThe basis set used was 6-311G* for Zn and 6-31G* for P, C, N, O and H
27
3 Aza-Diels-Alder Reaction of Heterocyclic Imine Dienophiles
3.1 IntroductionAs previously mentioned, the aza-Diels-Alder reaction is one of the most powerful methods for the synthesis of nitrogen containing heterocyclic struc-tures. These products are in turn highly useful for the synthesis of many natural products. As it has been previously shown (vide infra) a major draw-back of this reaction is the narrow scope of the dienophile, with the original aldehyde needing to be either electron deficient (as in Paper I) or very small. Since the isolation of the highly potent, non-selective opioid receptor an-tagonist epibatidine in 1992,[46, 47] possessing an aza-norbornyl framework, extensive work has been undertaken on the synthesis of aza-norbornyl struc-tures with the nitrogen located in different positions in the ring.[48, 49] Some of these products have displayed promising analgesic properties, without the acute toxicity of epibatidine itself.[50] Furthermore, these substances can be considered as bicyclic nicotine analogues, and have been evaluated as thera-peutical substitutes for drugs of abuse due to their high nicotinic receptor affinity.[51]
In order to develop a bicyclic (P,N)-ligand for asymmetric Ir-catalysed olefin hydrogenation from a aza-Diels-Alder adduct, a study concerning the possibility of incorporating an exo-oriented heterocycle on a 2-aza-norbornyl framework was undertaken. Retrosynthetic analysis of ligand structure 30,gave imine 26a as suitable starting point, employing aza-Diels-Alder meth-odology (Figure 4). Although we were not successful in developing the chemistry all the way to the ligand structure, a conceptually similar terpene-based (P,N)-ligand appeared in the literature from Knochel et al. recently[52]
(Figure 4).
28
PN
MeMe
Me
Knochel et al. 2003
31
NP
NNH
N
N
Ph Me
NN Ph
MeN
26a29 27a
Envisioned ligandstructure Hedberg 1999
NP
N
30
30
Figure 4. Retrosynthetic analysis of ligand structure 30, leading to development of new aza-Diels-Alder methodology.
3.2 Synthesis and Evaluation It was concluded that an imine derived from a protonable heterocyclic alde-hyde would behave in the same way as the glyoxalimine. An initial study revealed that two equivalents of strong acid at low temperature is necessary for the reaction to proceed (Scheme 5). Less or more than two equiv. of Brønstedt acid provided a sluggish reaction, yielding only traces of cycload-dition product 27a. In the case of more than two equivalents of Brønstedt acid, polymerization of the diene was instant, even at low temperatures. Also the choice of acid proved to be crucial for the outcome of the reaction. The use of Lewis acid like borontrifluoride, which is beneficial in the cycloaddi-tion of glyoxylate-derived imines, only resulted in a fast polymerization of the cyclopentadiene. On the other hand, strong Brønstedt acids, such as methane sulfonic acid and trifluoroacetic acid proved to be efficient in this reaction, and the use of either alone, or as a 1:1 mixture, resulted in good reactivity of the imine towards cycloaddition and a high stereoselectivity. The isolated yields were far superior to any reaction condition employing Lewis acids.
29
N
Ph Me
N
N Ph
MeN
N Ph
MeN
N Ph
Me
1 equiv. acid
2 equiv. acid
H
H
H
Unreactive dienophile
Reactive dienophile
Only traces of 27a
27a
26a
H2N Ph
Me
O
High isolated yield
N N
Scheme 5 Initial study of heteroaryl imine activation towards 4+2 cycloaddition by Brønstedt acids.
The relative rate between diene polymerization and cycloaddition was found to be strongly temperature dependent. Performing the reactions at low tem-peratures suppressed the unwanted polymerization of cyclopentadiene. The actual cycloaddition reaction was found to start at approximately -50 °C. In order to evaluate the substrate scope of the newly discovered reaction a sub-strate study was undertaken. Eight different commercially available hetero-cyclic carbaldehydes were screened under the previously established reac-tion conditions (Table 6, entries 1 to 8). In all cases, the corresponding im-ines were formed, even if some of the five member ring carbaldehydes had low solubility under the reaction conditions. As expected, it was found that heteroaromatic imines possessing the heterocyclic nitrogen three bonds away from the formed imine did not react at all in the cycloaddition reaction. This clearly defines the scope of this reaction to heteroaromatic imines having the second basic nitrogen in conjugation with the imine carbonyl (Table 6).
30
Table 6. Substrate study of heteroaromatic imines towards [4+2] cycloaddition.
Entry Aldehydea Reactionconditions Yieldb exo/endo
Selectivity cDiastereo-selectivityd
Major exo-product
1
3
2
4
5
6
7
8
NO
N O
NO
NO
N
O
NH
O
N
NH
O
N
SO
N
Ph Me
N
N
Ph Me
N
26a
26c
26b
26d
26e
26f
26g
26h
N
Ph Me
N
N
Ph Me
N
N
Ph Me
N
NH
N
Ph Me
N
S
CH3SO3H / TFA
CH3SO3H / TFAor CH3SO3H
CH3SO3H / TFA
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H
CH3SO3H / TFAor CH3SO3H
27a
27b
27d
27e
27g
27h
80%
---- ---- ----
---- ---- ----
>99%
>99%
>99%
>99%
>99%
>99%
87:13
e
80:20
90:10
90:10
e
75:25
90:10
60%
80%
79%
60%
80%
aAll aldehydes were obtained from commercial sources; bRefers to the isolated yield of major diastereomer; cNo endo isomer could be detected in crude reaction mixture, nor isolated during purification; dDeterminedfrom the crude 1H NMR; eThe imine of the corresponding aldehyde was formed, but no cycloaddition occured.
HetAr O HetAr N Ph
Me
HetAr N Ph
Me
H
N
Ph MeHetAr
26a-h 27a-hReagents and Conditions: i) (S)- -phenylethylamine, Ms 4 Å, CH2Cl2, rt; ii) acid, 2 equiv., -78°C; iii) Cyclopentadiene, -78°C to rt, o.n. HetAr= Heteroaromatic substituent
i ii iii
Although good yields were achieved, separation of the exo-diastereomers proved to be problematic, reverse phase HPLC separation was necessary in order to get diastereomeric pure material in all cases (Table 6, entries 1-8). Further studies on the scope of diene revealed that only cyclopentadiene gave good results in terms of isolated yields. However, when 26c imine was
31
used together with ZnCl2·OEt2 and isoprene, cycloaddition reaction took place (Scheme 6). Cycloaddition adduct 32 is previously not known and the absolute stereochemistry not assigned. In all other cases, ZnCl2·OEt2 was not effective as Lewis acid.
ON
26c
N Ph
Me
NN
Me
N
Ph Me
Absolute configurationunknown
32
i ii
Reagents and Conditions: i) (S)- -phenylethylamine, Ms 4 Å, CH2Cl2, rt; ii) ZnCl2•Et2O, isoprene, CH2Cl2, rt.
H
Scheme 6. The isoprene case.
All attempts to deprotect 27a-h by debenzylation proved to be unsuccessful, both directly on the cycloadduct and on the saturated compounds, only ring opened products were obtained. The benzylic carbon-nitrogen bond within the heterocyclic substituent breaks much easier than the one to the phenethyl moiety. Release of ring tension in the norbornyl skeleton, or sterical hin-drance around the chiral auxiliary, are postulated explanations for these ob-servations. Derivatives containing the (S)-2’-methoxy and 4’-methoxy -phenethylamine as chiral auxiliary were prepared and oxidative debenzyla-tion by DDQ performed. Although traces of deprotected product were de-tected, the method seemed to be of little practical value in this case. The mechanism of this aza-Diels-Alder cycloaddition reaction have been studied computationally by DFT-methods by Domingo et al.[53, 54] Their study concluded that the cycloadditon takes place in a stepwise manner with a discrete allyl cationic intermediate along the reaction coordinate. However, the experimentally observed excellent endo/exo-selectivity could not be ex-plained from a theoretical point of view, as the relative difference between the two pathways was found to be only 2 kcal mol-1. Due to this fact, and to the lack rationalization of the low reactivity of m-pyridine derivatives, the computational study by Domingo and co-workers seems to add very little to the understanding of this reaction.
32
4 Catalytic Asymmetric Total Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine
4.1 IntroductionTolterodine 33 (Figure 5) is the first muscarinic receptor antagonist that has been specifically developed for treatment of overactive bladder.[55, 56]
Tolterodine is non-selective with respect to the muscarinic M1-M5 subtypes, but has a greater effect on the bladder than on the saliva glands in vivo, in both animals and humans.[57] Tolterodine (Detrol®) is equipotent to oxybu-tynin, another therapeutic agent against overactive bladder, but shows less impact on saliva output than oxybutynin. Several studies suggests that tolterodine may give rise to fewer side effects related to decreased saliva production compared to oxybutynin. Tolterodine can today be regarded as the drug of choice to treat overactive bladders in most patient groups.[58]
Me
OH
N(i-Pr)2
Ph
33
Figure 5. (R)-Tolterodine
Production scale synthesis of tolterodine has been executed in a racemic route until the final step, where it is resolved by diastereomeric salt forma-tion with tartaric acid. This synthetic approach has been problematic due to the large amounts of chemical waste formed, as it is not possible to racemize the unwanted stereoisomer, resulting in low atom efficiency of the process, together with low robustness of the resolution step.[59] During a few years we had cooperation with Pharmacia Corporation to establish an asymmetric synthesis, preferably catalytic, of tolterodine, in order to solve the above-mentioned problems. An initial study on an auxiliary based asymmetric syn-thesis of tolterodine was undertaken by our group,[60] with the goal of estab-lishing a catalytic asymmetric hydrogenation method.
33
4.2 Retrosynthetic Analysis Tolterodine 33 possesses a problematic kind of trisubstituted stereogenic center, with two different substituted aryl groups and a two-carbon side chain attached. This fact can be turned into an advantage, as a 4-aryl cou-marin 34 or 3-aryl indenone 37 can be regarded as a synthon with defined olefin geometry, due to its cyclic structure. In the case of an indanone, it can be converted to a dihydrocoumarin by a Baeyer-Villager oxidation (Figure6).
Me
OH
N(i-Pr)2
Ph
Ph
O
MeMe
O
Ph
O
Me
O
Ph
Oor
33 34
or
Ph
O
Me
37
40 39
Figure 6. Retrosynthetic analysis of (R)-tolterodine.
With the retrosynthetic analysis at hand, we assumed that coumarin 34would be the optimal starting material for an asymmetric hydrogenation approach. The Pechmann condensation of ethyl benzoylacetate with p-creosol has been reported in literature, but reaction conditions and yields have not been mentioned.[61] All our attempts to prepare 34 by the Pechmann condensation proved to be problematic, yields around 25-30% were achieved. As the direct asymmetric hydrogenation of 34 to 40 by route 1 (Scheme 7) did not work at all, a second route 2, was considered, involving the saponification of the coumarin 34 into the cis-cumaric acid sodium salt and hydrogenation of the ring opened product. Unfortuently, this elegant pathway was already discovered and claimed by another major pharma com-pany[62, 63] (Scheme 7).
Me
OH
Ph
OEt
Me
O
Ph
O
Me
O
Ph
OO
OPechmanncondensation
1. Asymmetrichydrogenation
Me
ONaCO2Na
Ph
Me
ONaCO2Na
Ph2. Asymmetrichydrogenation
34 40
Scheme 7. Different hydrogenation methods for synthesis of dihydrocumarin 40.
After a lot of fruitless work with a hydrogenation approach towards key in-termediate 40, our efforts were instead focused on intermediate 37 and the
34
possibilities to reduce it by a Me-CBS-reduction[64] into an indenol 38, fol-lowed by a novel three consecutive [1,5]-sigmatropic rearrangement to yield indanone 39 by suprafacial chirality transfer between the 1- and 3-position. Such a rearrangement has been reported in the literature for a similar sub-strate to be completely stereoselective, with minimal loss of optical purity.[65,
66] It is concluded that the reaction goes via three consecutive counter-clockwise [1,5]-hydride shifts, as the suprafacial [1,3]-hydride shift in not thermally allowed according to Woodward-Hoffmann rules concerning con-servation of orbital symmetry (Figure 7).[67-69]
PhMe
-O H
PhMe
First counter-clockwise suprafacial[1,5] hydride shift H O-
PhMe
O-
H PhMe
O-
HSecond counter-clockwise suprafacial[1,5] hydride shift
Third counter-clockwise suprafacial[1,5] hydride shift
PhMe
HO H
Deprotonation
Ph
O
MeProtonation
H
38
39
Figure 7. Threefold sigmatropic suprafacial [1,5]-hydride shift rearrangement of indenol 38 into indanone 39.
This rearrangement of indenes have been studied by experimental kinetics, mainly by the primary deuterium KIE, and it has been concluded that the driving force of the reaction is the formation of the thermodynamically more stable enolate, which upon protonation yields the indanone.[66, 68] With this knowledge in hand, we executed the synthesis of (R)-tolterodine.
4.3 Synthesis and Evaluation The synthesis of the key chiral intermediate, 40, starts with the condensation of acetophenone 35 with benzaldehyde to give the correct substituted chal-cone 36 in high yield. Palladium-catalysed Heck cyclisation of chalcone 36under standard conditions provide 3-phenylindenone 37 in good yield.[66, 70]
Compound 37 is light- and oxygen-sensitive and should be processed as fast as possible after its preparation. Enantioselective reduction of indenone 37was performed by slow addition (1.5 hour) to a solution of (S)-Me-CBS cata-lyst (5 mol%) together with a stoichiometric amount of BH3·THF at -20 °C. Fast quenching of the reaction mixture at -20 °C, upon complete consump-tion of 37, was necessary to achieve high enantioselectivity. Prolonged reac-
35
tion times, even at low temperature, led to partial racemization of product 38. Indenol 38 (97% ee) was then heated with base (DABCO/Et3N) in THF at 60 °C for 3h, which furnished the desired indanone 39 with almost com-plete retention of chirality (94% ee) in high yield. Baeyer-Williger oxidation of indanone 39 proceeded sluggishly with commercial 60% m-CBPA; though the use of 98% m-CPBA and the addition of 4Å molecular sieves it was possible to raise the yield of 40 from 45-50% to 92% isolated yield. Only trace amounts of the other regioisomer from the Baeyer-Villiger oxida-tion could be observed. Recrystallisation of 40 gave, in principal, enantio-pure material (+99% ee) in 85% isolated yield (Scheme 8).
Ph
O
MeMe
O
Ph
O
O
Me
Me Br
O
Me Br
Ph
Ph
O
Me
PhMe
HO H
i ii iii
iv v
Reagents and Conditions: i) PhCHO, MeOH, NaOMe, 0°C to rt, 16h (95%); ii) PdCl2 (5 mol%), PPh3(15 mol%), K2CO3, DMF, 130°C, 1h (73%); iii) (S) -Me -CBS (5 mol%), BH3•THF, THF, -20°C, 2h (91%, 97% ee); iv) Et3N, DABCO (20 mol%), THF, 60°C, 4h (90%, 94% ee); v) m-CPBA, TsOH•H2O,Ms 4Å, CH2Cl2, 4°C, 18h (92%, 94% ee, recryst. 85% recovery, +99% ee)
35 36 37
38 39 40
Scheme 8. Synthesis of chiral intermediate dihydrocoumarin 40.
To complete the synthesis of (R)-tolterodine, dihydrocoumarin 40 was treated with MeOH/K2CO3 in acetone, followed by benzylbromide and po-tassium iodide to give the corresponding O-benzylated ring opened methyl ester 41, containing some of the benzyl ester as an impurity. Direct reduction with LiAlH4 of the mixture gave alcohol 42 in 87% yield over two steps. Nosylation followed by substitution with DIPA gave 44 in high yield. De-benzylation of 44 furnished (R)-tolterodine 33 in excellent yield (Scheme 9).
36
Me
OBn
CO2Me
PhMe
O
Ph
O
Me
OBn
N(i-Pr)2
Ph
Me
OBn
OH
Ph
Me
OBn
ONs
PhMe
OH
N(i-Pr)2
Ph
i ii iii
iv v
Reagents and Conditions: i) MeOH, Acetone, K2CO3, BnBr, NaI, reflux, 16h; ii) LiAlH4, THF, rt (87%over two steps); iii) NsCl, Et3N, DMAP, CH2Cl2, 0°C to rt, o.n. (83%); iv) DIPA, K2CO3, MeCN, reflux, 48h (81%); v) Pd(C) (10 wt%), MeOH, H2 (1 atm.), rt, 12h (97%, 99%ee).
40 41 42
43 44 33
Scheme 9. Synthesis of (R)-tolterodine from intermediate 40.
Although the initial goal to develop an asymmetric hydrogenation of an Pechmann condensation product (coumarin 34, Scheme 7) was not possible to realize, we have developed an efficient catalytic asymmetric synthesis of (R)-tolterodine in high overall yield from commercially available starting materials. The desired compound is produced in ten steps with an overall yield of 30% and in greater than 99% enantiomeric excess.
37
5 Iridium-Catalysed Asymmetric Hydrogenation of Olefins
5.1 IntroductionSince the first report of Ir-catalysed hydrogenation of simple olefins by Crabtree et al. in the late 1970’s, the “Crabtree catalyst” (45, Figure 8) has been an established tool in organic synthesis.[71, 72] The primary use has been for the hydrogenation of tri- and tetra-substituted olefins not suitable for treatment with heterogeneous catalysts like Pd(C) or Adams catalyst (PtO2). Although very general in its application, the major drawbacks of 45 have been high catalyst loadings and sensitivity towards heteroatom functional-ities in the substrates. In 1998, Pfaltz and coworkers reported the first effi-cient asymmetric hydrogenation of unfunctionalized tri-substituted olefins[73]
with a series of chiral “Crabtree catalyst” mimics (46, Figure 8), based on a previously reported (P,N)-ligand structure by Helmchen et al.[74] Up to 1998, very few examples of asymmetric hydrogenations of unfunctionalised ole-fins have been reported in literature; furthermore all have been based on either rhodium (Wilkinson type), ruthenium complexes[75] or titanocenes.[76]
However, none have been reported for iridium. The crucial thing discovered by Pfaltz and coworkers, was the fact that the counterion of the complex was of tremendous importance. To achieve high activity and enantioselectivity, an extremly weakly coordinating ion, like tetrakis[3,5-trifluoromethylphenyl] borate[77], also known as BArF
- (Figure 8).[73]
PPh2
NO
t-Bu
Ir
P(Cyclohexyl)3
N Ir
PF6BArF
Crabtree et al. 1977 Pfaltz et al. 1998
45 46 F3C
F3C
B
4
BArF =
Figure 8. Crabtree’s catalyst 45 and chiral analogue 46 by Pfaltz et al.
Another important discovery by Pfaltz was the fact that catalysts of type 46were not only active in the hydrogenation of olefins but also in the asymmet-ric hydrogenation of aryl imines.[78]
38
5.2 Mechanistic Studies 5.2.1 Introduction
The mechanisms of hydrogenation of activated olefins with cationic rhodium and ruthenium complexes have been studied in detail and most of its mecha-nistic aspects are known. In the case of Crabtree’s iridium catalyst 45 and chiral analogues by the groups of Pfaltz,[73, 79-83] Zhang,[84] Knochel,[52] and Burgess,[85] nothing is, in principle, known about the catalytic cycle. How-ever, the importance of a coordinating diene like 1,5-cyclooctadiene (COD) or norbornadiene (NBD) in the pre-catalyst has been stated earlier in the literature.[86, 87] The presence of a diene (COD or NBD) in the pre-catalyst assures irreversible formation of free coordination sites at the metal. Thus, in the activation of the catalyst, this ligand is reduced and the corresponding saturated compound is released. Several studies have been devoted to the understanding of this process and the oxidative addition of dihydrogen to Ir-(COD) complexes is known in some detail.[88] However, the knowledge of the real catalyst and the exact mechanism for the Ir-catalysed hydrogenation of olefins is very limited. It is our belief that a deeper mechanistic under-standing is necessary in order to develop catalysts that display higher enanti-oselectiviy and broader substrate scope.
To increase the understanding of this reaction we performed a combined experimental and computational (DFT) study of the reaction covering both the experimental kinetics, and a large range of the potential intermediates and transition states by quantum chemical methods (Paper IV). Because of the large number of different iridium coordination isomers possible in this reaction, a model of reduced size had to be used in the initial DFT-study. This model was constructed from the previously reported complex 46 from Pfaltz and coworkers[73]: The oxazoline moiety was replaced by an N-methyl imine functionality and the diarylphosphine functionality by a dimethyl-phosphine moiety; a cis-vinyl group, instead of a 1,2-substituted benzene, connected these two moieties. This manipulation reduced the total amount of atoms to 21, instead of 88, as in the full system 46 (Figure 9).
P NMeMe
MeIrSS
Brandt et al. DFT-model system
47
PPh2
NO
t-Bu
Ir
Pfaltz et al.
46
Figure 9. Construction of model system for DFT-calculations.
As previously stated, formation of the active catalyst takes place by an irre-versible hydrogenation of the coordinating diene in the starting complex,
39
followed by displacement by either solvent, dihydrogen, or an alkene (sub-strate). Considering how facile the oxidative addition of dihydrogen is to a cationic IrI-complex,[89, 90] the starting point for the mechanistic evaluation is chosen as a set of IrIII-dihydrides in different coordination modes. The theo-retical DFT-calculations, including screening of intermediates and their po-tential surfaces according to the mechanistic assumptions in Figure 10, is presented in Paper IV and its supplementary material.
5.2.2 Derivation of Rate Expression and Experimental Kinetics
In order to differentiate among the mechanistic alternatives; an expression for the relative rates between different pathways based on the calculated barrier for migratory insertion (MI) and reductive elimination (RE). The underlying mechanistic basis assumes a common resting state for the catalyst where R is coordinated, a semi-reversible formation of the Ir-alkyl complex (I) present in a steady-state concentration and an irreversible reductive elimination, resulting in the formation of P (Figure 10).
HIrLH
RE
IrHLH
MI
GMI‡
G MI‡
GRE‡
GMI‡
GRE‡
Reactants IrHLH
IR P
Productsk1
k-1
k2
GR
GI
GP
Figure 10. Mechanistic basis for the derivation of relative rates.
The kinetic expressions can now be written as Equations (1) and (2):
[R]t
k1[R] k 1[I] (1)
[I]t
k1[R] k 1[I] k2[I] (2)
40
Where [R] is the concentration of the olefin, [I] is the concentration of the intermediate iridium complex, and [P] is the concentration of the alkane product.
At steady state: [P]
t[R]t
;[I]t
0 (3)
Equations (2) and (3) [I] k1[R]k 1 k2
(4)
Equations (1) and (4) [R]t
k1[R] k 1k1[R]
k 1 k2
(5)
[R]t
[R] k1k 1
k 1 k2
k1 [R] k1k2
k 1 k2
(6)
Inserting k1 ce GMI‡ RT , k 1 ce G MI
‡ RT , and k2 ce GRE‡ RT in which
GMI‡ , G MI
‡ and GRE‡ are defined as in Figure 10, and c kT h results
in Equation (7) and finally in the rate expression described by Equation (8):
[R]t
c[R] e GMI‡ RTe GRE
‡ RT
e G MI‡ RT e GRE
‡ RT
c[R] e (GMI GR ) RTe (GRE GI ) RT
e (GMI GI ) RT e (GRE GI ) RT
(7)
[R]t
c[R] e (GMI GR GRE ) RT
e (GMI ) RT e (GRE ) RT (8)
Obvious from Equation 8 is that, within the limits of the approximations, the rate of the reaction is independent of the absolute energy of the intermediate iridium alkyl complex. Furthermore, the relative rates between different reaction pathways of equal molecularity are independent of the energy of the catalyst resting state. An endergonic addition of dihydrogen to the postulated resting state iridium dihydrido complex would lead to a first order depend-ence on hydrogen pressure. Similarly, endergonic addition of alkene would lead to a first order dependence on substrate concentration. In order to ex-perimentally verify the postulated kinetics, catalyst 46 was used to hydro-genate (E)-1,2-diphenylpropene 56 and the H2-consumption versus time was used as kinetic trace (Scheme 10).
41
PPh2
NO
t-Bu
Ir
Me
BArF
Me
H2, CH2Cl2
46
56
Scheme 10. System studied by kinetic measurements.
Two different series of experiments were performed and every data point was run in duplicate. Primarily, a series of reactions were run at 10.0 bar hydrogen pressure using 0.50 mmol of 56 as substrate and 0.50 mol% of catalyst in 1.0, 2.0, 3.0, and 4.0 ml of dichloromethane. This resulted in a first order dependence on catalyst concentration and a zeroth order depend-ence in substrate concentration indicated by the conversion as independent rates (Figure 11).
Figure 11. Observed rates of the reduction vs. concentration of catalyst. (slope = 0.877, I = 0.0120, r2= 0.996).
In the second series of experiments, 0.50 mmol of 56 was reduced at hydro-gen pressures of 2.0, 4.0, 6.0, and 8.0 bar using 0.50 mol% of catalyst in 2.0 ml of dichloromethane. This revealed a first order dependence in hydrogen pressure (Figure 12).
0.0
0.1
0.2
0.3
0.4
0.5
0.0 0.1 0.2 0.3 0.4 0.5 0.6
c/M
dc/dt / mM
S-1
42
Figure 12. Observed rates of the reduction vs. hydrogen pressure (slope = 0.0414, I= 0.0243, r2 = 0.963).
We have confirmed the results previously reported by Pfaltz et al., that the reaction rate is independent of the alkene concentration, within the concen-tration range 0.125-0.500 M and 10 bar hydrogen pressure.[91, 92] This indi-cates a reaction mechanism where the coordination of alkene to catalyst is not rate determining. As indicated by the DFT calculations, binding of ethyl-ene to A (Scheme 11) by displacement of a solvent molecule is exothermic. This exothermicity in combination with the zeroth order dependence on al-kene concentration suggests that the catalyst coordinates an alkene in the resting state.
According to the kinetic measurements, the reaction is first order in hy-drogen pressure. This could mean one of two things; either the reaction be-tween the catalyst in the resting state and H2, by ligand displacement, is rate determining, or the coordination of H2 is endergonic. According to the calcu-lations, the displacement of one dichloromethane in the mono-solvated Ir(H)2(ethylene) complexes by H2 is only weakly exothermic. An exother-micity that could easily by outbalanced by the difference in activity between H2 and dichloromethane. Thus, the calculations offer two alternative expla-nations for the first order dependence on H2. As expected, the reaction is first order with respect to catalyst concentration.
5.2.3 Reaction Mechanism
Based on the extensive calculations presented in paper IV, we proposed the reaction mechanism depicted in Scheme 11 to be operative in the hydrogena-tion of alkenes using IrI(P,N-ligand)(diene) catalyst precursors. This cycle starts with the most stable IrIII-dihydride complex found in the study (A). In
0.0
0.1
0.2
0.3
0.4
0 2 4 6 8 10
p(H2)/Bar
dc/dt / mM
S-1
43
two consecutive steps, an olefin is coordinated trans to phosphorous and in an endergonic step, with dihydrogen coordinated in the remaining axial posi-tion (A B). The coordination of dihydrogen might be either dissociative with an energy cost of the iridium-dichloromethane bond, or associative as shown in TSB C. The olefin in this complex can then undergo a migratory insertion into the axial Ir-H bond, a reaction that occurs simultaneously with an oxidative addition of dihydrogen to the other axial position (C D, viaTSC D). The resulting IrV-species (D) is now labile and the reductive elimi-nation occurs with a negligible barrier (D E, via TSD E) (Scheme 11).
IrS
N P
H
H
S
S = Solvent: CH2Cl2
Add
Loss of SIr
N P
H
H
S
IrN P
H
H
SH H
IrN P
H
H
H H
IrH
N P
H
H
H
Add S
Loss of C2H6
IrN P
H
H
H H
IrN P
H
H
HH
TS(D E)
E
TS(C D)
IrN P
H
H
HH
Add H2Reversible
TS(B C)
A B
CD
Scheme 11. Proposed catalytic cycle for the (P,N)-Ir hydrogenation of unfunctional-ised olefins.
The strong binding of alkenes to iridium should be reflected in the kinetic measurements as a zeroth order dependence on alkene concentration, the resting state of the catalyst would contain one bound alkene. The rate-determining step is either the coordination of dihydrogen or the migratory insertion.
The catalysis is taking place without the intervention of IrI in any step in contrast to the analogous rhodium system, where the oxidation state of the metal alters between (I) and (III).[93, 94] However, a recent publication by Burgess and co-workers suggest a similar mechanism to that described in Scheme 11, also involving a IrV-transition species , but differing slightly in character, probably due to that the system studied involved a seven member Ir-chelate and a N2C-carbene instead of phosphorous.[95] Calculations by Dr.
It is important to distinguish between an IrV-transition species and an IrV-intermediate. The transition species is not detectable, compared to the intermediate. In a recent publication from Peter Chen and coworkers concerning the mechanism of Ir-(P,N) catalysed hydrogenation of olefins, this fact is ignored; see reference 94 for details.
44
Brandt on Burgess’ mechanistic alternative revealed that it can be ruled out for (P,N)-Ir systems possessing a six-member Ir-chelate.[96]
5.2.4 Rationalization of Enantioselectivity In order to establish a model for the enantiodetermining step, calculations were performed on the full-sized Pfaltz catalyst 46, with 56 as the substrate. The bulky substituent on the chiral center of the ligand creates an almost perfect pocket; open only for olefin coordination trans to phosphorus, recog-nizing the least sterically demanding olefin position, in case of a tri-substituted olefin, a proton. The two large trans-substituents are oriented towards the fully open quadrants, located trans to each other. By adding a quadrant scheme over the catalyst with the olefin coordination site in origo and orienting the steric bulk into one quadrant, a schematic description of the catalytic system is available (Figure 13).
P
C
IrN
O
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
Matchfavoured
Hindered
Semi-hindered
Open
Open
Ir
Bulk
Hindered
Semi-hindered
Open
Open
Ir
Bulk
Hindered
Semi-hindered
Open
Open
Ir
Bulk
Empty catalystMis-matchunfavoured
AlkeneSi-sidecoordination
AlkeneRe-sidecoordination
H HH
C
C
C
C
C
C
CCC C
CC
C
CP
1.38Å
C
C
CC
C
C
Ir
CC
C
C
C
CC
O N
C
C
C
C
C
C
C
C
C
C
CC
C
Bulk
Figure 13. Full system transition state of MI for the real catalyst 46 with 56 as the substrate, used in the kinetic study (upper left). Simplified selectivity model of enan-tiodetermining step (MI) describing ligand recognition of least substituted olefin position (upper right). Schematic quadrant model of real catalyst illustrating alkene facial recognition (lower part).
45
Coordination of a tri-substituted olefin into the empty quadrant model (Figure 13, lower middle) reveals that the olefin will only be able to coordi-nate to the catalyst from the Si-side, as the opposite coordination mode will result in unfavoured interaction with one of the large trans-substituents with the steric bulk of the ligand. This defines the stereochemical outcome of the reaction and sets the facial recognition of an electronically neutral tri-substituted olefin.
In this study we have found that the Ir-catalyzed hydrogenation of un-functionalized olefins proceeds via a non-classic mechanism, involving an IrIII-IrV cycle, without participation of any IrI, except in the formation of the active catalyst from the IrI-catalyst precursor. This is based on the fact that IrIII-dihydrides display unsaturation and the oxidative addition of dihydrogen are facile according to DFT-calculations. The kinetic experiments have shown that the reaction is zero order in olefin concentration; this fact can be seen as an indication of a bound substrate molecule in the catalyst resting state. This fact is supported by computational data, which states that alkene binding is favored over solvent coordination (CH2Cl2). As expected, the reaction is first order in catalyst concentration and hydrogen pressure. We have also been able to rationalise the enantioselectivity in terms of facial recognition of tri-substituted olefins.
5.3 Application of Selectivity Model in Ligand Design
5.3.1 General Guidelines from Mechanistic Study With the knowledge in hand from the mechanistic study, it is possible to list the important factors governing selectivity in the Ir-catalysed hydrogenation of olefins. First of all, the ligand should be bidentate and possess two elec-tronically different coordinating atoms; preferably phosphorus and het-eroaromatic nitrogen, in order to induce a strong trans-effect, necessary for the definition of olefin orientation in the complex. Studies on both steric and electronic factors suggests that a six membered Ir-(P,N)-chelate is preferred. The ligand should possess an element of chiral recognition, preferably steric bulk for tri-substituted olefins, oriented in such a way that one quadrant is completely blocked, as close to the Ir-site as possible. This can be affected by moving the center of chirality from the N-substituent (oxazoline in cata-lyst 46) to within the chelate. By locking up the chelate by a cyclic back-bone, a strong “twist” is induced in the ligand, when coordinated to Ir, bring-ing the steric bulk closer to the reaction center, making the chiral pocket more well defined.
46
5.3.2 Design of First Generation Ligands Starting out from a schematic 3D picture of the catalyst prior to migratory insertion (A, Figure 14), it is clearly illustrated that the center of the 2D quadrant model (B, Figure 14) is the olefin coordinating site, located transto phosphorus. By filling the lower N-quadrant in the 2D quadrant model with a steric bulk, enantiofacial selectivity is established. The large trans-substituents of the substrate are forced into the open quadrants and the un-substituted olefin position will be recognized by the filled quadrant. In order to design a ligand structure from the quadrant model, including the features listed in section 5.3.1, the following manipulations were performed as seen in Figure 14:1. The P- and N-coordinating atoms are connected through a three-atom
linker, giving C.2. Stereochemistry of the catalyst complex is established by the following
manipulations: 2.1. Incorporation of coordinating N-atom into a five member heteroaromatic group. 2.2. Locking up the chelate and het-eroaromatic substituent with a cyclic backbone. 2.3. Establishing the stereogenic center within the chelate, preferably at the point where the backbone and chelate connect to each other. 2.4. Connecting the steric bulk located in the lower N-quadrant to the five-member heteroaromatic substituent, giving hypothetic structure D.
3. In order to turn D into a chemical structure, steric bulk is added in terms of a phenyl group, connected to the five-member heteroaromatic includ-ing the coordinating N-atom. The heteroaromatic is chosen as a 1,3-heterocycle at this point, locating the phenyl group at the 2-position. The correct twist angle of the ligand, locating the steric bulk as close to the Ir-center as possible, is achieved by setting the cyclic ligand backbone to six atoms, where two of them is sp2-hybridized (planar). The P-moiety is connected as a phosphinite, giving X as oxygen, leading to final structure E (Figure 14).
47
NX X
PAr2
Alkene coordination site = Origo of quadrants
IrN
PAr2
H
H
H H
X
IrH
H
H H
2.2
2.32.1
Open
OpenHindered
Hindered
Semi-hinderedOpen
Open
Ir
Bulk
H
Bulk
2.4
IrN
PAr2
H
H
H H
X
Bulk
1. Add coordinating P,Nligand frame
2. Add stereochemistry
Ir H
H H
HP
3. Transforminto chemical structure
N
Schematic 3D model of Ir-catalyst
Schematic 2D quadrant model of Ir-catalyst
A B C
D E
Figure 14. Rational ligand design from quadrant model to ligand structure.
Removal of the quadrant framework and Ir from structure E and adding oxygen’s at positions marked X, results in structure F, which serves as “lead structure” for ligand group 48. An interesting feature of ligand type 48 is that an element of symmetry concerning its starting material, is preserved in the final structure; it contains two oxygens in the 1,3-positions, within a six-member carbon skeleton. This fact can be a great advantage when planning and executing the synthesis of ligands of type 48 (Figure 15).
NO
OPAr2
N
OPh
OPAr2
NX
XPAr2IrH
H
H H
Ligand type 48E F
Figure 15. Creation of ligand type 48 from model E.
48
5.4 Synthesis and Evaluation of Designed Ligands
5.4.1 Synthesis and Evaluation of First Generation Ligands Retrosynthetic analysis of oxazole-based ligands of type 48 suggests, that after disconnection of the phosphinite moiety (A), introduction of chirality by an asymmetric reduction of corresponding ketone is possible (B). Dis-connection of the heterocyclic moiety in the ketone suggests a 1,3-dipolar intermediate, available from a Rh2(OAc)4-catalyzed 3+2 dipolar cycloaddi-tion over benzonitrile (C).[97] With the diazoketone easily prepared from the corresponding 1,3-dicarbonyl compound by the action of a sulfonyl azide (D) (Scheme 12).
N
OPh
OPAr2
A. Disconnect
N
OPh
OH
B. FGI
N
OPh
O
O
ON
Ph
C. Disconnect
O
O
O
ON2
OH
O
N3SO2R
D. Disconnect48
Scheme 12. Retrosynthetic analysis of ligand type 48.
Following the outlined approach from the retrosynthetic analysis synthesis we executed the synthesis of ligands type 48 and its Ir-complexes. Initial studies on the formation of 2-diazo-1,3-carbonyl compounds revealed that dimedone 50 was a much more convenient starting material for the synthesis of its diazocompound than 1,3-cyclohexanedione. Therefore dimedone 50was chosen as starting material for the synthesis. Treatment of dimedone with tosyl azide (TsN3) in the presence of triethylamine at 0 °C furnished diazodimedone in excellent yield.[98] Decomposition of 51 in the presence of bensonitrile by a catalytic amount of Rh2(OAc)4 yielded ketone 52 in moder-ate yield.[99] It was found that the purity of reactants was of importance for the outcome of this reaction. Performing it at temperatures higher than 60 °C resulted in the formation of large amounts of byproducts. Ketone 52 was then reduced by slow addition to a solution of (R)-Me-CBS catalyst[64] (10 mol%), employing BH3·Me2S (2 equiv.) as stochiometric reductant, in THF at room temperature. The resulting alcohol 53 was obtained in 91% yield with 90% enantiomeric excess. A single recrystallisation from 95% ethanol yielded practically enantiopure material (+99.5% ee) with 86% recovery. Treatment of 53 with n-BuLi/ TMEDA at low temperature (-78°C), followed by addition of Ar2PCl yielded the ligands 48a-c in good yield. Purification of the crude 48a-c was performed as a rapid filtration through a short plug of
49
degassed silica gel, as it was found that the phosphinite moieties in ligands 48a-c are extraordinary sensitive to both hydrolysis and oxidation. Therefore 48a-c were converted into their corresponding iridium complexes 49a-cimmediately after preparation by treatment with half an equivalent of [IrCl(COD)]2 in refluxing dichloromethane, directly followed by ion ex-change from Cl- to BArF
- under aqueous two-phase conditions. Complexes 49a-c was isolated in good yields by precipitation from absolute ethanol, induced by the slow addition of H2O (Scheme 13).
O
OMe
Me
O
OMe
Me
N2
O
MeMe
N
OPh
MeMe
N
OPh
OH
MeMe
N
OPh
OPAr2
MeMe
N
OPh
O
Ar2P Ir
i ii iii
iv v
BArF
Reagents and Conditions: i) TsN3, Et3N, CH2Cl2, 2h, 0°C (94%); ii) Benzonitrile, Rh2(OAc)4 (0.17 mol%), 60°C, 30 min (52%); iii) (R)-Me-CBS (10 mol%), BH3•Me2S (2 equiv.), THF, rt (91%, 90% ee, Recryst. +99% ee); iv) TMEDA, n-BuLi, THF, -78°C, then Ar2PCl, raise to rt, 16h (50-80%); v) [IrCl(COD)]2, CH2Cl2, reflux 30 min, then H2O, NaBArF•3H2O, rt, 1h (60-80%).
48a Ar = Ph48b Ar = o-Tol48c Ar = 3,5-MePh
50 51 52
53 49a Ar = Ph49b Ar = o-Tol49c Ar = 3,5-MePh
Scheme 13. Synthesis of first generation oxazole ligands 48a-c and their Ir-complexes 49a-c.
In order to establish the absolute configuration of complexes 49a-c, either an heavier atom derivative, or a diastereomeric derivative was needed for X-ray crystallographic investigation of alcohol 53. Treatment of alcohol 53 with (S)- -phenetylamine isocyanate in the presence of a catalytic amount of DMAP in toluene at 80 °C gave the corresponding diastereomeric crystalline carbamate 54 in high yield. Crystallization from 95% ethanol gave crystals suitable for X-ray crystallographic investigations (Scheme 14). From the X-ray structure of 54, the configuration of the alcohol 53 was found to be (S),as assumed from the empirical selectivity model of the CBS catalyst (Figure16).[100]
50
MeMe
N
OPh
O
X-Ray 54
MeMe
N
OPh
OH
53
i
Reagents and Conditions: i) (S)- -phenetylamine isocyanate, toluene, DMAP, 80°C, 2h, 85%.
NH
O
Ph
Me
Scheme 14. Synthesis of diastereomeric derivative 54 for assignment of absolute configuration of alcohol 53.
Figure 16. ORTEP plot at 50% probability of crystal dimer of compound 54, clearly showing the (S)-configuration at the chiral center.
During the preparation and synthetic manipulations of ketone 52, a byprod-uct appeared displaying a similar 1H NMR spectra to 52, but from 13C NMR it was obviously not an oxazole. As pathway A is considered to operate un-der catalytic conditions, 55 was believed to originate from the non-catalytic pathway B (Scheme 15). It was found in the literature that 1,3-dicarbonyl diazocompounds can undergo a Wolff rearrangement into an acyl ketene under thermal decomposition conditions (pathway B, Scheme 15).[101, 102] In case of too high reaction temperature, prolonged reaction time, or less pure
51
starting materials in the preparation of 52, compound 55 appeared in consid-erable amounts. A blank experiment without catalyst at 60 °C showed no conversion of 51 into 52 or 55, even after prolonged heating (several days). The set off point for the thermal decomposition of 51 was found to be ca 135 °C. Therefore, it was assumed that either Rh-carbene complex of pathway Acan rearrange into an acyl ketene product (pathway C), leading to a leakage from pathway A to pathway B; or that ketone 52 could undergo a retro- 3+2dipolar reaction, followed by Wolff rearrangement (1,2-alkyl shift) into an acyl ketene and then react according to pathway B (pathway D, Scheme 16). An important observation was that ketone 52, upon recrystallisation from absolute ethanol became contaminated with small amounts of 55. Refluxing ketone 52 in absolute ethanol over night completely converted it into 55,although in modest yield. Thermal decomposition of 51 in the presence of an excess benzonitrile at 160 °C, afforded 55 in excellent yield (Scheme 16). The chemical structures of 52 and 55 were verified by a single crystal X-ray diffraction (Figure 17).[100] However, the mechanism for the formation of 55from 52 remains an unanswered question.
O
OMe
Me
N2
O
OMe
Me
Rh2
O
OMe
Me
:Me
Me
•O
O
1,2-alkyl shift
O
O-MeMe
Rh2+-N2, Rh2
-N2
O
MeMe
N
OPh
[2+3]-Cycloadd.
[2+4]-Cycloadd.
O
N
O
Ph
Me
Me
X-Ray
X-Ray
PhCN
PhCN
Path C PathD
Path A
Path B
52
55
51
Scheme 15. Description of pathways A and B of decomposition of diazodimedone in presence of PhCN.
O
MeMe
N
OPh
O
N
O
Ph
Me
Me
O
OMe
Me
N2
5152 55
Reagents and Conditions: i) Abs. EtOH, reflux, 16h, 45%; ii) PhCN, 160°C, 1h, 91%.
i ii
Scheme 16. Independent synthesis of byproduct 55 from 51 and 52 via Wolff rear-rangements.
52
Figure 17. ORTEP plots at 50% probability of compound 52 (top) and compound 55(bottom).
Thereafter, the potential of the new catalysts 49a-c was evaluated. Hydro-genation of substrate 56 using 0.5 mol% of catalyst 49a under varius condi-tions showed a slight enantioselectivity dependence on hydrogen pressure. However, enantioselectivity remained constant above 30 bar. For substrate 63 a slight increase in enantioselectivity (89 to 93% ee) was noticed when hydrogen pressure was increased from 30 to 50 bar, therefore standard pres-sure was set to 50 bar. Complexes 49a-c proved to be highly efficient in the hydrogenation of a wide range of substrates (Table 7, entries 1-9), with 49bas overall best. As predicted by the selectivity model, tetra-substituted olefin 60 (Table 7, entry 5) gave poor conversion and low enantioselectivities.
53
Table 7. Results from asymmetric hydrogenation of olefins 56-64 by Ir-complexes 49a-c.
1
2
3
4
5
6
7
8
9
substrate abs.config.
MePh Ph
Ph OH
Ph OAc
MePh CO2Et
MePh
CO2Et
Mep-MeO-C6H4
Me
p-MeO-C6H4Me
Me
MeO
Me
Me
Mep-MeO-C6H4
MeMe
S
S
S
R
S
S
S
S
R
49aconv. ee
49bconv. ee
49cconv. ee
>99
>99
>99
>99
37
96
>99
>99
50
>99
>99
>99
>99
46
95
>99
>99
50
>99
>99
>99
>99
47
95
>99
>99
48
>99
89
95
92
15
92
99
66
rac.
>99
96
99
94
rac.
98
>99
93
33
>99
97
96
90
rac.
97
99
72
38
entry
56
57
58
59
60
61
62
63
64
Conditions: pressures: 30 bar (entry 1), 50 bar (entries 2-4, 6-9), 100 bar (entry 5); Allreactions were performed at room temperature for 2h, except for entries 5 and 6, wherethe reaction was run over night; Catalyst loading 0.5 mol% in all entries, except 5 and 6where 1 mol% were used. All reactions were performed in freshly destilled (CaH2, ethanol free) CH2Cl2 as 0.25 M solutions.
To get a firmer hold on the substrate-catalyst interactions in the enantio-determinating transition state of these systems, designed according to Figure14, we optimized the coupled migratory insertion/oxidative addition step for the full system of complex 49a with substrate 56. The calculated transition state structure being very similar to those reported in paper IV, clearly shows a chiral pocket well suited to accommodate a tri-substituted alkene according to our selectivity model. As assumed, the enantiofacial selectivity is primar-ily based on discrimination between a larger and a smaller geminal substitu-ent (Figure 18).
54
Figure 18. Structure of the selectivity determinating transition state of the coupled olefin migratory insertion / dihydrogen oxidative addition (top). Selectivity model using the ligand structure of the optimized transition state and a schematic substrate molecule (bottom).
Substrates possessing a polarized double bond, like , -unsaturated esters add a complicating electronic effect. DFT-calculations on trans-methyl cro-tonate suggest a strong preference for -addition of the hydride in the migra-tory insertion step (5 kcal mol-1), while a similar effect of reversed direction is observed for an enol ether, which prefers -addition. This results in low conversion and poor enantioselectivity in the reduction of ethyl trans- -methyl cinnamate, which behaves in a similar manner to tetra-substituted olefins. This fact gave us another tool to rationalize and predict enantioselec-tivity and the reactivity of substrates towards asymmetric hydrogenation by Ir-(P,N) systems. For successful reaction, a steric and electronic match be-tween substrate and catalyst is necessary. This fact can be rationalized by the
55
addition of a direction of the enantio-determinating migratory insertion step in the quadrant selectivity model. A substrate possessing a conjugated elec-tron-withdrawing group (EWG) will show a strong -preference for the ini-tial hydride addition, while a substrate possessing an electron-donating group (EDG) will show a strong -preference. These effects have to be matched with the steric requirements of the ligand (Figure 19).
EWG
H
EDG
Ir
Hindered
Semi-hinderedOpen
Open
Ir
Bulk
Empty catalyst
H EWG
EWG
Hindered
Semi-hinderedOpen
Open
Ir
Bulk
H
EWG
Sterical and electronical match.Reaction
H
Ir
Hindered
Semi-hinderedOpen
Open
Ir
Bulk
HEWG
Sterical match, electronical mis- match. No reaction
Hindered
Semi-hindered
Open
Open
Ir
Bulk
Catalyst with coordinated polarized olefin
H
Hydride transfered in MI is locatedtrans to sterical bulk. Can only be transfered to position of a polarized alkeneAlkene polarisation adds a component
of direction in migratory insertion step
A B
Figure 19. Rationalization of electronic and steric match/miss-match in enantio-determinating migratory insertion step into polarised alkenes.
In Figure 19, two different cases A and B are illustrated, describing the im-portance of steric and electronic match. In case A, an , -unsaturated ester like ethyl -methyl trans-cinnamate, known from our studies to give very modest results (low conversion, racemic product), is coordinated into a quadrant model of complex type 49, clearly showing the mismatch of the electronically preferred direction of the migratory insertion, compared to the steric requirements of the ligand. Its corresponding electronically neutral allylic alcohol and its acetate (entries 6 and 7, substrates 61 and 62, Table 7) works excellent. In case B, ethyl -methyl trans-cinnamate (entry 8, sub-strate 63, Table 7) is coordinated to a quadrant model of complex type 49,showing a match between the steric and electronic components, leading to high conversion (+99%) and good enantioselectivity (93% ee). Its cis-isomer (entry 9, substrate 64, Table 7) would have to put its large phenyl substituent into the semi-hindered quadrant to obey the electronic requirements, this
56
leads to an unfavored steric interaction, resulting in low enantioselectivity (33% ee) and modest conversion (48%). As the absolute configuration of the product shifts between entries 8 and 9, it is clear that the coordination mode to the catalyst of the substrates is the same, but entry 8 is favored over entry 9 in terms of selectivity and activity.
5.4.2 Design Modifications Leading to Second Generation Ligands
In order to expand the scope and tunability of ligands of type 48, we under-took a synthetic study of the structural elements contained in 48. First of all, we were limited by the instability of structures of type 48, when not directly converted into the corresponding metal complex. Attempts to evaluate 48 in other reactions, using in situ formed metal complexes (e.g. cationic RhI and Pd0) were not successful. Obviously, the phosphinite moiety is too unstable for storage and excessive handling. Another serious drawback of structure 48is that it only offers modularity at one point, the phosphinite moiety. As al-ready defined, the steric bulk on the heteroaromatic substituent is important for the outcome of the reaction, we wanted to be able to vary the steric bulk on the heteroaromatic substituent and the phosphine independently from each other, preferably from the same synthetic intermediate. With the previ-ous conclusions in mind, we envisioned a structure offering late stage diver-sity, from one single intermediate. The objectives were: A. By changing the phosphinite moiety into a phosphine by introduction of a methylene group instead of the oxygen eliminates the labile P,O-bond. B. By removing the aryl substituent on the heterocycle and changing it into a good leaving group, we open the 2-position of the heteroaromatic moiety for synthetic modifica-tions. C. At the same time, we change the heteroaromatic moiety from an oxazole into a thiazole, as the preparative chemistry of thiazoles are much more facile and oxazoles lacks the diazotation chemistry, necessary for the introduction of a halogen at the 2-position. This gives us a late stage inter-mediate 65, ready for diversification in two different directions. D. By em-ploying either reduction or, palladium catalyzed couplings, it should be pos-sible to vary the substituent on the heteroaromatic moiety from 2-H, via al-kyls to large bulky aromatics. This fact offers us the possibility to fully con-trol the steric and electronic components of the heteroaromatic substituent. E. Phosphine moiety is introduced by nucleophilic substitution with a borane protected phosphine ion, offering full diversity in terms of choice of sub-stituents. This results in the scaffold based ligand type 79, possessing the sought after late stage diversity (Figure 20).
57
O
O
N
PAr2
Me
Me
A. Change O to CH2
B. Change into halogen
C. Change O into S
S
NBr
OTs
Single scaffold for all ligands
65
E. Substitution with Ar2P(BH3)Li
D. Functionalization via Pd-chemistry
S
NR1
P(R2)2
Scaffold based ligands type 79 possessing full late stage diversity
Figure 20. Synthetic modifications on first generation ligands.
Retrosynthetic analysis of 65 suggests that, after removal of the tosylate group, reduction of an ester to get the corresponding bromo alcohol, fol-lowed by a diazotation to introduce the halogen at the 2-position on an amino thiazole. The thiazole ring is then constructed by a Hantzsch conden-sation[103] with a bromo ketone and thiourea.[104] As it is known in literature that -keto esters are brominated at the least substituted activated position by Br2 under anhydrous acidic conditions,[105] the bromoketone is synthesized by direct bromination of commercially avalible -keto ester 67 (Scheme 17).
S
NBr
OTs
S
NBr
OH
S
NBr
CO2R
S
NNH2
CO2R CO2RO
X
CO2RO
S NH2
NH2
FGI FGI
Disconnect
Disconnect 67
65
Scheme 17. Retrosynthetic analysis of intermediate 65.
5.4.3 Synthesis and Evaluation of Second Generation Ligands
Initial synthetic studies of proposed intermediate 65 showed that nucleo-philic substitution by Ph2P(BH3)Li exclusivley took place at the 2-bromo thiazole moiety, yielding product 66a, without a trace of 66b. Changing the tosylate leaving group into a iodide mainly provided elimination products instead of 66b (Scheme 18). This fact called for a modified synthetic route and the original idea of one single intermediate, only two steps from the ready ligand had to be changed. Instead, modification of 74 by palladium
58
chemistry, followed by tosylation and substitution proved to be synthetically feasible.
S
NBr
OH
S
NBr
OTs
Ph2P(BH3)LiS
NP(BH3)Ph2
OTs
THF, 0°C to rt
S
NBr
P(BH3)Ph2
Single product
Not observed
74 rac 65 rac
66a
66b
Scheme 18. Initial synthetic study on nucleophilic addition to intermediate 65.
The only questionmark in the synthetic planning of ligands type 79 was when, and how, to introduce the chiral center. The initial synthetic study established that an intermediate of type 74 or 75 easily could be resolved by preparative chiral HPLC. Such a methodology would be considered as a serious drawback, thus we investigated lipase-catalyzed kinetic resolution of intermediate racemic 74 as a possible route into enantiopure material.[106, 107]
Several different lipases were evaluated for the kinetic resolution of racemic 74, but the selectivities achieved were disappointingly low. The break-through came when it was found that racemic aminothiazole 70 could be resolved as its dibenzoyl tartaric acid salt. This is, according to our knowl-edge, the first example of an optical resolution of a chemical compound by salt formation on a remote aminothiazole moiety.
With the encouring results from the initial study, the synthesis of second generation ligands was outlined in the following way: Bromination of ke-toester 67 with Br2 in anhydrous Et2O at 0 °C gave the corresponding 3-bromo derivative 68 in almost quantitative yield. Treatment of 68 with thio-urea in absolute ethanol at room temperature gave aminothiazole hydrobro-mide 69 in excellent yield.[108, 109] Base 70 was then resolved as its (L)-dibenzoyltartrate salt, formed by addition of (L)-DBTA·H2O to 70 in a care-fully controlled volume of hot 80% aqueous MeCN. The resolution step was optimized in terms of mass yield and enantioselectivity by initial DoE screening, followed by steepest ascent method.[110] It was found that the yield of pure 71 could be increased even further from 37% up to 42%, but at the cost of the robustness. The reaction conditions giving 37% yield proved to be the best compromise, producing a crystal crop of 95-98% enantiomeric excess, directly from the racemic mixture, if filtered at the right temperature. One single recrystallisation yielded material of more than 99% enantiopu-
Best result: Pseudomonas Cepacia, vinyloctanoate, rt. i-Pr2O, E = 9.
59
rity. The unwanted enantiomer of 72, isolated from the mother liquids, could if needed, be recycled by racemization employing a catalytic amount of so-dium ethoxide in refluxing absolute ethanol (typically 2 hours and 5 mol% sodium ethoxide). Treatment of 71 with aqueous potassium carbonate gave the enantiopure free base 72 (Scheme 19).
CO2EtO
CO2EtO
Br
CO2Et
S
NNH3
+Br-
CO2Et
S
NNH3
+
L-DBTAH-
i ii iii
Reagents and Conditions: i) Br2, Et2O, 0°C, 3h, 95%; ii) thiourea, abs. EtOH, rt, 18h, 94%; iii)10% aq. K2CO3, warm (40°C) CHCl3, quantitative; iv) (L)-DBTA•H2O, MeCN/H2O 80:20, 37% over two recrystallisations, +99.5% ee.
CO2Et
S
NNH2
iv iii
CO2Et
S
NNH2
67 68 69
70 71 72
Scheme 19. Synthesis and optical resolution of chiral intermediate 72.
Converting 72 in situ to its hydrogen bromide salt, followed diazotation un-der anhydrous conditions employing t-BuONO in acetonitrile with CuBr2 as halogen source, gave 73 in good yield.[111] Intermediate 73 could then be converted either into bromothiazole alcohol 74 by treatment with two equivalents of DIBAL at -40 °C, or into the debrominated 2-H-thiazole de-rivative 76 by the action of an excess DIBAL at 0 °C.[112] Compound 74smoothly underwent Suzuki coupling with PhB(OH)2 according to a stan-dard protocol, which gave 75 in high yield.[113] No racemization of 72-76could be detected by chiral HPLC during the synthetic sequence, by compar-sion of retention times of previously synthesised racemic material. Alcohols 75 and 76 were then converted into their corresponding tosylates 77a-b in good yields. Treatment of tosylates 77a-b with Ar2P(BH3)Li at 0 °C, fol-lowed by stirring at room temperature over night in THF/DMF yielded P-borane protected phosphines 78a-d in high yields. At this point, 78a-d are completely stable to hydrolysis and oxidation, compared to the first genera-tion phosphinite ligands. Removal of the borane protecting group by stirring in neat Et2NH gave the free deprotected phosphines 79a-d. Complex forma-tion according to the previously employed protocol worked excellent, and complexes 80a-d were isolated in high yields (Scheme 20).
60
CO2Et
S
NNH2
CO2Et
S
NBr
S
NBr
OH
S
NH
OH
S
NPh
OH
S
NPh
OTs
S
NH
OTs
i ii iii
iv
v v
Reagents and Conditions: i) HBr, CuBr2, t-BuONO, MeCN, 0°C, 2h, 78%, +99.5% ee; ii) 2.2 equiv.DIBAL, THF, -40°C, 1.5h, 85%, +99.5% ee; iii) PhB(OH)2, DPPF•PdCl2 (5 mol%), K2CO3,toluene/H2O, 80°C, 3h, 87%, +99.5% ee; iv) 4 equiv. DIBAL, THF, -40° to 0°C, 4h, 73%, +99.5% ee;v) TsCl, pyridine, 0°C to rt, o.n.; vi) Ar2P(BH3)H, n-BuLi, THF, DMF, -78°C to rt, 16h; vii) Et2NH (large excess), 18h, rt; viii) [IrCl(COD)]2, CH2Cl2, reflux 30 min, then H2O, NaBArF•3H2O, rt, 1h.
72 73 74
75 7677a 85% 77b 87%
N
SR
Ar2P BArF
Ir
S
NR
OTs
S
NR
P(BH3)Ar2
S
NR
PAr2
vi vii viii
77a R = Ph77b R = H
78a R = Ph, Ar = Ph 85%78b R = Ph, Ar = o-Tol 79%78c R = H, Ar = Ph 75%78d R = H, Ar = o-Tol 76%
79a R = Ph, Ar = Ph 96%79b R = Ph, Ar = o-Tol 93%79c R = H, Ar = Ph 91%79d R = H, Ar = o-Tol 92%
80a R = Ph, Ar = Ph 86%80b R = Ph, Ar = o-Tol 81%80c R = H, Ar = Ph 72%80d R = H, Ar = o-Tol 68%
Scheme 20. Synthesis of ligands 79a-d and their Ir-complexes 80a-d.
In order to evaluate the importance of backbone size, a synthetic sequence was undertaken in order to synthesize the five- (90a) and seven- (90b) mem-bered analogues of 79a. Treatment of 83a-b with Br2 under previously estab-lished conditions gave 84a-b in decent yields. Hantzsch reaction on 84a-b with PhC(S)NH2 yielded the corresponding thiazole esters in, for the five membered analouge 85a good yield,[114] but for 85b modest yield. Reduction of 85a-b with LiAlH4 gave the corresponding racemic alcohols 86a-b in good yields. Resolution of racemic 86a-b into their enantiomers by prepara-tive chiral HPLC (Chiracel OD) and correlation of the absolute configuration by their elution order compared to the known absolute configuration of 75,yielded the (S)-enantiomers 87a-b. The resolved alcohols were then con-verted to their tosylates 88a-b, followed by substitution with Ph2P(BH3)Liand deprotection with Et2NH to give free phosphines 90a-b. Complex for-mation according to the standard procedure yielded the Ir-complexes 91a-b(Scheme 21).
61
CO2RO
n
CO2RO
n Br
CO2R
n
N
SPh
n
N
SPh
OH
n
N
SPh
OH
n
N
SPh
OTs
n
N
SPh
P(BH3)Ph2
n
N
SPh
PPh2
n
N
SPh
Ph2P
i ii
iii iv v
vi vii viii
Reagents and Conditions: i) Br2, Et2O, 0°C, 3h. ii) PhC(S)NH2, MeOH (84b) or EtOH (84a), 1h rt,then reflux over night, then aq. K2CO3; iii) LiAlH4, THF, 0°C to rt; iv) Preparative HPLC; ChiracelOD; v) TsCl, pyridine, CH2Cl2, 0°C to rt; vi) Ph2P(BH3)H, n-BuLi, THF, DMF, -78°C to rt over 16h; vii) Et2NH (large excess), 18h, rt; viii) [IrCl(COD)]2, CH2Cl2, reflux 30 min, then H2O,NaBArF•3H2O, rt., 1h.
83a n = 0, R = Et83b n = 2, R = Me
84a n = 0, R = Et, 97%84b n = 2, R = Me, 76%
85a n = 0, R = Et, 85%85b n = 2, R = Me, 37%
86a n = 0, 85%86b n = 2, 73%
87a n = 0, 44%87b n = 2, 48%
88a n = 0, 78%88b n = 2, 71%
91a n = 0, 75%91b n = 2, 63%
90a n = 0, 95%90b n = 2, 89%
89a n = 0, 81%89b n = 2, 73%
BArFIr
Scheme 21. Synthesis of five- (91a) and seven- (91b) membered ring analogues of series 80 complexes.
As all attempts to grow crystals suitable for single crystal X-ray analysis from aminothiazole-(L)-DBTA salt 71 failed, a heavier atom derivative was considered instead. Treatment of 72 with one equivalent tosyl chloride in pyridine gave ca 45% yield of the bis-tosylated aminothiazole 81, and only a trace of the originally considered mono-N-tosylated derivative. Increasing the amount of tosyl chloride to 2.1 equivalents yielded the highly crystalline bis-tosylate 81 in excellent isolated yield (Scheme 22). The absolute con-figuration of 72, via its derivative 81, proved to be (S) (Figure 21).[100]
CO2Et
S
NNH2
72
CO2Et
S
NN
Ts
Ts
81Reagents and Conditions: i) 2.1 equiv. TsCl, pyridine, CH2Cl2, 0°C to rt, 16h, 86%.
i
Scheme 22. Synthesis of heavy atom derivative 81 for determination of absolute configuration by single crystal X-ray diffraction spectroscopy.
62
Figure 21. ORTEP plot at 50% probability of compound 81, clearly showing the (S)-configuration at the stereogenic center.
The new complexes 80a-d proved also to be highly efficient, with a few exceptions, for the asymmetric hydrogenation of a vide variety of tri-substituted olefins. As expected, the steric bulk of the heteroaromatic sub-stituent is very important for achieving high enantioselectivity, which is clearly seen in Table 8, entry 1, for substrate 56, where a dramatic drop in enantioselectivity is observed for complexes 80c-d, lacking the phenyl group. Also the size of the phosphine substituents, occupying the semi-hindered quadrant, is of importance for some substrates like 57 and 92, en-tries 2-3 where changing from 80a (Phenyl) into 80b (o-Tolyl) leads to a dramatic loss of enantioselectivity in both cases. One example of an electron rich enol ether is included in the study, substrate 99, entry 4, clearly demon-strating its mesomeric effect, leading to low conversions and poor enantiose-lectivity. Between entries 5 and 6, a slight change of a single methoxy group makes a large difference in enantioselectivity between substrate 59 and 93for complex 80a. Allylic alcohol 61, entry 8, worked surprisingly perfect for all complexes 80a-d. Allylic acetate 62, entry 9, gave disappointingly low conversions with complexes 80a-d and poor enantioselectivity, with re-versed asymmetric induction than expected. This was a surprise as substrate 62 has provided excellent results with the oxazole phosphinite complexes 49a-c (Table 7, entry 7). Ethyl -methyl trans cinnamate 95, entry 10, gave good enantioselectivities with o-Tol-complexes 80b and 80d, while its cyclic analogue 96, entry 11, gave low conversions and poor enantioselectivity. Only for substrate 64, entry 12, did 2-H-thiazole complexes 80c-d prove to be superior, giving high conversions and excellent enantioselectivities for
63
the previous very unreactive substrate. Substrate 63, entry 13, gave excellent conversions and enantioselectivities with complexes 80a-b (Table 8).
Table 8. Asymmetric hydrogenation with complexes 80a-d.
1
2
3
4
5
6
7
8
9
10
11
12
13
substrate 80aconv. ee (%)
>99
>99
>99
16
>99
99
99
>99
6
>99
5
85
>99
>99 (S)
99 (S)
99 (S)
35a
93 (R)
55 (R)
98 (S)
99 (S)
64 (R)
40 (S)
72a
rac
98 (S)
entry
Absolute configurations of products given in paranthesis after ee-value. a Absolute configurationnot known. Conditions: Pressures: 50 bar in all entries; All reactions were performed at roomtemperature over night; Catalyst loading 0.5 mol% in all entries, except 10-13 where 1 mol% were used. All reactions were performed in freshly destilled (CaH2, ethanol free) CH2Cl2 as 0.25 Msolutions.
>99
>99
99
23
99
99
99
>99
8
>99
47
99
>99
>99 (S)
58 (S)
60 (S)
rac.
31 (R)
19 (S)
75 (S)
99 (S)
72 (R)
80 (S)
46a
90 (R)
98 (S)
>99
>99
35
11
>99
74
99
>99
8
50
21
99
91
77 (S)
98(S)
16 (S)
2a
78 (R)
50 (R)
26 (S)
99 (S)
65 (R)
40 (S)
rac.
95 (R)
87 (S)
>99
>99
30
10
>99
90
99
>99
6
95
32
99
99
48 (S)
30 (S)
rac.
rac.
40 (R)
15 (R)
rac.
99 (S)
67 (R)
80 (S)
rac.
95 (R)
69 (S)
80bconv. ee (%)
80cconv. ee (%)
80dconv. ee (%)
PhMe
Ph
p-MeO-C6H4
MeMe
Ph
MeCO2Et
Ph
Me
CO2Et
Ph CO2Et
Me
O
CO2Et
PhMe
OAc
PhMe
OH
Me
MeOMe
Me
Ph
MeMe
56
57
92
99
59
93
94
61
62
95
96
64
63
OMe
64
In order to verify if the size of the cyclic backbone is important for the enan-tioselectivity, a series of experiments were performed with the five (91a), six (80a), and seven (91b) member backbone complexes. For substrate 56, entry 1, a slight effect on enantioselectivity could be detected at 10 bar, in favor of 80a over 91a-b. However, at 50 bar, entry 2, no effect of the backbone size on the enantioselectivity could be detected, this was also the case for sub-strate 57, entry 3. Substrate 62, entry 4, was performing notoriously bad for all complexes, giving no effect at all. Substrate 63, entry 5, gave excellent results with all complexes, clearly showing a strong effect between five (91a) and six (80a) member backbone, followed by a slight decrease again for the seven member 91b. Substrate 64 gave, as expected, close to racemic material and somewhat low conversions (Table 9).
Table 9. Comparison of ligand backbone size and enantioselectivity for a representa-tive selection of substrates.
1a
2
3
4
5
6
substrate
MePh Ph
Ph OAc
MePh CO2Et
MePh
CO2Et
Mep-MeO-C6H4
Me
Me
91a conv. ee (%)
80a conv. ee (%)
91b conv. ee (%)
>99
>99
>99
8
99
99
94 (S)
99 (S)
99 (S)
65 (R)
86 (S)
3 (R)
entry
56
57
62
63
64
Conditions: aPressure 10 bar (entry 1), 50 bar (entries 2-6); All reactions wereperformed at room temperature over night; Catalyst loading 0.5 mol% in all entries. All reactions were performed in freshly destilled (CaH2, ethanol free) CH2Cl2 as 0.25 Msolutions.
>99
>99
>99
6
>99
85
>99 (S)
>99 (S)
99 (S)
64 (R)
98 (S)
rac.
>99
>99
99
9
99
97
98 (S)
99 (S)
99 (S)
66 (R)
95 (S)
3 (S)
N
SPh
Ph2P BArF
Ir
N
SPh
Ph2P BArF
IrN
SPh
Ph2P BArF
Ir
91a 80a 91b
Complexes:
MePh Ph
56
65
As it is clearly seen from the results in Table 9, the size of the backbone has an effect on the enantioselectivity, especially for substrate 63, entry 5. Also the standard substrate 56 shows a dependance on the backbone size, al-though it is outbalanced by a positive pressure effect at higher pressures. These results verify that, by the model proposed, a six-membered backbone is optimal for most tri-substituted olefins. The case of exception is the tetra-substituted olefins that probably prefer an open backbone, due to their need of a higher degree of flexibility in the complex.
Tetra-substituted olefins have not been included in Tables 8 and 9, mainly due to their very poor performance, both in terms of activity and enantiose-lectivities. It was our belief that complexes 80c-d would perform well with tetra-substituted olefin 60 and related, polarized tetra-substituted olefins, like cis- and trans-ethyl , -dimethyl cinnamate, but this was not realized. Fur-ther development of the thiazole ligand class is necessary in order to succeed with the asymmetric hydrogenation of tetra-substituted olefins.
5.5 Conclusions In conclusion, we have developed a new type of heterocyclic (P,N)-ligands for the asymmetric Ir-catalysed hydrogenation of olefins. Starting from a mechanistic study, we have established a mechanistic proposal for the reac-tion (Paper IV). The mechanistic work led into a computational derived se-lectivity model, suitable for ligand design. From this model, two generations of highly enantioselective catalysts have been developed. The results, in terms of enantioselectivites for particularly difficult substrates, are the best so far reported (Paper V-VI). From the results with the second-generation thiazole ligands, a more detailed selectivity model will be derived, revealing the relation between steric and electronic effect and its importance for activ-ity and enantioselectivity.
66
6 Catalytic Asymmetric Hydrogenation of Ketones by Phosphine Free Ruthenium Catalysts.
6.1 IntroductionOf comparable practical interest to the enantioselective reduction of C,Cdouble bonds previously mentioned in this thesis, is the hydrogenation of C,O and C,N double bonds.[115] Two methods have been developed for cata-lytic homogeneous enantioselective hydrogenation of ketones. These are transfer hydrogenation, using organic sources of dihydrogen, or the direct use of molecular hydrogen. In the transfer hydrogenation reaction the proton is transferred from iso-propanol or formic acid to the ketone through an irid-ium, ruthenium, or rhodium catalyst. The most efficient ligands used for this reaction is based on -amino alcohols or N-sulfonyl- -diamines together with RuII-arene (C) or RhIII/IrIII-cyclopentadiene complexes.[116-119] The most efficient catalysts for hydrogenation of activated ketones with H2 are based on RuII-diphosphine catalysts (B).[120] The method of choice for reducing unactivated ketones, on the other hand, is Noyori’s newly developed bifunc-tional Ru-diphosphine/diamine catalyst system (A) (Figure 22).[121-125]
RuP
PH2N
NH2
X
X
RuP
P X
X
* *
NH2Ru
NCl
Me
MeMe
Me
MeMeMe
XRu
H2N Cl
X= N-sulfonylamideor oxygen
Mei-Pr
X = halogen or hydrideA B C D
Figure 22. Previous used systems for ketone hydrogenation.
Recently, Ikariya et al. demonstrated that Cp*RuIICl-1,2-diamine complexes of general type D which are isoelectronic to the transfer hydrogenation cata-lyst C, were active catalysts for the hydrogenation of ketones with H2 as hydrogen source.[126] This finding is spectacular, as it appears to be the only known example of a homogeneous hydrogenation catalyst, which is capable of activating molecular hydrogen without having at least one phosphine ligand around the metal center. This study also concluded that the most ac-
67
tive catalyst was obtained with a diamine having one tertiary and one pri-mary amino function.
Based on these findings, we postulated that an even more potent catalyst could be obtained by increasing the Lewis basicity of the tertiary nitrogen center of the ligand.[127] One possibility to accomplish this would be to in-corporate a quinuclidine function into the ligand. Gratifyingly, two pseudo-enantiomeric 1,2-diamines containing a quinuclidine function and a primary amino function are commercially available. The quincorine-amine (QCI-amine) 117a and quincoridine-amine (QCD-amine) 117b are derived from the Cinchona alkaloids quinine and quinidine, respectively (Scheme 23).[128]
Quincorine amine(QCI-amine 117a)
Quincoridine amine(QCD-amine 117b)
N
H2N
N NH2NN
N
OMe
N
OMe
OH
OH
Quinine Quinidine
Scheme 23. Preparation of QCI/QCD-amines.
These -diamines, containing four stereogenic centers each, including a fixed stereogenic (S)-configured N-bridgehead, have previously been used as ligands in Ir-catalyzed asymmetric transfer hydrogenation of ketones,[129] and as chiral acylation catalysts.[130] Other ligands based on the quincorine and quincoridine scaffold, including (P,N)-ligands, have also been described.[131-
133] However, to the best of our knowledge, no QCI/QCD-based ligands have previously been used in asymmetric hydrogenation reactions.
68
6.2 Results and Discussion 6.2.1 Hydrogenation of Aryl alkyl ketones; Results
In an initial study, we compared the two diamines used by Ikarya and co-workers, 115 and 116 with 117b, employing identical reaction conditions, except using Cp*RuCl 4 instead of Cp*Ru(COD)Cl as catalyst precursor. It is worth mentioning that the observed reaction rates for 115-116 were faster than reported by Ikarya; the metal precursor used by us probably generates a more active catalyst. To our delight, it was found that QCD-amine 117bgave ca 25 times faster reaction (relative rate) than 116 with similar enanti-oselectivity (Figure 23).
NH2N
Quincoridine amine(QCD-amine )
NEt
NH2
Me2N NH2
N,N-dimethyl etylendiamine
(S)-(1-ethylpyrrolidin-2-yl)
methyl amine
116115 117b
75% ee73 %ee
117b116
[Cp*RuCl]4diamine 115-117b
25 bar H2, KOt-Bu
Ligand
116
115
117b
Rate ( mol s-1)
RelativeRate
0.086
0.39
2.18
1
4.5
25.3
S/C = 100, 0.47 M in i-PrOH
Me
O
Me
OH*
100
Figure 23. Initial results comparing QCD-amine 117b with previously reported ligands 115-116 in the phosphine free asymmetric hydrogenation of unfunctional-ized ketones.
Encouraged by the high reaction rates obtained by the initial studies on ace-tophenone with the QCD-amine, a substrate study was undertaken. A wide variety of sterically and electronically different aryl-alkyl ketones were hy-drogenated. Interestingly, pseudoenantiomeric QCI-amine 117a gives lower enantioselectivity, probably due to a steric miss-match between the vinyl group and the substrate (entry 2, table 8). Good activity in terms of conver-sion was achieved for both QCD and QCI-amine (Table 10).
69
Table 10. Results of the asymmetric hydrogenation of aryl alkyl ketones by QCI/QCD-amines.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
QCD
QCI
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
QCD
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
o-CH3OC6H4
p-CF3C6H4
p-ClC6H4
3,4,5-F3C6H2
2,6-F2C6H3
1-naphtyl
CH3
CH3
i-C3H7
t-C4H9
n-C4H9
i-C4H9
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
+99
+99
99
99
99
99
+99
+99
99
+99
99
99
99
99
99
+99
75
41
74
90
81
90
82
71
76
79
86
62
64
44
50
81
(S)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
Conditions: S/C 100, 25 bar H2, 0.47M substrate in i-PrOH, rt, 2h.
Entry Ar R Diamine Conversion (%) ee (%) Abs. Config.
ArCOR ArCH*OHR[Cp*RuCl]4, diamine
H2, KOt-Bu
100
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
Substrate
6.2.2 Rationalizing Mechanism and Enantioselectivity It has been postulated earlier that the mechanism of ketone hydrogenation by Ru-catalysts that contains at least one sp3 NH donor atom proceeds via a concerted proton-hydride transfer from the complex to the substrate.[134, 135]
This mechanism can be regarded as commonly accepted, considering the reduction step, but very little is known about how the dihydrogen is hetero-lytically activated into a metal bound hydride and a nitrogen bound proton. This part of the reaction is of considerable interest as its calculated barrier is estimated to be high (ca 20 kcal mol-1) and possibly over all rate determinat-ing (Figure 24, pathway B).[136] In conflict with the calculated barrier, Morris
70
et al. reported an experimental activation enthalpy of only 7.6 to 8.6 kcal mol-1.[137, 138] The difference between the calculated and experimental barriers could be a consequence of the active participation of an alcohol molecule in the coordination and cleavage of dihydrogen (Figure 24, pathway A). Such a mechanism has been proposed and experimentally supported by deuterium labeling experiments by Ikarya and coworkers in 2001.[126] However, the possibility for i-PrOH-assisted heterolytic dihydrogen activation at the Ru-center has been ignored in computational studies so far, although often men-tioned in a speculative way.[136, 139] We have used our Cp*RuII(QCD)Cl-catalyst to investigate the possibility of such mechanism by theoretical and experimental methods. This mechanism is currently under investigation in our laboratory (Figure 24).
HNH
OH
HRu
R
HNH
O
Ru
R
HH
HNRu
+
-
--
++
HNH
OH
HRu
R
+
-
--
++
HNH
HRu
H HH
OR
HNRuH H
HH HN
Ru
HH
+
-
+
-
Path A
Path B
Figure 24. Activation through heterolytic cleave of dihydrogen by zwitter-ionic 16eRuII-complex (left), by either alcohol mediated reaction (pathway A), or by direct activation (pathway B), leading to active catalyst RuH-NH2 (right).
As the first step in the mechanistic evaluation, we undertook a kinetic inves-tigation into the Cp*RuII(QCD)Cl catalyzed reaction. According to DFT-calculations, it should be first order with respect to catalyst and hydrogen pressure. In a series of experiments, 1.5 mmol of 100 was reduced at hydro-gen pressures of 5.0, 10.0, 15.0, 20.0 and 25.0 bar using 1.00 mol% of Cp*RuII(QCD)Cl at 0.470 M in i-PrOH under previously used conditions. This revealed a first order dependence in hydrogen pressure (Figure 25) We did also experimentally verify the expected zeroth order dependence in sub-strate concentration.
71
0
0.0005
0.001
0.0015
0.002
0 10 20 30
p(H2) Bar
Figure 25. Pressure dependence on rate for the hydrogenation of acetophenone with Cp*RuII(QCD)Cl under standard conditions. (Slope = 9.8x10-5, I = -3.3x10-4, R2 = 0.995)
In order to see how well the postulated mechanism correlates with the ex-perimental results we next compared the selectivities obtained for the ke-tones with the catalyst structure derived from the DFT-calculations. This is greatly facilitated by the presence of the 5-bonded Cp*-ligand, since it oc-cupies three coordination sites on the octahedral Ru and thus reduces the number of possible diastereomeric complexes. Starting from the planar zwit-ter-ionic 16e complex C, addition of dihydrogen can take place from two sides, leading to two diastereomeric complexes. Calculations favour forma-tion of intermediate A which has a lower activation energy for the hetero-lytic, alcohol mediated cleavage of the coordinated dihydrogen (8.8 kcal mol-1 for A compared to 11.6 kcal mol-1 for B) (Figure 26).
C
C
CC
C
C
C
C
C
C
N
C
CC
C
Ru
C
CC
C
C
N
C
C
C
CC
C
C
C
C
C
C
C
N
C
C
Ru
C
C
C
C
C
C
N
CC
C
CC
C
C
CC
C
C C
N
C
CC
C
Ru
CC C
C
N
C
H2i-PrOH
H2i-PrOH
Ea = 11.6 kcal/molEa = 8.8 kcal/mol
CA B
Figure 26. Formation of two diastereomeric Ru-hydride complexes by Re- (A, left) or Si- (B, right) face, alcohol assisted, dihydrogen coordination and splitting from planar zwitter-ionic 16e-complex C (middle).
dc/d
t mM
S-1
72
The modelled transition state of the reduction is a concerted, but asynchro-nous, addition of a hydride to the carbonyl carbon, followed by the transfer of a proton from nitrogen to oxygen. In this model, the addition to the Si-face of the ketone is favored by 2.2 kcal mol-1 since this will avoid interac-tion between the phenyl and the Cp*-ligand of the complex that takes place in the corresponding addition to the Re-face (Figure 27).
C
CC
C
C
C
C
CC
C
C
C
C
N
C
Ru
C
C
C
C
C
CC
N
C
C
C
C
O
C
C
C
C
C
C C
CC
C
C
C
C
C
C
C
N
C
C
Ru
C
C
C
C
C
CC
C
C
C
N
C
CO
C
Figure 27. Full system transition states for the Re-face (unfavored, left) and the Si-face (favored, right) reduction of acetophenone by Cp*RuH(QCD) (A, Figure 26). The unfavored interaction between substrates aryl ring and Cp*-ligand in the cata-lyst is clearly visible (left).
The lower selectivities obtained for the QCI-amine originates from a colli-sion between the vinyl group in the ligand and the phenyl ring in the sub-strate. This interaction leads to destabilization of the transition state giving Re-addition and the calculated energy difference between the two di-astereomeric transition states is now only 1.2 kcal mol-1, compared to 2.2 kcal mol-1 for the QCD-complex (Figure 28).
73
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
C
Ru
C
C
C
C
C
C
C
C
C
C
N
C
O
3.80Å (3.80)
3.87Å (3.58)
C
C
C C
CC
C
C
C
C
C
C
C
N
C
C
Ru
C
C
C
C
C
CC
C
C
C
N
C
CO
C
Figure 28. Transition state for the reduction of acetophenone by QCI-complex showing the steric interaction between the vinyl group of the ligand and the phenyl group of the substrate (left), and the corresponding transition state for the more se-lective QCD-complex (right).
Interestingly, it was found that enantioselectivity strongly depends on the electronic character of the substrates aromatic substituent pattern. By de-creasing the electron density of the aromatic moiety, a strong negative effect on the enantioselectivity can be seen (Table 10). Recalculating the enanti-omeric excess value (ee), into the corrresponding enantiomeric ratio value (er) and plotting the ln(er) against literature values of [140] gave a surpris-ingly good correlation (Figure 29).
1
2
3
4
5
108
107
100
111
110
CH3O
CH3
H
Cl
CF3
79
76
75
64
62
9.00
7.33
6.69
4.55
3.24
-0.28
-0.14
0
0.24
0.53
Entry Substrate R ee (%) er
1
1.5
2
2.5
-0.4 0.1 0.6p
Figure 29. ln(er) versus . (slope = -1.264, I = 1.845, r2 = 0.993).
This fact can only be explained by the influence of a dipole-dipole stabiliz-ing/destabilizing interaction in the enantiodetermining transition state; de-pending on the electron density and dipole moment of the aromatic ring and its recognition of the strongly negative Cp*-ligand. This leads to an attrac-tive interaction in case of a electron poor aromatic ring and the opposite
74
repulsive effect, in case of an electron rich aromatic substrate. As the aro-matic substituent should point away from the Cp*-ligand in the transition state giving the major enantiomer, the repulsive effect can be considered as positive, in terms of enantioselectivity. Similar electrostatic effects, but in the opposite direction, have been observed by our group in the Ru-catalysed transfer hydrogenation of a serie of acetophenones.[141] In sharp contrast with other asymmetric ketone hydrogenation catalysts, alkyl-aryl ketones having bulkier alkyl groups reacted with higher enantioselectivity than those having smaller alkyl groups. While acetophenone was hydrogenated to phenyletha-nol in 75% enantiomeric excess, the sterically more demanding 2,2-dimethylpropiophenone and valerophenone (Table 10, entries 4 and 6, re-spectively) gave the corresponding alcohols in 90% enantiomeric excess. This fact can be explained by the DFT-calculations, showing a difference between the Re- and Si-face reduction of 2,2-dimethylpropiophenone of 5.5 kcal mol-1, compared to 2.2 kcal mol-1 for acetophenone (75% ee), which well corresponds to the observed 90% enantiomeric excess. This can be at-tributed to the almost perfect fit of the t-butyl group into the pocket formed between the coordinated carbonyl and the Cp*-ligand.
6.3 Conclusions In conclusions, we have established a highly efficient, phosphine free cata-lytic system for the asymmetric hydrogenation of unfunctionalised ketones. Compared to previously reported Cp*RuII-diamine systems, our catalyst displays considerable higher reaction rates. The reaction mechanism and the steric and electronic factors governing enantioselectivity have been studied by experimental kinetics and theoretical DFT-calculations. The knowledge about Cp*RuII-diamine systems will be used for designing new systems with higher selectivity for a wider range of substrates.
75
7 Acknowledgements
I would like to express my sincere gratitude to my supervisors during this work: Prof. Pher G. Andersson for providing the necessary resources and environment for doing creative organic chemistry, and Dr. Peter Brandt for excellent cooperation at the point where experimental science stops and quantum chemical calculations take over.
I would also like to thank:
All past and present members of the PGA group for an, in all senses, unfor-gettable time, especially; Dr. Mikael Södergren, Dr. Pedro Pinho and Dr. Diego Alonso for revealing the secrets of preparative organic chemistry for me as a new student. Klas Källström and Magnus Engqvist for good coop-eration during the years.
The people at Solvias AG Basel for providing me the opportunity to work in an industrial environment, especially: Dr. Benoit Pugin, Dr. Martin Studer, Dr. Hans Ulrich Blaser, and my favorite laborantin Heidi Landert.
Førsteamanuensis Dr. Annette Bayer and Prof. Lars Kristian Hansen at the University of Tromsø for excellent cooperation. Prof. Rolf Carlson, Univer-sity of Tromsø, for providing me with an elementary knowledge of statistical experiment design in terms of its scope and limitations.
All the people within the SSF SELCHEM program, both PhD-student col-leagues and the senior board members. Especially: Program coordinator Tekn. Lic. Gunnar Erlandsson and senior consultant Dipl. Chim. Rolf Bader.
The people who proof read and corrected the manuscript of this thesis: Dr. Christopher Chapman, Dr. Per Arvidsson, Dr. Henrik Ottosson and Dr. Stefan Modin. Fil Lic. Lauri Toom for excellent help with graphical illustra-tions.
76
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