Solution-phase parallel synthesis of spirohydantoins

Spirohydantoins are considered privileged structures, making them attractive for the preparation of compound libraries with the potential for diverse biological activity. However, very few modifications of this scaffold have been reported to date. The spirohydantoin template was elaborated into a library of 168 compounds through a two-step solution-phase parallel synthesis starting from various N-substituted piperidinones. The Strecker reaction was employed to generate alpha-amino nitriles from aniline and TMSCN (or KCN). Subsequent reaction of the anilido nitrogen with a diverse set of isocyanates, followed by refluxing under acidic conditions, afforded the title library in high yield and purity.     

Solution-phase library synthesis of furanoses

The solution-phase synthesis of amido-, urea-, and aminofuranoses was achieved. Alkylated furanose aldehydes were treated with primary amines in the presence of sodium triacetoxyborohydride to give secondary amines. Subsequent acylation with acid chlorides and isocyanates afforded amidofuranoses and ureafuranoses, respectively. Second, reductive amination of furanose aldehydes with secondary amines yielded tertiary amines. The resulting acetonides were treated with alcohols in the presence of acid to yield mixed acetals. In the library syntheses, functionalized scavenger resins were used in the purification of intermediates and products.     

Solution-phase parallel synthesis of substituted benzimidazoles

A solution-phase parallel synthesis of o-phenylenediamines is described. These intermediates were then subsequently converted to benzimidazole scaffolds (three-point diversity) in excellent purities and yields. High-throughput purification of this multistep synthetic sequence was accomplished using polymer-bound scavengers and reagents and liquid-liquid extraction protocols.     

Solution-phase hexasaccharide synthesis using glucosyl iodides

[reaction: see text] Oligosaccharides composed of 1,6-glucosyl residues have been prepared from glucosyl iodides. The reactions are highly stereoselective, giving the alpha-glycosides as the only isolated products in yields ranging from 84% to 94%. Oligomer synthesis can take place in an iterative 1 + 1 + 1 fashion or in a convergent manner where dimer iodides serve as donors for higher order acceptors.     

Solution-phase parallel synthesis of highly diverse spiroisoxazolinohydantoins

Practical and efficient solution-phase parallel synthesis of spiroisoxazolinohydantoins under mild conditions has been developed. This spiroisoxazolinohydantoin skeleton possesses three diversity points. The key intermediate, exo-methylenehydantoin bearing two positions of diversification, is prepared via a one-pot synthetic route from N-substituted methyl ester serine. Employing various alkyl halides, isocyanates, and oximes, this chemistry is applied in the generation of an 18-member demonstration library with high yield, high purity and excellent regioselectivity.     

Solution-phase synthesis of spherical zinc sulfide nanostructures

A facile solution-phase method has been developed to synthesize specially hollow and solid ZnS nanospheres. High-resolution TEM images on the nanospheres suggest their formation via the oriented aggregation of the primary ZnS nanocrystals. The morphology and size of the ZnS nanospheres can also be tuned easily by controlling the experimental conditions. These special spherical structures are very easily encapsulated within a uniform silica layer without any surface modification, suggesting potential applications in biochemistry and biodiagnostics.     

Solution-phase parallel synthesis of carbamates using polymer-bound N-hydroxysuccinimide

[formula: see text] A convenient method for the synthesis of carbamates using polymer-supported N-hydroxysuccinimide is described. Various carbamates were synthesized in highly pure form without the need for chromatographic purification. This new "catch and release"-type solid-phase synthesis should be useful for combinatorial synthesis of various carbamates.     

Solution-phase parallel synthesis of carbamates as gamma-secretase inhibitors

A novel methodology for parallel liquid-phase synthesis of carbamates suitable for the preparation of sterically hindered molecules is disclosed. The alcohols are converted to 4-nitrophenylcarbonates, followed by the reaction with amines. Side product 4-nitrophenol and the unreacted excess amines are scavenged by appropriately chosen cleanup resins, selected among Amberlyst A26 (hydroxide form) and macroporous sulfonic acid (MP-TsOH) or polystyrene isocyanate (PS-NCO) and polystyrene benzaldehyde (PS-PhCHO) resins. As a part of a medicinal chemistry program directed toward finding gamma-secretase inhibitors as prospective drug candidates for Alzheimer's disease, a 6 x 24 library of carbamates was prepared. Out of 144 library members, 133 had a purity for the targeted compound of 80% or better. The prepared compounds were assessed in the gamma-secretase inhibition assay and demonstrated activity with IC 50 values in the range from 1 microM to 5 nM, with the activity of 7 compounds being better than 10 nM.     

Solution-phase synthesis of nucleobase-substituted analogues of triostin A

A synthesis of novel analogues of triostin A presenting two identical or different nucleobases instead of the original quinoxaline substituents has been developed. The DNA bisintercalator triostin A (1) with its rigid backbone provides an optimal scaffold for a parallel preorganization of the intercalating moieties. The bicyclic octadepsipeptide is built up stepwise in solution and modified with various nucleobase-substituted acetic acids at a late stage. The choice of orthogonal protecting groups allows for the synthesis of triostin analogues bearing two different substituents.     

Solution-phase synthesis of a muramyl dipeptide analogue MDA

The solution-phase synthesis of a muramyl dipeptide(MDP) analogue of N~α-[4-chlorocinnamoyl-L-alanyl-D-isoglutaminyl]-L-lysine (MDA,2) is reported that possesses the features of easy feasibility,safety and low cost in large scale of synthesis.     

Solution-phase parallel synthesis of S-DABO analogues

A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective S-benzylation of 5 was achieved in few minutes under microwave irradiation to give the title compounds 1, which were oxidized in parallel to the corresponding sulfones 2. Some of the new compounds 1 showed potent inhibitory activity against HIV-1 RT.     

Solution-phase synthesis of diaryl selenides using polymer-supported borohydride

[reaction: see text] A new series of selenium-containing diaryl retinoids have been prepared by a new direct nickel(II)-catalyzed coupling of a diselenide with an iodoaryl in the presence of polymer-supported borohydride.     

Chemoenzymatic synthesis of ketomethylene tripeptide isosteres

A chemoenzymatic method is described for the synthesis of a desired ketomethylene tripeptide isostere. The key step is an enzymatic hydrolysis, which removes the C-terminal ester-protecting group under mild conditions without epimerizing the existing stereogenic center and produces the desired stereoisomer in high enantiomeric excess (98% de, 97% ee). The method is short with overall 15–20% yields after seven synthetic steps from readily available starting materials being obtained.     

Solution-phase synthesis of heteroatom-substituted carbon scaffolds for hydrogen storage

This paper reports a bottom-up solution-phase process for the preparation of pristine and heteroatom (boron, phosphorus, or nitrogen)-substituted carbon scaffolds that show good surface areas and enhanced hydrogen adsorption capacities and binding energies. The synthesis method involves heating chlorine-containing small organic molecules with metallic sodium at reflux in high-boiling solvents. For heteroatom incorporation, heteroatomic electrophiles are added to the reaction mixture. Under the reaction conditions, micrometer-sized graphitic sheets assembled by 3-5 nm-sized domains of graphene nanoflakes are formed, and when they are heteroatom-substituted, the heteroatoms are uniformly distributed. The substituted carbon scaffolds enriched with heteroatoms (boron ～7.3%, phosphorus ～8.1%, and nitrogen ～28.1%) had surface areas as high as 900 m(2) g(-1) and enhanced reversible hydrogen physisorption capacities relative to pristine carbon scaffolds or common carbonaceous materials. In addition, the binding energies of the substituted carbon scaffolds, as measured by adsorption isotherms, were 8.6, 8.3, and 5.6 kJ mol(-1) for the boron-, phosphorus-, and nitrogen-enriched carbon scaffolds, respectively.     

Solution-phase oligosaccharide synthesis in a cycloalkane-based thermomorphic system

The cycloalkane-based thermomorphic (CBT) system is a convenient and practical method for oligosaccharide synthesis, and hydrophobically modified oligosaccharides have a remarkable affinity for CBT solutions composed of methylcyclohexane and propionitrile.     

Solution-phase parallel synthesis of diverse 1,5-benzodiazepin-2-ones

A practical and efficient parallel method has been developed for the synthesis of 1,5-benzodiazepin-2-ones with a large variety of substituents at the 3-, 4-, 5-, 7-, and 8-positions using 1,5-difluoro-2,4-dinitrobenzene as the starting material. All the reactions involved here are highly effective in giving the desired products under mild conditions.     

Solution-phase synthesis of branched DNA hybrids via H-phosphonate dimers

A method for the solution-phase synthesis of branched oligonucleotides with tetrahedral or pseudo-octahedral geometry is described that involves the coupling of 3'-H-phosphonates of protected dinucleoside phosphates and organic core molecules. The dimer building blocks are produced by a synthesis that requires no chromatographic purification and that produces the dimer H-phosphonates in up to 44% yield in less than three days of laboratory work. A total of seven different branched hybrids were prepared, including a new hybrid of the sequence (CG)(4)TBA, where TBA stands for tetrakis(p-hydroxybiphenyl)adamantane that assembles into a material from micromolar aqueous solution upon addition of MgCl(2).     

Solution-phase parallel synthesis of 3,5,6-substituted indolin-2-ones

A practical and efficient new parallel method has been developed for the synthesis of 3-substituted indolin-2-ones with a large variety of substituents at the 5- and 6-positions using 1,5-difluoro-2,4-dinitrobenzene. This 3,5,6-substituted indolin-2-one skeleton possesses three points of diversification and, thus, affords new opportunities for identification and optimization of leads in drug discovery.