Stereoselective synthesis of N-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides

The stereoselective synthesis of N-acyl- and N-Boc-protected pyrrolidines via Pd-catalyzed reactions of γ-(N-acylamino) alkenes and γ-(N-Boc-amino) alkenes with aryl bromides is described. These reactions effect formation of two bonds in a single operation and proceed with generally high levels of diastereoselectivity. In contrast to previously described reactions of γ-(N-arylamino) alkenes, these transformations proceed in high yield and high regioselectivity with both electron-rich and electron-deficient aryl bromides as well as vinyl bromide substrates.     

Efficient synthesis of N,N′-dialkyl-N″-dialkylaminocarbothioyl thioureas from cyclic secondary amines, CS2, and N,N′-dialkyl carbodiimides in water

A mild, convenient, and practical one-pot procedure for direct synthesis of N,N′-dialkyl-N″-dialkylaminocarbothioyl thioureas is described via three-component reaction of cyclic secondary amines, CS₂, and N,N′-dialkyl carbodiimides in water at room temperature.     

Total synthesis of malayamycin A and analogues

The total synthesis of the bicyclic C-nucleoside malayamycin A is described starting with d-ribonolactone. A new method was developed to obtain preparatively important quantities of β-pseudouridine, which was used as an intermediate. The synthesis of a carba N-nucleoside analogue of malayamycin A is also described.     

Synthesis of N-substituted aziridine-2-carboxylates

The synthesis of the methyl esters of N-methoxycarbonyl- and N-benzyloxycarbonylaziridine-2-carboxylic acid 2 by reacting methyl 2-chloro-N-carbalkoxyglycinate 1 with diazomethane is described. The aziridines were readily converted to derivatives of O-methylserine 5 and S-methylcysteine 6.     

PTSA catalyzed straightforward protocol for the synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzothiazoles in PEG

An efficient PTSA catalyzed synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzothiazoles has been described using S-ethylated-N-acylthioureas as substrates and polyethylene glycol as solvent.     

Direct arylation of azine N-oxides with aryl triflates

Palladium catalyzed direct arylation of azine N-oxides using aryl triflates to afford the corresponding 2-aryl azine N-oxides is described. The reaction is carried out with a range of both N-oxides and aryl triflates. The arylation can be carried out in sequence to yield differentially diarylated products. The regioselectivity and scope of 3-substituted azine N-oxides are investigated. The method is applied to the synthesis of a compound that exhibits antimalarial and antimicrobial activities.     

Regioselective ring opening of β-phenylglycidate and aziridine-2-carboxylates with N-alkylhydroxylamines: synthesis of isoxazolidinones

A simple and efficient method for the synthesis of 4-hydroxy or 4-alkylamino isoxazolidin-3-ones and 4-hydroxy isoxazolidin-5-ones is described. The synthesis involved the ring opening of ethyl β-arylglycidates or ethyl N-alkylaziridine-2-carboxylates by free N-alkylhydroxylamines or hydroxylamine anions, followed by cyclization to give the title isoxazolidinones in moderate to good yields.     

Copper catalyzed arylation with boronic acids for the synthesis of N-aryl purine nucleosides

The synthesis of a series of N¹-aryl inosine and guanosine derivatives is described. The procedure for chemoselective N¹-arylation involves the mild oxidative copper(II) mediated coupling with boronic acids. This approach provides access to substituted N¹-aryl purines with interesting structural characteristics and novel scaffolds for drug discovery.     

Reductive alkylation of thioureas: a highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas

A highly practical synthesis of unsymmetrical N,N′-disubstituted thioureas by the reductive alkylation of N-monosubstituted thioureas with aldehydes is described. N-Monosubstituted thioureas can in turn be synthesized by the reductive amination of thiourea with an appropriate aldehyde. This reductive alkylation methodology was also extended to carbamates.     

Novel coupling reaction between sulfonyl azide and N,N,N',N'-tetramethylthiourea

The synthesis of sulfonylguanidines from N,N,N',N'-tetramethylthiourea and sulfonyl azides is described. This method serves as an alternative route for generating sulfonylguanidines via the use of stable starting materials.     

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.     

Synthesis of aryl benzyl NH-sulfoximines

Efficient synthesis and characterisation of a series of aryl benzyl NH-sulfoximines are described. While N-protected versions of aryl benzyl sulfoximines have been previously described, reports of their deprotection are very limited, presumably due to lability under the typically harsh deprotection conditions which can be employed with the less reactive aryl alkyl derivatives. Use of N-cyanosulfoximines as key intermediates overcomes these difficulties leading to an effective synthetic route to these compounds.     

Investigation for the cyclization efficiency of linear tetrapeptides: Synthesis of tentoxin B and dihydrotentoxin

Investigation of the cyclization efficiency of N-methyl linear tetrapeptides using a molecular modeling study and chemical synthesis is described. The linear peptide with two N-methyl groups, MeAla-Leu-MePhe-Gly, forms γ-turn like conformation with the amine at N-terminus and the carbonyl at C-terminus in closer proximity to give the desired cyclic tetrapeptide, dihydrotentoxin. In addition, synthesis of tentoxin B by the combination of Fmoc solid-phase peptide synthesis and cyclization in solution phase has been reported. An unusual amino acid, an L-N-methyl-β-hydroxyphenylalanine derivative, which was assembled on solid support, was prepared from ethyl cinnamate. Cyclic tetrapeptide formation and cleavage of benzyl ether were optimized with DIPCI/HOBt/DIPEA and Et₃SiH/Pd(OH)₂, respectively.     

Peptide thioester preparation based on an N-S acyl shift reaction mediated by a thiol ligation auxiliary

Formation of peptide thioesters, based on an N to S acyl shift mediated by an auxiliary, N-4,5-dimethoxy-2-mercaptobenzyl (Dmmb) group, under acidic conditions, is described. The protected peptide was assembled on a hydroxymethylphenylacetamidomethyl resin via an N-Dmmb-amino acid residue according to standard Fmoc solid-phase peptide synthesis following treatment with trifluoroacetic acid. The peptide α-thioester was released from the resin by reaction with 2-mercaptoethanesulfonic acid in the presence of N,N-diisopropylethylamine.     

Development of a practical and scalable synthesis of anti-HBV drug Y101

The process research and development of a practical and scalable synthetic method towards Anti-HBV Drug N-[N-benzoyl-O-(2-dimethylaminoethyl)-l-tyrosyl]-l-phenylalaninol (Y101) was described. Initial synthetic routes of Y101 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the collaboration between Medicinal Chemistry and Research active pharmaceutical ingredient (API), a fit for purpose route for the kilo scale synthesis of Y101 was developed. In contrast, the improved route described here did not require purification by column chromatography for all steps, and the formation of impurities was effectively suppressed. This highly efficient and scalable process was successfully demonstrated in the large-scale synthesis of Y101.     

An efficient and facile synthesis of N-Cbz-β-aminoalkanesulfonamides

An efficient method for the synthesis of N-Cbz-β-aminoalkanesulfonamides was described.N-Cbz-β-aminoalkanesulfonamides were readily prepared in good yields from a variety of amino alcohols,including optically active ones,via N-Cbz protection with benzyl chloroformate,Mitsunobu esterification reaction with thiolacetic acid,N-chlorosuccinimide oxidation,and ammonolysis process.     

A practical and efficient synthesis of chiral N,N-disubstituted C2 symmetric diamines derived from (R,R)-1,2-diaminocyclohexane

An improved synthesis of chiral diamine ligands derived from (R,R)-1,2-diaminocyclohexane is described, providing N-substituted diamines. The synthesis of other new ligands based on this methodology is also reported.     

First total synthesis and biological evaluation of the cyclic heptapeptide rhizonin A

The first total synthesis and biological evaluation of the naturally occurring cyclic heptapeptide rhizonin A are described. The synthesis includes solution-phase peptide synthesis and the preparation of NMe-3-(3-furyl)alanine (NMe-FurAla), a unique component of rhizonin A, which was prepared in chiral form via Barton-MacCombie deoxygenation as a key step. The bioactivity was assessed using 3T3-L1 murine adipocytes.     

Efficient synthesis of N-Me, N-Boc-protected α-hydrazinoacids: access to 1:1:1 [N-Me α-hydrazino/α/N-Me α-hydrazino]trimers

The preparation of optically pure N^α-Me, N^β-Boc-protected α-hydrazinoacids in large scale is described via a S_N2 protocol. These compounds were used as starting materials for the synthesis of 1:1:1 [N^α-Me α-hydrazino/α/N^α-Me α-hydrazino]trimers.     

Rapid and efficient microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles

The microwave-assisted synthesis of 5-amino-3-aralkoxy(methoxy)amino-1,2,4-oxadiazoles starting from N¹-aralkoxy-(methoxy)-N³-cyano-O-phenylisoureas and hydroxylamine is described. N¹-Aralkoxy(methoxy)-N³-cyano-O-phenylisoureas are readily accessible by treatment of diphenyl N-cyanimidocarbonate with O-substituted hydroxylamines.