Programmable enantioselective one-pot synthesis of molecules with eight stereocenters.

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.

Biology-oriented synthesis of a natural-product inspired oxepane collection yields a small-molecule activator of the Wnt-pathway.

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).

Natural product-inspired cascade synthesis yields modulators of centrosome integrity.

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.

Supramolecular isomerism of 2,2'-bipyrazine complexes with cis-(NH(3))(2)Pt(II): ligand rotational state and sequential orientation determine the 3D shape of metallacycles.

2,2'-Bipyrazine (2,2'-bpz) reacts with cis-(NH(3))(2)Pt(II) in water to give a variety of products, several of which were isolated and characterized by X-ray analysis: cis-[Pt(NH(3))(2)(2,2'-bpz-N4)(2)](NO(3))(2)·3H(2)O (1), [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(3)]-(PF(6))(5)NO(3)·7H(2)O (2a), [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(3)](BF(4))(2)-(SiF(6))(2)·15H(2)O (2b), and [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(4)]-(SO(4))(4)·22H(2)O (3). In 1, 2b, and 3 the 2,2'-bpz ligands adopt approximately C(2h) symmetries, hence the two pyrazine halves are in trans orientation, whereas in 2a all three 2,2'-bpz bridges are approximately C(2v) symmetric, with the pyrazine halves cis to each other. The topologies of the two triangular complexes 2a and 2b are consequently distinctly different, but nevertheless both cations act as hosts for anions. In 2a a PF(6)(-) and a NO(3)(-) anion are associated simultaneously with the +6 cation, whereas in 2b it is a BF(4)(-) anion and a water molecule, which are trapped in its cavity. There is no anion inclusion in case of the metallasquare 3. In principle, 3 can exist in a large number of stereoisomers, depending on the rotational states of the bridging 2,2'-bpz ligands. Isolation of a single rotamer form of 3 with C(2h) symmetric 2,2'-bpz ligands and an overall meso form is proposed to be a consequence of a highly efficient self-assembly process that starts from the precursor 1 and reaction with two cis-(NH(3))(2)Pt(II) units. This process leads to the isolated rotamer of 3 regardless of whether two cations 1 in head-head form react with two cis-(NH(3))(2)Pt(II), or whether the Δ enantiomer of the chiral head-tail form of 1 combines with its Λ enantiomer through two cis-(NH(3))(2)Pt(II) entities.

The first examples of a crown ether intramolecularly encapsulating mono- and diorganotin dications: synthesis and structures of [PhSnCH2([16]crown-5)][ClO4]2 and [HOSnCH2([16]crown-5)][Y]2 (Y=ClO4, CF3SO3).

The reaction of silver perchlorate with [PhI(2)SnCH(2)([16]crown-5)] (1) and [I(3)SnCH(2)([16]crown-5)] (2) gave the organotin(IV)-substituted crown ether complexes [PhSnCH(2)([16]crown-5)][ClO(4)](2) (3) and [HOSnCH(2)([16]crown-5)][Y](2) (4: Y=ClO(4), 5: Y=CF(3)SO(3)), respectively. All compounds have been isolated as air-stable materials and characterised by (1)H, (13)C, (119)Sn and (119)Sn MAS (5) NMR spectroscopy, ESIMS spectrometry, elemental analysis and by single-crystal X-ray diffraction analysis. The molecular structures of 3-5 show that the tin(IV) cation fits perfectly into the crown ether cavity and is coordinated by the five oxygen atoms of the ring to give a pentagonal bipyramidal configuration about the central metal cation. Notably, compounds 4 and 5 contain the first monomeric monoorganotin dication. Moreover, there are (3)J((1)H,(119)Sn) coupling constants to the CH(2)CH proton of 377 (3) and 470 Hz (4, 5) that are, to the best of our knowledge, the biggest such couplings ever reported.

(2SR,3SR)-Isopropyl 3-{[dimeth-yl(phenyl)-sil-yl]meth-yl}-2-hy-droxy-2-vinyl-pent-4-enoate.

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 1.858 (2)-1.880 (2) Šand an intra-molecular O-H⋯O hydrogen bond helps to stabilize the mol-ecular conformation.

para-Functionalized aryl-di-tert-butylfluorosilanes as potential labeling synthons for (18)F radiopharmaceuticals.

Broad spectrum: Novel para-functionalized aryl-di-tert-butylfluorosilanes, p-(tBu(2)FSi)C(6)H(4)X (X=functional group), have been made available and broaden the spectrum of silicon-based (18)F acceptors (SiFAs) for potential PET applications. For example, the [(18)F]maleimido derivative 1 has been employed for the synthesis of [(18)F]1- labeled rat serum albumin (RSA), the applicability of which for PET has been verified by in vivo experiments.The syntheses of the functionalized triorganofluorosilanes tBu(2)(p-XC(6)H(4))SiF (3 a, X=SH; 4 a, X=NCS; 4 b, X=NCO; 5, X=NC(4)H(2)O(2); 7, X=COOH; 8 a, X=COONC(4)H(4)O(2); 8 b, X=COOC(6)F(5)) are reported. These compounds display potential as silicon-based fluoride acceptors (SiFAs). The molecular structures of compounds 5, 7, and 8 a have been determined by single-crystal X-ray diffraction studies. With the exception of compounds 8 a and 8 b, all of the compounds could be (18)F-labeled by isotopic exchange in good to high radiochemical yields (RCY) with good to excellent specific activities. As proof of applicability, the maleimido-functionalized SiFA derivative 5, which is specific for thiol groups, has been used for the labeling of rat serum albumin (RSA) that had been derivatized with 2-iminothiolane. The incorporation of [(18)F]5 into the derivatized RSA reached a maximum yield after 30 min at ambient temperature. After purification, the [(18)F]RSA was evaluated in a healthy rat by means of muPET and displayed an expedient in vivo stability over 180 min.

7,7-Dimethyl-4a-(3-methyl-2-buten-yl)-2-oxo-4a,5,6,7-tetra-hydro-2H-chromen-4-yl benzoate.

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 0.682 (3) Šon one side of the plane of the ring containing an O atom and by up to 0.415 (3) Šon opposite sides of the other ring. The dihedral anglebetween the planar fragments of the six-membered rings is 41.76 (10)°

(3R,4R,5S)-4-Hydr-oxy-3-methyl-5-[(2S,3R)-3-methyl-pent-4-en-2-yl]-4,5-dihydro-furan-2(3H)-one.

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 29.46 (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-H⋯(O,O) hydrogen bonds, generating [010] chains.

{2,2-Bis[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]propane}bis-(N,N-di-methyl-formamide)copper(II) bis-(hexa-fluoridoantimonate).

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-H⋯O contacts occur within the ligand and two weak inter-molecular C-H⋯F bonds may help to establish the packing.

(±)-syn-Isopropyl 4-(1,1,1,3,3,3-hexa-fluoro-propan-2-yl-oxy)-1-hydr-oxy-3-methyl-2-(prop-1-yn-yl)cyclo-pent-2-ene-carboxyl-ate.

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.

7,7-Dimethyl-3,3,4a-tris-(3-methyl-but-2-en-yl)-4a,5,6,7-tetra-hydro-2H-chromene-2,4(3H)-dione.

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.

Regioselective de novo synthesis of cyanohydroxypyridines with a concerted cycloaddition mechanism.

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.

(3S,4S,5S)-4-Hydr-oxy-3-methyl-5-[(2S,3R)-3-methyl-pent-4-en-2-yl]-4,5-dihydro-furan-2(3H)-one.

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-H⋯O hydrogen bonds, forming a chain along the b axis.

(1R,4'S)-4-(tert-Butyl-dimethyl-silan-oxy)-1-[2,2-dimethyl-3-(p-tolyl-sulfon-yl)-1,3-oxazolidin-4-yl]but-2-yn-1-ol.

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 41.4 (7) and -84.5 (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-H⋯O hydrogen bonds.

(3R,4S,5S)-4-Hydr-oxy-3-methyl-5-[(2S,3R)-3-methyl-pent-4-en-2-yl]tetra-hydro-furan-2-one.

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-H⋯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.

Solvent-controlled assembling by hydrogen bridges and halogen-halogen interactions of novel organotin oxo clusters.

The crystal structure of the novel methylene-bridged tetraorganodistannoxane ([Ph(HO)SnCH2Sn(I)Ph]O)4 (1) depends on the solvent it is crystallised from and is controlled by hydrogen bridges and interhalogen interactions.

Reactions of [t-Bu(2)SnO](3) with [t-BuX(2)Si](2) (X = F, Cl). Syntheses and Structures of Novel Stannasiloxanes and of [(t-Bu(2)FSn)(2)O](2), the First Fluorine-Containing Tetraorganodistannoxane(,).

Di-tert-butyltin oxide, (t-Bu(2)SnO)(3) (1), reacts with 1,2-di-tert-butyltetrachlorodisilane, (t-BuCl(2)Si)(2) (2), to provide the stannasiloxane t-Bu(2)Sn[OSi(OSnCl-t-Bu(2))-t-Bu](2) (4, racemate). The reaction of 1 with 1,2-di-tert-butyltetrafluorodisilane, (t-BuF(2)Si)(2) (3), provides the stannasiloxane [t-Bu(F)SiOSn-t-Bu(2)](2)O (5, meso/racemate mixture) and the tetraorganodistannoxane [t-Bu(2)(F)SnOSn(F)-t-Bu(2)](2) (6). Under loss of (1)/(3) mole equiv of 1, the stannasiloxane 5 is transformed into t-Bu(2)Sn[OSi(F)-t-BuSi(F)-t-BuO](2)Sn-t-Bu(2) (7). Its ten-membered ring structure was elucidated by X-ray analysis. In solution, 7 forms the five-membered ring t-Bu(2)Sn[OSi(F)-t-Bu](2) (7a). The dimeric nature of 6 was confirmed by its crystal structure determination. In solution, 6 exhibits a unique valence tautomerism as evidenced by (19)F and (119)Sn NMR spectroscopy.

Synthesis, structural characterization and in vitro cytotoxicity of organotin(IV) derivatives of heterocyclic thioamides, 2-mercaptobenzothiazole, 5-chloro-2-mercaptobenzothiazole, 3-methyl-2-mercaptobenzothiazole and 2-mercaptonicotinic acid.

Five new organotin(IV) molecules with the heterocyclic thioamides; 2-mercaptobenzothiazole (Hmbzt), 5-chloro-2-mercaptobenzothiazole (Hcmbzt), 3-methyl-2-mercaptobenzothiazole (mmbzt) and 2-mercaptonicotinic acid (H(2)mna) of formulae [(n-C(4)H(9))(2)Sn(mbzt)(2)] (1), [(C(6)H(5))(2)Sn(mbzt)(2)] (2), [(CH(3))(2)Sn(cmbzt)(2)].1.7(H(2)O)] (3), [(n-C(4)H(9))(2)SnCl(2)(mmbzt)(2).(CH(2)Cl(2))] (4) and [[(C(6)H(5))(3)Sn](2)(mna).[(CH(3))(2)CO]] (5) have been synthesized and characterized by elemental analysis, 1H-, 13C-NMR, FT-IR and Mössbauer spectroscopic techniques. Crystal structures of molecules 1, 3 and 5 have been determined by X-ray diffraction at 173(1) K (1 and 5) and 293(2) K (3). Compound 1 C(22)H(26)N(2)S(4)Sn, is monoclinic, space group C2/c, a=44.018(2), b=8.8864(5), c=12.8633(7) A, beta=104.195(5) degrees, Z=8. Compound 3 is also monoclinic, space group P2(1)/c and a=17.128(2) A, b=17.919(2) A, c=7.3580(10) A, beta=98.290(10) degrees, Z=4. In both molecules 1 and 3, two carbon atoms from aryl groups, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(IV) with trans-C(2), cis-N(2), cis-S(2) configurations. Compound 5 C(45)H(39)NO(3)SSn(2) is monoclinic, space group P2(1)/n, a=9.1148(2) A, b=29.2819(6), c=15.5556(4) A, beta=106.2851(9) degrees, Z=4. Complex 5 contains two [(C(6)H(5))(3)Sn(IV)] moieties linked by a double deprotonated 2-mercaptonicotinic acid (H(2)mna). Both tin(IV) ions are five coordinated. This complex is the an example of a pentacoordinated Ph(3)SnXY system with an axial-equatorial arrangement of the phenyl groups at Sn(1) atom. Compounds 1, 3 and 5 were tested for in vitro cytotoxicity against the cancer cell line of sarcoma cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (benzo[a]pyrene) carcinogenesis. Compound 5 exhibits strong cytotoxic activity, while complexes 1 and 3 show less cytotoxic activity.