The search for effective therapeutics for cryptosporidiosis and toxoplasmosis has led to the discovery of novel inhibitors of dihydrofolate reductase (DHFR) that possess high ligand efficiency: compounds with high potency and low molecular weight. Detailed analysis of the crystal structure of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis and a homology model of DHFR from Toxoplasma gondii inspired the synthesis of a new series of compounds with a propargyl-based linker between a substituted 2,4-diaminopyrimidine and a trimethoxyphenyl ring. An enantiomerically pure compound in this series exhibits IC50 values of 38 and 1 nM against C. hominis and T. gondii DHFR, respectively. Improvements of 368-fold or 5714-fold (C. hominis and T. gondii) relative to trimethoprim were generated by synthesizing just 14 new analogues and by adding only a total of 52 Da to the mass of the parent compound, creating an efficient ligand as an excellent candidate for further study.

Highly substituted carbocyclic seven-membered rings are frequently found in natural products and their synthesis represents a significant challenge to the synthetic chemist. Direct intramolecular cyclization of these systems often proves difficult and this fact has catalyzed the development of a variety of strategies based on a convergent intermolecular cycloaddition strategy. This concept article discusses the major cycloaddition approaches utilized to access these types of structures and primarily focuses on examples employed in the synthesis of natural products.

Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 Å resolution. The structure reveals several features that can be exploited for further development of this lead series.

Reactions of secondary amides 2a-i with 1-chloro-1H-benzotriazole and triphenylphosphine give imidoylbenzotriazoles 3a-i. The treatment of 3a,b,e,g with silyl enol ethers 5a,b in the presence of potassium tert-butoxide provides a new general approach to enaminoketones 6a-h.

The metal‐catalyzed reactions of diazo compounds have broad utility in organic synthesis. The resulting high‐energy metal carbenoid intermediates are capable of a range of useful transformations, including cyclopropanation, ylide formation, and C‐H insertion. The intermolecular C‐H insertion by metal carbenoids is the most versatile reaction to date for stereoselective C‐H functionalization. This chapter covers the historical background of C‐H insertions and describes how the utilization of new catalysts and more stabilized carbenoids has resulted in major advances in the field. Now that highly diastereoselective and enantioselective C‐H functionalization can be achieved, the method can be effectively applied to the synthesis of pharmaceutical agents and natural products. This chapter focuses exclusively on intermolecular C‐H insertions of metal carbenoids in sp 3 ‐hybridized C‐H bonds. The carbenoids can be classified into three major classes: 1, acceptor‐substituted carbenoids; 2, acceptor/acceptor‐substituted carbenoids; and 3, donor/acceptor‐substituted carbenoids

We have been interested in exploiting the highly functionalized oxabicyclo[3.2.1]octadienes that are produced by the cycloaddition of furan and tetrabromocyclopropene as synthetic building blocks. As part of this program, we have prepared non-racemic derivatives of these adducts containing an α,β-dibromoenone moiety embedded in the bicyclic

The cyclocondensation of tetrabromocyclopropene and furan leads directly to a halogenated oxabicyclo[3.2.1]octadiene derivative. Over the past several years, we have utilized these compounds as intermediates for natural product synthesis. Herein, we describe the preparation of nonracemic dibromoenone building blocks from the racemic cycloadduct. Conversion of the adduct to a mixture of tartrate-derived ketals followed by separation of the diastereomers and hydrolysis allows for the formation of novel chiral synthons with either absolute configuration.

A Novel Route to Imidoylbenzotriazoles and Their Application for the Synthesis of Enaminones. -Treatment of secondary amides with the benzotriazole (I) and PPh3 offers a mild and easy approach to imidoylbenzotriazoles. Basic reaction of the latter with silyl enol ethers provides a new and general method to prepare enaminoketones such as (V) as are useful synthons. -(KATRITZKY*, A. R.; HAYDEN, A. E.; KIRICHENKO, K.; PELPHREY, P.; JI, Y.; J. Org. Chem. 69 (2004) 15, 5108-5111; Cent. Heterocycl. Compd., Univ. Fla., Gainesville, FL 32611, USA; Eng.) -Jannicke 46-130