Diversity in the Synthesis of Functionalized Cyclohexene Oxide Derivatives by a Cycloaddition-Fragmentation Sequence from Benzene Oxide.

A cycloaddition-fragmentation sequence from benzene oxide and a nitroso- or azo-dienophile was investigated as a tool for access to highly substituted cyclohexene oxide derivatives. Alkyl lithium-promoted fragmentation of the cycloadducts led to the cyclic derivatives after 1,4- or 1,2-addition of a second equivalent of the lithium reagent. New fragmentation processes were observed when using non-nucleophilic bases of highly hindered alkyl lithium reagents. All reactions proceeded with complete stereocontrol.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4-Addition of an Organolithium Reagent.

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C-fluorocurine, C-profluorocurine, C-mavacurine, normavacurine, 16-epi-pleiocarpamine and taberdivarine H. We designed a strategy involving late-stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2-indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4-addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C-profluorocurine and C-fluorocurine were finalized by the dihydroxylation of C-mavacurine and a pinacol rearrangement, respectively.

Gram-Scale Enantioselective Synthesis of (+)-Lucidumone.

The first enantioselective total synthesis of (+)-lucidumone is described through a 13-step synthetic pathway (longest linear sequence). The key steps involve the formation of a bridged bicyclic lactone by an enantioselective inverse-electron-demand Diels-Alder cycloaddition, C-O bond formation to assemble two fragments, and a one-pot retro-[4 + 2]/[4 + 2] cycloaddition cascade. The synthesis is scalable, and more than one gram of natural product was synthesized in one batch.

Total Synthesis of Ophiorrhine†A, G and Ophiorrhiside†E Featuring a Bioinspired Intramolecular Diels-Alder Cycloaddition.

We report the first total synthesis of the monoterpene indole alkaloids ophiorrhine A via a late stage bioinspired intramolecular Diels-Alder cycloaddition to form the intricate bridged and spirannic polycyclic system. Several strategies were investigated to construct the indolopyridone moiety of ophiorrhiside E, the postulated biosynthetic precursor of ophiorrhine A. Eventually, the Friedel-Crafts-type coupling of N-methyl indolyl-acetamide with a secologanin-derived acid chloride delivered ophiorrhine G. Cyclodehydration of a protected form of the latter was followed by the desired spontaneous intramolecular Diels-Alder cycloaddition of protected ophiorrhiside E leading to ophiorrhine A.

Diastereo- and Enantioselective Inverse-Electron-Demand Diels-Alder Cycloaddition between 2-Pyrones and Acyclic Enol Ethers.

A broadly applicable diastereo- and enantioselective inverse-electron-demand Diels-Alder reaction of 2-pyrones and acyclic enol ethers is reported herein. Using a copper(II)-BOX catalytic system, bridged bicyclic lactones are obtained in very high yields (up to 99 % yield) and enantioselectivities (up to 99 % ee) from diversely substituted 2-pyrones and acyclic enol ethers. Mechanistic experiments as well as DFT calculations indicate the occurrence of a stepwise mechanism. The synthetic potential of the bridged bicyclic lactones is showcased by the enantioselective synthesis of polyfunctional cyclohexenes and cyclohexadienes, as well as a carbasugar unit.

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition.

A convergent strategy for the synthesis of leustroducsins and phoslactomycins has been designed, relying on the synthesis and the coupling of three main fragments. The central fragment was synthesized via a regio-and stereoselective nitroso Diels-Alder reaction with an enol phosphate, followed by reductive cleavage of the phosphate to the ketone 11b. Coupling studies of this fragment with the lactone fragment was accomplished in a stereoselective fashion through a vinyllithium intermediate. An advanced synthetic intermediate was then obtained after functional group transformation.

Total synthesis of grayanane natural products.

Grayananes are a broad family of diterpenoids found in Ericaceae plants, comprising more than 160 natural products. Most of them exhibit interesting biological activities, often representative of Ericaceae use in traditional medicine. Over the last 50 years, various strategies were described for the total synthesis of these diterpenoids. In this review, we survey the literature for synthetic approaches to access grayanane natural products. We will focus mainly on completed total syntheses, but will also mention unfinished synthetic efforts. This work aims at providing a critical perspective on grayanane synthesis, highlighting the advantages and downsides of each strategy, as well as the challenges remaining to be tackled.

The chemistry of mavacurane alkaloids: a rich source of bis-indole alkaloids.

Covering: since early reports up to the end of 2020This review presents a complete coverage of the mavacuranes alkaloids since early reports till date. Mavacuranes alkaloids are a restrictive sub-group of monoterpene indole alkaloids (MIAs), which are represented by their two emblematic congeners, namely, C-mavacurine and pleiocarpamine. Their skeleton is defined by a bond between the indolic N1 nitrogen and the C16 carbon of the tetracyclic scaffold of the corynanthe group in MIA. A limited number of congeners is known as this skeleton can be considered as a cul-de-sac in main MIA biosynthetic routes. Thanks to the enhanced enamine-type reactivity, mavacuranes are frequently involved in the formation of multimeric MIA scaffolds. This review covers isolation aspects and synthetic approaches towards the mavacurane core and bisindole assemblies. To access the mavacurane core, only a few strategies are reported and the main synthetic difficulties usually originate from the important rigidity of the pentacyclic system. For the bisindole assemblies, biomimetic routes are privileged and deliver complex structures using smooth conditions.

Inverse-Electron-Demand Diels-Alder Reactions of 2-Pyrones: Bridged Lactones and Beyond.

Inverse-electron-demand Diels-Alder (IEDDA) reactions of electron-poor 2-pyrones as electrophilic dienes have been extensively studied in the past fifty years. These reactions provide an efficient access to bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3-cyclohexadienes after CO2 extrusion and polysubstituted aromatic compounds through elimination. This reaction has been used for the synthesis of many biologically active natural products and drug candidates. In this review, the developments of these IEDDA reactions including non-catalytic, Lewis acid-catalyzed and organocatalytic IEDDA reactions, and their applications in total synthesis are discussed in detail.

Synthesis of a Seco iso-Secologanin Aglycone Analogue of Interest toward Secoiridoids and Monoterpene Indole Alkaloids.

We report the access to an acyclic iso-secologanin aglycone analogue relevant to secoiridoids and monoterpene indole alkaloids. Its synthesis involved the regioselective allylic alkylation of a linear dienyl carbonate with dimethyl malonate, which was catalyzed by an iridium complex, and an anti-Markovnikov Wacker-type oxidation of the terminal alkene of the branched product that was obtained. The thus-formed aldehyde was engaged in a Pictet-Spengler reaction with tryptamine toward monoterpene indole alkaloids.

Bioinspired Divergent Oxidative Cyclization from Strictosidine and Vincoside Derivatives: Second-Generation Total Synthesis of (-)-Cymoside and Access to an Original Hexacyclic-Fused Furo[3,2-b]indoline.

The second-generation synthesis of (-)-cymoside as well as the formation of a new hexacyclic-fused furo[3,2-b]indoline framework is reported. After a Pictet-Spengler condensation between secologanin tetraacetate and tryptamine, the course of the cyclization of the 7-hydroxyindolenine intermediate, generated by oxidation with an oxaziridine, depended on the stereochemistry of the 3-position. The 3-(S)-strictosidine stereochemistry delivered efficiently the scaffold of cymoside via intramolecular coupling with the C16-C17 enol ether, while the 3-(R)-vincoside stereochemistry directed towards the reaction with the C18-C19 terminal alkene and the formation of the unexpected caged compound.

Enantioselective Total Synthesis of Cymoside through a Bioinspired Oxidative Cyclization of a Strictosidine Derivative.

The first total synthesis of the caged monoterpene indole alkaloid cymoside is reported. This natural product displays a unique hexacyclic-fused skeleton whose biosynthesis implies an early oxidative cyclization of strictosidine. Our approach to the furo[3,2-b]indoline framework relied on an unprecedented biomimetic sequence which started by the diastereoselective oxidation of the indole ring into a hydroxyindolenine which triggered the addition of an enol ether and was followed by the trapping of an oxocarbenium intermediate.

Electrochemical Dearomative 2,3-Difunctionalization of Indoles.

We report the use of electrochemistry to perform a direct oxidative dearomatization of indoles leading to 2,3-dialkoxy or 2,3-diazido indolines under undivided conditions at a constant current. This operationally simple electro-oxidative procedure avoids the use of an external oxidant and displays excellent functional group compatibility. The formation of the two C-O or C-N bonds is believed to arise from the oxidation of the indoles into radical cation intermediates.

Unexpected dimerization of a tripeptide comprising a ß,γ-diamino acid.

We have previously reported the synthesis of enantiopure ß,γ-diamino acids and relevant short α/γ-peptide containing such building blocks. Complete nuclear magnetic resonance (NMR) studies, together with molecular modeling, highlighted the ability of a ß,γ-diamino acid to induce various intramolecular turns. In this paper, we describe for the first time the formation of a dimeric structure constituted by α/γ/α-tripeptide and stabilized by intermolecular interactions. A structural model is proposed based on extensive NMR measurements.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids.

Reported is the enantioselective total syntheses of mavacuran alkaloids, (+)-taberdivarine H, (+)-16-hydroxymethyl-pleiocarpamine, and (+)-16-epi-pleiocarpamine, and their postulated biosynthetic precursor 16-formyl-pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1-C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for the Total Synthesis of (-)-17-nor-Excelsinidine.

We report the first total synthesis of (-)-17-nor-excelsinidine, a zwitterionic monoterpene indole alkaloid that displays an unusual N4-C16 connection. Inspired by the postulated biosynthesis, we explored an oxidative coupling approach from the geissoschizine framework to forge the key ammonium-acetate connection. Two strategies allowed us to achieve this goal, namely an intramolecular nucleophilic substitution on a 16-chlorolactam with the N4 nitrogen atom or a direct I2 -mediated N4-C16 oxidative coupling from the enolate of geissoschizine.

Frozen Chirality of Tertiary Aromatic Amides: Access to Enantioenriched Tertiary α-Amino Acid or Amino Alcohol without Chiral Reagent.

One of the fundamental and intriguing aspects of life is the homochirality of the essential molecules. In this field, the absolute asymmetric synthesis of α-amino acids is a major challenge. Herein, we report access, by chemical means, to tertiary α-amino acid derivatives in up to 96 % ee without using any chiral reagent. In our strategy, the dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the subsequent steps. Furthermore, we could control the configuration of the final product by manually sorting and selecting the initial crystals. Based on vibrational circular dichroism studies, we could rationalize the observed stereoselectivity.

Efficient synthesis of both diastereomers of ß,γ-diamino acids from phenylalanine and tryptophan.

We synthesized in a few steps both diastereomers of orthogonally protected ß,γ-diamino acids starting from L-phenylalanine or L-tryptophan. These final compounds are interesting building blocks for peptide synthesis and foldamer chemistry. The key step is a Blaise reaction performed under ultrasound conditions.

Connecting Tyrosine and Tryptophan Units of Diazonamide A and Azonazine by a Diastereodivergent Arylative Dearomatization.

We report the Friedel-Crafts coupling of a tyrosine unit with tryptophan-derived pyrrolindolenium ions which are configurationally stable. The reaction allowed the stereoselective and divergent access to the required quaternary stereocenters found in diazonamide A and azonazine at the junction of the tyrosine and tryptophan units.

Regioselective hydroarylation reactions of C3 electrophilic N-acetylindoles activated by FeCl3: an entry to 3-(hetero)arylindolines.

A method for the direct and rare umpolung of the 3 position of indoles is reported. The activation of N-acetylindole with iron(III) chloride allows the C-H addition of aromatic and heteroaromatic substrates to the C2=C3 double bond of the indole nucleus to generate a quaternary center at C3 and leads regioselectively to 3-arylindolines. Optimization, scope (50 examples), practicability (gram scale, air atmosphere, room temperature), and mechanistic insights of this process are presented. Synthetic transformations of the indoline products into drug-like compounds are also described.