Photoisomerizations of N4-hydroxycytosines

A series of N4-hydroxycytosines, unsubstituted or substituted with methyl groups at N3 or C5 atoms of the heterocyclic ring, was studied using the matrix-isolation method. Depending on the absence or presence of the methyl substituent at N3 or C5 atoms (or at both of them) the syn or anti form of the compounds (or a mixture of both forms) was trapped from the gas phase into a low-temperature matrix. Upon UV (lambda > 295 nm) irradiation of the matrixes the syn --> anti as well as the anti --> syn photoisomerization reactions were observed. The syn and anti isomers of N4-hydroxycytosines were identified by comparing their experimental IR spectra with the theoretical spectra calculated at the DFT(B3LYP)/6-31G(d,p) level. For the majority of the studied compounds, the UV induced reactions led to a photostationary state. The position of the final photostationary state was found to be a sensitive function of weak interactions of a studied N4-hydroxycytosine with the matrix environment: solid argon or solid nitrogen. However, not all of the studied photoisomerizations led to a classical photostationary state. For some of the investigated N4-hydroxycytosines, the position of the photostationary state was shifted very strongly in favor of the photoproduct, whereas for some others the position was shifted so strongly in favor of the starting isomer that no photoisomerization was observed. These experimental findings were elucidated by theoretical investigations of the potential energy surfaces of the ground (S0) and first excited (S1) electronic states of N4-hydroxycytosine. The crucial result of these calculations (carried out at the CASSCF level) was the localization of a conical intersection between S0 and S1 at a structure with perpendicular orientation of the hydroxylimino group with respect to the heterocyclic ring.     

Studies on the biosynthesis of paraherquamide A and VM99955. A theoretical study of intramolecular Diels-Alder cycloaddition

Intramolecular Diels-Alder reactions of 2-azadiene models have been studied quantum chemically at the B3LYP/6-31G level in order to elucidate the stereochemical features of the cyclization step involved in the biosynthesis of paraherquamide A and VM99955. These cycloadditions take place through concerted transition states associated with [4 + 2] processes. Analysis of the energies along the competitive paths reveals that while the cycloadditions of the oxindoles present a large anti selectivity, the indoles show a low syn selectivity for the formation of the C20 stereogenic center that is larger for the reduced tertiary amide form. The presence of the C14 methyl of the beta-methylproline ring produces a low hindrance along the reaction coordinate for the syn approach of the isoprene framework, in agreement with the low facial selectivity found experimentally. An analysis of the electrophilicity and activation parameters for experimental models of the inter- and intramolecular Diels-Alder reactions reveals several significant factors controlling these biosynthetic cyclizations. The results are in reasonable agreement with the available experimental data.     

Deuterium-labeling studies establishing stereochemistry at the oxypalladation step in Wacker-type oxidative cyclization of an o-allylphenol

The stereochemical pathway (syn or anti) of the oxypalladation step was studied in the palladium(II)-catalyzed Wacker-type cyclization of stereospecifically deuterated 6-(2-hydroxyphenyl)-3-deuteriocyclohexenes, cis-3-d-1 and trans-3-d-1, giving dihydrobenzofuran derivatives. The stereochemistry was determined to be syn in the reaction catalyzed by a dicationic palladium(II) catalyst generated from Pd(MeCN)4(BF4)2 and (S,S)-ip-boxax in the presence of benzoquinone in methanol, while it is mainly anti in the reaction catalyzed by PdCl2(MeCN)2 in the presence of a chloride ion.     

Different modes of cyclization in zoanthamine alkaloid system, bisaminal versus spiroketal formation

Bisaminal cyclization in the zoanthamine alkaloid system was strongly affected by the stereochemistry of the C4 methyl. While cyclization of the (4S)-methyl precursor gave only a bisaminal compound, cyclization of the (4R)-methyl isomer produced both spiroketal and bisaminal products.     

Synthesis of Polyketide Stereoarrays Enabled by a Traceless Oxonia‐Cope Rearrangement

Polyketide antibiotics bearing skipped polyols represent a synthetic challenge. A SiCl₄‐promoted oxonia‐Cope rearrangement of syn,syn‐2‐vinyl‐1,3‐diols was developed to forge an array of 1,5‐pentenediols, thus providing versatile motifs for the preparation of 1,2,3,5‐stereoarrays in a highly stereoselective manner. Further exploration with Sn(OTf)₂ realized the rearrangement of a cross‐aldehyde which tactically warrants the utility of the current approach to access complex polyketides. The origin of high stereoselectivity is attributed to a chairlike anti‐conformation of the oxonium ion intermediate.     

Total synthesis and structural elucidation of (-)-maurenone

[reaction: see text] The total synthesis of (2S,3S)-2,3-dihydro-6-[(1'S, 2'R)-2-hydroxy-1-methylbutyl]-3,5-dimethyl-2-[(1'S)-1-methylpropyl]-4H-pyran-4-one (3), the (-)enantiomer of the marine polypropionate, maurenone, was achieved in nine linear steps (13% overall yield) from (R)-2-benzylpentan-3-one ((R)-14) and (R)-2-benzoyloxypentan-3-one ((R)-15). Key fragments were synthesized using highly diastereoselective syn and anti boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic acid-promoted cyclization/dehydration was then used to install the gamma-dihydropyrone ring. Eight isomers of one enantiomeric series were synthesized by coupling two ketones with each of four aldehydes. Comparison of the 13C NMR data for the eight isomers with that reported for maurenone established the relative stereochemistry of the natural product.     

Synthesis and cytotoxic activity of derivatives of 6<Emphasis Type="Italic">Z</Emphasis>-acetylmethylenepenicillanic acid <Emphasis Type="Italic">tert</Emphasis>-butyl ester

The sulfoxide of 6Z-[2-(methoxyimino)propylidene]penicillanic acid tert-butyl ester and the sulfones of 6Z-[2-(hydroxyimino-, methoxyimino-, benzyloxyimino-, 2-bromo- and 4-bromobenzyloxyimino)-propylidene]penicillanic acid in the syn and anti forms have been synthesized by the condensation of the sulfoxide and sulfone of 6Z-acetylmethylenepenicillanic acid tert-butyl ester with hydroxylamine, methoxyamine, benzyloxyamine, 2-bromo- and 4-bromobenzyloxyamines. The syn and anti isomers of 3Z-(2-methoxyiminopropylidene)-4R-(benzothiazolyl-2-dithio)-2-oxoazetidinyl-1R-(2-propenyl)acetic acid tert-butyl ester were obtained by opening of the thiazolidine ring in 6Z-[2-(methoxy-imino)propylidene]-1-oxopenicillanic acid tert-butyl ester with 2-mercaptobenzothiazole. The 3Z-(2-methoxyiminopropylidene)-4R-(methylsulfonyl)-2-oxoazetidinyl-1-(2-propylidene)acetic acid tert-butyl ester was synthesized by the interaction of 1,8-diazobicyclo[5.4.0]undec-7-ene and methyl iodide with 6Z-[2-(methoxyimino)propylidene]-1,1-dioxopenicillanic acid tert-butyl ester. A dependence of the cytotoxic effect in relation to cancer and normal cells in vitro on the structure of the substituent in position 6 and the syn and anti isomerism of the oxyimino group was established for the synthesized compounds.     

Syntheses of syn and anti doublebent [5]phenylene

[structure: see text] The parent and dipropyl-substituted anti (1a,b) and syn doublebent (2a,b) [5]phenylenes have been assembled by CpCo-catalyzed double cyclization of regiospecifically constructed appropriate hexaynes. (1)H NMR, NICS, and an X-ray structural analysis of 1a reflect the aromatizing effect of double angular fusion on the central ring of the linear [3]phenylene substructure.     

Samarium(II)-promoted radical spirocyclization onto an aromatic ring

Samarium(II)-mediated spirocyclization onto an aromatic ring was achieved by the reaction of methyl 4-(4-oxoalkyl)benzoates with SmI(2) in the presence of i-PrOH and HMPA, yielding methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields. Utilizing this chemistry, spiro[3.5] and -[5.5] systems, and sterically congested spiro[4.5] systems, were easily synthesized. For the successful conversion, appropriate activation of the aromatic ring has proven to be extremely important: while an ester or amide functionality on the aromatic ring can promote the spirocyclization, a sulfonamide substituent causes ortho cyclization.     

Enantioselective organocatalytic intramolecular Diels-Alder reactions: a computational study

The diastereo- and enantioselectivity obtained experimentally by Christmann in the amine-catalyzed intramolecular Diels-Alder reaction of α,β-unsaturated carbonylic compounds were fully rationalized using density functional theory methods at the PBE1PBE/6-311+G** level. A polarizable continuum model was used to describe solvent effects. The selectivity is induced in the cyclization step, and while the enantioselectivity results from the syn/anti orientation around the C-N enamine bond, the diastereoselectivity mainly results from the syn/anti configuration of the substituents in the forming cyclopentane ring. The remarkable reaction rate experimentally observed when an external protic acid is used is attributed to the strong decrease in the activation energy of all steps needed for the enamine formation, while the external acid marginally influences the cyclization step. When hydrogen-bond-donor catalysts are used, the formation of one hydrogen bond in the cyclization step inverts the configuration and reduces the selectivity. The different behavior between dialdehydes and ketoaldehydes is suggested to be resulting from different reaction rates in the catalyst elimination step.     

Conformational studies by dynamic NMR. 86. Structure, stereodynamics, and cryogenic enantioseparation of the stereolabile isomers of o-dinaphthylphenyl derivatives

Static and dynamic stereochemistry of the hydrocarbon comprising a phenyl ring bearing two alpha-naphthyl substituents in the ortho positions, i.e., 1,2-di-(4-methyl-naphth-1-yl)-benzene 1, has been studied by a combination of variable temperature NMR, cryogenic HPLC, and MM calculations. Whereas in solution both syn (meso) and anti (chiral) forms were observed and the corresponding interconversion barrier was determined (Delta G(++) = 19.5 kcal mol(-1)), only the diastereoisomer anti was found to be present in the crystalline state (X-ray diffraction). When the molecule is rendered asymmetric by introduction of a nitro group in the phenyl ring as in 1,2-di-(4-methyl-naphth-1-yl)-4-nitrobenzene 2, the chiral syn and anti diastereoisomers are simultaneously present both in solution and in the solid state, albeit in different proportions. Cryogenic chromatography on a HPLC chiral stationary phase at 20 degrees C allowed the stereolabile diastereoisomers and the corresponding enantiomers to be separated.     

Acidolysis of poly(4-methyl-1,3-dioxolane)

The onset of decomposition of poly(4-methyl-1,3-dioxolane) was lowered to 70°C by 0.1 wt% p -toluene sulfonic acid from 170°C in the absence of acid to produce more than 81% yield of monomer. Protonation forms cyclic oxonium ion followed by depolymerization. Minor products are isomers of hydroxymethyl-2-hydroxyl-2-methyl ethyl ether and bis(2-hydroxyl-2-methyl ethoxyl)methane from rearrangements of the oxonium ions. The first order rate constant of acidolysis of poly(4-methyl-1-1,3-dioxolane) is about 8.5 kcal mol^?1, which is much smaller than about 17 kcal mol^?1 for the acidolysis of poly(1,3-dioxolane).     

The mechanistic puzzle of transition-metal-catalyzed skeletal rearrangements of enynes

Three pathways actually compete in metal-catalyzed cyclizations of enynes in which the metal selectively activates the alkyne: an endocyclic process and two exo-cyclizations, one proceeding by anti attack of the alkene and a second one resulting in a syn addition. Although cyclobutenes may be formed in transition-metal-catalyzed cyclization of some enynes, particularly, 1,7-enynes, these compounds are not necessarily the intermediates in the skeletal rearrangement. Cyclobutenes are formed by ring expansion of syn-cyclopropyl metal-carbenes formed in the syn pathway.     

l, 9-Substituted fluorenes

The synthesis of 2-methyl (phenyl)-2, 3H-pyridazino-[4, 5, 6-m- l] fluorene-3-methylthionium methylsulfates and of derivatives with substituents in the fluorene ring, is described. Reaction of the latter with heterocyclic hydrazones, and also with compounds containing an active methylene or methyl group, gives cyanine dyes. The electronic spectra of the dyes are measured.For Part III see [3].     

Stacking interactions between nitrogen-containing six-membered heterocyclic aromatic rings and substituted benzene: studies in solution and in the solid state

The stacking interactions between an aromatic ring and a pyridine or a pyrimidine ring are studied by using a series of triptycene-derived scaffolds. The indicative ratios of the syn and anti conformers were determined by variable-temperature NMR spectroscopy. The syn conformer aligns the attached aromatic ring and the heterocycle in a parallel-displaced orientation while the anti conformer sets the two rings apart from each other. Comparing to the corresponding control compounds where a benzene ring is in the position of the heterocycle, higher attractive interactions are observed as indicated by the higher syn/anti ratios. In general, the attractive interactions are much less sensitive to the substituent effects than the corresponding nonheterocycles. The greatest attractive interactions were observed between a pyrimidine ring and a N,N-dimethylaminobenzene, consistent with a predominant donor-acceptor interaction. The interactions between a pyridine ring and a substituted benzene ring show that the pyridine is comparable to that of a NO2- or a CN-substituted benzene ring except for the unpredictable substituent effects.     

Synthesis of 3,9-dihydro-3,9-dioxo-2H-indeno[2,1-c] pyridine-4-carbonitriles

The annelation of α-pyridones to five membered ring systems is demonstrated by the synthesis of a series of 2-azafluorenones. These tricyclic heterocycles could be optionally substituted with methyl or phenyl groups by varying the orthoester reagent in the cyclization reaction. The conversion of the resultant cyanopyridones to pyridonecarboxamides and their N-methyl homologs is also described.     

Synthesis and bioactivity of novel coumarin derivatives

A series of coumarin derivatives (6-8) containing (E)-methyl 2-(methoxyimino)-2-phenylacetate, (E)-2-(methoxyimino)-N-methyl-2-phenylacetamide and methyl methoxy(phenyl)carbamate were synthesized from substituted resorcinols (1) and substituted beta-keto esters (2) as starting material via cyclization and condensation reactions. The test results indicated that (E)-methyl 2-{2-[(3-hexyl-4-methyl-coumarin-7-yloxy)methyl]phenyl}-2-(methoxyimino)acetate (6f) was the optimal structure with good fungicidal activity against cucumber grey mold (CGM) giving 100% control at 100 mg L(-1) concentration, much higher than that of coumoxystrobin. Methyl 2-[(3,4-dimethyl-coumarin -7-yloxy)methyl]phenyl(methoxy)carbamate (8a) was another optimal structure with good fungicidal activity against wheat powdery mildew (WPM) showing 100% control at 50 mg L(-1) concentration, at the same level as that of the commercial kresoxim-methyl, and very significantly higher than that of coumoxystrobin (no control against WPM at 400 mg L(-1)).     

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.     

Highly diastereoselective cyanation of methyl ketimines obtained from (R)-glyceraldehyde

[reaction: see text] Addition of trimethylsilyl cyanide to ketimines derived from (R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ketone to generate a quaternary stereocenter has been achieved with high yields and excellent diastereoselectivity. The stereoselectivity was found to be temperature and solvent dependent. The beta-hydroxy-alpha-amino nitrile of syn configuration was the major compound in kinetically controlled reactions, whereas the anti stereoisomer was obtained in excess in thermodynamically controlled reactions. Double stereodifferentiation under kinetic control conditions was successful, and the cyanation reaction occurred with complete syn diastereoselectivity using the matched pair. The versatility of the resulting amino nitrile as a synthetic intermediate was tested by performing the synthesis of orthogonally protected (R)-(2-aminomethyl)alanine.     

Total synthesis and biological evaluation of +-kalkitoxin, a cytotoxic metabolite of the cyanobacterium Lyngbya majuscula

+-Kalkitoxin, a metabolite of the marine cyanobacterium Lyngbya majuscula, was synthesized from (R)-2-methylbutyric acid, (R)-cysteine, and (3S, 4S, 6S)-3,4,6-trimethyl-8-(methylamino)octanoic acid. A key step in the synthesis was installation of the anti,anti methyl stereotriad by means of a tandem asymmetric conjugate addition of an organocopper species to an alpha,beta-unsaturated N-acyl oxazolidin-2-one followed in situ by alpha-methylation of the resultant enolate. The thiazoline portion of kalkitoxin was assembled by titanium tetrachloride catalyzed cyclization of a vinyl substituted amido thiol.