Mild and efficient Lewis acid-promoted detritylation in the synthesis of N-hydroxy amides: a concise synthesis of (-)-Cobactin T

An efficient, high-yielding Lewis acid promoted deprotection of O-trityl hydroxylamine derivatives is described. A range of acid-labile protecting groups, such as N-Boc and O-TBS, were tolerated under these mild conditions. The present method is applicable to the synthesis of a broad range of hydroxylamine derivatives, including N-hydroxy amides (hydroxamic acids), N-hydroxy sulfonamides, and N-hydroxy ureas, which often exhibit significant biological activities. An application of this methodology for a concise synthesis of (-)-Cobactin T (18) is also demonstrated.     

A convenient one-step synthesis of fluoroethylidene derivatives

A convenient one-step synthesis of gem-monofluoroalkylolefins starting from aldehydes or ketones was developed. This method comprises the utilisation of 2-(1-fluoroethyl)sulfonyl-1,3-benzothiazole according to Julia's procedure and opens a new opportunity for the synthesis of fluoroalkylidene derivatives.     

Application of an automated synthesis suite to parallel solution-phase peptide synthesis

An in-house developed automated synthesis suite was used to prepare a library of 72 tetrapeptide derivatives, the starting materials for pharmaceutically attractive pentapeptides, employing a convergent strategy. An initial set of 18 dipeptides were synthesized on a large-scale (100-1000 g) using automated synthesis workstations, and then 72 tetrapeptides were synthesized on a medium scale (5-10 g) using an automated system. Each di- or tetrapeptide was prepared in a single operating cycle using a modified methanesulfonic acid method, then a sub-library of 56 pentapeptides were synthesized in parallel, on a small-scale (100 mg-1 g) using a robotic workstation.     

Catalytic asymmetric aza-Darzens reaction with a vaulted biphenanthrol magnesium phosphate salt

Conditions for a catalytic asymmetric aza-Darzens aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium phosphate salt is described. Using simple substrates, this methodology explores the scope and reactivity of a new magnesium catalyst for an aziridination reaction capable of building chirality and complexity simultaneously.     

An improved synthesis of isonitrosoacetanilides

A novel two-step synthesis of isonitrosoacetanilides [2-(hydroxyimino)-N-phenylacetamides] has been developed, involving the initial acylation of aniline derivatives with 2,2-diacetoxyacetyl chloride, followed by reaction with hydroxylamine hydrochloride. The method works equally well with a variety of different aniline derivatives, including those with poor aqueous solubility and those containing electron rich ortho-substituents, neither of which react well under traditional conditions.     

Diastereoselective synthesis of glutamate-appended oxolane rings: synthesis of (s)-(+)-lycoperdic acid

The stereocontrolled synthesis of the glutamate-containing natural product (S)-(+)-lycoperdic acid is described. The key transformation in the synthetic route was an efficient diastereoselective annulation of an oxolane ring onto a pyroglutamate scaffold to construct either a gamma,gamma-disubstituted glutamate-appended tetrahydrofuran or a gamma-lactone. The reaction sequence also featured an improved method for the halogenation of pyroglutamate derivatives in high yield with enhanced stereoselection.     

One-pot synthesis of 5-amino 4-cyano pyrrole derivatives

One-pot synthesis of 5-amino 4-cyano pyrrole derivatives is herein disclosed. The described method consists of four steps and gives new pyrrole derivatives in moderate to good yields. This synthesis can be used for a large scale preparation.     

Palladium acetate-catalysed one-pot green synthesis of bis α-aminophosphonates

Research on Chemical Intermediates - A simple and effective green method has been developed for the synthesis of a series of novel bis α-aminophosphonate derivatives (4a–j) by the...     

Electroreductive synthesis of 1-(bromobenzyl)-isoquinoline derivatives and its application to cularine synthesis

Electrochemical reduction of immonium salts in the presence of bromobenzylbromide derivatives gave 1-(bromobenzyl)-isoquinoline derivatives in moderate yields. This reaction is useful in the synthesis of several natural alkaloids as exemplified in the synthesis of Cularine.     

Catalytic synthesis of thiazolidines by the reaction of Nef-isocyanide reaction

Research on Chemical Intermediates - A practical and efficient method for the synthesis of thiazolidine derivatives via Nef-isocyanide three-component reaction using supported phosphoric acid on...     

An efficient one-pot three-component synthesis and antimicrobial evaluation of tetra substituted thiophene derivatives

A convenient one-pot three-component method for the preparation of tetra-substituted thiophene derivatives has been developed. Reaction of acetyl acetone 1, phenyl isothiocynate 2 and 2-chloromethyl derivatives 3a–3c in the presence of potassium carbonate afforded the target compounds, namely ethyl2-(4-acetyl-3-methyl-5-(phenylamino)thiophen-2-yl)-2-oxoacetate derivatives 4a–4e, ethyl 3-(4-acetyl-3-methyl-5-(phenylamino)thiophen-2-yl)-3-oxopropanoate derivatives 4f–4i, di((4-acetyl-3-methyl-5-phenylamino)thiophen-2-yl)ketone derivatives 4j–4n in reasonable overall yields. The synthesized compounds were screened for antimicrobial activity. The detailed synthesis, spectroscopic data and antimicrobial activities of synthesized compounds were reported.     

Enantioselective synthesis of (2-pyridyl)alanines via catalytic hydrogenation and application to the synthesis of L-azatyrosine

[reaction: see text] A novel method for the synthesis of (2-pyridyl)alanines 2a-b was developed by converting (2-pyridyl)dehydroamino acid derivatives 1a-b to the corresponding N-oxides 3a-b followed by asymmetric hydrogenation using (R,R)-[Rh(Et-DUPHOS)(COD)]BF(4) [(R,R)-6] catalyst and subsequent N-oxide reduction in 80-83% ee. This methodology was applied to the total synthesis of L-azatyrosine [(+)-12], an antitumor antibiotic, starting from (5-benzyloxy)-2-pyridylmethanol (7), in >96% enantiomeric purity.     

Bioinspired total synthesis and human proteasome inhibitory activity of (-)-salinosporamide A, (-)-homosalinosporamide A, and derivatives obtained via organonucleophile promoted bis-cyclizations

A full account of concise, enantioselective syntheses of the anticancer agent (-)-salinosporamide A and derivatives, including (-)-homosalinosporamide, that was inspired by biosynthetic considerations is described. The brevity of the synthetic strategy stems from a key bis-cyclization of a β-keto tertiary amide, which retains optical purity enabled by A(1,3)-strain rendering slow epimerization relative to the rate of bis-cyclization. Optimization studies of the key bis-cyclization, enabled through byproduct isolation and characterization, are described that ultimately allowed for a gram scale synthesis of a versatile bicyclic core structure with a high degree of stereoretention. An optimized procedure for zincate generation by the method of Knochel, generally useful for the synthesis of salino A derivatives, led to dramatic improvements in side-chain attachment and a novel diastereomer of salino A. The versatility of the described strategy is demonstrated by the synthesis of designed derivatives including (-)-homosalinosporamide A. Inhibition of the human 20S and 26S proteasome by these derivatives using an enzymatic assay are also reported. The described total synthesis of salino A raises interesting questions regarding how biosynthetic enzymes leading to the salinosporamides proceeding via optically active β-keto secondary amides, are able to maintain the stereochemical integrity at the labile C2 stereocenter or if a dynamic kinetic resolution is operative.     

New method for the synthesis of indenes

A new two-step method was developed for the synthesis of 2-sulfonyl-substituted indenes from aromatic aldehydes. The reactions of 1-phenylsulfonyl-1-(trimethylsilyl)ethylene with ortho-lithiated derivatives of aromatic and heteroaromatic aldehydes afford conjugate addition products whose subsequent cyclization gives substituted 2-sulfonylindenes in preparative yields. The reactions of 2-(phenylsulfonyl)indenes with Grignard reagents were studied. It was shown that the sulfonyl group can be replaced in the presence of iron(iii) acetylacetonate.     

Bis(oxazoline) Lewis acid catalyzed aldol reactions of pyridine N-oxide aldehydes--synthesis of optically active 2-(1-hydroxyalkyl)pyridine derivatives: development, scope, and total synthesis of an indolizine alkaloid

A new, short, and simplified procedure for the synthesis of optically active pyridine derivatives from pro-chiral pyridine-N-oxides is presented. The catalytic and asymmetric Mukaiyama aldol reaction between ketene silyl acetals and 1-oxypyridine-2-carbaldehyde derivatives catalyzed by chiral copper(II)-bis(oxazoline) complexes gave optically active 2-(hydroxyalkyl)- and 2-(anti-1,2-dihydroxyalkyl)pyridine derivatives in good yields and diastereoselectivities, and in excellent enantioselectivities-up to 99 % enantiomeric excess. As a synthetic application of the developed method, a full account for the asymmetric total synthesis of a nonnatural indolizine alkaloid is provided.     

Eco-friendly synthesis of novel pyrimidine derivatives as potential anticancer agents

Herein, a rapid and highly efficient method for the synthesis of a new series of pyrimidine derivatives was demonstrated. The strategy was emanated from the reaction of hydrazinyl pyrimidine derivative ( 1 ) with different electrophilic species such as ethyl acetoacetate, ethyl 4,4,4-trifluoro acetoacetate, and phenyl isothiocyanate following cyclocondensation mechanism to afford the corresponding derivatives ( 2-6 ). Furthermore, condensation of hydrazine derivative ( 1 ) with different carbonyl compounds via conventional heating and microwave irradiation conditions was employed as a source of Schiff base derivatives bearing pyrimidine moiety ( 7-12 ). The structural features of all newly synthesized compounds were characterized by elemental and spectroscopic evidences. Some of the synthesized compounds were evaluated for in vitro cytotoxicity. The preliminary screening results showed that most of the tested compounds have moderate cytotoxic activity against HepG2 and HCT-116 cell lines. Finally, a molecular docking study was conducted to reveal the probable interaction with the thymidylate synthase enzyme.     

A ring expansion-annulation strategy for the synthesis of substituted azulenes. Preparation and Suzuki coupling reactions of 1-azulenyl triflates

[structure: see text]. A new strategy for the synthesis of substituted azulenes is reported, based on the reaction of beta'-bromo-alpha-diazo ketones with rhodium carboxylates. The key transformation involves intramolecular addition of a rhodium carbenoid to an arene pi-bond, electrocyclic ring opening, beta-elimination, tautomerization, and trapping to produce 1-hydroxyazulene derivatives. The synthetic utility of the method is enhanced by the ability of the triflate derivatives to participate in Suzuki coupling reactions, as illustrated in a synthesis of the antiulcer drug egualen sodium (KT1-32).     

Solid phase synthesis of cyclopropenes

Cyclopropene derivatives of high purity were prepared by reaction of acetylenes with a rhodium carbenoid bound to a polystyrene resin. This solid phase method avoids the formation of undesired byproducts obtained in the corresponding solution reaction and an eventual extension to combinatorial synthesis of cyclopropene derivatives could be achieved.     

Enantiomerically pure synthesis of beta-substituted gamma-butyrolactones: a key intermediate to concise synthesis of pregabalin

Chiral beta-substituted gamma-butyrolactones are known to be important intermediates for many biologically active compounds such as gamma-aminobutyric acid (GABA) derivatives and lignans. We have developed a general, convenient, and scalable synthetic method for enantiomerically pure beta-substituted gamma-butyrolactones, with either configuration, via nucleophilic cyclopropane ring opening of (1S,5R)- or (1R,5S)-bicyclic lactone followed by decarbethoxylation. The utility of our method was demonstrated by streamlined synthesis of pregabalin ((S)-3-isobutyl-gamma-aminobutyric acid), an anticonvulsant drug for the treatment of peripheral neuropathic pain.     

Facile synthesis of optically active imidazole derivatives

Five optically active imidazole derivatives have been synthesized via a facile 4-step reaction sequence starting from commercially available and inexpensive N-Cbz amino acids. While microwave assisted condensation was unsuccessful, the condensation of the corresponding alpha-bromoketones with formamidine acetate in liquid ammonia was revealed to be a useful method for the synthesis of such imidazole derivatives. The derivatives thus prepared are structurally-related to histamine.