Aza-Annulation Strategies in Alkaloid Total Synthesis

This review highlights the synthesis of nitrogen-containing natural products via aza-annulation. Strategic, tactical, and methodological perspectives are discussed, including recent developments such as metal- or organocatalyzed reactions, oxidative or reductive cyclizations, biomimetic processes, cascade reactions, and cycloadditions. Such key steps are presented in the context of the total syntheses of tropinone, batzelladine, lyconadin, FR901483, strychnofoline, discorhabdin, necatarone, aspidophytine, dibromophakellstatin, anachelin, the acridones, alkaloid GB13, cephalotaxine, strychnine, setoclavine, porantherine, vallesamine, nitraramine, cylindricine, the daphniphyllines, symbioimine, alstonerine, tangutorine and flustramine.

Development of remote C-H bond functionalization of redox-active alcohol derivatives and oxidative transformations under photoredox catalysis

Alexandre Julien Florent Leclair

The development of radical-based remote C(sp3)-H functionalizations of redox-active alcohol derivatives, oxidative cycloaddition and rearrangement transformations under visible light photocatalysis constitute the basis of this thesis.The first chapter describes the exploration of several strategies to effect the Î²- and Î³-C(sp3)-H functionalization of alcohols under reductive conditions through the 1,5-hydrogen atom transfer of reactive radical intermediates. Two types of N-phthalimidoyl precursors were synthesized and used under metal and photoredox catalysis to effect a formal Î³-C(sp3)-H functionalization. The fragmentation of primary N-phthalimidoyl oxalates could be smoothly realized under photoredox catalysis. However, the generated alkoxycarbonyl radicals did not allow for a distal functionalization and instead could only be trapped by direct addition to electron-poor alkenes. More potent 1-alkoxy vinyl radical intermediates proved to be too unstable and no control of the fragmentation could be achieved. Two approaches were designed to pursue the Î²-C(sp3)-H functionalization of redox-active alcohols. An iron-catalyzed C-H azidation of N-acyloxy imidates was discovered and optimized to enable, after simple hydrolysis, the synthesis of valuable Î²-azido alcohols. N-phthalimidoyl carbonates were also investigated to this end, however the exceptional hydrogen abstracting properties of these electrophilic (alkoxycarbonyl)oxyl radicals could not be tempered and only decomposition to the parent alcohol was detected.The study of two photoredox catalyzed oxidative transformations is discussed in the second chapter. Building on the propensity of indoles to produce radical cation intermediates under photoinduced single electron oxidation, an innovative oxidative ring-expansion of 1-(indol-2-yl)cyclobutan-1-ols was developed. Under mild aerobic visible-light conditions, a series of 2,3,4,9-tetrahydro-1H-carbazol-1-ones were accessed with complete regioselectivity in the presence of a catalytic amount of mesityl acridinium salt. Gratifyingly, this reaction could be extended to benzo[b]thiophenes analogues. The synthetic potential of this transformation was demonstrated by achieving a total synthesis of (Â±)-uleine, using our methodology to furnish one of the key fragment. A series of experiments were performed to gain insights in the mechanism of this transformation. A complex cascade reaction was suggested, involving two successive oxidative 1,2-alkyl shifts and initiated by the formation of a radical cation. Next were started synthetic studies toward the total synthesis of (Â±)-decursivine, a moschamine-related indole alkaloid, with the aim of developing an intramolecular oxidative [3+2]-cycloaddition under photoredox catalysis. Several precursors were synthesized and attempted under a large variety of reaction conditions to effect the cycloaddition, unfortunately without success. At best, the dimerization of a transient phenolic radical was observed. Efforts to promote an intramolecular reaction remained unsuccessful.

EPFL2021

Cyclization and Cycloaddition Reactions of Cyclopropyl Carbonyls and Imines

Filippo De Simone, Jérôme Waser

Abstract: Activated cyclopropanes, such as vinyl and carbonyl cyclopropanes, are useful building blocks in organic chemistry due to their exceptional reactivity. This review focuses on the use of cyclopropyl carbonyls and imines in cyclization and cycloaddition reactions for the synthesis of cyclic compounds. Cycloisomerization and other cyclization reactions are treated first, followed by formal cycloaddition reactions and applications in total synthesis. For each class of reactions, key pioneering works are shortly presented and emphasis is then set on recent results. Indeed, the utility of activated cyclopropanes in organic synthesis have been significantly increased in the last years by combining modern catalytic methods with the well-established reactivity of these building blocks. Together with progress in the synthesis of the cyclopropanes, these new methods allowed a better control over the diastereoselectivity and enantioselectivity of the reactions as well as their use for the synthesis of complex natural products.

2009

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.