Lactone Ester Research Articles

Highly Enantioselective Construction of Sterically Hindered α-Allyl-α-Aryl Lactones via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

Pd-catalyzed decarboxylative asymmetric allylic alkylation has been developed for sterically hindered α-aryl, β-oxo-allyl ester lactone substrates. Pb-mediated α-arylation of the β-oxo-allyl ester was used as the key step to synthesize the substrates for catalysis in moderate to high yields. Optimization studies for decarboxylative asymmetric allylic alkylations (DAAA) were conducted using δ-valerolactone-derived α-aryl β-oxo-allyl ester with 2,4,6-trimethoxyphenyl as the aryl substituent. Using (R,R)-ANDEN-phenyl Trost as the chiral ligand, enantioselectivities of up to >99% ee and 98% ee were achieved with the six-membered and five-membered lactone substrates, respectively. Bulky aryl groups containing di-ortho substitutions and naphthyl groups gave the highest enantioselectivities. This synthetic route allows for the simple modification of aryl groups, giving highly enantioselective access to important structural motifs.

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Simvastatin (SV) is marketed as a lactone ester prodrug which is hydrolyzed to the active simvastatin hydroxyacid (SVA). SV is characterized by a low solubility and undergoes extensive first-pass metabolism. In this study, the influence of the upper gastrointestinal environment on the intraluminal behavior of simvastatin was investigated by a series of in vitro experiments. Dissolution, stability and two-stage dissolution tests were performed using simulated and human gastrointestinal fluids.The dissolution studies revealed a relatively slow dissolution of SV as well as conversion of SV to SVA. The hydrolysis of SV was further examined and stability studies indicated a faster conversion in gastric fluids than in intestinal fluids. These isolated phenomena were then confirmed by the more integrative two-stage dissolution studies.To estimate the predictive value of the in vitro tests, an additional in vivo study was performed in which the gastrointestinal concentration-time profiles also revealed a slow dissolution of SV and faster degradation of SV to SVA in the stomach than in the intestinal tract. However, the plasma concentrations of SV and SVA did not directly correlate with the observed gastrointestinal concentrations, suggesting that gut wall and hepatic metabolism have a greater impact on systemic exposure of SV than the intraluminal interconversion between SV and SVA.

Crystal structure of N-(3-oxo-butano-yl)-l-homoserine lactone.

The structure and absolute configuration of the title compound, C8H11NO4, which is a known quorum-sensing modulator, have been determined. The mol-ecule exhibits signs of an intra-molecular attractive carbon-yl-carbonyl n→π* inter-action between the amide and lactone ester groups, specifically - a short contact of 2.709 (2) Å between the amide oxygen atom and ester carbon atom, approach of the amide oxygen atom to the ester carbonyl group along the Bürgi-Dunitz trajectory, at 99.1 (1)°, and pyramidalization of the ester carbonyl group by 1.1 (1)°. Moreover, a similar n→π* inter-action is observed for the amide carbonyl group approached by the ketone oxygen donor. These inter-actions apparently affect the conformation of the uncomplexed mol-ecule, which adopts a different shape when bound to protein receptors. In the crystal, the mol-ecules form translational chains along the a axis via N-H⋯O hydrogen bonds.

Difference Spectroscopy in the Analysis of the Effects of Coffee Cherry Processing Variables on the Flavor of Brewed Coffee

Infrared difference spectroscopy was used to study how changes in the processing of Arabica coffee cherries into green beans affected the flavor of coffee brewed from roasted green beans. Paired samples of green beans, in which the drying step or fermentation/washing step in their processing was altered, were roasted and brewed in a standard manner and their ATR‐FT‐IR spectra obtained. Difference spectra of the 1800 to 1680 cm−1 carbonyl region of water‐subtracted spectra of paired samples of these brewed coffees provided data which indicated differences in brewed coffee flavor due to changes in fermentation/washing steps and drying steps involved in the processing of coffee cherries. The role of acid, ketone, aldehyde, ester, lactone, and vinyl ester carbonyl components on the flavor of brewed coffee is proposed that is consistent with the flavors as perceived by the coffee tasters.

Palmyrolide A, an unusually stabilized neuroactive macrolide from Palmyra Atoll cyanobacteria.

Palmyrolide A (1) is a new neuroactive macrolide isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf. and Oscillatoria spp. collected from Palmyra Atoll. It features a rare N-methyl enamide and an intriguing t-butyl branch; the latter renders the adjacent lactone ester bond resistant to hydrolysis. Consistent with its significant suppression of calcium influx in cerebrocortical neurons (IC(50) = 3.70 μM), palmyrolide A (1) showed a relatively potent sodium channel blocking activity in neuro-2a cells (IC(50) = 5.2 μM), without appreciable cytotoxicity.

Sesquiterpene Lactones from Daucus glaber

AbstractSix new sesquiterpene lactone esters, daucoguaianolactones A–F (1–6), and one new sesquiterpene lactone, daucoeudesmanolactone A (7) were isolated from the leaves and stems of Daucus glaber (Forssk.) Thell., along with the known sesquiterpene lactones talasins A and B and badkhysin. The structures of 1–6 were established on the basis of extensive 1D‐ and 2D‐NMR spectroscopic studies and that of 7 by X‐ray crystallography. Compounds 4, 7, and talasins A and B showed moderate cytotoxicity against P‐388 leukemia cells.

Furanoditerpene ester and thiocarbonyldioxy derivatives inhibit photosynthesis

6α,7β-Dihydroxyvouacapan-17β-oic acid ( 1) and methyl 6α,7β-dihydroxyvouacapan-17β-oate ( 8) were isolated from Pterodon polygalaeflorus Benth. 1 was modified to obtain 6α-hydroxyvouacapan-7-β,17β lactone ( 2). Then, 6- oxovouacapan-7β,17β lactone ( 3) was obtained from 2. The furanoditerpene ester derivatives: propyl 7β-hydroxy-6-oxovouacapan-17β-oate ( 4), butyl 7β-hydroxy-6-oxovouacapan-17β-oate ( 5), 2-methoxyethyl 7β-hydroxy-6-oxovouacapan-17β-oate (6) and 3-methylbut-2-enyl 7β-hydroxy-6-oxovouacapan-17β-oate ( 7) were synthesized from ( 3) and methyl 6α,7β-thiocarbonyldioxyvouacapan-17β-oate ( 9) was obtained from ( 8). In this work, the lactone ester derivatives 4– 7 and 9 were tested on photosynthetic activities in an attempt to search for new compounds as potential herbicide agents that affect photosynthesis. All compounds inhibited ATP synthesis and electron flow from water to MV, therefore, they act as Hill reaction inhibitors, being 4- to 9-fold more potent than 2 and 3 as inhibitors of ATP synthesis. Their interaction site was located at PSII in a similar way to diuron. Furthermore, furanoditerpene esters 6 and 7 act as uncouplers, and were corroborated by enhancement of the light-activated Mg 2+-ATPase, while 5 act as an energy transfer inhibitor. Finally 5– 7 behave as herbicides, since they inhibit the biomass production of weeds assay.

Development of palladium(II)-catalyzed oxidative cyclization of olefinic keto and/or lactone esters

A highly efficient palladium-catalyzed oxidative cyclization of olefinic keto and/or lactone esters, which features a catalytic cyclization employing one atmosphere of oxygen as a reoxidizing agent, is developed.

Synthesis of optically active α-benzyl paraconic acids and their esters and assignment of their absolute configuration

The cis- and trans-4-benzylparaconic acids and their ethyl esters were synthesized with high enantiomeric excess by hydrolysis of the corresponding diastereomeric lactonic esters using α-chymotrypsin. Thus, at low conversion values, cis- and trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also obtained in enantiopure form. The absolute configuration of the trans-lactonic acid was assigned by 1H NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while that of the cis-lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The circular dichroism curves of the products obtained are also reported.

Concise Assembly of the BCD Ring Part of Ginkgolide C via a Novel Cyclization Reaction

Efforts to synthesize a 6-oxatricyclo[6.3.0.0 1.5 ]undecane ring system are described. A novel Pd(II)-promoted oxidative cyclization of the lactone ester constructs the tricyclic core of ginkgolide C.

Why δ-Valerolactone Polymerizes and γ-Butyrolactone Does Not

gamma-Butyrolactone, unlike delta-valerolactone, does not polymerize despite a strain energy of approximately 8 kcal mol-1 which could be relieved by opening the s-cis lactone ester bond to an s-trans ester bond in the polymer. To explain this anomaly, we have applied quantum mechanical methods to study the thermochemistry involved in the ring-opening reactions of gamma-butyrolactone and delta-valerolactone, the conformational preferences of model molecules that mimic their corresponding homopolyesters, and the variation of enthalpy associated to the polymerizability of such two cyclic lactones. The overall results indicate that the lack of polymerizability of gamma-butyrolactone should be attributed to the low strain of the ring, which shows much less geometric distortion in the ester group than delta-valerolactone, and the notable stability of the coiled conformations found in model compounds of poly-4-hydroxybutyrate.

The role of mosquito olfaction in oviposition site location and in the avoidance of unsuitable hosts.

Developments in the exploitation of mosquito olfaction are traced, in collaborative studies with various groups, from the first identification of a mosquito pheromone through to a discussion of non-host avoidance. The characterization of the oviposition pheromone for mosquitoes in the genus Culex, e.g. Culex quinquefasciatus, as a novel chiral lactone ester provided the impetus for a number of sophisticated asymmetric syntheses and economical large-scale routes to racemic products. The latter have provided material for successful field trials in three continents. During the course of this field work, we obtained evidence that semiochemicals originating directly from the oviposition site are essential for activity of the oviposition pheromone. Recent studies are elucidating the nature of these agents and their geographical variability. Initially, we used synthetic oviposition pheromone to attract mosquitoes to sites treated with a biorational larvicide. However, recyclable biological control agents offer better prospects for resource-poor regions. A biotechnological approach to pheromone production has been devised involving the generation of inexpensive starting materials by the cultivation of a higher plant. New studies on dipterous pests feeding on farm animals indicate a semiochemically based mechanism by which unsuitable individuals within the host species are avoided. There appears to be an analogous process in which mosquitoes avoid certain potential human hosts, thereby raising prospects for the development of novel, rationally identified repellents once the semiochemical/olfactory interactions have been fully elucidated.

TheO,O′-diacetyl (R,R)-hydrogentartrate ester of (S)-pantolactone

The synthesis of the title compound, (1R,2R)-1-carb­oxy-2-[(3S)-4,4-dimethyl-2-oxotetra­hydro­furan-3-yloxycarbonyl]ethane-1,2-diyl diacetate, C14H18O10, from diacetyl­tartaric acid anhydride and pantolactone gave two enanti­omeric pairs and the crystal structure of the R,R,S enanti­omer is presented here. The mol­ecule consists of a hydrogen tartrate fragment in which the carboxyl group and the lactone ester group are in an anti conformation. In the crystal structure, mol­ecules are linked into C(10) chains by an inter­molecular O—H⋯O hydrogen bond and further by C—H⋯O inter­actions to form a layer structure with the second-level graph-set descriptor R22(8)[R44(26)].

TheO,O′-diacetyl (R,R)-hydrogentartrate ester of (R)-pantolactone monohydrate

In the synthesis of (1R,2R)-1-carb­oxy-2-[(3R)-4,4-dimethyl-2-oxotetra­hydro­furan-3-yloxycarbon­yl]ethane-1,2-diyl diacetate from diacetyl­tartaric acid anhydride and pantolactone, two enantio­meric pairs were obtained and the structure of the R,R,R enanti­omer is presented here. The compound crystallizes as a monohydrate, C14H18O10·H2O. The main mol­ecule consists of a hydrogentartrate fragment in which the carboxyl group and the lactone ester group are in an anti conformation. In the crystal structure, mol­ecules are linked via O—H⋯O hydrogen bonds, involving water mol­ecules, to form a layered structure.

Chemoenzymatic synthesis of diastereomeric ethyl γ-benzyl paraconates and determination of the absolute configurations of their acids

Enantiopure (99% ee) cis- and trans-γ-benzylparaconic acids and their ethyl esters were synthesized by a procedure involving kinetic enzymatic resolution of the corresponding lactonic esters with α-chymotrypsin (α-CT) with acetone added as a cosolvent. Their absolute configurations were determined by 1H NMR analysis of their 1-(9-anthryl)-2,2,2-trifluoroethyl esters.

A combined experimental and computational strategy in the assignment of absolute configurations of 4-methyl-5-oxo-tetrahydrofuran-3-carboxylic acids and their esters

Enantiopure cis- and trans-4-methylparaconic acids and their alkyl esters were synthesized by a procedure involving the kinetic enzymatic resolution of diastereomeric lactonic esters. Thus, ethyl cis- and trans-4-methyl-5-oxo-tetrahydrofuran-3-carboxylates were isolated, at high conversion values, with 99% ee from the hydrolyses with HLAP and α-CT, respectively. The corresponding enantiopure cis- and trans-lactonic acids were also obtained. The absolute configurations of the products were assigned by chemical correlation, by analysis of their circular dichroism spectra and by electronic structure calculations. All three methodologies lead to the same assignment for the species considered, another example of successful interplay between experiment and theory.

Mechanisms for the Formation of Diamides and Polyamides by Aminolysis of d‐Glucaric Acid Esters

1H and 13C NMR were employed to chart the conversion of the five‐membered lactone esters methyl d‐glucarate 1,4‐lactone (1) and ethyl d‐glucarate 6,3‐lactone (5) to N,N′‐dipropyl‐d‐glucaramide with n‐propylamine in DMSO‐d6. These experiments were carried out to model the amide forming steps in polycondensation reactions between esterified d‐glucaric acid and diamines to give poly(d‐glucaramides). It was clear from the resulting NMR spectra that the lactones 1 and 5 were each converted in three consecutive steps to the product diamides; aminolysis of the lactone ester to the corresponding acyclic N‐propyl‐d‐glucaramide monoester, followed by lactonization to a five‐membered lactone amide, and concluding with aminolyis of the lactone amide to N,N′‐dipropyl‐d‐glucaramide (4). Comparison of the reaction pathways from 1 and 5 by 1H NMR analysis suggests that ring opening of the 1,4‐lactone ester (1) and 1,4‐lactone amide (7) is faster than ring opening of the corresponding 6,3‐lactone ester (5) and 6,3‐lactone amide (3). Aminolysis of dimethyl l‐tartrate, which cannot form a five‐membered lactone, with n‐propylamine in DMSO‐d6 was much slower than aminolysis of esterified glucaric acid, indicating that the lactone forming/lactone aminolysis steps are the dominant aminolysis rate enhancing steps from glucarate.

Approach toward the total synthesis of griseoviridin: formation of thioethynyl and thiovinyl ether-containing nine-membered lactones through a thioalkynylation-macrolactonization-hydrostannylation sequence.

Synthesis of the lactone core 17 of 8-epi-griseoviridin is reported. Thioethynyl derivative 11 was easily prepared via an anionic coupling reaction between acetylenic compound 9 and sulfone 10. After desilylation of 11, saponification of the resulting hydroxy ester 12 followed by a Mitsunobu macrolactonization furnished the unusual triple-bond-containing nine-membered lactone 13 in 50% yield for the last two steps (39% after recrystallization). Stannylation under Magriotis conditions led to the pure regio- and stereocontrolled vinyltin 14 (80% yield). After a Sn/I exchange, palladium-catalyzed carbonylation delivered either the ester lactone 16 in 67% yield or the propargyl amide 17 in 65% yield. Synthesis of propargyl amide 17 of the lactone core of 8-epi-griseoviridin was achieved in 11.9% overall yield from commercial L-cystin dimethyl ester (nine steps).

Lipase-catalyzed synthesis of a tri-substituted cyclopropyl chiral synthon: a practical method for preparation of chiral 1-alkoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane

An efficient method for the preparation of optically active enantiomers of 1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1 has been developed. Treatment of 1 with lipase Amano PS gave (1 S,5 R)-1-carboxy-2-oxo-3-oxabicyclo[3.1.0]hexane 4a which was converted to (1 S,5 R)-1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1a with high enantiomeric purity (98.0% ee, 75% yield), while the (1 R,5 S)-lactone ester 1b remained intact. A simple procedure for the recovery of 4a from the reaction mixture was also established.

Asymmetric Michael Additions via 6- and 7-Membered Lactone SAMP-Hydrazones: Diastereo- and Enantioselective Synthesis of Substituted Lactone Esters

Lactone esters (S/R,S)-5a-f were synthesized in good overall yields (37-61%, two steps) and diastereo- and enantiomeric excesses (de = 88-≥96%, ee = 81 -≥96%) by 1,4-addition of metalated lactone-SAMP-hydrazones (S)-2 to enoate Michael acceptors 3 and subsequent oxidative cleavage of the product hydrazones by ozonolysis. The relative and absolute configuration was determined by X-ray structure analysis of (R,S)-5c.