Cycloaddition | EPFL Graph Search

In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity". The resulting reaction is a cyclization reaction. Many but not all cycloadditions are concerted and thus pericyclic. Nonconcerted cycloadditions are not pericyclic. As a class of addition reaction, cycloadditions permit carbon–carbon bond formation without the use of a nucleophile or electrophile. Cycloadditions can be described using two systems of notation. An older but still common notation is based on the size of linear arrangements of atoms in the reactants. It uses parentheses: (i + j + …) where the variables are the numbers of linear atoms in each reactant. The product is a cycle of size (i + j + …). In this system, the standard Diels-Alder reaction is a (4 + 2)-cycloaddi

Copper-Catalyzed 1,2-Methoxy Methoxycarbonylation of Alkenes with Methyl Formate and Synthetic Studies Towards the Total Synthesis of Koumine, Voacafricine A and Voacafricine B

Balázs Budai

The development of an unusual oxidative alkene difunctionalization using methyl formate and syn-thetic studies towards alkaloid natural products provide the basis of the thesis. The first chapter details the development of a method that forges methoxycarbonyl radical direct-ly from its most accessible precursor: methyl formate. Although the aforementioned transfor-mation was documented in the literature, no synthetically useful method was developed at the time. We were able to identify conditions that transform methyl formate and simple styrene de-rivatives to value added ï¢-methoxy alkanoates and cinnamic acid derivatives under copper cataly-sis. We also demonstrated that by tethering nucleophilic moieties to the styrene substrates, we could access medicinally important heterocycles such as pyrrolidines, tetrahydrofurans and ï§-lactones. Our method proved to be scalable on each classes of substrates. Mechanistic studies re-vealed that methyl formate has an unprecedented double role in the transformation. It acts as a precursor for methoxycarbonyl radical; furthermore, it is the direct source of the ï¢-methoxy func-tion in the synthesis of ï¢-methoxy alkanoates. A ternary ï¢-diketiminato-Cu(I)-styrene complex, fully characterized by NMR spectroscopy and X-ray crystallographic analysis is capable of catalyz-ing the same transformation. We hypothesize that pre-coordination of electron-rich double bond to copper might play an important role in the polarity-mismatched addition between nucleophilic methoxycarbonyl radical and electron rich olefins. Synthetic studies toward the total synthesis of koumine is discussed in the second chapter. Our synthetic strategy features an oxidative ring closing, Fukuyama indole synthesis and an enantiose-lective Diels-Alder cycloaddition for the construction of the core of koumine skeleton. We designed a rapid route to access 1,2-dihydropyridine derivatives and these compounds were examined as dienes in the Diels-Alder cycloaddition reaction. Despite our efforts, we were unable to effect the [4+2] cycloaddition, which eventually lead us to decide to discontinue our campaign. In chapter three, our synthetic efforts toward voacafricine A and voacafricine B is presented. In our pursuit towards the natural products, we devised and followed a divergent and potentially en-antioselective strategy. We successfully developed a synthetic route to reach the key intermediate in five steps. Despite our efforts, we were not able to construct the remaining F ring of the natural product. Our conformational analysis of advanced intermediates suggest that epimerization of the C14 stereocenter potentially unlocks the desired reactivity and enables us to reach the target mol-ecules. Work towards the total synthesis of voacafricine A and voacafricine B is underway and may focus on the conformational manipulation of advanced intermediates to allow the elaboration of the F ring and complete the synthesis.

EPFL2020

New Vinylation and Alkynylation Strategies with Hypervalent Iodine Reagents and Diazo Compounds

Guillaume Dominique Pisella

The development of a sequential copper-catalyzed oxy-alkynylation/intramolecular [4+2] cycloaddition of allenes and arenes was investigated at first. This one-pot protocol allowed the construction of complex polycylic architectures with high efficiency from aryldiazo esters and ethynylbenziodoxolone reagents (EBX). The mild reaction conditions (23 to 90 Â°C) for the dearomatization step was unusual compared to previous literature reports and DFT computations showed that substituents on the aryl ring resulted in favorable dispersive interactions, decreasing the activation energy barrier of the cycloaddition. The bicyclo[2.2.2]octadiene products were successfully applied as ligands for rhodium. The prepared diene-rhodium complexes were extensively characterized by NMR spectroscopy and X-ray crystallography. Finally, an enantiopure ligand having a pseudo C2-symmetry was used in the conjugate addition of phenylboronic acid to cyclohexenone and furnished the Î²-functionalized ketone in good yield and with high enantioselectivity.The vinylation reactions of diazo compounds are scarce. A successful copper-catalyzed vinylation of diazo compounds with vinylbenziodoxolone reagents (VBX) as partners was reported. The transformation allowed an unprecedented gem-oxy-vinylation at the carbene center, providing functionalized Î±-vinyl-hydroxyacid derivatives in high atom and step economy. The products were obtained in excellent yields and contained synthetically versatile functional groups for post-modifications. The development of an enantioselective version of this reaction was limited and further investigations will be required to obtain high enantioselectivities. In addition, a practical synthesis of alkyl-substituted VBX reagents has been established; VBX reagents being limited to aryl substituents until then. Multicomponent reactions provide efficient means to rapidly access molecular diversity. A copper(I)-catalyzed threeâcomponent reaction utilizing diazo compounds, alcohols as nucleophiles and vinyl- or ethynylbenziodoxole reagents, was successfully developed. The transformation allowed the synthesis of highly functionalized allyl and propargyl ethers. The scope is broad, and extensive variations of the three partners of the reaction is possible, leading to maximal structural diversity. Extension of this work to N-nucleophiles was not as straightforward as anticipated, but good results could be obtained with anilines, trifluorodiazoethane and EBX reagents as components.Questions about the reaction mechanisms of the copper-catalyzed difunctionalizations of diazo compounds with VBX and EBX reagents have been frequent all-along this research work. Preliminary results of in-depth mechanistic investigations have been obtained. The initial assumption of an internal alkyne transfer step was first invalidated by DFT computations and was latter refuted experimentally. A complexation between the carboxylate of ethynylbenziodoxolone reagents and the copper catalyst was characterized by NMR spectroscopy and contrasted to a alkyne-copper interaction observed with ethynylbenziodoxole reagents. These two possible complexes were supported by DFT calculations. Finally, non-classical sigmoidal kinetic profiles of the oxy-alkynylation reaction were obtained by in situ 19F NMR monitoring and the Cu-EBX complex is presumably involved in the observed induction periods.

EPFL2021

Catalytic Formal Homo-Nazarov Reaction and Other Cyclizations of Cyclopropanes

Filippo De Simone

The increasing progress in medicinal chemistry and chemical biology requires more versatile synthetic strategies for the generation of libraries of active compounds and theirs analogues. A wide range of biologically active natural and synthetic compounds contain a complex polycyclic heterocyclic scaffold as core structure. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. The goal of my PhD thesis was the development of a new catalytic cyclization reaction – the formal homo-Nazarov reaction. Starting from cyclopropanes as the smallest carbocycles, we were able to build-up complex carbocyclic and heterocyclic molecules, including alkaloid natural products. This thesis is divided in three main chapters, introduction, formal homo-Nazarov reaction and cyclization reactions of aminocyclopropanes. In the introductory part, the electronic properties and synthetic approaches to generate cyclopropanes are first described. Next, important examples of annulation and cyclization reactions involving cyclopropanes are discussed, pointing out the importance of activating and/or polarizing substituents on the three member ring. The second chapter of this thesis is dedicated to the development of a new catalytic method for the cyclization of vinyl cyclopropyl ketones –the formal homo-Nazarov cyclization. Optimization of the catalytic conditions is described, as well as extension of the substrate scope to a wide range of heterocycles and carbocycles. The reaction mechanism is then investigated using kinetic, labeling and trapping experiments. The results of these investigations indicate a stepwise mechanism through carbocationic intermediates. Moreover, the influence of an additional polarizing ester substituent on the cyclopropane is discussed, as well as the resulting scope extension. Finally, a first example of asymmetric induction for the catalytic formal homo-Nazarov cyclization using chiral Lewis acid catalysts is presented. The third chapter reports the extension of the catalytic homo-Nazarov cyclization to aminocyclopropanes. The reaction occurs under mild conditions and highly diastereoselective cyclizations are obtained via an acyliminium intermediate generated through opening of the cyclopropane. The presented methodology allowed an excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners. The utility of the developed methodology is demonstrated by the generation of two different polycyclic scaffolds of natural products starting from a common intermediate. Based on this method, a formal total synthesis of the Aspidosperma alkaloid aspidospermidine is presented. The scope and limitations of our methodology are presented on an extended range of aryl- and vinyl- cyclopropyl ketones bearing indole, pyrrole, pyran, benzofuran or thiophene groups as electron-rich aryl or alkene substituents, and cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane. Finally, the versatility of our cyclization method is demonstrated by its successful application in the total synthesis of the natural alkaloid goniomitine, accomplished in 13 linear steps with an overall yield of 11%. The availability of goniomitine and several of its analogues in significant amount allowed the first studies of the bioactivity of this class of alkaloids, which displayed only low cytotoxicity (IC50: 15-123 µM).

EPFL2012