A novel solid-phase synthesis of di- and trisubstituted N-acyl ureas

A novel, mild method for the synthesis of di- and trisubstituted N-acyl ureas on solid support is described. Addition of carboxylic acids to a resin-bound carbimidoyl chloride gave, initially, an O-acyl isourea which subsequently rearranged to the corresponding N-acyl urea. Trisubstituted N-acyl ureas were assembled on a Wang resin from a wide range of Fmoc amino acids, secondary amines and carboxylic acids. Acid mediated cleavage yielded the products in good yields and excellent purities. In addition, the regioselective synthesis of disubstituted N-acyl ureas is demonstrated with four examples.     

High throughput synthesis of diverse 2,5-disubstituted indoles using titanium carbenoids bearing boronate functionality

A titanium benzylidene complex bearing a boronate group converted resin-bound esters into enol ethers. Suzuki cross-coupling with aryl iodides followed by cleavage with acid completed the solid-phase synthesis of 2,5-disubstituted N-Boc-indoles. Also reported is the use of tert-butyllithium and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to convert an aryl bromide into an arylboronate in the presence of a dithiane, with simultaneous reduction of an aryl azide to an amine.     

Traceless solid-phase synthesis of 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinoline-2-ones

A traceless solid-phase route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones is described. N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was tethered to Rink resin via its carboxylic group. The protected amine was coupled with an organic acid after Alloc-deprotection and the arylfluorine was displaced with a primary amine to generate a resin-bound aniline with two diversity points. The aniline was released via cleavage to produce the desired products in high yield and purity.     

A new and efficient multicomponent solid-phase synthesis of 2-acylaminomethylthiazoles

A new multicomponent reaction (MCR) for the preparation of 2-substituted thiazole libraries using Rink amide resin is described. Thiazoles are assembled in a one-pot MCR of a thiocarboxylic acid, aldehyde, 3-(N,N-dimethylamino)-2-isocyanoacrylate with a resin-bound primary amine. Aliphatic and aromatic thiocarboxylic acids as well as aliphatic and (hetero-) aromatic aldehydes work in the reaction. Cleavage of the product yields the substituted thiazoles in reasonable to good purity.     

Introduction of the Aib-Pro unit into peptides by means of the ‘azirine/oxazolone method’ on solid phase

A method for the direct introduction of Aib-Pro into peptides on solid phase was developed. The Aib-Pro unit was introduced by means of the ‘azirine/oxazolone method’ using allyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate as the synthon. After the reaction of the resin-bound amino or peptide acid with allyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate, the allyl protecting group of the resulting extended peptide could be removed by a mild Pd⁰-promoted procedure. Cleavage of the peptide from the resin was performed with UV light at 352 nm and yielded C-terminal protected peptides. The method found a successful application in the syntheses of different Aib-Pro containing peptaibol segments. Furthermore, a protected derivative of the peptide antibiotic Trichovirin I 1B was prepared by segment condensation.     

Parallel synthesis of 19-membered ring macro-heterocycles via intramolecular thioether formation

Starting from resin-bound orthogonally protected lysine, the generation of 19-membered ring macro-heterocycles via intramolecular thioether formation is described. The on resin cyclization occurred by the coupling of p-fluoro-m-nitro benzoic acid or bromo acetic acid followed by intramolecular substitution S_NAr or S_N2 displacement of the fluoro and bromo groups, respectively. The described approaches present versatile synthetic routes toward the synthesis of libraries of macro-heterocycles in an attempt to establish lead drug candidates. The desired cyclic products were obtained in good yields and good purities.     

Ugi four-center three-component reaction for the parallel solid-phase synthesis of N-substituted thiomopholinones

Starting with resin-bound bifunctional 2-(2-aminoethylthio)acetic, an efficient synthesis of a variety of N-cycloakyl thiomopholinones is described utilizing the Ugi four-center three-component reaction (U-4C-3CR).     

Solid-phase synthesis of 3-alkyl-2-arylamino-3,4-dihydroquinazolines

The solid-phase synthesis of 3-alkyl-2-arylamino-3,4-dihydroquinazolines using an N-Fmoc-β-amino-2-nitrobenzenepropanoic acid scaffold is described. The resin-bound scaffold was reductively alkylated with aldehydes or ketones after Fmoc deprotection, followed by reduction of the nitro group with tin(II) chloride. Subsequent cyclization of the 1,3-diamine intermediates with aryl isothiocyanates in the presence of 1,3-diisopropylcarbodiimide (DIC) afforded the desired products in high purity with moderate to good yield after trifluoroacetic acid (TFA) cleavage.     

Synthesis of N′-substituted Ddz-protected hydrazines and their application in solid phase synthesis of aza-peptides

Hydrazine derivatives are of considerable scientific and industrial value. Substituted hydrazines are precursors for many compounds of great interest and importance, among them aza-peptides. (Aza-peptides are peptide analogues in which one or more of the α-carbons, bearing the side chain residues, has been replaced by a nitrogen atom.) Aza-amino acid residues conserve the pharmacophores necessary for biological activity while inducing conformational changes and increased resistance to proteolytic degradation. These properties make aza-peptides attractive tools for structure-activity relationship studies and drug design. We describe the synthesis of N′-substituted 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) protected hydrazines. A general approach for solid phase synthesis of aza-peptides has been developed based on the in-situ activation of the N-Ddz,N′-substituted hydrazines with phosgene, followed by introduction to the N-terminus of a resin-bound peptide. The Ddz-aza-amino building units include aliphatic, aromatic and functionalized side chains, protected for synthesis by the Fmoc strategy. Solid phase aza-peptide synthesis is demonstrated including selective mild deprotection of Ddz with Mg(ClO₄)₂ and coupling of the next amino acid with triphosgene. Ddz deprotection is orthogonal with the Fmoc and Boc protecting groups, making the solid phase Ddz-aza-peptide synthesis compatible with both the Fmoc and the Boc strategies. The Ddz-protected hydrazines have wide applications in the synthesis of substituted hydrazines and in the synthesis of aza containing peptidomimetics.     

Measurements of the solubilities of derivatized amino acids in supercritical carbon dioxide

The solubilities of phenylalanine and tyrosine in supercritical carbon dioxide (SCCO₂) were measured after derivatization as the N-acetyl amino acid ethyl ester, N-carbobenzoxy amino acid and N-acetyl amino acid. Using an SCCO₂ flow system, a measuring method of the saturated solubilities of the derivatized amino acids was established in which the contact height of the extraction cell, i.e. a packed column, is increased till the concentration of a derivatized amino acid at the exit of the cell reaches a plateau. The solubilities of N-acetyl phenylalanine ethyl ester (APEE) exceeded 0.001 mole fraction, which is higher than those of caffeine produced in industrial SCCO₂ processes. A possible way of separating the amino acid mixtures using polarity differences in different amino acid side chains was demonstrated using the solubility data of the N-acetyl-amino acid ethyl esters in SCCO₂, as the solubilities of APEE are higher than those of N-acetyl tyrosine ethyl ester by two orders of magnitude.     

Solid-phase synthesis of 3-amino-1,2,4-triazoles

A solid-phase synthesis of 3-amino-1,2,4-triazoles is described. Reaction of resin bound S-methylisothiourea 2 with carboxylic acids yielded resin-bound S-methyl-N-acylisothioureas 3, which reacted with hydrazines under mild conditions to afford the corresponding resin-bound 3-amino-1,2,4-triazoles 4 with regioselectivity. Following cleavage, the desired products 5 were obtained in good yields and purities.     

A triazene-based new photolabile linker in solid phase chemistry

An extension of the T2 linker methodology by showing its applicability as a photocleavable linker is reported. Photocleavage was carried out with 355 nm UV laser irradiation (3ω Nd-YAG) in methanol/diethyl ether and is suitable for protected amino acid derivatives, as well as simple small organic molecules including resin-bound biotin. The linker is stable under a wide range of conditions with the exception of strongly acidic media.     

Diversity-oriented synthesis of N-aryl-N-thiazolyl compounds

An efficient approach toward the parallel solid-phase synthesis of highly diversified N-aryl-N-thiazolyl compounds is presented. The treatment of resin-bound aniline derivatives with Fmoc-isothiocyanate generated aryl thioureas which, following Hantzsch’s reaction with a variety of α-haloketones and cleavage of the solid support, led to the desired N-aryl-N-thiazolyl compounds in good yield and high purity.     

Parallel Solid-Phase Synthesis of disubstituted 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones

A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimidazole provided following Fmoc elimination free amine. Treatment of the free amine with 1,1′-carbonyldiimidazole or 1,1′-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoins or thiohydantoins were isolated in good yields.     

Synthesis of N-phosphoryl amino acids using bis(9-fluorenylmethyl)phosphite

Bis(9-fluorenylmethyl)phosphite (BFMP) was found to be an effective reagent for the N-phosphorylation of various amino acid methyl esters. BFMP was prepared from N,N-diisopropyl phosphoramidous dichloride in a one-pot two-step reaction and was obtained as a crystalline solid. N-Phosphorylation of the methyl esters of seven representative amino acids with BFMP was high-yielding and generally resulted in crystalline products. Complete deprotection of both the 9-fluorenylmethylphosphosphate esters and the amino acid methyl esters was accomplished concomitantly with LiOH to give N-phosphoryl amino acids.     

A methylenic group binds guanidinoacetic acid to glycine and serine in two novel copper(II) complexes: Synthesis,X-ray structure and spectroscopic characterization

New condensed amino acids were observed in two Cu(II) complexes, both involving guanidinoacetic acid (GAA). The copper(II) complexes, 1 and 2, were synthesized and characterized by X-ray crystallography and infrared spectroscopy. Vibrational assignments were performed with the aid of density functional theory (DFT) calculations. Both complexes present an elongation of the carbon chain of the starting amino acid, GAA. One methylenic group binds GAA to the other amino acid, which can be glycine or serine. Complex 1 presents a new condensed synthetic amino acid, glycine-3-N-methylguanidino acetic acid (Gly-mGAA) that is the result/product of the reaction between GAA and glycine, with an addition of one carbon in the chain. In complex 2, a similar ligand to Gly-mGAA was observed, but in this case it is a product of the reaction between GAA and serine, that is, serine-3-N-methylguanidino acetic acid (Ser-mGAA). Gly-mGAA and Ser-mGAA coordinate to Cu(II) through two nitrogen atoms and two oxygen atoms. In addition, we attempt to propose the mechanism for formation of Ser-mGAA and Gly-mGAA in two steps. The first one involves a deamidination reaction between two GAA species, producing the intermediate N,N′-guanidinodiacetic acid. The second step involves a decarboxylation process between GAA and Ser or Gly.     

Cellulose chiral induction during the synthesis of cellulose N-phthaloyl-amino acid esters

Cellulose was acylated by N-phthaloyl amino acid chlorides in the presence of pyridine to prepare an original library of cellulose N-phthaloyl-amino acid esters as chiral solid supports for enantioselective adsorption of racemates. Cellulose esters derived from N-phthaloyl glycine, alanine, valine, leucine, phenylalanine, phenylglycine and isoleucine were isolated in high yields and with degrees of substitution approaching 3. Interestingly, the use of an optically pure (d or l) or a rac-amino acid led to the same cellulose ester according to (1) the measured optical rotation, (2) the enantiomeric excesses of the amino acids resulting from a non-racemising and total hydrolysis and (3) the enantioselective adsorptions of rac-benzoin, rac-Pirkle’s alcohol and rac-Tröger’s base. This suggests that either the formation of a prochiral ketene intermediate which was diastereoselectively attacked by the cellulose alcohols or, alternatively (or concomitantly), the occurrence of a chiral induction in the formed triesters during prolonged contact with the pyridine base in the reaction medium. Enantiomeric excesses in favour of the (S) form ranged from 8 % to 50 % depending on the N-phthaloyl amino acid. The memory of the chirality of the starting material was lost and new chirality was imprinted by the cellulose backbone on the amino acid residues.     

An N-protection free ligation of the peptide thioester and the peptide with an N-alkoxy- or N-aryloxyamino group at its N-terminus

Peptides with an N-alkoxy or N-aryloxy amino acid at their N-terminus were synthesized and successfully ligated with a peptide thioester by silver ion activation under a slightly acidic condition without requiring protection of the side chain amino groups. The N-methoxy group was easily cleaved by the SmI₂ reduction in CH₃OH aq. to obtain the desired peptide with a native peptide bond. This method was successfully applied to the synthesis of the human atrial natriuretic peptide showing the efficiency of the novel ligation.     

Dibutylphosphate (DBP) mediated synthesis of cyclic N,N′-disubstituted urea derivatives from amino esters: a comparative study

The N,N′-disubstituted urea derivatives such as amino acid hydantoins and dihydrouracil derivatives were prepared starting from natural and unnatural amino acid esters using dibutylphosphate (DBP). During the attempted synthesis of N-heterocycles with larger than six-membered rings containing the N,N′-disubstituted urea functionalities, three unexpected products namely squamolone, N-methyl pyrrolidine-2-one, and diketopiperazine were isolated.     

On the easy oxidation of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid to its disulfide dimer

The physical and spectroscopic data of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid are reviewed and the synthesis of (R)-di-[2-(N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid disulfide is described. The product resulting from the conjugate addition of the dithioacid to 2(5H)-furanone is also characterised.