Diels–Alder reaction | EPFL Graph Search

In organic chemistry, the Diels–Alder reaction is a chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene derivative. It is the prototypical example of a pericyclic reaction with a concerted mechanism. More specifically, it is classified as a thermally-allowed [4+2] cycloaddition with Woodward–Hoffmann symbol [π4s + π2s]. It was first described by Otto Diels and Kurt Alder in 1928. For the discovery of this reaction, they were awarded the Nobel Prize in Chemistry in 1950. Through the simultaneous construction of two new carbon–carbon bonds, the Diels–Alder reaction provides a reliable way to form six-membered rings with good control over the regio- and stereochemical outcomes. Consequently, it has served as a powerful and widely applied tool for the introduction of chemical complexity in the synthesis of natural products and new materials. The underlying concept has also been ap

Investigations of Diels-Alder reactions in ionic liquids

Ana Vidis

Room temperature ionic liquids comprise an unique class of solvent composed of organic and inorganic-based ions that are molten under ambient conditions. They are characterised by high solvent polarity and low vapour pressure, and can be tailored to have specific physical and chemical properties. Consequently, there has been great interest in exploiting these attributes to accelerate and control organic reactions. One such reaction, the Diels-Alder reaction, is an important [4+2] cycloaddition reaction used extensively in the preparation of cyclic and heterocyclic compounds. Understanding the factors involved in the enhancing this reaction in ionic liquids remains a subject of intense interest and the centrepiece of the dissertation. The objective of the research is to explore the Diels-Alder cycloaddition reaction in ionic liquids, with a view of developing high effective reactions systems, that operate under mild reaction conditions. The role that ionic liquid media plays in facilitating the Diels-Alder reaction is discussed. A range of physical and chemical modes of activating the reaction are discussed including pressure, the application of Lewis acid catalysts, microwave irradiation and ultrasound sonication and a comparison on the various modes of activation is provided. Importantly, the results of this study can lead to a better understanding of the ionic liquids as well as their utilization for other organic reactions.

EPFL2007

New developments on silyl 2-alkenyl sulfinates and their applications to the asymmetric synthesis of polypropionate fragments

Xiaogen Huang

Sulphur dioxide reacts with 1-oxydienes generating zwitterions which are quenched by enoxysilanes to form substituted silyl alkenylsulfinates. These intermediates are desilylated with Bu4NF and the resulting sulfinates react with MeI giving the corresponding methyl sulfones. This new SO2 reaction cascade, hetero-Diels-Alder addition of SO2/oxyallylation/alkylation, was expanded to a variety of electrophiles successfully. Several functional sulfones have been synthesized in modest to high yields. A number of chiral Lewis acids have been prepared and applied into this reaction cascade. Two common techniques were employed to analyze the enantiomeric excess in the resulted sulfones: chiral HPLC and chemical shift reagents. No interesting result was obtained. The removal of water in the reaction system indeed made the reaction better but did not lead to any increase in the enantioselectivity. Silyl sulfinate itself was found not to be able to catalyze the reaction. The formation of (E)-product was discovered in some cases. The introduction of another coordinating oxy-substitution into the dienes did not change the reaction. So the asymmetric catalytic version could not be realized. Silyl sulfinates were found to undergo the silicon/palladium transmetallation. This process could be realized by catalysis with either Pd(PPh3)4 or Pd(OAc)2. The driving force is the formation of silyl acetate. When the sulfinyl palladium complex forms, it can undergo either reductive elimination to give allyl sulfones, or elimination of SO2 in the presence of proton source, such as isopropanol or methanol, giving retro-ene products in good yields. The success of the reactions depended on the amount of the ligand, the solvent and the temperature. More ligand, such as triphenylphosphine, and THF as solvent favor the reductive elimination, while less ligand and CH3CN as solvent favor the retro-ene reaction. The reaction mechanism was studied by NMR experiments which afforded the direct proofs for transmetallation reactions. Kinetic studies on the decomposition of simple silyl alkenylsulfinate into retro-ene products indicated that the cleavage of silicon-oxygen bond could be simply realized by isopropanol. CD3CN was found to have an enormous solvent effect. The presence of Pd(II) species made the reaction somehow faster and cleaner. Related with the studies above it was discovered that trialkylsilyl 2-methylprop-2-enesulfinates are good silylation reagents. For TMS and TES sulfinates, the reactivities were the same and led to 100% conversion in a few minutes for all kinds of alcohols. But for TBS sulfinate, the reactivity decreased significantly due to steric hindrance. Silyl sulfinates were also found to undergo silyl exchange with carboxylic anhydride and acetal/ ketal. The synthetic potential of the sequence hetero-Diels-Alder of SO2, quenching of zwitterions intermediate with an enoxysilane, desilylation and retro-ene elimination of SO2 was demonstrated by the synthesis of (βR,4R,5S,6R)-β,2,2,5-tetramethyl-6-{(1R)-1-[(4S,5S)-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl}-1,3-dioxane-4-ethanol, a known synthetic intermediate in the total, asymmetric synthesis of Rifamycin S.

EPFL2004

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.