Total synthesis of cis-solamin A, a mono-tetrahydrofuran acetogenin isolated from Annona muricata

Total synthesis of cis-solamin A was accomplished without using protecting groups starting from (−)-muricatacin in 11 steps with an overall yield of 4.5%. The backbone of cis-solamin A was constructed by olefin cross-metathesis between the tetrahydrofuran moiety and γ-lactone moiety. An enzymatic kinetic transesterification procedure was successfully applied to the synthesis of an optically pure γ-lactone moiety.     

Synthesis of pyranicin and its deoxygenated analogues and their inhibitory action with bovine heart mitochondrial complex I

Total synthesis of pyranicin and its deoxygenated analogues was achieved using Cl₂Pd(CH₃CN)₂ catalyzed diastereoselective cyclization of the allylic ester as the key step. The inhibitory activity of these compounds for mitochondrial NADH-ubiquinone oxidoreductase (complex I) was poorer than those of ordinary mono-THF acetogenins such as annonacin.     

Synthetic approach toward cis-disubstituted γ- and δ-lactones through enantioselective dialkylzinc addition to aldehydes: application to the synthesis of optically active flavors and fragrances

A versatile and straightforward approach to optically active cis-4,5-disubstituted γ- and δ-lactones by catalytic enantioselective addition of dialkyzincs to cinnamic aldehydes and RCM ring closure has been reported. The synthetic importance of the enantioselective dialkylzinc alkylation of aldehydes has been thus widened. Such an approach has then been employed for the enantioselective synthesis of naturally occurring γ-lactone flavors like (S)-5-ethyl-butanolide (6a) and (4S,5S)-cis-whisky lactone (6b) and extended to the preparation of δ-lactones like (5S,6S)-5-methyl-6-ethylpentanolide (9a), precursor of the pheromone serricornin.     

Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives

Non-epimerizable cis and trans δ-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer 4 has been achieved in 8 steps and 4% overall yield from podophyllotoxin 1 via the reduction of the γ lactone ring into the trans diol, selective protection of the 4-OH and 11-OH as a benzylidene acetal, and Wittig elongation at C-13 with inversion of configuration at C-2. Same elongation at C-13 but via the formation of a mesylate and introduction of a cyano group, led to the trans δ-lactone 5 (7 steps from 1 and 6% overall yied) with a small amount of its C-4 epimer 6. The synthesis of non-epimerizable δ-lactone analogues of 4′-demethyl-epipodophyllotoxin 7 and of 4-demethyl podophyllotoxin 8 are also reported. The synthesis of 7 and 8 was based upon the reduction of the γ-lactone ring of 4′-demethyl-4-epipodophyllotoxin followed by selective protection at C-11 and elongation at C-13. (8-15% and 4% overall yields). Compounds 4, 5 and 7 did not display relevant cytotoxicity in vitro against L1210 murine leukemia.     

Limonoids from the aerial parts of Munronia pinnata

Six new limonoids, munropins A?F (1–6), were isolated from the aerial parts of a Chinese medicinal plant, Munronia pinnata (Meliaceae). The structures of 1–6 were assigned by detailed analyses of their spectroscopic data. Munropins A (1) and B (2) are limonoids possessing a prieurianin skeleton with α,β-unsaturated γ-lactam moieties at C-17. Munropins C (3), D (4), and E (5) are also prieurianin type limonoids with an α,β-unsaturated γ-lactone moiety, an acetyl group, and an acetoxyacetyl group at C-17, respectively. Munropin F (6) was assigned as a nimbolinin type limonoid with a γ-hydroxy-α,β-unsaturated γ-lactone moiety.     

An iterative acetylene-epoxide coupling strategy for the total synthesis of longimicin C

Longimicin C, a naturally occurring annonaceous acetogenin possessing a C₂-symmetrical bis-THF moiety and a short hydrocarbon chain between its THF-containing region and a terminal γ-lactone, was synthesized for the first time. The total synthesis was successfully achieved by an iterative acetylene-epoxide coupling strategy. d-Mannitol was used to establish the bis-THF-containing segment, in which the additional stereochemistries were introduced by Sharpless dihydroxylations and intramolecular Williamson etherifications. Regioselective epoxide-openings by the appropriate terminal acetylenes allowed coupling and elaboration of all four fragments including the introduction of three essential hydroxyls into the proper sites of the target skeleton.     

Novel cyclic sesquiterpene peroxides from the Formosan soft coral Sinularia sp.

Four novel cyclic peroxide-containing sesquiterpenes (1-4), with a γ-alkylidene-α-methyl-α,β-unsaturated γ-lactone moiety, have been isolated from a Formosan soft coral of the genus Sinularia. Their structures were elucidated mainly by extensive 1D and 2D NMR experiments.     

Formal synthesis of（＋）-tashiromine and study toward the total synthesis of（＋）-stemoamide

An effcient formal synthesis of（＋）-tashiromine was achieved by employing an intermolecular asymmetric Mannich-type reaction as the key step.Concurrently,a novel approach toward the total synthesis of（＋）-stemoamide through dyotropic rearrangement of 3,4-cis-b-lactone was also explored.     

Samarium(II) iodide-induced cascade reaction for tricyclic γ-lactone synthesis from acyclic keto diesters

Cascade reaction involving reductive cyclization, Dieckmann condensation, and lactonization of E- and Z-dimethyl 2-methyl-8-oxoundec-2-enedioates and Z-dimethyl 2-methyl-7-oxodec-2-enedioate with samarium(II) iodide was found to stereospecifically produce cis and trans bicyclo[4.4.0]decane (decalin) ring systems and trans bicyclo[4.3.0]nonan (perhydroindane) ring system each consisting of γ-lactone, respectively.     

Rumphellaone A, a novel caryophyllane-related derivative from the gorgonian coral Rumphella antipathies

A novel 4,5-seco-caryophyllane sesquiterpenoid derivative, rumphellaone A (1), which was found to possess an unprecedented γ-lactone moiety, was isolated from the gorgonian coral Rumphella antipathies. The structure of 1 was elucidated by spectroscopic method. A plausible biosynthetic pathway of compound 1 was proposed.     

The santonins : Qantitative conformational analysis

Empirical valence force-field calculations have been used to investigate the conformations and relative strain energies of α-santonin, β-santonin, and their C(6) epimers. The cis-fused γ-lactone ring is energetically preferred over the trans and the nearly eclipsed C(13)-C(11)-C(12) = 0 torsion angle plays a key role in stabilising the isomers with a pseudo-equatorial Me group at C(11).     

The ethoxyethynyl carbinol—αβ-unsaturated ester conversion: Stereomutation accompanying a selenium dioxide oxidation

Benzsuberone reacts with ethoxyethynyl magnesium bromide to give 1-ethoxyethynyl-1-hydroxy-2,3-benzocycloheptene, which on rearrangement with mild acid (carbon dioxide) yields ethyl cis-1,2-benzo-3-cycloheptenylidene acetate (4, R′= CO₂Et, R¹ = H) and the corresponding trans -compound. With selenium dioxide, both esters yield the same γ-lactone,     

Synthesis of pyranicin and its inhibitory action with bovine heart mitochondrial complex I

Total synthesis of pyranicin was achieved using Cl2Pd(CH3CN)2-catalyzed diastereoselective cyclization of the allylic ester as the key step. The inhibitory activity of this compound for mitochondrial NADH-ubiquinone oxidoreductase (complex I) was slightly poorer than that of ordinary mono-THF acetogenins such as cis-solamin.     

A formal convergent synthesis of (+)-trans-solamin

A formal convergent synthesis of solamin is disclosed. The synthetic strategy exploits the potential of the sulfinyl group as an auxiliary, nucleophile and in C-C bond formation. The synthetic route can be adapted to the synthesis of stereoisomers of solamin, analogs with variable carbon side chains, and other members of mono-THF acetogenins.     

Studies Directed Towards the Biosynthesis of the C7N Unit of Rifamycin B: A New Synthesis of Quinic Acid from Shikimic Acid

The synthesis of quinic acid ( 4 ) via epoxide 13 , starting from shikimic acid ( 5 ), is described (Scheme 1). Treatment of 13 with thiophenol yielded not only 17 , but also the γ-lactones 18 and 19 as result of migration of silyl groups within a cis- and trans-diol system. The conversion provides a direct stereoselective epoxidation of a shikimic-acid derivative as well as an alternative pathway for the preparation of 4 . A shorter approach via the disilylated epoxide 22 was unsuccessful because the γ-lactone 25 was obtained in place of the desired α-hydroxy ester 24 (Scheme 2).     

Stereochemistry of terpene derivatives. Part 5: Synthesis of chiral lactones fused to a carane system—insect feeding deterrents

Chiral iodo- 9, bromo- 10 and hydroxylactones 12 condensed with the carane system were obtained. In each case, the synthetic pathway led to an enantiomerically pure diastereoisomer to generate two stereogenic centers. Iodo- 9 and bromolactone 10 possess a γ-lactone group while the hydroxylactone 12 possesses a δ-lactone moiety situated trans to the gem-dimethylcyclopropyl ring. The structures of the products were confirmed by X-ray crystallography. These lactones were tested for antifeedant activity against storage pest insects.     

Effect of stereochemistry of Δlac-acetogenins on the inhibition of mitochondrial complex I (NADH-ubiquinone oxidoreductase)

Δlac-Acetogenins are a new type of inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase). We synthesized a series of Δlac-acetogenins in which the stereochemistry around the hydroxylated tetrahydrofuran (THF) ring moiety was systematically modified, and examined their inhibitory effect on complex I. The present results revealed that the inhibitory effects of the bis-THF ring analogs are much more potent than those of the mono-THF ring analogs and that the stereochemistry around the bis-THF ring moiety significantly influences the inhibitory effect. The profiles of the structure-activity relationship observed for Δlac-acetogenins were entirely different from those for natural-type acetogenins.     

Synthesis of (2,2,2-trifluoroethyl) substituted pyridazin-3(2H)-ones and 1,5-dihydropyrrol-2-ones from α,β-unsaturated γ-lactones and hydrazines

This paper presents the transformation of α,β-unsaturated γ-lactones into 2,2,2-trifluoroethyl substituted pyridazin-3(2H)-ones and 1,5-dihydropyrrol-2-ones starting from various hydrazines. The influence of the γ-lactone substitution (sulfanyl versus sulfonyl moiety) and the nature of the hydrazines (unsubstituted, alkyl- or aryl-substituted) on the outcome of the reaction were studied. All new heterocycles were characterized using 1D NMR, IR, MS and their data was compared with those of two reported X-ray diffraction structures. The two possible competitive pathways leading to pyridazin-3(2H)-ones and/or 1,5-dihydropyrrol-2-ones are discussed. Abinitio DFT calculations were also performed in order to rationalize several experimental results.     

Stereoselective synthesis of γ-lactone fused cyclopentanoids

The stereoselective synthesis of γ-lactone fused cyclopentanoids applying chemoenzymatic methods is described. rac-2-Hydroxymethyl-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-ene and rac-2-hydroxymethyl-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene were successfully resolved by Candida rugosa lipase (CRL), to afford enantiomerically enriched products with an ee of 94 and 97%, respectively. The enantiomerically enriched acetates were then subjected to ruthenium and/or cerium catalyzed oxidation to afford α-diketones and subsequent alkaline H₂O₂ mediated oxidative cleavage reaction of α-diketones, followed by CH₂N₂ esterification, gave enantiomerically enriched γ-lactone fused cyclopentanoids with known absolute configurations.     

Convergent synthesis of stereoisomers of THF ring moiety of acetogenin thiophene analogue and their antiproliferative activities against human cancer cell lines

The convergent synthesis of thiophene-3-carboxamide analogues of annonaceous acetogenins was accomplished through the asymmetric alkynylation of a 2-formyl THF ring fragment with an alkyne having a thiophene ring as the key step. Eight stereoisomers of the THF ring moiety were synthesized by this convergent route and their antiproliferative activities against 39 human cancer cell lines were evaluated. It was revealed that derivatives having the threo configuration between C17–C18 positions showed more potent activities than the corresponding erythro ones.