ABSTRACT
A convenient, one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by tandem decarboxylation/beta-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones was developed. In addition, several 1-benzoyl-2(S)-substituted-5-bromo-2,3-dihydro-4(H)-pyrimidin-4-ones were readily prepared by bromination of 1-benzoyl-2(S)-substituted-2,3-dihydro-4(H)-pyrimidin-4-ones. Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihydro-4(H)-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C-C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched alpha-substituted beta-amino acids.
Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Halogens/chemistry , Hydrogen/chemistry , Pyrimidinones/chemistry , Catalysis , Hydrolysis , Molecular Structure , Pyridines/chemistry , Pyrimidinones/chemical synthesis , Stereoisomerism , Uracil/chemistryABSTRACT
Nineteen chiral amines and their derivatives were prepared and investigated as organocatalytic Lewis bases in the alpha-amination of ethyl alpha-phenyl-alpha-cyanoacetate. For comparison purposes, a few natural products were also examined as catalysts in this study. Among the results obtained, (R)-N-benzyl-N-(1-phenylethyl)-amine and (R,R)-N,N'-bis(1-phenylethyl)-propane-1,3-diamine as the catalysts afforded the amination products in excellent yields and with up to 84% ee. By contrast, under comparable conditions the two derivatives of natural products (DHQ)2PYR and (DHQD)2PYR provided the product of amination with lower than 10% enantiomeric excess.
ABSTRACT
The synthesis of four novel analogues of metoprolol, a well-known beta1-blocker used to reduce arterial blood pressure, is described. The preparation of (2S,2'S)-7, (2R,2'S)-7, (2R,2'R)-8, and (2S,2'R)-8 was based on the reaction of racemic 2-[4-(2'-methoxyethyl)-phenoxymethyl]-oxirane (4) with (R)- or (S)-2-amino-1-butanol. Salient characteristics of analogues 7 and 8 relative to metoprolol are the incorporation of an additional stereogenic center, as well as a methyl group and a hydroxyl function on the nitrogen-containing chain. These novel derivatives present significant hypotensive and bradycardiac activity, although no blocking action toward beta1 and beta2 adrenergic receptor.