The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds.

The nitro-Mannich (aza-Henry) reaction, in which a nitroalkane and an imine react to form a ß-nitroamine, is a versatile tool for target-oriented synthesis. Although the first stereoselective reaction was developed only 20 years ago, and enantioselective and diastereoselective versions for the synthesis of non-racemic compounds soon after, there are nowadays a variety of reliable methods which can be used for the synthesis of APIs and other biologically active substances. Hence many anticancer drugs, antivirals, antimicrobials, enzyme inhibitors and many more substances, containing C-N bonds, have been synthesized using this reaction. Several transition metal complexes and organocatalysts were shown to be compatible with the presence of a wide range of functional groups in these molecules, and very high levels of asymmetric induction have been achieved in some cases. The reaction has also been applied in cascade processes. The structural diversity of the products, ranging from simple heterocycles or azabicycles to complex alkaloids, iminosugars, amino acids or diamino acids and phosphonates, shows the versatility of the nitro-Mannich reaction and its potential for future developments.

Recent advances in organocatalytic enantioselective transfer hydrogenation.

The organocatalytic reduction of C[double bond, length as m-dash]C and C[double bond, length as m-dash]N double bonds with biomimetic reductants, e.g. Hantzsch 1,4-dihydropyridine esters and benzothiazolines, is reviewed. Very high yields and stereoselectivities have been achieved with a variety of catalysts, including chiral amines, thioureas and phosphoric acids, even with loadings equivalent to those of transition metal-catalyzed reactions in some cases. Reductive amination reactions and the dearomatization of heteroaromatic substrates are the subject of more than one half of the contributions. Of lately, methodologies based on kinetic resolution, cascade reactions involving transfer hydrogenation and the development of novel reductants have become prominent in an area which brings great prospects for the future of target oriented-synthesis.

Synthesis and antimalarial evaluation of prodrugs of novel fosmidomycin analogues.

The continuous development of drug resistance by Plasmodium falciparum, the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells.

Synthesis and biological evaluation of α-hydroxyalkylphosphonates as new antimicrobial agents.

A set of α-quaternary 3-chloro-1-hydroxyalkylphosphonates, analogues of fosfomycin and fosfonochlorin, some of which are new compounds, was synthesized. The compounds were screened for bioactivity against several clinical and standard microbial isolates. Some were found to have moderate activity. The activity was higher with phenyl protection of the phosphoryl ester groups and α-phenyl substitution. Compound 11 was as effective or more potent than fosfomycin or chloramphenicol against several Gram-negative bacteria as well as against some Gram-positive ones.

Synthesis of geminal bisphosphonates via organocatalyzed enantioselective Michael additions of cyclic ketones and 4-piperidones.

A Michael addition reaction of cyclic ketones and piperidones to a vinyl phosphonate is described. The reaction, catalyzed by chiral diamines, produced geminal γ-oxobisphosphonates in high yields (up to 92%) and very high ees (up to >99%). Disubstituted ketones gave drs of up to 8 : 92. The synthesis and characterization of several new compounds with potential biological activity is described.