Solid phase synthesis of hydantoins by thermal cyclization and screening of reaction conditions using APOS 1200

A novel strategy for solid-phase synthesis of hydantoins with highoptical purity is described using a thermal pH-neutral cyclization and simultaneous release from resin. Hereby even hydantoins bearinga pH-sensitive side chain (protection) are available. The reaction conditions are well screened applying the parallel organic synthesizerAPOS 1200.     

Efficient library synthesis of imidazoles using a multicomponent reaction and microwave irradiation

Optimization of Radziszewski's four-component reaction employing a microwave-assisted protocol, led to a small library of 48 imidazoles with a success rate of 65% (conversion > 45%). All three diversity points of the four-component reaction were varied. Aromatic and aliphatic inputs were successfully implemented and mono-, di-, tri- and tetrasubstituted imidazoles with various substitution patterns were synthesized. Furthermore, unsymmetrical diketones could successfully be used which improved the intrinsic diversity of the method significantly. If the unsymmetrical diketone 1,2-phenylpropanedione (R¹ and R²) was used two regioisomers were formed. Depending on the type of amine (R⁴) and aldehyde (R³) applied, regioselectivity was modest to good. Based on these results, a reaction mechanism is proposed.     

Solid phase synthesis of combinatorial libraries using anhydrides as templates

A simple and general approach to the synthesis of chemical libraries based on a universal anhydride template allows the preparation of large number of compounds. Various cyclic/acyclic amines, primary/secondary amines, differentially protected bifunctional amines were used as nucleophiles to react with anhydrides. The free carboxylic acid generated was then coupled with solid-bound amines. The facile and rapid generation of compounds through this multi-component assembly can be accomplished in a combinatorial parallel synthesis. This revised version was published online in August 2006 with corrections to the Cover Date.     

Solid-phase synthesis of tetrahydro-1,4-benzodiazepin-2-one derivatives

An efficient method for solid-phase construction of tetrahydro-1,4-benzodiazepin-2-one scaffold is described. Polymer-bound 4-(bromomethyl)-3-nitrobenzoic acid was reacted with alpha-amino acid methyl esters, followed by nitro group reduction and hydrolysis. Subsequent intramolecular cyclization and alkylation at N(4) afforded the structurally diverse products in high yields and excellent purities.     

Six new photolabile linkers for solid-phase synthesis. 1. Methods of preparation

In the synthesis of combinatorial chemical libraries on solid phase, there is a need to cleave the compounds from the solid support before the library can be tested for biological activity. It is advantageous to use linkers which will release the libraries by mild photolytic cleavage. We have developed six new linkers of the photosensitive α-methyl 2-nitrobenzyl type containing amino, hydroxy, bromo and methylamino groups, and also 4-nitrophenoxycarbonyl activated OH and NH₂ groups. This revised version was published online in August 2006 with corrections to the Cover Date.     

Solid phase synthesis of benzamidine-derived sulfonamide libraries

Using solid phase synthesis, a library has been constructed of benzamidine-derived sulfonamides which have strong inhibitory activity against blood coagulant thrombin. The library compounds were obtained in good yield and high purity. This revised version was published online in August 2006 with corrections to the Cover Date.     

Exploring privileged structures: The combinatorial synthesis of cyclic peptides

Head-to-tail cyclic peptides have been reported to bind to multiple, unrelated classesof receptor with high affinity. They may therefore be considered to beprivileged structures. This review outlines the strategies by which bothmacrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines havebeen synthesised in combinatorial libraries. It also briefly outlines someof the biological applications of these molecules, thereby justifying theirinclusion as privileged structures.     

Application of an almost traceless linker in the synthesis of 2-alkylthiobenzimidazole combinatorial libraries

Resin-bound triphenylphosphine was coupledto 4-fluoro-3-nitrobenzyl bromide, and2-alkylthiobenzimidazoles were synthesized onresin in 4 steps using standard chemistries. Cleavage of the compounds from the resin wasachieved with 10% NaOH in MeOH to leave amethyl group at the attachment point. A totalof 47 amines and 40 electrophiles wereevaluated, defining the scope of the reactions,culminating in the synthesis of an 80-membertest library of high purity as determined by HPLC.     

Solid phase synthesis of benzamidine and butylamine-derived hydantoin libraries

We have constructed a number of benzamidine- and butylamine-based hydantoin compounds by means of an efficient route using solid phase synthesis in which neat diisopropylamine was employed for a novel cyclization/traceless cleavage step. All library compounds were obtained in excellent yield and high purity. This revised version was published online in August 2006 with corrections to the Cover Date.     

Recent advances in 1,3-dipolar cycloaddition reactions on solid supports

Solid-phase methods are of a great significance in organic synthesis. Recent developments of these methods are providing new ways to construct libraries of small organic molecules. Five-membered heterocyclic compounds, which can be utilized in a variety of applications, are formed in the 1,3-dipolar cycloaddition reaction between dipolarophiles and dipoles. This review deals with the solid-phase synthesis of heterocycles via [3+2] cycloaddition reaction. Cycloaddition reactions of polymer-bound dipoles and polymer-bound dipolarophiles and intramolecular solid-phase cycloadditions are discussed in separate sections. Reactions of dipolarophiles such as alkenes, alkynes, and imines with dipoles such as azomethine ylides, azomethine imines, nitrile imines, azides, nitrones, and nitrile oxides are described. The recent literature up to December 2003 is covered.     

Solid phase synthesis of azapeptides using an automatic synthesizer

Peptides containing azaglycine located terminally or within the backbone have been prepared in the solid phase by means of an automatic synthesizer.     

Solid-phase synthesis of 2-substituted 4-amino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines: An example of cyclization-assisted cleavage

An efficient solid-phase synthesis of 2-substituted 4-aminopyrido[2,3-d]pyrimidines 12 by cyclization-assisted cleavage from resin is reported. The procedure starts by solid supporting an ,-unsaturated acid 8 to the Wang resin 13 by using DCC and 4-DMAP in THF. The resulting ,-unsaturated ester 14 is converted to the Michael adduct by treatment with malononitrile in NaOMe/THF. Such Michael addition constitutes the first example of a Michael reaction with malononitrile in solid-phase. Finally, the Michael adducts 15 are treated with an amidine system in MeOH to yield the corresponding pyridopyrimidines 12. Compounds 12 present three diversity centers R1, R2 and G. Having validated the chemistry on solid support, a 40-membered combinatorial library was obtained using this protocol.     

Solid-phase total synthesis of (–)-Phenylhistine and (–)-Aurantiamine. Synthesis of a diverse dehydro-2,5-diketopiperazine library. Part II

The preparation of solid supported glycine phosphonate and its utilization for the total synthesis of two natural products is presented. The proposed protocol combines diversity with accessibility and speed, which makes this scaffold suitable for automated parallel synthesis and combinatorial chemistry. The preparation of a small library of dehydro-2,5-diketopiperazines, combining several natural amino acids with diverse heterocycles (including thiazoles, pyridines, indoles and imidazoles), is also demonstrated.     

Six new photolabile linkers for solid phase synthesis. 2. Coupling of various building blocks and photolytic cleavage

Photolabile linkers are very useful in the generation of combinatorial libraries as they offer compound cleavage under mild conditions directly into a solvent suitable for biological testing. Six new photolabile linkers have been developed which allow coupling of building blocks with a carboxy, amino, hydroxy and sulfonyl group. Photolytic cleavage of these building blocks will give libraries with carboxy, amido, methylamido, amino, ureido, hydroxy, aminocarbonyloxy and aminosulfonyl terminal groups. Coupling conditions for these reactions were elucidated and the photolytic cleavage reaction was studied.     

Single bead parallel synthesis and screening

Microstructured silicon wafers were employed as miniaturized solid-phase reaction vessels as well as miniaturized micro titer plates. Employing piezoelectric drop-on-demand liquid jets, a combinatorial library of 256 Peptides was synthesized on single beads. The synthesis protocol was associated to the location in the silicon nano-well arrangement. Products were photolytically cleaved in the same well that was used for synthesis and subsequently interrogated for thrombin inhibition in a homogeneous competition assay. The assay procedure was based on drop-on-demand liquid delivery and laser induced fluorescence imaging. The novel format proved useful for the integration of both synthesis and screening into one platform, a prerequisite for an iterative, evolutionary approach towards drug discovery.     

Solid phase organic synthesis (SPOS): A novel route to diketopiperazines and diketomorpholines

Summary The solid phase synthesis of libraries containing a 1,3,4,6-tetrasubstituted-2,5-diketo-1,4-piperazine scaffold (DKP) or a 3,4,6-trisubstituted-2,5-diketo-1,4-morpholme scaffold (DKM) from -bromocarboxylic acids and amines is described. Using a design strategy which we refer to as divergent library design, both templates were prepared from a common intermediate. The general utility of this synthetic route in creating novel, non-peptidyl chemical libraries is discussed.     

Metal free synthesis of homoallylic alcohols promoted by ultrasound

The use of ultrasound irradiation to promote the allylation of aldehydes containing different functionalities with potassium allyltrifluoroborates is described. The method features the use of a minimum amount of acetone as solvent, without any other catalyst or promoter. The products were obtained in high yields, short reaction times, at room temperature and without the need of further purification.     

A novel three-component reaction designed by the combinatorial method: Heteroarenes, isothiocyanates and isocyanides

The novel three-component reaction of isoquinoline with isothiocyanates and isocyanides leads to a variety of new imidazoisoquinolines. The zwitterionic ground state of these new ring systems is established by means of NMR and X-ray analysis. Use of phthalazine instead of isoquinoline gives access to imidazole annulated phthalazines.     

Solid phase vs. solution phase differential behavior: Formation of a salicylate structure from a malondialdehyde moiety

Treatment of 2, solid supported synthetic equivalent of 3-formylchromone (4), and ethyl acetoacetate affords the salicylate structure 8 instead of the previously reported isophtalate 7. This is the first formation of a salicylate by a double carbonyl condensation of a malondialdehyde moiety ever reported.