Hans Preut

Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products

In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3′-pyrrolidinyl spirooxindoles—which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1–3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF6(CH3CN)4. Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity. A Lewis-acid-catalysed 1,3-dipolar cycloaddition provides rapid access to a variety of substituted spirooxindoles. Initial cellular evaluations supports the view that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry, and decorated with assorted substituents, will be a rich source of compounds with diverse bioactivity.

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.

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).

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.

Highly Enantioselective Catalytic Synthesis of Neurite Growth-Promoting Secoyohimbanes

Natural products endowed with neuromodulatory activity and their underlying structural scaffolds may inspire the synthesis of novel neurotrophic compound classes. The spirocyclic secoyohimbane alkaloid rhynchophylline is the major component of the extracts of Uncaria species used in Chinese traditional medicine for treatment of disorders of the central nervous system. Based on the structure of rhynchophylline, a highly enantioselective and efficient organocatalyzed synthesis method was developed that gives access to the tetracyclic secoyohimbane scaffold, embodying a quaternary and three tertiary stereogenic centers in a one-pot multistep reaction sequence. Investigation of a collection of the secoyohimbanes in primary rat hippocampal neurons and embryonal stem cell-derived motor neurons led to discovery of compounds that promote neurite outgrowth and influence the complexity of neuronal network formation.

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.

Synthesis of tetraphenylstibonium alkyl- and aryl- sulphonates. Crystal structure of tetraphenylstibonium benzenesulphonate hydrate

Abstract The tetraphenylstibonium sulphonates Ph 4 SbO 3 SR· n H 2 O ( n = 1, R = C 6 H 5 ; n = 0, R = CH 3 , CF 3 , CH 2 CH 2 OH, 4-CH 3 C 6 H 4 , 2,4(NO 2 ) 2 C 6 H 3 ) have been obtained by neutralization of tetraphenylstibonium hydroxide with the appropriate alkyl- or aryl-sulphonic acid. The crystal structure of tetraphenylstibonium benzenesulfonate hydrate has been determined by single crystal X-ray diffraction. The sulphonate group is unidentately coordinated to antimony, which has a distorted trigonal bipyramidal environment. The rather long SbO bond, (2.506(4) A) and the distortion of the polyhedron around Sb, and the IR data for the sulphonate group are consistent with the assumption of a large ionic bond character in the SbO bond. From IR data analogous molecular structures are inferred for the other tetraphenylstibonium sulphonates.

Mixed nucleobase, amino acid complexes of Pt(II). Preparation and X-ray structure of trans-[(CH3NH2)2Pt(1-MeC-N3)(gly-N)]NO3.2H2O and its precursor trans-[(CH3NH2)2Pt(1-MeC-N3)Cl]Cl.H2O

The preparation and crystal structures of two Pt(II) complexes are reported. trans -[(NH 2 CH 3 ) 2 Pt (1-MeC)Cl]Cl·H 2 O ( 1 ) and trans -[(NH 2 CH 3 ) 2 Pt(1- MeC)(gly)]NO 3 ·2H 2 O ( 2 ) with 1-MeC= 1-methylcytosine and gly = glycine anion are considered a precursor ( 1 ) and a product ( 2 ) of a hypothetical cross-linking reaction of a trans -diamineplatinum(II) moiety with a nucleic acid and the amino terminus of a protein, peptide, or amino acid. Compound 1 crystallizes in the space group P and has cell dimensions a = 7.749(1), b = 9.854(2), c = 10.100(1) A; α = 101.45(1), β = 103.81(1), γ = 95.46(1)°, Z = 2. Compound 2 crystallizes in the space group P as well, cell dimensions being a = 8.790(2), b = 9.839(3), c = 11.580(4) A; α = 75.42(2), β = 71.64(2), γ = 86.92(2)°, Z = 2. pH-dependent 1 H NMR spectra of 2 in D 2 O have been recorded in the range 0.4 with p K a values of 2.5 and c . 12.5.

Complexes of organometallic compounds : XXXIX. synthesis, infrared and mössbauer studies on monoorganotin(IV) complexes with tridentate ligands

Abstract Novel complexes RClSntrid, where R is Me, Ph, n-Oct, and trid 2− are dianions of tridentate “planar” ligands with ONO and SNO donor atoms, were synthesized and investigated in the solid state by infrared and Mossbauer spectroscopy. Possible configurations are discussed; polymeric trigonal bipyramidal structures seem to occur, although five-coordinated monomers as well as octahedral dimers (via oxygen or sulfur bridges) are not excluded.

Alkali-nucleobase interactions: Involvement of exocyclic oxygens of 1-methyluracil and 1-methylthymine in Na+ binding

Abstract Co-crystallization of Na[AuCl4] with 1-methyluracil, C5H6N2O2 (1-MeUH), and 1-methylthymine, C6H8N2O2 (1-MeTH), at pH 0.8 yields predominently salts of composition [Na(1-MeUH)4][AuCl4] (1) and [Na(1-MeTH)(H2O)4][AUCl4]·1-MeTH·2H2O (2). Both 1 and 2 crystallize in space group P 1 with cell dimensions a = 10.531(3), 1, 8.436(5), 2; b = 9.194(3), 1, 10.521(7), 2; c = 7.924(2), 1, 15.917(11) A, 2; α = 96.68(3), 1, 102.61(5), 2; β = 85.09(3), 1, 90.45(5), 2; γ = 103.88(3), 1, 108.10(5)°, 2; U = 738.4, 1, 1306(2) A3, 2; Z = 1, 1, 2, 2. Na+ binding to 1-MeUH is through O(4) in 1 and O(2) in 2. The packing of cations and anions in 1 is special in that infinite stacks of alternating [Na(1-MeUH)4]+ and [AuCl4]− are formed with the metals 3.962(1) A apart.