Divergent kinetic control of classical versus ozonolytic lactonization: mechanism-based diastereoselection

A strategy has been developed in which mechanistically distinct lactonization reactions are used to prepare diastereomeric delta-lactones relevant to the C1-C9 fragment of (+)-peloruside A. Depending upon which of two reaction types is used, the central (C5) hydroxyl group can be directed to differentiate the C1 versus C9 termini of pseudosymmetric substrates to provide diastereomeric lactones. Thus, the 5-hydroxy-1,9-diester substrate 1 (an azelaic ester) cyclizes under classical (acid- or base-catalyzed) lactonization conditions to give a predominance of one diastereomer, whereas the 5-hydroxy-1,10-diene congener 2 provides the opposite sense of diastereoselectivity when subjected to ozonolytic lactonization (O3, MeOH, NaOH, at -78 degrees C). Thus, this under-utilized oxidative transformation is mechanistically orthogonal to the classical reaction.     

Metal-free tandem Friedel-Crafts/lactonization reaction to benzofuranones bearing a quaternary center at C3 position

A metal-free tandem Friedel-Crafts/lactonization reaction to 3,3-diaryl or 3-alkyl-3-aryl benzofuranones catalyzed by HClO(4) was reported. A variety of tertiary α-hydroxy acid esters could readily react with substituted phenols to afford the desired products in rich diversity. The synthetic utility of the products was demonstrated by the synthesis of polycyclic compounds. (1)H NMR studies supported that this tandem reaction proceeded via tandem Friedel-Crafts/lactonization sequence.     

First enantioselective total synthesis of penicimarin B,aspergillumarins A and B

A convergent enantioselective synthesis of penicimarin B, aspergillumarin A and B has been reported using Brown’s allylation, DeBrabander–Bhattacharjee lactonization and Grubbs cross coupling metathesis. During this synthesis we have standardized the conditions for DeBrabande–Bhattacharjee lactonization to obtain excellent yield (>90%).     

Trapping phosphodiester-quinone methide adducts through in situ lactonization

The goal of in situ modification of DNA via phosphodiester alkylation has led to our design of quinone methide derivatives capable of alkylating dialkyl phosphates. A series of catechol derivatives were investigated to trap the phosphodiester-quinone methide alkylation adduct through in situ lactonization. The catechol derivatives were uniquely capable of characterizable p-quinone methide formation for mechanistic clarity. These investigations revealed that with a highly reactive lactonization group (phenyl ester), lactonization competed with quinone methide formation. Lactone-forming groups of lower reactivity (methyl ester, n-propyl ester, and dimethyl amide) allowed quinone methide formation followed by phosphodiester alkylation; however, they were ineffective at in situ lactonization to drain the phosphodiester alkylation equilibrium to the desired phosphotriester product. The derivatives tethered with lactone-forming functionality of intermediate reactivity (chloro-, trichloro-, and trifluoroethyl esters), allowed quinone methide formation, phosphodiester alkylation, and in situ lactonization to efficiently afford the trapped phosphotriester adduct.     

Structure determination of some quinazolone lactones

A series of quinazolone lactones were prepared and their structures analyzed by 360 MHz proton and carbon-13 nmr. It was found that the compound capable of lactonization to yield either a six or seven-membered ring forms only the six-membered system.     

NMR studies of the reversible and regioselective lactonization of α-2,8-linked trisialic acid in aqueous acid

The pH dependent lactonization of trisialic acid was examined using NMR and CE techniques. The combined studies indicate that lactonization is a dynamic, pH dependent process that occurs with preferential lactonization between the carbonyl of the central residue and the reducing end C-9 hydroxyl group.     

Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.     

Synthesis of dibenzo[b,d]pyran-6-ones based on [3 + 3] cyclizations of 1,3-bis(silyl enol ethers) with 3-silyloxy-2-en-1-ones

Functionalized dibenzo[b,d]pyran-6-ones were prepared by formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 3-silyloxy-2-en-1-ones or 1,1-diacetylcyclopropane to give functionalized salicylates, Suzuki cross-coupling reactions of the corresponding triflates, and subsequent BBr3-mediated lactonization. A second approach to dibenzo[b,d]pyran-6-ones relies on the [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 1-(2-methoxyphenyl)-1-(trimethylsilyloxy)alk-1-en-3-ones and subsequent BBr3-mediated lactonization.     

A new method for the chiral HRGC assay of L-2-hydroxyglutaric acid in urine

L -2-Hydroxyglutaric aciduria is a recently discovered inherited neurometabolic disease for which diagnostic identification of the right enantiomer is required. A method is described where alkyl esters of both L -and D -2-hydroxyglutaric acids are prepared without side lactonization. Esterification is achieved at room temperature by reaction with appropriate alkyl chloroformates. This method avoids lactonization, in contrast to esterification with alcohols in acidic media or with diazomethane. The identity of the derivatives is established by HRGC-FTIR and HRGC-MS. Chiral HRGC separation with capillaries coated with 1(R)-trans-N-N'-1,2-cyclohexylenebisbenzamideoligodimethyL-siloxane and with a cyclodextrin is compared. The method is adequate for quantitative determinations.     

Lactones. Part 16: Lactonization of γ,δ-epoxy esters with p-toluenesulfonic acid monohydrate

The reaction of cyclic γ,δ-epoxy esters with p-toluenesulfonic acid monohydrate is described. The reaction carried out in benzene or methylene chloride gave tosyloxy lactones as product. The ethoxy or methoxy lactones were obtained when ethanol or methanol were used as solvent. A mechanism of this lactonization is proposed.     

Lactonisierung von makrolid-secosäuren mit “push-pull acetylenen”

A highly efficient method for the macrolactonization of seco-acids is described. Seco-acids are converted into stable enolesters 3 by the acetylene 1, which are cyclized under proton or Lewis acid catalysis. This new method has been successfully applied to the lactonization of the 7-epi-brefeldin A seco-acids 8a,b.     

Intramolecular reaction of a phenonium ion. Novel lactonization of 4-aryl-5-tosyloxypentanoates and 4-aryl-5-tosyloxyhexanoates concomitant with a phenyl rearrangement

The novel lactonizations of methyl 4-aryl-5-tosyloxypentanoate 1 and 4-aryl-5-tosyloxyhexanoate 3 concomitant with a phenyl rearrangement are reported. The lactonizations were promoted by silica gel or heating in various solvents. By examining the effects of substituents of the aromatic ring on the reactivity, it was found that the reaction proceeded via a phenonium ion. This finding was supported by the stereochemical results for the lactonization of optical active 1. Silica gel-promoted lactonization of 1 gave only gamma-lactone 2, whereas that of 3 afforded gamma-lactone 4 and delta-lactone 5. These lactonizations proved to be kinetically controlled. On the other hand, when 3c was heated in CH(3)NO(2) at 70 degrees C, the highly selective formation of 4c was observed. Further detailed experiments confirmed that the thermal lactonization in CH(3)NO(2) was thermodynamically controlled.     

Post-lactonization of vinyl polymers containing pendent ester and hydroxymethyl groups

Copolymers of methyl methacrylate with methyl and ethyl α-hydroxymethylacrylate and with α-hydroxymethylstyrene have been prepared with free-radical initiators at temperatures below 80°C. At higher reaction temperatures or under extrusion conditions, alcohol was eliminated and the free hydroxyl content was greatly decreased. All evidence indicates the formation of six-membered lactone groups in this post-polymerization reaction: direct evidence for their formation is lacking, however, since neither infrared nor nuclear magnetic resonance spectra could be used to detect lactonization in this system. The loss of activity from ¹⁴C ester-labeled methyl methacrylate copolymer on heating could be correlated with the extent of lactonization. The degree of lactonization is relatively less with copolymers containing higher amounts of hydroxymethyl groups. The resulting polymers exhibit higher heat distortion temperatures and decreased impact resistance when compared to poly(methyl methacrylate). Attempts were made to incorporate similar lactone structures by cyclocopolymerization with methyl methacrylate of α-methacryloxymethylstyrene or ethyl α-methacryloxymethylacrylate, but only crosslinked polymers or polymers with pendent unsaturation were found.     

Studies on the Total Synthesis of Crotocembreneic Acid and Neocrotocembreneic Acid:A Perchloric Acid-induced Lactonization Reaction of Epoxy Ester

Cembranoids, a large family of diterpenoid natural products characterized by the presence of fourteen-membered ring, have been isolated from various marine sources as well as some terrestrial organisms since the 1960's1. Crotocembraneic acid 1 and neocrotocembraneic acid 2 have been isolated from the stem bark of Croton oblongifolius Roxb. (Euphorbiaceae)2. In our studies on the total synthesis of 1 and 2, we find a novel perchloric acid-induced lactonization reaction of epoxy ester 9 (Scheme…     

Synthesis of (9E)-isoambrettolide, a macrocyclic musk compound, using the effective lactonization promoted by symmetric benzoic anhydrides with basic catalysts

Two alternative methods for the synthesis of (9E)-isoambrettolide are established via the rapid lactonization of the free threo-aleuritic acid or its protected seco-acid using substituted benzoic anhydrides with basic catalysts. The most efficient lactonization of the threo-aleuritic acid is performed using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-dimethylaminopyridine N-oxide (DMAPO).     

First stereoselective total synthesis of helicascolides A and C

The first total synthesis of helicascolides A and C is reported via acid catalyzed acetonide deprotection followed by intramolecular lactonization in one-pot as the key step.     

Erythromycin as a supramolecular receptor

When Erythromycin A (E) is added to a solution of Rhodamine B base (Z) dissolved in chloroform, dioxane or DMSO the color disappears immediately and this effect is attributed to the formation of a Host-Guest complex between Z and E followed by a fast lactonization of Z.     

Rhodium or palladium-catalyzed cascade aryl addition/intramolecular lactonization of phthalaldehydonitrile to access 3-aryl and 3-alkenyl phthalides

A rhodium or palladium-catalyzed addition of boronic acids to phthalaldehydonitrile, followed by an intramolecular lactonization of cyano to access 3-substituted phthalides, is described. This procedure tolerates a series of functional groups, such as methoxy, fluoro, chloro, and vinyl groups. It is a novel procedure for the synthesis of 3-arylphthalides.     

The first stereoselective total synthesis of nicotlactone A

Herein we report the first stereoselective total synthesis of nicotlactone A via acid catalyzed acetonide deprotection followed by intramolecular lactonization in one pot as the key step.     

Formal total synthesis of cyanolide A

Formal total synthesis of cyanolide A, aglycosidic dimeric macrolide is accomplished. The key reactions involved are asymmetric acetate aldol reaction, CBS reduction, and Shiina's lactonization.