Stereospecific interconversion of cis- and trans-γ,δ-epoxy α,β-unsaturated ester systems

The unprecedented, stereospecific interconversion of cis- and trans-γ,δ-epoxy α,β-unsaturated ester systems has been realized, which involves the palladium-catalyzed stereospecific alkoxy or hydroxy substitution reaction with double inversion of configuration at the γ-position as the key step. The new methodology is not only applicable to various disubstituted and trisubstituted epoxy unsaturated esters, but also these interconversions proceed with an extremely high degree of stereoselectivity and efficiency.     

Facile synthesis of (Z)- and (E)-3-allylidene-β-lactams via thermal β-elimination of trans-3-allyl-3-sulfinyl-β-lactams

A competent synthetic route for the synthesis of novel (Z)- and (E)-3-allylidene-β-lactams is described. The strategy involves oxidation of trans-3-allyl-3-phenylthio-β-lactams 1 using sodium metaperiodate (NaIO₄) to diastereomeric trans-3-allyl-3-phenylsulfinyl-β-lactams 2 and 3, which further undergo thermal β-elimination in refluxing carbon tetrachloride to furnish (Z)- and (E)-3-allylidene-β-lactams 5 and 6 in good to excellent yields. The molecular structure of 3b has been established with the help of single crystal X-ray analysis.     

Synthesis of cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives via thio-Michael addition

The reactivity of 2,3-dehydroproline and 2,3-dehydropipecolic acid methyl ester derivatives with S-nucleophiles in the thio-Michael addition reaction has been explored. The addition of triphenylmethanethiol and subsequent trityl cleavage led to the corresponding cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives in good yields.     

Syntheses of β- and γ-fluorophenyl cis- and trans-α-methylene-γ-butyrolactones

Preparation of a series of cis-γ-fluorophenyl-β-phenyl-α-methylene-γ-butyrolactones is reported via ‘allylboration’ of fluorobenzaldehydes with (E)-methyl 3-phenyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)acrylate. The corresponding trans-γ-fluorophenyl lactones were prepared either (i) via ‘allylboration’ using the (Z)-reagents or (ii) via an indium triflate-mediated isomerization of the cis-products. The difficulty in isomerizing difluorinated cis-products confirms the probable intermediacy of carbocations. Finally, the synthesis of cis-β-fluorophenyl-γ-phenyl-α-methylene-γ-butyrolactones was achieved via an indium-catalyzed allylation–lactonization of aldehydes with (Z)-2-(bromomethyl)-3-(fluorophenyl)acrylates.     

Synthesis of cis-3-arylated cycloalkylamines through palladium-catalyzed methylene sp carbon–hydrogen bond activation

Methylene sp³ carbon–hydrogen bond activation of N-picolinoylcycloalkylamines provides a useful method for synthesizing cis-3-arylated cycloalkylamine derivatives. Pd(II) species catalyzed the γ-arylation of N-picolinoylcycloalkylamines with aryl iodides in the presence of silver carbonate to afford cis-3-arylated N-picolinoylalkylamines in up to 87% yield. Hydrolysis of the amide linkage to give the corresponding cis-3-arylated cycloalkylamines was also demonstrated.     

Efficient synthesis of 3-hydroxymethylated cis- and trans-cyclobutane β-amino acids using an intramolecular photocycloaddition strategy

Uracil bearing a tethered allyl alcohol appendage at N1 undergoes a [2+2] photocycloaddition reaction to provide a single tricyclic adduct in high yield. This compound is transformed in one step into a cis-cyclobutane β-amino acid bearing a 3-hydroxymethyl group. Through appropriate functionalization and epimerization, the trans isomer is obtained therefrom in only three further steps.     

Synthesis of cis-3-hydroxypipecolic acid via SmI2-mediated cyclization of aldehydo β-aminovinyl sulfoxides

Stereoselective synthesis of cis-3-hydroxypipecolic acid was achieved via chirality transfer in the SmI₂-mediated cyclization reactions of aldehydo β-aminovinyl sulfoxides.     

Stereoselective synthesis of 1-O-β-feruloyl and 1-O-β-sinapoyl glucopyranoses

1-O-β-Feruloyl and 1-O-β-sinapoyl glucopyranoses are two common substrates for serine carboxypeptidase-like acyltransferases and serve as acyl donors in the biosynthesis of numerous secondary metabolites. In addition, they are involved in plant cell wall cross-linking and are also ideal substrates for studying the kinetics of lignification involving hydroxycinnamates. We report the first chemical (and multi-gram scale) synthesis of 1-O-β-feruloyl and 1-O-β-sinapoyl glucopyranoses.     

Synthesis of cis-3,4-diaryl α-methylene-γ-butyrolactams via sonochemical Barbier-type reaction

A series of cis-3,4-diaryl α-methylene-γ-butyrolactams were synthesized by the addition reaction of 3-phenylallyl bromide with N-tosyl aldimine via sonochemical Barbier-type reaction condition and then followed by the in situ intramolecular amidation. The cis-3,4-diaryl α-methylene-γ-butyrolactam was obtained as the sole regio- and stereoisomeric product when N-tosyl aldimine was used as the substrate whereas the monoaryl α-methylene-γ-butyrolactam was also generated when N-phenyl aldimine was used.     

Asymmetric synthesis of erythro-β-hydroxyasparagine

erythro-Hydroxyasparagine (eHyAsn, 1) occurs in a number of naturally occurring peptides and proteins. Previous syntheses have relied on enzyme-catalyzed reactions to produce relevant, optically active intermediates. We report herein a completely chemical synthesis that intercepts Boger’s synthesis of the diastereomer (tHyAsn, 4), utilizing a Sharpless asymmetric aminohydroxylation reaction to introduce the two stereocenters. Boc-HyAsn(OTBS)-OH (10) was coupled effectively with phenylalanine methyl ester using EDC/HOBt.     

The reactions of 3,7-dimethylenebicyclo[3.3.1]nonane, norbornadiene and cis,cis-1,5-cyclooctadiene with pentafluoro-λ-sulfanyl chloride

Radical transannular cyclizations of the non-conjugated dienes, such as 3,7-dimethylenebicyclo[3.3.1]nonane and norbornadiene with SF₅Cl upon UV-irradiation led to the corresponding SF₅-substituted 3,7-noradamantane and nortricyclanes with high yields. Radical reaction of cis,cis-1,5-cyclooctadiene with SF₅Cl led to a product of SF₅Cl addition to one of the diene double bonds either UV-irradiation or triethylborane were used for radical initiation.     

Alternative cocrystallization of “almost” enantiomers and true enantiomers in some cis-β-organocobalt salen-type complexes with α-amino acids

The reaction of a chiral cis-β-organocobalt salen-type complex, 1, racemic mixture of Δ and Λ enantiomers, with enantiomerically pure l-histidine and a non-chiral monocationic cobalt complex, 3, resulted quite unexpectedly in the cocrystallization of diastereomers. Each diastereomer is a dicobalt monocationic complex, where four positions around one metal center are occupied by the tetradentate ligand in a cis fashion, the remaining two positions being occupied by l-histidinate. Histidinate further axially coordinates the other Co atom through the nitrogen of the imidazole residue. The two diastereomers are related by a quasi-symmetry center. In this case, the opposite helical chirality of the metal complex 1 prevails over the identical configuration of the asymmetric carbon in the crystallization process and the diastereomers behave as if they were enantiomers.The reaction of the same cobalt complexes 1 and 3 with dl-histidine led to the formation of two pairs of enantiomers, which crystallized separately as racemic compound. Therefore, in this case, the chirality of the asymmetric center is the property that allows the mutual selective recognition of the “true” enantiomers and drives their cocrystallization.     

Intramolecular allylboration of γ-(ω-formylalkoxy)allylboronates for syntheses of trans- or cis-2-(ethenyl)tetrahydropyran-3-ol and 2-(ethenyl)oxepan-3-ol

3-Alkoxy-1-alkynes 4 were hydroborated with pinacolborane (HBpin) to give 3-alkoxy-1-alkenylboronates 5. The latter gave (E)-3-alkoxyallylboronates (8: (E)-(MeO)₂CHCH₂(CH₂)_nCH₂OCHCHCH₂Bpin, n=1-3) when they were subjected to iridium-catalyzed isomerization of the double bond. The corresponding (Z)-isomers 10 were synthesized by nickel-catalyzed isomerization of 5. Both allylboronates underwent intramolecular allylboration leading to the formation of trans-2-(ethenyl)tetrahydropyran-3-ol or 2-(ethenyl)oxepan-3-ol from 8 and the corresponding cis-isomers from 10 in the presence of Yb(OTf)₃ (20 mol%) in aqueous acetonitrile at 90°C.     

Diastereoselective synthesis of trans-trifluoromethyl-β-lactams and α-alkyl-β-trifluoromethyl-β-amino esters

The diastereoselective synthesis of β-lactams was examined from N-tosyl-1-chloro-2,2,2-trifluoroethylamine 3 and various nonactivated aliphatic acid chlorides in the presence of a Brønsted base. The mild reaction conditions allowed to get trifluoromethyl-β-lactams in good yields with high trans-diastereo selectivity. In addition, we also demonstrated that ring-opening of β-lactams easily provided α-alkyl-β-trifluoromethyl-β-amino esters.     

β-lactams from esters and silylimines: A revaluation. Synthesis of N-unsubstituted 4-alkyl-β-lactams

The first preparation of enolizable silylimines is reported. The “in situ” trapping of these species with lithium enolates of esters gives rise in fairly good yields to N-unsubstituted 4-alkyl-β-lactams.     

Chiral spiro-β-lactams from 6-diazopenicillanates

Chiral spiro-β-lactam derivatives have been prepared via stereoselective 1,3-dipolar cycloaddition of 6-diazopenicillanates. Using dipolarophiles such as acrylonitrile, acrylates or methyl vinyl ketone spiro-2-pyrazoline-β-lactams were obtained, whereas the cycloaddition with N-substituted-maleimides afforded spiro-1-pyrazoline-β-lactams. 6-Diazopenicillanates also reacted with electron-deficient alkynes to give the corresponding spiro-3H-pyrazole-β-lactam as single product. The observed stereoselectivity can be explained considering that the major product results from the addition to the less sterically hindered α-side of the β-lactam. Microwave-induced denitrogenation of spiro-1-pyrazoline-β-lactams allowed the stereoselective synthesis of novel spirocyclopropyl-β-lactams. The rationalization of the observed selectivity was supported by electronic structure calculations.     

Flavonol 3-O-robinobiosides and 3-O-(2″-O-α-rhamnopyranosyl)-robinobiosides from Sesuvium portulacastrum

Six new flavonol 3-O-robinobiosides and 3-O-(2″-O-α-l-rhamnopyranosyl)-robinobiosides, sesuviosides A-F, were isolated from the aerial portion of Sesuvium portulacastrum together with ecdysterone, adenosine, 2′-O-methyladenosine, and l-tryptophan. The structure elucidations were based on analyses of chemical and spectroscopic data including 1D and 2D-NMR. Sesuviosides A-F and their aglycones exhibited radical scavenging activity using DPPH and ORAC assays.     

Preferential formation of cis-4,5-dihydrooxazole derivatives via photoinduced electron transfer-initiated cyclization of N-acyl-α-dehydroarylalanine alkyl esters

The alkyl, aryl, and acyl substituent effects on the photoinduced electron transfer-initiated cyclization reaction of the title compounds (1) were investigated in polar solvents from mechanistic and synthetic points of view. The irradiation of (Z)-1 in methanol containing triethylamine (TEA) was found to quantitatively give cis- and trans-4,5-dihydrooxazole derivatives (cis-2 and trans-2). In addition to thermodynamic considerations for electron transfer and fluorescence quenching in the presence of TEA, acyl and aryl substituent effects on the emission intensity and photoreactivity of 1 confirmed the involvement of consecutive electron transfer reactions that form (E)-arylmethylene radical anion and (E)-N-acyl radical anion intermediates. It was also confirmed that the cyclization of the latter intermediate eventually leads to 2. On the basis of the finding that the selectivity for cis-2 is greatly increased with increasing the steric bulkiness of alkyl and aryl substituents in 1, it was concluded that steric hindrance of these substituents toward hydrogen shift in the cyclized biradical intermediate, precursor of 2, is responsible for the kinetically controlled hydrogen shift in this intermediate. A product composition analysis showed that the protic polar solvent, methanol, of hydrogen-bonding solvation ability is a most suitable solvent for the photocyclization reactions examined.     

Diastereoselective synthesis of novel 3-aryloxy/alkoxy-4-benzothiazolylpyrazolyl-β-lactams: Potential synthons for novel aminoacids/nanocopolymers

A fast, efficient, and diastereoselective synthesis of novel 3-oxo-4-benzothiazolylpyrazolyl-β-lactams is described. The reaction between 2-aryloxy/alkoxyacetic acid and novel benzothiazolylpyrazole-substituted imines afforded exclusive formation of trans-β-lactams. The scope of the reaction was investigated by varying different groups on substrates (R¹, R², R³, Z). All the novel compounds were characterized using various spectroscopic techniques such as FT-IR, ¹H NMR, ¹³C NMR, elemental analysis, and mass spectrometry in representative cases. No report has been listed in the literature for the synthesis of these types of β-lactam heterocycles so far.     

Stereoselective synthesis and Lewis acid mediated functionalization of novel 3-methylthio-β-lactams

A proficient etiquette for the stereoselective synthesis of novel 3-methylthio-β-lactams and their Lewis acid mediated functionalization is described. Treatment of 2-methylthioethanoic acid and appropriate imines in the Staudinger reaction leads to the stereocontrolled synthesis of novel trans-3-methylthio-β-lactams in excellent yields. cis-3-Chloro-3-methylthio-β-lactams, obtained from stereoselective chlorination of trans-3-methylthio-β-lactams using N-chlorosuccinimide (NCS) and AIBN, were subjected to Lewis acid (TiCl₄ or SnCl₄) mediated functionalization using various active aromatic, heterocyclic and aliphatic compounds (nucleophiles). This reaction provides an easy access to novel, stereoselective cis-3-monosubstituted-3-methylthio-β-lactams, which further undergo smooth desulfurization with Raney-nickel to afford C-3 cis- and trans-monosubstituted-β-lactams. The cis or trans configuration of the hydrogen/chloro/nucleophile substituent at C-3 was assigned with respect to C4–H.