The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies.1,2 Among all asymmetric catalytic methods, asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines, have become one of the most efficient methods for constructing chiral compounds.3 The development of homogeneous asymmetric hydrogenation was initiated by Knowles4a and Horner4b in the late 1960s, after the discovery of Wilkinson’s homogeneous hydrogenation catalyst [RhCl(PPh3)3]. By replacing triphenylphosphine of the Wilkinson’s catalystwithresolvedchiralmonophosphines,6Knowles and Horner reported the earliest examples of enantioselective hydrogenation, albeit with poor enantioselectivity. Further exploration by Knowles with an improved monophosphine CAMP provided 88% ee in hydrogenation of dehydroamino acids.7 Later, two breakthroughs were made in asymmetric hydrogenation by Kagan and Knowles, respectively. Kagan reported the first bisphosphine ligand, DIOP, for Rhcatalyzed asymmetric hydrogenation.8 The successful application of DIOP resulted in several significant directions for ligand design in asymmetric hydrogenation. Chelating bisphosphorus ligands could lead to superior enantioselectivity compared to monodentate phosphines. Additionally, P-chiral phosphorus ligands were not necessary for achieving high enantioselectivity, and ligands with backbone chirality could also provide excellent ee’s in asymmetric hydrogenation. Furthermore, C2 symmetry was an important structural feature for developing new efficient chiral ligands. Kagan’s seminal work immediately led to the rapid development of chiral bisphosphorus ligands. Knowles made his significant discovery of a C2-symmetric chelating bisphosphine ligand, DIPAMP.9 Due to its high catalytic efficiency in Rh-catalyzed asymmetric hydrogenation of dehydroamino acids, DIPAMP was quickly employed in the industrial production of L-DOPA.10 The success of practical synthesis of L-DOPA via asymmetric hydrogenation constituted a milestone work and for this work Knowles was awarded the Nobel Prize in 2001.3k This work has enlightened chemists to realize * Corresponding author. 3029 Chem. Rev. 2003, 103, 3029−3069

New Chiral Phosphorus Ligands for Enantioselective Hydrogenation

Hydrogenation is a core technology in chemical synthesis. High rates and selectivities are attainable only by the coordination of structurally well-designed catalysts and suitable reaction conditions. The newly devised [RuCl(2)(phosphane)(2)(1,2-diamine)] complexes are excellent precatalysts for homogeneous hydrogenation of simple ketones which lack any functionality capable of interacting with the metal center. This catalyst system allows for the preferential reduction of a C=O function over a coexisting C=C linkage in a 2-propanol solution containing an alkaline base. The hydrogenation tolerates many substituents including F, Cl, Br, I, CF(3), OCH(3), OCH(2)C(6)H(5), COOCH(CH(3))(2), NO(2), NH(2), and NRCOR as well as various electron-rich and -deficient heterocycles. Furthermore, stereoselectivity is easily controlled by the electronic and steric properties (bulkiness and chirality) of the ligands as well as the reaction conditions. Diastereoselectivities observed in the catalytic hydrogenation of cyclic and acyclic ketones with the standard triphenylphosphane/ethylenediamine combination compare well with the best conventional hydride reductions. The use of appropriate chiral diphosphanes, particularly BINAP compounds, and chiral diamines results in rapid and productive asymmetric hydrogenation of a range of aromatic and heteroaromatic ketones and gives a consistently high enantioselectivity. Certain amino and alkoxy ketones can be used as substrates. Cyclic and acyclic alpha,beta-unsaturated ketones can be converted into chiral allyl alcohols of high enantiomeric purity. Hydrogenation of configurationally labile ketones allows for the dynamic kinetic discrimination of diastereomers, epimers, and enantiomers. This new method shows promise in the practical synthesis of a wide variety of chiral alcohols from achiral and chiral ketone substrates. Its versatility is manifested by the asymmetric synthesis of some biologically significant chiral compounds. The high rate and carbonyl selectivity are based on nonclassical metal-ligand bifunctional catalysis involving an 18-electron amino ruthenium hydride complex and a 16-electron amido ruthenium species.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1521-3773%2820010105%2940%3A1%3C40%3A%3AAID-ANIE40%3E3.0.CO%3B2-5

Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo‐ and Stereoselective Hydrogenation of Ketones

10. Patented Literature 2616 10.1. Esterification 2616 10.2. Ether Formation 2619 10.2.1. Etherification without Cyclization 2619 10.2.2. Etherification with Cyclization 2624 10.3. N-Alkylation 2625 10.4. Other Reactions 2627 11. Summary and Outlook 2628 12. Note Added in Proof 2628 13. Abbreviations Used in This Review 2629 14. Acknowledgments 2629 15. Supporting Information Available 2630 16. References 2630

Mitsunobu and Related Reactions: Advances and Applications

Ruthenium-Catalyzed Reactions for Organic Synthesis.

The question of concerted or consecutive bond formation arises in all types of cycloaddition reactions. Stereochemical investigations and studies of regiospecificity as well as intensive kinetic investigations with regard to substituent and solvent effects, and the dependence of the reaction on temperature and pressure permit in many cases mechanistic conclusions concerning the Diels-Alder reaction. Efforts towards a theoretical interpretation, ab initio and semiempirical calculations, the application of frontier molecular orbital theory (FMO) as well as thermochemical measurements permit a description of the energy hypersurface of these [4+2]-cycloadditions. An attempt is made here to draw a line of distinction between the mechanistic alternatives—one-step reaction versus two-step reaction—considering all experimental and theoretical criteria.

Mechanistic Aspects of Diels‐Alder Reactions: A Critical Survey

Cyclobutanones and Cyclobutenones in Nature and in Synthesis [New Synthetic Methods(71)]

The modern agrochemical industry is searching, more intensively than ever, for new substances to combat pests (weeds, deleterious insects, plant pathogens, etc.). In the complex and costly selection and optimization process, state-of-the-art scientific methods are always needed. The aims of the interdisciplinary optimization are mainly the reduction of the rate of application of the new substance, an increase in the selectivity against the target organism, and the optimal ecological profile. If a promising crop protection compound is a racemate or a diastereoisomeric mixture, the chemist has a unique opportunity to contribute to this optimization process through the synthesis of enantiomerically pure isomers for testing purposes. If the single isomer proves to be biologically superior to the racemate, the development of an economical and ecologically sound process for the production of the single isomer presents an even greater challenge. The average price of a crop protection compound is much lower than that for a pharmaceutical product, and this fact imposes a severe limitation upon the flexibility of the chemist who is concerned with the synthesis and production of a stereochemically pure agrochemical. This forces the crop protection chemist to make full use of both his scientific and creative capabilities. Fortunately, parallel to the development of the above optimization aims of a modern and ecologically sound crop protection research, there has been a continuous and worldwide advance in the area of asymmetric synthesis. Due to the interplay of these two parallel efforts there has been a great accumulation of chemical, biological, and agronomical knowledge in recent years, which should have implications beyond merely the synthesis of enantiomerically pure agrochemicals.

Chirality and Crop Protection

Syntheses of Moniliformin, a Mycotoxine with a Cyclobutenedione Structure



Six different routes to 3-hydroxy-3-cyclobutene-1, 2-dione (4), the free acid of the mycotoxine Moniliformin (=alkali salt of 4) are described. A common feature of all pathways is the synthesis of cyclobutanes having the oxidation level 6. Moniliformin precursors which are easily transformed to 4 by acid catalysed hydrolysis include [2+2]-cycloadducts of ketene with tetraalkoxy-olefins, 3,4,4-trialkoxycyclobutenes, derivatives of polyfluorinated cyclobutenes, the brominated [2+2]-cycloadduct of ethyl vinyl ether and dichloroketene, tetrabromocyclobutanone, [2+2]-photocycloadducts of dichlorovinylenecarbonate with dichloroethylenes, and the dimer of chloroketene. The most convenient synthesis via the [2+2]-cycloadduct of tetraethoxyethylene and ketene (14b) is reported in detail and produces 4 in four simple steps in 57% overall yield. In addition, two new syntheses of squaric acid (56) are described.

Synthesen von Moniliformin, einem Mycotoxin mit Cyclobutendion-Struktur

Physical Quenchers of Singlet Molecular Oxygen

Die chemische Reaktivitat der Cyclobutanone und Cyclobutenone unterscheidet sich deutlich von derjenigen der hohergliedrigen cyclischen Ketone; ein Hauptgrund ist die hohe Ringspannung von etwa 25 kcal mol−1. Die detaillierte Kenntnis des Einflusses dieser Ringspannung auf regio-, chemo- und stereoselektive Umwandlungen von Vierringketonen ist von besonderem Wert. Wahrend einige Reaktionen wie die Baeyer-Villiger-Oxidation, die Beckmann- und die Favorskii-Umlagerung sowie die cine-Substitution oft vierringspezifisch verlaufen, lassen sich andere Reaktionen wie die leichte Ringoffnung mit Nucleophilen, die Umlagerung zu Tropolonen, die thermische [2 + 2]-Cycloreversion, die Isomerisierung zu Vinylketenen und die photochemische Oxacarbenbildung vorwiegend oder ausschlieslich mit Cyclobutanonen und Cyclobutenonen durchfuhren. Die oft hervorragende Selektivitat und die ausgezeichneten Ausbeuten solcher Umwandlungen, welche durch die Ringspannung als inharente treibende Kraft begunstigt oder bedingt sind, bieten dem praparativ arbeitenden Chemiker faszinierende Moglichkeiten zum Entwurf neuer Strategien fur moderne Wirkstoff- und Naturstoffsynthesen.

Daniel Bellus

Papers

Cyclobutanones and Cyclobutenones in Nature and in Synthesis [New Synthetic Methods(71)]

Chirality and Crop Protection

Synthesen von Moniliformin, einem Mycotoxin mit Cyclobutendion-Struktur

Physical Quenchers of Singlet Molecular Oxygen

Cyclobutanone und Cyclobutenone in der Natur und in der Synthese