Enol Lactones Research Articles

Palladium-Catalyzed [7 + 5] and Higher-Order Annulations of Oxa-1,n-dipoles: Synthesis of 12- to 15-Membered Lactones.

Macrolactones are commonly found in natural products and pharmaceuticals. Herein, we present Pd-catalyzed [7 + 5] and higher-order annulations between unprecedented oxa-1,n-dipoles (n = 7-9) with active enol lactones. This protocol enables the rapid synthesis of complex 12 to 15-membered lactones bearing internal E-alkenes. Density functional theory calculations have revealed the favorable reaction pathway and identified coordination interactions between active enol lactones and palladium centers of π-allyl dipole species as key factors in manipulating these dipoles in annulations.

Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones.

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

Catalytic Enantioselective Steglich-Type Rearrangement of Enol Lactones: Asymmetric Synthesis of Spirocyclic 1,3-Diketones.

An example of asymmetric Steglich-type rearrangement of enol lactones is reported. This highly enantioselective acyl transfer reaction is catalyzed by chiral isothiourea at ambient temperature and provides a useful synthetic approach to access enantioenriched spirotricyclic β,β'-diketones from a broad range of indanone or tetralone-derived lactones. Preliminary mechanistic studies suggest the initial formation of an N-acylated iminium cation intermediate that induces a following facial selective condensation.

Recent Advances in the Transition Metal-Catalyzed Addition of Carboxylic Acids to Alkynes

: Recent advances in the metal-catalyzed hydrofunctionalization of alkynes with carboxylic acids are comprehensively reviewed. Both inter- and intramolecular processes, leading respectively to enol esters and lactones, are discussed, as well as the involvement of these transformations in the synthesis of natural products and biologically active molecules, and the assembly of elaborated heterocyclic compounds though cascade processes. Literature published since 2011 is covered.

Rhenium‐Catalyzed Arylation–Acyl Cyclization between Enol Lactones and Organomagnesium Halides: Facile Synthesis of Indenones

A set of rhenium-catalyzed aryl-acylcyclization between (hetero)arylmagnesium halides and enol lactones through a cascade Csp 2 -Csp 2 /Csp 2 -Csp 2 bond formation has been developed under mild reaction conditions. Indeed, a wide range of functional groups on both organomagnesium halides and enol lactones are well tolerated by the simple rhenium catalysis, thus furnishing polyfunctionalized indenones in one-pot fashion and with complete control of the regioselectivity. Moreover, this approach also provides a straightforward synthesis to neo-lignan and ( iso )pauciflorol F . Mechanistic studies demonstrated that the reaction involves a sequential of syn -carborhenation and intramolecular nucleophilic addition process.

Rhenium‐Catalyzed Arylation–Acyl Cyclization between Enol Lactones and Organomagnesium Halides: Facile Synthesis of Indenones

AbstractA set of rhenium‐catalyzed arylation–acyl cyclizations between (hetero)arylmagnesium halides and enol lactones through a cascade C(sp2)−C(sp2)/C(sp2)−C(sp2) bond formation under mild reaction conditions has been developed. Indeed, a wide range of functional groups on both organomagnesium halides and enol lactones is well tolerated by the simple rhenium catalysis, thus furnishing polyfunctionalized indenones in one‐pot fashion and with complete control of the regioselectivity. Moreover, this approach also provides a straightforward synthetic route to neolignan and (iso)pauciflorol F. Mechanistic studies demonstrated that the reaction involves a sequence of syn‐carborhenation and intramolecular nucleophilic addition.

Catalytic enantioselective synthesis of chiral spirocyclic 1,3-diketones via organo-cation catalysis.

An SPA-triazolium bromide-catalyzed transannular C-acylation of enol lactones is presented. This methodology provides convenient access to a range of enantioenriched spirocyclic 1,3-diketones in moderate to high yields and enantioselectivities and features a broad substrate scope in terms of enol lactones. The catalytic capability of this triazolium salt catalyst is also demonstrated in this enantioselective transformation, which could inspire its further application.

Total Synthesis of (±)-Leonuketal.

Leonuketal is an 8,9-seco-labdane terpenoid with a unique tetracyclic structure, owing to a diversity-generating biosynthetic C-C bond cleavage event. The first total synthesis of leonuketal is reported, featuring a Ti(III)-mediated reductive cyclization of an epoxy nitrile ether, an unusual ring-opening alkyne formation as part of an auxiliary ring strategy, and the previously undescribed Au(I)-catalyzed cyclization of a β-keto(enol)lactone to assemble the core spiroketal motif.

Desymmetrization construction of chiral lactones by synergistic Cu(II) complex and organic base

A highly enantioselective construction of quaternary carbon center has been realized by the desymmetrization strategy. Chiral enol lactones with up to 95% ee could be synthesized from prochiral dialkynoic acid under the catalysis of synergistic chiral Cu(II) complex and chiral (DHQ)2-PHAL base.

14C-Labelling of the natural steroid estrogens 17α-estradiol, 17β-estradiol, and estrone.

The worldwide environmental occurrence of natural steroid estrogens has drawn increasing concerns. However, the fate of the estrogens, especially the α-isomer of estradiol, in the environmental matrices is still obscure. Using 14C-radioactively labelled forms of these estrogens can facilitate and is sometimes a prerequisite for studying their transformation and residual distribution in the environment, but the availability of labelled compounds (owing to commercially high prices or unavailable) hampers such studies. Here we developed simple and stable methods to synthesize 14C-labelled estradiol isomers and estrone using relatively low-priced [carboxyl-14C]-labelled sodium acetate as a precursor. The radiochemical syntheses started from an enol lactone, which was prepared from nandrolone by oxidation to open the A-ring followed by recyclization. Inversion of the 17β-hydroxyl group into its 17α-form was achieved via the Walden inversion using the Mitsunobu reaction. [3-14C]-17β-estradiol, [3-14C]-17α-estradiol, and [3-14C]-estrone were synthesized in five, six, and seven steps with an overall radiochemical yield of 17.4%, 16.2%, and 13.9%, respectively. The synthesized 14C-labelled compounds provide materials for studying the fate and behavior of estrogens in complex environmental matrixes and for further synthesis of their 14C-labelled sulfate and glucuronide conjugates.

Group VIII carbamoyl complexes as catalysts for alkyne hydrocarboxylation and electrochemical proton reduction

A series of group VIII carbamoyl complexes, [M(2-NHC(O)C5H4N)(CO)2(2-SC5H4N)] [where M = Fe, Ru and Os], was found to be efficient and regioselective catalysts for the intramolecular hydroxycarboxylation of α,ω-alkynoic acids, yielding exocyclic enol lactones for ring sizes up to 7 atoms, and endocyclic enol lactones for ring sizes up to 12 atoms. They also catalysed the regioselective intermolecular hydroxycarboxylation reaction between propargylic alcohol and carboxylic acids to form β-oxo-esters. These complexes could also function as electrocatalysts in proton reduction, and evaluation of their redox potentials revealed that the iron complex was much more efficient than the ruthenium or osmium analogues.

Total Synthesis of (-)-Merochlorin A.

The first asymmetric total synthesis of the meroterpenoid (-)-merochlorin A is described. The route features enantiospecific gold-catalyzed tandem 1,3-acyloxy migration/Nazarov/aldol reaction sequence to furnish the bicyclo[3.3.0]octane core in a single step from a linear propargylic 1,3-enyne aldehyde. After completion of the central skeleton by reductive enol lactone rearrangement, late stage Diels-Alder cycloaddition/aromatization sequence installed the resorcinol. An additional salient feature of the synthesis is the assignment of the absolute configuration, which had not been determined previously.

Total Synthesis of (−)‐Merochlorin A

AbstractThe first asymmetric total synthesis of the meroterpenoid (−)‐merochlorin A is described. The route features enantiospecific gold‐catalyzed tandem 1,3‐acyloxy migration/Nazarov/aldol reaction sequence to furnish the bicyclo[3.3.0]octane core in a single step from a linear propargylic 1,3‐enyne aldehyde. After completion of the central skeleton by reductive enol lactone rearrangement, late stage Diels–Alder cycloaddition/aromatization sequence installed the resorcinol. An additional salient feature of the synthesis is the assignment of the absolute configuration, which had not been determined previously.

Single-Molecule Observation of the Intermediates in a Catalytic Cycle.

The development of catalysts benefits from knowledge of the intermediate steps that accelerate the transformations of substrates into products. However, key transient species are often hidden in ensemble measurements. Here, we show that a protein nanoreactor can sample the intermediate steps in a catalytic cycle by the continuous single-molecule observation of a stoichiometric reaction in solution. By monitoring changes in the flow of ionic current through an α-hemolysin protein pore, we observed three intermediate metal-ligand complexes in a gold(I)-catalyzed reaction that converts an acetylenic acid to an enol lactone, revealing a transitional coordination complex that had been previously unobserved. A kinetic isotope effect helped assign the various metal-ligand species. Measurements of the lifetimes of the intermediates allowed a full kinetic analysis of the metal-catalyzed reaction cycle.

Synthesis, DFT and biological studies of novel 3,6-dimethyl-1,8-diphenyl-diazocino[3,4-c:7,8-c’]bispyrazole

The condensation reaction of 5-amino-3-methyl-1-phenylpyrazole-4-carboxaldehyde with enol lactone was carried out to get the expected compound involving translactonization type rearrangement. However, the reaction did not proceed as visualized and afforded rather unexpected compound 3,6-dimethyl-1,8-diphenyl-diazocino [3,4-c:7,8-c’]bispyrazole as a result of Friedlander condensation. The structure was confirmed by spectroscopic determination and further studied using density functional theory (DFT) calculations. The FT-IR and 1H NMR values were calculated and compared with those experimentally obtained in spectra. The frontier molecular orbitals (HOMO and LUMO) and molecular electrostatic potential were computed to determine the distribution of charge density and possible site for electrophilic and nucleophilic reactions. The newly synthesized compound was screened for their anti-inflammatory and antibacterial activities using formalin-induced paw edema and agar diffusion methods respectively. It was found to possess significant activities on animals models and against Gram-positive and Gram-negative bacteria.

Correction to "A General Synthesis of Substituted Indoles from Cyclic Enol Ethers and Enol Lactones".

Correction to "A General Synthesis of Substituted Indoles from Cyclic Enol Ethers and Enol Lactones".

An Enantioselective Iodolactonization/Cross‐Coupling Protocol for the Synthesis of Highly Substituted Enol Lactones

γ‐Alkynoic acids readily undergo iodolactonization to give iodoenol lactones. Using commercially available (DHQD)2PHAL this transformation can be rendered asymmetric. In desymmetrization reactions of dialkynoic acids, good to very good enantioselectivities can be observed. Alternatively, kinetic resolution of already chiral, racemic γ‐alkynoic acids can be carried out. The products of these iodolactonizations, iodoenol lactones, are suitable substrates for Palladium catalyzed cross‐couplings. Negishi‐ as well as Sonogashira couplings can be carried out and allow the efficient synthesis of highly substituted enol lactones.

Studies on the Synthesis of Endocyclic Enol Lactones via a RCM of Selected Vinyl Esters.

The novel and efficient approach toward the synthesis of endocyclic enol lactones was devised based on ring-closing metathesis of unsaturated carboxylic acids vinyl esters. Systematic studies revealed that vinyl esters are suitable substrates for RCM reaction. The developed methodology offers an easy route for synthetically challenging target molecules with different functional groups and substitution. We have also demonstrated that vinyl esters of cyclic carboxylic acids can be successfully applied for domino ring-opening ring-closing metathesis sequences.

Serendipitous Observation of Liquid‐Phase Size Selectivity inside a Mesoporous Silica Nanoreactor in the Reaction of Chromene with Formic Acid

AbstractAn unprecedented product shape/size selectivity in the hydrolysis/decarboxylation reaction sequences of chromene with formic acid within MCM‐41 as a nanoreactor in the liquid phase is observed. Chromene is expected to form pyrimidine in the reaction with HCOOH. However, here, serendipitously, the product switches from pyrimidine to enol lactones and δ‐keto acids inside the nanoreactor. The shape/size selectivity in the liquid phase is a highly desired phenomenon in organic synthesis. We prepared four different varieties of porous silica materials to obtain this product selectivity. Very high yields of these biologically relevant compounds surpass that achieved by existing methodologies. Again, though there are few reports of coumarin‐fused enol lactones, this approach enables the easy synthesis of naphthalene‐fused enol lactones. Moreover, this is the first generalized synthesis of δ‐keto acids following a number of hydrolysis/decarboxylation/ring opening/tautomerization/decarboxylation steps.

Palladium NNC Pincer Complex as an Efficient Catalyst for the Cycloisomerization of Alkynoic Acids

AbstractA two‐step (nucleophilic substitution/palladation by oxidative addition) sequence provides a high‐yielding access to a non‐symmetrical palladium NNC pincer complex. A number of terminal and internal alkynoic acids with different substitution patterns at the α‐ and β‐positions are regio‐ and diastereoselectively cycloisomerized to the corresponding exocyclic enol lactones in the presence of exceedingly low amounts of the latter palladium complex, so that unprecedented turnover numbers and frequencies ranging from 1,000,000 to 700,000 and from 41,667 to 9722 h−1, respectively, are achieved. The optimized protocol, based on the use of a catalytic amount of triethylamine as base, allows an easy real‐time monitoring of the reaction by NMR spectroscopy. Several pieces of evidence in favor of the direct participation of the above pincer complex as the catalyst of the reaction have been gathered from kinetic and poisoning experimentsmagnified image