Coibacins A and B: total synthesis and stereochemical revision.

The interface between synthetic organic chemistry and natural products was explored in order to unravel the structure of coibacin A, a metabolite isolated from the marine cyanobacterium cf. Oscillatoria sp. that exhibits selective antileishmanial activity and potent anti-inflammatory properties. Our synthetic plan focused on a convergent strategy that allows rapid access to the desired target by coupling of three key fragments involving E-selective Wittig and modified Julia olefinations. CD measurements and comparative HPLC analyses of the natural product and four synthetic stereoisomers led to determination of its absolute configuration, thus correcting the original assignment at C-5 and unambiguously establishing those at C-16 and C-18. Additionally, we synthesized coibacin B on the basis of the assignment of configuration for coibacin A.

Synthesis and insecticidal activity of an oxabicyclolactone and novel pyrethroids.

Deltamethrin, a member of the pyrethroids, one of the safest classes of pesticides, is among some of the most popular and widely used insecticides in the World. Our objective was to synthesize an oxabicyclolactone 6 and five novel pyrethroids 8–12 from readily available furfural and D-mannitol, respectively, and evaluate their biological activity against four insect species of economic importance namely A. obtectus, S. zeamais, A. monuste orseis, and P. americana. A concise and novel synthesis of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (6) from furfural is described. Photochemical addition of isopropyl alcohol to furan-2(5H)-one afforded 4-(1'-hydroxy-1'-methylethyl)tetrahydro-furan-2-one (3). The alcohol 3 was directly converted into 4-(1'-bromo-1'-methylethyl)-tetrahydrofuran-2-one (5) in 50% yield by reaction with PBr(3) and SiO(2). The final step was performed by cyclization of 5 with potassium tert-butoxide in 40% yield. The novel pyrethroids 8–12 were prepared from methyl (1S,3S)-3-formyl-2,2-dimethylcyclopropane-1-carboxylate (7a) by reaction with five different aromatic phosphorous ylides. Compounds 6–12 presented high insecticidal activity, with 6 and 11 being the most active. Compound 6 killed 90% of S. zeamais and 100% of all the other insects evaluated. Compound 11 killed 100% of all insects tested.

Facile synthesis of Koser's reagent and derivatives from iodine or aryl iodides.

The first one-pot synthesis of neutral and electron-rich [hydroxy(tosyloxy)iodo]arenes (HTIBs) from iodine and arenes is presented, thereby avoiding the need for expensive iodine(III) precursors. A large set of HTIBs, including a polyfluorinated analogue, can be obtained from the corresponding aryl iodide under the same conditions. The reaction proceeds under mild conditions, without excess reagents, and is fast and high-yielding. Together, the two presented routes give access to a wide range of HTIBs, which are useful reagents in a variety of synthetic transformations.

A ring contraction strategy toward a diastereoselective total synthesis of (+)-bakkenolide A.

A diastereoselective route to (+)-bakkenolide A is presented from the readily available optically active Wieland-Miescher ketone. This novel synthesis of this sesquiterpene lactone features the following as key stereoselective transformations: (i) the ring contraction reaction of a octalone mediated by thallium(III) nitrate (TTN); (ii) a hydrogenation to create the cis-fused junction; and (iii) the formation of the C7 quaternary center through an enolate intermediate. Furthermore, during this work, the absolute configuration of a trinorsesquiterpene isolated from Senecio humillimus was assigned.

Is RK-682 a promiscuous enzyme inhibitor? Synthesis and in vitro evaluation of protein tyrosine phosphatase inhibition of racemic RK-682 and analogues.

RK-682 (1) is a natural product known to selectively inhibit protein tyrosine phosphatases (PTPases) and is used commercially as a positive control for phosphatase inhibition in in vitro assays. Protein phosphatases are involved in several human diseases including diabetes, cancer and inflammation, and are considered important targets for pharmaceutical development. Here we report the synthesis of racemic RK-682 (rac-1) and a focused set of compounds, including racemic analogues of 1, dihydropyranones and C-acylated Meldrum's acid derivatives, the later obtained in one synthetic step from commercially available starting material. We further characterized the behavior of some representative compounds in aqueous solution and evaluated their in vitro PTPase binding and inhibition. Our data reveal that rac-1 and some derivatives are able to form large aggregates in solution, in which the aggregation capacity is dependent on the acyl side chain size. However, compound aggregation per se is not able to promote PTPase inhibition. Our data disclose a novel family of PTPase inhibitors (C-acylated Meldrum's acid derivatives) and that rac-1 and derivatives with an exposed latent negatively charged substructure (e.g.: the tetronic acid core of 1) can bind to the PTPase binding site, as well promiscuously to protein surfaces. The combined capacity of compounds to bind to proteins together with their intrinsic capacity to aggregate in solution seems essential to promote enzyme aggregation and thus, its inhibition. We also observed that divalent cations, such as magnesium frequently used in enzyme buffer solutions, can deplete the inhibitory activity of rac-1, thus influencing the enzyme inhibition experiment. Overall, these data help to characterize the mechanism of PTPase inhibition by rac-1 and derivatives, revealing that enzyme inhibition is not solely dependent on compound binding to the PTPase catalytic site as generally accepted in the literature. In addition, our results point to promiscuous mechanisms that influence significantly the in vitro evaluation of enzyme inhibition by rac-1. Therefore, we recommend caution when using natural or synthetic RK-682 (1) as an internal control for evaluating PTPase inhibition and selectivity, since many events can modulate the apparent enzyme inhibition.