New Frontiers in Peptide Catalysis Multicatalysis, Challenging Reactions, and the Importance of Dispersion Interactions Dissertation zur Erlangung des Doktorgrades der Naturwissenschaftlichen Fachbereiche (Fachbereich 08 – Biologie und Chemie) der Justus-Liebig-Universität Gießen vorgelegt von Raffael Christoph Wende aus Aßlar Gießen 2016 Die vorliegende Arbeit wurde in der Zeit von März 2011 bis Juni 2016 am Institut für Organische Chemie der Justus-Liebig-Universität Gießen unter Anleitung von Herrn Prof. Dr. Peter R. Schreiner, Ph.D. angefertigt. Mein aufrichtiger Dank gebührt meinem Doktorvater, Herrn Prof. Dr. Peter R. Schreiner, für die Vergabe dieses interessanten und aktuellen Forschungsthemas, die gewährte Freiheit bei dessen Bearbeitung, sowie die vielen anregenden und lehrreichen Diskussionen. für Lena, Nele, Carlotta und Janne „So eine Arbeit wird eigentlich nie fertig, man muss sie für fertig erklären, wenn man nach Zeit und Umständen das möglichste getan hat.“ – Johann Wolfgang von Goethe – Eidesstattlich Erklärung nach §17 der Promotionsordnung „Ich erkläre: Ich habe die vorgelegte Dissertation selbständig und ohne unerlaubte fremde Hilfe und nur mit den Hilfen angefertigt, die ich in der Dissertation angegeben habe. Alle Textstellen, die wörtlich oder sinngemäß aus veröffentlichten Schriften entnommen sind, und alle Angaben, die auf mündlichen Auskünften beruhen, sind als solche kenntlich gemacht. Bei den von mir durchgeführten und in der Dissertation erwähnten Untersuchungen habe ich die Grundsätze guter wissenschaftlicher Praxis, wie sie in der „Satzung der Justus-Liebig-Universität Giessen zur Sicherung guter wissenschaftlicher Praxis“ niedergelegt sind, eingehalten.“ Ort, Datum Unterschrift Table of Contents Publications in Peer Reviewed Journals ………………………………………………… 1 Motivation and Research Objectives .……………………………………………………. 3 Summary ..…………………………………………………………………………………… 5 Zusammenfassung .………………………………………………………………………… 9 Chapter I – Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis … 13 1. Introduction 17 2. Multicatalysis – A Survey 19 2.1 Taxonomy of One-Pot Reactions Using Multiple Catalysts 19 2.2 Reaction Efficiency and Sustainability Aspects of Multicatalysis 22 3. Secondary Amine Catalysts 25 3.1 The Beginnings of Organomulticatalysis – Merging Iminium and Enamine Catalysis 25 3.2 Combinations of Secondary Amine Catalysts with Brønsted Acids and Bases 37 3.3 Miscellaneous Combinations with Secondary Amines 43 4. N-Heterocyclic Carbene Catalysts 47 4.1 Combinations with Secondary Amine Catalysts 47 4.2 Miscellaneous Combinations with N-Heterocyclic Carbenes 59 5. Thiourea Catalysts 62 5.1 Combinations of Thioureas with Secondary Amine Catalysts 62 5.2 Combination of Thiourea Catalysts with Brønsted Acids and Bases 65 6. Non-Natural Oligopeptides for Acyl Transfer Reactions 70 7. Multicatalyst Approaches 72 7.1 Miscellaneous Examples of Oligopeptide Catalyzed Reactions 74 8. Conclusions 76 9. Notes and References 77 Chapter II – Lipophilic Oligopeptides for Chemo- and Enantioselective Acyl Transfer Reactions onto Alcohols .………………………………… 85 1. Introduction 86 2. Results and Discussion 89 2.1 Catalyst Screening Using the Acylative KR of trans-Cyclohexane-1,2-diol as Test Reaction 89 2.2 Substrate Scope for Peptide 12b-Catalyzed Acylations 94 2.3 Chemoselectivity of 12b 97 2.4 Mechanistic Model for the Enantioselective Acylation with 12b 99 2.5 Alternative Electrophiles in Group Transfer Reactions Catalyzed via Peptide 12b 101 3. Conclusion and Outlook 107 4. Experimental Section 108 4.1 Availability and Characterization of the Catalysts 108 4.2 Chiral-GC Properties and Characterization Data of the Alcohols 114 4.3 Procedure for the Competitive Catalytic Run with Alcohols 1, 41, 42, and 43 124 4.4 Description of the Preparative Kinetic Resolution Experiment of (±)-1 with Boc2O 126 4.5 Sulfonylation of rac-1 Using 12b as Catalyst 127 4.6 Sulfonylation Test Reactions 127 4.7 Competition Experiment with Different Electrophiles 129 5. References 130 Chapter III – En Route to Multicatalysis: Kinetic Resolution of trans-Cyclo- alkane-1,2-diols via Oxidative Esterification .………………………… 137 Chapter IV – Functionality, Effectiveness, and Mechanistic Evaluation of a Multicatalyst-Promoted Reaction Sequence by Electrospray Ionization Mass Spectrometry …………………………………………… 147 1. Introduction 148 2. Results and Discussion 149 3. Conclusion 154 4. Experimental Section 154 5. References 156 Chapter V – Towards the Multicatalytic Synthesis of 2-Deoxygalactosides: Peptide-Catalyzed Regioselective Acetylation .………………………… 161 1. Introduction 162 2. Results and Discussion 164 3. Conclusions and Outlook 177 4. Experimental Section 178 4.1 Synthesis of Mono- and Diacetylated Carbohydrate Derivatives for Elucidation of Product Distribution and Conversion 179 4.2 Availability of Catalysts 182 4.3 Description of Catalytic Experiments 189 4.4 Computational Details 190 4.5 NMR Spectra 197 5. References 204 Chapter VI – The Enantioselective Dakin–West Reaction …………………………… 207 1. The Enantioselective Dakin–West Reaction 210 1.1 References 216 2. Supporting Information 218 2.1 General Remarks 218 2.2 Starting Materials and Reaction Intermediates 219 2.2.1 Synthesis of starting materials 219 2.2.2 Synthesis of possible reaction intermediates 225 2.3 Synthesis of Racemic Products 228 2.4 Availability of Catalysts 240 2.5 Catalytic Experiments 254 2.5.1 Reaction optimization 254 2.5.2 Catalyst screening 257 2.5.3 Preparative enantioselective Dakin–West reaction 259 2.6 Mechanistic Investigations 262 2.6.1 Computational details 262 2.6.2 Additionally performed reactions towards the investigation of the enantioselective decarboxylative protonation 266 2.7 NMR Spectra 269 2.8 References 307 Chapter VII – Unpublished Results ……………………………………………………… 309 1. The Importance of Side-Chain Interactions 311 2. Binding of the Transient Enolate 314 3. Synthesis of Protease Inhibitor Warheads 318 4. Enantioselective Decarboxylative Protonation and the Acetylation of In Situ Formed Azlactones 320 5. Conclusions and Outlook 324 6. Experimental Section 326 6.1 General Remarks 326 6.2 Availability of Starting Materials 327 6.3 Synthesis of Racemic Products 332 6.4 Opening of C-Acetylated Azlactones with Different Nucleophiles 337 6.5 Availability of Catalysts 342 6.6 Procedures for Catalytic Experiments 343 6.7 Energies and Cartesian Coordinates for Computed Structures 344 6.8 NMR Spectra 355 7. References 371 Acknowledgement ………………………………………………………………………… 373 New Frontiers in Peptide Catalysis 1 Publications in Peer Reviewed Journals Raffael C. Wende, Alexander Seitz, Dominik Niedek, Sören M. M. Schuler, Christine Hofmann, Jonathan Becker, Peter R. Schreiner, The Enantioselective Dakin–West Reaction, Angew. Chem. Int. Ed. 2016, 55, 2719–2723; Angew. Chem. 2016, 128, 2769–2773. M. Wasim Alachraf, Raffael C. Wende, Sören M. M. Schuler, Peter R. Schreiner, Wolfgang Schrader, Functionality, Effectiveness, and Mechanistic Evaluation of a Multicatalyst-Promoted Reaction Sequence by Electrospray Ionization Mass Spectrometry, Chem.–Eur. J. 2015, 21, 16203–16208. Christine Hofmann, Sören M. M. Schuler, Raffael C. Wende, Peter R. Schreiner, En Route to Multicatalysis: Kinetic Resolution of trans-Cycloalkane-1,2-diols via Oxidative Esterification, Chem. Commun. 2014, 50, 1221–1223. Christian E. Müller, Daniela Zell, Radim Hrdina, Raffael C. Wende, Lukas Wanka, Sören M. M. Schuler, P. R. Schreiner, Lipophilic Oligopeptides for Chemo- and Enantioselective Acyl Transfer Reactions onto Alcohols, J. Org. Chem. 2013, 78, 8465–8484. Raffael C. Wende, Peter R. Schreiner, Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis, Green Chem. 2012, 14, 1821–1849. Radim Hrdina, Christian E. Müller, Raffael C. Wende, Lukas Wanka, Peter R. Schreiner, Enantiomerically Enriched trans-Diols from Alkenes in One Pot: A Multicatalyst Approach, Chem. Commun. 2012, 48, 2498–2500. Christian E. Müller, Radim Hrdina, Raffael C. Wende, Peter R. Schreiner, A Multicatalyst System for the One-Pot Desymmetrization/Oxidation of meso-1,2-Alkane Diols, Chem.–Eur. J. 2011, 17, 6309–6314. adim Hrdina, hristian . ller, Raffael C. Wende, Katharina M. Lippert, Mario Benassi, Bernhard Spengler, Peter . Schreiner, Silicon−(Thio)urea Lewis Acid atalysis, J. Am. Chem. Soc. 2011, 133, 7624–7627. Christian M. Kleiner, Luise Horst, Christian Würtele, Raffael Wende, Peter R. Schreiner, Isolation of the key intermediates in the catalyst-free conversion of oxiranes to thiiranes in water at ambient temperature, Org. Biomol. Chem. 2009, 7, 1397–1403. New Frontiers in Peptide Catalysis 3 Motivation and Research Objectives Nature’s biosynthetic machinery undeniably is a paragon in terms of efficiency, reactivity as well as selectivity and consequently has fascinated and challenged alike generations of chemists. This extraordinary effectiveness often relies on the direct coupling of concurrent reaction steps, thus allowing the assembly of complex molecules from readily available starting materials. Mammalian fatty acid synthase as a representative model is an outstanding example for this assembly line approach (Figure 1). This multienzyme complex catalyzes all necessary reaction steps of fatty acid biosynthesis consisting of a transesterification and a number of consecutive reduction, elimination, and condensation steps (Figure 1; see: T. Maier, S. Jenni, N. Ban, Science 2006, 311, 1258–1262 and M. Leibundgut, T. Maier, S. Jenni, N. Ban, Curr. Opin. Struct. Biol. 2008, 18, 714–725). The development and application of novel, efficacious catalysts to achieve the performance of enzymes is an unambiguously important issue at the forefront of synthetic organic chemistry. Consequently, the application of small organic molecules for the acceleration of chemical reactions, i.e., organocatalysis, was a milestone in the field of catalysis. In the early days of asymmetric organocatalysis, chemists delved into the chiral pool making use of, e.g., simple amino acids as chiral catalysts. Various different catalyst types were subsequently developed and laid the foundation for this nowadays vibrant area of research. Later, the abovementioned principles of biosynthesis were also applied to catalysis, enabling the synthesis of complex molecular frameworks from simple starting materials (see Chapter I). However, the possibilities of using distinct organocatalysts for one-pot reactions still are limited, due to compatibility issues, the proper reaction sequence, or regio- and chemoselectivity, amongst other difficulties, that become apparent with an increasing number of catalyzed steps. Therefore, most examples rely on the combination of only two catalysts. The application of oligopeptides as catalysts in order to mimic the performance of enzymes is a particularly elegant approach to asymmetric chemical synthesis. Arguably, such catalysts can be seen as “minimal” artificial enzymes as they often rely on comparable activation modes, reaction types as well as catalyst–substrate interactions (e.g., hydrogen bonding, electrostatic or dispersion interactions). The diversity of available amino acids (natural and synthetic), well- established coupling techniques, and the ease of modification makes peptides ideally suited for the design of potent catalysts. Moreover, the possible incorporation of orthogonal (i.e., independent) catalytic moieties into a single peptide backbone may not only overcome some of the potential problems discussed above, but even lead to enhanced reactivities and selectivities. Indeed, such multicatalysts have now been realized. Motivation and Research Objectives 4 Figure 1. Top: Crystal structure of mammalian fatty acid synthase as ribbon representation; the structure was obtained from the RCSB Protein Data Bank (PDB code: 2CF2) and was generated with JSmol. Bottom: Complete catalytic cycle for fatty acid biosynthesis. CoA = coenzyme A; ACP = acyl carrier protein; NADPH = nicotinamide adenine dinucleotide phosphate; TE = thioesterase. The research presented in this doctoral thesis is dedicated to the development of synthetic oligopeptides and their application in enantioselective concurrent “assembly line” approaches and as catalysts for demanding reactions. New Frontiers in Peptide Catalysis 5 Summary Chapter I Published as: R. C. Wende and P. R. Schreiner, Green Chem. 2012, 14, 1821–1849 The first part of this thesis is a Critical Review on multicatalysis that is used as a general introduction to this rapidly growing field of research. We define the different types of one-pot reactions employing multiple catalysts, introduce the concept of retrocatalysis and discuss the significant advantages and potential problems associated with multicatalysis. Reactions using combinations of secondary amines, N-heterocyclic carbenes and thiourea catalysts, amongst others, are presented. Finally, we introduce our previous achievements in multicatalysis and disclose the development of the first peptidic multicatalyst. Chapter II Published as: C. E. Müller, D. Zell, R. Hrdina, R. C. Wende, L. Wanka, S. M. M. Schuler, P. R. Schreiner, J. Org. Chem. 2013, 78, 8465–8484 This chapter serves as an introduction to peptide catalysis in general and gives detailed insights into our catalyst design concept. The oligopeptide presented herein, was previously developed in our group but recently provided the basis for further developments, such as multicatalytic reactions and the expansion to the first organic multicatalysts (also see Chapter I). From a library of various peptides Boc-L-Pmh- A Gly-L-Cha-L-Phe-OMe was identified as an remarkably efficient catalyst for the kinetic resolution of trans-cycloalkane-1,2-diols. The ee values are typically >99% (for the remaining diols) corresponding to S-values >50. Whereas the catalyst is also highly selective for the desymmetrization of meso-alkane-1,2-diols other substrates, e.g., 1,3-diols, provide only low selectivities. The extraordinary chemoselectivity of the peptide is also revealed by competition experiments. Thus, this small tetrapeptide already shows a behavior that may be compared with enzymes. Moreover, computational investigations on complexes of the acylium ion of the catalyst with the fast reacting enantiomer of trans- cyclohexan-1,2-diol were performed. The exceptionally high selectivities are made possible by the interplay of the aminoadamantane carboxylic acid that froms a dynamic binding pocket as well as by attractive dispersion interactions of the cyclohexyl residue with the substrate. Summary 6 Chapter III Published as: C. Hofmann, S. M. M. Schuler, R. C. Wende, P. R. Schreiner, Chem. Commun. 2014, 50, 1221–1223 A multicatalytic enantioselective oxidative esterification is reported. The combination of TEMPO as oxidation catalyst and p-nitrobenzoic acid as additive allows the oxidation of a variety of aldehydes to their mixed anhydrides. These are enantioselectively transferred by the peptide catalyst described in Chapter II onto trans‐cycloalkane‐1,2‐diols with up to 94% ee for the recovered diol and 93% ee for the corresponding acylated derivative. The reaction progress and the formation of the mixed as well as symmetric anhydrides was followed by NMR spectroscopy. The reaction could also be performed with our previously developed multicatalyst (see Chapter I) instead of the two individual catalysts. Chapter IV Published as: M. W. Alachraf, R. C. Wende, S. M. M. Schuler, P. R. Schreiner, W. Schrader, Chem.–Eur. J. 2015, 21, 16203–16208 In cooperation with Prof. Dr. Wolfgang Schrader a multicatalyst incorporating π-methyl histidine and a diacid as catalytic moieties was studied by high-resolution mass spectrometry. The peptide was previously used for a one-pot epoxidation/hydrolysis/kinetic resolution sequence starting from simple alkenes and affording enantiomerically enriched trans-cycloalkane-1,2-diols (see Chapter I). Although the selectivities are synthetically useful (64 – 99% ee for the remaining diol) they can not compete with the selectivities achieved with the corresponding tetrapeptide alone. All important intermediates have been identified and characterized. It was found that the epoxidation step also leads to a partial oxidation of the imidazole moiety and consequently to a reduced catalytic performance of the multicatalyst. New Frontiers in Peptide Catalysis 7 Chapter V Unpublished results We envisaged the development of a multicatalytic reaction sequence for the synthesis of 2-de- oxygalactosides. Our approach is based on the partial protection of carbohydrates that may subsequently act as glycosyl donors. We identified Boc-D-Pmh- A Gly-L-Val-L-Phe-OMe to be a highly regioselective catalyst in the acetylation of methyl 4,6-O-benzylidene-α-D-gluco- pyranoside. In comparison to simple N-methylimidazole, which mostly leads to the acetylation of the 3-hydroxy group on the substrate (2-OAc/3-OAc/diacetylated: 22:70:8; 93% conversion), the peptide preferentially gives the 2-acetylated product (2-OAc/3-OAc/diacetylated: 85:9:6; >95% conversion). Thus, this catalyst is not simply enhancing but completely overriding the inherent reactivity of the substrate. Chapter VI Published as: R. C. Wende, A. Seitz, D. Niedek, S. M. M. Schuler, C. Hofmann, J. Becker, P. R. Schreiner, Angew. Chem. Int. Ed. 2016, 55, 2719–2723; Angew. Chem. 2016, 128, 2769–2773 The Dakin–West reaction is one of the most viable methods for the preparation of α-acylamido ketones directly from the corresponding primary α-amino acids. Although this reaction was known for decades no enantioselective variant has been reported previously. We found that the complexity of the mechanism of the reaction requires the separation of the two crucial steps: the acetylation of the azlactone intermediate and the final decarboxylation step. Under optimized reaction conditions the Pmh-containing peptide catalysts act as a Lewis base in the first step and as a Brønsted base in a final enantioselective decarboxylative protonation. With the best-working catalyst selectivities with up to 58% ee were achieved with good yields. Two of the obtained products were recrystallized once to achieve up to 84% ee. Importantly, computational investigations further proved the importance of dispersion interactions in the enantioselectivity determining reaction step. Summary 8 Chapter VII Unpublished results The last chapter describes further experiments regarding the enantioselective Dakin–West reaction. Computational and experimental investigations were performed to provide further evidence for attractive dispersion interactions and to give insights how the selectivities could be enhanced. Leucine derivatives with diverse protecting groups and different anhydrides were explored. Although the previously observed selectivities could not be increased, the performed experiments support our proposal for substrate-binding by the catalyst in the stereochemistry determining reaction step. Moreover, a potential synthesis of protease inhibitors applying the Dakin–West reaction is reported. Both important reaction steps, the enantioselective decarboxylative protonation and the acetylation of the azlactone, are studied individually and may lead to additional developments. New Frontiers in Peptide Catalysis 9 Zusammenfassung Kapitel I Veröffentlicht als: R. C. Wende and P. R. Schreiner, Green Chem. 2012, 14, 1821–1849 Der erste Teil der vorliegenden Doktorarbeit ist eine kritische Übersicht zur Multikatalyse und dient als Einleitung in dieses sich schnell entwickelnde Forschungsfeld. Wir definieren die verschiedenen Typen von Eintopfreaktionen mit mehreren Katalysatoren, stellen das Konzept der Retrokatalyse vor, und diskutieren die signifikanten Vorteile und potentiellen Probleme, welche mit der Multikatalyse assoziiert werden. Kombinationen von sekundären Aminen, N-heterocyclischen Carbenen und Thioharnstoffkatalysatoren, neben weiteren anderen, werden präsentiert. Schließlich stellen wir unsere bisherigen Erfolge in der Multikatalyse und die Entwicklung des ersten peptidbasierten Multikatalysators vor. Kapitel II Veröffentlicht als: C. E. Müller, D. Zell, R. Hrdina, R. C. Wende, L. Wanka, S. M. M. Schuler, P. R. Schreiner, J. Org. Chem. 2013, 78, 8465–8484 Dieses Kapitel dient als generelle Einleitung in die Peptidkatalyse und gewährt einen detaillierten Einblick in unser Konzept des Katalysatordesigns. Das hier präsentierte Oligopeptid wurde zuvor in unserer Arbeitsgruppe entwickelt und bildete jüngst die Basis für weitere Entwicklungen, wie multikatalytische Reaktionen und die Weiterentwicklung des ersten peptidischen Multikatalysators (siehe auch Kapitel I). Aus einer Bibliothek unterschiedlicher Peptide wurde Boc-L-Pmh- A Gly-L-Cha-L-Phe-OMe als bemerkenswert effizienter Katalysator für die kinetische Racematspaltung von trans-Cycloalkan- 1,2-diolen identifiziert. Die Enantiomerenüberschüsse liegen typischerweise bei >99% (für das verbliebene Diol), was sich in S-Werten >50 äußert. Obwohl der Katalysator auch hochselektiv für die Desymmetrisierung von meso-Alkan-1,2-diolen ist, werden für andere Substrate, z.B. 1,3-Diole, nur geringe Selektivitäten erhalten. Die außergewöhnliche Chemoselektivität dieses Peptides wird zudem durch Konkurrenzexperimente offenbart. Dieses kleine Tetrapeptid zeigt somit bereits ein Verhalten, welches mit dem von Enzymen vergleichbar ist. Zudem wurden computerchemische Untersuchungen der Komplexe des Katalysator Acyliumions mit dem schnell reagierenden Enantiomer von trans-Cyclohexan-1,2-diol durchgeführt. Die außer- ordentlich hohen Selektivitäten werden durch das Zusammenspiel der Aminoadamantan- Zusammenfassung 10 carbonsäure, welche eine dynamische Bindungstasche ausbildet, und attraktive Dispersions- wechselwirkungen des Cyclohexylrestes mit dem Substrat ermöglicht. Kapitel III Veröffentlicht als: C. Hofmann, S. M. M. Schuler, R. C. Wende, P. R. Schreiner, Chem. Commun. 2014, 50, 1221–1223 Eine multikatalytische enantioselektive oxidative Veresterung wird beschrieben. Die Kombination von TEMPO als Oxidationskatalysator und p-Nitrobenzoesäure als Additiv erlauben die Oxidation einer Reihe von Aldehyden zu den entsprechenden gemischten Anhydriden. Diese werden enantioselektiv durch den in Kapitel II beschriebenen Katalysator auf trans-Cycloalkan-1,2-diole mit bis zu 94% ee für das zurückgewonnene Diol und 93% ee für das entsprechende acylierte Derivat übertragen. Der Reaktionsverlauf und die Bildung des gemischten und symmetrischen Anhydrides wurden NMR-spektroskopisch verfolgt. Zudem konnte die Reaktion auch mit unserem zuvor entwickelten Multikatalysator (siehe Kapitel I), anstelle der beiden individuellen Katalysatoren, durchgeführt werden. Kapitel IV Veröffentlicht als: M. W. Alachraf, R. C. Wende, S. M. M. Schuler, P. R. Schreiner, W. Schrader, Chem.–Eur. J. 2015, 21, 16203–16208 In Kooperation mit Prof. Dr. Wolfgang Schrader wurde ein mit π-Methylhistidin und einer Disäure bestückter Multikatalysator mithilfe von hochauflösender Massenspektrometrie untersucht. Das Peptid wurde zuvor für eine Reaktionssequenz bestehend aus Epoxidierung, Hydrolyse und kinetischer Racematspaltung verwendet, welche es erlaubt enantiomeren- angereichterte trans-Cycloalkan-1,2-diole ausgehend von einfachen Alkenen zu erhalten (siehe Kapitel I). Obwohl synthetisch akzeptable Selektivitäten (64 – 99% ee für das verbleibende Diol) beobachtet werden, reichen diese nicht an die Werte heran, die bei Verwendung des entsprechenden Tetrapeptides alleine erhalten werden. Alle wichtigen Intermediate wurden identifiziert und charakterisiert. Es konnte gezeigt werden, dass der Epoxidierungsschritt teilweise auch zu einer Oxidation des Imidazols und folglich zu einer herabgesetzten katalytischen Aktivität des Multikatalysators führt. New Frontiers in Peptide Catalysis 11 Kapitel V Unveröffentlichte Ergebnisse Wir fassten die Entwicklung einer multikatalytischen Reaktionssequenz für die Synthese von 2-Deoxygalaktosiden ins Auge. Unser Ansatz basiert hierbei auf der partiellen Schützung von Kohlenhydraten, welche anschließend als Glykosyldonor fungieren könnten. Boc-D-Pmh- A Gly- L-Val-L-Phe-OMe wurde als Katalysator für die regioselektive Acetylierung von Methyl-4,6-O- benzyliden-α-D-glucopyranosid identifiziert. Im Vergleich zu einfachem N-Methylimidazol, welches hauptsächlich zur Acetylierung der 3-Hydroxygruppe des Substrates führt (2-OAc/ 3-OAc/diacetyliert: 22:70:8; 93% Umsatz), wird mit dem Peptid überwiegend das 2-acetylierte Produkt gebildet (2-OAc/3-OAc/diacetyliert: 85:9:6; >95% Umsatz). Somit verstärkt dieser Katalysator nicht einfach die inhärente Reaktivität des Substrates, sondern setzt sich vollständig über diese hinweg. Kapitel VI Veröffentlicht als: R. C. Wende, A. Seitz, D. Niedek, S. M. M. Schuler, C. Hofmann, J. Becker, P. R. Schreiner, Angew. Chem. Int. Ed. 2016, 55, 2719–2723; Angew. Chem. 2016, 128, 2769– 2773 Die Dakin–West– eaktion ist eine der brauchbarsten ethoden zur Darstellung von α-Acyl- amidoketonen ausgehend von den entsprechenden primären α-Aminosäuren. Obwohl diese Reaktion seit Jahrzehnten bekannt ist, wurde zuvor keine enantioselective Variante beschrieben. Wir fanden, dass die Komplexität des Reaktionsmechanismus eine Trennung der beiden entscheidenden Schritte erfordert: der Acetylierung des intermediär gebildeten Azlactons und des abschließenden Decarboxylierungsschrittes. Unter optimierten Reaktionsbedingungen fungieren die Pmh-enthaltenden Peptidkatalysatoren als eine Lewisbase im ersten Schritt und als eine Brønstedbase in der finalen enantioselektiven decarboxylativen Protonierung. Mit dem besten Katalysator konnten Selektivitäten von bis zu 58% ee bei guten Ausbeuten erzielt werden. Durch einfache Umkristallisation von zwei der erhaltenen Produkte konnten die Selektivitäten auf bis zu 84% ee gesteigert werden. Durch computerchemische Untersuchungen konnte auch hier die Bedeutung von Dispersionswechselwirkungen für den enantioselektivitäts- bestimmenden Reaktionsschritt nachgewiesen werden. Zusammenfassung 12 Kapitel VII Unveröffentlichte Ergebnisse Im letzten Kapitel werden weitere Experimente zur Dakin–West–Reaktion vorgestellt. Computerchemische und experimentelle Untersuchungen wurden durchgeführt um attraktive Dispersionwechsel-wirkungen nachzuweisen und einen Einblick zu erhalten, wie die Selektivitäten verstärkt werden könnten. Leucin-Derivate mit diversen Schutzgruppen und unterschiedliche Anhydride wurden untersucht. Obwohl die zuvor beobachteten Selektivitäten nicht weiter erhöht werden konnten, stützen die durchgeführten Experimente unsere vorgeschlagene Bindung des Substrates durch den Katalysator im selektivitätsbestimmenden Reaktionsschritt. Zudem wird die Anwendung der Dakin–West–Reaktion für eine potentielle Synthese von Proteaseinhibitoren vorgestellt. Die beiden entscheidenden Reaktionsschritte, die enantioselektive decarboxylative Protonierung und die Acetylierung der Azlactone, werden separat untersucht und könnten zu weiteren Entwicklungen führen. New Frontiers in Peptide Catalysis 13 – Chapter I – New Frontiers in Peptide Catalysis 15 Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis Raffael C. Wende and Peter R. Schreiner, Green Chem. 2012, 14, 1821–1849 “Reproduced from Green Chemistry 2012, 14, 1821–1849 with permission from The Royal Society of Chemistry.” Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 16 Abstract The evolution of organocatalysis led to various valuable approaches, such as multicomponent as well as domino and tandem reactions. Recently, organomulticatalysis, i.e., the modular combination of distinct organocatalysts enabling consecutive reactions to be performed in one pot, has become a powerful tool in organic synthesis. It allows the construction of complex molecules from simple and readily available starting materials, thereby maximizing reaction efficiency and sustainability. A logical extension of conventional multicatalysis is a multi- catalyst, i.e., a catalyst backbone equipped with independent, orthogonally reactive catalytic moieties. Herein we highlight the impressive advantages of asymmetric organomulticatalysis, examine its development, and present detailed reactions based on the catalyst classes employed, ranging from the very beginnings to the latest multicatalyst systems. New Frontiers in Peptide Catalysis 17 1. Introduction The development of resource-efficient and sustainable chemical methodologies and processes has become one of the most important goals of synthetic organic chemistry in the 21 st century. Various attempts were undertaken to minimize the adverse environmental impact and maximize the efficiency of chemical reactions. As one of numerous advances, multicatalysis, i.e., the modular combination of distinct catalysts for consecutive transformations in a single flask, emerged as a highly valuable tool for the construction of complex molecular frameworks from simple and readily available starting materials. [1] Since its fundamental “renaissance” organocatalysis became a vibrant area of research and grew rapidly to become a pillar in organic synthesis. [2] Further developments mainly focused on novel catalyst classes and activation modes, and their use in iterative single step operations. [2] Simultaneously, multistep processes, such as domino/cascade and tandem reactions, [3-5] as well as asymmetric multicomponent reactions [6] gained increasing attention and have soon been adopted to organocatalysis. [5,7-9] Multicatalysis may condense the operational simplicity and synthetic efficiency provided by the aforementioned concepts to allow the rapid synthesis of even complex molecules in one pot syntheses. [10-12] However, this concept only recently started flourishing in the field of organocatalysis. [1] An approach that is even rarer and a logical extension of conventional multicatalysis is a multicatalyst [13] (‘assembly line’ approach), i.e., an arbitrary catalyst backbone equipped with independently reactive catalytic moieties, which are separated by an appropriate spacer (Figure 1). The design of a multicatalyst system hinges on the concept of retrosynthesis for assembling complex molecules. Whereas in retrosynthesis the target structure is disassembled into synthons (as equivalents for starting materials or intermediates) and steps, the development of a multicatalyst relies on the judicious choice of Figure 1. Schematic representation of a multicatalyst and the concept of retrocatalysis. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 18 catalytic moieties that can be brought together in a single catalyst structure. Such a multicatalyst should then be able to allow the synthesis of the target structure from simple starting materials in a sequence of highly chemoselective reactions in one pot. This systematic strategy toward reverse catalyst design is therefore complementary to retrosynthesis (a target structure oriented approach) and may therefore be labelled as retrocatalysis (a reaction step oriented approach) [14] to emphasize their close conceptional relationship (Figure 1). The main challenge in the development of multicatalytic reactions is to ensure compatibility of reactants, intermediates and catalysts throughout the whole reaction sequence. Many organo- catalytic reactions are nowadays well understood. Their underlying activation modes, reaction pathways and intermediates have been precisely elucidated, experimentally [15] as well as theoretically, [16] for a variety of reactions, allowing reasonable predictability for the realization of organomulticatalysis (indicating that the reaction is purely organocatalyzed). In order to circumvent compatibility problems, the following strategies have been adopted: the use of obviously compatible catalysts, sequential addition of catalysts, and the site-isolation or phase- separation of catalysts. Additional challenges appear in the case of a multicatalyst. The choice of a proper catalyst backbone should allow easy preparation, alteration as well as modification. Moreover, appropriate spacers may be crucial for the separation of the catalytically active moieties. The envisioned multicatalyst must be compatible with all required reaction conditions and intermediates. Interestingly, many examples of multicatalysis have not been recognized as such. Amongst other things, this may be due to the following reasons: not taking into account simple achiral Brønsted acids and bases as organocatalysts and inconsistent terminology (many multicatalytic reactions are lost amidst publications dealing with domino or tandem reactions). For this reason we will first define the prevalent types of one-pot organocatalysis employing multiple steps, illustrated with selected examples, before examining the advantages of multicatalysis and discussing representative examples. New Frontiers in Peptide Catalysis 19 2. Multicatalysis – A Survey 2.1 Taxonomy of One-Pot Reactions Using Multiple Catalysts There are many examples of one-pot reactions where multiple organocatalysts are employed, [10,11,17] and these have been termed cooperative catalysis, [18] multifunctional catalysts, [19] and dual catalysis. [20] For simplicity, we schematically depict the catalytic cycles for a general reaction of two starting materials (A and B) affording a product (P). As evident from this simplified picture, multicatalysis should be clearly distinguished from cooperative catalysis where neither catalyst one nor catalyst two are sufficient to perform a desired reaction individually, and only a combination of both catalysts (sharing a single catalytic cycle) leads to a significant increase in the reaction rate (Figure 2). [18] Figure 2. The concept of cooperative catalysis taking the co-catalyzed asymmetric Povarov reaction as an example; see ref. 18c and 18d. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 20 Moreover, multicatalysis and especially a multicatalyst (compare Figure 1) are different from multifunctional catalysts [19] (Figure 3), and dual catalyst systems [20] (Figure 4). In the case of a multifunctional catalyst one catalytic functionality mutually enhances the activity of another catalytically active center on the same catalyst via the separate activation of multiple reaction partners (mostly a nucleophile and an electrophile). [19] The types of catalysts which are able in simultaneously activating two reactants are manifold, ranging from, e.g., proline [21] to cinchona alkaloid derivatives [22-23] and bifunctional (thio)urea derivatives [24] (such as Takemoto’s catalyst; Figure 3), [25] and proved their efficiency in a variety of reactions. [19,21-25] Figure 3. The concept of a multifunctional catalyst taking proline and Takemoto’s catalyst as representative examples; see ref. 21 and 25. The third type of catalysis that should be distinguished from multicatalysis is dual catalysis (Figure 4). [20] It should be mentioned that dual catalysis is inconsistently used and may lead to confusion as it is indeed used for multicatalytic reactions in some cases. Very recently, Allen and MacMillan defined synergistic catalysis as the simultaneous activation of an electrophile and a nucleophile by independent catalysts in directly coupled catalytic cycles. [26] Indeed, the same is true for dual catalysis. From our point of view synergistic catalysis is a better terminology for reactions wherein two directly coupled catalytic cycles lead to the formation of a product (see example in Figure 4). New Frontiers in Peptide Catalysis 21 Figure 4. The concept of dual catalysis/synergistic catalysis taking the kinetic resolution of cyclic amines as an example; see ref. 20c. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; Mes = mesityl (2,4,6-trimethylphenyl). Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 22 For clarity, the term multicatalysis should be solely used for combinations of distinct catalysts to perform consecutive reactions, whereby the starting materials (A and B) react to form an intermediate (IM) in a first catalytic cycle (Figure 5). Subsequently, this intermediate is converted to the final product (P) by another independent catalyst (or catalytic moiety in the case of a multicatalyst) without intermittent work-up and purification procedures (Figure 5). Based on the way of their execution, multicatalytic reactions employing two (or more) catalysts can be further categorized. For instance, the term sequential (multi)catalysis [4,11] is typically used to describe multicatalytic reactions that rely on the addition of another catalyst or reagent (C, Figure 5), or an intermittent alteration of reaction conditions (e.g., solvent, temperature) to initiate a subsequent catalytic cycle. Tandem catalysis [4] or relay catalysis, [11] respectively, refer to a multicatalytic reaction whereby the product formed in the first catalytic cycle is directly fed into a subsequent one without a change in the reaction conditions. Moreover each of the employed catalysts may independently allow for domino/cascade or tandem reactions. Therefore, we recommend using the comprehensive expression organomulticatalysis for the overall reaction and more specific terms only for the distinct reactions. Figure 5. Possible types of multicatalysis. 2.2 Reaction Efficiency and Sustainability Aspects of Multicatalysis What are the benefits of multicatalyses relative to well-established traditional synthetic strategies and domino reactions, and how do they contribute to an environmentally benign chemistry? These questions can be answered when considering multicatalysis in the context of GreenChemistry [27-30] and its Twelve Principles, [27,31] taking into account the Environmental factor (E-factor), [32] as well as the concepts of atom economy, [33] step economy, [34] and redox New Frontiers in Peptide Catalysis 23 economy [35] as key parameters. [36] However, the rapid increase in reaction efficiency and sustainability from the ‘stop-and-go’ to multicatalysis is based on some simple considerations. Catalysis is a key to sustainability and is superior compared to the use of stoichiometric amounts of reagents. [28] Organocatalysis often circumvents many of the drawbacks usually associated with transition-metal catalysis and biocatalysis. Organocatalysts are usually non-toxic, readily available (either commercially or derived from natural sources), and in many cases allow reactions under mild conditions. They are robust catalysts, e.g., tolerate air and moisture, and are compatible with a large variety of functional groups. One-pot multistep reaction sequences, may they be promoted by a single organocatalyst or of multicatalytic nature, avoid costly and time- consuming, intermittent work-up and purification steps, thus preventing yield losses, saving energy, time and effort, and reducing waste (indeed, most waste originates from work-up and purification procedures in the form of solvents, drying, and separation agents). As a consequence, considerably lower E-factors, which is the mass ratio of generated waste to desired product, can be achieved. Moreover, the mentioned functional group tolerance of organocatalysts may permit protecting-group free syntheses [37] and avoid other unnecessary functional group conversions (e.g., non-strategic oxidation and reduction steps), thus leading to high step [34] as well as redox economy. [35] Recently, pot economy [38] has been suggested with the ultimate goal of performing entire multistep syntheses in a single reaction vessel. Multicatalysis also appreciably broadens the spectrum of applicable substrates and achievable transformations when employing independent catalysts with orthogonal reactivity. Hence, it may be more easily combined with multicomponent reactions [6,9,6] leading to overall high atom economy, [33] which is defined as the ratio of the molecular weight of desired product to the sum of molecular weights of the reactants. Equilibrium reactions can be driven to completeness, avoiding the use of excess reagents, and possible side-reactions can be circumvented by direct consumption of reactive intermediates in a concurrent catalytic cycle. This is especially important in cases where potentially toxic or unstable intermediates are formed; these can be directly converted into safer or lower energy species, thus lowering the risks of transportation, storage, and handling. An additional factor for high reaction efficiency in catalysis undoubtedly is selectivity, [39] namely chemo-, regio- or stereoselectivity (in cases where any other than the desired isomers can be regarded as waste). Multicatalysis may not only improve the reactivity, but lead to an amplification of stereoselectivity due to synergistic effects or to an enantioenrichment in subsequent catalytic cycles when a set of chiral catalysts is used. [5] Moreover, it provides an elegant approach to attain products with the desired stereochemistry depending on the configuration of the catalysts employed. [5] Further advantages may be offered by a multicatalyst: the close proximity of the catalytic moieties ensures higher local concentrations of the formed intermediates at the common catalyst backbone for consecutive reactions (if the reaction rates are such that each subsequent reaction Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 24 comes is faster). This leads to an efficient feeding of the intermediates into the next catalytic cycle, therefore, improving reactivity and material-balance. This Critical Review examines and highlights the impressive developments and advances of asymmetric organocatalyzed multicatalysis (at least one chiral catalyst is used) with the focus on different organocatalyst classes. At the beginning of each chapter we will provide a short introduction in the common activation modes and reaction types discussed herein. The reactions presented are classified depending on the different catalyst classes employed and their specific activation modes. In particular, these are:  Secondary amines – enamine/iminium activation  N-heterocyclic carbenes – Umpolung  Thiourea derivatives – hydrogen bonding  Non-natural oligopeptides – acyl transfer reactions Wherever necessary for a better understanding we will present mechanistic details for selected transformations. We cover only enantioselective approaches; diastereoselective reactions are not included. Multicatalysis employing metal catalysts, [1,4,11,13,40] multienzymatic reactions, [41-42] as well as combinations of metal-, bio-, and organocatalysis [1,4,11,42-43] are beyond the scope of this review and have been covered elsewhere. New Frontiers in Peptide Catalysis 25 3. Secondary Amine Catalysts 3.1 The Beginnings of Organomulticatalysis – Merging Iminium and Enamine Catalysis Chiral secondary amines are commonly employed as organocatalysts as these are in most cases readily available and show remarkable performance in a variety of carbonyl functionalizations via iminium ion (LUMO lowering) and enamine (HOMO raising) catalysis. [44] Both activation modes have been elegantly combined in asymmetric domino reactions, which now constitute possibly one of the most applied one-pot multistep approaches in organocatalysis. [7,44e] This strategy is outlined in Figure 6: an α,β-unsaturated aldehyde (or ketone) is activated by a secondary amine catalyst, reversibly forming an iminium ion that is able to undergo a conjugate addition of a nucleophile (Nu). The enamine intermediate formed as a result of the first reaction step enables a consecutive reaction with an electrophile ( ) to afford the α,β-disubstituted aldehyde usually containing two newly formed stereogenic centers. Figure 6. Simplified general mechanism for a secondary amine catalyzed domino reaction and prevalent reaction types. R = alkyl, aryl; Nu = nucleophile; E = electrophile. The way to secondary amine-catalyzed multicatalytic reactions was paved by MacMillan et al. in 2005, as they realized that two discrete imidazolidinones, 1 and 2, respectively, can be combined to enforce cycle-specific selectivities (Scheme 1). [45] To the best of our knowledge this was the Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 26 earliest example of asymmetric multicatalysis employing two chiral organocatalysts. The transfer hydrogenation reaction [46] with Hantzsch ester 3 as organic hydride source in conjunction with direct α-fluorination using N-fluorodibenzenesulfonamide (NFSI; 4) as electrophile allowed the formal asymmetric addition of HF across β-methylcinnamaldehyde (5; Scheme 1). This multicatalytic reaction sequence showed for the first time one of the advantages of the multicatalysis approach, namely the easy modulation to provide the required diastereo- and enantioselectivity via the judicious choice of the enantiomeric forms of the secondary amine catalysts. For example, catalyst combination A, with iminium catalyst (5R)-1 and enamine catalyst (2S)-2, gives access to the anti-diastereomer 6 in 16:1 d.r. with 99% ee. Employing Scheme 1. Cycle-specific catalysis for the transfer hydrogenation/α-fluorination of β-methylcinnamaldehyde (5). New Frontiers in Peptide Catalysis 27 catalyst combination B, with enamine catalyst (2R)-2, provides a direct entry to the syn-addition product epi-6 in 9:1 d.r. and 99% ee, respectively (Scheme 1). When (5R)-1 was used for both iminium and enamine activation the syn-addition product epi-6 was obtained with a diminished diastereomeric ratio of 3:1 (Scheme 1). [45] This result clearly demonstrates that multicatalysis may not only allow controlling the diastereo- and enantioselectivity of the final product it may also significantly enhance stereoinduction. Soon after ac illan’s pioneering work [45] related reactions comprising the sequential iminium- enamine activation by distinct secondary amines have been published. For example, a similar procedure for a reductive Mannich-type reaction was reported by Córdova et al. (Scheme 2). [47] Scheme 2. Enantioselective reductive Mannich-type reaction reported by Córdova. a Yield of isolated product based on N-PMP-protected α-iminoglyoxylate (10). Instead of imidazolidinone (5R)-1 used by MacMillan, they applied the Jørgensen–Hayashi catalyst [48] ((S)-7; TMS = trimethylsilyl) with benzoic acid as co-catalyst, which proved to be more reactive in the transfer hydrogenation step under the applied conditions. The reactions gave the corresponding amino acid derivatives, such as 12, in good yields and excellent stereo- selectivities using Hantzsch ester 9, para-methoxyphenyl (PMP)-protected α-iminoglyoxylate Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 28 (10), α,β-unsaturated aldehyde 11, and (S)-7 as catalyst for both reaction steps (Scheme 2). By analogy to the reactions reported by MacMillan et al., [45] the sequential addition of D-proline ((R)-8) and electrophile 10 in the second reaction step altered the diastereoselectivity: the syn- product epi-12 was obtained instead of the anti-isomer 12, albeit with significantly diminished selectivity (5:1 instead of 50:1 d.r.; Scheme 2). Later, the same group reported the cycle-specific four-component reaction of (E)-hex-2-enal (13), benzyl methoxycarbamate (14; Cbz = benzyloxycarbonyl), acetone (15) and p-anisidine (16) under multicatalysis conditions, which gives direct access to the chiral, orthogonally protected diamine derivatives 17 and epi-17 through an asymmetric aza-Michael/Mannich reaction cascade catalyzed by (S)-7, and (S)-8 or (R)-8 (Scheme 3). [49] The subsequent (S)-8 catalyzed Mannich reaction thereby kinetically resolved the β-amino aldehyde intermediate (96% ee) to give the diamine products 17 with 98% ee (for catalyst combination C) and epi-17 with 99% ee (for catalyst combination D), respectively, in good yields and high diastereomeric ratios (> 19:1 d.r. in both cases). Scheme 3. Aza-Michael/Mannich reaction cascade for the synthesis of orthogonally protected diamine derivatives. In order to expand their cycle-specific multicatalysis approach to a variety of other trans- formations, MacMillan and co-workers investigated imidazolidinones (5R)-1 and (2S,5S)-23 as iminium catalysts and either (S)-8 or (R)-8 as enamine catalyst (Scheme 4 and Scheme 5). [50] New Frontiers in Peptide Catalysis 29 Scheme 4. Cycle-specific reaction cascades employing Hantzsch ester 3 as hydride nucleophile and different electrophiles. (5R)-1 was used as its corresponding TCA salt. E = electrophile. While imidazolidinones are principally able to serve as iminium and enamine catalysts, they are not capable of participating in bifunctional enamine catalysis (in which activation of the electrophile is performed by the same amine catalyst). In contrast, bifunctional activation is a standard mode of activation for proline 8 (due to its acid functionality; compare Figure 3), [21] but this catalyst is generally ineffective as iminium catalyst particularly with enals or enones. Owing to this orthogonal reactivity, the combination of (5R)-1 or (2S,5S)-23 with 8 enabled a broader spectrum of valuable transformations by using different electrophiles (Scheme 4) and nucleo- philes (Scheme 5). [50] For example, a combination of (5R)-1 and (S)-8 as catalysts (catalyst combination ), β-methylcinnamaldehyde (5), Hantzsch ester 3 as nucleophile and dibenzyl- Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 30 Scheme 5. Cycle-specific reaction cascades employing dibenzylazodicarboxylate (21) or nitrosobenzene (22) as electrophiles and different nucleophiles. (2S,5S)-23 was used as its corresponding TCA or TFA salt. E = electrophile; Nu = nucleophile. New Frontiers in Peptide Catalysis 31 azodicarboxylate (21) as aza-Michael acceptor afforded the desired hydroamination product 18 (6:1 anti/syn, 99% ee). As expected, the combination of (5R)-1 and (R)-8 (catalyst combination F) led to an inversion in diastereoselectivity furnishing epi-18 (8:1 syn/anti, 99% ee). Employing nitrosobenzene 22 as electrophile provided the hydro-oxidation products 19 (11:1 anti/syn, and 99% ee with catalyst combination E) and epi-19 (10:1 syn/anti and 99% ee with catalyst combination F). Moreover, a reductive Mannich reaction cascade, similar to the one reported by Córdova [47] (compare Scheme 2) using N-PMP-protected α-iminoglyoxylate (10) as electrophile could be realized. The corresponding products were obtained in high yields, diastereomeric ratios and excellent enantiomeric excess (20: 14:1 d.r., 99% ee; epi-20: 80% yield, 12:1 d.r., 99% ee). The same methodology was applicable for a variety of nucleophiles, using a combination of imidazolidinone (2S,5S)-23 and both enantiomeric forms of proline 8 as catalysts, croton- aldehyde (24) as enal substrate and dibenzylazodicarboxylate (21) as electrophilic reagent (Scheme 5). [50] With 1-methylindole (29) as π-nucleophile the corresponding arylamination products were obtained (25: 14:1 syn/anti, 99% ee with catalyst combination G; epi-25: 7:1 anti/syn, 99% ee with catalyst combination H). An alkylamination reaction cascade with silyl- oxyoxazole 30 (TIPS = triisopropylsilyl) as nucleophile afforded the desired product 26 with three contiguous stereogenic centers (5:1 d.r. and 99% ee) for catalyst combination G, whereas catalyst combination H gave the corresponding anti-isomer epi-26 (13:1 d.r., 99% ee). The cycle-specific reaction was also applicable to olefin diamination and amino-oxidation reactions. Employing N-Boc-protected silyloxycarbamate (31; Boc = tert-butyloxycarbonyl, TBS = tert- butyl dimethylsilyl) in conjunction with dibenzylazodicarboxylate (21) afforded the diamination products 27 (7:1 anti/syn, 99% ee with catalyst combination G) and epi-27 (8:1 syn/anti, 99% ee with catalyst combination H). A related Cbz-protected amine nucleophile 32 and nitrosobenzene (22) as electrophile formed the amino-oxidation products with excellent diastereo- and enantio- selectivities (catalyst combination G for 28: 17:1 anti/syn, 99% ee; catalyst combination H for epi-28: 14:1 syn/anti, 99% ee). In order to further demonstrate its viability, MacMillan et al. applied their multicatalysis system in combination with a metal-catalyzed olefin cross-metathesis to a triple cascade reaction for thesynthesis of an intermediate of the natural product (–)-aromadendranediol [51] (37; Scheme 6). Thus, the use of Grubbs’ second generation catalyst 33, 5-hexene-2-one (34) and crotonaldehyde (24) allowed the formation of ketoenal 35 in the first step. The sequential addition of imidazolidinone catalyst (2S,5S)-23 and silyloxyfuranyl 36 as nucleophile led to the formation of intermediate 37 through an iminium-activated Mukaiyama-Michael reaction. Upon addition of (S)-8 as enamine-catalyst, intermediate 37 underwent a diastereoselective intramolecular aldol reaction furnishing the complex key intermediate 38 (64% yield, 5:1 d.r., 95% ee), which already contains four of the six required stereogenic centers and 12 of the 15 necessary carbon atoms. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 32 The synthesis of (–)-aromadendranediol (39) could then be accomplished in eight further linear steps with 40% overall yield (starting from 38). For comparison, a previously reported synthesis starting from enantiomerically pure (+)-spathulenol afforded (–)-aromadendranediol (39) in only 13% total yield over three steps. [51a] Although we will exclusively focus on organocatalyzed reactions in the following, we show this example because it beautifully demonstrates the applicability of organomulticatalysis in the total synthesis of complex natural products. Scheme 6. Multicatalysis approach for the preparation of key intermediate 38 in the total synthesis of the natural product (–)-aromadendranediol (39). Catalyst (2S,5S)-23 was used as its corresponding 2,4-dinitrobenzoic acid salt. Cy = cyclohexyl; Mes = mesityl (2,4,6-trimethylphenyl). Note that although Hantzsch esters (as well as analogues thereof and, e.g., benzothiazolines or benzoimidazolines) suffer from poor atom economy they are the hydride source of choice in organocatalysis. [46] Metal-free transfer hydrogenations with Hantzsch esters proceed under mild reaction conditions and are compatible with various functional groups, making them ideal for domino, tandem, and multicatalytic reactions. [46] In 2008, Fréchet and co-workers reported the combination of non-interpenetrating star polymers SP1 and SP2 with core-confined catalysts, and hydrogen bonding additive 40 (Scheme 7). [52] This site-isolation approach allowed the use of otherwise incompatible catalysts, circumventing undesired catalyst interactions. Indeed, small molecule reagents are able to freely diffuse to the core of the star polymers, allowing catalysis to take place. For example, the addition of imidazolidinone (2S,5S)-23 to star polymer SP1 resulted in the formation of salt (2S,5S)-23 • SP1, which acts as iminium catalyst, thus enabling the conjugate addition of 1-methylindole (29) to (E)-hex-2-enal (13). Addition of SP2, methylvinyl ketone (41) and 40 New Frontiers in Peptide Catalysis 33 (which was expected to activate the relatively unreactive Michael acceptor 41) afforded the desired indole derivative 42 with high yield and excellent stereoselectivity (89% yield, 25:2 d.r., > 99% ee) through the second Michael reaction. When star polymer SP1 was replaced with para-toluenesulfonic acid and/or SP2 with the analogues free secondary amine catalyst no desired product was observed. Only traces of product formed when linear polymer analogues of SP1 and SP2 were used. Additionally, the use of (2R,5R)-23 as iminium catalyst afforded the other diastereomer epi-42 (80% yield, 2:25 d.r., > 99% ee) similar to the aforementioned examples. Scheme 7. Combination of iminium, enamine and H-bonding catalysis using non-interpenetrating starpolymer catalysts (2S,5S)-23 • SP1 and SP2 for the one-pot synthesis of indole derivative 42. a Values in parentheses indicate reaction using (2R,5R)-23 as iminium catalyst. Later, the same group reported a multicatalysis reaction in aqueous buffer, enabling the polarity- directed, chemoselective formation of desired cross-cascade products. [53] Employing (S)-8 and (S)-7 as catalysts, this biphasic reaction allowed the differentiation of two aldehydes with similar chemical reactivity based on their different polarity to form a major cross-cascade product 51 (Scheme 8). Preliminary studies indicated that the success of this reaction is based on some special requirements. Hence, the first amine catalyst (S)-8, dissolves well in the aqueous phase, but poor in organic solvents. The other amine catalyst (S)-7, in conjunction with lauric acid as hydrophobic acid co-catalyst, shows a greater miscibility with the organic phase rather than water (even slightly water-miscible organic acids turned out to be problematic because they lower the pH of the aqueous phase and therefore slow down the condensation reaction). Moreover, (S)-8 is an efficient catalyst for the condensation reaction, but a poor catalyst for the conjugate addition under aqueous conditions. In sharp contrast, diphenylprolinol (S)-7 is Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 34 inefficient in the condensation reaction, but an efficient and highly enantioselective catalyst for the conjugate addition of aldehydes to nitroalkenes. On the basis of these requirements, Fréchet and co-workers succeeded in the development of a biphasic reaction facilitating the selective activation of the two aldehydes. In aqueous phase, the use of a large amount of (S)-8 (40 mol%, respectively) efficiently catalyzes the reversible condensation of the less hydrophobic aldehydes 43 – 46 (R 1 = Et, n-Pr, i-Pr, n-Bu) and nitromethane (50). In the organic phase, the use of only 1 mol% of catalyst S)-7 slows down the addition reaction, so that the aldehydes 43 – 46 are readily consumed in the condensation step, suppressing the addition of the more hydrophobic aldehydes 46 – 49 (R 2 = n-Bu, n-hexyl, n-octyl, n-decyl) to the nitroalkene intermediate 52, thus avoiding the formation of undesired by-products. Consequently, the aldehydes 46 – 49 survive the condensation step and react with the nitroalkene intermediate 52 in the organic phase to give exclusively 51. Indeed, only traces of by-products could be detected. This approach sheds light on the cycle-specific activation of reagents as well as intermediates based on physical (polarity) rather than chemical properties. Scheme 8. Biphasic polarity-directed reaction in aqueous buffer employing two aldehydes with similar reactivity but different polarity. Contrary to the above examples, Moreau and Greck envisaged a multicatalytic reaction comprising two consecutive enamine cycles, based on two previously developed reactions, a ichael addition of aldehydes to β-nitrostyrene (55) [48b] and a ichael addition/α-amination cascade reaction, [54] respectively (Scheme 9 and Table 1). [55] Indeed, the combination of (S)-7 and 9-amino(9-deoxy)epi-cinchonine (53; 5 mol% for both), propionaldehyde (54), nitrostyrene New Frontiers in Peptide Catalysis 35 (55), and electrophilic dibenzylazodicarboxylate (21) afforded the desired α-hydrazino aldehyde 57a (80% yield, >95:5 d.r., 96% ee). When both reactions were performed independently, 10 mol% of 7 and a tenfold excess of aldehyde 54 (instead of 1.2 equivalents) were necessary to to afford the intermittent Michael addition product 56 (82% yield, 95:5 d.r.) in the first reaction (Scheme 9). The second reaction, using the previously reported conditions [54] (20 mol% 53, 30 mol% TFA, 1.5 equivalents of 21), gave the expected product 57a in 80% yield (66% yield overall) and in >95:5 d.r. Various other nitroalkenes 58 bearing electron-rich (57b and 57c; Table 1, entries 2 and 3) and electron-deficient aryl groups (57d–57h; entries 4–8) with different substitution pattern (i.e., para- or meta-substituted) could be used under the optimized conditions, affording the corresponding products 57 as a single diastereomer with good yields (73 – 85%) and high enantioselectivities (96 – 98% ee). Very recently, the combination of Jørgensen’s T S-protected diarylprolinol (S)-59 [56] and (S)-8 was reported by the group of Díez to participate in the sequential Michael/Morita-Baylis- Hillman with concomitant Knoevenagel condensation reaction cascade of Nazarov reagent 60 with α,β-unsaturated aldehydes leading to 2-alkylidene cyclohexanones 65 (Scheme 10). [57] The success of the reaction was based on the combination of the two amine catalysts (S)-59 and (S)-8. For example, using only (S)-59 gave the Michael addition product as a mixture of diastereomers (syn/anti 1:1), but did not afford any cyclization product. The same was observed when (S)-7 was used as catalyst; with ac illan’s imidazolidinone (2S,5S)-23 only starting material could be detected. When (S)-8 was applied for the total reaction the desired products 65 formed with reasonable diastereomeric ratio (E/Z = 2:1) and yields, but no enantioselectivity could be achieved under these conditions. In contrast, the conjugate addition reaction of 60 with α,β- unsaturated aldehydes 13 and 61–64 catalyzed by (S)-59 and sequential addition of (S)-8 after consumption of the starting material afforded the cyclized products 65 (E/Z = 2:1 in all cases) with moderate to good yields and high enantiomeric ratios (41 – 77% yield; up to 98:2 e.r.). However, the reaction did not proceed with aryl aldehydes. [57] As the scope of secondary amines is limited to carbonyl compounds the combination of these catalysts with other organocatalysts is highly desirable to provide a way to reactions otherwise not attainable. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 36 Scheme 9. Comparison of the sequential preparation and the one-pot multicatalytic synthesis of product 57a. a No enantiomeric excess given. Table 1. ichael addition/α-amination reaction sequence through double enamine activation. Table corresponds to Scheme 9. Entry R Product Yield (%) ee (%) 1 Ph 57a 90 96 2 1-naphthyl 57b 73 96 3 4-MePh 57c 85 96 4 4-MeOPh 57d 85 97 5 4-ClPh 57e 85 98 6 4-FPh 57f 81 97 7 3-ClPh 57g 85 98 8 a 3-MeOPh 57h 76 96 a 10 mol% of (S)-7 were used. New Frontiers in Peptide Catalysis 37 Scheme 10. Michael/Morita-Baylis-Hillman/Knoevenagel condensation reaction sequence for the preparation of 2-alkylidene cyclohexanones 65. MOM = methoxymethyl. 3.2 Combinations of Secondary Amine Catalysts with Brønsted Acids and Bases During the last few years, the group of Ramachary reported a variety of multicatalytic approaches based on the sequential combination of multicomponent reactions and multicatalysis providing direct excess to a variety of valuable compounds (most of them being achiral), such as agrochemicals, fine chemicals, as well as pharmaceutical drugs, drug intermediates, and building blocks for the synthesis of natural products. [58] However, as already mentioned above we focus on asymmetric organocatalyzed variants here. After the successful demonstration of the one-pot asymmetric syntheses of the Wieland- Miescher [59] and Hajos-Parrish [60] ketones and their analogues via a three-component reductive alkylation and Robinson annulation, [61,62] Ramachary et al. investigated the one-pot asymmetric synthesis of the corresponding hydrogenated derivatives by combining three components and four catalysts, triethylamine, (S)-8, perchloric acid, and (S)-1-(2-pyrrolidinyl-methyl)pyrrolidine (66), respectively (Scheme 11). [63] Therefore, they suggested a triethylamine-catalyzed regio- selective Michael reaction of diketones 67 and methylvinyl ketone (41) followed by a Robinson annulation of intermediate Michael adducts 68 through amino acid/Brønsted acid catalysis furnishing the chiral Wieland-Miescher and Hajos-Parrish ketones 69 (n = 1, 2). Final iminium activated stereoselective hydrogenation of the respective intermediates 69 with Hantzsch ester 9 and diamine catalyst 66 would then lead to hydrogenated Hajos-Parrish ketone 70a or Wieland- Miescher ketone 70b. Indeed, the sequential combination of 67 and 41 with Hantzsch ester 9 and catalytic amounts of triethylamine, (S)-8, perchloric acid, and 66 afforded the hydrogenated Wieland-Miescher ketone 70b in 45% yield with >99% d.r. and 75% ee. However, the hydro- genated Hajos-Parrish ketone 70a was obtained in 45% yield and >99% d.r., but only 20% ee (the corresponding (S)-8 catalyzed two-component reaction affords the intermediate Hajos- Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 38 Parrish ketone (69, n = 1) with 86% ee). [62] This was proposed to be because of the involvement of triethylamine in the transition state of the (S)-8 promoted intramolecular aldol reaction. [63] Another multicatalysis reaction was reported by the same group, combining amino catalysis and Brønsted acid catalysis for the synthesis of a chiral chromane 76 (Scheme 12). [64] The trans-4- Scheme 11. Asymmetric synthesis of hydrogenated Hajos-Parrish ketone 70a and Wieland-Miescher ketone 70b through the one-pot combination of three components and four catalysts reported by Ramachary. Scheme 12. Multicatalytic synthesis of chromane derivatives reported by Ramachary. NMP = N-methyl- pyrrolidinone. New Frontiers in Peptide Catalysis 39 hydroxy-L-proline (71) catalyzed reaction of acetone (15) and 2-hydroxybenzaldehyde (73) via Barbas-List aldol reaction gave intermediate 74 which is in a fast dynamic equilibrium with its lactol form 75. Subsequent treatment with para-toluenesulfonic acid (p-TSA; 72) in methanol selectively afforded the chiral trans-2-methoxy-2-methylchroman-4-ol (76) in 55% yield with >95% de and 77% ee (Scheme 12). [64] An impressive example of stereocontrol was reported by Jørgensen et al. employing (S)-7 and piperidine (77) as catalysts for the formation of complex chiral bicyclo[3.3.1]non-2-enes 80, starting from simple α,β-unsaturated aldehydes 78 and dimethyl 3-oxopentanedioate (79; Table 2). [65] Four new carbon–carbon bonds formed, affording the desired product 80 bearing six stereogenic centers with excellent diastereo- and enantioselectivity (up to >99:1 d.r. and 96% ee) out of 64 theoretically possible stereoisomers. Jørgensen and co-workers proposed the following mechanism for the formation of the six stereogenic centers in 80 (Scheme 13). [65] The reaction is initiated by standard iminium ion catalysis by diphenylprolinol silylether (S)-7 with Table 2. Asymmetric two-component reaction for the formation of bicyclo[3.3.1]non-2-enes. Entry R Product Yield (%) d.r. ee (%) 1 Et 80a 48 >99:1 94 2 i-Pr 80b 65 >99:1 96 3 n-heptyl 80c 69 88:12 95 4 EtO2C 80d 38 >99:1 89 5 (Z)-hex-3-enyl 80e 51 94:6 94 6 Ph 80f 70 >99:1 93 7 4-MeOPh 80g 93 92:8 91 8 2-furyl 80h 86 94:6 90 9 2-BrPh 80i 86 >99:1 96 Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 40 Scheme 13. Mechanistic proposal for the formation of bicyclo[3.3.1]non-2-enes 80. enals 78 generating 81, which is nucleophilically attacked at the β-carbon atom by dimethyl 3-oxopentanedioate (79), thus leading to enamine 82. Formation of iminium ion intermediate 83 and subsequent hydrolysis releases 84 with the first two stereogenic centers. In the second cyclization reaction of intermediate 84 with its second activated methylene functionality leads to 85 which, after elimination of water, gives intermediate 86. The cyclization step is possibly preceded by hydrolysis of secondary amine catalyst (S)-7, however, this could not be clarified. Conjugate addition with a second molecule of 79 leads to 87 (the stereoinduction in this step arises from steric hindrance of the former created stereogenic center bearing R). [65] Final ring closure between the last free activated methylene and the central ketone furnishes product 88. Due to strong intramolecular hydrogen bonding, tautomeric equilibration leads to the more stable aldehydes 78. For example, aliphatic aldehydes (80a – 80c; Table 2, entries 1 – 3), esters (80d; entry 4), and olefins (80e; entry 5) were applicable. Superior yields were achieved employing aromatic compounds, e.g., para- and ortho-substituted phenyls (80g and 80i; entries 7 and 9) or heteroaromatic substituents, such as furyl (80h; entry 8). Importantly, the products 80 could be purified by crystallization after completion of the reaction, thus avoiding waste-generating chromatographic steps. [65] One year later, the same group reported an organocatalytic Michael/Knoevenagel domino reaction for the synthesis of optically active 3-diethoxyphosphoryl-2-oxocyclohex-3-ene- carboxylates. [66] In order to demonstrate the synthetic feasibility of these products, Jørgensen et al. performed consecutive reactions, one of it being multicatalytic. Hence, Jørgensen and co- workers envisioned a hydrolysis/decarboxylation reaction as an entry to 5-substituted New Frontiers in Peptide Catalysis 41 2-diethoxyphosphorylcyclohex-2-enones, such as 90 (Scheme 14). In this example, the (S)-59 catalyzed domino Michael/Knoevenagel condensation reaction of 4-diethoxyphosphoryl-3-oxo- butanoate (90) and cinnamaldehyde (91) afforded tert-butyl-2-oxocyclohex-3-carboxylate (92). Subsequent methanesulfonic acid (MSA; 89) catalyzed hydrolysis/decarboxylation then gave the target compound 2-diethoxyphosphoryl-5-phenylcyclohex-2-enone (93) in 52% yield and 96% ee. The stepwise synthesis yielded 93 in slightly lower yield (43% over two steps) and same enantiomeric excess. [66] However, the one-pot synthesis avoids intermediate work-up, isolation, and purification of 92, thus is more time-cost-efficient. Scheme 14. Stepwise and multicatalytic synthesis of 2-diethoxyphosphor-yl-5-phenylcyclohex-2-enone 93. a First reaction was performed in dichloromethane. In the same year, García Ruano and Alemán reported the successful combination of amino catalysis and fluoride catalysis using (S)-59 and n-tetrabutylammonium fluoride (TBAF; 94) for the synthesis of pentasubstituted cyclohexanes 96 (Table 3). [67] The reaction proceeds via a Michael addition of diketones 95 to α,β-unsaturated aldehydes 78 promoted by (S)-59. Subsequent addition of nitromethane (50) and TBAF (94) leads to the generation of a nitro- methane anion (by fluoride) which first reacts with the Michael adduct in an intermolecular Henry reaction, thus affording a nitroalcohol intermediate. This subsequently undergoes a second, intramolecular Henry reaction catalyzed by 94 to give the densely functionalized cyclohexanes 96 with high stereoselectivities (>98:2 d.r., 92 to >99% ee) although in only moderate yields (35 – 57%). The stereochemical outcome of the reaction was proposed to be due Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 42 to the reversibility of the two Henry reactions, leading to the thermodynamically favoured (equatorial arrangement of all substituents except the hydroxyl group that is intramolecularly associated to the nitro group) instead of the kinetically favoured product. Therefore, the enantioselectivity is defined by amine catalyst (S)-59 in the first step (employing (R)-59 as amine catalyst afforded the enantiomer ent-96b; Table 3, entry 4). When other fluoride sources were used instead of 94 the corresponding product was isolated with decreased enantioselectivity, possibly due to a retro-Michael side-reaction. [67] Table 3. Combination of amino and fluoride catalysis for the synthesis of cyclohexane derivatives with five contiguous stereogenic centers. Entry R 1 R 2 R 3 Product Yield (%) d.r. ee (%) 1 a Et Ph Ph 96a 45 >98:2 99 2 a Me Ph Ph 96b 55 >98:2 >99 3 a,b Me Ph Ph 96b 47 >98:2 99 4 c Me Ph Ph ent-96b 57 >98:2 >99 5 n-Pr Ph Ph 96c 46 >98:2 92 6 n-pentyl Ph Ph 96d 40 >98:2 >99 7 n-nonyl Ph Ph 96e 40 >98:2 92 8 n-Bu Ph Ph 96f 43 >98:2 92 9 n-hexyl Ph Ph 96g 42 >98:2 >99 10 (Z)-hex-3-enyl Ph Ph 96h 42 >98:2 94 11 C2H4Ph Ph Ph 96i 46 >98:2 >99 12 Me PMP PMP 96j 35 >98:2 98 13 Me Ph Me 96k 44 >98:2 98 14 Et Ph Me 96l 47 >98:2 94 15 c Ph Ph Ph 96m – – – a First step was performed at rt for 4 h; second step was performed for 18 h. b Preparative experiment on 2.0 mmol scale. c (R)-59 was used. New Frontiers in Peptide Catalysis 43 3.3 Miscellaneous Combinations with Secondary Amines In 2009, Jørgensen and coworkers reported the combination of prolinol (S)-59 and chiral Lygo- type ammonium salt (S)-97 [68] as phase-transfer catalyst [69] for a novel one-pot synthesis of 4,5-substituted isoxazoline-N-oxides 101 (Scheme 15). [70] The reaction is initiated by the asymmetric epoxidation of α,β-unsaturated aldehydes by hydrogen peroxide through iminium catalysis, followed by a base-mediated intermolecular Henry reaction with nitroacetate 100 under phase-transfer conditions. Consecutive intramolecular SN2-like O-alkylation then affords the isoxazoline-N-oxides 101. Aromatic, aliphatic and functionalized aldehydes 91, 98, and 99 were applicable providing the desired products 101 in good yields (65 – 71%) and diastereo- meric ratios (up to 78:22 d.r.), and excellent enantioselectivities (99% ee). These products are only a few reaction steps from highly valuable synthetic targets. For instance, 101c could be readily converted into a β,γ,δ-trihydroxylated α-amino acid derivative. [70] Scheme 15. Merging amino and phase-transfer catalysis for the synthesis of isoxazoline N-oxides. The concept of photoredox catalysis was first disclosed by MacMillan through the combination of organometallic complexes and secondary amine catalysts. [71] However, the applied ruthenium and iridium salts are expensive and potentially toxic, which represents a major drawback of these catalysts. A metal-free, organocatalytic photoredox reaction was presented recently by Zeitler et al. using ac illan’s imidazolidinone 102 [71] in conjunction with readily available, inexpensive xanthene dye eosin Y (103) as photosensitizer (Table 4). [72] The reaction gave the desired products 105 with good yield and high enantioselectivities. However, the selectivities showed to be temperature dependent (Table 4, entries 1, 4, and 5). For instance, at room temperature 105a Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 44 Table 4. Metal-free, asymmetric organophotoredox catalysis with visible light. Entry Conditions Product Yield (%) ee (%) 1 as shown above 105a 63 77 2 23 W fluorescent bulb was used instead of LED 105a 78 80 3 23 W fluorescent bulb and [Ru(bpy)3]Cl2 were used instead of LED 105a 75 76 4 reaction was performed at 0 °C 105a 70 81 5 reaction was performed at –5 °C 105a 85 88 6 a sunlight; reaction performed at ≈ 30 ° 105a 77 76 7 b reaction was performed at 5 °C 105b 82 95 8 c as described above 105c 76 86 9 d reaction was performed at –15 °C 105d 56 96 a Full conversion after 4 h. b para-nitrophenacyl bromide was used instead of diethyl bromomalonate (104). c Phenylpropionaldehyde was used instead of octanal (47). d 1-Iodoperfluorobutane was used instead of diethyl bromomalonate (104). New Frontiers in Peptide Catalysis 45 was isolated with 77% ee (Table 4, entry 1) whereas a decrease of the reaction temperature to –5°C led to an increase of the enantioselectivity to 88% ee (entry 5). Conducting the reaction under direct sunlight led to faster conversion (4 h) but again decreased enantioselectivity, possibly due to the higher reaction temperature (approximately 30 °C; entry 6). The methodology was also applicable to the stereoselective addition of nitrophenacyl (105b; entry 7) and polyfluorinated alkyl substituents (105d; entry 9) which showed superior selectivities up to 96% ee. Additionally, an example was presented using phenylpropionaldehyde instead of diethyl bromomalonate (104). Although the mechanism of this reaction is not yet fully understood (initially irradiated samples which were kept in the dark showed an increase in yield), a possible reaction path is depicted in Scheme 16. Thus, eosin Y (103; EY) is excited with visible light to its singlet state ( 1 EY*) which in turn converts to its more stable triplet state ( 3 EY*) through intersystem crossing (ISC). Simultaneously, the amino catalysis cycle is initiated by the formation of iminium ion 106, consequently generating enamine 107. Addition of the electron- deficient alkyl radical to 107 gives amino radical 108, which is subsequently oxidized to iminium species 109 thereby providing the necessary electron for the reductive quenching of the dyes excited state ( 3 EY*) through single-electron transfer (SET). The thus generated radical anion (EY •– ) in turn acts as a reductant to furnish the alkyl radical by SET with the alkyl halide. Scheme 16. Proposed mechanism for the organophotoredox catalysis reported by Zeitler et al. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 46 According to the proposed reaction pathway a catalytic amount of 108 has to be present as the initial electron reservoir. [72] This type of reaction is at the border to a dual or synergistic catalysis reaction as the two catalytic cycles are directly coupled. [26] However, the radical produced in the photoredox cycle independently enters the next cycle. New Frontiers in Peptide Catalysis 47 4. N-Heterocyclic Carbene Catalysts N-heterocyclic carbenes (NHCs) are versatile organocatalysts [8,73] due to their ability to render aldehydes nucleophilic, hence inverting their classical reactivity (“Umpolung”). [74] The nucleo- philic addition of a carbene to an aldehyde leads to the formation of a tetrahedral intermediate which undergoes proton transfer to a nucleophilic enaminol, commonly referred to as the Breslow intermediate. [75] This can act as an acyl anion equivalent (d 1 -synthon), allowing reactions with electrophiles to take place. Depending on the kind of electrophilic component utilized, either benzoin condensation (the electrophile is an alkyl/aryl aldehyde or ketone) or Stetter reaction (the electrophile is an α,β-unsaturated aldehyde or ketone) takes place (Figure 7). [8,73] In the case of aldehydes bearing a leaving group at the α-position the enaminol can undergo an intramolecular redox reaction (extended Umpolung). [8,73b,e,f] The elimination of the leaving group generates an enol and after isomerization an activated carboxylate, which is prone to nucleophilic attack. 4.1 Combinations with Secondary Amine Catalysts Apart from the mentioned combinations of secondary amines with other organocatalysts, multicatalytic reactions employing combinations of chiral secondary amine catalysts and NHCs have begun growing rapidly in the last years. Due to their inherently Lewis basic nature these two catalyst classes can be combined in one pot; both act on carbonyl compounds but show complementary reactivities. The approach of asymmetric amino and heterocyclic carbene catalysis (AHCC) was first demonstrated in 2007 by Córdova et al. for epoxidation–esterification, cyclopropanation– esterification, and aziridination–esterification reactions (Scheme 17). [76] Employing diphenyl- prolinol silylether (S)-7 and thiazolium salt 110 [77] (Bn = benzyl) as catalysts, and hydrogen peroxide, diethylbromomalonate (104), or Cbz-protected carbamate 117 enabled the enantio- selective synthesis of β-hydroxy esters 113 (up to 82% yield, 95% ee), β-malonate esters 116 (up to 74% yield, 97% ee), and β-amino ester derivative 118 (41% yield, 61% ee) from various readily available α,β-unsaturated aldehydes through the intermediacy of the corresponding 2,3-epoxy, cyclopropyl, and 2,3-aziridine aldehydes (Scheme 17). [76] Although very useful chiral molecules were accessible by this approach, the reactions suffered from relatively high catalyst loadings of 10 – 20 mol% for amine catalyst (S)-7 and up to 40 mol% for carbene catalyst 110. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 48 Figure 7. General representation of N-heterocyclic carbene catalysis and reactions important in the context of this publication. By employing (S)-59 and Rovis et al.’s N-heterocyclic carbene catalyst precursor 119 [78] Jørgensen and co-workers could employ drastically lower catalyst loadings (2.5 mol% of amine catalyst (S)-59 and down to 1 mol% for the carbene 119) for similar transformations, thus significantly improving the efficiency and sustainability of these reactions (Scheme 18). [79] The addition of 4 Å molecular sieves to remove excess water from the epoxidation step that competes as nucleophile with the alcohols in the final esterification step proved to be crucial to achieve high yields. Linear and γ-branched, as well as functionalized α,β-unsaturated aldehydes provided the β-hydroxylated esters in good yields and enantioselectivities (up to 84% yield, 98% ee). However, cinnamaldehyde (91) as the enal component required higher catalyst loading of (S)-59 (10 mol%) for the epoxidation step (Scheme 18). Various alcohols were applicable as nucleo- New Frontiers in Peptide Catalysis 49 philes (i-PrOH gave only poor yields due to increased steric bulk and reduced nucleophilicity; for 124 used as enal: 34% yield). Moreover, employing different enals and 125 (Tos = 4-toluenesulfonyl (tosyl)) significantly higher yields and enantioselectivities compared to the previously reported procedure could be achieved for the preparation of β-amino esters 126. [80] The active carbene catalyst was generated by remaining NaOAc from the aziridination step, thus avoiding the addition of H nig’s base for the second reaction. Note, however, that the carbamate 117 used by Córdova is more environmentally friendly and atom economy is better compared to 125 due to the release of acetate instead of tosylate. Both epoxidation–esterification as well as aziridination–esterification were additionally tested employing the commercially available citral 127 as enal substrate under the developed conditions (Scheme 19). Starting from a 1:1 (E/Z) mixture in 127 the intermediate 2,3-epoxy aldehyde 128a and aziridine aldehyde 128b formed in 3:1 diastereomeric ratio, due to possible isomerisation during the reaction. Subsequent ring- Scheme 17. AHCC catalysis for the synthesis of β-substituted esters reported by Córdova. a Epoxidation was performed at 4 °C for 6 h; b BnOH was added after completion of the epoxidation; c 30 mol% 110 were used for the esterification with MeOH; d Cyclopropanation was performed for 1.5 h; e Cyclopropanation was performed at 4 °C for 6 h. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 50 opening gave the desired products 129 bearing tertiary hydroxyl or amino moieties, however, with moderate enantioselectivities (the significant amount of the minor diastereomers 128a and 128b possibly leads to the formation of the wrong enantiomer; 129a: 66% yield, 48% ee; 129b: 81% yield, 57% ee). [79] Scheme 18. AH catalysis for the synthesis of β-substituted esters reported by Jørgensen. a 10 mol% (S)-59 were used; 5 h for epoxidation. b 2.5 mol% (R)-59, 2 mol% 119, and 4 mol% DiPEA were used. A generalized mechanistic picture for the mentioned combinations of amino and N-heterocyclic carbene catalysis is presented in Scheme 20. The reaction is initiated through the reversible formation of an iminium ion 130 allowing the conjugate addition of the O-, C-, or N- nucleophiles to the β-carbon at the Re face generating the chiral enamine intermediate 131 (similarly to the examples described above for combinations of secondary amines). In the next step, 131 performs an intramolecular 3-exo-tet cyclization from its Re face under release of the leaving group forming 132. This cyclization step is irreversible and governs the stereoselective outcome of the overall reaction. Hydrolysis gives the corresponding epoxide, cyclopropyl, or aziridine aldehydes 133. After in situ generation of the NHC 134 from its corresponding precatalyst, it nucleophilically attacks the carbonyl carbon of 133, thus forming the zwitterionic species 135. Subsequent generation of the Breslow intermediate 136, and following intra- molecular redox reaction leads to the activated carboxylate 138 via intermediate 137. Final transesterification with an alcohol as nucleophile releases the carbene catalyst and gives the corresponding products (compare Figure 7). New Frontiers in Peptide Catalysis 51 Scheme 19. AH reactions for the preparation of β-substituted esters bearing a quaternary carbon center. Scheme 20. Possible general mechanistic picture for the AHCC reactions shown in Schemes 17 and 18, and Scheme 15 (secondary amine catalyzed epoxidation step only). Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 52 In 2011, Córdova et al. reported a related enantioselective AHCC three-component reaction of α,β-unsaturated aldehydes, tosylated hydroxycarbamates 139 and 140, and different alcohols yielding Cbz- or Boc-protected β-amino acid ester derivatives 141 (Scheme 21). [81] Similarly to Jørgensen’s work, the use of (S)-7 and 119 as catalysts afforded various β-amino acid esterderivatives 141 in moderate to good yields (up to 80% yield) with 92 – 99% ee. When aromaticenals such as 91 or 115 were used the corresponding products were obtained with significantly lower yield (25 – 54% yield) although with excellent stereoselectivities (94 – 99% ee) due to abase-catalyzed rearrangement side-reaction. According to the mechanistic picture provided in Scheme 20 the use of α-substituted enal 142 formed the intermediate aziridine 143 with high 95% ee (Scheme 22). Subsequent ring-opening/esterification afforded nearly racemic β 2 amino acid ester 144 in 69% yield. However, employing enal 145 the corresponding product 146 was isolated in 59% yield with low diastereoselectivity, albeit with excellent enantioselectivity for both isomers (anti-isomer: 97%; syn-isomer: 99% ee) as shown in Scheme 22. Scheme 21. AHCC reactions for the enantioselective synthesis of protected β-amino acid ester derivatives. Scheme 22. AH reactions for the preparation of α,β-substituted amino acid ester derivatives. New Frontiers in Peptide Catalysis 53 In 2009, Lathrop and Rovis demonstrated another example of AHCC for the realization of a Michael addition/cross-benzoin reaction (Scheme 23). [82] This multicatalytic tandem reaction enabled the synthesis of highly functionalized cyclopentanones 147 containing three stereogenic centers (including a quaternary stereogenic center) from readily available starting materials. By using silyl-protected prolinol catalyst (S)-59, asymmetric conjugate addition of α,β-unsaturated aldehydes to β-dicarbonyl compounds 151 – 159 was induced via iminium activation. The following carbene 119 catalyzed intramolecular benzoin condensation produced the densely substituted cyclopentanones 147 in high yields and enantioselectivities, however, with only moderate diastereoselectivities (Scheme 23). The reaction showed a broad scope with respect to the aldehyde and the β-dicarbonyl starting materials leading to a variety of possible products, while branched aliphatic aldehydes (such as 98) gave considerably lower yields. For example, bicyclic products 147p and 147q could be obtained using β-ketoesters 158 or 159. Mechanistic investigations revealed that the performance of iminium catalyst (S)-59 and carbene 119 in a tandem reaction is crucial for the high yield and selectivity of this reaction. When the transformation is performed in stepwise manner the intermediate aldehydes probably undergo retro-Michael reaction in the presence of (S)-59 and are prone to epimerization during purification by column chromatography. [82] As a consequence, the desired products 147 are obtained in lower yield and significantly lower enantioselectivity (46% yield, 58% ee for two sequential reactions), showing the sharp contrast to the yield and enantioselectivity of the one- pot tandem reaction (93% yield, 86% ee). When the two steps are combined into a tandem reaction, the carbene catalyst 119 effectively suppresses the retro-Michael reaction by direct consumption of the intermediate aldehyde in the following benzoin reaction, hence achieving the high enantioselectivity (Scheme 23). This work further emphasizes one of the advantages of multiple catalysts promoted asymmetric tandem reactions: the fast consumption of intermediates in a concurrent catalytic cycle allows catalysts to work synergistically, thereby suppressing side reactions. The orthogonal reactivity of secondary amines and N-heterocyclic carbenes for the asymmetric synthesis of highly functionalized cyclopentanones was shown with another example by Ozboya and Rovis in 2011 (Scheme 24). [83] In contrast to the previous work which relied on iminium catalysis as the first step, this reaction was initiated by enamine activation using secondary amine catalyst 7 followed by direct benzoin condensation catalyzed by chiral triazolium catalyst precursor 160. [78,84] Aliphatic aldehydes and various α,β-unsaturated ketones provided the desired products in good yield and high enantio- and diastereoselectivity. Employing isovaleraldehyde (45) competitively formed the corresponding Stetter product in a 1:1 ratio with the desired product 161c. However, the sequential addition of 160 after complete formation of the corresponding intermediate avoided the formation of the side-product, thus affording 161c (98% yield, 96:4:<1:<1 d.r., 88% ee). Aldehydes 163 and 164, and α,β-unsaturated ketones 167 173 bearing sterically more demanding substituents were also applicable but usually required Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 54 Scheme 23. AHCC tandem reaction for the synthesis of cyclopentanone derivatives reported by Lathrop and Rovis. Diastereomeric ratios are shown for major diastereomer : sum of three possible minor diastereomers. New Frontiers in Peptide Catalysis 55 Scheme 24. AHCC tandem reaction for the synthesis of cyclopentanone derivatives reported by Ozboya and Rovis. Diastereomeric ratios are shown for major diastereomer : sum of three possible minor diastereomers. PMB = para- methoxybenzyl. a Catalyst 160 was added after complete consumption of starting material. b Carbene precatalyst 119 was used instead of 160. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 56 and longer reaction times and led to lower yields. When, for example, 173 was used as enone the intramolecular benzoin reaction could only be accomplished using smaller achiral carbene catalyst 119, however with diminished enantioselectivity (51% ee). Diketones 174 and 175 gave the corresponding products 161p and 161q in considerably lower yields. Additional mechanistic investigations again showed that the one-pot tandem reaction leads to better selectivities compared to the single step reactions via a dynamic kinetic resolution of intermediate 176 by chiral NHC 160 (Schemes 25 and 26). Control experiments revealed that when prepared from butyraldehyde (43) and enone 165 with catalyst(S)-7 and catalytic acetic acid the corresponding intermediate aldehyde 176 formed in 91% yield with only 2:1 diastereomeric ratio. The consecutive benzoin reaction afforded 161a in comparable yield and enantioselectivity to the multicatalytic one-pot reaction, but in lower diastereomeric ratio (78% yield, 4:1:1:<1 d.r., 95% ee for two consecutive reactions; 87% yield, 19:1:<1:<1 d.r., 95% ee for the tandem reaction). Indeed, in the presence of (S)-7 the diastereo-selectivity of the final product could be significantly improved (10:1:<1:<1 d.r.; Scheme 25). Thus, the secondary amine catalyst (S)-7 possibly epimerizes the α-position of the intermediate aldehyde 176, leading to epi-176, and the chiral triazolium catalyst 160 preferentially reacts with intermediate 176 instead of epi-176 to form the enantioenriched product 161a (Scheme 26). In the same year, Enders et al. employed (S)-59 and 119 for the sequential multicatalytic Michael addition/cross-benzoin reaction of α,β-unsaturated aldehydes and β-oxo sulfones 178 – 189 for the preparation of polysubstituted cyclopentanones 177 (Scheme 27). [85] Hence, they first applied the conditions reported previously for the reaction of β-dicarbonyl compounds with enals by Lathrop and Rovis. [82] Under these conditions (compare Scheme 23) the reaction of crotonaldehyde (24, 1.0 equivalents) with phenylsulfonylacetone (178, 2.0 equivalents) afforded mainly two of the four possible diastereomers of 177b in high yield and enantioselectivity, however, in an only moderate diastereomeric ratio (85% yield, 63:37 d.r., 88% ee). After re- optimization of reaction conditions the desired product 177b could be obtained in quantitative yield while stereoselectivity was retained. With these conditions at hand, Enders and co-workers studied the scope of the reaction. A wide range of different sulfones 179 – 189 was applicable using 24 as aldehyde component to generate cyclopentanones 177d – 177k in 70 – 96% yield, in most cases as a single diastereomer (99:1 d.r.), and with up to 97% ee. Interestingly, the benzoin condensation proceeded with cis-selectivity (contrary to the reactions reported by Rovis; compare Scheme 23) [82] when sulfones bearing an aromatic moiety were employed. Using α-substituted α-(phenylsulfonyl)ketones as nucleophiles significantly decreased the reaction rate and the yield. For instance, the cyclic sulfone 187 formed product 177l in 53% yield even when the reaction time was prolonged to three days with moderate selectivities (67:33 d.r.), whereas 188 gave 177m in only 20% yield, albeit with very good stereoselectivity (99:1 d.r., 91% ee). When acyclic 189 was used as sulfone component the desired product was not produced. Similarly to the reactions reported by Rovis and co-workers, [83] Enders observed epimerization New Frontiers in Peptide Catalysis 57 of the corresponding Michael adduct. Hence, the achieved diastereoselectivities result from the preference of one of the diastereomers to react with the carbene catalyst (also compare Scheme 26). Scheme 25. Single step reactions for the preparation of 161a. Scheme 26. Mechanistical proposal for the observed reaction outcome in the multicatalytic synthesis of 161a. Evolution of Asymmetric Organocatalysis: Multi- and Retrocatalysis 58 Scheme 27. AHCC cascade reactions for the synthesis of cyclopentanone derivatives reported by Enders. Diastereomeric ratio