RESUMO
We developed an enantioselectively catalyzed tandem synthesis of structurally and stereochemically complex molecules that forms four carbon-carbon bonds and sets eight stereocenters with high regio-, diastereo- and enantioselectivity. It can be programmed to yield different stereoisomers by varying only the order of combination of a common set of reagents and catalysts. We report what is to our knowledge the first synthesis of both enantiomers of a chiral compound using the same chiral catalyst.
Assuntos
Benzoquinonas/síntese química , Catálise , Compostos Azo/química , Ciclização , Estrutura Molecular , Estereoisomerismo , Tiossemicarbazonas/químicaRESUMO
In Biology Oriented Synthesis the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is met by the structurally complex scaffolds of natural products (NPs) selected in evolution. The synthesis of NP-inspired compound collections approaching the complexity of NPs calls for the development of efficient synthetic methods. We have developed a one pot 4-7 step synthesis of mono-, bi-, and tricyclic oxepanes that resemble the core scaffolds of numerous NPs with diverse bioactivities. This sequence entails a ring-closing ene-yne metathesis reaction as key step and makes productive use of polymer-immobilized scavenger reagents. Biological profiling of a corresponding focused compound collection in a reporter gene assay monitoring for Wnt-signaling modulation revealed active Wntepanes. This unique class of small-molecule activators of the Wnt pathway modulates the van-Gogh-like receptor proteins (Vangl), which were previously identified in noncanonical Wnt signaling, and acts in synergy with the canonical activator protein (Wnt-3a).
Assuntos
Compostos Heterocíclicos , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/metabolismo , Proteínas de Transporte/metabolismo , Células HEK293 , Células HeLa , Células Hep G2 , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Proteína Wnt3 , Proteína Wnt3ARESUMO
In the title compound, C23H31NO2S, the geometry of the triiso-propyl-phenyl group is slightly distorted, with elongated C-C bonds at the ipso-C atom, and an S atom which deviates from the benzene ring plane by 0.228â (2)â Å. This distortion is caused by the bulky substituents and, in comparison, an unbent geometry is observed in N-toluene-sulfonyl-aziridine [Zhu et al. (2006 â¶). Acta Cryst. E62, o1507-o1508]. π-π inter-actions between adjacent benzene rings [centroid-centroid distance = 3.7928â (11)â Å] and are observed.
RESUMO
In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.
Assuntos
Produtos Biológicos/síntese química , Centrossomo/efeitos dos fármacos , Alcaloides/síntese química , Alcaloides/farmacologia , Indóis/síntese química , Indóis/farmacologia , Carioferinas/efeitos dos fármacos , Proteínas Nucleares/efeitos dos fármacos , Nucleofosmina , Quinolizinas/síntese química , Quinolizinas/farmacologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Proteína Exportina 1RESUMO
The Pd(II)-catalyzed cycloisomerization of 3-alkoxycarbonyl-3-hydroxy-substituted 1,5-hexadienes has been studied experimentally and computationally. Experimentally, the reaction is characterized by a rapid room temperature formation of monomeric as well as dimeric cycloisomerization products using the commercially available precatalyst [(CH(3)CN)(4)Pd](BF(4))(2). In situ NMR measurements indicate the initial kinetic advantage of the desired cycloisomerization pathway to methylene cyclopentanes; however, double bond isomerization, elimination, and dimer formation are competitive undesired pathways. Evaluation of the obtained product structures by NMR spectroscopy and X-ray crystallography indicates that the sole determinant for the monomer/dimer ratio is the regioselectivity of the initial hydropalladation in favor of the allylic (monomer formation) or the homoallylic double bond (dimer formation). In order to account for the experimental results, we propose the coexistence of two product-forming catalytic cycles, an open, monomer generating, as well as an interrupted and redirected, dimer generating, hydropalladation/carbopalladation/ß-hydride elimination (HCHe) process. Results from computational studies of the proposed competing catalytic cycles are supportive to our mechanistic hypothesis and pinpoint the pivotal importance of Pd(II)-hydroxo-chelate complexes for the reactivity-stability interplay of on- and off-pathway intermediates.
Assuntos
Alcadienos/química , Paládio/química , Catálise , Cristalografia por Raios X , Ciclização , Espectroscopia de Ressonância Magnética , Estrutura Molecular , EstereoisomerismoRESUMO
The title compound, C(19)H(24)ClNO(5), was synthesized and subsequently employed in an Evans alkyl-ation. The purpose was to prove the absolute configuration in the projected synthesis of the side chain of (-)-Lytophilippine A. The oxazolidinone and the isopropylidene acetal rings have twisted conformations. The oxazolidinone and side-chain carbonyl groups are orientated in an anti-periplanar arrangement to minimize van der Waals repulsions. Furthermore, the Cl atom and the acetonide-protected secondary alcohol are also in an anti-periplanar arrangement with a torsion angle of 173.64â (14)°. The absolute configuration was determined and agrees with the configuration of the used chiral auxiliary.
RESUMO
In the title compound, C(21)H(18)Si, the coordination geometry around the Si atom is a slightly distorted tetra-hedron with C-Si-C angles in the range 106.05â (11) to 110.58â (10) ° and Si-C bond lengths in the range 1.855â (2) to 1.883â (3)â Å. The alkyne C-C bond length is 1.167â (4)â Å. The dihedral angles between the three phenyl rings are 63.89â (7), 86.38â (7) and 70.51â (8)°. In the crystal, mol-ecules inter-act only by van der Waals forces.
RESUMO
The title compound, C(12)H(18)N(4)O(2)SSi, was synthesized to be employed in a Julia-Kocienski olefination. In the mol-ecule, the dihedral angle between the phenyl ring and the tetra-zole ring is 41.50â (5)°. The significantly longer Si-C(methyl-ene) bond [1.8786â (13)â Å] and the shortened adjacent C-C bond [1.5172â (18)â Å], as well as the significant deviation of the corresponding Si-C-C angle [114.16â (9)°] from the ideal tetra-hedral angle, can be attributed to the ß-effect of silicon. In the crystal, mol-ecules are held together by van der Waals inter-actions.
RESUMO
The relative configuration of the title compound, C(19)H(28)O(3)Si, which was synthesized using a dienolate-[2,3]-Wittig rearrangement, was corroborated by single-crystal X-ray diffraction analysis. The Si-C bond distances are in the range 1.858â (2)-1.880â (2)â Å and an intra-molecular O-Hâ¯O hydrogen bond helps to stabilize the mol-ecular conformation.
RESUMO
In the title compound, [Cu(C(15)H(26)N(2)O(2))(C(3)H(7)NO)(2)][SbF(6)](2), which is a potential catalyst in the catalytic asymmetric Gosteli-Claisen rearrangement, the central Cu(II) atom is in a nearly square-planar cis-N(2)O(2) environment in the cation arising from its coordination by an N,N-bidentate 2,2-bis-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]propane ligand and two O-bonded N,N-dimethyl-formamide mol-ecules. Two SbF(6) (-) anions are positioned on opposite sides of the plane through the CuN(2)O(2) unit, generating an axially distorted CuN(2)O(2)F(2) octa-hedral geometry for the metal ion.
RESUMO
An intra-molecular Claisen-like cyclization of ethyl 2-acet-oxy-4,4-dimethyl-1-(3-methyl-but-2-en-yl)cyclo-hex-2-enecarboxylate followed by dialkyl-ation yielded the bicyclic title compound, C(23)H(26)O(4). In both of the fused six-membered rings exist fragments of four atoms which are planar, whereas the remaining two atoms deviate by up to 0.682â (3)â Å on one side of the plane of the ring containing an O atom and by up to 0.415â (3)â Å on opposite sides of the other ring. The dihedral anglebetween the planar fragments of the six-membered rings is 41.76â (10)°
RESUMO
The relative configuration of the title compound, C(11)H(18)O(3), which was synthesized using a catalytic asymmetric Gosteli-Claisen rearrangement, a diastereoselective reduction with K-Selectride and an Evans aldol addition, was corroborated by single-crystal X-ray diffraction analysis. The five-membered ring has an envelope conformation with a dihedral angle of 29.46â (16)° between the coplanar part and the flap (the hydr-oxy-bearing ring C atom). In the crystal, mol-ecules are connected via bifurcated O-Hâ¯(O,O) hydrogen bonds, generating [010] chains.
RESUMO
In the title compound, [Cu(C(17)H(30)N(2)O(2))(C(3)H(7)NO)(2)][SbF(6)](2), which is a potential catalyst in the asymmetric Gosteli-Claisen rearrangement, the Cu atom adopts a distorted cis-CuN(2)O(2) square-planar geometry arising from N,N'-bidentate coordin-ation by the chiral ligand and two O-bonded dimethyl-formamide mol-ecules. Two short C-Hâ¯O contacts occur within the ligand and two weak inter-molecular C-Hâ¯F bonds may help to establish the packing.
RESUMO
The title compound, C(16)H(18)F(6)O(4), was obtained through an unprecedented one-pot reaction sequence involving a Gosteli-Claisen rearrangement and a cyclo-isomerization. The constitution and relative configuration were determined by single-crystal X-ray diffraction analysis. In the crystal, mol-ecules are connected via O-H ⯠O hydrogen bonds.
RESUMO
The title compound, C(26)H(38)O(3), was prepared by an intra-molecular Claisen-like cyclization of ethyl 2-acet-oxy-4,4-dimethyl-1-(3-methyl-but-2-en-yl)cyclo-hex-2-enecarboxyl-ate followed by dialkyl-ation. One of the methyl groups is disordered over two sets of sites in a 0.67:0.33 ratio.
RESUMO
An efficient cycloaddition reaction of 1-alkoxy-1-azadienes with alpha,alpha-dicyanoalkenes is described, which gives facile access to highly substituted 3-hydroxypyridines in very good yields and with complete regiocontrol and chemoselectivity. The reaction path was investigated in detail by quantum mechanics calculations, reporting that a concerted cycloaddition mechanism and thermodynamic control synergistically contribute to the observed selectivity.
Assuntos
Cianetos/química , Piridinas/síntese química , Alcenos/química , Compostos Aza/química , Ciclização , Modelos Moleculares , Estrutura Molecular , Piridinas/químicaRESUMO
The title compound, C(11)H(18)O(3), was synthesized to prove the relative configuration of the corresponding acyclic C1-C8 stereopentade. Mol-ecules are linked via O-Hâ¯O hydrogen bonds, forming a chain along the b axis.
RESUMO
The chiral title compound, C(22)H(35)NO(5)SSi, is a precursor of novel furan-omycin derivatives. It crystallizes with two molecules in the asymmetric unit; these show different conformations of the silyl substitutent, as indicated by the Si-O-C-C torsion angles of 41.4â (7) and -84.5â (5)° in the two mol-ecules. The anti configuration of the adjacent stereogenic centers is consistent with the Felkin-Anh model. Each of the two crystallographically independent mol-ecules is connected with a neighbouring mol-ecule of the same type via two symmetry-equivalent O-Hâ¯O hydrogen bonds.
RESUMO
The title compound, C(11)H(18)O(3), was synthesized to prove the relative configuration of the corresponding acyclic C1-C8 stereopentade. It crystallizes with two mol-ecules in the asymmetric unit, which show only slight differences. The mol-ecules are linked via O-Hâ¯O hydrogen bonds, resulting in two crystallographically independent chains of mol-ecules propagating in the a-axis direction. The absolute configuration was known from the synthesis.
RESUMO
The relative configuration of the title compound, C(11)H(18)O(3), was corroborated by single-crystal X-ray diffraction analysis. In the crystal, mol-ecules are linked via a O-Hâ¯O hydrogen bond and a chain of mol-ecules is formed along [010].