The synthesis of novel nonclassical reversed bridge quinazoline antifolates as inhibitors of thymidylate synthase

2‐Amino‐6‐methyl‐5‐(pyridin‐4‐ylsulfanyl)‐3H‐quinazolin‐4‐one ( 3 , AG337) a lipophilic thymidylate synthase inhibitor, is currently in clinical trials as an antitumor agent. On the basis of the crystal structure of 3 and the classical inhibitor 10‐propargyl‐5,8‐dideazafolic acid ( 1 , PDDF) with thymidylate synthase, we designed and synthesized a series of nonclassical 2‐amino‐6‐substituted‐3H‐quinazolin‐4‐ones 4–13 , with a variety of electron withdrawing groups in the side chain (with the exception of compound 4 ). Molecular modeling indicates that these reversed bridge (N9–C10) 6‐substituted analogues orient their side chain C10‐substituent such that it lies between that of 1 and 3 . These compounds were obtained by reduc tive amination of 6‐aminoquinazoline 16 and the appropriate aryl aldehyde 17 or aryl ketone 18 . For ana logues 11–13 , the yield depended on the substitutents on the aryl ketone 18 (comparison of 11 and 13 ). With the exception of analogue 13 , all the compounds in the series were poor inhibitors of thymidylate synthase from Lactobacillus casei, Pneumocystis carinii and human sources.     

Diastereoselective synthesis of fluorinated,seven-membered beta-amino acid derivatives via ring-closing metathesis

[reaction: see text] Cis and trans seven-membered gamma,gamma-difluorinated beta-amino acid derivatives (III) have been prepared with a sequence that starts with imidoyl halides (I), which are condensed with suitable ester enolates to give intermediates (II). These, in turn, can be cyclized by means of a ring-closing olefin metathesis reaction and the product stereoselectively reduced to yield compounds (III) in good overall yields.     

The synthesis of fluorinated aminophosphonic acid inhibitors of alanine racemase

The synthesis of β-trifluoro, β-difluoro, and β-monofluoro-1-aminoethanephosphonic acids is described utilizing fluorinated acetic acids as tarting materials.     

Diastereoselective synthesis of piperidine imino sugars using aldol additions of metalated bislactim ethers to threose and erythrose acetonides

A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the gamma-alkoxy protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides, high trans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis of the glycosidase inhibitors 1-deoxy-d-allonojirimycin, 1-deoxy-L-altronojirimycin, 1-deoxy-D-gulonojirimycin, 1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin and 1-deoxy-D-talonojirimycin.     

A new synthesis of 3-arylthioindoles as selective COX-2 inhibitors using PIFA

The direct 3-arylthiolation of 2-substituted indoles using phenyliodine(III)bis trifluoroacetate (PIFA) in (CF₃)₂CHOH with a wide variety of benzenethiols has been accomplished. In particular, indoles bearing a 6-MeSO₂ and either a 2-methyl or 2-carboxymethyl substituent could be 3-arylthiolated in good to excellent yields to afford the corresponding 3-arylthioindoles as selective COX-2 inhibitors. In a study varying the electronic nature of the 5-substituent of 2-CO₂Et indoles, it was discovered that the yield of the reaction improved as the substituent became more electron withdrawing. This result was consistent with a proposed mechanism involving benzenethiol displacement of an intermediate 3-IPh indole complex.     

Diastereoselective synthesis of cyclosaligenyl-nucleosyl-phosphotriesters

A diastereoselective synthesis of cycloSal-phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal-pronucleotides. In previously described synthesis routes, the cycloSal-compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5-methyl-cycloSal-phosphotriesters in 48 and ≥95% de (de=diastereomeric excess). However, this approach failed to give the important group of 3-substituted cycloSal-nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (R(P))- and (S(P))-3-methyl-cycloSal-phosphotriesters as well. The antiviral activity was found to be five- to 20-fold different between the two individual diastereomers, which proved the importance of this approach.     

Asymmetric synthesis of aza-diospongin A as an iNOS inducer

The synthesis of the aza-analogue of diospongin A is described. The key steps in the synthetic sequence are Mitsunobu inversion, cross olefin metathesis and intramolecular aza-Michael addition reactions. The biological activity of this new analogue was also evaluated in the induction of nitric oxide synthase and was found to be better when compared to its natural counterpart.     

Phosphorylated flavonoids as selective carboxylesterase inhibitors

1. Download high-res image (133KB)
2. Download full-size image

     

Diastereoselective silver-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with fluorinated imine

We described hereby an instance of diastereoselective silver-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with imine compounds. This new method provided synthetically useful, highly substituted tetrahydroimidazole derivatives with efficiency and high diastereoselectivity. We can conveniently obtain fluorinated dihydroimidazole, imidazole, and diamino esters through simple modification.     

Microwave-assisted synthesis of triazole derivatives conjugated with piperidine as new anti-enzymatic agents

The current study was aimed for the study of piperidine-based triazole compounds for their biological potential against various enzymes. A novel library of compounds, 9a-r , having piperidine, 1,2,4-triazole, and propanamides was synthesized through consecutive steps including the formation of sulfonamide, hydrazide, 1,2,4-triazole, and thio-ether. Initially, 4-methoxybenzenesulfonyl chloride ( 1 ) and ethyl isonipecotate ( 2 ) were utilized to develop ethyl 1-(4-methoxyphenylsulfonyl)-4-piperidinecarboxylate ( 3 ). The product 3 was converted into respective hydrazide ( 4 ) which was further cyclized into 1,2,4-triazole ( 5 ) nucleus. A series of propanamides, 8a-r , were synthesized from different amines, 6a-r . These electrophiles, 8a-r , were reacted with compound 5 under conventional and microwave-assisted protocols to acquire the library of hybrids, 9a-r . The structural confirmations were availed by ¹H-NMR, ¹³C-NMR, and IR techniques. The whole series was evaluated for biological potential against acetylcholinesterase (AChE) and α-glucosidase enzymes. The biological evaluation ranges low to high in potential for different compounds based on the structural variations of synthesized compounds. Almost all the compounds remained active against both the enzymes except a few ones. The bovine serum albumin (BSA) binding study demonstrated the flow of drug in the body, and the docking study explained the interactions responsible for active behavior of synthesized compounds.     

Diastereoselective synthesis of polyfunctionalized piperidines as precursors of dopamine transporter imaging agents

The design and synthesis of a new kind of precursors of radiolabelled tracer agents for dopamine transporters imaging is described. The concept is based on the possibility of introducing the radioelement far from the sites of recognition and on the fact that only the labelled marker could cross the blood brain barrier to reach the dopamine transporters. For this purpose, a polyfunctionalized piperidine was synthesized bearing two aldehyde functions in the configuration allowing the formation of a tropane analog after the introduction of complexing moieties and complexation of a radioactive metal.     

New synthesis of spirocycles by utilizing in situ forming hypervalent iodine species

A very effective spirocyclization procedure for installing nucleophiles (Nu = N(3), NO(2), SCN, SO(2)Tol, and halogens) via iodonium(III) salts has been developed using the combination of iodoarene and mCPBA. The high-yielding syntheses of the cyclohexadienone-type spirocyclic compounds 2 having varied functionalities in the skeletons have been achieved from the aryl alkynes 1 with the optimized bis(iodoarene) 3h.     

Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid catalyzed desymmetrization

A straightforward method for the asymmetric preparation of novel lactone and lactam spirocycles is described. An initial desymmetrization via a chiral Brønsted acid yields enantioenriched lactones which readily undergo a second cyclization to give the desired spirocycle.     

Diastereoselective synthesis of vicinal amino alcohols

The vicinal amino alcohol is a common motif in natural products and pharmaceuticals. Amino acids constitute a natural, inexpensive, and enantiopure choice of starting material for the synthesis of such functionalities. However, the matters concerning diastereoselectivity are not obvious. This Perspective takes a look in the field of diastereoselective synthesis of vicinal amino alcohols starting from amino acids using various methods.     

Diastereoselective synthesis of 2,5-disubstituted tetrahydrofurans

This review focuses on synthetic methods allowing the preparation of 2,5-disubstituted tetrahydrofurans reported in the literature between 1993 and 2008.     

Diastereoselective total synthesis of 8-epigrosheimin

The first diastereoselective total synthesis of 8-epigrosheimin was accomplished relying entirely on substrate-controlled methods. 8-Epigrosheimin, isolated as an amoebicidal and antibiotic compound from Crepis virens, is a multi-chiral-centered guaianolide with a cis-hydroazulene and a trans-annulated γ-butyrolactone ring. Our approach featured that the γ-butyrolactone unit was formed firstly before the construction of the cycloheptane ring system. The key steps of the synthesis involved (1) a stereoselective Mukaiyama aldol addition; (2) an oxidative γ-lactonization; and (3) an intramolecular aldehyde-ene cyclization.