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Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis. Syntheses may sometimes conclude at a precursor with further known synthetic pathways to a target molecule, in which case it is known as a formal synthesis. Total synthesis target molecules can be natural products, medicinally-important active ingredients, known intermediates, or molecules of theoretical interest. Total synthesis targets can also be organometallic or inorganic, though these are rarely encountered. Total synthesis projects often require a wide diversity of reactions and reagents, and subsequently requires broad chemical knowledge and training to be successful. Often, the aim is to discover a new route of synthesis for a target molecule for which there already exist known routes. Sometimes, however, no route exists, and chemists wish to find a viable route for the first time. Total synthesis is particularly important for the discovery of new chemical reactions and new chemical reagents, as well as establishing synthetic routes for medicinally important compounds. There are numerous classes of natural products for which total synthesis is applied to. These include (but are not limited to): terpenes, alkaloids, polyketides and polyethers. Total synthesis targets are sometimes referred to by their organismal origin such as plant, marine, and fungal. The term total synthesis is less frequently but still accurately applied to the synthesis of natural polypeptides and polynucleotides. The peptide hormones oxytocin and vasopressin were isolated and their total syntheses first reported in 1954. It is not uncommon for natural product targets to feature multiple structural components of several natural product classes. Although untrue from a historical perspective (see the history of the steroid, cortisone), total synthesis in the modern age has largely been an academic endeavor (in terms of manpower applied to problems).

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Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

Bastien Delayre

The development of a titanium(III)-mediated cascade electrocyclisation/rearrangement for theenantioselective total synthesis of indole alkaloids (+)-condyfoline and (-)-tubifoline serve as the basisof the first chapter of this thesis. An introduction will focus on the use of domino sequencesincorporating a 1,2-shift in the context of complex natural product synthesis. The design of such adomino process is then presented, along with preliminary results originating from our research groupconcerning the titanium(III)-mediated Cadogan cyclisation. This novel domino sequence enabled thefirst enantioselective total synthesis of (+)-condyfoline. These results provided insights into themechanistic nature of the formal 1,2-shift, indicating that the formal 1,2-migration most likelyproceeds via 1,5-sigmatropic rearrangement rather than retro-Mannich/Mannich sequence. Theisolation of (+)-condyfoline enabled a re-investigation of its isomerisation process to Strychnos isomer(-)-tubifoline. The chapter concludes with synthetic studies towards (+)-tronoharine and (+)-tubotaiwine.The second chapter of this thesis deals with the development of an integratedOxidation/Reduction/Cyclisation (iORC) sequence for the enantioselective total synthesis of the Uleinefamily of monoterpene indole alkaloids. A brief introduction will review our group's previous effortsto implement iORC sequences for the total synthesis of alkaloids. The step-by-step development of theiORC sequence is described, along with the endgame strategy for the synthesis of (+)-nordasycarpidone, (+)-dasycarpidone, (-)-dasycarpidol and (+)-uleine. The chapter ends with theattempted titanium(III)-mediated cyclisation/rearrangement sequence towards (+)-uleine, andattempted iORC sequence towards (+)-condyfoline.The third chapter of this thesis reports a novel synthesis of benzofuro[3,2-b]indolines from onitrostylbene precursors using a titanium(III)-mediated interrupted Cadogan reaction. A rapidinvestigation of the substrate scope is presented. The remaining of the chapter reports our efforts toapply this newly developed transformation for the total synthesis of bis-indole alkaloid phalarine.The last chapter is dedicated to our synthetic studies towards (+)-pestalustaine A, a recently isolatedsesquiterpene possessing a unique 5/6/7-fused tricyclic system. A designed formal [3+2] reaction wasenvisioned to provide access to this novel sesquiterpene, but resulted in the isolation of a Wilson-Clokerearrangement product.

EPFL2022

Catalytic enantioselective Pictet-Spengler reaction of carbonyl compounds: Development and application to the asymmetric total synthesis of indole alkaloids

Rémi Julien Sylvain Andres

This thesis consists in an extensive study about the enantioselective Pictet-Spengler reaction (EPSR) and its application to the total synthesis of monoterpene indole alkaloids (MIAs). The general introduction presents the literature background about this powerful yet still unsolved synthetic transformation. The use of ketone derivatives up to date is mainly underlined.The first chapter describes the enantioselective total synthesis of arborisidine for which an unprecedented EPSR with an Î±-diketone was developed. An oxidative cyclization allowed to build a strained bridged system which was rearranged following a one-pot aza-Cope/Mannich â oxidation â epimerization sequence to reach the natural product. We discovered an interesting epimerization phenomenon between arborisidine and its epimer which, after being conscienciously studied, raised the question of which isomer is the natural product.The development of a new class of single H-bond donor organocatalysts identified in the previous structure-enantioselectivity relationship process is then detailed. These prolinamides present the advantages to be cheap, easier to prepare and to purify than other known catalysts, and provide a new molecular scaffold for enantioselective H-bonding catalysis. They allow a general access to quaternary-center containing tetrahydro-Î²-carbolines derived from Î±-diketones, bulky Î±-ketoesters and Î±-ketoamides, the latter being extensively explored. They also compete with known methods with aldehydes as substrates. The products can all be obtained in good yields and enantioselectivities. The scope is large and shows excellent functional group tolerance to the exception of acidic protons close to the ketone center and sterically hindered ketone derivatives. In line with Jacobsenâs recent discovery, rearomatization is the rate- and enantioselectivity-determining step. The transformation of Î±-diketones is investigated by Vincent, Morgane and Julia, and that of Î±-ketoesters by Fenggang. Of interest, Fenggang showed that the use of two H-bond donor squaramide-organocatalysts was mandatory in order to make the reaction general with Î±-ketoesters.The power of this method was then further demonstrated. The stereocontrolled divergent total synthesis of voacafricines A and B thanks to an asymmetric PSR is the object of the third chapter. Its application allowed to install all the carbons contained in the natural products in a controlled manner, and a complexity-generating oxidative cleavage â cascade cyclization â selective reduction allowed to reach a key hemiacetal intermediate. On one hand this moiety was activated to generate the desired ammonium which provided voacafricine A after in situ hydrolysis. It could on the other hand be used to functionalize the adjacent carbon atom and the same synthetic sequence was applied to get voacafricine B.The enantioselective total synthesis of alstratine A is finally reported. Believing that the aminal could be made at the last step of the synthesis, we identified a precursor whose structure analysis suggested a possible application of an intramolecular inverse electron demand Diels-Alder reaction. The synthesis began with an EPSR of an Î±-ketoester. Funtional group manipulations followed by IMDA successfully built most of the contiguous stereocenters in a controlled fashion. The acid-mediated cyclization then took place without any issues. Alstratine A specific rotation reported in the isolation paper is corrected herein.

EPFL2022

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A single-electron transfer (SET) oxidation of indole or benzo[b]thiophene to a radical cation reverses the intrinsic polarity of these pi-excessive bicyclic heteroarenes. Here we report an oxidative two-carbon homologation of cyclobutanols to cyclohexenones under a visible-light photoredox catalysis. 1-(Indol-2-yl)cyclobutan-1-ols are converted to 2,3,4,9-tetrahydro-1H-carbazol-1-ones, important structural motifs found in alkaloids and pharmaceuticals, with a broad substrate scope. A mechanistic study suggests that the reaction is initiated by an SET from an indole to an excited acridinium salt to generate the radical cation, which is followed by two consecutive 1,2-alkyl migrations and a rearomatization. Benzo[b]thiophene-substituted cyclobutanols are similarly converted to 2,3-dihydrodibenzo[b,d]thiophen-4(1H)-ones. A total synthesis of (+/-)-uleine featuring this ring-expansion process is documented.

AMER CHEMICAL SOC2022

A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis (both semisynthesis and total synthesis) and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets.

Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds with distinct chemical and medicinal properties. The novel compounds generally have a high molecular weight or a complex molecular structure, more so than those produced by total synthesis from simple starting materials.

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Total Synthesis of Discodermolide CH-335: Asymmetric synthesis and retrosynthesis

Covers the total synthesis of Discodermolide, a potent immunosuppressive and cytotoxic compound.

CH-711: Inorganic chemistry "Applications and spin-offs"

Present and discuss important recent contributions in the field of inorganic chemistry. This will be achieved by student literature seminars based on selected publications,emanating from the last 12 m

CH-622: Synergism between Art of Total Synthesis and High Level Strategic Design (MOM)

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CH-335: Asymmetric synthesis and retrosynthesis

La première partie du cours décrit les méthodes classiques de synthèse asymétrique. La seconde partie du cours traite des stratégies de rétrosynthèse basées sur l'approche par disconnection.