Regio- and Chemoselective Double Allylic Substitution of Alkenyl vic-Diols.

Double allylic substitution is an attractive approach to building molecular complexity from simple starting materials by creating two new bonds in one pot. However, this type of reaction has been doomed by chemoselectivity and regioselectivity issues. In this letter, we describe a new approach to introduce a-la-carte two new C-C, C-N, C-O, or C-S bonds in a chemo- and regioselective fashion. The reaction relies on sequential dual catalysis with a Lewis acid and palladium. The scope is remarkably broad, and the reaction can be diastereoselective by using secondary alcohols as the first nucleophile.

Natural Product Synthesis: The Endless Quest for Unreachable Perfection.

Total synthesis is a field in constant progress. Its practitioners aim to develop ideal synthetic strategies to build complex molecules. As such, they are both a driving force and a showcase of the progress of organic synthesis. In this Perspective, we discuss recent notable total syntheses. The syntheses selected herein are classified according to the key strategic considerations for each approach.

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.

Using the Noncanonical Metallo-Amino Acid [Cu(II)(2,2'-Bipyridin-5-yl)]-alanine to Study the Structures of Proteins.

Genetic code expansion allows modification of the physical and chemical properties of proteins by the site-directed insertion of noncanonical amino acids. Here we exploit this technology for measuring nanometer-scale distances in proteins. (2,2'-Bipyridin-5-yl)alanine was incorporated into the green fluorescent protein (GFP) and used as an anchoring point for Cu(II) to create a spin-label. The incorporation of (2,2'-bipyridin-5-yl)alanine directly into the protein resulted in a high-affinity binding site for Cu(II) capable of outcompeting other binding positions in the protein. The resulting Cu(II)-spin label is very compact and not larger than a conventional amino acid. By using 94 GHz electron paramagnetic resonance (EPR) pulse dipolar spectroscopy we have been able to determine accurately the distance between two such spin-labels. Our measurements revealed that GFP dimers can adopt different quaternary conformations. The combination of spin-labeling using a paramagnetic nonconventional amino acid with high-frequency EPR techniques resulted in a sensitive method for studying the structures of proteins.

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.

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.

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.

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.

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.

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.

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.

Bioinspired Early Divergent Oxidative Cyclizations toward Pleiocarpamine, Talbotine, and Strictamine.

Toward the mavacurane and akuammilane monoterpene indole alkaloids, we developed divergent oxidative couplings between the indole nucleus (at N1 or C7) and the C16-malonate of a common tricyclic model related to strictosidine according to a biosynthetic hypothesis postulated by Hesse and Schmid. These oxidative cyclizations led selectively to the formation of the N1-C16 bond of pleiocarpamine or to the C7-C16 bond of strictamine. We were then able to obtain the scaffold of talbotine.

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.

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.

Electrochemical synthesis of 3a-bromofuranoindolines and 3a-bromopyrroloindolines mediated by MgBr2.

We report an efficient and environmentally friendly electrochemical approach to perform the bromo cyclization of tryptophol, tryptamine and tryptophan derivatives. The 3a-bromofuranoindolines and 3a-bromopyrroloindolines obtained are of interest in the total synthesis of natural products. This dearomative procedure relies on the generation of an electrophilic bromine reagent by the electrochemical oxidation of MgBr2. No organic byproducts are generated with this protocol which avoids the use of an additional electrolyte.

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.

Synthesis of 3,3-Spirocyclic 2-Phosphonoindolines via a Dearomative Addition of Phosphonyl Radicals to Indoles.

The diastereoselective synthesis of α-amino phosphonate derivatives embedded in spirocyclic indolines is reported. The present method proceeds via the dearomative addition of phosphonyl radicals at the C2-position of the indole nucleus in oxidative conditions followed by the intramolecular trapping of the resulting carbocation before rearomatization. trans-3,3-Spirocyclic 2-phosphonoindolines were thus obtained.

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.

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.