Catalytic Asymmetric Synthesis, 3rd Edition, 2010, Ojima. ISBN 978-0-470-17577-4
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Jia-Lei Yan, Hongling Wang, and Yonggui Robin Chi
16 Asymmetric Nucleophilic Addition to Ketones and Ketimines and Conjugate Addition Reactions
Luo Ge and Syuzanna R. Harutyunyan
Tyler J. Fulton, Yun E. Du, and Brian M. Stoltz 18
Ken Tanaka
Shaohua Xiang, Jun Kee Cheng, and Bin Tan
Takanori Shibata
Jie Li and Xiao-Bing Lu
Haruro Ishitani, Yuki Saito, and Shu Kobayashi
PREFACE
The first, second, and third editions of Catalytic Asymmetric Synthesis published in 1993, 2000, and 2010, respectively, were warmly received by research communities in academia and industries, from graduate students, research associates, faculty, staff, senior researchers, and others. Catalytic Asymmetric Synthesis has become a common tool for the synthesis of enantiopure compounds in both industry and academia.
The Nobel Prize in Chemistry 2001 was given to W. Knowles, K. B. Sharpless, and R. Noyori for their outstanding contributions to the advancement of catalytic asymmetric synthesis, using transition-metal catalysis. Quite recently it was announced that Benjamin List and David MacMillan won the Nobel Prize in Chemistry 2021 for their work on the development of asymmetric organocatalysis, using small organic molecule. This is the second Nobel Prize given to the field of asymmetric catalysis, following the Nobel Prize in Chemistry 2001, which clearly indicates the profound importance of asymmetric catalysis.
More than 10 years have passed after the third edition was published, and 2010s has witnessed revolutionary advancement of asymmetric catalysis. Therefore, the publication of the fourth edition of this book series, capturing the highly innovative progress in this field, deemed in demand and was fully justified. In order to cover the revolutionary advances in the last decade, Takahiko Akiyama joined as the leading editor in this fourth edition.
In the first and second editions, chiral metal-based catalysts played the central roles for the asymmetric synthesis because transition-metal-catalyzed enantioselective reactions were extensively studied, in particular, in the 1980s and 1990s. Organocatalysis, Lewis and Brønsted acids, C–H activation, carbonheteroatom bond forming reactions, and enzyme-catalyzed reactions were introduced in the third edition.
After 2010, in addition to transition-metal catalyzed reactions, organocatalysis, including Brønsted acids and C–H activation reactions, has been making remarkable advances. Photoredox catalysis emerged as a useful new synthetic reaction mainly after 2008 and has been rapidly growing and has become a critical methodology. Because the chapters in the third edition are still very informative and the methodologies described therein are still inspiring and stimulating even today, those methodologies are considered “classics” in catalytic asymmetric synthesis.
We decided to edit a new book, which would be the most useful desktop reference book by covering new methodologies, but at the same time keeping the progress in the “classics” of the third edition. In order to capture the most significant progress in the 2010s, several new chapters of organocatalysis are introduced, i.e., enamine and iminium catalysis (Chapter 1), acid catalysis (Chapter 2), base catalysis (Chapter 3), phase transfer catalysis (Chapter 4), peptide catalysis (Chapter 5), carbene catalysis (Chapter 6), and hypervalent catalysis (Chapter 7). Photochemical reactions are also introduced, i.e., photoredox catalysis (Chapter 8), photoredox reactions in the absence of photoredox catalysis (Chapter 9), and [2 + 2] cycloaddition reactions (Chapter 10). The asymmetric C–H bond activation reactions are covered by two chapters, i.e., C(sp2)–H bond (Chapter 11) and C(sp3)–H bond (Chapter 12).
Asymmetric halogenation reaction, enzyme-catalyzed asymmetric synthesis, asymmetric hydrogenation, and asymmetric polymerization are presented in Chapters 13, 14, 15, and 21. The construction of noncentrochiral compounds are discussed in two chapters, i.e., axially chiral compounds (Chapter 19) and planar chiral and helically chiral compounds (Chapter 20). Finally, applications of continuous flow technology to catalytic asymmetric synthesis, which may dramatically change manufacturing processes for pharmaceutical drugs and chiral materials, is discussed in Chapter 21.
We sincerely hope that this book attracts the interest of broad range of synthetic, organic, medicinal, and material chemists, in particular, among the younger generation researchers in both academia and industry, who can bring in creative ideas and innovative approaches to Catalytic Asymmetric Synthesis and advance it to the new height.
Iwao Ojima November, 2021
Takahiko Akiyama
PREFACE TO THE FIRST EDITION
Biological systems, in most cases, recognize a pair of enantiomers as different substances, and the two enantiomers will elicit different responses. Thus, one enantiomer may act as a very effective therapeutic drug, whereas the other enantiomer is highly toxic. The sad example of thalidomide is well-known. It is the responsibility of synthetic chemists to provide highly efficient and reliable methods for the synthesis of desired compounds in an enantiomerically pure state, that is, with 100% enantiomeric excess (% ee), so that we shall not repeat the thalidomide tragedy. It has been shown for many pharmaceuticals that only one enantiomer contains all of the desired activity, and the other is either totally inactive or toxic. Recent movements of the Food & Drug Administration (FDA) in the United States clearly reflect the current situation in “Chiral Drugs,” that is, pharmaceutical industries will have to provide rigorous justification to obtain the FDA’s approval of racemates. Several methods are used to obtain enantiomerically pure materials, which include classical optical resolution via diastereomers, chromatographic separation of enantiomers, enzymic resolution, chemical kinetic resolution, and asymmetric synthesis.
The importance and practicality of asymmetric synthesis as a tool to obtain enantiomerically pure or enriched compounds have been fully acknowledged to date by chemists in synthetic organic chemistry, medicinal chemistry, agricultural chemistry, natural products chemistry, pharmaceutical industries, and agricultural industries. This prominence is due to the explosive development of newer and more efficient methods during the last decade.
This book describes recent advances in catalytic asymmetric synthesis with brief summaries of the previous achievements as well as general discussions of the reactions. A previous book reviewing this topic, Asymmetric Synthesis, Vol. 5—Chiral Catalysis, edited by J. D. Morrison (Academic Press, Inc., 1985), compiles important contributions through 1982. Another book, Asymmetric Catalysis, edited by B. Bosnich (Martinus Nijhoff, 1986) also concisely covers contributions up to early 1984. In 1971, an excellent book, Asymmetric Organic Reactions, by J. D. Morrison and H. S. Mosher, reviewed all earlier important work on the subject and compiled nearly 850 relevant publications through 1968, including some papers published in 1969. In the early 1980s, a survey of publications dealing with asymmetric synthesis (in a broad sense) indicated that the total number of papers in this area of research published in the 10 years after the Morrison/ Mosher book, that is, 1971–1980, was almost the same as that of all the papers published before 1971. This doubling of output clearly indicates the attention paid to this important topic in 1970s. Since the 1980s, research on asymmetric synthesis has become even more important and popular when enantiomerically pure compounds are required for the total synthesis of natural products, pharmaceuticals, and agricultural agents. It would not be an exaggeration to say that the number of publications on asymmetric synthesis has been increasing exponentially every year.
Among the types of asymmetric reactions, the most desirable and the most challenging is catalytic asymmetric synthesis because one chiral catalyst molecule can create millions of chiral product molecules, just as enzymes do in biological systems. Among the significant achievements in basic research: (i) asymmetric hydrogenation of dehydroamino acids, a groundbreaking work by W.S. Knowles et al.; (ii)
the Sharpless epoxidation by K.B. Sharpless et al.; and (iii) the second-generation asymmetric hydrogenation processes developed by R. Noyori et al. deserve particular attention because of the tremendous impact that these processes have made in synthetic organic chemistry. Catalytic asymmetric synthesis often has significant economic advantages over stoichiometric asymmetric synthesis for industrial-scale production of enantiomerically pure compounds. In fact, a number of catalytic asymmetric reactions, including the “Takasago Process” (asymmetric isomerization), the “Sumitomo Process” (asymmetric cyclopropanation), and the “Arco Process” (asymmetric Sharpless epoxidation), have been commercialized in the 1980s. These processes supplement the epoch-making “Monsanto Process” (asymmetric hydrogenation), established in the early 1970s. This book uncovers other catalytic asymmetric reactions that have high potential as commercial processes. Extensive research on new and effective catalytic asymmetric reactions will surely continue beyond the year 2000, and catalytic asymmetric processes promoted by man-made chiral catalysts will become mainstream chemical technology in the twenty-first century.
This book covers the following catalytic asymmetric reactions: asymmetric hydrogenation (Chapter 1), isomerization (Chapter 2), cyclopropanation (Chapter 3), oxidations (epoxidation of allylic alcohols as well as unfunctionalized olefins, oxidation of sulfides, and dihydroxylation of olefins) (Chapter 4), hydrocarbonylations (Chapter 5), hydrosilylation (Chapter 6), carbon–carbon bond-forming reactions (allylic alkylation, Grignard cross-coupling, and aldol reaction) (Chapter 7), phase-transfer reactions (Chapter 8), and Lewis acid-catalyzed reactions (Chapter 9). The authors of the chapters are all world leaders in this field, who outline and discuss the essence of each catalytic asymmetric reaction. In addition, a convenient list of the chiral ligands appearing in this book, with citation of relevant references, is provided as an Appendix.
This book serves as an excellent reference for graduate students as well as chemists at all levels in both academic and industrial laboratories.
Iwao Ojima March, 1993
LIST OF CONTRIBUTORS
Lutz Ackermann, Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany and Wöhler Research Institute for Sustainable Chemistry (WISCh), Georg-August-Universität Göttingen, Göttingen, Germany
Takahiko Akiyama, Department of Chemistry, Gakushuin University, Tokyo, Japan
Andrés R. Alcántara, Department of Chemistry in Pharmaceutical Sciences, Section of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
Thorsten Bach, School of Natural Sciences, Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Garching, Germany
Eva Bednár ˇ ová, Department of Chemistry, Columbia University, New York, NY, USA
Jun Kee Cheng, Department of Chemistry, Southern University of Science and Technology, Shenzhen, China
Aurélie Claraz, Institut de Chimie des Substances Naturelles, Université Paris Saclay, Gif-sur-Yvette, France
Uttam Dhawa, Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany
Yun E. Du, California Institute of Technology, Pasadena, CA, USA
Jorge Escorihuela, Department of Organic Chemistry, Pharmacy Faculty, University of Valencia, Valencia, Spain
Tyler J. Fulton, California Institute of Technology, Pasadena, CA, USA
Santos Fustero, Department of Organic Chemistry, Pharmacy Faculty, University of Valencia, Valencia, Spain
Luo Ge, Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands
Gonzalo de Gonzalo, Department of Organic Chemistry, University of Seville, Seville, Spain
Arnald Grabulosa, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Barcelona, Spain, and Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, Spain
Syuzanna R. Harutyunyan, Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands
Freya M. Harvey, School of Natural Sciences, Department Chemie and Catalysis Research Center (CRC), Technische Universität München, Garching, Germany
Yujiro Hayashi, Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, Japan
Kazuaki Ishihara, Graduate School of Engineering, Nagoya University, Nagoya, Japan
Haruro Ishitani, Green & Sustainable Chemistry Social Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Tokyo, Japan
Loránd Kiss, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary
Shu Kobayashi, Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan and Green & Sustainable Chemistry Social Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Tokyo, Japan
Kazuaki Kudo, Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
Azusa Kondoh, Graduate School of Science, Tohoku University, Sendai, Japan
Jie Li, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China
Xiao-Bing Lu, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, China
Jiyuan Lyu, Institut de Chimie des Substances Naturelles, Université Paris Saclay, Gif-sur-Yvette, France
Dengke Ma, ICIQ – Institute of Chemical Research of Catalonia, Tarragona, Spain
Géraldine Masson, Institut de Chimie des Substances Naturelles, Université Paris Saclay, Gif-surYvette, France
Mercedes Medio-Simón, Department of Organic Chemistry, Pharmacy Faculty, University of Valencia, Valencia, Spain
Paolo Melchiorre, ICIQ – Institute of Chemical Research of Catalonia, Tarragona, Spain and ICREA – Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
Edward Miller, University of California, Berkeley, Berkeley, CA, USA
Patrick J. Moon, University of California, Berkeley, Berkeley, CA, USA
Attila M. Remete, Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary and Interdisciplinary Excellence Centre, Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary
Antoni Riera, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Barcelona, Spain and Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Yonggui Robin Chi, Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore and Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, China
Tomislav Rovis, Department of Chemistry, Columbia University, New York, NY, USA
Yuki Saito, Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
Daniel M. Sedgwick, Department of Organic Chemistry, Pharmacy Faculty, University of Valencia, Valencia, Spain
Yangyang Shen, Department of Chemistry, Columbia University, New York, NY, USA
Takanori Shibata, Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, Tokyo, Japan
Brian M. Stoltz, California Institute of Technology, Pasadena, CA, USA
Bin Tan, Department of Chemistry, Southern University of Science and Technology, Shenzhen, China
Ken Tanaka, Department of Chemical Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan
Masahiro Terada, Graduate School of Science, Tohoku University, Sendai, Japan
F. Dean Toste, University of California, Berkeley, Berkeley, CA, USA
Muhammet Uyanik, Graduate School of Engineering, Nagoya University, Nagoya, Japan
Xavier Verdaguer, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Barcelona, Spain and Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
Anton Vidal-Ferran, Departament de Química Inorgànica i Orgànica, Facultat de Química, Universitat de Barcelona, Barcelona, Spain and Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain and Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, Spain
Hongling Wang, Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, China
Tomasz Wdowik, Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Göttingen, Germany
Thomas Hin-Fung Wong, ICIQ – Institute of Chemical Research of Catalonia, Tarragona, Spain
Shaohua Xiang, Department of Chemistry, Southern University of Science and Technology, Shenzhen, China
Jia-Lei Yan, Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore, Singapore
Xiao Zhang, Department of Chemistry, Columbia University, New York, NY, USA
PART I
ASYMMETRIC
ORGANOCATALYSIS
ASYMMETRIC
ENAMINE AND IMINIUM ION CATALYSIS
Yujiro Hayashi
Department
of Chemistry,
Graduate School of Science, Tohoku University, Sendai, Japan
1.1. INTRODUCTION
Enamines are key reactive species in many asymmetric organocatalytic reactions. The field of asymmetric catalytic reactions involving an enamine as a reactive intermediate dates back to the seminal work in the 1970s on proline-mediated intramolecular aldol reaction of triketone reported by Hajos and Parrish at Hoffmann-La Roche [1] and Eder, Sauer, and Wiechert at Schering AG [2] (Eq. 1.1). In 2000, List, Lerner, and Barbas reported a proline-mediated intermolecular aldol reaction (Eq. 1.2) [3], in which enamine is a key intermediate. In the same year, MacMillan reported a Diels-Alder reaction catalyzed by a chiral imidazolidinone via an iminium ion as a reactive intermediate (Eq. 1.3) [4]. In these reactions, small organic molecules catalyze reactions enantioselectively. Since these discoveries, chemistry based on organocatalysts involving an enamine and an iminium ion as an intermediate has developed dramatically [5]. There are several advantages to performing reactions with organocatalysts: (i) exclusion of water and air is not necessary, (ii) the product is free from metal contamination, (iii) most of the organocatalysts are nontoxic, (iv) most reactions do not need low temperature or high temperature, and (v) it is easy to carry out the reaction on a large scale. Given these merits, many catalysts and reactions have been developed. In the previous book of this series published in 2010 [6], progress in the field of organocatalysis is nicely summarized up to 2010. In this chapter, a brief introduction to enamine and iminium ion species will be presented, including work before 2010, and more recent developments in this field will be expanded. Reactions using a combination of organocatalyst and photocatalyst, which have been developed recently, will be described in Chapter 9 of this book.
Enamines are generated from aldehydes or ketones upon reaction with secondary or primary amines, and the enamine can react with an electrophile to give an α-functionalized derivative of the carbonyl compounds (Eq. 1.4).
α,β-Unsaturated aldehydes or ketones also react with secondary or primary amines to generate an iminium ion, which has lower LUMO (lowest unoccupied molecular orbital) level compared with the parent α,β-unsaturated carbonyl compound. A nucleophile reacts with the iminium ion to afford a βfunctionalized derivative of the carbonyl compound (Eq. 1.5).
Enamine and iminium ions are reactive species and many reactions involving these intermediates have been developed. Representative organocatalysts that have been used to generate enamines and iminium ions are presented in Figure 1.1.
Proline is a secondary amine catalyst that was first used in the intramolecular aldol reaction in the 1970s (Eq. 1.1). It is a bifunctional catalyst, possessing an amine moiety and an acid moiety (carboxylic acid) vide infra [3]. Imidazolidinone catalyst, which was developed by MacMillan, is a secondary amine catalyst prepared from phenylalanine [4]. Diarylprolinol silyl ether [7], which was developed by Jørgensen [8] and Hayashi [9] independently at the same time, is synthesized from proline; it is also a secondary amine catalyst. These two catalysts are not bifunctional catalysts, and do not possess an acid moiety. Cinchona amine-based catalysts [10] are prepared from cinchona alkaloids, which are primary amines. This catalyst has several functional groups, and acts as a bifunctional catalyst.
Figure 1.1. Representative organocatalysts.
Cinchona amine-based catalyst
Figure 1.2. The reaction of enamines generated from diphenylprolinol silyl ether and proline.
The design concepts underlying bifunctional and monofunctional organocatalysts are different. Diphenylprolinol silyl ether, a monofunctional catalyst, reacts with an aldehyde to generate an enamine, in which one of the enantiofaces of the enamine is completely shielded by the bulky diphenyltrimethylsiloxymethyl moiety, and an electrophile approaches from the opposite side of this bulky substituent (Figure 1.2). Thus, the steric shielding of one of the enantiofaces is a key for the high enantioselectivity. Irrespective of the electrophile, high enantioselectivity is expected because the enantioface selectivity of the nucleophile is controlled by the catalyst. This is a contrast to bifunctional catalysts such as proline, in which an acid moiety activates the electrophile. Thus, the most suitable catalyst for a given reaction depends on the electrophile.
1.2.2. Reactivity of Diphenylprolinol Silyl Ether Catalyst and MacMillan’s Catalyst
Diphenylprolinol silyl ether catalyst and MacMillan’s catalyst are widely used in reactions involving enamine or iminium ion intermediates. In this section, the reactivity of these catalysts will be discussed. Mayr investigated the nucleophilicity (N) of enamines, and the electrophilicity (E) of iminium ions of several pyrrolidines and imidazolidinones (Figure 1.3) [11]. For enamines, the nucleophilicity is evaluated by the reaction with diarylcarbenium ions, and it correlates poorly with the Brønsted basicities. The enamine, which is derived from diphenylprolinol silyl ether catalyst 2, is almost two orders of magnitude less reactive than the corresponding enamine prepared from pyrrolidine. The reduction of the reactivity is primarily due to the electron-withdrawing inductive effect of the trimethylsiloxybenzhydryl group in diphenylprolinol silyl ether catalyst. The reactivity of the enamine generated from MacMillan’s catalyst 1 is another two to three orders of magnitude less reactive relative to the enamine of diphenylprolinol silyl ether catalyst, because of the inductive electron-withdrawing effect of the extra endocyclic amide group in the catalyst, the pyramidalization of the enamine nitrogen, and the steric shielding of both faces of the C=C bond by the two alkyl groups at the 2-position of the imidazolidinone ring.
In the case of iminium ions, the iminium ion generated from diphenylprolinol silyl ether is 20 times more electrophilic than the iminium ion derived from the parent pyrrolidine because of the electronwithdrawing substituents. The iminium ion of MacMillan’s catalyst, which is useful for the Diels-Alder reaction, is more reactive than the iminium ion derived from diphenylprolinol silyl ether.
These investigations indicate that MacMillan’s catalyst is more electron deficient, and that its iminium ion is reactive because of the lower LUMO level. Diphenylprolinol silyl ether catalyst possesses suitable nucleophilicity and electrophilicity of its enamine and its iminium ion, respectively. Thus, this catalyst is effective for domino reactions (see Figure 1.3).
Figure 1.3. Nucleophilicity and electrophilicity of enamines and iminium ions. Source: Based on [11].
1.2.3. Cinchona Amine-Based Catalysts
Some secondary amine catalysts, such as diphenylprolinol silyl ether, are effective catalysts in Michael reactions using an aldehyde as a Michael donor (see Scheme 1.1), but these catalysts are not effective in Michael reactions using a ketone as a Michael donor because generation of an enamine from a ketone using diphenylprolinol silyl ether is hindered by its steric bulk. On the other hand, a primary amine can easily generate an enamine from a ketone. Primary amine catalysts derived from cinchona alkaloids have enabled the stereoselective functionalization of a variety of sterically hindered carbonyl compounds, which cannot be realized by secondary amine catalysts (Scheme 1.1) [10]. Moreover, primary amine catalysts can activate structurally substituted substrates such as α-branched substituted aldehydes and ketones. They also activate α-substituted α,β-unsaturated aldehydes and ketones. The reactions of these substrates using chiral cyclic secondary amine catalysts are difficult.
Scheme 1.1. Reactions of cinchona alkaloid catalysts. Source: Based on [10].
Cinchona alkaloid catalysts act as efficient bifunctional catalysts. They possess a primary amine moiety that can react with aldehydes, ketones, and α,β-unsaturated carbonyl compounds to generate enamines and imines. The catalysts have a basic quinuclidine moiety, which acts as a base, and a hydroxy or alkoxy group on C9, which can make a hydrogen-bonding interaction. Thus, they can simultaneously activate both electrophilic and nucleophilic reagents in a reaction.
1.3. ENAMINE
1.3.1.
Aldol Reaction
Aldol reaction is one of the most important carbon–carbon bond-forming reactions in synthetic organic chemistry, and the application of organocatalysts in this reaction has been investigated intensively [12]. The basic design of catalysts for aldol reactions is a bifunctional catalyst such as proline, with acid and basic moieties (Figure 1.4) [13]. The amine moiety reacts with a carbonyl group to generate an enamine, while the acid moiety activates the electrophile. Based on this concept, many bifunctional aldol catalysts have been developed.
Although proline is an effective and inexpensive organocatalyst, its solubility in organic solvents is poor; rather large loading of the catalyst is necessary, and applicable aldol reactions are limited. This has driven the development of organocatalysts that are more reactive and selective than proline, and the substrate scope has been expanded greatly. These developments have been nicely summarized in several reviews [12].
In the proline-mediated aldol reactions, the anti-isomer was obtained predominantly, which is explained by List–Houk model (Figure 1.4). In most of the aldol reactions catalyzed by organocatalyst, the anti-isomer is generated predominantly. The development of syn-selective and enantioselective aldol reactions catalyzed by organocatalyst is a challenging problem. Maruoka developed a biphenyl-based axially chiral amine with a triflamide moiety (Eq. 1.6). This catalyst is a syn-selective catalyst and gave excellent enantioselectivity [14].
Acetaldehyde is a synthetically useful aldehyde that can act as both a nucleophile and an electrophile. Given its high reactivity, it is difficult to use acetaldehyde as a nucleophile in the aldol reaction even with a metal catalyst. Hayashi developed diarylprolinol, which is an effective catalyst with acetaldehyde as a nucleophile (Eq. 1.7) [15]. This catalyst is also effective in the other cross-aldol reactions of two different aldehydes [16].
Figure 1.4. Transition state for the aldol reaction catalyzed by proline. Source: Based on [13].
1.3.2. Mannich Reaction
The Mannich reaction is important for the construction of nitrogen-containing molecules. List reported the three-component Mannich reaction of aldehyde, ketone, and anisidine catalyzed by proline in 2000 (Eq. 1.8) [17]. Barbas reported the syn-selective Mannich reaction of N-PMP-protected α-imino ethyl glyoxylate and an aldehyde, or ketone, in 2002 (Eq. 1.9) [18]. Whereas syn-selectivity is explained by the model shown in Figure 1.5, the anti-selective Mannich reaction is a challenging task. Nevertheless, an axially chiral sulfonamide, developed by Maruoka, was successfully used to afford anti-selective Mannich products [19]. In addition to simple aliphatic aldehydes, an α-amino acetaldehyde as a nucleophile afforded an anti-vicinal diamine derivative (Eq. 1.10).
Antiselective, 97 – 99% ee
Instead of using a bifunctional catalyst, organocatalysts without an acid moiety, such as diphenylprolinol silyl ether, are effective catalysts in the Mannich reaction to afford the anti-product selectively with excellent enantioselectivity (Eq. 1.11) [20].
Figure 1.5. Transition state of the Mannich reaction.
1.3.3. Other Functionalization of the α-Position of Carbonyl Groups
Bifunctional organocatalysts are effective not only for the aldol and Mannich reactions but also for functionalization of the α-position of carbonyl compounds. α-Fluorination [21], α-bromination [22], and αiodination [23] of aldehydes are successfully carried out by the use of organocatalyst. Azodicarboxylate is used in the α-amination of aldehydes catalyzed by proline [24]. α-Aminoxylation of carbonyls is catalyzed by proline [25] and proline salt [26] using nitrosobenzene as an electrophile. These reactions are summarized in the previous book [6].
1.3.4. Michael Reaction
Organocatalysts are also useful for the addition of carbonyl compounds to electron-deficient alkenes, known as the Michael reaction. The reaction of aldehydes and nitroalkenes catalyzed by organocatalyst is a wellinvestigated reaction. In 2005, diphenylprolinol silyl ether was applied to this reaction, which afforded a Michael product with excellent diastereo- and enantioselectivity (Eq. 1.12) [9]. It was also found that an acid additive accelerates the reaction, and the effect of the acid has been investigated in detail (Scheme 1.2) [27]. An enamine and a nitroalkene react to afford cyclobutane A and dihydro-oxazine N oxide B as initial products, which were converted into the Michael product, and acid affects this conversion step.
syn:anti = >95: 5, 99% ee
As a Michael acceptor, not only nitroalkene but also vinyl sulfones [28], β-substituted α-nitroacrylates [29], dicyanoalkenes [30], and β-substituted α-cyano α,β-unsaturated esters [31] can be successfully employed to afford the Michael products with excellent diastereo- and enantioselectivity (Eq. 1.13).
Low catalyst loading and the development of a reactive catalyst are important issues for the asymmetric synthesis of chiral molecules. For the Michael reaction of aldehydes and nitroalkenes, Wennemers reported a very active tripeptide catalyst H- d - Pro- Pro- Glu- NH 2, which catalyzes the Michael reaction of butanal and nitrostyrene in the presence of only 0.1 mol% of the catalyst (Eq. 1.14) [32]. This catalyst is a bifunctional catalyst, possessing a secondary amine moiety and an acid moiety.
CHCl3:i-PrOH = 9: 1, rt, 48 h
87%, syn:anti = 94: 6, 97% ee
1.3.5. Dienamine and Trienamine as an Intermediate [33]
Enamine chemistry was extended to dienamine chemistry: diarylprolinol silyl ether reacts with an α,βunsaturated aldehyde to generate an iminium ion, which is further converted into a dienamine. As dienamines are electron-rich, they act as reactive dienes in the Diels-Alder reaction. The 1,4-position of the original aldehyde reacts with a dienophile. Jørgensen reported the reaction of a dienamine with azodicarboxylate, in which only the s-cis dienamine from a mixture of s-cis and s-trans isomers reacts in a concerted fashion (Diels-Alder reaction) to afford the product with excellent enantioselectivity (Eq. 1.15) [34].
Scheme 1.2. The reaction mechanism of the Michael reaction of aldehyde and nitroalkene. Source: Based on [27].
A dienamine is successfully utilized in the enantioselective synthesis of a key intermediate of 14βsteroids by the reaction of an enal with a cyclic dienophile in the presence of diphenylprolinol silyl ether (Eq. 1.16). This reaction allows easy access to an optically active steroid core with a variety of substituents in the A ring in high yields and up to more than 99% ee. (+)-Estrone was efficiently synthesized by using this reaction as a key step [35].
This dienamine system was further extended to trienamine chemistry. Chen and Jørgensen reported the generation of an electron-rich trienamine from a polyconjugated 2,4-dienal. By a reaction with a dienophile, a cycloaddition reaction proceeded to afford a spirocyclic oxindole possessing a cyclohexene moiety with an exclusive β,ε-regioselectivity and excellent stereoselectivity (Eq. 1.17) [36].
1.4. IMINIUM ION
1.4.1. Introduction of an Iminium Ion
MacMillan reported the Diels-Alder reaction using a chiral imidazolidinone, which reacts with an α,βunsaturated aldehyde to afford an iminium ion. The iminium ion is a highly electron-withdrawing group; its alkene has a lower LUMO level than the parent α,β-unsaturated aldehyde. Thus, the Diels-Alder
reaction proceeds via the iminium ion intermediate not from the α,β-unsaturated aldehyde. By the appropriate design of the chiral amine moiety, an enantioselective reaction can be realized. In fact, the chiral imidazolidinone catalyst afforded an excellent enantioselectivity (see above; Eq. 1.3) [4]. Many reactions have been developed involving the iminium ion as a key intermediate.
1.4.2. Two Reaction Paths
Two reaction paths, Diels-Alder type reaction and Michael reaction, involve an iminium ion as a reactive intermediate [37]. These two reaction paths will be discussed in the reactions of cinnamaldehyde and cyclopentadiene catalyzed by diarylprolinol silyl ether (Table 1.1).
The Diels-Alder reaction was catalyzed by diarylprolinol silyl ether 6, with trifluoromethyl groups on the aryl moiety (Figure 1.6) with a combination of a strong acid such as CF3CO2H [38]. It should be noted that the exo-isomer was obtained predominantly.
On the other hand, when a mixture of cinnamaldehyde and cyclopentadiene was treated with diphenylprolinol silyl ether 5 (Figure 1.6) with a combination of p-nitrophenol or NaOAc, Michael products were obtained with excellent enantioselectivity without formation of the Diels-Alder products [39]. Iminium ions are key intermediates in both reactions.
As the pyrrolidine moiety of catalyst 6 is more electron deficient than that of catalyst 5 because of the electron-withdrawing CF3 group, the LUMO of the iminium ion generated from 6 is lower than that of the iminium ion generated from 5. The Diels-Alder reaction proceeds smoothly when the LUMO of the dienophile is lower. Thus, the Diels-Alder reaction proceeded in the case of 6 (Scheme 1.3). On the other hand, in the Michael reaction (Scheme 1.4), after the formation of the iminium ion, counterion (OH ) reacts with p-nitrophenol to generate phenoxide, which reacts with cyclopentadiene to generate an anion of cyclopentadiene. This anionic nucleophile reacts with the iminium ion to afford the Michael product. For the generation of anionic nucleophile, the nucleophile is limited to the active methylene compounds, and a strong acid cannot be employed.
TABLE 1.1. The two reaction paths in the reaction of cinnamaldehyde and cyclopentadiene
Figure 1.6. Diarylprolinol silyl ether in this study.
CF3CO2 N H2 Ar Ar OTBS H O R + N OTBS Ar Ar R H CF3CO2 N OTBS Ar Ar R H CF3CO2 R N TBSO Ar Ar H CF3CO2 OHC R CF3CO2 N H2 Ar Ar OTBS + H2O H2O
Scheme 1.3. The reaction mechanism of the Diels-Alder reaction.
NO2 pKa = 10.8 N Ph Ph Ph OTBS HO NO2 H H pKa = 18 N Ph Ph Ph OTBS O Ph H O Ph H H2O N H Ph Ph OTBS
O Ph
N Ph Ph OTBS H H pKa = 11.1 N OTBS Ph Ph Ph H O NO2
Scheme 1.4. The reaction mechanism of the Michael reaction.
1.4.3.
Diels-Alder Type Reaction
The Friedel-Craft reaction belongs to the Diels-Alder type set of reactions, and pyrroles, indoles, and aniline react readily with α,β-unsaturated aldehydes in the presence of MacMillan’s catalyst to afford the products with excellent enantioselectivity (Eq. 1.18) [40]. [3+2] Nitrone cycloaddition also belongs to this type of reaction [41].
1.4.4. Michael Reaction
Active methylene compounds such as nitroalkanes (Eq. 1.19), malonates, and β-keto esters are suitable Michael donors in the Michael reaction using α,β-unsaturated aldehydes as a Michael acceptor, catalyzed by diphenylprolinol silyl ether catalyst [42].
Oximes, such as benzaldehyde oxime, also act as suitable Michael donors to afford β-hydroxy carbonyl compounds after hydrogenolysis (Eq. 1.20) [43]. Given that asymmetric oxy-Michael reactions are difficult because of the facile retro-Michael reaction, this two-step reaction is synthetically useful.
Thiol is also a good Michael donor and chiral β-thio aldehydes were obtained with excellent enantioselectivity [44].
Aza-Michael reactions were also reported using thiazoles, tetrazoles, and succinimides, and the products were generated with excellent enantioselectivity [45].
Construction of a C–P bond by the Michael reaction was reported. Asymmetric hydrophosphination proceeded by a reaction of diphenylphosphine and α,β-unsaturated aldehydes catalyzed by diarylprolinol silyl ether (Eq. 1.21) [46].
Nonactivated ketones such as cyclohexanone are also employed as Michael donors in the reaction of α,β-unsaturated aldehydes catalyzed by a combination of diphenylprolinol silyl ether and hydroxyproline (or pyrrolidine), to afford the Michael products with excellent enantioselectivity (Eq. 1.22) [47]. The key nucleophile is not an enamine but an enolate, which is generated from a secondary amine by combination with p-nitrophenol (Eq. 1.23) [48].
1.5.1. Introduction of Domino (Cascade and Tandem) Reactions
Domino reactions offer a powerful way to construct complex structures in a single reaction vessel; each reaction occurs as a consequence of the intermediates generated in previous steps without changing any reaction conditions [49]. Most of the asymmetric domino reactions are composed of two reactions occurring one after the other. Organocatalysts can also be effective in domino reactions [50]. List [51], MacMillan [52], and Jørgensen [44] reported the domino iminium/enamine reaction at the same time in 2005. List reported conjugate reduction−Michael cyclization of enal enones, in which treatment of the enal enone with Hantzsch dihydropyridine in the presence of a catalytic amount of MacMillan’s catalyst provided cyclic keto aldehydes with excellent enantioselectivity (Eq. 1.24). MacMillan reported an iminium/enamine domino reaction employing several nucleophiles and electrophiles catalyzed by MacMillan’s catalyst (Eq. 1.25). Jørgensen reported that a domino reaction of conjugate addition of thiol and amination, which was catalyzed by diarylprolinol silyl ether, afforded 1,2-aminothiol derivatives in nearly optically pure form (Eq. 1.26).
1.5.2. Enders’ Work
In 2006, Enders reported a seminal paper on organocatalyst- mediated domino reaction (Eq. 1.27) [53]. He reported an excellent domino reaction catalyzed by diphenylprolinol silyl ether, wherein three reactions such as Michael/Michael/intramolecular aldol condensation reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. Rather complex skeletons were synthesized only by mixing the substrates via a domino reaction.
Enders’ group reported many useful domino reactions [54]. For instance, functionalized complex tricyclic polyethers were synthesized by one-pot quadruple domino oxa-Michael/Michael/Michael/aldol condensation/hetero-Diels-Alder reaction in nearly enantiomerically pure form (Eq. 1.28) [55]. Tetracyclic pyridocarbazole derivatives were synthesized by the three-component triple cascade reaction such as Diels-Alder/aza-Michael/intramolecular aldol condensation reactions with excellent enantioselectivity (Eq. 1.29) [56].
1.6. DOMINO REACTION AND TOTAL SYNTHESIS
Many domino reactions have been developed that use organocatalysts. Domino reaction catalyzed by organocatalysts can generate complex structures in a single reaction vessel. This is a very powerful method for the synthesis of natural products and drugs [57]. Organocatalytic domino reactions have been successfully applied to natural product synthesis. In this section, selected domino reactions will be described with an application to total synthesis.
1.6.1. Steroid Skeleton
Hong reported the synthesis of a steroid skeleton by a one-pot reaction starting from an α,β-unsaturated aldehyde and a nitroalkane (Eq. 1.30). A domino Michael/Michael reaction proceeded, followed by aldol and Henry reaction in a one-pot operation, to afford a steroid skeleton with excellent enantioselectivity [58].
1.6.2. α-Skytanthine and Quinine
Ishikawa reported a domino Michael reaction/hemiacetal formation/dehydration for the synthesis of C4-alkyl substituted chiral piperidines using diphenylprolinol silyl ether (Eq. 1.31) [59]. This is a formal aza [3+3] cycloaddition reaction with aliphatic α,β-unsaturated aldehydes and thioamide derivatives. Thioamide is a reactive nucleophile. The reaction proceeded efficiently, and only 0.1 mol % catalyst loading is sufficient for a multigram-scale synthesis to complete within a suitable reaction time. This reaction was applied to the total synthesis of several alkaloids such as α-skytanthine [59a] and quinine [59b].
1.6.3. (+)-Lycoposerramine Z
Bradshaw and Bonjoch reported a domino Michael/aldol (Robinson annulation)/aza-Michael reaction to afford a substituted decahydroquinoline with a high diastereo- and enantioselectivity in a one-pot operation (Eq. 1.32). (+)-Lycoposerramine Z was synthesized from this intermediate [60].
1.6.4. Estradiol Methyl Ether
Bicyclo[4.3.0]none derivatives, which are C and D rings of the steroids, were synthesized as a single isomer with excellent enantioselectivity by diphenylprolinol silyl ether mediated Michael reaction of nitroalkane possessing a diketone moiety and an α,β-unsaturated aldehyde, followed by aldol reaction (Eq. 1.33). This domino reaction was used as a key reaction for the total synthesis of estradiol methyl ether, which was synthesized using five reaction vessels with four purifications [61].
1.6.5. MacMillan’s Alkaloid Synthesis
MacMillan reported the domino Diels-Alder reaction/β-elimination of methyl selenide/aza-Michael reaction to afford a spiroindoline intermediate (Eq. 1.34). The first Diels-Alder reaction and the third aza-Michael reaction were catalyzed by the same MacMillan’s catalyst via an iminium ion as an intermediate, and an excellent enantioselectivity was obtained. From the intermediate, (-)-strychnine, (-)-akuamicine, (+)-aspidospermidine, (+)-vincadifformine, (-)-kopsinine, and (-)-kopsanone were synthesized efficiently [62].
