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Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene. The most commonly synthesized ring sizes are between 5-7 atoms; however, reported syntheses include 45- up to 90- membered macroheterocycles. These reactions are metal-catalyzed and proceed through a metallacyclobutane intermediate. It was first published by Dider Villemin in 1980 describing the synthesis of an Exaltolide precursor, and later become popularized by Robert H. Grubbs and Richard R. Schrock, who shared the Nobel Prize in Chemistry, along with Yves Chauvin, in 2005 for their combined work in olefin metathesis. RCM is a favorite among organic chemists due to its synthetic utility in the formation of rings, which were previously difficult to access efficiently, and broad substrate scope. Since the only major by-product is ethylene, these reactions may also be considered atom economic, an increasingly important concern in the development of green chemistry. There are several reviews published on ring-closing metathesis. The first example of ring-closing metathesis was reported by Dider Villemin in 1980 when he synthesized an Exaltolide precursor using a WCl6/Me4Sn catalyzed metathesis cyclization in 60-65% yield depending on ring size (A). In the following months, Jiro Tsuji reported a similar metathesis reaction describing the preparation of a macrolide catalyzed by WCl6 and dimethyltitanocene (Cp2TiMe2) in a modest 17.9% yield (B). Tsuji describes the olefin metathesis reaction as “...potentially useful in organic synthesis” and addresses the need for the development of a more versatile catalyst to tolerate various functional groups. In 1987, Siegfried Warwel and Hans Kaitker published a synthesis of symmetric macrocycles through a cross-metathesis dimerization of starting cycloolefins to afford C14, C18, and C20 dienes in 58-74% yield, as well as C16 in 30% yield, using Re2O7 on Al2O3 and Me4Sn for catalyst activation.

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Ring-closing metathesis

Persistent carbene

A persistent carbene (also known as stable carbene) is a type of carbene demonstrating particular stability. The best-known examples and by far largest subgroup are the N-heterocyclic carbenes (NHC) (sometimes called Arduengo carbenes), for example diaminocarbenes with the general formula (R2N)2C:, where the four R moieties are typically alkyl and aryl groups. The groups can be linked to give heterocyclic carbenes, such as those derived from imidazole, imidazoline, thiazole or triazole.

Alkene

In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or in the terminal position. Terminal alkenes are also known as α-olefins. The International Union of Pure and Applied Chemistry (IUPAC) recommends using the name "alkene" only for acyclic hydrocarbons with just one double bond; alkadiene, alkatriene, etc., or polyene for acyclic hydrocarbons with two or more double bonds; cycloalkene, cycloalkadiene, etc.

The work presented in this thesis focuses on the synthesis of monoterpene indole alkaloids. The first part describes the divergent total synthesis of (-)-rhazinilam, (-)-leucomidine B and (+)-leuconodine F, three structurally distinct natural products of the Aspidosperma family. The key step involves the heteroannulation of an advanced tetrahydropyridine with bromoacetaldehyde or oxalyl chloride in order to afford the corresponding tetrahydroindolizine and 2,3-dioxopyrrole moieties, respectively. By fine tuning of the reaction conditions, the former was converted into rhazinilam while the latter led to the syntheses of leucomidine B and leuconodine F. In the case of leucomidine B, the development of a substrate-directed diastereoselective reduction of a sterically unbiased double bond is also discussed. The second part details the synthetic studies towards various members of the Sarpagan family. After the exploration of several strategies and indoles alkaloids, the enantioselective total synthesis of N(1)-demethyl-3,5-diepi-alstolactone was accomplished. This synthesis features three key points: 1) the incorporation of a vinyl ketone function in the C-2 position of indole by using the Liebeskind-Srogl coupling in order to afford, after ring-closing metathesis, an advanced eight-membered cyclic enone, 2) a highly diastereoselective intramolecular Michael addition and 3) the formation of an azabicyclo[3.3.1]nonane bridged system from the corresponding eight-membered ring via a dehydration / transannular cyclization process.

EPFL2017

CH-422: Catalyst design for synthesis

This course on homogeneous catalysis provide a detailed understanding of how these catalysts work at a mechanistic level and give examples of catalyst design for important reactions (hydrogenation, ol

CH-432: Structure and reactivity

To develop a detailed knowledge of the key steps of advanced modern organic synthesis going beyond classical chemistry of olefins and carbonyls.

Metathesis: Catalyst Reactivity and Initiation Rate CH-422: Catalyst design for synthesis

Explores catalyst reactivity in metathesis reactions, emphasizing initiation rates and ligand effects.

Organometallic Reactions Overview CH-422: Catalyst design for synthesis

Covers organometallic reactions, carbene complexes, metathesis, and polymerization.

Computational Chemistry: Olefin Metathesis CH-431: Physical and computational organic chemistry

Delves into the role of computational chemistry in enhancing Olefin Metathesis, emphasizing theory's predictive power and the Nobel Prize-winning contributions of Chauvin, Grubbs, and Schrock.