Jens Christoffers

Enantioselective Construction of Quaternary Stereocenters

The stereoselective formation of C-C bonds is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. A broad repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the reliable generation of tertiary stereocenters. In contrast, the synthesis of organic compounds with quaternary stereocenters is a much more demanding and challenging task. Every enantioselective synthetic method can demonstrate its value through the generation of a fully substituted carbon center. In this Minireview examples of newer stoichiometric and catalytic methods are summarized which have proved their suitability for the enantioselective construction of quaternary stereocenters.

Quaternary stereocenters : challenges and solutions for organic synthesis

Foreward. Preface. List of Contributors. Symbols and Abbreviations. 1 Important Natural Products (Hirokazu Arimoto and Daisuke Uemura). 1.1 Introduction. 1.2 Alkylation of Tertiary Carbon Centers. 1.3 Cycloaddition to Alkenes. 1.4 Rearrangement Reactions. 1.5 Carbometallation Reactions. 1.6 C-H Functionalization Reactions. 1.7 Asymmetric Modification of Enantiotopic/Diastereotopic Substituents of Quaternary Carbon Centers. 1.8 Summary. 2 Important Pharmaceuticals and Intermediates (Johannes G. de Vries). 2.1 The Chirality of Drugs and Agrochemicals. 2.2 Steroids. 2.3 Pharmaceuticals and Agrochemicals Based on a-Dialkylated Amino Acids. 2.4 Azole Antimycotics. 2.5 Alkaloids. 2.6 HIV Inhibitors. 2.7 &beta -Lactam Antibiotics. 2.8 The Tetracyclines. 2.9 Summary and Outlook. 3 Aldol Reactions (Bernd Schetter and Rainer Mahrwald). 3.1 Introduction. 3.2 Metal Enolates. 3.3 Catalytic Aldol Additions. 3.4 Conclusions. 3.5 Note Added in Proof 79 4 Michael Reactions and Conjugate Additions (Angelika Baro and Jens Christoffers). 4.1 Introduction. 4.2 Chiral Bronstedt Bases. 4.3 Chiral Metal Complexes. 4.4 Chiral Auxiliaries. 5 Rearrangement Reactions (Annett Pollex and Martin Hiersemann). 5.1 Introduction. 5.2 Applications. 5.3 Summary. 6 Cycloaddition Reactions (Giovanni Desimoni and Givseppe Faita). 6.1 Introduction. 6.2 [2+1] Cycloaddition Reactions. 6.3 [2+2] Cycloaddition Reactions. 6.4 1,3-Dipolar Cycloaddition Reactions. 6.5 Diels-Alder Reactions. 6.6 Hetero-Diels-Alder Reactions. 6.7 Consecutive Cycloaddition Reactions. 7 Asymmetric Cross-coupling and Mizoroki-Heck Reactions (Louis Barriault and Effiette L. O. Sauer). 7.1 The Asymmetric Heck Reaction. 7.2 Metal-catalyzed Cross-coupling Reactions. 7.3 Summary. 8 Alkylation of Ketones and Imines (Diego J. Ramon and Miguel Yus). 8.1 Introduction. 8.2 Diastereoselective Additions. 8.3 Enantioselective Additions by Modulated Processes. 8.4 Enantioselective Additions by Promoted Processes. 9 Asymmetric Allylic Alkylation (Manfred Braun). 9.1 Introduction. 9.2 Electrophilic Allylic Alkylation. 9.3 Nucleophilic Allylic Alkylation. 9.4 Miscellaneous Methods. 9.5 Outlook. 10 Phase-Transfer Catalysis (Takashi Ooi and Keiji Maruoka). 10.1 Introduction. 10.2 Carbon-Carbon Bond Formation Through PTC. 10.3 Carbon-Heteroatom Bond Formation Through PTC. 10.4 Conclusion. 11 Radical Reactions (Kalyani Patil and Mukund P. Sibi). 11.1 Introduction. 11.2 Radical Cyclization. 11.3 Atom- and Group-transfer Cyclizations. 11.4 Intermolecular Radical Allylations. 11.5 Other Metallic Reagents. 11.6 Radical Reactions in the Solid State. 11.7 Conclusion. 11.8 Experimental. 12 Enzymatic Methods (Uwe T. Bornscheuer, Erik Henke, and Jurgen Pleiss). 12.1 Introduction. 12.2 Strategies for the Kinetic Resolution of Sterically Demanding Substrates. 12.3 Conclusion. Index.

Enantioselektiver Aufbau quartärer Stereozentren

Die stereoselektive Knupfung von C-C-Bindungen ist von zentraler Bedeutung fur die Synthese enantiomerenreiner Natur- und Wirkstoffe. Dank eines grosen Arsenals chiraler Auxiliare, Reagentien und Katalysatoren ist der Aufbau tertiarer Stereozentren in der Regel mit hoher Zuverlassigkeit moglich. Dagegen ist die Synthese komplexer Molekule mit quartaren Stereozentren eine wesentlich anspruchsvollere Aufgabe. Jede enantioselektive Synthesemethode demonstriert ihren Wert, wenn es um den Aufbau dieser vollstandig substituierten Kohlenstoffzentren geht. Der vorliegende Kurzaufsatz stellt exemplarisch einige neuere stochiometrische und katalytische Methoden zusammen, die ihre besondere Eignung mit dem enantioselektiven Aufbau von quartaren Stereozentren bewiesen haben.

Transition-Metal Catalysis of the Michael Reaction of 1,3-Dicarbonyl Compounds and Acceptor-Activated Alkenes

Transition-metal catalysis of the Michael reaction of 1,3-dicarbonyl compounds with acceptor-activated alkenes is introduced as a valuable alternative to the classic base catalysis of this reaction. Owing to the mild, neutral reaction conditions, the chemoselectivity of these processes is superior to that offered by the base catalysis, since the latter suffers from various unwanted side- and subsequent reactions, such as aldol cyclizations and ester solvolyses. The most efficient transition-metal catalysts do not require inert or anhydrous conditions, even solvents are unnecessary in some cases, and quantitative conversions can be achieved at room temperature. Furthermore, the development of transition-metal catalysts on solid supports has allowed very simple work-up procedures. Despite the extraordinary chemoselectivity, in terms of diastereoselectivity transition-metal catalysis gives better results than base catalysis only in a very few special cases. Also, in terms of enantioselectivity, results recently achieved with basic rare-earth metal catalysts cannot be reproduced by transition metals. Nevertheless, with transition-metal catalysis, even new reactivities can be observed, which have hitherto been unknown for base-catalyzed systems. For example, Michael donor molecules have been found to react in an unprecedented vinylogous fashion.

Construction of Quaternary Stereocenters by Nickel-Catalysis of Asymmetric Michael Reactions

Quaternary stereocenters were constructed with an enantioselectivity of up to 91% ee under aerobic conditions and at ambient temperature in the Michael reaction of β-dicarbonyl compounds and methyl vinyl ketone with Ni(OAc)2·4H2O and optically active trans-1,2-diaminocyclohexane as a chiral catalyst.

New auxiliaries for copper-catalyzed asymmetric Michael reactions: generation of quaternary stereocenters at room temperature.

Dialkyl amides of L-valine, L-isoleucine, and L-tert-leucine (2) are excellent chiral auxiliaries for the construction of quaternary stereocenters at ambient temperature. Enaminoesters 3, prepared from these auxiliaries 2 and Michael donors 1, undergo a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone (MVK, 4) to afford products 5 in 70-90% yield and 90-99% ee (enantiomeric excess). The exclusion of moisture or oxygen is not necessary. The auxiliaries 2 are readily available by standard procedures. After workup they can be recovered almost quantitatively.

Investigations into the metal species of the homogeneous iron(III) catalyzed Michael addition reactions

An investigation into the species formed in the first step of the solvent free homogeneous Michael reaction of alpha,beta-unsaturated ketones with 2-oxocyclopentanecarboxylate (1) is presented. This reaction is catalyzed by FeCl(3).6H(2)O (2) and Fe(ClO(4))(3).9H(2)O (3). EXAFS, XANES, Raman and UV-Vis studies were carried out to explain the experimentally found higher catalytic activity of Fe(ClO(4))(3).9H(2)O (3) compared to FeCl(3).6H(2)O (2). A very intense pre-edge peak is found for a 1.6 mol% solution of FeCl(3).6H(2)O (2) in 1, suggesting a tetrachloroferrate(III) compound to be present in this solution. This is proved by UV-Vis and Raman spectroscopy. The counterion of this anionic complex is an octahedral [Fe(III)(1-H)(2)(H2O2)](+) complex with two deprotonated 2-oxocyclopentanecarboxylate (1) as the chelating ligand, (1-H)(-), as suggested by the examination of the XANES region, the obtained coordination numbers from the EXAFS analysis and by UV-Vis and Raman spectroscopies. In summary, the anion-cation species [Fe(III)Cl(4)](-)[Fe(III)(-H)(2)(H2O2)](+) is formed with FeCl(3).6H(2)O (2), whereas in the case of Fe(ClO(4))(3).9H(2)O (3) XAFS, Raman and UV-Vis investigations suggest the presence of a complex of the form [Fe(III)(1-H)(2)(H2O2)](+)[ClO(4)](-). The obtained results are discussed to explain the reduced catalytic activity of FeCl(3).6H(2)O (2) in comparison to Fe(ClO(4))(3).9H(2)O (3).

Catalysis of the Michael reaction by iron(III): calculations, mechanistic insights and experimental consequences

The Fe III catalysed Michael reaction of b-oxo esters 1 with methyl vinyl ketone ( 2a ) and methyl acrylate ( 2b ) as acceptors is in vestigated. The proposed mechanism, based on experimental results, is supported for the first time by ab initio calculations. Thereby different Fe III complexes 4, deri ved from the catalyst and 1, with either neutral (H 2O) or anionic (a second diketonate 1) coligands are considered and their stabilities calculated. Ligand exchange in 4 by acceptors 2 gi ves intermediates 5 and subsequent C � /C bond formation affords complexes 6. Both 5 and 6 are found to be minima on the potential hypersurface and a pathway from 5 to 6 via transition states 7 could be identified. For the reaction of 4a (L � /H2O) with 2a , b no reacti vity difference was found. The anionic coligand, howe ver, causes a significant change in the reaction profile: due to the higher reaction barrier for the C � /C coupling for 2b (5d to 6d ) compared to 2a (5f to 6f ) a fast subsequent reaction and thus, catalytic turno ver is inhibited. # 2003 Else vier B.V. All rights reserved.

Synthesis of chiral tridentate oxazolines with thioether and heteroaryl donor groups and their application in the catalysis of asymmetric Michael reactions

Abstract Four chiral amino alcohols 1 derived from the natural α-amino acids L -cysteine and L -methionine have been converted with 2-thiophene and 2-pyridine carboxylic acid derivatives 2 to give eight tridentate oxazoline ligands 3a-d and 4a-d with a heteroaryl and a thioether donor function. In one case the coordination geometry at copper(II) was established by X-ray single crystal structure analysis. All ligands have been screened with 13 metal compounds 8 with regard to the asymmetric catalysis of the Michael reaction of a β-keto ester 6 with methyl vinyl ketone ( 7 ) to give an optimal result of 19% ee .

Copper-Catalyzed Asymmetric Michael Reactions with α-Amino Acid Amides: Synthesis of an Optically Active Piperidine Derivative

Quaternary stereocenters are obtained at room temperature in copper-catalyzed asymmetric Michael reactions with α-amino acid amides as chiral auxiliaries. L-Valine diethylamide was applied as a chiral auxiliary, and an optically active piperidine derivative was prepared with 97% ee. The optical purity of the product was established by GLC after cyclization to a hexahydroisoquinolonecarboxylate. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)