Fluorescent detection of carbon-carbon bond formation

We have developed a new spectroscopic system for detecting carbon-carbon bond formation by fluorescence to enhance high-throughput catalyst screening and rapid characterization of catalysts on a small scale. Fluorogenic substrates composed of a fluorophore possessing an amino group are readily prepared as amides of alpha,beta-unsaturated carbonyl compounds and generally exhibit low fluorescence, while Michael or Diels-Alder reactions of these fluorogenic substrates provide products of significantly increased fluorescence. The product's fluorescence is approximately 20- to 100-fold higher than that of the substrate. The assay system was validated by screening potential catalysts of the Michael reaction and in solvent optimization experiments. The covalent combination of fluorophores possessing an amino group with alpha,beta-unsaturated carbonyl compounds should provide a diverse range of fluorogenic substrates that may be used to rapidly screen catalysts and to optimize reaction conditions.     

Organocatalytic asymmetric allylic carbon-carbon bond formation

Organocatalytic allylic C-C bond-forming addition of activated alkylidenes to alkyl and aryl nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine catalysts are used to give allyl intermediates which exhibit gamma-selectivity in the C-C bond forming step. The reactions proceed with up to >99:1 syn:anti ratio for both the alkyl- and aryl nitroalkenes with up 96% and 98% ee, respectively. The products of this conjugate addition are transformed into a range of intermediates, such as optically active conjugated dienes and 1-substituted tetralones, which are difficult to access via alternative methods.     

The role of water in lanthanide-catalyzed carbon-carbon bond formation

Luminescence-decay measurements in combination with high-performance liquid chromatography analyses were used to study the relationship between rates of catalysis and water-coordination numbers of europium-based precatalysts in the aqueous Mukaiyama aldol reaction. A correlation between reactivity and water-coordination number was observed and is reported here.     

Fast carbon-carbon bond formation by a promiscuous lipase

Lipase B from Candida antarctica was redesigned to catalyze the promiscuous reaction of carbon-carbon bond formation. Mutation of the catalytic serine to alanine afforded a mutant that catalyzed Michael additions of 1,3-dicarbonyls to alpha,beta-unsaturated carbonyl compounds at high specific rates, such as 4000 s-1. The enzyme-catalyzed Michael addition reaction followed saturation kinetics and showed substrate inhibition. The designed enzyme showed high rate enhancements with a catalytic proficiency higher than 108, which is on the same level as that observed for enzymes with native substrates.     

Consecutive carbon-carbon bond formation approach in tandem cyclization reactions

The conventional tandem cyclization reactions involve the formation of alternating carbon-carbon bonds, whereas the newly developed cyclization reactions involve the formation of consecutive carbon-carbon bonds, in which N-aziridinylimines have been utilized as geminal radical acceptor and donor equivalents in a single operation. This unprecedented tandem cyclization approach becomes feasible by the successful generation of 5- and 6-membered ring radicals by radical cyclizations of N-aziridinylimines. The same notion can be applied to the anionic cyclizations of N-aziridinylimines, thereby allowing anionic consecutive carbon-carbon bond formation. This approach has great synthetic potential, particularly for the construction of quaternary carbon centers, and it provides highly efficient routes for the synthesis of natural products.     

Heteroatom-facilitated ortho carbon-carbon bond formation in nucleophilic F-phenyl substitution

Regioselective ortho-substitutions in F-phenyl carboxylic acid and its derivatives were accomplished by conversion into F-phenyloxazoline (1a) or F-phenyldihydrooxazine (1b), followed by nucleophilic displacements of one or two ortho-fluorines with organometallic reagents in nonpolar solvents. Requisite 1a and 1b were readily prepared by treating F-benzoyl chloride with 2-amino-2- methyl-1-propanol, and F-benzonitrile with 2-methyl-2,4- pentanediol, respectively. Treating 1a or 1b with either Grignard reagents (CH₃MgI, C₂H₅MgBr, nC₃H₇MgBr) or organolithium reagents (CH₃Li, nC₄H₉Li) gave appreciable yields of the 2-substituted F-phenyloxazoline (2a) or F- phenyldihydrooxazine (2b), while no 4-substituted ones were identified. The use of an excess of the organometallic reagents afforded 2,6-disubstitution in preference to 2,4-disubstitution. The ortho-directing effects here observed are conceivably caused through a mechanism like that suggested by Meyers(Tetrahedron Lett., 223(1978)).

     

碳-碳重键的新合成方法学研究

本研究工作包括下列8方面:(1)一种不同于Wittig反应的新的烯化方法,含氟β-酮基磷盐在有机合成中的应用。(2)"一锅"法的碳-碳双键形成反应。(3)一种新的叶立德阴离子的形成方法。(4)消去三苯基胂形成碳-碳双键的合成方法学。(5)立体选择性地控制合成(Z)或(E)-碳-碳双键化合物的新方法。(6)亲核试剂对全氟酰基膦酸酯进攻为基础的新合成方法学。(7)还原烯化反应的合成方法学。(8)含氟碳-碳叁键的合成方法学。     

A carbon-carbon bond formation using endoperoxides of 1,2-dihydropyridines

A novel type of a nucleophilic substitution on the piperidine ring was achieved by a stannous chloride-effected reaction of endoperoxides of N-alkoxycarbonyl-1,2-dihydropyridines with various kinds of carbon nucleophiles.     

An oxidative carbon-carbon bond formation system in cycloalkane-based thermomorphic multiphase solution

A selective anodic oxidation system in which a carbocation intermediate is generated exclusively by use of a temperature-controlled multiphase solution to separate the different stages of the reaction from each other and from the products is described. The formation of a thermomorphic middle layer in an electrolytic solution composed of c-Hex and LPC/MeNO2 results in enhanced interaction between aliphatic alkenes and polar unstable cation.     

Palladium-catalyzed sequential carbon-carbon bond cleavage/formation producing arylated benzolactones

3-(2-Hydroxyphenyl)cyclobutanones react with aryl bromides in the presence of palladium catalysts to afford 4-arylmethyl-3,4-dihydrocoumarins in high yields through a sequence involving carbon-carbon bond cleavage and formation. In the case of the reaction with 2-(2-hydroxyphenyl)cyclobutanones, five- or seven-membered lactones were produced depending on the presence of an additional substituent at the 2-position.     

Asymmetric direct vinylogous carbon-carbon bond formation catalyzed by bifunctional organocatalysts

The bifunctional chiral thiourea-tertiary amine organocatalysts have been applied to a direct asymmetric vinylogous Michael addition of α,α-dicyanoolefins to nitroolefins with 2-10 mol % catalyst loadings. The electronic properties of the thiourea-based catalysts have significant influences on this reaction. Moderate to excellent enantioselectivities (57-95% ee) have been achieved with low to good isolated yields through fine tuning the structures of the bifunctional organocatalysts. Much better ees were obtained for some α,α-dicyanoolefinic substrates compared with that catalyzed by modified cinchona alkaloids.     

carbon-carbon bond formation between 1,3-dienes and electron deficient alkenes

1,3-Dienes and electron deficient alkenes are coupled in a one pot carbon-carbon bond formation reaction under mild conditions.     

A theoretical study of carbon-carbon bond formation by a Michael-type addition

A theoretical study of the Michael-type addition of 1,3-dicarbonyl compounds to α,β-unsaturated carbonyl compounds has been performed in the gas phase by means of the AM1 semiempirical method and by density functional theory (DFT) calculations within the B3LYP and M06-2X hybrid functionals. A molecular model has been selected to mimic the role of a base, which is traditionally used as a catalyst in Michael reactions, an acetate moiety to modulate its basicity, and point charges to imitate the stabilization of the negative charge developed in the substrate during the reaction when taking place in enzymatic environments. Results of the study of six different reactions obtained at the three different levels of calculations show that the reaction takes place in three steps: in the first step the α proton of the acetylacetone is abstracted by the base, then the nucleophilic attack on the β-carbon of the α,β-unsaturated carbonyl compound takes place generating the negatively charged enolate intermediate, and finally the product is formed through a proton transfer back from the protonated base. According to the energy profiles, the rate limiting step corresponds to the abstraction of the proton or the carbon-carbon bond formation step, depending on substituents of the substrates and method of calculation. The effect of the substituents on the acidity of the α proton of the acetylacetone and the steric hindrance can be analyzed by comparing these two separated steps. Moreover, the result of adding a positive charge close to the center that develops a negative charge during the reaction confirms the catalytic role of the oxyanion hole proposed in enzyme catalysed Michael-type additions. Stabilization of the intermediate implies, in agreement with the Hammond postulate, a reduction of the barrier of the carbon-carbon bond formation step. Our results can be used to predict the features that a new designed biocatalyst must present to efficiently accelerate this fundamental reaction in organic synthesis.     

Selective palladium-catalyzed C-F activation/carbon-carbon bond formation of polyfluoroaryl oxazolines

A selective palladium-catalyzed Suzuki-Miyaura coupling reaction of polyfluorophenyl oxazolines through ortho C-F activation is described. It was found that reactions with DPPF as the ligand occurred much faster than those with other ligands. A variety of arylboronic acids including challenging functionalized arylboronic acids such as enolizable ketones, aldehyde, cyano, ester, and trifluoromethyl groups were tolerated with the reaction conditions.     

Benzylic intermolecular carbon-carbon bond formation by selective anodic oxidation of dithioacetals

[reaction: see text]. Novel anodic intermolecular carbon-carbon bond formation has been accomplished by the oxidative carbon-sulfur bond fission of benzylic dithioacetals to give a wide variety of aromatic compounds. The substitution reaction successfully took place by the selective anodic oxidation of a sulfur atom of a dithioacetal. Stepwise double-substitution reactions were also achieved by the regulation of oxidation potential.     

Reversible binding of nitric oxide and carbon-carbon bond formation in a meso-hydroxylated heme

Exposure of a pyridine solution of (py)2Fe(OEPO) (1) (OEPO is the trianion of octaethyloxophlorin, py is pyridine) at 22 degrees C to nitric oxide under the strict exclusion of dioxygen results in a color change from green to red-brown and the formation of {(py)(ON)Fe(OEPO)}2 (2). Monitoring the reaction by 1H NMR spectroscopy shows that the reaction is reversible. The air-sensitive product {(py)(ON)Fe(OEPO)}2 has been isolated and characterized by X-ray crystallography. NO binding is accompanied by association of two hemes through the formation of a new C-C bond between two meso carbon atoms on the porphyrin periphery. The macrocyclic ligand has a ruffled distortion that positions the C5-O1 group with its short C=O bond distance (1.237(3) A) in close proximity to the NO ligand. Since further attack upon 1 by O2 during heme degradation involves reaction in the vicinity of the oxygenated meso position, the positioning of the NO ligand so that the O2...C5 distance is only 3.100(3) A presents a highly suggestive model for the next stage of attack upon the heme periphery.     

二碘化钐在脱氧、还原和碳-碳键形成反应中的应用

本文研究了二碘化钐对一些有机化合物的脱氧反应, 以及它在醇存在下对α-卤代酮、偶氮苯和苯醌的还原反应。首次报道了在二碘化钐作用下α-卤代酮与醛之间的碳-碳键形成瓜在, 高产率地制备了各种α,β-不饱和酮; 同时提出了涉及由α-卤代酮同时与Sm(II)和Sm(III)/I^-物种作用形成烯醇钐盐中间体的可能机理。