Stereoselective Organocatalysis: Bond Formation Methodologies and Activation Modes

Preface

Imagination is more important than knowledge.

—Albert Einstein

This book is intended to provide an overview of organocatalysis from its renaissance in 2000 until now, and it focuses on the nature of the bond built rather than on the mode of activation.

The chapters included in the present book deal with the nature of the bond formed by organocatalytic methodologies, ranging from C–C to C–heteroatom, and from the original aldol reaction to the highly enantioselective organocascades that improve reaction outcomes.

It was a pleasure to be the editor of this compendium, since it provided me with the opportunity to survey the field of organocatalysis and to honor the work of so many fine chemists.

I would like to thank all the distinguished scientists and their co-authors for their rewarding and timely contributions. I acknowledge the great work done by the Wiley editorial staff—in particular that of Jonathan Rose, whose help was invaluable.

I also want to thank Professors G. C. Fu, P. Walsh, B. List, and A. Cordóva, who introduced me to the world of chemistry. Particularly, I want to express my deep gratitude to Professors List and Cordóva, who gave me the opportunity to start my work in organocatalysis. They introduce me to that world and guided my first steps; thanks to them I picked up not only knowledge about organocatalysis but also their love for it.

Finally, I want to thank my parents for all their support and help. Without them I could never have carried out this project.

Ramon Rios Torres

Southampton

January 2013

Contributors

José Alemán, Departamento de Quimica Organica (C-I), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Maurizio Benaglia, Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, 20133 Milano, Italy

Damien Bonne, Aix-Marseille Universite, iSm2, UMR CNRS 6263, Centre St. Jerome, service 531, 13397 Marseille Cedex 20, France

Martina Bonsignore, Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, 20133 Milano, Italy

Stacey E. Brenner-Moyer, Department of Chemistry, Brooklyn College and the City University of New York, 2900 Bedford Avenue, Brooklyn, New York 11210, United States

Xiang-Yu Chen, Institute of Chemsitry, CAS, Beijing, 100190, China

Xavier Companyó, Universitat de Barcelona, Martí i Franquès 1-11, Barcelona 08028, Spain

Thierry Constantieux, Aix-Marseille Universite, iSm2, UMR CNRS 6263, Centre St. Jerome, service 531, 13397 Marseille Cedex 20, France

Yoann Coquerel, Aix-Marseille Universite, iSm2, UMR CNRS 6263, Centre St. Jerome, service 531, 13397 Marseille Cedex 20, France

Armando Córdova, Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden; and Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University, SE-851 70 Sundsvall, Sweden

Giorgio Della Sala, Dipartimento di Chimica, Universita di Salerno, 84084, Fisciano, Italy

Jorge Esteban, Universitat de Barcelona, Martí i Franquès 1-11, Barcelona 08028, Spain

Johan Franzén, Royal Institute of Technology (KTH), Department of Chemistry, Organic Chemistry, S-100 44, Stockholm, Sweden

Andrea Genoni, Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, 20133 Milano, Italy

Dorota Gryko, Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

Yi-Xia Jia, College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou, China

Xuefeng Jiang, Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai, 200062, People's Republic of China

Aitor Landa, Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, UPV/EHU, Paseo Manuel Lardizabal, 3, 20018, San Sebastián, Spain

Alessandra Lattanzi, Dipartimento di Chimica, Universita di Salerno, 84084, Fisciano, Italy

Rosa López, Departamento de Química Orgánica I Facultad de Química, Universidad del País Vasco, UPV/EHU, 20018, San Sebastián, Spain

Antonia Mielgo, Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, UPV/EHU, 20018, San Sebastián, Spain

Albert Moyano, Universitat de Barcelona, Martí i Franquès 1-11, Barcelona 08028, Spain

Mikel Oiarbide, Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, UPV/EHU, 20018, San Sebastián, Spain

Claudio Palomo, Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco, UPV/EHU, 20018, San Sebastián, Spain

Marek Remeš, Charles University in Prague, Hlavova 2030, Prague 12840, Czech Republic

Ramon Rios, University of Southampton, Highfield Campus, SO17 1BJ Southampton, United Kingdom

Jean Rodriguez, Aix-Marseille Universite, iSm2, UMR CNRS 6263, Centre St. Jerome, service 531, 13397 Marseille Cedex 20, France

Mariola Tortosa, Departamento de Quimica Organica (C-I), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Jan Veselý, Charles University in Prague, Hlavova 2030, Prague 12840, Czech Republic

Dominika Walaszek, Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

Wei Wang, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, People's Republic of China

Song Ye, Institute of Chemsitry, CAS, # 2 Zhongguancun Beiyi St., Beijing, 100190, China

Yongcheng Ying, Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, Shanghai, 200062, People's Republic of China

Tiexin Zhang, College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou, China

Yong Zhang, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, People's Republic of China

Chapter 1

Introduction: A Historical Point of View

Organocatalysis is commonly accepted as the use of small organic molecules to catalyze organic transformations. The term organocatalysis was coined by David W. C. MacMillan at the beginning of the twenty-first century and was the starting line for breathtaking progress in this area over the last decade. During recent years, this area has grown into one of the three pillars of asymmetric catalysis, complementing and sometimes improving bio- and metal catalysis. The rapid growth in this area can be easily explained: The field offers several advantages to researchers in academia and industry, such as (a) easy and low-cost reactions and (b) reactions that are insensitive to air or moisture (unlike organometallic chemistry). Furthermore, the small chiral organic molecules used as catalysts can be often be derived from nature; thus, they are accessible and inexpensive to prepare, and often the processes are environmentally friendly. Moreover, the need in industrial large-scale production for removal of impurities related to toxic metal catalysts from the waste stream, which has a huge financial impact, could be avoided with the use of organocatalysts; this has made the field very interesting from the industrial point of view.

The renaissance of organocatalysis was at the beginning of the twenty-first century, but the origins of small organic molecules acting as catalysts can be traced back to the earliest works of Emil Knoevenagel [1]. In these works, Knoevenagel studied the use of primary and secondary amines, as well as their salts as catalysts for the aldol condensation of β-ketoesters or malonates with aldehydes or ketones. Knoevenagel also suggested the same intermediates that Westheimer later proposed in his retro-aldolization studies. Another key development in the history of organocatalysis was the work of Dakin in 1910 regarding the catalytic activity of primary amino acids in the Knoevenagel reaction [2]. Twenty years later, Kuhn and Hoffer found secondary amines that catalyzed not only the Knoevenagel reaction but also the aldol reactions between aldehydes [3].

Another important highlight in organocatalysis was developed by Bredig, who reported the addition of HCN to benzaldehyde in the presence of cinchona alkaloids as catalysts to obtain mandelonitrile with less than 10% ee. However, the importance of this reaction is, from a conceptual point of view, groundbreaking (Scheme 1.1) [4].

Scheme 1.1 Hydrocyanation reported by Bredig in 1913.

Following the earliest works of Bredig, Pracejus developed the first reactions with good levels of enantioselectivity. Pracejus reported the addition of methanol to methyl phenyl ketene catalyzed by O-acetyl quinine (Scheme 1.2) [5].

Scheme 1.2 Addition of methanol to ketenes reported by Pracejus.

Later, Fisher and Marshall used primary amino acids to catalyze aldol and condensation reactions of acetaldehyde [6]. Following these inspiring results, in 1936 Kuhn discovered that carboxylic acid salts of amines effectively catalyze the aldol reaction [7]. Piperidinium acetate was used by Langenbeck and Sauerbier in their studies on the catalytic hydration of crotonaldehyde [8]. Interestingly, Langenbeck suggested a Kuhn–Knoevenagel-type covalent catalysis mechanism and introduced secondary amino acids (sarcosine) as catalysts for aldolization. An important contribution to the field of organocatalysis was made by G. Stork with his work on enamine chemistry. Most of the subsequent work in organocatalysis was first conducted by Stork's research group with preformed enamines (Scheme 1.3) [9]. These studies and findings arguably led to one of the most important highlights in organocatalysis: the Hajos–Parrish–Eder–Sauer–Wiechert reaction.

Scheme 1.3 Reactions developed by Stork with preformed enamines.

As stated above, the studies of Wieland and Miescher, as well as Woodward, on the intramolecular aldol reaction of diketones and dialdehydes were encouraged by this previous work. Wieland, Miescher, and Woodward studied the application of the intramolecular aldol reaction, catalyzed by secondary amine salts, to the synthesis of steroids and believed that their aldolizations proceed via enamine intermediates [10]. This was corroborated by the mechanistic studies carried out by Spencer in 1965 [11]. Based on these works, Hajos and Parrish (1974) and Eder, Sauer, and Wiechert (1971) independently developed the first asymmetric, amine-catalyzed aldolization [12]. They choose proline as a catalyst based on previous work that showed the viability of amino acids as catalysts for aldol reactions (Scheme 1.4). However, neither of these groups proposed the enamine mechanism for the reaction.

Scheme 1.4 Reaction of Hajos and Parrish in 1974.

Woodward probably conducted the most outstanding work on iminium catalysis before its rebirth in 2000. In this work, Woodward applied proline catalysis in a triple organocascade reaction consisting of a deracemization (via a retro-Michael, Michael addition) and an intramolecular aldol reaction that determine the stereochemical outcome of the reaction (Scheme 1.5), leading to the synthesis of erythromycin [13].

Scheme 1.5 Key step for Woodward's synthesis of erythromycin.

Based on Pracejus's previous work with cinchona alkaloids, Bergson and Langstrom developed the Michael addition of β-ketoesters to acrolein catalyzed by 2-(hydroxymethyl)quinuclidine. Soon after, Wynberg developed several organocatalytic reactions using cinchona alkaloids as chiral Lewis base/nucleophilic catalysts [14].

During the period between the late 1970s and early 1980s, a large number of reactions that proceeded via ionic pairs were developed. Inoue conducted remarkable work on the use of chiral diketopiperazines as chiral Brønsted acids in the hydrocyanation of aldehydes [15]. The mechanism of this reaction, which exhibits high levels of autocatalysis, remains elusive despite the work of Schvo that suggests the presence of two molecules of the catalyst in the transition state [16]. This early work is the first example illustrating that a simple peptide-based catalyst could perform asymmetric transformations and was probably the source of inspiration of the later works of Lipton, Jacobsen, and Miller [17].

Another important fact was reported in the 1980s; Agami and co-workers studied the application of proline in an enolendo aldolization reaction. Their mechanistic studies showed nonlinear and dilution effects that suggested the involvement of two molecules of proline in the transition state (Scheme 1.6) [18].

Scheme 1.6 Mechanism suggested by Agami.

Another important highlight in organocatalysis was also developed in the 1980s. Julia and Colonna reported the epoxidation of enones by H2O2 catalyzed by poly-l-leucine. This example is formally the first use of hydrogen-bonding catalysis in asymmetric synthesis (Scheme 1.7) [19].

Scheme 1.7 Julia–Colonna epoxidation.

In middle of the 1980s, efficient asymmetric phase-transfer reactions using catalytic amounts of N-benzylcinchoninium chlorides were developed by researchers at Merck. This catalyst was able to alkylate 2-substituted-2-phenyl indanones with high ee (up to 94% ee) [20].

An important addition was the work by Kagan involving chiral amines in cycloaddition reactions. Kagan showed that chiral bases such as quinidine or prolinol catalyze the cycloaddition between anthrones and maleimides with moderate enantioselectivities [21].

In the 1990s, Yamaguchi and Taguchi used proline derivatives (or lithium or rubidium salts of proline) as catalysts for the enantioselective Michael reactions of enals and suggested iminium ion activation as the catalytic principle [22].

In the late 1990s, several research groups worked on the development of chiral DMAP analogs. The works of Fu [23], Vedejs [24], and Fuji [25] led to the synthesis of powerful catalysts and the development of enantioselective organocatalytic reactions such as Steglich rearrangements, kinetic resolutions of secondary alcohols, kinetic resolution of amines, and so on (Scheme 1.8).

Scheme 1.8 Steglich rearrangement developed by Fu.

In 1996, Shi made a huge development in this area, reporting the asymmetric epoxidation of alkenes using chiral dioxiranes generated in situ. The epoxidation works well for disubstituted trans-olefins, and trisubstituted olefins using a fructose-derived ketone as a catalyst and oxone as an oxidant (Scheme 1.9) [26].

Scheme 1.9 Shi epoxidation of olefins.

However, all of these wonderful contributions had a limited impact in the field of organic chemistry. The renaissance of organocatalysis came with the works of List, Barbas, and Lerner [27] in enamine chemistry and the works of D. W. C. MacMillan [28] in iminium chemistry in 2000. Since then, enormous efforts have been made by the chemical community toward the development of new catalysts and methodologies without the use of metals.

Owing to the huge number of reactions and methodologies, it would be difficult to highlight the most important developments. However, some of the most significant achievements in the area of organocatalysis in later years are as follows: the Friedel–Crafts reaction developed by MacMillan in 2001 [29], development of bifunctional base–thiourea catalysts by Takemoto in 2003 [30], reduction of enals developed independently by List and MacMillan in 2005 [31], development of new phosphoric acid derivatives as chiral Brønsted acids by Akyama and Terada in 2004 [32], the first organocascade reaction by MacMillan in 2005 [33], enantioselective reductive amination developed almost simultaneously by Rueping, List, and MacMillan in 2005 [34], epoxidation of enals reported by Jorgensen in 2005 [35], the first aldehyde addition of nitroalkenes developed by Hayashi in 2005 [36], the multicomponent organocatalytic cascade developed by Enders in 2006 [37], development of asymmetric counteranion-directed catalysis (ACDC) by List in 2006 [38], the first amine conjugate addition to enals developed by MacMillan in 2006 [39], the first organocatalytic aziridination of enals developed by Cordova in 2007 [40], development of SOMO catalysis by MacMillan in 2007 [41], and development of photoredox catalysis by MacMillan in 2009 (Figure 1.1) [42].

Figure 1.1 Organocatalysis timeline.

The importance of organocatalysis is clear, owing to the number of studies reported in the literature. In recent years, new avenues have been explored in organocatalysis, providing new activation modes and new powerful methodologies. Moreover, the possibility of joining an organocatalytic reaction and organometallic reaction together in a one-pot procedure has recently increased the scope of this field. For this reason, I envision a great future for organocatalysis in which reactions of increasing complexity, along with new and more active catalysts, will be developed.

In this book, we try to give an overview of the field of organocatalysis with particular emphasis on later developments in the field. First, we will introduce the different activation modes and catalysts. Next, we show a different approach of organocatalysis not based on the different activation modes, but based on the nature of the bond formed. From C–C bond forming reactions to C-heteroatom bond formation through cascade, multicomponent reactions, we will try to give a clear of the state-of-the-art picture of this field.

References

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Chapter 2

Activation Modes in Asymmetric Organocatalysis

Albert Moyano

Schon das Wesen aller Wissenschaft besteht darin, daβ wir das endlos Mannigfaltige der anschaulichen Erscheiningen unter komparativ wenige abstrakte Begriffe zusammenfassen, aus denen wir ein System ordnen, von welchem aus wir alle jene Erscheinungen völlig in der Gewalt unserer Erkenntniβ haben, das Geschehene erklären und das Künftige bestimmen können.

A. Schopenhauer, Die Welt als Wille und Vorstellung, Vol. 1, 3rd ed., 1859, Brockhaus, Leipzig, p. 538.

2.1 Introduction

Asymmetric organocatalysis, in which small chiral organic molecules are used as catalysts for the stereocontrolled assembly of structurally diverse molecules, has emerged in the past 10 years as a powerful tool in contemporary organic synthesis. Due to its associated advantages of easy catalyst availability, and of carrying out asymmetric transformations in a metal-free environment and under mild and simple reaction conditions, asymmetric organocatalysis is now considered as the third pillar of enantioselective catalysis and, together with biocatalysis and with metal catalysis, is currently being used in the key steps in the total synthesis of bioactive compounds or of complex natural products [1].

Asymmetric organocatalysis is remarkable both for the variety of its modes of activation and for the structural simplicity of most organocatalysts, a feature that has been crucial for the generation of mechanistic working models that are able to rationalize, and in some cases even predict, the stereochemical outcome of organocatalyzed reactions. From a mechanistic perspective, organocatalytic modes of activation can be classified according to (a) the covalent or noncovalent character of the substrate–atalyst interaction and (b) the chemical nature (Lewis base, Lewis acid, Brønsted base, Brønsted acid) of the organocatalyst [2]. It is important to bear in mind, however, that many organocatalysts (cf. amino acids, phosphoric acids) act through both covalent and noncovalent interactions and/or display a dual acid–base character (bifunctional catalysts). In contrast to the enormous body of work devoted to the synthetic applications of asymmetric organocatalysis, there are relatively few studies on the mechanisms of organocatalytic reactions, in particular on the experimental determination of kinetic data, and much of our mechanistic understanding about these processes has arisen from quantum chemical calculations [3]. On the other hand, the number of reports on mechanistic investigations on asymmetric organocatalysis is growing at a breathtaking pace, so that the aim of this chapter is not to cover in depth the detailed mechanisms of individual organocatalytic transformations, but instead to present an overview of the most important, currently accepted mechanistic features of the modes of activation operative in asymmetric organocatalysis.

2.2 Covalent Organocatalysis

2.2.1 Aminocatalysis

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels–Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic studies in organocatalysis.

2.2.1.1 Enamine Catalysis

Enamine catalysis has become one of the most intensively used organocatalytic modes of activation [12], allowing for the enantioselective α-functionalization of enolizable aldehydes and ketones with a huge variety of electrophiles. The standard catalytic cycle for a chiral amine-catalyzed α-functionalization of a carbonyl compound is depicted in Scheme 2.1. A chiral, 2-substituted pyrrolidine has been chosen as the most representative type of catalyst, acting together with an external Brønsted acid co-catalyst AH. The generalized enamine mechanism involves in the first step the acid-promoted condensation of the carbonyl with the amine to form an iminium ion. One of the α-acidic protons of the iminium ion is then removed by the conjugate base of the acid AH, and the key nucleophilic enamine intermediate is formed. Reaction with the electrophile (generally protonated; the protonation can take place before or during this step) generates another iminium ion, whose hydrolysis liberates the product, the acid, and the amine catalyst, which can reenter the catalytic cycle. The Brønsted acid co-catalyst can be a protic solvent (water, alcohols) or an added external acid, or it can be a functional group present in the amine catalyst (very commonly, the carboxyl moiety of an α-amino acid). The efficiency of this catalytic cycle relies on three important factors: (a) the fast and quantitative generation of the first iminium ion; (b) the regio- and stereoselective conversion of this iminium ion to the (E)-enamine intermediate; and (c) a high stereochemical bias in the electrophilic attack. The natures of the carbonyl compound, of the chiral amine catalyst and of the Brønsted acid co-catalyst are crucial for the first two of these factors. Thus, the highly reactive 2-substituted pyrrolidines are good catalysts for the α-functionalization of α-unsubstituted aldehydes in protic solvents [13]; the somewhat less nucleophilic chiral imidazolidinones require a relatively strong acid as a co-catalyst; and the use of primary amines (also in the presence of an acid co-catalyst, even in protic media) is necessary in some processes involving branched aldehydes or acyclic ketones. An obvious requirement of the catalytic cycle, the fast hydrolysis of the second iminium intermediate relative to its deprotonation to form a β,β-disubstitued enamine, is usually not problematic (at least in the case of secondary amine catalysts) due to the increase in steric hindrance accompanying the electrophilic reaction step. Finally, it is also important that the possible reaction between the nucleophilic amine catalyst and the electrophile is very slow or reversible.

Scheme 2.1 Generalized mechanism for the chiral amine-catalized α-functionalization of carbonyls.

The stereochemical outcome of the reaction of the enamine with the electrophile can easily be predicted in the case of 2-substituted pyrrolidine (or piperidine) catalysts. If the chiral amine bears a hydrogen-bond directing group (a carboxylic acid, an amide or thioamide, a protonated amine) the attack of the electrophile takes place in an intramolecular fashion, via a cyclic transition state (he so-called List–Houk model; Figure 2.1a); on the other hand, if the amine substituent is bulky and without acidic protons, it directs the attack of the electrophile with purely steric effects, leading to the opposite facial stereoselectivity (Figure 2.1b). On the other hand, Seebach, Eschenmoser, and co-workers have proposed an alternative transition state for the first case, in which (after protonation of the electrophile) the electrophilic attack is directed by an intramolecular reaction of the conjugated base of the amine substituent (Figure 2.1c) [14].

Figure 2.1 Working transition state models for the electrophilic attack to the enamine intermediate. (a) List–Houk model. (b) Steric model. (c) Seebach–Eschenmoser model.

Representative chiral primary or secondary amines with carboxylic acid or other hydrogen-bond directing groups used in enamine catalysis are depicted in Figure 2.2, and examples of chiral secondary amines with bulky nonacidic substituents can be found in Figure 2.3. It is important to note, however, that compounds shown in Figure 2.3 bearing both a primary or secondary amine and a tertiary amine, if used in conjunction with an acidic co-catalyst, can act as amine catalysts shown in Figure 2.2 by means of the tertiary ammonium cation.

Figure 2.2 Representative chiral amines with hydrogen-bond directing groups used in asymmetric enamine and iminium catalysis.

Figure 2.3 Representative chiral amines with bulky nonacidic substituents used in enamine and iminium catalysis.

2.2.1.2 Enamine Catalysis with Proline

Proline is arguably the most important asymmetric organic catalyst [15], and in particular the mechanism of proline-catalyzed aldol and related reactions have been the object of numerous experimental and theoretical investigations. The first mechanistic studies on the proline-catalyzed (intramolecular) aldol reaction were reported by Hajos and Parrish in 1974 [5b]. In the first place, these authors demonstrated that both the secondary amine and the carboxylic acid moieties of proline were essential for the reaction (Scheme 2.2). Hajos and Parrish considered two possible mechanisms for the asymmetric catalysis with proline. The first (Figure 2.4A) would involve the formation of a protonated enamine and of an oxazolidinone ring; preliminary results, however, failed to demonstrate the incorporation of ¹⁸O in the optically active ketol when the reaction was run in the presence of ¹⁸O-labeled water and seemed to rule out this mechanism. Therefore they proposed an alternative and less intuitive mechanism, which involved the addition of proline in its zwitterionic form to one of the carbonyl groups of the cyclopentadienone ring (Figure 2.4B).

Figure 2.4 Transition states for the proline-catalyzed intramolecular aldol reaction proposed by Hajos and Parrish (1974).

The relevance of transition state 4B was questioned by Jung [16] and by Brown et al. [17] soon after this initial proposal; these authors favored an enamine transition state similar to that of Figure 2.4A, but in which a nucleophilic attack of the enamine was accompanied by proton transfer from the carboxylic acid to the developing alkoxide. Subsequently, Agami and co-workers observed a small negative nonlinear effect in the Hajos–Parrish reaction [18], and they forwarded a side-chain enamine mechanism that involved two proline molecules in the carbon–carbon bond-forming step, one engaged in enamine formation and the other acting as a proton-tranfer mediator (Figure 2.5).

Figure 2.5 Agami's two-proline transition state model for the Hajos–Parrish reaction (1986).

Agami's model was subsequently challenged by List, Lerner, and Barbas III in 2000 [8a], when they proposed a one-proline enamine mechanism for the proline-catalyzed intermolecular aldol reaction between ketones and aldehydes. Shortly afterwards, on the basis of DFT calculations, Houk and co-workers proposed a very similar mechanism for the Hajos–Parrish intramolecular aldol [19]. Using the B3LYP/6-311+G(2df,p) level of DFT theory, Houk and co-workers [20] have seen that the energy difference between the two possible chair Zimmermann–Traxler-like transition states, which differ in the orientation of the enamine with respect to the carboxylic acid and that lead two opposite enantiomers of the final ketol, is of 2.2 kcal/mol, matching the exact experimental enantioselectivity of the Hajos–Parrish reaction (Figure 2.6). The apparent discrepancy with Agami's model was resolved by experiments carried out by List, Houk, and co-workers [19c], which revealed that a perfect linearity existed between the enantiomeric excess of the proline catalyst and that of the ketol product. The different results were explained by the fact that Agami's experiment was based on only five data points and on optical rotation measurements; List's experiment used 10 data points and HPLC analysis on a chiral stationary phase.

Figure 2.6 The Houk–List model for the Hajos–Parrish reaction (2001).

It is worth noting, however, that nonlinear effects are actually observed in aldol and in other proline (or amino acid)-catalyzed reactions when proline is not completely solubilized in the reaction medium; this phenomenon, which is due to the differential solubility of racemic and of enantiopure solid proline, was independently uncovered by Hayashi, Blackmond, and Breslow [21] and has been proposed as one of the possible mechanisms that led to biomolecular homochirality in prebiotic chemistry [22].

Further experimental support to the Houk–List mechanism was provided by the observation that when the Hajos–Parrish reaction was carried out with a 25 mol% of proline and in the presence of a 3 vol% of H2O¹⁸ in DMSO at rt, after 4 days under argon, rigorously excluding air and moisture, more than 90% incorporation of ¹⁸O had taken place on the aldol product [23].

The Houk–List model was also applied to explain the origin of stereoselectivity in proline-catalyzed intermolecular aldol reactions [19c, 24]. Contrary to the Hajos–Parrish reaction, there is no restriction on the approach of the electrophile. Interestingly enough, theoretical calculations strongly favour an anti proline enamine structure, as well as a re-face attack to the aldehyde carbonyl, minimizing the steric interaction between the enamine and the aldehyde substituent (Figure 2.7), as hypothesized by List, Lerner and Barbas III [8a]. This model correctly predicts the preferential formation of anti-aldol adducts [25].

Figure 2.7 The Houk–List model for intermolecular proline-catalyzed aldol reactions.

In the l-proline-catalyzed intermolecular Mannich reaction [9], the stereoselectivity is opposite that of the aldol reaction: the si face of the imine is preferentially attacked, and the major Mannich adducts have a syn relative configuration. Computational investigations by Bahmanyar and Houk [26] show that the more stable trans-imine acceptor is placed so as to accommodate proton transfer to the nitrogen lone pair which is in a cis relationship with the imine C-substituent; this forces this substituent to occupy a more crowded pseudoaxial position (Figure 2.8). The anti-re Mannich transition state was calculated (in a model compound) to be 3 kcal/mol less stable than the anti-si one. It is worth noting that this model also accounts for the fact that, contrary to aldol reactions, best enantioselectivities are obtained when the C-imine substituent R is a relatively unhindered planar aryl group.

Figure 2.8 The Houk transition state for intermolecular proline-catalyzed Mannich reactions.

The proline-catalyzed nitroso aldol reaction of aldehydes with nitrosobenzene derivatives, simultaneously reported by MacMillan, Zhong, and Hayashi in 2003 [27] has been shown to be a very useful method for the highly enantioselective formation of carbon–oxygen bonds. Different (but closely related) transition state models were initially proposed for this reaction, but theoretical calculations show [28] that that the most favorable transition structure involves proton transfer from the carboxylic acid to the nitrogen atom of the nitroso compound, with anti addition of the enamine to the oxygen atom, in close analogy to the List–Houk model for aldol or Mannich reactions (Figure 2.9).

Figure 2.9 Transition state for the proline-catalyzed nitroso aldol reaction of aldehydes.

Chirality amplification in the proline-catalyzed α-aminoxylation of aldehydes was uncovered and analyzed by Blackmond and co-workers in 2004 [29]. These researchers found that, contrary to what happens in proline-catalyzed aldol reactions, when the reaction was carried out with non-enantiopure proline, the enantiomeric excess of the product was higher than that expected from a linear relationship, and this enantiomeric excess rose over the course of the reaction. These results were rationalized by assuming an autoinductive behavior of the α-aminoxylation product, which formed a new catalytic species via enamine formation with proline, with the additional hypothesis of a matched interaction of l-Pro with the (R)-enantiomer of the product (Scheme 2.3).

Scheme 2.2 Catalysis of the intramolecular aldol reaction by proline, proline methyl ester, and N-methyl proline.

Scheme 2.3 Blackmond's mechanism for product induction and kinetic resolution in the proline-catalyzed α-aminoxylation of aldehydes.

The enantioselectivity of a closely related reaction, the proline-catalyzed α-amination of aldehydes with diazodicarboxylic esters, independently disclosed by List and by Jørgensen in 2002 [30], can also be accounted for by a List–Houk transition state model (Figure 2.10).

Figure 2.10 Transition state for the proline-catalyzed α-amination of aldehydes.

This process, like the proline-catalyzed nitroso aldol reaction, has been shown to exhibit the unusual characteristics of a rising reaction rate and a positive nonlinear effect [31]. An autoinductive reaction resulting in selective formation of a proline-product species in the catalytic cycle, analogous to that depicted in Scheme 2.3, has been invoked by Blackmond [32] to account for these results.

The proline-catalyzed intermolecular Michael reaction of unactivated ketones with nitroalkenes [33] can also be fitted in a mechanistic scenario involving the List–Houk transition state model (Figure 2.11).

Figure 2.11 Transition state for the proline-catalyzed Michael addition of ketones to nitroalkenes.

The intramolecular organocatalytic asymmetric α-alkylation of aldehydes was developed by Vignola and List in 2004 [34]. Experimentally, it was found that 2-methylproline was a much better catalyst than proline itself, and triethylamine accelerated the reaction. A subsequent theoretical study by Fu, List, and Thiel [35] concluded that the reaction proceeds via an enamine displacement of the halogen. Triethylamine was found to provide a salt bridge between the carboxylic acid and the departing halide, and the stereoselectivity of the reaction was shown to arise from preferred cyclization (by ~1 kcal/mol) of an anti-enamine relative to that of the syn-enamine (Figure 2.12). The calculations also indicated that the enhanced enantioselectivity of the 2-methylproline catalyzed aldol reaction compared with the proline-catalyzed process is due to the inherently larger steric interactions between the methyl and the aldehyde substituent in the syn transition state.

Figure 2.12 Lowest-energy transition states for the 2-methylproline-catalyzed intermolecular alkylation of aldehydes.

Thus, a unified model for proline-catalyzed asymmetric α-functionalization of carbonyl compounds by electrophiles uncovered in the period 1971–2006 is provided by the Houk–List transition state and its analogs, which embody three important and general structural elements: (a) preferred anti conformation between the carboxylic acid and the alkene moieties in the intermediate enamine; (b) (E) geometry of the enamine double bond; and (c) protonation of the incoming electrophile by the carboxylic acid that accelerates the reaction by compensating the developing negative charge density and that dictates the stereofacial selectivity of the attack. This model was challenged by Seebach and co-workers in 2007 [14], when they proposed an alternative to the standard enamine catalysis depicted in Scheme 2.1. In Seebach's proposal, the pivotal role is played by a proline-derived oxazolidinone (Seebach's oxazolidinone) instead of an enamine (Scheme 2.4).

Scheme 2.4 Seebach's oxazolidinone pathway for proline catalysis.

In this mechanistic scheme, assumed to take place in an organic solvent, the initial formation of an oxazolidinone between proline and a carbonyl compound brings the highly insoluble proline in solution. This is followed by the slow transformation of the oxazolidinone into an unstable enamine carboxylate intermediate by β-elimination with an external base; in the stereoselectivity-determining step, a trans-addition to the enanime double bond in an electrophile-induced γ-lactonization takes place; finally, hydrolitic cleavage of the product oxazolidinone regenerates proline and affords the α-functionalized carbonyl. The intramolecular Brønsted acid activation of the electrophile of the Houk–List model is replaced by external proton transfer from a protic solvent or from excess proline, and the base necessary for the generation of the enamine carboxylate can again be the conjugate base of the protic solvent, an oxazolidinone itself, or proline. Seebach's model successfully predicts that in the case of unsymmetrical ketones, the smaller substituent will be placed in the more hindered concave face of the bicyclic oxazolidinone intermediate, so that the formation of the enamine carboxylate will be highly regioselective, with elimination taking place at the substitutent on the convex face (of course, in the case of aldehydes, the hydrogen atom will majoritarily end up in the concave face of the oxazolidinone). The enamine carboxylate is formed in a syn-conformation; electrophile-induced trans-addition from this conformer leads to the product oxazolidinone in which the smallest carbonyl substituent is in the concave face. This oxazolidinone (whose hydrolysis liberates the product with the experimentally observed major configuration) is more stable than the one that would arise from an anti-conformer of the enamine carboxylate (Scheme 2.5).

Scheme 2.5 Regio- and stereoselectivity of the proline-catalyzed α-electrophilic substitution of an unsymmetrical ketone, according to Seebach's model.

The regio- and the stereoselectivity of proline-catalyzed α-electrophilic substitution of carbonyl compounds can therefore be successfully explained by the oxazolidinone model, although the diastereoselectivity of the aldol and Mannich reactions was not taken into account in Seebach's discussion. Moreover, the model also could explain the autoinductive effects observed by Blackmond in the proline-catalyzed nitroso aldol and α-amination reactions of aldehydes [29, 31], by simply assuming that the oxazolidinone product acts as a base in the rate-determining enamine formation step. Kinetic resolution of proline, leading to chirality amplification effects, would be accounted for by the greater thermodynamic stability of the matched oxazolidinone product. In fact, the formation of Seebach's oxazolidinones, rather than enamines or iminium ion intermediates, from ketones and proline in DMSO solution had been described by List et al. in 2004 [23], but they concluded that this was a parasitic equilibrium leading to an unproductive intermediate. On the other hand, the product oxazolidinone in the proline-catalyzed α-amination of propanal with diethyl azodicarboxylate had been isolated in the same year by Blackmond [31, 32] and was shown to be a catalytically competent species. The catalytic ability of preformed proline-derived oxazolidinones, much more soluble than proline in organic solvents, had been demonstrated by Seebach and co-workers [14] and was corroborated shortly afterwards by Vilarrasa and co-workers [36]. In the course of studies devoted to the clarification of the role of water in proline-mediated intermolecular aldol reactions, Blackmond and co-workers [37] observed the fast and irreversible formation of an oxazolidinone between p-nitrobenzaldehyde and proline, which leads to catalyst inactivation by means of a decarboxylation reaction followed by dipolar cycloaddition to benzaldehyde (Scheme 2.6).

Scheme 2.6 Proline deactivation by oxazolidinone formation from electron-deficient aldehydes.

Moyano, Rios, and co-workers [38] have shown that the beneficial effect of hydrogen-bond donors in proline-catalyzed aldol reactions in nonpolar solvents [39] is due both to the facilitation of proline solubilization by formation of an oxazolidinone with the ketone and to the stabilization of the iminium carboxylate zwitterionic form that is the direct precursor of the reactive enamine intermediate, and not to proline solubilization by formation of a hydrogen-bonded complex (Scheme 2.7) [40].

Scheme 2.7 Thiourea-assisted oxazolidinone formation and aldol reaction in nonpolar solvents.

McQuade and co-workers [41] found that while the rate of proline-catalyzed α-aminoxylation of aldehydes in chloroform or ethyl acetate is significantly increased by the presence of a bifunctional urea, this effect is not observed when the catalyst is a 2-pyrrolidine-tetrazole, which cannot form an oxazolidinone. On the other hand, a similar rate acceleration was observed when the catalyst was the preformed Seebach oxazolidinone derived from proline and hexanal, or the soluble trans-4-(tert-butyldimethylsilyloxy)proline. NMR studies also showed that the role of the urea was to promote both (a) proline solubilization by formation of the oxazolidinone (not by direct solubilization of proline, in agreement with the results of Moyano et al. [38]) and (b) enamine generation from the intermediate oxazolidinone. Moreover, a kinetic analysis proved that the autoinductive effects previously disclosed by Blackmond and co-workers [29] were suppressed by the presence of the urea. These results appear to give support to the Blackmond's autoinduction hypothesis of Scheme 2.3, and the authors suggest the coexistence of two reaction pathways (Scheme 2.8). In the absence of urea, enamine generation from the initially formed oxazolidinone is slow, and rate acceleration by product autoinduction is observed; when urea is present, the rate of enamine generation is increased, and the standard noninductive pathway is favored. The catalytic activity of proline-derived imidazolidinethiones and of imidazolidinones in aldol reactions has been demonstrated by Gryko and co-workers [42] and by Morán and co-workers [43], respectively.

Scheme 2.8 MacQuade's merging of Seebach and Blackmond pathways for proline-catalyzed aldehyde α-aminoxylation.

The equilibria between bicyclic oxazolidines and enamines derived from prolinol derivatives and aldehydes have been studied spectroscopically by Schmid et al. [44] In the case of prolinol, the less stable endo-oxazolidinone is the kinetic product, which is in equilibrium with the anti-enamine conformer. The zwitterionic amonium alkoxide, not detected, is the key intermediate in the oxazolidine–enamine equilibrium. For diarylprolinol derivatives, minor amounts of enamine can be detected, and only the endo-oxazolidinone is observed (Scheme 2.9).

Scheme 2.9 Oxazolidine–enamine equilibria for prolinol derivatives.

Recently, Domínguez de María and co-workers [45] have studied experimentally the influence of the organocatalyst on the outcome of the aldol reaction reaction between acetone and isobutyraldehyde. Organocatalysts able to form bicyclic oxazolidine intermediates (proline and prolinol) led predominantly to aldol adducts, while organocatalysts unable to form these oxazolidines (pyrrolidine, O-methyl prolinol and proline tert-butyl ester) afforded preferently (>2.5:1) the condensation product. In summary, most of the experimental evidence points toward a distinct catalytic role of oxazolidinone intermediates in proline-catalyzed reactions. It should be pointed out, however, that DFT studies of the proline-catalyzed self-aldol reaction of propanal, in which the enamine carboxylic acid and the oxazolidinone pathways were compared, concluded that the Seebach model was inadequate for rationalizing the stereochemical outcome of the reaction, since it predicted the majoritary formation of the syn diastereomer of the aldol product [46].

On the other hand, several specific features of Seebach's mechanistic scheme have met considerable criticism. The assumption that the enamine formation is the rate-determining step in proline-mediated aldol reactions (in DMSO or DMF as the solvent) has been experimentally challenged by Blackmond and co-workers [47], since the reaction rate depends on the concentrations of both the donor ketone and the electrophilic aldehyde. Instead, the observed kinetics and deuterium isotope effects are consistent with formation of the product iminium (or oxazolidinone) as being the rate-determining step. Building on these results, Armstrong, Blackmond, and co-workers [48] have proposed that the differences in the kinetic behavior of proline-catalyzed aldol reactions compared to aminoxylation and amination reactions can be explained by assuming that in the former reaction the product-forming step is the rate-determining step, while in the latter the enamine generation step is the slowest one, in line with the proposal of McQuade and co-workers [41]. Houk's theoretical and experimental studies (kinetic isotope effects) of the intramolecular proline-catalyzed aldol reaction [19e] suggest, however, that in that case enamine generation could be the rate-limiting step. High-level theoretical calculations on the proline-catalyzed aldol addition of acetone to acetaldehyde (including solvation correction) show that the enamine generation step has a somewhat higher activation energy (by 1–3 kcal/mol) than the carbon–carbon bond formation step [3, 24b, 24c, 49]. The nature of the transition state in proline-catalyzed α-electrophilic substitution of carbonyl compounds has also been the object of intense debate after the publication of Seebach's proposal. List and co-workers [50] have isolated both aldehyde and ketone enaminones (for which oxazolidinone formation is thermodynamically disfavored) and examined their crystal structures. The vast majority (only one exception) of the X-ray diffraction structures resolved showed an anti conformation, in accordance to the List–Houk transition state (Figure 2.13). It can be argued, however, that this does not strictly apply to Seebach's mechanism, which assumes a kinetically controlled generation of the less stable syn-enamine carboxylate.

Figure 2.13 Proline-derived enaminones prepared by List.

Blackmond, Armstrong, and co-workers [51] have studied the effect of base in the proline-catalyzed α-amination of propanal. In the presence of 0.9 molar equivalents of DBU with respect to proline (fully solublized in chloroform), the kinetic profile is altered, indicating the absence of autoinductive processes; moreover, the presence of DBU induces a reversal of the absolute configuration of the major product from 85% ee (R) to 46% (S) (Scheme 2.10).

Scheme 2.10 Reversal of enantioselectivity in the proline-mediated α-amination of aldehydes induced by tertiary amines.

This reversal was explained by a change from the List–Houk transition state (see Figure 2.10) to an anti-enamine carboxylate transition state induced by the tertiary amine additive. The role