Application In Total Synthesis Research Articles

Stereocontrolled Synthesis of 1,4-Dicarbonyls via [3,3]-Sulfonium Rearrangement and Application to the Synthesis of Heterocycles

Due to an inherent polarity mismatch of the corresponding retrosynthetic synthons, 1,4-dicarbonyl synthesis through polar pathways requires a retrosynthetic rethink. While Umpolung-based approaches exist, efficient control of both the absolute and relative configuration of newly formed stereogenic centres within this motif has long proven particularly challenging. In this Synpacts, we highlight our work on the stereodivergent synthesis of 1,4-dicarbonyl compounds through an unusual transformation that relies on vinyl sulfoxides and ynamides as reactants. This method allows stereoselective access to each and every one out of the four possible stereoisomers of a generic 1,4-dicarbonyl target in a process where enantio- and diastereoselectivity are “dialled into” the vinyl sulfoxide partner. Recent studies show that the thus formed 1,4-dicarbonyls serve as excellent linchpins for structural diversification into highly substituted heterocycles, including those found in natural products. 1. Introduction 2. Synthesis of 1,4-dicarbonyl compounds under acid catalysis 3. Cyclisation towards γ-lactones and γ-lactams 4. Application in total synthesis 5. Conclusion

4+1] Heteroannulation to Form 1‐Pyrrolines through Alder‐Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine

AbstractWe report in this paper a novel Cu‐catalyzed synthesis of polysubstituted 1‐pyrrolines. The reaction of β,γ‐unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2′‐biquinoline affords the corresponding 1,6‐enynimines, which undergo a highly stereoselective Alder‐ene reaction to afford 1‐pyrrolines with concomitant generation of a quaternary carbon and a 2‐azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1‐difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron‐rich alkyne during the pericyclic reaction. The resulting 1‐pyrrolines undergo facile acid‐catalyzed regioselective Wagner–Meerwein rearrangement to provide 2H‐pyrroles in excellent yields. The 2H‐pyrroles are also accessible from 4 and 5 in a one‐pot manner without isolation of the 1‐pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5‐tetrasubstituted pyrrolidine, is accomplished.

Palladium-catalyzed intramolecular Heck-type carbonylative cyclization cascade reaction and its application in total synthesis of complex natural products

Palladium-catalyzed intramolecular Heck-type carbonylative cyclization cascade reaction and its application in total synthesis of complex natural products

4+1] Heteroannulation to Form 1-Pyrrolines through Alder-Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine.

We report in this paper a novel Cu-catalyzed synthesis of polysubstituted 1-pyrrolines. The reaction of β,γ-unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2'-biquinoline affords the corresponding 1,6-enynimines, which undergo a highly stereoselective Alder-ene reaction to afford 1-pyrrolines with concomitant generation of a quaternary carbon and a 2-azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1-difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron-rich alkyne during the pericyclic reaction. The resulting 1-pyrrolines undergo facile acid-catalyzed regioselective Wagner-Meerwein rearrangement to provide 2H-pyrroles in excellent yields. The 2H-pyrroles are also accessible from 4 and 5 in a one-pot manner without isolation of the 1-pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5-tetrasubstituted pyrrolidine, is accomplished.

Organocatalytic, Chemoselective, and Stereospecific House–Meinwald Rearrangement of Trisubstituted Epoxides

AbstractWe present a novel method for the chemoselective House–Meinwald rearrangement of trisubstituted epoxides under mild conditions with the use of simple perfluorinated disulfonimides as Brønsted acid catalysts. We isolated the α-quaternary aldehyde products in yields of 27–97% using catalyst loadings as low as 0.5 mol% on a scale of 1 mmol. In addition, we show the stereospecific rearrangement using an enantioenriched substrate, which makes this method suitable for applications in total synthesis of natural products.

Enolates ambushed - asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles.

Metal enolates are useful intermediates and building blocks indispensable in many organic synthetic transformations. Chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents are structurally complex intermediates that can be employed in many transformations. In this review, we describe this burgeoning field that is reaching maturity after more than 25 years of development. The effort of our group to broaden possibilities to engage metal enolates in reactions with new electrophiles is described. The material is divided according to the organometallic reagent employed in the conjugate addition step, and thus to the particular metal enolate formed. Short information on applications in total synthesis is also given.

Efforts and Strategies for the Syntheses of Clavine‐Type Ergot Alkaloid Aurantioclavine

AbstractAurantioclavine, isolated by Kozlovskii from Penicillium aurantiovirens, is a unique member of the 3,4‐disubstituted indole alkaloids distinguished by an azepino[5,4,3‐cd]indole. As an essential intermediate in the biosynthesis of the complex polycyclic alkaloids of the fungal communesin, it has attracted considerable attention as a synthetic target. The development of various synthetic strategies for their application in total synthesis has been described. An overview focused on the synthesis of aurantioclavine from its first synthesis to the most recent one is present.

Solvent Dependency in Stereoselective δ‐Lactam Formation of Chiral α‐Fluoromalonate Derivatives: Stereodivergent Synthesis of Heterocycles with Fluorine Containing Stereocenters Adjacent to Tertiary Stereocenters

AbstractThe discovery and investigation of solvent dependency in stereoselective intramolecular amidation of chiral 5‐aminofunctionalized‐2‐fluoromalonate ester derivatives, which gives access to highly functionalized δ‐lactams with a quaternary fluorine‐containing stereocenter, is disclosed. Experimental work together with density functional theory calculations led to understanding of how to direct and switch the stereochemical outcome of the stereoselective δ‐lactam formation. The merging of this solvent‐dependent stereoselective switch with asymmetric catalysis and cascade reactions gives access to an unprecedented strategy for stereodivergent synthesis of all possible stereoisomers of fluorine‐containing stereocenters adjacent to tertiary stereocenters of a wide range of heterocyclic compounds with 95‐>99% ee in one‐pot. It is also useful for application in total synthesis of fluorine‐containing pharmaceuticals.magnified image

Synthesis of Cyclopentenones with C4-Quaternary Stereocenters via Stereospecific [3,3]-Sigmatropic Rearrangement and Applications in Total Synthesis of Sesquiterpenoids.

A cationic gold(I)-catalyzed asymmetric [3,3]-sigmatropic rearrangement of sulfonium leads after cyclization to cyclopentenones with a C4-quaternary stereocenter. Starting with simple vinyl sulfoxides and propargyl silane, numerous compounds were isolated with moderate to good yields and excellent enantiomeric excesses (26 examples). The application of this simple methodology allowed the efficient total synthesis of five natural sesquiterpenoids, including enokipodin A and B, hitoyopodin A, lagopodin A, and isocuparene-3,4-diol.

Synthesis of α-exo-Methylene-γ-butyrolactones: Recent Developments and Applications in Natural Product Synthesis

AbstractThe α-exo-methylene-γ-butyrolactone moiety is present in a vast array of structurally diverse natural products and is often central to their biological activity. In this short review, we summarize new approaches to α-exo-methylene-γ-butyrolactones developed over the past decade as well as their applications in total synthesis.1 Introduction2 Approaches to α-exo-Methylene-γ-butyrolactones2.1 Enantioselective Synthesis via Lactonization Approaches2.2 Enantioselective Halolactonizations2.3 Enantioselective Barbier-Type Allylation2.4 C–H Insertion/Olefination Sequences2.5 Alkene Cyclization2.6 Strain-Driven Dyotropic Rearrangement3 β-(Hydroxymethylalkyl)-α-exo-methylene-γ-butyrolactones4 Applications in Total Synthesis4.1 Sesquiterpene Lactones4.2 Lignans4.3 Other Monocyclic Natural Products4.4 Choice of Methodology in Recent Total Syntheses5 Summary and Outlook

Advances in the E → Z Isomerization of Alkenes Using Small Molecule Photocatalysts.

Geometrical E → Z alkene isomerization is intimately entwined in the historical fabric of organic photochemistry and is enjoying a renaissance (Roth et al. Angew. Chem., Int. Ed. Engl. 1989 28, 1193-1207). This is a consequence of the fundamental stereochemical importance of Z-alkenes, juxtaposed with frustrations in thermal reactivity that are rooted in microscopic reversibility. Accessing excited state reactivity paradigms allow this latter obstacle to be circumnavigated by exploiting subtle differences in the photophysical behavior of the substrate and product chromophores: this provides a molecular basis for directionality. While direct irradiation is operationally simple, photosensitization via selective energy transfer enables augmentation of the alkene repertoire to include substrates that are not directly excited by photons. Through sustained innovation, an impressive portfolio of tailored small molecule catalysts with a range of triplet energies are now widely available to facilitate contra-thermodynamic and thermo-neutral isomerization reactions to generate Z-alkene fragments. This review is intended to serve as a practical guide covering the geometric isomerization of alkenes enabled by energy transfer catalysis from 2000 to 2020, and as a logical sequel to the excellent treatment by Dugave and Demange (Chem. Rev. 2003 103, 2475-2532). The mechanistic foundations underpinning isomerization selectivity are discussed together with induction models and rationales to explain the counterintuitive directionality of these processes in which very small energy differences distinguish substrate from product. Implications for subsequent stereospecific transformations, application in total synthesis, regioselective polyene isomerization, and spatiotemporal control of pre-existing alkene configuration in a broader sense are discussed.

Palladium catalyzed reductive Heck coupling and its application in total synthesis of (−)-17-nor-excelsinidine

Monoterpene indole alkaloids, bearing a highly substituted piperidine ring, are a structurally diverse class of bioactive natural products, found in various parts of the world. Herein, we reported the construction of the key piperidine ring via palladium catalyzed reductive Heck coupling with a good syn selective manner, avoiding the usage of stoichiometric, highly toxic, air sensitive and moisture sensitive Ni(COD)2. To further showcase the value of this methodology, we realized the total synthesis of the structurally unique zwitterionic monoterpene indole alkaloid (−)-17-nor-excelsinidine in 9 steps, in which the key ammonium–acetate connection (N4–C16) of (−)-17-nor-excelsinidine was constructed via oxidative coupling in excellent yield and high regioselectivity under NBS/pyridine from the enolate of geissoschizine.

Evolution towards green radical generation in total synthesis.

The use of radicals as intermediates in total synthesis has evolved since their initial use in the latter half of the twentieth century. Radical generation from metal hydride methodologies has shifted to "greener" techniques including catalytic metal-mediated systems, electrochemical and photoredox-mediated processes. This review will focus on these classical and contemporary methods for radical generation and their applications in recent total syntheses.

Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020)

Metal-mediated cyclizations are important transformations in a natural product total synthesis. The Pauson-Khand reaction, particularly powerful for establishing cyclopentenone-containing structures, is distinguished as one of the most attractive annulation processes routinely employed in synthesis campaigns. This review covers Co, Rh, and Pd catalyzed Pauson-Khand reaction and summarizes its strategic applications in total syntheses of structurally complex natural products in the last five years. Additionally, the hetero-Pauson-Khand reaction in the synthesis of heterocycles will also be discussed. Focusing on the panorama of organic synthesis, this review highlights the strategically developed Pauson-Khand reaction in fulfilling total synthetic tasks and its synthetic attractiveness is aimed to be illustrated.

Aza‐Piancatelli Cyclization as a Platform for the Preparation of Scaffolds of Natural Compounds: Application to the Total Synthesis of Bruceolline D

The aza‐Piancatelli cyclization provides an expedient synthesis of 4‐aminocyclopentenone building blocks that may be converted into aminocyclopentitols, which are heavily represented motifs among natural products. However, its use as a key step in total synthesis was still unprecedented. Here, we disclose our in‐depth investigations regarding this reaction in order to access highly complex structures representing the core of some natural molecules. The applicability of the cyclization was highlighted by the 3‐step total synthesis of bruceolline D. Thus, we anticipate that this work will lay the ground for further applications in total synthesis.

Catalytic Domino Annulations through η3‐Allylpalladium Chemistry: A Never‐Ending Story

Annulative η3‐allylpalladium chemistry has been a longstanding trending research topic since the 80's. Nowadays, this research area is still providing challenges to the catalysis community leading to the development original and brand‐new transformations. Several reaction partners have been used as precursors for η3‐allylpalladium species, namely allyl diacetates, allyl monoacetates, 3‐acetoxy‐2‐trimethylsilylmethyl‐1‐propene (ASMP), alkylidene cyclopropanes (ACPs), vinyl cyclopropanes (VCPs), vinyl aziridines, and vinyl epoxides. This minireview is intended to show the recent developments in the field of annulative η3‐allylpalladium chemistry with emphasis on new reactivity, enantioselective transformations as well as potential applications in total synthesis.

Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives

This review summarizes the progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives and their applications in total synthesis of natural products, and gives some insights into challenging issues in this research field.

Indole Alkaloid Synthesis Facilitated by Photoredox Catalytic Radical Cascade Reactions

The monoterpene indole alkaloids, containing over 3000 known members and more than 40 structural types, represent one of the largest natural product families that have proven to be an important drug source. Their complex chemical structures and significant biological activities have rendered these alkaloids attractive targets in the synthetic community for decades. While chemists have developed many synthetic methodologies and tactics toward this end, general strategies allowing divergent access to a large variety of structural types and members of monoterpene indole alkaloids are still limited and highly desirable. Photoredox catalysis has emerged in recent years as a powerful tool to realize chemical transformations via single electron transfer (SET) processes that would otherwise be inaccessible. In particular, when the radical species generated by the visible light photoinduced approach is involved in well-designed cascade reactions, the formation of multiple chemical bonds and the assembly of structurally complex molecules would be secured in a green and economic manner. This protocol might serve to remodel the way of thinking for the preparation of useful pharmaceuticals and complex natural products. Due to a long-standing interest in the synthesis of diverse indole alkaloids, our group previously developed a cyclopropanation strategy ( Qin , Y. Acc. Chem. Res. 2011 , 44 , 447 ) that was versatile to access several intriguing indole alkaloid molecules. With an idea of developing more general synthetic approaches to as many members of various indole alkaloids as possible, we recently disclosed new radical cascade reactions enabled by photoredox catalysis, leading to the collective asymmetric total synthesis of 42 monoterpene indole alkaloids belonging to 7 structural types. Several important discoveries deserve to be highlighted. First, the use of photocatalytic technology allowed us to achieve an unusual reaction pathway that reversed the conventional reactivity between two nucleophilic amine and enamine groups. Second, a crucial nitrogen-centered radical, directly generated from a sulfonamide N-H bond, triggered three types of cascade reactions to deliver indole alkaloid cores with manifold functionalities and controllable diastereoselectivities. Moreover, expansion of this catalytic, scalable, and general methodology permitted the total synthesis of a large collection of indole alkaloids. In this Account, we wish to provide a complete picture of our studies concerning the original synthetic design, method development, and applications in total synthesis. It is anticipated that the visible-light-driven cascade strategy will find further utility in the realm of natural product synthesis.

Recent Advances in the Chemistry of Doubly Activated Cyclopropanes: Synthesis and Reactivity

Diactivated cyclopropanes containing two geminal electron withdrawing groups, commonly called as ‘Doubly Activated Cyclopropanes’ are useful synthons for the synthesis of many interesting natural products and functionalized molecules. These geminal electron withdrawing groups (EWG’s) facilitate the regioselective ring opening of cyclopropanes by polarizing the C-C bond adjacent to it. This polarization also allows them to undergo 1,3 dipolar cycloaddition reactions when substituted with a suitable electron donor substituent at the adjacent carbon (donor-acceptor cyclopropanes) in the presence of suitable dipolarophiles. In this review, we discuss the recent advances in the chemistry of doubly activated cyclopropanes: their synthesis, reactions and applications in total synthesis.

Doyle‐Kirmse Rearrangement Reactions of Difluoroacetates

AbstractIn this report, we describe an application of ethyl difluoroacetate‐substituted allylic sulfides in Doyle‐Kirmse rearrangement reactions that allow efficient access to valuable fluorinated small molecules with applications in total synthesis and drug discovery. A cheap and readily available rhodium catalyst or – in a metal‐free variant – visible light was used to generate a carbene intermediate to access rearrangement reactions in high yield.