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ChemInform Abstract: NHC-Catalyzed Ring Expansion of Oxacycloalkane-2-carboxaldehydes: A Versatile Synthesis of Lactones.
Abstract
Imidazolinium-derived carbenes catalyze the ring-expansion lactonization of oxacycloalkane-2-carboxaldehydes. A variety of functionalized five-, six-, and seven-membered lactones can be formed efficiently under mild reaction conditions. The success of this new method for the construction of lactones is highly influenced by the electronic nature of the carbene catalyst.
... Zn/ EtOH [13] mediated reductive ring opening of iodo-intermediate 15 furnished the hydroxy olefin 16 in 96 % yield. Epoxidation of 16 with m-CPBA in dichloromethane followed by treatment with a catalytic amount of CSA [14] provided the cis-and trans -THP compounds 17 a and 17 b in 7 : 3 ratio in 90 % yield. In order to establish the stereochemistry at the newly generated stereocenter at C-16, 17 a and 17 b were subjected to hydrogenation to produce 18 and 13. ...
Herein, we describe a simple and efficient pathway for the total synthesis of pyranicin and 4‐epi‐pyranicin by utilizing carbohydrates as chiral raw materials for the first time. The general synthetic strategy involves the formation of two main fragments: Fragment 1 is the central tetrahydropyran core, which was constructed in a total of 10 steps from 2,3,4,6‐tetra‐O‐acetyl D‐glucal via Ferrier‐type rearrangement and oxidative cyclization as the key steps. Fragment 2 is the butenolide fragment, which was obtained in a gram scale with a total of 14 steps from diacetyl‐L‐rhamnal involving a ring contraction strategy.
... Although the treatment of isothiocyanate 209 with nitroalkene 147 gives [2+2] cycloadduct azatidinethione 211 [92] through the enethiol intermediate 210, the use of isocyanate 212 furnishes [2+2+2] cycloadduct 213 [93] (Scheme 49). The reaction of an aryl ketene with substrate 214 or 216 in the presence of NHC furnishes the respective adduct 215 or 217 [94, 95] (Scheme 50).NHC-catalyzed reaction of carbon dioxide with tosylaziridine 218 followed by desulfonylation with samarium diiodide in a one-pot manner gives the insertion product 219[96] (Scheme 51).Ring expansion of cyclic aldehydesBecause the saturated C-N and C-O bond migrate to the acyl anion intermediate generated by the reaction of cyclic aldehyde and NHC, the treatment of pyrrolidine, azetidine, oxetane, oxolane, and hydropyran 220-222 furnish the corresponding ring-expanded lactams and lactones 223-225[97][98][99] (Scheme 52). Successive enantioselective Michael reaction and ring expansion of aldehyde 226 yields chromanone 228[100] (Scheme 53). ...
After a long history of medical and biochemical investigations of vitamin B1, N-heterocyclic carbenes (NHCs) have recently been used as organocatalysts for a variety of synthetic reactions. This review article highlights the application of NHC-catalyzed reactions including enantioselective reactions to the heterocyclic synthesis. NHC-catalyzed benzoin condensation and Stetter reaction of ether- and amine-linked aldehydes give four- to six-membered oxygen and nitrogen heterocycles. NHC-catalyzed conjugate additions of enals to ketones and imines afford γ-lactones and γ-lactams. When the NHC-catalyzed reaction intermediates of enals are protonated, the reaction of the resulting enols with enones and ene-imines furnish formal hetero-Diels-Alder products. Acyl fluoride and esters can be activated by NHCs, and subsequent aldol and Michael reactions give β-lactones. Oxidation of intermediates derived from enals or the intermediates from ynals provide unsaturated acyl azolium which are transformed into cyclic products via subsequent nucleophilic reactions. NHCs also catalyze [2+2] cycloadditions of ketenes and other heterocumulenes and ring expansion of cyclic aldehydes.
... Cependant l'analyse par RMN de ce dernier a montré qu'il s'agissait d'un tout autre produit. Schéma 71 -Synthèse de coumarines parélimination de type internal redox Gravel a quantà lui utilisé cette réactivité pour réaliser la synthèse de lactones par expansion d'hétérocycles oxygénés [186] (Schéma 72). Dans ce cas, la réaction d'élimination permet l'ouverture d'un tétrahydrofurane. ...
Les nucléolipides sont des molécules hybrides amphiphiles de faible poids moléculaire composées de deux parties liées de façon covalente : la première est un acide nucléique, un nucléotide, un nucléoside ou une nucléobase et la seconde un lipide. En combinant les propriétés physicochimiques de deux des biomolécules parmi les plus représentées dans le vivant, les nucléolipides présentent la capacité à former des auto-assemblages supramoléculaires d’intérêt pour la conception de biomatériaux. L'étude des capacités d’auto-assemblage des GlycoNucléoLipides, qui possèdent un lien aromatique de type triazole, a démontré que la nature du lien covalent qui unit les deux parties du nucléolipide a un effet déterminant sur l’assemblage. Ce travail a porté sur l'utilisation et le développement d'une réaction de Stetter, organocatalysée par des carbènes N-hétérocycliques et bioinspirée, pour obtenir un lien de type dicétone-1,4 entre la thymidine et différents lipides. Ce motif, précurseur de cycles hétéroaromatiques, a notamment conduit à la formation de liens de type pyrrole par une réaction de type Paal-Knorr. Les propriétés gélatrices de ces nucléolipides originaux ont été comparées à celles de ceux portant un motif triazole. Parmi les nucléolipides obtenus, un composé particulièrement lipophile, porteur du lien 1,4- dicétone, a montré la capacité de former un gel dans des huiles (soit un oléogel). Une étude structurepropriétés a été effectuée pour comprendre le rôle de chaque partie de la molécule. Ce type de formulation présentant un intérêt tout particulier pour le développement de systèmes de délivrance contrôlée de substances actives lipophiles, les propriétés physicochimiques de cet oléogel ont par ailleurs été étudiées. La réaction de Stetter présentant la plupart des caractéristiques d'une réaction dite de "chimie click", des conditions de réaction plus éco-compatibles et adaptées à la fonctionnalisation d’autres biomolécules ont ensuite été développées en milieu aqueux.
... 13 C NMR (100 MHz, CDCl3) δ 171.4, 138.5, 129.0, 128.8, 126.8, 73.2, 38.1, 34.8, 29.1, 25.4.Spectroscopic data were consistent with those previously reported.12 ...
... NMR (100 MHz, CDCl 3 ), (ppm): 63.8, 52.5, 44.6, 26.0, 18.5, −5.1, −5.2. The spectral data for this compound match that reported in the literature[2].1-StearoyI-3-(tert-butyldimethylsilyl)-sn-glycerol (4a) Molecular formula: C 27 H 56 O 4 Si Molecular Mass: 472.8260 g/mol Physical appearance: white-yellowish solid TLC: R f (silica gel) = 0.32 (n-pentane/EtOAc 10:1); KMnO 4 active. 1 H NMR (400 MHz, CDCl 3 ), (ppm): 4.17-4.08 ...
In recent times, many biologically relevant building blocks such as amino acids, peptides, saccharides, nucleotides and nucleosides, etc. have been prepared by mechanochemical synthesis. However, mechanosynthesis of lipids by ball milling techniques has remained essentially unexplored. In this work, a multistep synthetic route to access mono- and diacylglycerol derivatives by mechanochemistry has been realized, including the synthesis of diacylglycerol-coumarin conjugates.
... If this reactivity is widely described in the literature, it concerns properly tuned leaving groups as OAr. 16 In particular, α-aroyloxyaldehyde substrates 17 were designed on the basis of the high leaving group ability of the α-functional group. ...
N-Heterocyclic Carbene (NHC) catalyzed biomimetic Stetter reaction was applied for the first time as a bioconjugation reaction to sensitive nucleoside-type biomolecules to provide original pyrrole linked nucleolipids. A versatile approach allowed the functionalization of thymidine at the three reactive positions (O-5', O-3' and N-3) providing a structural diversity oriented synthesis. This strategy was applied to the synthesis of an original GlycoNucleoLipid amphiphile in the hope that pyrrole aromatic moiety would induce additional self-assembling properties.
Transforming alkane C−H bonds into carbon‐carbon and carbon‐heteroatom bonds represents a paramount objective in synthetic chemistry with significant implications for sustainable production. Although transition‐metal catalysts such as Pd, Rh etc have dominated this field, recent breakthroughs in metal‐free approaches leveraging small‐molecule catalysts or photogenerated intermediates have emerged as efficient and sustainable alternatives. These approaches facilitate precise C−H bond activation and selective formation of C−X (e. g., C, halogen, N, O) bonds under mild conditions, thereby paving a promising avenue for eco‐friendly alkane transformations. This review provides an overview of recent advancements in homogeneous metal‐free alkane functionalization, focusing on organocatalytic and photoinduced strategies, with the aim of enhancing mechanistic understanding and inspiring the development of innovative synthetic methodologies for the conversion of alkanes into high‐value compounds.
Developing methods to directly transform C(sp³) −H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of “inert” C(sp³) −H bonds for cross C−C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp³) −H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp³)−H substrates, such as ethers, amines, and alkanes. This mini‐review summarizes the progress in carbene organocatalytic functionalization of inert C(sp³)−H bonds enabled by HAT processes, categorizing them into two sections: 1) C−H functionalization involving acyl azolium intermediates; and 2) functionalization of C−H bonds via reductive Breslow intermediates.
Oxidative cyclization of 4-penten-1-ols using a Pd catalyst and n -BuONO or n -BuONO/ p -benzoquinone afforded 3-hydroxy- and 3-methoxytetrahydropyrans via terminal selective nucleophilic attack. The radicals formed from n -BuONO and O 2 operate as...
N-Heterocyclic carbene (NHC) organocatalyzed transformations of redox-active chemical manifolds is a powerful strategy for interconverting and expanding the chemical space. This approach in the context of ring expansion holds promise for preparing lactones from plentiful redox active aldehydes, despite a lack of rigorous mechanistic insights into the underlying elements governing this reactivity and with-it relevance to other NHC organocatalyzed transformations. Herein, in investigating this reactivity under the lens of modern day quantum mechanical calculations, we explore the mechanism of redox-active/ring expansion reactions of aldehydes furnishing lactone products by means of NHC organocatalysis. Through this comprehensive study, the underpinning mechanism of Breslow intermediate formation and ensuing downstream processes such as intermolecular C-C bond formation providing benzoin products versus intramolecular redox pathways are outlined. Notably, this study of NHC organocatalysis reveals the diverse role of bases as cooperative agents in directing and selectively routing reactivity, as highlighted here toward ring expanded lactone products.
The stereoselective synthesis of complex targets requires the precise orchestration of chemical transformations that simultaneously establish the connectivity and spatial orientation of desired bonds. In this work, we describe a complementary paradigm for the synthesis of chiral molecules and their isomers, which tunes the three-dimensional structure of a molecule at a late stage. Key to the success of this strategy is the development of a mild and highly general photocatalytic method composed of decatungstate polyanion and disulfide cocatalysts, which enable the interconversion of unactivated tertiary stereogenic centers that were previously configurationally fixed. We showcase the versatility of this method-and the implementation of stereoediting logic-by the rapid construction of chiral scaffolds that would be challenging to access using existing tools and by the late-stage stereoediting of complex targets.
This chapter summarizes the new advancements of N ‐heterocyclic carbene (NHC) organocatalysis in the recent decade (roughly between 2010 and 2020). Particular focus is drawn to the basic activation and reaction modes enabled by NHC as a key catalyst. Examples of these key development include NHC‐catalyzed reactions beyond simple aldehydes to unsaturated aldehydes and functionalized aldehydes as substrates, activation of carboxylic esters for asymmetric reactions, single‐electro‐transfer radical reactions, cooperative catalysis involve NHC and other catalysts such as transition metals, and applications of NHC‐catalyzed reactions in the synthesis of sophisticated molecules.
As minimizing the ecological effects of plastics is of ever greater importance, the replacement of certain conventional fossil‐based plastics with biobased and degradable polymers has become an important strategy. Ring‐opening polymerization (ROP) is a well‐established, industrial polymerization technique especially suited for the production of aliphatic polyesters – a range of polymers susceptible to degradation through the ester linkages in their polymer backbones. While degradable polymers are certainly not limited to this category, this promising field is the focus of a lot of research. Notable polyesters made from ROP of cyclic lactones include the commodity bioplastics poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(ϵ‐caprolactone) (PCL). Herein we first provide a brief overview of the mechanisms and thermodynamics of ROP, as well as tools to enhance the biodegradability of ROP‐based polyesters. Following that, this chapter reviews ROP of various standard and functionalized lactones of different sizes (four‐ to seven‐membered rings), as well as the resulting polymer properties including their relation to degradability. Assessment methods of the latter are briefly discussed critically.
Imidazoles and benzimidazoles together with their partly or fully saturated derivatives particularly as carbenes, are very important and useful heterocycles with applications in the chemical, biological, material and pharmaceutical sciences. The general trend of the previous edition has been followed with emphasis on developments regarding structure, reactions and synthesis, reported in the literature from 2007 to 2019. A large part of the current review describes the reactivity and synthesis of conjugated and nonconjugated imidazoles and their substituents whereas theoretical and experimental structure elucidation methods, as well as applications, are also presented.
We report the discovery that simple carboxylic acids, such as benzoic acid, boost the activity of N‐heterocyclic carbene (NHC) catalysts in the oxidative esterification of aldehydes. A simple and efficient protocol for the transformation of a wide range of sterically hindered α‐ and β‐substituted aliphatic aldehydes/enals, catalyzed by a novel and readily accessible N‐Mes‐/N‐2,4,6‐trichlorophenyl 1,2,4‐triazolium salt, and benzoic acid as co‐catalyst, was developed. A whole series of α/β‐substituted aliphatic aldehydes/enals hitherto not amenable to NHC‐catalyzed esterification could be reacted at typical catalyst loadings of 0.02–1.0 mol %. For benzaldehyde, even 0.005 mol % of NHC catalyst proved sufficient: the lowest value ever achieved in NHC catalysis. Preliminary studies point to carboxylic acid‐induced acceleration of acyl transfer from azolium enolate intermediates as the mechanistic basis of the observed effect.
While N-heterocyclic carbene (NHC) catalyzed oxidative esterification of aldehydes/enals is synthetically highly attractive, it is plagued by poor conversions/yields for sterically demanding substrates. The triazolium catalyst shown, with benzoic acid as co-catalyst, overcomes this deficiency. A variety of hitherto recalcitrant aldehydes/enals are efficiently converted to esters with very low catalyst loadings (down to 50 ppm).
Abstract
We report the discovery that simple carboxylic acids, such as benzoic acid, boost the activity of N-heterocyclic carbene (NHC) catalysts in the oxidative esterification of aldehydes. A simple and efficient protocol for the transformation of a wide range of sterically hindered α- and β-substituted aliphatic aldehydes/enals, catalyzed by a novel and readily accessible N-Mes-/N-2,4,6-trichlorophenyl 1,2,4-triazolium salt, and benzoic acid as co-catalyst, was developed. A whole series of α/β-substituted aliphatic aldehydes/enals hitherto not amenable to NHC-catalyzed esterification could be reacted at typical catalyst loadings of 0.02–1.0 mol %. For benzaldehyde, even 0.005 mol % of NHC catalyst proved sufficient: the lowest value ever achieved in NHC catalysis. Preliminary studies point to carboxylic acid-induced acceleration of acyl transfer from azolium enolate intermediates as the mechanistic basis of the observed effect.
Furan-2(5H)-one (γ-butenolide) and related γ-lactones are widely found in the structures of biologically active natural products. Such molecules are also used as potent building blocks in organic synthesis. In this chapter, recent achievements of γ-lactone synthesis are reviewed. In particular, catalytic methodologies directing to environment-friendly chemical processes are covered as a major topic.
Iridoids are a large family of monoterpenoids found in traditional medicinal plants and show significant effects for the human species. In addition to their wide range of biological activities, such as neuroprotective and antitumor activities, the cis‐fused bicyclic ring systems of iridoids are still attractive as synthetic targets to apply novel synthetic methodologies. Accordingly, recent progress regarding the biosynthesis and chemical synthesis of iridoids is covered in this minireview. Identification of new enzymes for the iridoid biosynthesis in Catharanthus roseus and ingenious synthetic strategies for the construction of the iridoid skeleton are described.
p>Pyridinium and related N-alkyl (heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transforms. Herein, we leverage (bis)cationic nitrogen-ligated I(III) hypervalent iodine reagents, or N -HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of (heteroaryl)onium salts via the aminolactonization of alkenoic acids. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N -HVI reagents can be generated in situ , the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles. Mechanistic studies indicate the reaction proceeds via initial olefin activation followed by lactonization and subsequent intermolecular nucleophilic displacement of an (alkyl)(aryl)iodonium salt hypernucleofuge.</p
This chapter summarizes N‐heterocyclic carbene (NHC) catalysis in the construction of natural products. The coupling between two aldehydes or an aldehyde and ketone through the formation of acyloins, also known as the benzoin condensation, is the most venerable of Umpolung reactions. The polyketide synthase found in the type‐II polyketide biosynthesis assembles densely functionalized polyclic aromatic polyketides encompassing an entire family of biologically active natural products. The Stetter reaction is the conjugate addition of acyl anion equivalents to α,ß‐unsaturated carbonyls and related conjugated acceptors. Homoenolates are broadly defined as reactive species in which the nucleophilic carbon is beta‐ to a carbonyl or carbonyl equivalent. Classically, these species have been used to produce both linear and cyclic frameworks through anionic metal‐mediated reactions. In addition to the Umpolung reactions catalyzed by NHCs such as benzoin, Stetter, and homoenolate addition reactions, NHCs can promote unique redox reactions that terminate with the addition of heteronucleophiles in a formal acylation step.
Two types of photoreactions between electronically-differentiated donor and acceptor alkenes assisted by nucleophilic addition using an organic photoredox catalyst efficiently afforded 1:1 or 2:1 cross-coupling adducts. A variety of alkenes and alcohols were employed in the photoreaction. Control of the reaction pathway (i.e., the formation of the 1:1 or 2:1 adduct) was achieved by varying the concentration of the alcohol used. Detailed mechanistic studies suggested that the organic photoredox catalyst acts as an effective electron mediator to promote the formation of the cross-coupling adducts.
A straightforward protocol integrating a sustainable approach for synthesis of new 2,5-trans-THF nitrile derivatives enabling an easy diversification of its side chain scaffolds is described. The reaction tolerated different aromatic and alkyl substituents, affording the corresponding 2,5-trans-THFs in high diastereoselectivity. A detailed mechanistic study using DFT calculation reveals details of the ligand-exchange step, suggesting an inner-sphere syn attack to form the 2,5-trans stereochemistry as the most likely pathway, excluding the previous cation radical intermediate. The formation of a Co-C intermediate is suggested based on the homolytic cleavage to give the previously proposed free carbon radical intermediate.
Enzymatic polymerization has emerged due to their advantages for polymer synthesis compared to conventional catalysts. This chapter presents an overview of the application of enzymatic polymerization to catalyze the synthesis of polyesters using different types of monomers prepared from biomass, where some recently and interesting published reports are highlighted. Lactones are an important class of monomers for the synthesis of aliphatic polyesters via chain‐growth mechanism, which offers a lot of attractive advantages over monomers that react via step‐growth mechanism. Polycondensation is considered as the main synthetic route to prepare commercial polyesters. This polymerization technique allows direct synthesis of wide spectrum of polyesters form naturally derived monomers. Utilization of sustainable saturated and unsaturated fatty acids as side chains to modify linear functional polyester, that is, prepared enzymatically by copolymerization of dicarboxylic acids or their esters with polyols, have attracted increasing attention due to the potential applications of the resulting polymers in many interesting fields.
The research in the field of asymmetric carbene organic catalysis has primarily focused on the activation of carbon atoms in non-aromatic scaffolds. Here we report a reaction mode of carbene catalysis that allows for aromatic aldehyde activation and remote oxygen atom functionalization. The addition of a carbene catalyst to the aldehyde moiety of 2-hydroxyl aryl aldehyde eventually enables dearomatization and remote OH activation. The catalytic process generates a type of carbene-derived intermediate with an oxygen atom as the reactive centre. Inexpensive achiral urea co-catalyst works cooperatively with the carbene catalyst, leading to consistent enhancement of the reaction enantioselectivity. Given the wide presence of aromatic moieties and heteroatoms in natural products and synthetic functional molecules, we expect our reaction mode to significantly expand the power of carbene catalysis in asymmetric chemical synthesis.
N-heterocyclic carbenes (NHCs) have emerged as powerful and elegant organocatalysts in a variety of newly developed and unprecedented enantioselective transformations due to the unique umpolung capacity. As a supplementary of convertional enantioselective organocatalysis, NHC-induced non-asymmetric catalysis gradually aroused more interest in recent years. Herein, this review aims to reveal the recent developments in NHC-promoted non-asymmetric umpolung transformations resulting in the expeditious construction of versatile achiral natural heterocycles, carbocycles and acylated products.
Aliphatic polyesters are important biodegradable polymers with wide applications. Polyesters prepared by ring-opening polymerization often have a limited range of properties owing to the minimal functional diversity of available lactone monomers. In this review, synthetic strategies in preparing functional lactone monomers are highlighted as well as recent controlled polymerization strategies to synthesize functional aliphatic polyesters, which include proton-transfer polymerization, ring opening polymerization of O-carboxyanhydrides, radical ring-opening polymerization of cyclic ketene acetals, and copolymerization of epoxide/anhydride. Thermal properties of many newly developed polyesters, such as their glass transition temperatures, are also included.
Michael reactions have drawn a great amount of interest from the synthetic community due to their ability to form C–C sigma bonds through the conjugate addition of carbon nucleophiles to many different types of Michael acceptors [1]. However, the analogous conjugate additions of other heteroatom nucleophiles such as amines, thiols, phosphines, and alcohols have not progressed at the same rate [2–5]. This is especially true for the application of these conjugate addition methodologies in the context of alcohol nucleophiles and α,β-unsaturated carbonyl compounds (oxa-conjugate addition reaction) in order to stereoselectively form tetrahydropyrans. This comparative lack of interest can be mainly attributed to the major disadvantages of the oxa-conjugate addition reaction, including the poor nucleophilicity of oxygen atoms, reversibility of the addition process (retro-oxa-conjugate addition reaction), and the lack of stereoselectivity [1].
An archetype of a green and sustainable strategy for the catalytic upgrading of both anilines and bio-based derivatives including glycerol acetals, p-coumaryl-like alcohols, and lactones can be devised by the use of dimethyl carbonate (DMC). In the presence of different heterogeneous catalysts such as alkaline carbonates and alkali metal-exchanged faujasites, DMC allows quantitative mono-N-methylation and O-methylation processes with excellent selectivity up to 99% and no by-products except for methanol (recyclable to the synthesis of DMC) and CO2. Also, selective transesterifications of DMC with glycerol acetals and lactones can be achieved under thermal or catalytic conditions. The mechanism of such reactions has been formulated based on the steric requisites and the amphoteric nature of faujasites, the combined effect of the temperature and base catalysts, and the ambident electrophilic reactivity of DMC. Overall, methylations and methoxycarbonylations mediated by DMC are not only more selective but far safer than conventional procedures involving noxious phosgene and methyl halides or dimethyl sulfate.
This review summarizes the recent advances on the redox reactions involving alpha-functionalized aldehydes catalyzed by N-heterocyclic carbenes. In the presence of N-heterocyclic carbene, alpha-functionalized aldehydes such as alpha-haloaldehydes, alpha-ring-fused aldehydes, alpha-aryloxyacetaldehydes and alpha-aroyloxyaldehydes undergo the redox reactions affording novel reaction types.
The total synthesis of (+)-tanikolide was accomplished by a traceless stereoinduction method using the key steps of a Rh(II)-catalyzed oxonium ylide formation-[2,3]-sigmatropic rearrangement and an N-heterocyclic carbene-catalyzed ring-expansion lactonization of tetrahydrofurfural. This synthetic route is applicable to the divergent synthesis of tanikolide analogues.
We report a highly stereocontrolled total synthesis of one of the possible stereoisomers of laurenidificin. Highlights of the synthesis include the formation of the 2,6-dioxabicyclo[3.3.0]octane framework by a stereospecific bromolactonization-alpha-bromination-ring contraction (oxy-Farvorskii rearrangement) sequence, followed by a stereoselective propargylation, an insertion of the Z-enyne side-chain by a hydroindation/cross coupling reaction, and ethylation at C13 with an organocuprate reagent. While the synthetic compound was not identical to the natural product, a most plausible absolute stereochemistry of the natural product was proposed on the basis of NMR analyses. Moreover, a formal total synthesis of (+)-aplysiallene was achieved by extending the ring contraction strategy.
Asymmetric C-H direct functionalization reactions are one of the most active and fascinating areas of research in organic chemistry due to their significance in the construction of molecular complexity without pre-activation, and the step economy and atom economy features in potential synthetic application. Distinguishing the reactivity among numerous C–H bonds in one single molecule represents one of the most challenging issues in organic synthesis and requires precise reaction design. As such, this field is now receiving increasing attention from researchers.
This book provides the first comprehensive review of this field, summarizing the origin, mechanism, scope and applications of the asymmetric C-H bond functionalization reaction. It covers organocatalytic reactions and transition-metal-catalyzed reactions, as well as asymmetric C-H functionalization reactions not described in other books.
Written by a leading expert in this field, the book is ideal for postgraduates and researchers working in organic synthesis, catalysis, and organometallic chemistry.
Compared to parent oxygenated five- and six-membered rings, oxepanes represent a rare structure found in Nature. Nevertheless, natural products with significant biological activities possess either only one seven-membered ring or one or multiple oxepane subunits fused to other oxygenated heterocycles. Therefore, a large number of methods have been designed to access these structures with a special attention on metal-catalysed coupling reactions.KeywordsCyclisationEpoxidesLactonesMetal-induced cyclisationsMetathesisOxepanesOxepinsOxidationPalladium-catalyzed couplingPrins reactionRadical cyclisationRing enlargementRing openingSamarium diiodide
The synthetic utility of azolium salts as catalysts was thought to be limited to the generation of acyl anion equivalents for use in benzoin and Stetter reactions. The discovery, in 2004, of new catalysts, substrates, and reaction manifolds has ignited a new generation of reactions that fall under the general rubrik of N-heterocyclic carbene (NHC) catalyzed reactions. These powerful new processes include the catalytic generation of activated carboxylates for α-functionalized aldehydes, enantioselective annulations via catalytically generated ester enolate equivalents, and the NHC-catalyzed generation of formal homoenolate equivalents. The history of these new reactions and an overview of the reactions, their substrate scope, and mechanistic pathways are summarized in this Chapter.
A copper-catalyzed borylation/ortho-cyanation/allyl group transfer cascade was developed. Initiated by an unconventional copper-catalyzed electrophilic dearomatization, this process features regio- and stereospecific 1,3-transposition of the allyl fragment enabled by an aromatization-driven Cope rearrangement. This method provides an effective means for the construction of adjacent tertiary and quaternary stereocenters with excellent diastereocontrol.
Dihydrofuran-2(3H)-one (γ-butyrolactone) and some related γ-lactones are widely found in the structures of biologically active natural products. Such molecular structures are also used as potent building blocks in organic synthesis. In this chapter, recent achievements of γ-lactone synthesis are reviewed. In particular, catalytic methodologies directing to environment-friendly chemical processes are covered as a major topic.
Enantiospecific and enantioselective approaches to the natural (16R,19R)- and the unnatural (16S,19S)- THF core of the bioactive acetogenin annonacin are described which utilizes both a chiral pool synthesis and enzymatic transformations. In the antipodal (2S,5S) THF series derived from D- (+)-glucosamine, the semi-protected THF aldehyde synthon allows for two-directional synthetic elaboration through a Henry reaction with a lipid-like nitroalkane. The resulting nitroalcohol having the unnatural (2S,5S)-THF core was oxidized to the corresponding α-nitroketone using a modified Collins oxidation. The intermediate α-nitroketone has potential for the preparation of the C15-C32 core and analogues through subsequent removal of the nitro group and reduction of the carbonyl.
This chapter describes the synthesis and chemistry of six-membered ring systems containing oxygen or/and sulfur atoms. The asymmetric hetero Diels–Alder (hDA) reactions of carbonyl compounds are reviewed and the scope and the limitations of the hDA approach to spiroacetals are discussed in the chapter. Routes to naphtho[2,1-b]pyrans and their 2,3-dihydro analogues and the asymmetric synthesis of chromans are reviewed in the chapter. Developments in the aryl propargyl ether route to chromenes include the fast direct synthesis of 3-bromo derivatives through Pd-catalyzed cyclization in the presence of stoichiometric amounts of CuBr2 and added LiBr in acetic acid. An introduction of a S or Se substituent into the terminal position of the alkyne followed by base-catalyzed electrophilic cyclization using I2 or ICl leads to 4-chalcogenyl-3-iodobenzopyrans; further manipulation through the halogen function is possible
The δ-lactone moiety is a common structural framework found in many natural products that exhibit interesting biological properties. This review details a collection of various selected methods developed for the synthesis of saturated δ-lactones. Synthesis of unsaturated δ-lactones and manipulation thereof to saturated δ-lactones are not covered in this review.
[258278-25-0] C27CIH39N2 (MW 427.06) InChI = 1S/C27H39N2.ClH/c1-18(2)22-11-9-12-23(19(3)4)26(22)28-15-16-29(17-28)27-24(20(5)6)13-10-14-25(27)21(7)8;/h9-14,17-21H,15-16H2,1-8H3;1H/q+1;/p-1 InChIKey = LWPXTYZKAWSRIP-UHFFFAOYSA-M (used as a precursor to the free carbene, 1,3-bis(2,6-diisopropyl-phenyl)-2-imidazolidinylidene, and as an in situ formed catalyst)Physical Data: mp 289–293°CSolubility: highly soluble: CH2Cl2; moderately soluble: CHCl3, H2O; slightly soluble: THF.Form Supplied in: microcrystalline white or light cream powder.Purification: recrystallization from acetonitrile and ether, dried in a well-ventilated oven at 120°C.Handling, Storage, and Precautions: compound is air stable over prolonged periods of time but is hygroscopic. When handling large quantities use dust mask.
Reactions catalyzed by N-heterocyclic carbenes (NHC) have been known longer than the NHCs themselves. This chapter provides an overview of the development of these catalysts, and a survey of the diverse and mechanistically intricate reactions they catalyzed. The chapter explains the origin of the superiority of these catalysts on new generation of NHC-catalyzed reactions. By combining the N-mesityl substituent and the triazolium core of 7, Bode and coworkers synthesized the novel catalyst 9, which has emerged as the prototypical catalyst for a remarkable range of new NHC-catalyzed reactions. The chapter shows that nearly all of these reactions require the N-mesityl group or a similar substituent for effective reactions. The authors anticipate that future innovations in catalyst design will make possible reactions from even simpler starting materials so that NHC catalysis can move beyond its current niche of fine chemical products to impacting the industrial production of organic molecules.
This chapter begins with a discussion on various reviews of carbenes and nitrenes. Triplet diphenylcarbenes bearing bulky substituents at the para positions have been generated and studied in rigid matrixes at low temperatures by electron spin resonance (ESR) and UV–Vis spectroscopy as well as by laser flash photolysis (LFP) in solution at room temperature. The stable nitrogen-free heterocyclic carbene has been generated by addition of a diphenylketene to a phosphagermaallene at low temperature and isolated by precipitation from diethyl ether. An extensive survey of various N-heterocyclic carbene (NHC) has allowed the development of a nickel-catalysed three-component coupling of benzaldehyde, norbornene, and trialkylsilane. The fluorocarbonyl nitrene FC(O)N: has been generated in high yield by ArF excimer laser photolysis of matrix-isolated FC(O)N3. This is the first example of a triplet carbonyl nitrene that has been fully and unambiguously characterized by means of spectroscopic techniques.
A marine polyether natural product okadaic acid is known to be a potent and specific inhibitor of protein phosphatases 1 and 2A. Herein, concise synthesis of the C15-C38 fragment of okadaic acid is reported. We investigated two different strategies for the construction of two spiroacetal substructures found in the target compound. The first strategy involved Suzuki-Miyaura coupling for the synthesis of endocyclic enol ethers and subsequent spiroacetalization. The second strategy exploited Suzuki-Miyaura coupling for the synthesis of exo-olefins as the precursor of spiroacetals. An alkynylaluminum-anomeric sulfone coupling effectively assembled the key spiroacetal substructures and completed the target compound.
Planar chirality remains an underutilized control element in asymmetric catalysis. Factors that have limited its broader application in catalysis include poor catalyst performance and difficulties associated with the economical production of enantiopure planar chiral compounds. The construction of planar chiral azolium salts that incorporate a sterically demanding iron sandwich complex is now reported. Applications of this new N-heterocyclic carbene as both an organocatalyst and a ligand for transition-metal catalysis demonstrate its unprecedented versatility and potential broad utility in asymmetric catalysis.
An efficient synthesis of optically pure cis-4-formyl-β-lactams (up to 99% ee) by a chiral NHC-catalyzed ring expansion reaction has been realized, featuring the ready availability of both the substrate and the catalyst, and the mild reaction conditions. The current method is also suitable for the synthesis of enantioenriched 4-formyl-β-lactams and succinimides containing quaternary carbon centers.
Treatment of (S)-1-benzyloxy-2-benzoylaminohex-5-ene with iodine in aqueous acetonitrile furnished (2S,5S)-5-benzoyloxymethyl-2-benzyloxymethylpyrroliaine stereoselectively in a single step. The product was converted into C2-symmetric (2S,5S)-2,5-dioxymethylpyrrolidines potentially utilizable as chiral auxiliaries and (2S,5S)-(—)-pyrrolidine-2,5-dicarboxylic acid isolated from marine alga Schizymenia dubyi.
The asymmetric intramolecular Stetter reaction of ω-formyl α,β-unsaturated carbonyl compounds was catalyzed by a C2 symmetric chiral carbene, generated from (4S,5S)-diphenyl-1,3-bis(mesitylmethyl)-4,5-dihydro-1H-imidazolium tetrafluoroborate, to afford 2-substituted cyclopentanones in good enantioselectivity of up to 80%.
N-Heterocyclic carbenes (NHCs) catalyze the reaction of formylcyclopropane 1,1-diesters with salicylaldehydes in a domino redox esterification/cyclization reaction to give coumarins in moderate to excellent yields. In addition, we also report the intramolecular conversion of compound 2f to dihydropyranone 4 catalyzed by NHC D. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Homoenolate equivalents are generated by Lewis basic N-heterocyclic carbene catalysts and then protonated to generate efficiently saturated esters from unsaturated aldehydes. This reactivity is extended to the generation of β-acylvinyl anions from alkynyl aldehydes. The asymmetric protonation of a homoenolate equivalent generated from a β,β-disubstituted aldehyde can be accomplished with a chiral N-heterocyclic carbene.
N-heterocyclic carbenes (NHCs) catalyze a domino Michael addition/acylation reaction to form 3,4-dihydrocoumarins. The reaction proceeds through addition of the NHC to an aryloxyaldehyde followed by elimination of a phenoxide leaving group, generating an enol intermediate. This transient nucleophile generated in situ performs a 1,4-addition onto a conjugate acceptor, and the carbene catalyst is regenerated upon acylation of the phenoxide anion resulting in formation of 3,4-dihydrocoumarins.
We report herein a nucleophilic carbene catalyzed redox azidation of epoxyaldehydes. The intermediate beta-hydroxy acyl azides undergo thermal Curtius rearrangement followed by trapping with excess azide to form carbamoyl azides or, in a complementary sequence, by the hydroxy group to form oxazolidinones. Both products are formed in modest to good yields and diastereoselectivities. The use of an enantioenriched triazolium catalyst leads to modest asymmetric induction.
[reaction: see text] An efficient, user-friendly procedure for the oxidation of alcohols using IBX is described. Simply heating a solution of the alcohol in the presence of suspended IBX followed by filtration and removal of the solvent gives excellent yields of the corresponding carbonyl compounds. We illustrate this procedure with a panel of primary and secondary alcohol substrates and note that it allows recycling and reuse of the oxidant.
The catalytic generation of activated carboxylates from epoxyaldehydes enables the direct, stereoselective synthesis of beta-hydroxyesters under mild, convenient reaction conditions. In addition to providing a new method for the synthesis of anti-aldol adducts, this chemistry unveils a mechanistically viable solution to the catalytic, waste-free synthesis of esters.
Reactivity umpolung allows us to consider nontraditional bond disconnections. We report herein that treatment of an alpha-haloaldehyde with a nucleophile in the presence of catalytic amounts of nucleophilic carbenes results in an internal redox reaction giving rise to a dehalogenated acylating agent as an intermediate by a new reaction manifold. A brief illustration of the scope of this reaction is presented along with evidence supporting the direct intervention of the carbene in the acylation step.
N-Heterocyclic carbenes derived from benzimidazolium salts are effective catalysts for generating homoenolate species from alpha,beta-unsaturated aldehydes. These nucleophilic intermediates can be protonated, and the resulting activated carbonyl unit is trapped with an alcohol nucleophile, thereby promoting a highly efficient conversion of an alpha,beta-unsaturated aldehyde into a saturated ester. A kinetic resolution of secondary alcohols can be achieved using chiral imidazoylidene catalysts. [reaction: see text]
N-Heterocycle carbenes generated in situ from imidazolium or triazolium salts and bases react with enals, leading to the catalytic generation of homoenolates. The fate of these intermediates is determined by the catalytic base: strong bases such as (t)BuOK lead to carbon-carbon bond formation, while weaker bases allow protonation of the homoenolate and subsequent generation of activated carboxylates. This discovery, along with the design of a new triazolium precatalyst, enables the catalytic, atom-economical redox esterification of enals. [reaction: see text]
Treatment of alpha,alpha-dichloroaldehydes with various phenols in the presence of chiral triazolium salt catalysts and excess base results in the synthesis of alpha-chloro aryl esters in good yield and enantioselectivity. The reaction is tolerant of various functionality on the aldehyde as well as several electronically diverse phenols. The product chloroesters were further transformed into chloroacid, chlorohydrin, and azidoesters with nearly complete retention of enantioselectivity.
[reaction: see text] Stereoselective, carbene-mediated redox esterification of alkynyl aldehydes provides mild and atom economical access to (E)-configurated, alpha,beta-unsaturated carboxylic esters. The organocatalytic method relies on the generation of activated carboxylates via extended/conjugated umpolung in the presence of catalytic amounts of carbene precursor and base.
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Simple chiral amines catalyze a highly chemo- and enantioselective aziridination of α,β-unsatd. aldehydes to provide 2-formylaziridines, e.g., I, in good yields and with up to 99% ee. The synthetic utility of this organocatalytic method was exemplified in a two-step asym. synthesis of β-amino acid esters with readily removable protecting groups (R1 = tert-butoxycarbonyl, benzyloxycarbonyl). [on SciFinder(R)]
Organocatalyzed reactions represent an attractive alternative to metal-catalyzed processes notably because of their lower cost and benign environmental impact in comparison to organometallic catalysis. In this context, N-heterocyclic carbenes (NHCs) have been studied for their ability to promote primarily the benzoin condensation. Lately, dramatic progress in understanding their intrinsic properties and in their synthesis have made them available to organic chemists. This has resulted in a tremendous increase of their scope and in a true explosion of the number of papers reporting NHC-catalyzed reactions. Here, we highlight the ever-increasing number of reactions that can be promoted by N-heterocyclic carbenes.
N-heterocyclic carbene (NHC) has been employed as an efficient catalyst for ring expansion of 4-formyl-beta-lactams, allowing the facile synthesis of succinimide derivatives. This organocatalytic process features readily availability of the catalyst, low catalyst loading, and mild reaction conditions.
A catalyzed internal redox process provides a route from alpha-reducible aldehydes and amines; to alpha-reduced amides. The chemistry is catalyzed by nucleophilic carbenes and common peptide cocatalysts such as HOBt and HOAt in a relay fashion. The transformation proceeds in excellent yields using a variety of primary and secondary alkyl and aryl amines. The aldehyde component may be varied from haloaldehydes to epoxy and aziridino aldehydes as well as enals. The latter three substrates provide for a waste-free amide bond forming reaction.
The extensive applications and reaction pathways of thiazol- (A), triazol- (B), imidazol- (C), and imidazolin-2-ylidenes (D) as versatile synthetic methods were discussed. The organocatalytic process have made synthetic strategies in addition to its facile reaction, selectivity and its being environmental friendly. The topics being described include the enzymes as archetypes, the benzoin condensation, the stetter reaction, the a3 to d3 umpolung, the transesterification reactions, the polymerization reactions, the ring-opening reactions, and finally the 1,2-additions.
A catalytic method for the direct synthesis of carboxylic acid amides from amines and alpha-functionalized aldehydes is possible through the synergistic role of a N-heterocyclic carbene catalyst and imidazole, affording amides via activated carboxylates catalytically generated via an internal redox reaction of the aldehyde substrates. The use of imidazole or other N-heterocycles as an additive is essential to overcoming imine formation and serves as a uniquely reactive substrate for the generation of an acyl imidazolium intermediate that is converted to the final amide product.
A single-step catalytic ring expansion approach from 4-oxoazetidine-2-carbaldehydes to enantiopure succinimides has been achieved by the use of a base (DBU) and a thiazolium salt precatalyst.
The development of one-pot organocatalytic domino Michael/alpha-alkylation reactions between bromomalonates or bromoacetoacetate esters and alpha,beta-unsaturated aldehydes is presented. The chiral-amine-catalyzed reactions with bromomalonates as substrates give access to the corresponding 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99 % ee. The catalytic domino Michael/alpha-alkylation reactions between 4-bromo-acetoacetate and enals provide a route for the synthesis of functionalized cyclopentanones in good to high yields with 93-99 % ee. The products from the organocatalytic reactions were also reduced with high diastereoselectivity to the corresponding cyclopropanols and cyclopentanols, respectively. Moreover, one-pot combinations of amine and heterocyclic carbene catalysis (AHCC) enabled the highly enantioselective synthesis of beta-malonate esters (91-97 % ee) from the reaction between bromomalonates and enals. The tandem catalysis included the catalytic domino reaction followed by catalytic in situ chemoselective ring-opening of the 2-formylcyclopropane intermediates.
- Zhao G.-L