Synthesis of the β-lactam antibiotic (+)- thienamycin via an intermediate π-allyltricarbonyliron lactone complex

The π-allyltricarbonyliron lactone complex (7), formed by reaction of E-1,2-epoxy-2-methyl-6,6-dimethoxyhex-3-ene(5) with co-ordinatively unsaturated iron carbonyl species, was reacted with benzylamine to give a lactam complex (8) by an S_N'-like mechanism. This complex upon oxidation with Ce(IV) afforded cis-3-isopropenyl-4-[(2',2'-dim (9) which was chemically modified into trans-3-(1'-hydroxyethyl)-4-[(2',2-dimethoxy)ethyl] azetidin-2-one (13), a key intermediate previously used in the synthesis of the antibiotic thienamycin. Similar reaction with (S)-(-)--methylbenzylamine afforded a separable mixture of diastereoisomeric iron lactam complexes (16 and 17). These complexes could be individually converted to the corresponding optically active β-lactam derivatives (27 and 28) and, hence, are precursors for the synthesis of either natural (+)-thienamycin or unnatural (-)-thienamycin.     

Bridge-substituted calix[4]arenes: syntheses, conformations and application

The bridge-substituted calix[4]arene carboxylic acid, 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxy-calix[4]arene-2-carboxylic acid (1), can be readily converted to various esters 2-4 and reduced to the alcohol 5, which reacts with methyl iodide to give the ether 6. The alcohol can be dansylated to give 7, the fluorescence of which is selectively quenched by Cu(II) in acetonitrile. An attempt to convert the acid 1 to an amide resulted unexpectedly in the formation of a lactone 8. The conformational characteristics of 1-8 have been studied in solution and, in the cases of 2 and 4, in the solid state by determination of their single-crystal X-ray structures. With the exception of 8, in all these compounds the bridge substituent adopts an equatorial (lateral) orientation.     

Asymmetric synthesis of [2,3-(13)C(2),(15)N]-4-benzyloxy-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazine-2-one via lipase TL-mediated kinetic resolution of benzoin: general procedure for the synthesis of [2,3-(13)C(2),(15)N]-L-alanine.

Lipase TL-mediated kinetic resolution of benzoin proceeded to give the corresponding optically pure (R)-benzoin (R)-1. On the other hand, (S)-benzoin O-acetate (S)-7 could be hydrolyzed without epimerization to give (S)-benzoin (S)-1 under alkaline conditions. Furthermore, both enantiomers of benzoin (1) were converted to [(15)N]-(1R,2S)- and (1S,2R)- 2-amino-1,2-diphenylethanol (3a and 3b), respectively, according to the procedure reported previously. [2,3-(13)C(2),(15)N]-(5S,6R)-4-benzyloxy-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazine-2-one (10) was synthesized from ethyl [1,2-(13)C(2)]bromoacetate and (1R,2S)-2-amino-1,2-diphenylethanol (3b) in three steps. Finally, [2,3-(13)C(2),(15)N]-L-alanine (12) was prepared via alkylation of the lactone 10 and hydrogenation of the alkylated product 11.     

四(苯甲酰甲硫基)四硫富瓦烯的合成及其有关电化学性质的研究

本文通过4, 5-二(苯甲酰甲硫基)-1, 3-二硫杂环戊烯-2-硫酮与乙二醇反应生成其缩酮, 然后在亚磷酸三甲酯作用下偶联,最后水解, 首次成功地制得了四(苯甲酰甲硫基)四硫富瓦烯(TBMT-TTF)。用循环伏安法和UV-Vis光谱研究了有关电化学性质。为制备含羰基四硫富瓦烯提供了一条可行途径。     

A one-pot sequence of Stille and Heck couplings: synthesis of various 1,3,5-hexatrienes and their subsequent 6pi-electrocyclizations

Palladium-catalyzed cross-coupling reactions of 2-bromocyclohex-1-enyl triflates 7 and 11 with a variety of alkenylstannanes occurred chemoselectively at the site of the triflate leaving group to give bromobutadienes which readily underwent Heck reactions with acrylates and styrene. Both steps could be performed in the same flask to give differentially functionalized hexatrienes in up to 88% overall yield. With simple stannanes, the same catalyst precursor could be used for both coupling steps making it possible to perform the whole sequence with only one portion of catalyst. For some of the functionally substituted stannanes, specifically adjusted catalyst systems had to be used. The 1,3,5-hexatrienes obtained were further transformed, in particular the methoxy-substituted compounds 14a-c were converted to bicyclo[4.4.0]decenones 30 (71-97%), bicyclo[4.3.0]nonenones 35 (74-93%), cyclodecynone 37a (47%), and cyclononynone 39a (15%). Thermal electrocyclizations of the other hexatrienes gave tetrahydronaphthalines 31 (60-61%), the tricyclic lactone 32 (72-75%) and decahydrophenanthrene 33 (75 %) in good yields.     

Synthesis of a novel ether-bridged GM3-lactone analogue as a target for an antibody-based cancer therapy

We describe herein the synthesis of a new analogue of the GM3-lactone containing a cyclic ether moiety. The ether moiety was chosen as a replacement for the regular lactone group since it shows high resemblance with the lactone and is completely stable under biological conditions. The cyclic ether moiety was formed by reduction of the corresponding lactone to give the lactol followed by formation of the S,O-hemiacetal and hydrogenation. In addition, we have prepared haptens with a hexanoic acid moiety, which can be used for the preparation of poly- and monoclonal antibodies after binding to BSA or KLH. This is the first example of an analogue of the GM3-lactone which is stable under hydrolytic conditions in vitro and probably also in vivo. Reaction of lactone 18 with a Red/Al derivative led to the lactol 19 which was transformed into the S,O-hemiacetal 20 using 2,2'-bis(pyridinium) disulfide in quantitative yield. Hydrogenation with Raney Nickel gave 21 from which after removal of the protecting group at C-1a the trichloroacetimidate 25 was prepared. Reaction with azidosphingosine to give 26 followed by reduction of the azido group with NHEt3+[(PhS)3Sn], acylation with stearic acid using EDC and removal of the protecting groups led to the desired ether analogue of GM3 lactone 4. In addition the trichloroacetimidate 25 was glycosidated with 6-hydroxyhexanoic acid methyl ester, which was deprotected to give 29. The compound will be used for the preparation of poly- and monoclonal antibodies after coupling with BSA and KLH.     

Lactone enols are stable in the gas phase but highly unstable in solution

2-Hydroxyoxol-2-ene (C(5)-1), the enol tautomer of gamma-butyrolactone, was generated in the gas phase as the first representative of the hitherto elusive class of lactone enols and shown by neutralization-reionization mass spectrometry to be remarkably stable as an isolated species. Ab initio calculations by QCISD(T)/6-311+G(3df,2p) provided the enthalpies of formation, proton affinities, and gas-phase basicities for gaseous lactone enols with four- (C(4)-1), five- (C(5)-1), and six-membered rings (C(6)-1). The acid-base properties of C(4)-C(6) lactones and enols and reference carboxylic acid enols CH(2)=C(OH)(2) (3) and CH(2)=C(OH)OCH(3) (4) were also calculated in aqueous solution. The C(4)-C(6) lactone enols show gas-phase proton affinities in the range of 933-944 kJ mol(-)(1) and acidities in the range of 1401-1458 kJ mol(-)(1). In aqueous solution, the lactone enols are 15-20 orders of magnitude more acidic than the corresponding lactones, with enol pK(a) values increasing from 5.6 (C(4)-1) to 14.5 (C(6)-1). Lactone enols are moderately weak bases in water with pK(BH) in the range of 3.9-8.1, whereas the lactones are extremely weak bases of pK(BH) in the range of -10.5 to -17.4. The acid-base properties of lactone enols point to their high reactivity in protic solvents and explain why no lactone enols have been detected thus far in solution studies.     

Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes

A combinatorial library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes was synthesized in high yield by C4-SMe substitution in N-alkyl/phenyl 4-(methylthio)-3-nitro-4H-chromen-2-amines with a variety of phenols. The reaction always provided C2 substitution in the phenol ring, dictated by hydrogen bond interactions between the phenolic hydroxyl group and the nitro group in 3-nitro-4H-chromenes. Reduction of the nitro group with concomitant hydrolysis of the enamine in 4-(2-hydroxyaryl)-3-nitro-4H-chromenes with Zn, Ac₂O in AcOH furnished hybrid amino-acid lactone incorporating ortho-tyrosine and phenyl alanine moieties.     

Efficient Syntheses of Traumatic Lactone and Rhizobialide

Herein, we report the total synthesis of traumatic lactone and rhizobialide by utilizing allenoic acid to construct the lactone ring. The key starting materials, allenoic acids, could be prepared by the ATA (allenation of terminal alkynes) of a terminal alkyne with an aldehyde that contained a protected hydroxyl group followed by hydrolysis. Importantly, the asymmetric synthesis could be realized just by replacing racemic diphenylprinol with (R)- or (S)-diphenylprinol to deliver the optically active allenoate.     

Evidence for [2+2] Photoreaction of α-Methylene-γ-Butyrolactones with Thymine: An Explanation for Chronic Actinic Dermatitis to Sesquiterpene Lactones?

The photoreactivity of isoalantolactone, a natural sesquiterpene lactone, toward thymine was studied. After 313 nm irradiation of a deoxygenated acetone solution of isoalantolactone (2 x 10(-3) M) and thymine (4 x 10(-3) M), two intermolecular [2 + 2] photoadducts, 3 and 4, were isolated with respective yields of 30% and 18%. The structures of these two photoadducts were determined by a combination of NMR experiments. Compound 3 was identified as a cis-syn-exo intermolecular [2 + 2] photoadduct involving the 5,6 double bond of thymine and the exomethylenic double bond of the lactone, while compound 4 was identified as an intermolecular [2 + 2] photoadduct involving the same bonds but with the cis-syn-endo conformation. This high photoreactivity of sesquiterpene lactones toward thymine could be an explanation of the progressive evolution of allergic contact dermatitis toward chronic actinic dermatitis.     

Copolymerization of the cyclic monomer, 5,5-dichloro-4-hydroxy-2,4-pentadienoic acid lactone

The copolymerization of 5,5-dichloro-4-hydroxy-2,4-pentadienoic acid lactone with methyl methacrylate, methyl acrylate, vinyl acetate, and vinylidene chloride to give yellow to red copolymers is described. Infrared, nuclear magnetic resonance, and ultraviolet spectroscopy indicate that the polymerization of the lactone proceeds by a 1,4-addition mechanism, followed by hydrogen chloride elimination, to give a highly conjugated structural unit closely related to the structure of the original monomer. The intense colors of the copolymers may arise from conjugated sequences of lactone units or through further eliminations along comonomer sequences.     

Novel Synthesis of Some Phthalazinone Derivatives

Dimethyl homophthalate condensed with isatin to give the unexpected five membered lactone 3 rather than the half ester 1 and the δ‐lactone 2 . Treatment of compound 3 with excess hydrazine hydrate afforded phthalazinone carbohydrazide 4 which represents a novel method for the synthesis of phthalazinone derivatives. The carbohydrazide 4 upon treatment with carbon disulphide afforded 1,3,4‐oxadiazole derivative 5 , which reacted with ethylchloroacetate to give the S‐alkylated product 6 . The structure of compound 3 compared with 2 was discussed using hyperchem professional (7) AM₁ calculations, X‐ray single crystal structure and complete spectral data.     

Asymmetric Synthesis of (3R, 5R)-3-((tert-Butyldimethylsily)oxy)-5-((Z)-2-Bromovinyl)-Tetrahydro-Furan-2-one, an Intermediate for the Synthesis of Fostriecin

Fostriecin(CI-920) 11 a potential anticancer agent presently in phase I clinical trials at NCI is a novel phosphate ester produced by Streptomyces pulveraceus. Scheme 1 1 2 3 5 4 Synthesis of C10 epimer of compound 1 had been reported by Just G2. during the determination of its structure. On the basis of Just’s synthesis, a revised retro-asymmetric synthetic route of Fostriecin (scheme 1) was designed here of which compound 3 was synthesized from 5 with C3 in R configuration correspondi…     

Site of nucleophilic attack and ring opening of five-membered heterocyclic 2,3-diones: a density functional theory study

The site of nucleophilic addition to five-membered heterocyclic 2,3-diones (4-iminomethylfuran-2,3-dione A1 and 4-formyl-pyrrole-2,3-dione B1) is studied by density functional theory calculations (B3LYP/6-31G) with water as the nucleophile. Both uncatalyzed and water-assisted 1,2-addition to the lactone (lactam) and the keto carbonyl group, and conjugate addition to C5 of the heterocycle and the heteroatom of the 4-iminomethyl (formyl) moiety are considered. In addition, concerted and stepwise ring fission of the lactone (lactam) ring is also treated. The effect of solvation (aqueous solution) is taken into account by the polarizable continuum model (PCM) and the Poisson-Boltzmann SCRF method (PB-SCRF), as well as explicit water molecules. Only this latter approach yields meaningful activation free energies. Barriers for addition of H2O increase in the order 1,4-addition to C5 < addition to the lactone (lactam) carbonyl < hydration of the 3-keto group. No reaction path for concerted water-assisted ring opening could be found.     

Study on the conversion of three natural statins from lactone forms to their corresponding hydroxy acid forms and their determination in Pu-Erh tea

Conversions of statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, from lactone forms to their corresponding hydroxy acid form in 0.1 N NaOH or 0.05 N KOH (prepared with 25, 50, 75, 90% acetonitrile or methanol in water or 100% water) were evaluated. Results showed that lactone form statins could be transformed almost completely only in alkaline solutions prepared with 25 or 50% acetonitrile. In all methanolic alkaline solutions, lactone form statins could also be converted entirely, nevertheless, they would be further transformed to the methyl ester of the hydroxy acid form and the transformation increased as methanol rises. When lactone and hydroxy acid forms of statins were in methanol, ethyl acetate, 70% acetonitrile in water (with 0.5% acetic acid or no) for 0-48 h at room temperature or in 100 degrees C water for 0-2 h, lactone form statins were converted to their corresponding hydroxy acids, which were raised as time extends and the highest conversions of them were about 35% in 100 degrees C water and 70% acetonitrile, slightly transformed for lactone form statins in 70% acetonitrile (with 0.5% acetic acid) after 8 h, and the other treatments for all statins showed no significant changes. Interferences would be reduced efficiently when statins were extracted from Pu-Erh tea with methanol, ethyl acetate or 100 degrees C water followed by purifying through a C18 solid-phase extraction cartridge. Lovastatin was the only statin found in Pu-Erh tea and the highest content of it was found under ethyl acetate extraction. In ethyl acetate and methanol extracts, lovastatin existed merely as lactone form. The lowest content of lovastatin was found in the 100 degrees C water extract of Pu-Erh tea, however, both of lactone and hydroxy acid forms were found to exist in the extract.     

Thuggacins, macrolide antibiotics active against Mycobacterium tuberculosis: isolation from myxobacteria, structure elucidation, conformation analysis and biosynthesis

Two novel antibiotics, thuggacin A (1) and B (2), were isolated from the myxobacterium Sorangium cellulosum. 1 and 2 are unique thiazole-containing macrolides with side chains on both sides of the lactone group. Upon standing in solution, thuggacin A (1) rearranges by acyl migration of the lactone group to give a mixture with thuggacins B (2) and C (3). NOEs and vicinal coupling constants within the lactone ring provided distinct data for the generation of a structure model by PM3 calculations, which allowed an analysis of the conformation in solution and the relative configuration of six asymmetric centres. A minor sorangium metabolite was identified as 13-methyl-thuggacin A (4). Furthermore, two natural thuggacin variants, 5 and 6, were found in another myxobacterium, Chondromyces crocatus. In these variants, one side chain is replaced by a methyl group and a hydroxy group is repositioned to give a primary alcohol at the former methyl site, in an alpha position with respect to the thiazole ring. 1 proved to be active against clinical isolates and reference strains of Mycobacterium tuberculosis. Preliminary studies on the mechanism of action indicate inhibition of the cellular electron-transport chain.     

Synthesis of N,N-Disubstituted Lactone Hydrazones via (Sulfonylimino)-ethers

The dihydropyran 3 reacts with sulfonyl azides to give the known (sulfonylimino)-ethers ( = lactone sul-fonylimines) 4 and 18 . Reaction of 4 with NH₂NH₂ · H₂O leads to the aminoiriazole-dibulanol 5 , characterized as its tetraacetate 8 , and not, as previously claimed, to 6 or 7 . Similarly, the dihydrofuran-derived (tosylimino)-ether 10 yields 11 The structure of 5 was established by X-ray analysis, and a mechanism for its formation is proposed. Reaction of 4 with NH₂NMe₂ afforded the lactone hydrazone 16 and the hydrazidine 17. Catalysis by imidazole suppressed the formation of 17 similarly, the [(trifluoromethyl)sulfonyl]imine 18 yielded 16, and, by reaction with NH₂N(Me)Ph or 4-amino-4H-1,2,4-triazole, the lactone hydrazone 19 and the adduct 20 , respectively. The 1,4-lactone hydrazone 21 was obtained from 10 or from 22 . The structure of 20 was established by X-ray analysis. Treatment of 16 with BuLi followed by BnBr yielded the α-alkylated lactone hydrazone 23 .     

Farbstoffsensibilisierte Photo-Oxygenierung von 6,6-Dimethylfulven. Eine neue 1,2-Dioxolan-Umlagerung

The dye sensitized photo-oxygenation of 6,6-dimethylfulvene ( 1 ) in solution at 15° gives enol lactone 2 , along with ketoles 3 and 4. The following mechanism is proposed: initially formed endoperoxide 11 undergoes a 1,2-dioxolan rearrangement to give allen epoxide 12 , which then isomerizes to cyclopropanone 13. 13 can then cyclise to give 2 and 3 .     

Solid-phase synthesis and spectroscopic studies of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline.

An efficient solid-phase synthesis of the TRH analogue Glp-His(Nim-Trt)-Hyp-OH is described. Na-Fmoc protected amino acids and DCC/HOBt activation were employed. The bulky and mild-acid-sensitive 2-chlorotrityl resin, utilised as the solid support, completely suppressed dioxopiperazine formation. The tripeptide is a key intermediate in the synthesis of TRH analogues incorporating cis- and trans-4-hydroxy-L-proline. The tripeptide was converted, with inversion of configuration at C-4 of the Hyp residue, to Glp-His(Nim-Trt)-cHyp lactone in the presence of triphenylphosphine-diethyl azodicarboxylate (TPP-DEAD). One-pot MeOH-TPP-DEAD transesterification of the lactone, followed by Nim-detritylation, provided Glp-His-cHyp-OMe. This ester gave the corresponding amide and acid on ammonolysis and saponification, respectively. A high-field 1H NMR investigation of Glp-His-cHyp-OH and its diastereomer Glp-His-Hyp-OH, obtained by Nim-detritylation of the key tripeptide, showed that the configuration at C-4 of the prolyl residues is critical for the determination of the preferred three-dimensional structure of the molecules.     

A new enantiodivergent synthesis of the Geissman-Waiss lactone

Intramolecular Michael reaction of methyl (R)-6-(tert-butoxycarbonylamino)oxy-4-hydroxy-2-hexenoate, in turn obtained from tert-butyl (R)-3-hydroxy-4-pentenoate, paved the way to the synthesis of both enantiomers of 2-oxa-6-azabicyclo[3.3.0]octan-3-one (the Geissman-Waiss lactone), a precursor for necine bases. Key intermediates in this approach were represented by enantiomeric bicyclic lactones incorporating a [1,2]-oxazinane nucleus, which has been conveniently used to install the pyrrolidine framework of the target compounds through a synthetic scheme featuring the reduction of the nitrogen-oxygen bond and an intramolecular S_N2 reaction.