Search

A new approach to form iminoisocoumarins from readily available and stable 2-alkynylbenzamides was developed by using a tandem copper-catalyzed N-arylation and regioselective 6-endo-dig cyclization in the presence of diaryliodonium salts, a copper catalyst, and 2,6-di-tert-butylpyridine. The arylation occurred at the nitrogen atom rather than the oxygen atom of the amide group, the alkynyl carbon, or the benzene ring of the benzamide. Cyclization occurred through a preferential nucleophilic attack by the oxygen rather than the nitrogen atom of the amide group to produce iminoisocoumarin derivatives in good to moderate yields.

An enantioselective Reformatsky reaction has been developed for the reaction of ethyl dibromofluoroacetate (1) with an imine. This method represents the first ligand-promoted imino-Reformatsky approach to use a halofluoroacetate. The use of an amino alcohol ligand allowed for the preparation of enantioenriched α-bromo-α-fluoro-β-lactams in good yields with enantioselectivities up to 96% ee. This process also provided access to β-lactam rings bearing two stereogenic centers.

A highly diastereoselective cross-coupling reaction of an α-bromo-α-fluoro-β-lactam with a wide range of aryl Grignard reagents was catalyzed by Ni/bis(oxazoline) in yields of up to 98%. The product was obtained diastereoselectively as an anti-isomer. This is the first successful α-arylation of an α-fluoro-β-lactam to produce diverse α-aryl-α-fluoro-β-lactams.

A new approach to form iminoisocoumarins from readily available and stable 2-alkynylbenzamides was developed by using a tandem copper-catalyzed N-arylation and regioselective 6-endo-dig cyclization in the presence of diaryliodonium salts, a copper catalyst, and 2,6-di-tert-butylpyridine. The arylation occurred at the nitrogen atom rather than the oxygen atom of the amide group, the alkynyl carbon, or the benzene ring of the benzamide. Cyclization occurred through a preferential nucleophilic attack by the oxygen rather than the nitrogen atom of the amide group to produce iminoisocoumarin derivatives in good to moderate yields.

Cu- and Rh-catalyzed coupling reactions of 2-azabicyclo[2.2.1]hept-5-en-3-ones (1) with arylboronic acids were successful carried out under microwave irradiation conditions and yielded N-aryl and C-aryl derivatives of 1, respectively.

The chemoselective and diastereoselective synthesis of syn-α-bromo-α-fluoro-β-lactams was achieved using the diethylzinc-mediated Reformatsky-type reaction of ethyl dibromofluoroacetate with imines. The reaction led to diastereomerically pure β-lactams in good to moderate yields (up to 78% yield) with only small amounts of aziridine derivatives. Noncyclized 3-amino-2-bromo-2-fluoro carboxylic esters, usual Reformatsky adducts, were not formed. In contrast, reactions carried out under typical Reformatsky conditions using zinc metal were poorly chemoselective, leading to mixtures of β-lactams and aziridine derivatives.

It was shown that dichloramine-T (1) reacted with cyclohexene in acetonitrile to give N1-(2-chlorocyclohexyl) amidine 2a and N-(2-chlorocyclohexyl)acetamide (3) via the competitive addition of acetonitrile and N-chloro-N-tosylamino anion to cyclohexenechloronium ion. This reaction can be catalyzed by Cu(OAc)2, primarily affording 2a. Furthermore, the resulting 2a can be cyclized to benzimidazol 14a in good yield by treating with KOH in dioxane.

Starting from ortho-alkynylbenzaldehydes and ortho-alkynylanilines, In(OTf)3-catalyzed synthesis of ring-condensed heteroaromatic compounds was developed via a domino intramolecular nucleophilic attack/intermolecular cycloaddition/dehydration reaction.

Aryl alkyl alkynes reacted with N-iodosuccinimide (NIS) and trimethylsilyl azide (TMSN3), leading to α,α-diazidoketones via the regioselective addition of IN3 to alkynes. Huisgen cyclization of α,α-diazidoketones generated bis-triazole compounds.

Aryl alkyl alkynes reacted with N-iodosuccinimide (NIS) and trimethylsilyl azide (TMSN3), leading to α,α-diazidoketones via the regioselective addition of IN3 to alkynes. Huisgen cyclization of α,α-diazidoketones generated bis-triazole compounds.

The relative stabilities of synthetically useful 2,3-cis/trans pairs of 2,3-disubstituted aziridines were investigated theoretically by performing molecular orbital calculations at the MP2/6-31G**/RHF/6-31G** level of theory. The results showed clearly that a functional group on the nitrogen atom of the aziridine ring plays a very important role in conjunction with the relative stabilities of these pairs of isomers. There is a tendency that the 2,3-cis isomer bearing tetrahedral structure on the aziridine nitrogen is preferable. Bulky substituents such as a phenyl group on aziridine atoms can also affect the relative stability sterically.

Organocopper-mediated alkylation of β-( N-Boc-2-oxo-1,3-oxazolidin-5-yl)-α,β-enoates has been intensively investigated. Alkylation proceeded regio- and stereoselectively by anti- SN2′ ring-opening to provide a new route to the synthesis of ψ[( E)-CHCH]-, ψ[( E)-CMeCH]- and ψ[( E)-CMeCMe]- type alkene dipeptide isosteres from chiral amino acid derivatives. These resulting agents are potential mimetics of type II and type II′ β-turn substructure.

The enantiopure synthesized bromolactams can be further converted to α-aryl-β-lactams (V) by asymmetric Ni-catalyzed Kumada coupling in good yields.

Chemical examination of the MeOH extract of the root of Taraxacum officinale, which exhibited inhibitory activity on the formation of leukotriene B4 from activated human neutrophils, has resulted in the isolation of 14-O-β-D-glucosyl-11,13-dihydro-taraxinic acid (1) and 14-O-β-D-glucosyl-taraxinic acid (2). The absolute stereostructure of 1 has been established by X-ray chrystallographic examination.

Treatment of acyclic conjugated (η4-4–7)-triene Fe(CO)3 complexes bearing an electron-withdrawing group at a terminal position with a base such as KN(SiMe3)2 and NaH promoted 1,3-migration of an Fe(CO)3 group on the triene, giving (η4-2–5)-triene Fe(CO)3 complexes. The 1,3-migration of an Fe(CO)3 group is revealed to proceed in a stereospecific manner.

Whereas treatment of the allylic mesylates of N -protected 2-alkyl-4-amino-( E )-2-alken-1-ols with sodium hydride in DMF yields exclusively the corresponding 2,3- trans -2-alkenyl-3-alkylaziridines, exposure of the methyl carbonates of N -protected 2-alkyl-4-amino-( E )-2-alken-1-ols to Pd(PPh 3 ) 4 (5–20 mol%) in THF or 1,4-dioxane affords predominantly the corresponding 2,3- cis -2-alkenyl-3-alkylaziridines. These reactions can be used to synthesize either of two diastereomers from single common intermediates.

Amino allenes have been synthesized from 2-ethynylaziridines via organocopper-mediated reactions. Whereas treatment of enantiomerically pure (2 R,3 S)-2,3-trans-3-alkyl-2-ethynylaziridines with RCu(CN)M (M = Li or MgX) yield exclusively (S,S)-allenylamines in high yields, isomeric (2 S,3S)-2,3-cis-3-alkyl-2-ethynylaziridines afford (S,R)-allenylamines in comparable high yields.

Based on the experimental evidence that Na(+)-Ca(2+) exchange participates in the regulation of intracellular Ca(2+) concentration in pancreatic beta-cells, we construct a mathematical model for the cyclic spike-bursts and oscillations of intracellular Ca(2+) concentration. In our model, an increase in ATP concentration by the stimulation of glucose metabolism leads to the closure of ATP-sensitive K(+) channels (K(ATP) channels) and gradual depolarization to the threshold of voltage-gated Ca(2+) channels. Spikes are generated by the alternate activation of voltage-gated Ca(2+) and K(+) channels, causing Ca(2+) entry. The accumulated Ca(2+) ions are extruded by Na(+)-Ca(2+) exchange and Ca(2+) active transport. An increase in Na(+) influx through Na(+)-Ca(2+) exchangers results in a rise in intracellular Na(+) concentration and the activation of Na(+)-K(+) active transport. The consumption of ATP during the process of Ca(2+) extrusion leads to the opening of K(ATP) channels and repolarization. The present model could reproduce the main experimental features of the spike-burst activity and Ca(2+) oscillations following changes in the extracellular glucose concentration. As the rate of ATP production increases, the spike-burst pattern changes from bursts with long silent phases to continuous spiking. Changes in the pattern of electrical activity produced by the alteration of extracellular Na(+) and K(+) concentrations and the addition of ouabain could be reproduced in the present model.

The enantiomers, (R)-(-)-1 and (S)-(+)-1, of (+/-)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide [(+/-)-1] were prepared from optically active benzyl 4-acetylamino-2,3-dihydro-2-methylbenzo[b]furan-7-carboxylate [(R)-(+)-6, (S)-(-)-6], respectively. The requisite (R)-(+)-6 and (S)-(-)-6 were prepared by large-scale preparative HPLC on chiral stationary phases (CSPs). The absolute configuration of (S)-(+)-1 was determined by single crystal X-ray analysis. The serotonin 5-HT4 receptor agonistic activity of (S)-(-)-1 hemifumarate (SK-951) which was hemifumarate of (S)-(+)-1 was about twice that of the other enantiomer (R)-(+)-1 hemifumarate which was hemifumarate of (R)-(-)-1.

Palladium(0)-catalyzed reactions of N-methanesulfonyl- or N-(arenesulfonyl)-3-alkyl-2-vinylaziridines reveal that 2,3-cis-isomers are more stable than the corresponding 2,3-trans-isomers in accord ...

Infrared absorption spectrum of formamide for the matrix isolated species has been simulated using the extended molecular mechanics method employing a force field which includes equilibrium bond charges and charge fluxes as coulomb potential parameters. The features of the simulated spectra are generally in good agreement with the observed spectra. The vibrational frequencies of several deuterated isotopomers of formamide have been calculated in satisfactory agreement with the experimental frequencies. The thermodynamic quantities, dipole moment and its orientation and equilibrium structure of formamide have also been successfully computed.

A highly diastereoselective cross-coupling reaction of an α-bromo-α-fluoro-β-lactam with a wide range of aryl Grignard reagents was catalyzed by Ni/bis(oxazoline) in yields of up to 98%. The product was obtained diastereoselectively as an anti-isomer. This is the first successful α-arylation of an α-fluoro-β-lactam to produce diverse α-aryl-α-fluoro-β-lactams.

Oxidative coupling reactions of the stereochemically defined S -tetrahydroxybinaphthalene derivative gave a separable mixture of two diastereomers of the quaternaphthalenes of S , S , S and S , R , S configurations, whose stereostructures were confirmed by an alternative chemical transformation through the ternaphthalenes as well as the X-ray structure analysis. The CD spectra of the corresponding diastereomers were indicative of the stereochemistry across the axis.

Regio- and stereo-selective synthesis of (E)-alkene dipeptide isosteres has been successfully achieved by exposing both (E)- and (Z)-N-(4-methylphenyl)sulfonyl-γ,δ-epimino-α,β-enoates to organocopper reagents at –78 °C for 30 min.

The crystal structures of the isovaline-containing dipeptides, Boc-D-Iva-L-Pro-NHBzl 4 and Boc-L-Iva-L-Pro-NHBzl 5 were determined by X-ray diffraction. The diastereoisomeric peptides adopt intramolecular hydrogen-bonded β-turn conformations closely similar to each other (4:φIva–51°, ψIva–38°, φPro–70° and ψPro–17° and 5: φIva–53°, ψIva–35°, φPro–72° and ψPro–14°). The Pro ring of each peptide is in Cγ-exo conformation. These conformations are essentially the same as those in the reported crystal structures of the Aib-L-Pro sequence possessing an NH group directly attached to the carbonyl of the L-Pro, indicating that replacement of either one of the two methyl groups of the Aib moiety with an ethyl group does not cause any significant change in the β-turn conformation of the Aib-L-Pro sequence in the crystalline state.CD spectral analysis of the terminal chromophoric group-carrying peptides Dnp-Gly-X-L-Pro-Gly-pNA (X = Aib 6 and D/L-Iva 7/8) has shown that these three tetrapeptides in CHCl3 and THF solutions also adopt a β-turn-type conformation. CD spectra of glycolic acid residue-containing analogues in place of the fourth Gly residue revealed a lack of β-turn tendency in these analogues, indicating the importance of intramolecular hydrogen bonding for the β-turn conformation of the central dipeptide moieties. The results are consistent with the reported unturned crystal structures of Aib-L-Pro arid D/L-Iva-L-Pro sequence-containing peptides lacking the NH group which directly follows the Pro residue available for intramolecular hydrogen bonding.

Treatment of alkynylbenzenes with NIS and carboxylic acids results in regio- and stereoselective formation of iodoalkenes.

Vibrational spectra of benzene and benzene-d6 in the gas and liquid phase have been simulated by a molecular mechanics method including the calculation of equilibrium structures, thermodynamic quantities, normal frequencies and vibrational transition probabilities. The potential parameters have been estimated by referring to the observed frequencies of benzene, benzene-d6 and 1,3,5-benzene-d3 and also to results of ab initio calculations. Four and ten independent parameters are required, respectively, for elucidating the infrared absorption and Raman intensities of these compounds in the gas and liquid phase. The infrared absorption spectrum of benzene-d1 is reproduced well by using the potential and the intensity parameters estimated for benzene and benzene-d6. The change of relative band intensities on the phase change has been elucidated in terms of the change of various intensity parameters.

Several chiral 2-nitro-1-sulfinylalkenes were prepared and examined for their utility as dienophiles for asymmetric [4+2] cycloaddition. Trisu- bstituted dienophiles (3-6) undergo distereoselective cycloaddition with cyclopentadiene in the presence of Lewis acids. Even the tetrasubsti- tuted chiral sulfinyl dienophiles (1) and (2) could be coerced into un- dergoing [4+2] cycloaddition to afford the cycloadducts in high yield without concomitant elimination if the reaction was conducted under high pressure. Generally, the Z-sulfinyl dienophiles (1-4) showed higher diastereo- and exdo/exo-selectivity than the E-dienophiles (5) and (6)

X-Ray crystallographic analysis of two steroid derivatives, 5α,6α-epoxyphysalin B and 2,3-dihydrophysalin B, have been undertaken, revealing their closely similar crystal structures to each other. Their 1H NMR spectra, as well as that of the parent compound physalin B, a 13,14-seco-16,24-cyclosteroid from Physalis alkekengi, have been analyzed based on the crystal structures of these derivatives.

Regio- and stereoselective cohalogenation of alkynes with NXS (X = Br, I) was achieved, and the stereoselectivity of the resulting alkenes was dependent on the substituent on the alkyne. Cohalogenation and successive cross-coupling gave multisubstituted enol esters in a one-pot process.

The crystal structures of the isovaline (Iva) containing dipeptides, Boc-D-Iva-L-Pro-OBzl and Boc-L-Iva-L-Pro-OBzl, were determined by x-ray diffraction. The diastereomeric peptides were shown to adopt unturned conformations closely similar to each other (phi Iva 52 degrees, psi Iva 46 degrees, phi Pro -65 degrees, and psi Pro 143 degrees for D-Iva-L-Pro sequence and phi Iva 52 degrees, psi Iva 44 degrees, phi Pro -63 degrees, and psi Pro 148 degrees for L-Iva-L-Pro sequence). The Pro ring of each peptide was in C gamma-endo conformation. The unusually large angle CIva-NPro-C delta Pro values (131 degrees in both peptides) were observed, that was due to steric repulsion between the delta-methylene of Pro and the alkyl side chain of Iva residue. These conformations were essentially the same as that of the corresponding alpha-aminoisobutyric acid (Aib)-containing peptide Boc-Aib-L-Pro-OBzl. The result has demonstrated that replacement of either one of the two methyl groups of the Aib residue in Boc-Aib-L-Pro-OBzl with an ethyl group does not cause any significant change in the unturned conformation of the dipeptide.

An extended molecular mechanics calculation of thermodynamic quantities, structure parameters, infrared absorption spectra, and Raman spectra of normal fatty acids was carried out on the basis of t...

Under microwave irradiation conditions, catalytic amounts of Cu(II) are sufficient to catalyze the N-arylation of bicycle (I) and analogues, whereas in the presence of a rhodium catalyst C-arylation occurs.

The Diels-Alder reaction of chiral 2-alkylsulfinyl-1-nitroalkene 1 and Danishefsky's diene (2) afforded adducts 3 and 4 in good chemical yield with a high enantiomeric excess, while diastereomeric nitroalkene 7 gave 8 and 9 , enantiomeric to 3 and 4 , respectively

Using the high pressure technique, asymmetric Diels-Alder reaction utilizing chiral 2-nitro-1-sulfinylolefins and dienes proceeded smoothly to give highly functionalized cyclohexene derivatives with satisfactory chemical yield and high diastereomeric excess.

The asymmetric total synthesis of thienamycin-like γ-lactam 1 and its analogue 2 has been accomplished by utilising highly diastereoselective alkylation of tin(II) enolate 5 on acyl imine obtained in situ from chiral 3-substituted 5-acetoxypyrrolidin-2-one 3.

New 5-deazaflavinocyclophane with planar chirality, a novel flavoenzyme model, has been synthesized. This compound provides the first example for selective diastereoface-differentiation during its own reduction and oxidation.

The stereoselective synthesis of biologically important vinylglycine derivatives by reaction of homochiral 4-methoxycarbonyl-5-vinyloxazolidin-2-ones with organocopper reagents is described; 4,5-trans-oxazolidin-2-one 6 yields (E)-vinylglycines as the major products by treatment with the ‘higher order’ cyanocuprate–BF3 reagents or trialkylzincates in the presence of cuprous cyanide, 4,5-cis-oxazolidin-2-one 10 affords only the desired (E)-vinylglycines.

Several chiral 2-nitro-1-sulfinylalkenes were prepared and examined for their utility as dienophiles for asymmetric [4+2] cycloaddition. Trisu- bstituted dienophiles (3-6) undergo distereoselective cycloaddition with cyclopentadiene in the presence of Lewis acids. Even the tetrasubsti- tuted chiral sulfinyl dienophiles (1) and (2) could be coerced into un- dergoing [4+2] cycloaddition to afford the cycloadducts in high yield without concomitant elimination if the reaction was conducted under high pressure. Generally, the Z-sulfinyl dienophiles (1-4) showed higher diastereo- and exdo/exo-selectivity than the E-dienophiles (5) and (6)

Regio- and stereo-selective synthesis of (E)-alkene dipeptide isosteres has been successfully achieved by exposing both (E)- and (Z)-N-(4-methylphenyl)sulfonyl-γ,δ-epimino-α,β-enoates to organocopper reagents at –78 °C for 30 min.

The stereospecific synthesis is described of the first member of a new class of C-nucleoside analogues in which the sugar ring is replaced with a 1, 3-thiazolidine ring. The 1, 3-thiazolidin-2-yl analogues (1) and (2) of pseudouridine were prepared stereospecifically via condensation of L or D-cysteine with a formylated nucleobase.

The chemoselective and diastereoselective synthesis of syn-α-bromo-α-fluoro-β-lactams was achieved using the diethylzinc-mediated Reformatsky-type reaction of ethyl dibromofluoroacetate with imines. The reaction led to diastereomerically pure β-lactams in good to moderate yields (up to 78% yield) with only small amounts of aziridine derivatives. Noncyclized 3-amino-2-bromo-2-fluoro carboxylic esters, usual Reformatsky adducts, were not formed. In contrast, reactions carried out under typical Reformatsky conditions using zinc metal were poorly chemoselective, leading to mixtures of β-lactams and aziridine derivatives.

The enantiomers, (R)-(-)-1 and (S)-(+)-1, of (+/-)-4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide [(+/-)-1] were prepared from optically active benzyl 4-acetylamino-2,3-dihydro-2-methylbenzo[b]furan-7-carboxylate [(R)-(+)-6, (S)-(-)-6], respectively. The requisite (R)-(+)-6 and (S)-(-)-6 were prepared by large-scale preparative HPLC on chiral stationary phases (CSPs). The absolute configuration of (S)-(+)-1 was determined by single crystal X-ray analysis. The serotonin 5-HT4 receptor agonistic activity of (S)-(-)-1 hemifumarate (SK-951) which was hemifumarate of (S)-(+)-1 was about twice that of the other enantiomer (R)-(+)-1 hemifumarate which was hemifumarate of (R)-(-)-1.

Amino allenes have been synthesized from 2-ethynylaziridines via organocopper-mediated reactions. Whereas treatment of enantiomerically pure (2 R,3 S)-2,3-trans-3-alkyl-2-ethynylaziridines with RCu(CN)M (M = Li or MgX) yield exclusively (S,S)-allenylamines in high yields, isomeric (2 S,3S)-2,3-cis-3-alkyl-2-ethynylaziridines afford (S,R)-allenylamines in comparable high yields.

Whereas treatment of the allylic mesylates of N -protected 2-alkyl-4-amino-( E )-2-alken-1-ols with sodium hydride in DMF yields exclusively the corresponding 2,3- trans -2-alkenyl-3-alkylaziridines, exposure of the methyl carbonates of N -protected 2-alkyl-4-amino-( E )-2-alken-1-ols to Pd(PPh 3 ) 4 (5–20 mol%) in THF or 1,4-dioxane affords predominantly the corresponding 2,3- cis -2-alkenyl-3-alkylaziridines. These reactions can be used to synthesize either of two diastereomers from single common intermediates.

Seven novel cycloartane-type triterpenes were isolated from Combretum quadrangulare , and their structures were elucidated on the basis of spectral analysis. All these compounds were tested for their cytotoxicity against murine colon 26-L5 carcinoma cells. Methyl quadrangularate B ( 2 ) and methyl quadrangularate D ( 4 ) exhibited potent cytotoxicity having ED 50 values 9.54 and 5.42 μM, respectively.