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Introduction 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 ?-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...