Synthesis of a new 1,4-dihydropyridine containing the imidazo[1,5-α]pyridine nucleus

The synthesis of the new dihydropyridine diethyl 1,4-dihydro-4-(imidazo[1,5-α]pyridin-8-yl)-2,6-dimethyl-pyridine-3,5-dicarboxylate ( 1 ) is described. After many attempts to prepare the key intermediate aldehyde 2a by different approaches, this compound has been obtained in good yields from methyl 2-cyano-3-pyridinecar-boxylate ( 10 ). A three-step procedure involving reduction to the amine, formylation with concomitant cyclization and reduction of the ester group was used.     

Tandem [5+1] annulation-isocyanide cyclization: efficient synthesis of hydroindolones

A new strategy for the rapid construction of functionalized reduced indoles starting from activated methylene isocyanides and 1,5-dielectrophilic 5-oxohepta-2,6-dienoates (and their equivalents) through a [5+1] annulation-isocyanide cyclization cascade under basic conditions has been developed. This strategy allows the synthesis of polysubstituted dihydroindolones and tetrahydroindolones in high to excellent yields under extremely mild conditions in a single step.     

Molecular diversity via amino acid derived alpha-amino nitriles: synthesis of spirocyclic 2,6-dioxopiperazine derivatives

[reaction: see text] Chiral spirocyclic 2,6-dioxopiperazines were synthesized from amino acid derived alpha-quaternary alpha-amino nitriles via H(2)SO(4)-promoted cyano hydration, followed by base-mediated cyclization and N-alkylation. This methodology, requiring the previous preparation of the amino nitrile by a modified Strecker reaction, was applied to Phe, Trp, Pro, Asp, Glu, and Ser derivatives. In the case of the Trp-derived amino nitrile the major product of the treatment with H(2)SO(4) was not the expected carboxamide, but a new tetracyclic indoline derivative containing the novel heterocyclic system hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indole, as a result of a domino tautomerization. The treatment of this indoline derivative with refluxing 1 N HCl led to a Trp-derived 2,6-dioxopiperazine. The 2,6-dioxopiperazine ring opened under the reaction conditions of methyl ester saponification, giving N-(carboxyalkyl)amino acid derivatives. Therefore, the synthesis of 2,6-dioxopiperazines containing free carboxylic acids from the respective methyl esters required transesterification to benzyl esters, followed by hydrogenolysis.     

Stereoselective synthesis of 2,6-cis-substituted tetrahydropyrans: Brønsted acid-catalyzed intramolecular oxa-conjugate cyclization of α,β-unsaturated ester surrogates

Intramolecular oxa-conjugate cyclization (IOCC) of α,β-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure of substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Br?nsted acid-catalyzed IOCC of α,β-unsaturated ester surrogates (e.g., α,β-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to >20:1). These α,β-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Br?nsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology.     

On-resin native chemical ligation for cyclic peptide synthesis

A novel cysteine derivative, N(alpha)-trityl-S-(9H-xanthen-9-yl)-l-cysteine [Trt-Cys(Xan)-OH] has been introduced for peptide synthesis, specifically for application to a new strategy for the preparation of cyclic peptides. The following steps were carried out to synthesize the cyclic model peptide cyclo(Cys-Thr-Abu-Gly-Gly-Ala-Arg-Pro-Asp-Phe): (i). side-chain anchoring of Fmoc-Asp-OAl via its free beta-carboxyl as a p-alkoxybenzyl ester to a solid support; (ii). stepwise chain elongation of the peptide by standard Fmoc/tBu solid-phase chemistry; (iii). removal of the N-terminal Fmoc group; (iv). coupling of Trt-Cys(Xan)-OH; (v). selective Pd(0)-promoted cleavage of the C-terminal allyl ester; (vi). coupling of the C-terminal residue, i.e., H-Phe-SBzl, preactivated as a thioester; (vii). selective removal of the N(alpha)-Trt and S-Xan protecting groups under very mild acid conditions; (viii). on-resin cyclization by native chemical ligation in an aqueous milieu; and (ix). final acidolytic cleavage of the cyclic peptide from the resin. The strategy was evaluated for three supports: poly[N,N-dimethacrylamide-co-poly(ethylene glycol)] (PEGA), cross-linked ethoxylate acrylate resin (CLEAR), and poly(ethylene glycol)-polystyrene (PEG-PS) graft resin supports. For PEGA and CLEAR, the desired cyclic product was obtained in 76-86% overall yield with initial purities of approximately 70%, whereas for PEG-PS (which does not swell nearly as well in water), results were inferior. Solid-phase native chemical ligation/cyclization methodology appears to have advantages of convenience and specificity, which make it promising for further generalization.     

A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction

The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na₂S₂O₄ in dioxane/water at reflux.     

A facile and effective synthesis of lipophilic 2,6-diketopiperazine analogues

Adamantane and cyclooctane lipophilic 2,6-diketopiperazines (2,6-DKPs) have been prepared by a simple and effective method, including the synthesis of the corresponding iminodiacetic amido-ester derivatives and their intramolecular cyclization. In this method, the key step of the imide formation was accomplished by a novel base-induced cyclization protocol, which involved the treatment of amido-ester 2,6-DKP precursors with potassium bis(trimethylsilyl)amide. Moreover, the cyclization methodology used allowed the synthesis of the respective 1-functionalized 2,6-DKPs in one pot and in excellent yields when the same primary amido-esters were treated with the previous base and the intermediate potassium imidate salts were then reacted with the electrophile benzyl bromoacetate. Hydrogenolysis of the benzyl 2,6-diketopiperazine acetates afforded the respective carboxylic acids, which constitute versatile intermediates in the synthesis of peptidomimetics and other bioactive molecules concerning our pharmacological studies.     

One-pot synthesis of pentacyclic diamines from quinolines by a new Zn/AcOH-promoted cascade reaction

A simple and efficient method for the one-pot synthesis of pentacyclic diamines from quinolines is described. It involves a new Zn/AcOH-promoted cascade reaction, in which two C[bond]C bonds and four to five stereogenic centers are established under mild conditions. The regiochemistry of the dimerization and cyclization step is governed by substituent effects, allowing access to a head-to-head (2, 3) or head-to-tail skeleton (4, 5).     

A Facile Solid—phase Synthesis of 3—Carboxycoumarins

3-Carboxycoumsrins were synthesized via the solid phase synthesis conviently. The resin bound cyclic malonic ester reacted with o-methoxy or o-hydroxybenzaldehydes. Then cyclization was processed under H2SO4 to afford the products in excellent purities and yields.     

A facile access to pyrroles from amino acids via an aza-Wacker cyclization

A facile and efficient synthesis of pyrroles from readily available amino acids is described. The key step in the method is an aza-Wacker oxidative cyclization catalyzed by palladium(II)/Cu(OTf)2. A series of pyrroles were obtained by this method under mild conditions.     

Solid-phase synthesis of beta-lactams via the ester enolate-imine condensation route

The ester enolate-imine condensation route to beta-lactams via an immobilized ester enolate has been achieved for the first time. The key reaction in the synthesis is the cyclization of the resin bound ester dianion and an imine. Traceless cleavage from the T1-triazene linker system yields the desired beta-lactams.     

Synthesis and characterization of pyridine-based polyamido-polyester optically active macrocycles and enantiomeric recognition for D- and L-amino acid methyl ester hydrochloride

Five new chiral macrocycles, 3a-e, have been prepared by the acylation cyclization of chiral diamine dihydrobromide intermediates 2a-c with 2,6-pyridinedicarbonyl dichloride in highly diluted solution at room temperature. The chiral diesters 1a-c needed for the preparation of the macrocycles were obtained from condensation of corresponding N-(Z)-L-amino acids and 2,6-bishydroxymethyl pyridine in the presence of DCC and DMAP. The enantiomeric recognition of chiral macrocycles 3a-e for D- and L-amino acid methyl ester hydrochlorides has been characterized by fluorescence spectra, which indicate that some of them exhibited significant chiral recognition for the enantiomers of D- and L-amino acid methyl ester hydrochlorides. The stoichiometry and binding constants of 3a-L-Am(2) and 3c-L-Am(2) complexes have been determined. An X-ray analysis of the chiral macrocycle 3b show that the chiral ligand is rather rigid and strained.     

A short-step synthesis of orally active carbapenem antibiotic CS-834

An orally bioavailable carbapenem CS-834, which is a pivaloyloxymethyl (POM) ester-type prodrug and has (R)-5-oxopyrrolidin-3-ylthio moiety at the C-2 position of the 1 beta-methylcarbapenem skeleton, is currently under clinical trial. We accomplished a short-step synthesis of CS-834 by using phosphorus ylide from the intramolecular Wittig-type reaction in the key step for cyclization to the bicyclic carbapenem system. The POM ester group was found to be suitable for the cyclization conditions.     

Application of Pac Ester in Thioester Method for the Synthesis of Cyclopentapeptides

Thioester method for the synthesis of cyclopeptides is improved by using Pac (Pac = phenacyl, CH2COC6Hs) ester as a protecting group of 3-mercaptopropionic acid. The Pac group is easy to be removed from C-terminal with zinc in acetic acid. The protected glycine thioester and peptide thioesters synthesized by the improved method, are easy to be purified, so the final linear peptides are pure enough for the following cyclization. Furthermore, this method is flexible for peptide chain elongation,either from C-termlnal or from N.terminal. So it is an efficient and practical method for synthesis of bioactive peptides. Two N-protected pentapeptide thioesters, Boc-Pro-Tyr-Leu-Ala-GIySCH2CH2COOPac and Boc-Ala-Tyr-Leu-Ala-Gly-SCH2CH2COOPac were synthesized by the improved thloester method.After deprotecting Pac ester with zinc in aqueous acetic acid and Boc group with trifluoroacetic acid in CH2C12, two free pentapeptide tldoesters were obtained. Ag^ -assisted cyclization in acetate buffered solution afforded two cyclic pentapeptides c(Pro-Tyr-Leu-Ala-Gly) and c(Ala-Tyr-Leu-Ala-Gly).Effects of different buffer pH, different Ag^ concentrations, etc. on the cyclization were studied.     

A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones

A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered indole pi-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under high dilution conditions. The six-membered cyclized product is generated through two reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the aspidospermidine skeleton was also developed.     

Oxidative amide synthesis and N-terminal alpha-amino group ligation of peptides in aqueous medium

A new method for oxidative synthesis of amides from alkynes and amines in high yields (up to 96%) using [Mn(2,6-Cl2TPP)Cl] 1 as a catalyst and Oxone/H2O2 as an oxidant in aqueous medium has been developed. This method could be used for N-terminal alpha-amino group ligation of unprotected peptides with aryl, aliphatic, and internal alkynes under mild conditions.     

A New Method for the Synthesis of Oxadiazine Insecticide Indoxacarb

9‐Fluorenylmethoxycarbonyl was a good protecting group in the field of chemical industry. In the present paper, a new approach for the synthesis of oxadiazine insecticides indoxacarb used 9‐fluorenylmethoxycarbonyl as protected group, and triphosgene for chloroformylation. A convenient synthesis of 9‐fluorenylmethoxycarbonylhydrazine can be achieved by the nucleophilic substitution reaction of 9‐fluorenylmethyl chloroformate and hydrazine hydrate. 4a‐Methyl‐2‐(9‐fluorenylmethyl)‐7‐chloro‐indeno [1,2e][1,3,4]oxadia zine‐2,4a (3H,5H)‐dicarboxylate can be produced via ketone ‐hydrazine crosslink reaction and cyclization. A preparation of carbamic acid‐(chlorocarbonyl)‐[(4‐trifluoromethoxy) phenyl] me ester can be obtained by the chloroformylation of triphosgene. Finally, the deprotection of 9‐fluorenylmethoxy carbonyl and condensation with carbamic acid‐(chlorocarbonyl)‐[(4‐trifluoromethoxy) phenyl] me ester can afford indoxacarb in good yield. A new method for the synthesis of oxadiazine insecticides indoxacarb used 9‐fluorenylmethoxycarbonyl‐protected group to produce 9‐?fluorenylmethoxycarb?onylhydrazine, then through the ketone–hydrazine crosslink reaction, cyclization, deprotection, chloroformylation, and condensation in good yield.     

Concise synthesis and revision of the proposed biogenesis of helicascolides

A concise synthesis of helicascolides A, B and C was achieved in three to five steps from commercially available materials. The key transformations of the synthesis include an Evans-Metternich anti-aldol reaction of the known β-keto imide 10 and strategic base-mediated one-pot cyclization/alkylation. Based on the new chemical evidence of ring-opening reaction of β-keto ester under biocompatible basic conditions, Krohn’s proposal for the biosynthetic relationship between helicascolide A (1) and a naturally co-existing acyclic dienone 4 was suggested in a reverse manner.     

Selective synthesis of 1,3-Di(pyridylimino)-isoindolines from tetracyanobenzene

The synthesis of substituted 1,3-bis-(2-pyridylimino)isoindoline 4 from 1,2,4,5-tetracyanobenzene and 2,6-diaminopyridine under mild and dilute conditions constitutes a new approach to produce a functionalized compound 4. The synthesis of an analogous compound 5 from 1,2,4,5-tetracyanobenzene and 2-amino-6-methylpyridine is also described.     

Rational synthesis of contra-thermodynamic spiroacetals by reductive cyclizations

A synthesis of spiroacetals was developed using a reductive cyclization strategy that leads stereoselectively to spiroacetals with a single anomeric stabilization. The method begins with the synthesis of spiro ortho esters. The ortho ester is converted to a cyano acetal. Reductive lithiation of the cyano acetal generates an axial dialkoxylithium reagent, and intramolecular cyclization produces a new ring with retention of configuration. The strategy is convergent and produces complex spiro acetals in only a few steps. The method will be useful in the synthesis of natural products and will facilitate the synthesis of previously inaccessible contra-thermodynamic acetals.