Synthetic studies on thiostrepton family of peptide antibiotics: synthesis of the pentapeptide segment containing dihydroxyisoleucine, thiazoline and dehydroamino acid

The dihydroxyisoleucine-, thiazoline- and dehydroamino acid-containing pentapeptide of the thiostrepton family of peptide antibiotics was synthesized, which featured the β-lactone opening by phenylselenylation, the vinylzinc addition to the chiral sulfinimine, the Wipf oxazoline-thiazoline conversion method and the oxidative syn-elimination of the phenylseleno group.     

Unexpected behavior of the reaction between acyl thioformanilides and acetonitrile derivatives—a useful entry to new penta-substituted dipyrrole disulfides

A convenient and unexpected synthesis of penta-substituted dipyrrole disulfides starting from readily available acyl thioformanilides and acetonitrile derivatives has been developed. The overall process leads to the creation of two C-C bonds, two C-N bonds, and one S-S bond with the concomitant formation of two pyrrole rings and disulfide from the fact that only two reagents need to be mixed together, and it complements the existing pyrrole disulfides chemistry.     

Unexpected behavior of the reaction between 1,2-diaza-1,3-butadienes and 3-dimethylaminopropenoates: a useful entry to new pyrrolines, pyrroles, and oxazolines

We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 degrees C, this attack produced 1-aminopyrrolines with a high degree of cis-stereoselectivity by means of an unusual zwitterionic adduct intermediate followed by intramolecular ring closure. In toluene under reflux, 1-aminopyrrolines produced oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-aminopyrrolines were directly obtained by reaction of 1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates in toluene under reflux. The ring opening of oxazoline-fused 1-aminopyrrolines in acidic or basic media provides highly substituted 1-aminopyrroles. 5-Unsubstituted 1-aminopyrrole derivatives were obtained from 1-aminopyrrolines under basic conditions by loss of dimethylamino and ester groups. We discuss the plausible mechanisms of the ring closure and opening.     

Hyperconjugation effect on diene reactivity in 1-methyltetrazolo[5,1-a]isoindole-derived amides and thioamides

Optimized synthesis of 1-methyltetrazolo[5,1-a]isoindole-derived amides and thioamides was elaborated. Based on ¹³C NMR spectroscopy and X-Ray diffraction studies data, it was proposed that zwitterionic resonance structures contributed significantly to the structure of these compounds. Geometry optimization was performed in vacuo using m06-2x/cc-pvtz method taking into account polarizing effect of environment (PCM model) and specific intermolecular interactions. Electronic density distribution in these molecules was analyzed using NBO method. Using Δ(HOMO_diene–LUMO_dienophile) for amides and thioamides in vacuo and in a protic solvent, possibility of Diels–Alder reaction was evaluated. Energies of π-π conjugation and n→σ* hyperconjugation for the amide derivative were estimated in vacuo, aprotic and protic solvents.     

Thiol-mediated tandem Michael-aldol reaction: a convenient method for the synthesis of fused cyclopentenones

A simple, convenient, one-pot synthetic approach towards substituted cyclopentenone derivatives via thiol-mediated tandem Michael-aldol reaction followed by acid-catalyzed thiol elimination and isomerization of 3-(2-formyl-3,4-dihydronapthalene 1-yl)-acrylic acid esters has been developed.     

Temperature coefficient of NH chemical shifts of thioamides and amides in relation to structure

NH chemical shift temperature coefficients have been measured in a large series of N-substituted-3-piperidinethiopropionamides in which the NN distances are short but of varied length, as well as in a couple of the corresponding amides and in some simpler amides and thioamides. Geometries are calculated by means of ab initio DFT methods. The N-substituted-3-piperidinethiopropionamides show in most cases strong intramolecular N–HN hydrogen bonds according to IR spectra and ab initio calculations. For compounds with rather short NN distances the S=C–N–H moiety is non-planar. Dihedral angles as small as 160° are found. The NH chemical shift coefficients measured in non-polar solvents in all the N-substituted-3-piperidinethiopropionamides are more negative (−8 to −17 ppb/K) than in non-hydrogen bonded thioamides. For the latter in non-polar solvents like CDCl₃ and toluene the temperature coefficients are as small as −1 to −4 ppb/K. The large negative effects can be related not only to the non-planarity of the thioamide group in a way that the more pronounced the non-planarity the more negative the temperature coefficients, but also to strong hydrogen bonding and the fact that the acceptor is a nitrogen. For similar amides with non-planar amide groups and nitrogen acceptor large negative temperature coefficients are likewise seen. In polar solvents like DMF the effects in simple thioamides are uniform and close to −6 ppb/K, whereas in the more complex compound like 4p(t) the temperature coefficient is close to 0. An essential feature of measuring temperature coefficients of compounds without strong intramolecular hydrogen bonds in non-polar solvents and at low temperatures is to keep the concentration low enough to avoid dimerisation.     

Unexpected regioselectivity in the palladium‐catalyzed reaction of silacyclobutanes with aryl iodides

The reaction of aryl iodides with 1,1‐diphenyl‐silacyclobutane in the presence of a catalytic amount of Pd(PPh₃)₄ affords unexpected ring‐opening adducts, 1‐ and 2‐propenyl(triaryl)‐silanes, in good yields. On the other hand, the PdCl₂(PhCN)₂‐catalyzed reaction of 1,1‐diphenylsilacyclobutanes with aryl halides gives ­unexpected products, triarylsilanols, after ­hydrolysis in moderate yields. The catalysis involves the reaction of aryl–palladium intermediates with silacyclobutanes along with ­regioselective aryl–silicon bond formation. Copyright © 2001 John Wiley & Sons, Ltd.     

The unique regioselectivity in the formation of disubstituted-1,4-benzoquinones generated from the reaction of 4-hydroxycoumarins with 1,4-benzoquinone

The 2,3-disubstituted 1,4-benzoquinones were synthesized through the regioselective addition of 4-hydroxycoumarins with 1,4-benzoquinone in aqueous acetone, which were different from 2,5-disubstituted adducts generated by the previously reported reaction of compounds possessing an activated methylene with 1,4-benzoquinone.     

Diastereoselective Michael additions to α,β-unsaturated α-sulfinyl phosphonates in the thiolane series

A chiral racemic 2-phosphono-2,3-didehydrothiolane sulfoxide was used as a Michael acceptor in the reactions with several nucleophiles, in particular thiols. In most cases the reactions were fully diastereoselective. The relative configuration of the resulting adducts was determined.     

Modified reaction conditions to achieve high regioselectivity in the two component synthesis of 1,5-diarylpyrazoles

The factors affecting regioselectivity during the formation of 1,5-diarylpyrazoles from aryl hydrazines and 1,3-diketones are identified and the regioisomers were characterized by 1D NOESY, LC-NMR and X-ray analyses. A simple alteration in the usual reaction conditions is reported, which allows the exclusive formation of 1,5-diarylpyrazoles.     

Diastereoselective conjugate addition to chiral alpha,beta-unsaturated carbonyl systems in aqueous media: an enantioselective entry to alpha- and gamma-hydroxy acids and alpha-amino acids

The stereoselectivity of the ultrasonically induced zinc--copper conjugate addition of iodides to chiral alpha,beta-unsaturated carbonyl systems under aqueous conditions was studied. Alkyl iodides add diastereoselectively to methylenedioxolanone 1 and methyleneoxazolidinone 2 to afford the 1,4-addition products in good yields (38-95 %) and with high diastereomeric excess (44-90 % de). The 1,4-addition to chiral gamma,delta-dioxolanyl-alpha,beta-unsaturated esters 3-5 also proceeds with good yields (51-99 %). The diastereoselectivity is dependent on the geometry of the olefin: the Z isomer 3 gives high diastereoselectivity, while the reactions with the E isomer 4 are nonstereoselective. The reaction proceeds with excellent chemoselectivity and allows the use of iodides bearing ester, hydroxy, and amino groups. Since the 1,4-addition products can be readily hydrolyzed, this methodology constitutes a novel entry for the enantioselective synthesis of alpha- and gamma-hydroxy acids and alpha-amino acids in aqueous media. The results obtained support the radical mechanism proposed by Luche, and represent one of the few examples of a radical stereoselective conjugate addition in aqueous medium.     

The photo-Nazarov cyclisation of 1-cyclohexenyl-phenyl-methanone revisited: II: Reaction between primary and secondary key intermediates

Trans-1-cyclohexenyl-phenyl-methanone (2) and enol 4, both key intermediates in the title reaction, react with each other in a Michael-type addition to form predominantly enol 10. This enol, kinetically stable but too reactive to be isolated, reveals its presence in the irradiated solutions by formation of the isomeric ketone 11 on acid catalysis, and by formation of the oxidation product 9 on exposure to atmospheric oxygen. In the absence of acid, formation of 10 competes significantly with the title reaction of cis-1-cyclohexenyl-phenyl-methanone (1). In a secondary photoreaction of 10, 1,6-hydrogen abstraction by the excited carbonyl group and cyclisation afford 13 and 14. Enols 4, 10, and 13, in striking contrast to enol ethers and to thermodynamically stable enols, are unstable towards atmospheric oxygen. Thus, 4 autoxidises to form five compounds (Ox-1 through Ox-5), 10 to form 9, and 13 to form 15.     

Domino reaction of arylaldehydes and 1-acetylcyclopropanecarboxamides: one-pot access to highly functionalized spiropiperidine-2,4-diones

A domino reaction based on arylaldehydes and 1-acetylcyclopropanecarboxamides has been developed, which allows one-pot and efficient synthesis of structurally complex piperidine-2,4-diones with multiple functionalities under mild conditions. The overall transformation involves tandem aldol/intramolecular aza-Michael/(aldol)/Michael sequences.     

Unexpected formation of 4-aryl-3-cyano-6-phenylpyridine-2(1H-thiones from the reaction of arylmethylenecyanothioacetamides with benzoyl-1,1,1-trifluoroacetone

4-Aryl-3-cyano-6-phenylpyridine-2(1H)-thiones, used in the synthesis of substituted 2-alkylthiopyridines, thieno[2,3-b]pyridines, and 1,4-di(pyridin-2-ylthio)butane, have been synthesized by the condensation of arylmethylenecyanothioacetamides with benzoyl-1,1,1-trifluoroacetone. The reaction path includes the formation of the Michael adduct which undergoes loss of the acyl group. The structure of 3-cyano-2-methylthio-4-(1-naphthyl)-6-phenylpyridine has been studied by X-ray crystallography. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1821–1828, December 2005.     

Unexpected regioselectivity observed in the bromination and epoxidation reactions of p-benzoquinone-fused norbornadiene: An experimental and computational study

The bromination reaction of p-benzoquinone-fused norbornadiene was studied at various temperatures (?78, ?50, 0, 25, and 77 °C). At room temperature, the double bonds of the p-benzoquinone units were mainly brominated. The double bond of the norbornene unit also underwent a bromination reaction in a yield of only 2%. However, the reaction at ?78 °C resulted in the formation of products derived from the attack of bromine on the norbornene double bond with higher charge density. In contrast to the bromination reaction, the epoxidation reaction of the same compound with m-chloroperbenzoic acid and dimethyldioxirane exclusively resulted in the formation of products derived from the addition to the double bond of norbornadiene. The regioselectivity observed was investigated and the results were supported by theoretical calculations.     

Studies on the oxidative addition reaction of 1,1-dibromo-1-alkenes, alpha-dehalopalladation, and the intramolecular bis(carbopalladation) reaction of alkenes. An efficient entry to fused bicycles

Twenty-three examples of 1,1-dihalo-1-alkenes were synthesized by the conventional alkylation methods. The oxidative addition reactions of 1,1-dibromo-2,2-diphenylethene or 1, 1-dibromo-2-phenylpropene with a stoichiometric amount of Pd(PPh(3))(4) afforded 1,2-diphenylacetylene and 1-phenylpropyne, respectively, indicating that alpha-dehalopalladation reaction occurred to afford vinylic carbene intermediates. However, alpha-dehalopalladation reaction was not observed in all 1, 1-dihalo-1-alkenes containing an extra C=C bond suitable for cyclic carbopalladation under the current reaction conditions probably due to the fast cyclic carbopalladation reaction of 40A-type of palladium intermediates; A series of bicycles, i.e., fused 5,6-, 6, 6-, 6,7-, and 7,7-bicyclic compounds, were prepared efficiently via this bicyclic carbopalladation protocol. Under condition A, within 0. 5 h, 10 afforded the monocyclic product 37 in 79%. With prolonged reaction time, 37 was converted to bicycle 36. Even with isolated 37, the corresponding reaction under condition A afforded 36 in 92% NMR yield, indicating a stepwise oxidative addition-cyclic carbopalladation-beta-elimination mechanism for this bicyclization reaction.     

Sodium borohydride or potassium carbonate-mediated intramolecular Michael addition: a general method for the synthesis of fused dihydrofuran and furan derivatives

A simple and convenient method for the synthesis of fused dihydrofuran derivatives using NaBH₄-mediated reductive cyclization and fused furan derivatives by K₂CO₃-mediated intramolecular Michael addition followed by acid-catalyzed methanol elimination has been developed.