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.     

Synthèse en une étape de N-méthoxyindolinones, de N-méthoxymaléimides et d’anhydrides maléiques à partir d’acides hydroxamiques α-halogénés

α-Halo hydroxamic acids were used in the synthesis of N-methoxyindolinones, symmetric and dissymmetric N-methoxymaleimides in good yields. The hydrolysis of N-methoxymaleimides constitues a new and good route to maleic anhydrides.     

Chiral pyridine N-oxides derived from monoterpenes as organocatalysts for stereoselective reactions with allyltrichlorosilane and tetrachlorosilane

The synthesis of enantiomerically pure C₂-symmetric dipyridylmethane ligands and related N,N′-dioxides is reported. A procedure for the synthesis of a few new enantiomerically pure C₂-symmetric pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as further coordinating elements in the heterocycle framework is described. All compounds were prepared from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetrachlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.     

Photolabile thymidine cleavable with a 532 nanometer laser

The synthesis and characterization of a novel 3′ p-hydroxyphenacyl-caged thymidine bearing a 5′ N,N-diisopropylcyanoethylphosphoramidite is presented representing a new methodology for the photoregulation of PCR and gene expression. Solid phase oligonucleotide synthesis affords a primer blocked at the 3′ position, which could function as a phototrigger for polymerase activity. The caging group exhibits quantitative photolysis in 15 s using a 532 nm green hand laser.     

Novel synthesis of α-nitroalkenes from nitroalkanes via halogenation of intermediate N,N-bis(silyloxy)enamines

An approach to conjugated nitroalkenes via oxidation of N,N-bis(silyloxy)enamines with bromine or iodine in the presence of tetra-n-butylammonium acetate is described. The acetate ion plays a key role by acting as a mild desilylating reagent. This new strategy allows the synthesis of α-nitroalkenes from the corresponding nitroalkanes.     

Single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo[1,2-c]quinazolin-2(3H)-ones

A single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo-[1,2-c]-quinazolin-2(3H)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitro-benzonitrile was developed. Key intermediates were N,N′-disubstituted amidines obtained by rearrangement of 4,5-dihydrotriazoles; the new heterocyclic rings were formed by spontaneous intramolecular reaction of the amino and cyano groups which are present in the intermediates.     

Synthesis of meso-tetraphenyl porphyrins via condensation of dipyrromethanes with N-tosyl imines

A new synthetic route for the synthesis of 5,10,15,20-tetraphenyl porphyrins has been developed based on the reaction of 5-substituted dipyrromethanes with N-tosyl imines in the presence of a metal triflate catalyst. meso-Substituted tetraphenyl porphyrins were synthesized in a two-step process. The first step of the method is the metal triflate-catalyzed condensation of 5-substituted dipyrromethanes with N-tosyl imines to form a porphyrinogen intermediate and the second step is the oxidation of the porphyrinogen to porphyrin. The method was applied to the synthesis of trans-A₂B₂-tetraarylporphyrins and the products were obtained with only a trace amount of one scrambling product. The synthesis of two important building blocks for porphyrin synthesis, mono and di-sulfonamide alkylated 5-substituted dipyrromethanes, was achieved by the addition of 5-substituted dipyrromethane to N-tosyl imine. The application of mono and di-sulfonamide alkylated 5-substituted dipyrromethanes in ‘2+2’ porphyrin formation reactions is presented.     

Synthesis of N-substituted 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-diones

The synthesis of 1,2,3,4-tetrahydrobenz[g]isoquinoline-5,10-dione hydrochlorides is reported starting from 1,4-dihydrobenz[g]isoquinoline-3(2H)-ones or ethyl (3-aminomethyl-1,4-dimethoxynaphth-2-yl)acetates. A third strategy relies on the synthesis of the title compounds via an N-protected 2-(3-bromomethyl-1,4-dimethoxynaphth-2-yl)ethylamine. The synthesized 1,2,3,4-tetrahydro-benz[g]isoquinoline-5,10-diones are a new class of quinones, which have not been reported yet.     

Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an N-acylation-SNAr sequence

A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a β-enaminoester with 2-fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by heating in the presence of base. The conversion, which proceeds by an N-acylation-S_NAr reaction sequence, affords 50–86% yields when R¹ is n-alkyl but ≤30% yields when R¹ is α-branched.     

(Z)-N-(4-Decenoyl)homoserine lactone, a new quorum-sensing molecule, produced by endobacteria associated with Mortierella alpina A-178

N-Acylhomoserine lactones (AHLs) are the conserved quorum-sensing signal molecules in Gram-negative bacteria. (Z)-N-(4-Decenoyl)homoserine lactone (1), a new AHL, was isolated from the culture broth of the fungus Mortierella alpina A-178 harboring bacterial endosymbionts, called endobacteria. The structure and absolute configuration of 1 were elucidated by EI-MS, chemical synthesis, and chiral GC analysis. The compound induced the expression of a QS-regulated reporter gene in Agrobacterium tumefaciens NTL4, although its activity was lower than that of N-decanoylhomoserine lactone (6).     

Synthesis of cis-2,5-disubstituted pyrrolidines via diastereoselective reduction of N-acyl iminium ions

A new procedure for forming cis-2,5-disubstituted pyrrolidines having unsaturated side chains has been developed that features the diastereoselective reduction of N-acyl iminium ions, which were formed in situ by acid-catalyzed cyclizations of unsaturated γ-keto carbamates, with triphenylsilane. The sequence was applied to a very concise synthesis of 16, a subunit in the nonpeptide cholecystokinin antagonist (+)-RP-66803.     

N,N-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent for the synthesis of pyrimidone and pyrimidine derivatives via Biginelli reaction

A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2-(1H)one and benzo[4,5]imidazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent. This method is found to be efficient and convenient for the synthesis of pyrimidone and pyrimidine derivatives.     

Synthesis of N-substituted 1,2-dihydrobenz[g]isoquinoline-5,10-diones

The synthesis of N-substituted 1,2-dihydrobenz[g]isoquinoline-5,10-diones was envisaged as part of our research on structural modifications of pentalongin, the active principle of Pentas longiflora Oliv. Therefore, a synthesis of the 2-aza analogues of this natural pyranonaphthoquinone with an acid-mediated intramolecular cyclization of different N-protected 2-(((2,2-dimethoxyethyl)amino)methyl)-1,4-naphthoquinones in the key step was conducted. The synthesized 1,2-dihydrobenz[g]isoquinoline-5,10-diones represent a new class of compounds, which has been undescribed in organic chemistry.     

Selective O-acylation of unprotected N-benzylserine methyl ester and O,N-acyl transfer in the formation of cyclo[Asp-Ser] diketopiperazines

The synthesis of two diastereomeric cyclo[Asp-N-Bn-Ser] diketopiperazines (2a and 2b) was investigated. Initial formation of the Boc-aspartyl-N-benzyl serine isopeptide methyl esters (4a and 4b) was observed, which derive from the selective O-acylation of unprotected (S)- or (R)-N-benzylserine. This unexpected O-acylation is preferred over the formation of the tertiary amide and the resulting ester bond is stable in solution to O,N-acyl transfer. The O,N-acyl migration is then triggered by cleavage of the Boc protecting group and treatment with base, which also promotes immediate cyclization to the diketopiperazines.     

A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

Solid-phase synthesis of benzimidazole N-oxides on SynPhase™ Lanterns

A solid-phase synthesis of benzimidazole N-oxides was developed while attempting to synthesize 1,5-benzodiazepine-2,4-diones. The key step of the synthesis involves the reduction of an arylnitro to a hydroxyamino intermediate which subsequently condenses with an internal carbonyl group to give a benzimidazole N-oxide. A library of nine benzimidazole N-oxides was prepared on SynPhase™ Lanterns using this reduction-cyclization methodology.     

Synthesis of N-linked glycan derived from Gram-negative bacterium, Campylobacter jejuni

Recent research has revealed the presence of asparagine (Asn)-linked (N-linked) glycoproteins in certain prokaryotes. In this paper, we describe the chemical synthesis of a novel N-glycan derived from Campylobacter jejuni, a heptasaccharide composed of Asn-linked bacillosamine (Bac), repeating GalNAc, and branching Glc, namely GalNAc-α(1,4)-GalNAc-α(1,4)-[Glc-β(1,3)-]GalNAc-α(1,4)-GalNAc-α(1,4)-GalNAc-α(1,3)-Bac. The synthesis started from a Bac-acceptor, which was consecutively glycosylated with 4-O-pentafluoropropionyl (PFP) protected donors to give heptasaccharide. Reduction of azide groups was followed by debenzylation to complete the synthesis of the target oligosaccharide.     

A new approach to fluorinated 4(3H)-quinazolinones

A new approach for the synthesis of fluorinated 1H-quinazolin-4-ones and 4-substituted quinazolines has been developed. 6-Fluoro-1H-quinazolin-4-ones were obtained by intramolecular cyclization of fluorine-containing S-ethyl N-benzoylisothioureas. Nucleophilic substitution reactions at positions 2 and 7, as well as alkylation at 1-position of quinazolinones were investigated. In addition, the synthesis of fluorine-containing 4-aminoquinazolines was carried out.     

Me3SiCl-promoted intramolecular cyclization of aromatic compounds tethered with N,O-acetals leading to the facile preparation of 1,4-benzodiazepine skeletons

The Me₃SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of functional groups is described. This method was successfully applied to the facile preparation of both tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.     

1,n-Diamines. Part 3: Microwave-assisted synthesis of N-acyl-N′-arylhexahydropyrimidines and hexahydro-1,3-diazepines

In this Letter we present a method for the synthesis of N-acyl-N′-arylhexahydropyrimidines 1, by ring closure of N-acyl-N′-aryl-1,3-propanediamines 3 with formaldehyde. Cyclodehydrations were performed in aqueous medium under microwave irradiation, and led to high yields of the desired compounds in remarkably short reaction times. The method also allowed for the synthesis of hitherto unreported N-acyl-N′-arylhexahydro-1,3-diazepines 2. The acyclic tetramethylenic precursors 4 were synthesized by selective functionalization of N-arylputrescines.