Approches de synthèse du tricycle ABC du FR182877.

This manuscript describes the work performed at the Ecole Polytechnique (November 2001 - September 2004) under the direction of Dr. Joëlle Prunet Synthesis in the Laboratory Organic headed by Professor Samir Zard. It details several approaches to synthesis of the tricycle ABC of FR182877, a new antimitotic agent found naturally in 1998. After presenting the FR182877 and different approaches to literature its total synthesis, the retrosynthesis proposed to construct the tricyclic ABC system using a strategy involving a Diels-Alder intermolecular reaction and ene-yne metathesis is detailed (Chapter I). The reaction of ene-yne metathesis will then the subject of a literature review (Chapter II) and its implementation in the context an approach to synthesis of ring A of FR182877 is described (Chapter III). Chapter Next (Chapter IV) for the second key step in the retrosynthetic scheme: the reaction Diels-Alder intermolecular and focuses on a methodological study carried out in the to understand the origin of an unexpected selectivity in the cycloaddition step. The Chapter V presents the results obtained in the context of a second retrosynthesis FR182877 based on a conjugate addition reaction of Michael. Finally, continuity this work, a quick and original functionalized tricyclic systems based on a series of tandem metathesis reactions has been developed and will be exhibited in the last chapter (Chapter VI). The experimental protocols and the description of synthesized products are presented in the experimental part, written in English.Ce manuscrit présente les travaux effectués à l'Ecole Polytechnique (novembre 2001- septembre 2004) sous la direction du Dr. Joëlle Prunet dans le laboratoire de Synthèse Organique dirigé par le Pr. Samir Zard. Il détaille plusieurs approches de synthèse du tricycle ABC du FR182877, un nouvel agent antimitotique naturel découvert en 1998. Après avoir présenté le FR182877 ainsi que les différents approches de la littérature en vue de sa synthèse totale, la rétrosynthèse envisagée pour construire le système tricyclique ABC selon une stratégie impliquant une réaction de Diels-Alder intermoléculaire et une réaction de métathèse ène-yne sera détaillée (Chapitre I). La réaction de métathèse ène-yne fera ensuite l'objet d'une étude bibliographique (Chapitre II) puis sa mise en place dans le contexte d'une approche de synthèse du cycle A du FR182877 sera décrite (Chapitre III). Le chapitre suivant (Chapitre IV) concerne la seconde étape-clé du schéma rétrosynthétique : la réaction de Diels-Alder intermoléculaire et se concentre sur une étude méthodologique réalisée dans le but de comprendre l'origine d'une sélectivité inattendue dans l'étape de cycloaddition. Le chapitre V expose les résultats obtenus dans le contexte d'une seconde rétrosynthèse du FR182877 fondée sur une réaction d'addition conjuguée de Michael. Enfin, dans la continuité de ces travaux, un accès rapide et original à des systèmes tricycliques fonctionnalisés fondé sur une succession de réactions de métathèse en tandem a été développé et sera exposé dans le dernier chapitre (Chapitre VI). Les protocoles expérimentaux ainsi que la description des produits synthétisés seront présentés dans la partie expérimentale, rédigée en anglais

Domino Metathesis Reactions for the Synthesis of Fused Tricyclic Frameworks

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Approches de synthèse du trycicle ABC du FR182877

PALAISEAU-Polytechnique (914772301) / SudocSudocFranceF

Enyne versus diene RCM in the synthesis of cyclopentene derivatives toward the A ring of FR182877

International audienceThe A ring of FR182877, exemplified by ent-4-b,c, has been synthesized, involving an enyne RCM as the key step. A systematic comparison of enyne vs diene RCM for the formation of cyclopentene derivatives showed that the latter metathesis proceeds much more easily even for this ring size

Reversal of facial selectivity in complex Diels-Alder reactions

3 pagesA complex Diels–Alder reaction between a semi-cyclic diene with allylic silyloxy substituents and a bromo enone presented an unusual diastereoselectivity: attack of the diene occured on its more hindered face, and this reversal of selectivity was shown to be induced by the presence of a bromo substituent in the dienophile

High-temperature Diels–Alder reactions : transfer from batch to continuous mode

The transfer of a Diels–Alder reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane with α-acetoxyacrylonitrile and acrylonitrile, respectively, from batch to continuous mode is presented, using standard and widely available laboratory equipment. A standard microwave-based system was used as probe for the transfer to flow reactors. Temperature and residence time have been optimized in small coiled-tube reactors and confirmed with two production runs in a flow reactor. The inherent increase in safety caused by the small volumes at high temperatures and the achieved productivity (approximately 100 g/h using acrylonitrile) are offering advantages over the batch mode which suffers from thermokinetic limitations for scale-up

Daring the Challenge and Thinking Big: The Value of Early Process R&D

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding

Daring the challenge and thinking big ::the value of early process R&D

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels–Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels–Alder reaction. This route relied on an efficient enantiomer separation on a ¼-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2nd enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates

Daring the Challenge and Thinking Big: The Value of Early Process R&D

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding

Design and Scale-Up of a Practical Enantioselective Route to 5-Phenylbicyclo[2.2.2]oct-5-en-2-one

A practical enantioselective route to chiral 5-phenylbicyclo[2.2.2]­oct-5-en-2-one <b>1</b> has been designed and developed. The target compound has been obtained as colorless crystals in 22% yield from 2-cyclohexenone, with an enantiomeric ratio higher than 99.5:0.5 and notably high chemical purity (> 99%). Three intermediates out of nine chemical steps are isolated. It is noteworthy that this process is devoid of any chromatography or distillation although all but one intermediate are oils. Key to success was the optimization of an intramolecular aldol reaction of an in situ prepared ketone aldehyde leading to the solid intermediate (1<i>R</i>,4<i>R</i>,4<i>S</i>,6<i>S</i>)-6-hydroxybicyclo­[2.2.2]­octan-2-one <b>9a</b> that is isolated in very high chemical and chiral purity. This is an example of an intramolecular crystallization-induced diastereomer transformation (CIDT). The dehydration of this secondary alcohol to <b>1</b> required an extensive screen of reaction conditions to secure an excellent purity, essential for crystallization of this low-melting compound. The final process is simple and concentrated as demonstrated by an expeditious synthesis of 1 kg of <b>1</b> in a 30-L reactor in 10 working days