The asymmetric organocatalyzed Michael addition of aldehydes to alpha,beta-gamma,delta-unsaturated nitro compounds has been accomplished using only 5 mol % of (S)-diphenylprolinol silyl ether and 2 equiv of aldehyde in a mixture of ethanol and water (5% v/v). The Michael adducts were obtained in good yields, diastereoselectivities up to 94/6, and ee's up to 99%. This process provides synthetically useful compounds which can easily lead to more complex molecules, as exemplified with substituted tetrahydropyran or cyclohexene.

A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1′ aromatic portion and a D-proline residue bearing the zinc-binding group. The affinity improvement provided by these modifications led us to discover a nanomolar MMP inhibitor bearing a carboxylate moiety as zinc-binding group, which might be a promising lead molecule. Notably, a significant selectivity for MMP-8, MMP-12, and MMP-13 was observed with respect to MMP-1 and MMP-7. KEYWORDS: MMP, X-ray, synthesis, desolvation, docking, free energy M atrix metalloproteinases (MMPs) are a family of extracellular zinc-and calcium-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix components, cell movement, proliferation, and tissues remodeling. 1,2 Aberrant MMPs activities are involved in several pathological states, and the design of synthetic MMP inhibitors represents an opportunity to develop new drug candidates. Recently, we reported on the use of a MMP-9 inhibitor for the potential treatment of Dry Eye Syndrome. 3 Here, we present a new scaffold for potent MMP inhibitors that was discovered by means of an integrated medicinal chemistry study, composed of computer-aided design, synthesis, X-ray analysis, and fluorimetric measurement of the binding affinity toward MMPs. A new strategy to improve the inhibitory activity toward MMPs by increasing the interactions with the S1′ pocket and, especially, by increasing the ligand solvation free energy is further presented. The different contributions to the binding affinity were further investigated with computational methods. 4 Human macrophagic metalloelastase (MMP-12) was selected as target because of its pathological relevance and of the availability of detailed structural information. Several potent inhibitors for MMP-12, such as phospinic peptides, sulfonamides, and bisphosphonic derivatives, have already been designed and tested. 5−10 For some of them a high selectivity toward MMP-12 has been observed, 5,6,8,10 although the molecular basis of this specificity is still a matter of research. Here, based on the classical arylsulfonamide scaffold, new MMP inhibitors were designed by introducing an ethylene linker between the sulfonamide moiety and the P1′ aromatic portion and by replacing the glycine residue with a D-proline within the zinc-binding group (ZBG). 11,12 The flexible linker was introduced to increase van der Waals interactions with the deep S1′ lipophilic cavity of MMPs, 13 without affecting the overall ligand binding mode. At the same time, the hydroxamate derivative of the rigid D-proline was evaluated as ZBGs for its possible favorable contribution to the solvation free energy of the ligand. It is interesting to note that these chemical substitutions do not sizably affect the ligand logP values, that remain within the tolerance limits described by the rule of three and...

Pyrrolidines and piperidines were synthesized from (aminoalkyl)pyridine N-oxides with a general and quite efficient method developed by using di-tert-butylsilyl bis(trifluoromethanesulfonate) as a new promoter for a Boekelheide-type

A general, mild and efficient procedure with which to access hydroxamic acids, in good yields and purity, is reported. Esters are used as substrates and reacted with hydroxylamine, in the presence of a base, under microwave activation. The method has been successfully applied to enantiomerically pure esters without loss of stereochemical integrity.Hydroxamic acids are bidentate chelating agents that interact with several zinc(II)-containing proteins. Molecules containing this functional group behave as powerful inhibitors of metalloproteinases 1-4 and histone deacetylase, 5-6 which are two important biological targets for anticancer therapy. Moreover, the hydroxamic acid motif occurs in other biomolecules such as naturally occurring siderophores 7,8 like pseudobactines, desferriooxamines, ferrichromes and the fosmidomycin antibiotic 9 and its analogues 10 which have been recovered and found to be potent antimalarial agents. [10][11] Due to its low stability, this hydroxamate moiety is usually introduced in the last step of the synthetic sequence and, recently, several methods have been developed for this purpose. So far, the most commonly used approaches can be summarized as: reaction of O/N-protected hydroxylamine with activated carboxylic acids, 12-15 reaction of esters with hydroxylamine, 16,17 treatment of N-acyloxazolidines with hydroxylamine in the presence of samarium triflate, 18 and coupling of carboxylic acids with hydroxylamine in the presence of 2,4,6-trichloro[1,3,5]triazine 19 or cyclic phosphonic anhydride (PPAA). 20 However, a general, mild and efficient procedure with which to access hydroxamic acids, in good yields and purities, is still required.Stemming from our interest in the development of new metalloproteinase inhibitors, 21,22 we have recently faced the problem of transforming esters into the corresponding hydroxamic acids at the end of multistep sequences without loss of stereochemical integrity in the final product. As a convenient methodology, we envisaged the use of microwave (MW) activation in this simple transformation, using hydroxylamine as a reagent, in the presence of bases such as potassium hydroxide or sodium ethoxide.Since it is known that MW irradiation generally speeds up slow reactions by simple, very efficient heating of the system, 23 we hoped to overcome the problems associated with the long reaction times that are normally required for the above transformation, in this way. To test our hypothesis, we submitted an array of methyl esters to MW irradiation, in the presence of hydroxylamine and potassium hydroxide as base; the results are collected in Table 1.The data reported in Table 1 clearly show that the formation of hydroxamic acids from esters under MW irradiation, occurs smoothly and is quite general; indeed it can be performed on simple alkylaryl esters (entry 1), on both Nprotected (entries 2, 3, 5, 6) and unprotected (entry 4) amino esters, on dipeptides (entries 7, 8), on protected hydroxyesters (entry 9) and on sulfonamido esters (entry 10), though in the latt...