Synthesis and Characterisation of Macrocyclic Diamino Chiral Crown Ethers
A benign and efficient synthesis of chiral macrocyclic ‘aza-crown’ ethers of varying ring size is reported. The synthesis involves a Schiff base condensation of ether linked dialdehydes of varying chain length and (1R,2R)-(–)-1,2-diaminocyclohexane under mild conditions to yield the macrocycles, which are subsequently reduced to yield the diamino analogues.
Synthesis of New Dihydroxy-dioxygenated ortho-[2,x]Cyclophanes
The synthesis of t it le compounds (la-I) by intramolecular reductive coupling is presented The reaction is carried out in water solution. in the presence of Zn or Al powder, in basic media. INTRODUCTION The reductive coupling of carbonyl compounds using different catalytic systems (such as metals, low-valent early transition metal species, salts or complexes) is known as pinacol coupling reaction, and various reducing agents for this reaction have been developed extensively over the last three decades' This particular method for constructing carbon-carbon bond, subsequently 1,2-diols, by reductive coupling of carbonyl compounds has received far more attention as an intermolecular process than as an intramolecular one. Nevertheless, several intramolecular versions of the above reaction were effectively employed as key steps in the total synthesis of some complex natural and unnatural products. Thus, we can easily classify the intramolecular eductive coupling processes as: l) starting from aliphatic dialdehydes,2 ) starting from thioether dicarbonyl compounds;r 3) starting from biphenyl derivatives;o 4) used in syntheses of natural products (such as taxoid ring systems,s trehazoline6 ortrehazolamine,? inositol derivatives,s cembranoiclse or other terpenoids'o) Furtherrnore, these syntheses imply the use ofsophisticated reagents in carefully chosen reaction conditions We developed recently a new method for performing the reductive coupling of carbonyl or imine compounds that proved to be effective in aqueous conditions, in the presence of cheap. commercially available metall ic powders of Al or Zn, in a basic media (usually lTY" aqueous NaOI] solution)rr This method has already been applied to the single-step synthesis of tetrahydroxyf2.2fmetocyclophanes via pinacol coupling reaction of 1,3-benzene dicarboxaldehydes t2 We wish to report now the synthesis of a series of bridge-hydroxylated [2,xlortho-cyclophanes (x=.3.-8), HETEROCYCLES, Vol. s3, No. 11, 2ooo with two hydroxyl groups in the first bridge and two or three oxygen atoms in the second bridge, namely 4,5-dihydroxy-1,8-dioxy-2,3.6,7-dibenzocyclononane (1a),4,5-dihydroxy-1,8-dioxy-2,3.6,1-dlbenzocyclodecane (tb),4,5-dihydroxy-1,8-dioxy-2,3'.6,7-dibenzocycloundecane (1c), a,5-dihydroxy-1,8-dioxy-2,3 6,7d ibenzocyclododecane ( ld) ,4,5-d ihydroxyl ,8 ,11tr ioxy-2,3 ' .6 ,7-d lbenzo-cyclot r idecane (1e) and 4 '5dihydroxy-1,8-dioxy-2,3.6,7-dibenzocyclotetradecane (1{), respectively' REST]LTS AND DISCU SSIONS Our approach strategy to the target molecules involves the intramolecular reductive coupling of aromatic aldehydes connectecl by a dietheric bridge. Such compounds can be readily obtained, using a two-step synthesis, from salicylaldehyde, as presented in the retrosynthetic scheme. (rX -r', a./ fA., i t i NoH t t l \.Ar t l ( ) -t 1a-f X = CIl z, (CI-lz)2, o o 2a-f (cHr3, (cHr4, (CH12-O-(CH2)2, (CIl2)6 Scheme I Retrosynthesis ,scheme for diols (1a-fl We have already investigated the behavior of oand p-anrsaldehydes toward pinacol coupling "' Both proved to be favorable substrates, yielding consequently the corresponding diols We decided therefore to submit some compounds with structures of type (2a-I) to the intramolecular reductive coupling. Moreover' a scrutinized investigation of the chemical l i terature showed us no mentions of diols with structures of t it le molecules (1a-fl. previous reports on the synthesis of some dialdehydes of type (2) showed two groups of processes a) the transformation of salicylaldehyde into the corresponding sodium alcoxyde and a subsequent Will iamson reaction with a dibrominated compound, in reflux of DMF13 or b) a one-pot reaction among salicylaldehyde. a dihalogenated compound and NaOH, without isolation of the sodium salt, in boil ing alcohol,4rlaOH solutionra or boil ing TItr/HMPA solution.rsWe performed the syntheses of compounds (2a-I) as one-pot reactions, using salicylaldehyde and the corresponding dibrominated compounds, in ethanol and in the presence of a diluted aqueous NaOH solution. All reactions were carried out by refluxing the reactton mixture for 72 h We also found out that nitrogen flow is not necessary (there are no changes concerning the total yield of the reaction), as it was previously mentioned in l iterature data 'n d $ d"p o ( ) 2r-l .) Na(lH, Br(Cl ) -X-Br{ Cl ) H2O, EIOH reflux,72 h ( ) J Scheme 2 Synthe,sis of dialdehydes (2a-fl )H HETEROCYCLES, Vol. 53, No. 11, 2OOO Table 1. Synthesis ofdialdehydes (2a-f) cpd. X Yield (%) mp ( 'C) ( l i t . , r3" m 2a -CH.. 5 7 1 3 11 3 1 1 3 2 ) 2b -(cH.) 45 1 3 0 f l 3 0 1 3 1 2c -(cH,) 62 98 (97-e8) 2d -(cH,),64 1 2 ( 1 1 2 5 l t 3 5 ) 2e -(cH,),-o-(cH,)"56 13 5-75 (66-67t1"1 2f -(cH.).23^) 77-79 (79 5-80\ a) 1,6-Dichlorohexane was used instead of the corresponding dibrominated compound Pinacol intramolecular condensations of compounds (2a-f) were carried out in l0% aqueous NaOH solution and in the presence of Zn or Al powder. The dialdehyde was dispersed in 10 mL of ethanol, the metall ic powder (Zn or Al) was added and after that the NaOH solution was poured into the reaction flask, in one portion The reaction mixture was kept at 60'C and ultrasonication for 5 h, under mechanical stirring (for Methods A and B). or at room temperature and magnetical stirring, for 5 h (for Methods C and D) The results of these Drocesses are summarized in Table 2
Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa
ABSTRACT Competitive inhibitors of dihydrofolate reductase (DHFR) are used in chemotherapy or prophylaxis of many microbial pathogens, including the eukaryotic parasites Plasmodium falciparum andToxoplasma gondii. Unfortunately, point mutations in the DHFR gene can confer resistance to inhibitors specific to these pathogens. We have developed a rapid system for testing inhibitors of DHFRs from a variety of parasites. We replaced the DHFR gene from the budding yeast Saccharomyces cerevisiaewith the DHFR-coding region from humans, P. falciparum,T. gondii, Pneumocystis carinii, and bovine or human-derived Cryptosporidium parvum. We studied 84 dicyclic and tricyclic 2,4-diaminopyrimidine derivatives in this heterologous system and identified those most effective against the DHFR enzymes from each of the pathogens. Among these compounds, six tetrahydroquinazolines were effective inhibitors of every strain tested, but they also inhibited the human DHFR and were not selective for the parasites. However, two quinazolines and four tetrahydroquinazolines were both potent and selective inhibitors of the P. falciparum DHFR. These compounds show promise for development as antimalarial drugs.