ABSTRACT
Securinine, an alkaloid originally isolated from Securinega suffruticosa, exhibits a wide range of biological activities, including anti-malarial activity. Along with securinine, 10 pyrrolidine derivatives, generated via the retrosynthesis of (-)-securinine, were selected and tested for their inhibitory activity against Toxoplasma gondii growth in vitro. Anti-Toxoplasma activity correlated to hydrophobicity of the tested compounds. Three pyrrolidine derivatives along with securinine inhibit Toxoplasma proliferation at the micromolar range. These compounds act on parasite proliferation in different capacities, either by slowing the growth rate or inhibiting invasion of host cells. Securinine induces bradyzoite differentiation at comparable levels to treatment with alkali media in vitro.
Subject(s)
Antiprotozoal Agents/pharmacology , Azepines/pharmacology , Lactones/pharmacology , Piperidines/pharmacology , Pyrrolidines/pharmacology , Toxoplasma/drug effects , Antiprotozoal Agents/chemistry , Azepines/chemistry , Cells, Cultured , Fibroblasts/drug effects , Fibroblasts/parasitology , Foreskin/cytology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Heterocyclic Compounds, Bridged-Ring , Humans , Lactones/chemistry , Male , Piperidines/chemistry , Pyrimethamine/pharmacology , Pyrrolidines/chemistry , Toxoplasma/growth & developmentABSTRACT
Two convenient highly diastereoselective protocols for the allylation and crotylation of ketones using practical, air- and water-stable potassium allyl and crotyltrifluoroborate salts have been developed. BF(3).OEt(2) and montmorillonite clay are used as catalysts to promote additions. The montmorillonite-catalyzed method in particular is very robust, providing a straightforward and scalable method for the allylation and crotylation of a range of ketones and aldehydes.
ABSTRACT
The alkaloid (-)-securinine was synthesized in 18 steps and 16% overall yield from trans-4-hydroxy-l-proline.
Subject(s)
Azepines/chemical synthesis , Lactones/chemical synthesis , Piperidines/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, Bridged-Ring , StereoisomerismABSTRACT
A variety of aryl and heteroaryl bromides were cross-coupled with ammonia in good to high yields in the presence of a copper-NHC catalyst.
ABSTRACT
N-acyl-alpha-amino amides were prepared, without the necessity of chromatographic purification, in a single step by heating the corresponding alpha-keto ester in methanolic ammonia.
Subject(s)
Amides/chemical synthesis , Ammonia/chemistry , Esters/chemistry , Keto Acids/chemistry , Aminoacylation , Hot Temperature , Models, ChemicalABSTRACT
Described is an efficient synthesis of silyl-substituted salen ligands, used for the preparation of enantioselective catalysts. The salicylaldehyde precursors are synthesized from the silyl ethers of 2,6-dibromophenols via a one-pot double lithium halogen exchanges, to induce an intramolecular retro-Brook rearrangement and allow introduction of the aldehyde group. Condensation of the salicylaldehyde products with a chiral diamine affords the silyl-substituted salen ligands in high yields. The use of other electrophiles allows easy access to silyl-substituted phenolic esters, ketones, and boronic acids.
Subject(s)
Ethylenediamines/chemical synthesis , Aldehydes/chemistry , Ethylenediamines/chemistry , Ligands , Methylation , Molecular StructureABSTRACT
Acyclic diaminocarbenes are found to be useful ligands for palladium catalyzed Suzuki-Miyaura, Sonogashira and Heck cross-coupling reactions of aryl/alkenyl bromides and chlorides.
ABSTRACT
A wide variety of tertiary carbinamines are synthesized in high yields via diastereoselective allylation and crotylation of in situ generated N-unsubstituted ketimines.
ABSTRACT
Like molecules of life (e.g., proteins and DNA), many pharmaceutical drugs are also asymmetric (chiral); they are not superimposable on their mirror images. One mirror image form (enantiomer) of a drug can have desirable activity, the other not. Consequently, the development of methods for the selective synthesis of one enantiomer is of great scientific and economic importance. We report here that a simple, commercially available chiral alcohol, alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), catalyzes the all-carbon Diels-Alder reactions of aminosiloxydienes and substituted acroleins to afford the products in good yields and high enantioselectivities (up to 92% enantiomeric excess). It is remarkable that the reactions are promoted by hydrogen bonding, the ubiquitous "glue" that helps to keep water molecules together and holds up the 3D structures of proteins. Hydrogen bond catalysis is little used in chemical synthesis, wherein most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. As it does for enzymes, hydrogen bonding not only organizes TADDOL into a well defined conformation, but, functioning as a Brønsted acid catalyst, it also activates the dienophile toward reaction with the diene. The gross structure of the TADDOL has been found to have a profound influence on both the rate and the enantioselectivity of the cycloadditions. These structure-function effects are rationalized by evaluating the conformation adopted by the TADDOLs in the crystal state. It is suggested that pi,pi-stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.
Subject(s)
Hydrogen Bonding , Catalysis , Magnetic Resonance Spectroscopy , Stereoisomerism , TemperatureABSTRACT
[reaction: see text] Multifunctional palladium catalysis is utilized in the one-pot stereocontrolled synthesis of tetrasubstituted alkenes. The homogeneous palladium dihalide catalyst utilized for bromo-/chloroallylation of alkynes is then reused in situ for a subsequent Suzuki cross-coupling reaction.
Subject(s)
Alkenes/chemistry , Alkenes/chemical synthesis , Palladium/chemistry , Bromine Compounds/chemistry , Catalysis , Chlorine Compounds/chemistry , Molecular Conformation , Molecular Structure , StereoisomerismABSTRACT
[reaction: see text] Multifunctional palladium catalysis is utilized in the one-pot stereocontrolled synthesis of tetrasubstituted methyl ketones and enynes. The homogeneous palladium dihalide catalyst utilized for the bromo-/chloroallylation of alkynes is reused in situ for subsequent Wacker-Tsuji oxidation or Sonogashira cross-coupling.
Subject(s)
Hydrocarbons, Halogenated/chemical synthesis , Ketones/chemical synthesis , Palladium/chemistry , Bromine Compounds/chemistry , Catalysis , Chlorine Compounds/chemistry , Hydrocarbons, Halogenated/chemistry , Ketones/chemistry , Molecular Conformation , Molecular Structure , Oxidation-ReductionABSTRACT
[formula: see text] Potassium allyl- and crotyltrifluoroborates undergo addition to aldehydes in biphasic media as well as water to provide the corresponding homoallylic alcohols in high yields (> or = 94%), excellent diastereoselectivity (dr > or = 98:2), and without the necessity of any subsequent purification. The presence of a phase transfer catalyst (e.g., nBu4NI) significantly accelerates the rate of reaction, whereas added fluoride ion retards the reaction.
