1 Stereodivergent Catalysis Irina P. Beletskaya,a Carmen Nájera,*b and Miguel Yusb aChemistry Department, M. V. Lomonosov Moscow State University, Leninskie Gory 1, 119992 Moscow, Russia bDepartamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO−CINQA), Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain This review covers diastereo- and enantiodivergent catalyzed reactions in acyclic and cyclic systems using metal complexes or organocatalysts. Among them, nucleophilic addition to carbon-carbon and carbon-nitrogen double bonds, a-functionalization of carbonyl compounds, allylic substitutions, and ring opening of oxiranes and aziridines are considered. The diastereodivergent synthesis of alkenes from alkynes is also included. Finally, stereodivergent intramolecular and intermolecular cycloadditions and other cyclizations are also reported. Contents 1. Introduction 2. Stereodivergence in Acyclic Systems 2.1. Nucleophilic Additions to Carbonyl Compounds 2.1.1. Addition of Organometallic Reagents 2.1.2. Aldol Reactions 2.1.2.1. Aldol Reactions Involving Metal Enolates 2.1.2.2. Organocatalyzed Aldol Reactions 2.1.3. Nitroaldol Reactions 2.1.4. Addition of Other Nucleophiles 2.1.5. Reduction of Ketones 2.1.5.1. Addition of Hydrides 2.1.5.2. Hydrogenation 2.1.5.3. Transfer Hydrogenation 2.1.5.4. Enzymatic Reduction * To whom correspondence should be addressed. Phone: +34 965903728. Fax: +34 965903549. E-mail: [email protected]. URL: www.ua.es/dqorg 2.2. Nucleophilic Addition to C=N Bonds 2.2.1. Addition of Organometallic Reagents 2.2.1.1. Imines 2 2.2.1.2. Nitrones 2.2.2. Mannich Reactions 2.2.2.1. Metal-Catalyzed Mannich Reactions 2.2.2.2. Organocatalyzed Mannich Reactions 2.2.3. Addition of Other Nucleophiles 2.2.4. Reduction of Ketimines 2.3. Addition to Alkenes 2.3.1. Conjugate Additions 2.3.1.1. Metal-Catalyzed Conjugate Additions 2.3.1.2. Organocatalyzed Conjugate Additions 2.3.2. Hydrogenation of Alkenes 2.3.2.1. Asymmetric Hydrogenation of Functionalized Alkenes 2.3.2.2. Asymmetric Hydrogenation of Unfunctionalized Alkenes 2.3.3. Hydroformylation of Alkenes 2.3.4. Other Addition Reactions 2.4. a-Functionalization of Carbonyl Compounds 2.5. Oxiranyl and Aziridinyl Ring Opening 2.6. Allylic Substitution Reactions 2.6.1. Carbon Nucleophiles 2.6.2. Nitrogen Nucleophiles 2.6.3. Oxygen Nucleophiles 2.6.4. Other Nucleophiles 2.7. Diastereodivergent Synthesis of Alkenes 2.7.1. Hydrometallation of Alkynes 2.7.1.1. Hydroboration of Alkynes 2.7.1.2. Hydrosilylation of Alkynes 2.7.1.3. Hydrostannation of Alkynes 2.7.2. Reduction of Alkynes 2.7.3. Other Reactions 3. Stereodivergence in Cyclic Systems 3.1. Addition to C=C Bonds 3.1.1. Conjugate Additions 3.1.2. Hydrogenation 3.1.3. Hydroboration 3.2. a-Functionalization of Carbonyl Compounds 3 3.3. Allylic Substitution Reactions 3.4. Other Reactions 4. Stereodivergence in Intramolecular Cyclizations 4.1. Intramolecular Nucleophilic Additions 4.1.1. Addition to Carbonyl Compounds 4.1.2. Addition to C=N Bonds 4.2. Intramolecular Conjugate Additions 4.3. Intramolecular Nucleophilic Substitution 4.4. Other Intramolecular Cyclizations 5. Stereodivergence in Intermolecular Cyclizations 5.1. [4+2] Cycloadditions 5.1.1. Diels-Alder Reactions 5.1.2. Hetero Diels-Alder Reactions 5.2. 1,3-Dipolar Cycloadditions 5.2.1. Nitrones 5.2.2. Azomethine Ylides 5.2.3. Diazo Compounds 5.2.4. Other [3+2] Cycloadditions 5.3. [2+2] Cycloadditions 5.4. Other Intermolecular Cyclizations 5.4.1. Five-Membered Rings 5.4.2. Six-Membered Rings 6. Conclusions Author Information Corresponding Authors Notes Biographies Acknowledgments Abbreviations References 1. INTRODUCTION Chemists have already synthesized ca. 40 million organic compounds and are able to synthesize almost any possible structure. Obviously, without solving selectivity 4 problems, no kind of chemistry is sufficiently efficient. However, there is also a problem of another kind, even more difficult to tackle: creating with minimum possible expenditure two stereoisomers, especially enantiomeric pure compounds. This problem is of paramount practical importance for pharmaceutical applications in order to evaluate the biological activity of both enantiomers. Normally, one can use separate reactions and starting compounds to prepare each diastereomer or enantiomer, but the simplest strategy is to use the same starting material and small variation of reaction conditions, including small changes in the structure of reagents, to obtain both stereoisomers in the individual form. Probably, one of the best solutions to the problem is provided by asymmetric catalysis by small changes of the catalyst and the reaction conditions as well. The concept of stereodivergence considers reactions which generate different stereoisomers starting from the same substrate, or practically the same, just by changing usually the catalyst, reagents or reaction conditions. Stereodivergence in organic synthesis has become in the last 30 years a fundamental strategy for the stereocontrol in synthetic processes. The synthetic potential of stereodivergent reactions has been demonstrated in the last 30 years in many fundamental reactions and synthetic strategies. This effect should be included in the concept of efficiency of a reaction as well as in atom economy process. According to the evolution of synthetic organic chemistry over the years, catalytic stereodivergent methods have become very important especially in the last 20 years. Metal-catalyzed and organocatalyzed processes are the main strategies in stereodivergent catalysis. Approaches to different diastereomers face the challenge of the relative configuration control of several stereocenters by a simple synthetic operation. Enantiodivergent reactions face the challenge of affording different enantiomers avoiding the use of opposite sources of chirality. These strategies have been applied to acyclic and cyclic substrates not only in inter- but also in intramolecular transformations and applied to the total synthesis of numerous natural products and related stereoisomeric compounds as well as bioactive molecules. For stereodivergent catalysis, structural modifications of the ligand or the metal in the case of metal complexes and in the organocatalysts are crucial. In addition, changes in the reaction conditions such as solvent, temperature, pressure, and additives, especially Lewis and Brønsted acids or bases, can also determine the stereodivergence. In the case of metal catalysis not only the ligand but also the metallic precursor used to form the catalytic species, even with the same element, can be an important strategy. The ligand-to-metal ratio has been also observed to switch the stereoselectivity. Chiral and achiral counteranions play an important role in the case of cationic metal complexes. Different diastereoselectivity has been also observed in the presence and in the absence of a catalyst and/or additive. Some small structural modifications in the substrate have been also observed to influence in the stereodivergence. Although important stereodivergent developments have been achieved, still there are not well-defined strategies, serendipity being the most important factor on these findings. However, this topic has been only partially covered.1-11 The aim of this review 5 is to overview, for the first time, this efficiency concept in synthetic organic chemistry to get some light about which reactions are good candidates for stereodivergent catalytic transformations. Although, asymmetric catalytic reactions have been mainly presented, some asymmetric processes using chiral substrates and achiral catalysts are also considered. We think that it would be very useful to have a comprehensive overview about this subject considering that it has a big impact in the development of stereocontrolled reactions in total synthesis of natural products and in general of biologically active compounds. We expect that this comprehensive information will be of interest for all the chemical community, both at the academia and at the industrial level. 2. STEREODIVERGENCE IN ACYCLIC SYSTEMS Acyclic systems bearing a functional group susceptible of synthetic transformation are widely applied in organic synthesis. Multiple C=X bonds such as carbonyl compounds and imines are able to generate a new stereocenter by nucleophilic addition of different types of nucleophiles through many fundamental processes for the acyclic control of several stereocenters. In addition, carbonyl compounds can also be functionalized at the a-position. In the case of carbon-carbon multiple bonds, conjugate additions to electron- deficient olefins is considered the most important reaction for the functionalization of the β-position of carbonyl compounds and related systems. Enantioselective hydrogenation and hydroformylation of alkenes by means of chiral complexes are important industrial processes for the synthesis of a-amino acids and aldehydes, respectively. The ring opening of epoxides by nucleophiles allows the synthesis of 1,2- difunctionalized compounds. Pd- and Ir-catalyzed allylations of carbon- and heteronucleophiles are excellent strategies for the enantio- and diastereodivergent synthesis of acyclic systems bearing a C=C bond in the aliphatic chain. Finally, in this section diastereodivergent methods for the synthesis of alkenes mainly based on the hydrometallation, and reduction of alkynes will be considered. 2.1. Nucleophilic Additions to Carbonyl Compounds In this section, the stereodivergent addition of different nucleophiles