Donor-Acceptor Cyclopropanes in Organic Synthesis E-Book

• Herausgeber: Wiley-VCH GmbH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 624

Veröffentlichungsjahr: 2024

Beschreibung

Facilitate milder, simpler reactions in organic synthesis with this cutting-edge family of building blocks

Donor-Accepted Cyclopropanes, or DACs, have attracted a resurgence of interest from organic chemists in recent decades for their role in facilitating various reactions such as cycloadditions, annulations, ring-opening and enantioselective transformations. The structural arrangement of DACs leads to milder, simpler reaction conditions, which have made them indispensable for a range of fundamentally and industrially important processes.

Donor-Acceptor Cyclopropanes in Organic Synthesis covers comprehensively the chemistry and applications of this compound class. The result is an invaluable guide for any researcher looking to bring DACs to bear in their own areas of research or development.

Readers will also find:

• A brief introduction of the history and reactivity of DACs
• Detailed discussion of reactions including Lewis acid-catalyzed cycloadditions, metal-free activation, asymmetric transformations, organocatalysis, and many more
• Application of DACs in natural product synthesis and pharmaceutical/agrochemical research

Donor-Acceptor Cyclopropanes in Organic Synthesis is ideal for organic chemists, experts in catalysis, pharmaceutical researchers, and any other scientists interested in facilitating milder, simpler reactions.

Leseprobe

Donor-Acceptor Cyclopropanes in Organic Synthesis

Edited byPrabal Banerjee and Akkattu T. Biju

Editors

Prof. Prabal BanerjeeIndian Institute of Technology RoparDepartment of ChemistryRupnagar‐140001 PunjabIndia

Prof. Akkattu T. BijuIndian Institute of ScienceDepartment of Organic ChemistryBangalore 560 012India

Cover Image: Courtesy of the Editors

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Print ISBN: 978‐3‐527‐34987‐6ePDF ISBN: 978‐3‐527‐83563‐8ePub ISBN: 978‐3‐527‐83564‐5oBook ISBN: 978‐3‐527‐83565‐2

Preface

Donor–Acceptor Cyclopropanes (DACs) constitute a preeminent class of building blocks in organic synthesis featuring a strain‐induced incredibly wide variety of reactivity. Besides, the cyclopropanes in general are also decorated with a plethora of structurally and biologically important scaffolds. The book is aimed at focusing on the chemistry involved with DACs and their utilization toward the construction of various carbo‐ and heterocycles of biological and industrial importance. Continuous progress made in the field of DACs, involving (3 + n) annulation, ring‐opening, molecular rearrangements, and the asymmetric versions of many of these reactions have captured the tremendous interest of organic chemists. Signing up of DACs toward the synthesis of an array of carbo‐ and heterocycles of pharmaceutical importance have proved very beneficial. However, the lack of a book in the area of DACs has prevented chemists from appreciating the complete developments in DAC chemistry. The focus of the book is on recent developments in cycloaddition, ring‐opening, and molecular rearrangements involving DACs. Examples from the literature that have demonstrated the synthetic application of these processes as well as unprecedented contributions that have directed research in the area are included in the book. In addition, the simpler and milder reaction conditions in DAC chemistry will inspire a broad range of organic and medicinal chemists to explore the applications of DACs in their respective fields.

The first chapter is documented by Hans‐Ulrich Reissig, who significantly contributed to the early phase of this chemistry and coined the term Donor–Acceptor Cyclopropanes. This chapter provides a detailed introduction with a historical and personal perspective on this field. An inward understanding of the structure, bonding, and reactivity plays a central facilitating role in engendering molecules of choice. From this perspective, Chapter 2, authored by Daniel B. Werz and coworkers, demonstrated the bonding and rationale of strain‐induced reactivity of these three carbon synthons, considering the structural and electronic insights. Chapters 3–12 focus on the chemistry of diverse DACs and their reactivity, including the mechanistic studies and utilization toward the construction of various carbo‐ and heterocycles of biological and industrial importance. Chapter 3, written by Roman A. Novikov and coworkers, covers the cycloaddition and annulation reactions of DACs. Moreover, it integrates a number of 1,3‐zwitterionic synthons that could be generated from DACs and their responsiveness toward the formation of carbon–carbon and carbon–heteroatom multiple bonds. The advent of organocatalysis has created new opportunities in organic synthesis. In Chapter 4, Jose L. Vicario and Efraim Reyes focus on the organocatalytic in‐situ generation of the DACs to undergo a variety of interesting transformations.

In continuation, Chapter 5 by Akkattu T. Biju and coworkers deals with the ring‐opening 1,3‐bisfunctionalization of DACs. The exercise of bisfunctionalization works through the introduction of two functional groups at the same time to the reacting partner. Rearranging the carbon skeleton is a recognized aspect of organic chemistry and demonstrates an alluring strategy to modify existing structures to construct important molecular frameworks. Chapter 6, authored by Igor V. Trushkov, demonstrates the detailed molecular rearrangements of DACs to produce a broad diversity of products. Because of their structural and pharmaceutical importance, the construction of nitrogenous compounds has always been an attractive area of research for organic chemists. Chapter 7, documented by Jerome Waser and coworkers, introduces DA aminocyclopropanes as a reliable building block and provides an in‐depth description of their synthetic applications in ring‐opening reactions and formal cycloadditions. DACs with one carbonyl group have emerged as interesting molecules with diverse reactivity lines as compared to the classical DACs with diester group as an acceptor. Chapter 8, written by Prabal Banerjee demonstrates the synthetic strategies and reactivity profile of these cyclopropyl carbonyls, followed by a discussion on their exploitation in the total synthesis of complex biologically important molecules.

The aroyl‐ and nitro‐substituted DACs are relatively emerging entities in the area of DAC chemistry, and Chapter 9, documented by Thangavel Selvi and Kannupal Srinivasan, focuses on the synthesis of these DACs and their further utilization toward the facile access to various acyclic, carbocyclic, and heterocyclic compounds. Fascinated by the metal‐free activation of DACs, Yong Tang and Lijia Wang have written Chapter 10. In the following chapter, they referred to various strategies for the C─C bond cleavage of the DACs by means of protic acids, non‐metal Lewis acids, bases, thermal reactions, and so on. Asymmetric catalysis has emerged as a robust platform with a huge potential in organic synthesis, despite the tremendous challenges associated. Chapter 11, documented by Xiaoming Feng and coworkers, summarizes the stereospecific transformations or enantioselective reactions of racemic, prochiral, or optically enriched cyclopropanes. Cyclopropanation followed by ring‐opening or cycloaddition and cyclopropanation ring‐opening cyclization are attractive strategies widely used in the total synthesis of complex natural products. Chapter 12, authored by Manas K. Ghorai and coworkers, demonstrates the exploitation of DACs in the total synthesis of bioactive natural products over the last two decades.

The crafting of this book was possible only because of the outstanding contributions of all the colleagues engaged in DAC chemistry, and we are very thankful to them. In addition, we thank all the authors for their invaluable contributions, and we appreciate their time and patience. We believe this book will be a source of inspiration for youngsters as well as senior chemists practicing synthetic organic chemistry. We are thankful to Katherine Wong and Dr. Sakeena Quraishi at Wiley‐VCH for their strong support and constructive suggestions in preparing this book.

Prabal BanerjeeRopar / Bangalore, November 2023

Akkattu T. Biju31 May 2023

1Introduction to the Chemistry of Donor–Acceptor Cyclopropanes: A Historical and Personal Perspective

Hans‐Ulrich Reissig

Institut für Chemie und Biochemie, Freie Universität Berlin, D‐14195, Berlin, Germany

CHAPTER MENU

1.1 Introduction

1.2 My Personal Entry to Donor–Acceptor Cyclopropanes

1.3 A Few Principles of the Chemistry of Donor–Acceptor Cyclopropanes

1.4 Remarks Regarding the Terminology Applied to the Use of Donor–Acceptor Cyclopropanes

1.5 Conclusions

Abbreviations

References

1.1 Introduction

During the past 15 years, we have seen tremendous progress in new applications of donor–acceptor cyclopropanes (DACs). Between 1980 and 2005, only a handful of papers per year were published mentioning this term; however, starting in 2006, a constant increase of interest could be observed, and recently, 80–100 articles dealing with this type of cyclopropanes as key compounds were released annually (Figure 1.1). This increasing number of contributions and the growing importance of this field are confirmed by the high number of recent review articles and, of course, by the fact that this book will collect articles from many of the key players in this research area. We introduced the term “donor‐acceptor‐substituted cyclopropane” in 1980 [1] and contributed to this field in its early phase. However, we did not use the term regularly; sometimes, we preferred the more specific name “siloxy‐substituted cyclopropanecarboxylate,” assuming that it is more precise. Also, several of the important contributions of Ernest Wenkert do not name their substrates DACs [2]. Therefore, the statistics in Figure 1.1 are not fully representative of the early period of 1980–2005.

Figure 1.1 Number of publications dealing with the topic “donor–acceptor cyclopropane” or synonyma (according to a search in Web of Knowledge on 26 September 2021).

Why did DACs receive this importance in organic synthesis? For a long time, cyclopropanes were regarded as exotic laboratory curiosa. In 1882, August Freund prepared the parent compound in Lemberg [3]; shortly after, in 1884, William Henry Perkin Jr. synthesized the first functionalized cyclopropane (diethyl cyclopropanedicarboxylate) [4] in the Munich laboratory of Adolf von Baeyer, who recognized the special properties of this type of hydrocarbons and formulated his famous concept of ring strain [5]. Over the years and decades, cyclopropane derivatives with different substituents and functional groups were prepared and investigated; however, in general, the reaction mechanisms involved were at the center of interest. The development of efficient methods for their synthesis was essential for this progress, in particular, the use of carbenes and carbenoids allowed simple and selective approaches to various classes of cyclopropanes. It was only in the 1960s and 1970s that it became evident that cyclopropanes can also serve as building blocks in organic synthesis, and very famous chemists were involved in exploring these possibilities. A systematic treatment of “Methods of Reactivity Umpolung” by Dieter Seebach [6] also included certain aspects of cyclopropane chemistry in this seminal review. Here the phrase “cyclopropane trick” was mentioned and connected with reactivity umpolung. A second early key player in this period was Armin de Meijere, who entered the field as a physical organic chemist but subsequently also provided important synthetic contributions in the cyclopropane field [7]. Very important contributors to the use of cyclopropanes in organic synthesis, in particular, in natural product synthesis, were Samuel Danishefsky, Robert V. Stevens, and Ernest Wenkert. Danishesky et al. exploited cyclopropanes activated by two acceptor substituents that can be smoothly ring‐opened (homo‐Michael addition), especially in an intramolecular fashion, to give skeletons suitable for further synthetic elaboration [8]. The known Cloke rearrangement of cyclopropyl imines to dihydropyrrole derivatives was further developed by Stevens and applied to natural product synthesis [9]. On the other hand, Wenkert et al. explored the chemistry of oxycyclopropanes for the synthesis of terpenes and alkaloids. His publications also contained a few examples of alkoxy‐substituted cyclopropyl ketones or esters; however, these DACs were semantically not distinguished from the other oxycyclopropanes [2]. Nevertheless, his group should receive the credit for being the first to use DACs in natural product synthesis.

1.2 My Personal Entry to Donor–Acceptor Cyclopropanes

After my doctoral studies with Rolf Huisgen [10] at Ludwig‐Maximilians University in Munich, I started a postdoctoral stint in the laboratory of Edward Piers at the University of British Columbia in Vancouver, Canada, in the fall of 1978. In Munich, I worked with diazoalkanes and studied kinetics, as well as the mechanistic aspects of their 1,3‐dipolar cycloadditions. In the group of Piers, I was trained as a synthetic chemist, with a research project dealing with cuprate chemistry, the generation of divinylcyclopropanes, and their Cope rearrangements to cycloheptadiene derivatives [11]. My project and the contemporary literature taught me that cyclopropanes are very suitable compounds to achieve synthetic processes, which are not easily possible by alternative methods. Afterward, I had the chance to start my independent academic career as an associate of the group of Siegfried Hünig [12] in Würzburg, and as my first research project, I suggested to use donor‐acceptor‐substituted cyclopropanes. This idea originated when reading the publications of Danishefsky [8]: instead of an external nucleophile, a directly connected nucleophilic center (donor center) should open the acceptor‐activated cyclopropane ring by a strain‐driven retro‐aldol reaction. For this type of process, only a few related examples could be found in the literature [2]. The original drawing of my grant application to the Fonds der Chemischen Industrie, a very supportive institution in Germany for young scientists, is shown as a copy in Figure 1.2. My proposal was apparently considered to be reasonable, and equipped with a Liebig fellowship, I could start with my project at the end of 1979.

Figure 1.2 Copy of a hand‐drawn scheme in a grant proposal submitted by the author to the Fonds der Chemischen Industrie in the summer of 1979.

In Vancouver, I had learned that silyl enol ethers are very useful starting materials for many synthetic operations, whereas during my doctoral work in Munich, methyl diazoacetate was one of the key compounds. It was, therefore, a nearby idea to combine this knowledge for the synthesis of siloxy‐substituted cyclopropanecarboxylate 2 (Scheme 1.1). They were efficiently available by copper‐catalyzed addition of the carbenoid derived from methyl diazoacetate to the silyl enol ethers 1. As the simplest subsequent reaction, we first studied the ring‐opening with fluoride sources to give 1,4‐dicarbonyl compounds 3 under very mild conditions. In my very first independent paper published in 1980, we used the term “donor‐acceptor‐substituted cyclopropanes” for this type of compound [1], which was later shortened to donor–acceptor cyclopropanes (DACs). I am not entirely sure why I had chosen this name, but my thoughts were probably influenced by the review of Seebach, who classified compounds by donor and acceptor centers [6].

Scheme 1.1 Synthesis and ring‐opening of siloxy‐substituted cyclopropanecarboxylate 2, the first cyclopropanes named DACs.

One of the initial ideas of this project – the ring‐opening with fluoride under aprotic conditions and the trapping of the resulting ester enolate with electrophiles – did not work satisfactorily [13]. However, as an excellent alternative, we found a step‐wise method for forming new C─C bonds at the acceptor‐substituted cyclopropane carbon atom. Methyl cyclopropanecarboxylate 2 could be smoothly deprotonated with lithium diisopropylamide (LDA) and subsequently trapped with a broad range of electrophiles (Scheme 1.2). This clean deprotonation reaction was not self‐evident, since enolates incorporating a cyclopropane ring were essentially unknown around 1980. The reaction with alkyl halides R′‐X occurred with surprisingly high stereoselectivity [14], leading to C‐1 substituted cyclopropanes 4, whose ring‐opening led to higher substituted 1,4‐dicarbonyl compounds. The trapping of the enolates with aldehydes or ketones furnished highly substituted tetrahydrofuran derivatives 5 (synthetically very useful γ‐lactols) after treatment with fluoride [15]. The reaction of the enolates with carbon disulfide or aryl isothiocyanates, followed by the addition of methyl iodide, provided a nice route to interestingly functionalized thiophene or pyrrole derivatives 6[16].

Scheme 1.2 Deprotonation of siloxy‐substituted cyclopropanecarboxylate 2 with LDA and subsequent reactions with electrophiles leading to products such as 4–6.