Current Organic Chemistry - Volume 8, Issue 11, 2004

Protein phosphatases are important in a sense that they regulate the phosphorylation level of various proteins and in turn many physiological processes. Aberration in a fine tune among protein phosphatases and their counterparts, protein kinases, results in various diseases. Hence, the inhibitors of these enzymes have gained importance in disease treatments. In recent years, some natural and synthetic compounds have shown promising activity for protein phosphatase inhibition. This review describes, in a brief, strategies used to design and synthesis various molecules having significant potential to inhibit some crucial protein phosphatases and also gives an overview of different kinds of protein phosphatase enzymes and their physiological significance.

Pentaerythritol and its congeners, such as pentaerythrityltetramine, 2,2-bis(aminomethyl)propane-1,3- diol, bis(hydroxymethyl)malonic acid, bis(aminomethyl)malonic acid and 2,2-bis(aminomethyl)-β-alanine, constitute an interesting class of tetrafunctional spiro compounds that allow the attachment of four different conjugate groups and, hence, the construction of highly branched and branched / cyclized structures. Accordingly, these compounds have received interest as orthogonally protected handles useful for the generation of combinatorial libraries and as building blocks that fit well in the general structure of oligonucleotides and peptides, providing additional functionalities for further derivatization. Another interesting feature is that 1,3-dicarbonyl spiro compounds and their analogues having an unprotected 2-(hydroxymethyl) group undergo a facile retroaldol condensation even under physiological conditions, although the compounds are entirely stable as long as the hydroxy function is masked with an acyl group. They have, hence, found applications as biodegradable protecting groups and linkers, the cleavage of which is triggered by intracellular esterases. The literature published on the synthesis of appropriately protected handles and building blocks from inexpensive starting materials, such as pentaerythritol or malonic esters, and their use in the synthesis of structural analogues and conjugates of oligonucleotides and peptides, glycoclusters and small molecule libraries is reviewed.

Aldol condensation of synthetic equivalents of acetacetic esters allows the formation of a polyfunctional C5 fragment and the corresponding aldols have proven to be versatile key-intermediates in the synthesis of complex, biologically active natural products. O-silyldienolates 1 and 2 can be considered among the most popular masked acetacetic esters and in these last years the silyl dienolate 1a (R1 = R2 = Me), deriving from commercially available 2,2,6-trimethyl-4H-1,3-dioxin-4-one, has been used in a variety of aldol reactions (based on the employment of Ti(IV), or Cu(II), chiral complexes) taking place with high efficiency and enantioselectivity; on the contrary, the highly oxygenated diene 2 (Chan's diene) has been essentially used in the synthesis of racemic aldols by TiCl4 catalysis. The aldol condensation of the synthetic equivalents of acetoacetic ester 1-2 can be conveniently performed in the presence of a chiral Ti(O-i-Pr)4 / BINOL complex under catalytic conditions. The reported procedure is of particular synthetic value since the addition of masked acetoacetic esters proceeds efficiently with aromatic, heteroaromatic, α,β-unsaturated and aliphatic aldehydes too. In the course of the investigation on the mechanistic aspects of the reaction, positive non-linear effects have been observed; rather interestingly, the mode of preparation and the concentration of the catalyst has been found to exert a marked influence on the non linear effects. Furhermore, the occurence of a concomitant auto-inductive process with amplification of the enantiomeric excess in the aldol reaction of 2 has been pointed out.

Lipases are biocatalysts most widely used in organic synthesis. Unusual but attractive feature of lipases is that, in addition to high catalytic activity and thermostability in organic solvents, lipases show high enantioselectivity and broad substrate specificity simultaneously. They show excellent enantioselectivity especially toward a wide range of secondary alcohols. The mechanistic details of stereoselective organic reactions are relatively well understood, and knowledge has been used to develop new chemical reagents. In contrast, biocatalysts are behind chemical reagents in rational design approaches, which is partly due to the mechanistic ambiguity of enzymatic reactions. The mechanistic aspects of enantioselective biocatalysts are nevertheless becoming clear. This review provides an overview of the studies aimed at understanding the mechanisms of enantioselectivity of synthetically useful hydrolases such as lipases, subtilisins and chymotrypsins toward unnatural chiral substrates. Several methods for addressing the mechanism are introduced: (i) substrate mapping, (ii) X-ray crystallographic analysis, (iii) computational calculations, (iv) kinetic analysis, (v) thermodynamic analysis, (vi) site-directed or random mutagenesis, (vii) spectroscopic methods such as fluorescence, ESR, and mass spectroscopy. Different models and mechanisms proposed so far are selected and explained. The chemical principles revealed by the mechanistic studies will be useful for (i) using the enzymes in organic synthesis efficiently, (ii) altering the features of the enzymes rationally, (iii) utilizing them as a tool for determining the absolute stereochemistry of molecules, and (iv) designing new artificial catalysts mimicking the catalytic machinery of the enzymes.

Aluminum (Al) is an ideal reducing agent (electron pool) since it is cheap, easy to handle, able to release enough electron (3 e- / atom), and environment friendly. However, the use of Al in organic synthesis is rather limited owing to lack of efficient electron transfer process between Al and organic substances. In last decay, we and some other groups developed multi-redox promoted reactions using Al as a terminal reductant in which Al act as an electron pool and a catalytic amount of metal salt(s) works as a mediator for electron transfer from Al to substrates. Indeed, various combinations of Al and metal salt(s), e.g., Al / PbBr2, Al / PbBr2 / AlBr3, Al / NiCl2 / CrCl2, Al / PbBr2 / TFA, Al / PbBr2 / NiCl2(bpy), etc., have been developed to promote carbon-carbon bond formation as well as highly selective functionalization. Further more, these multi-redox promoted reactions have been successfully utilized for the synthesis of useful compounds, such as β-lactam antibiotics and β-lactamase inhibitors. This review article will summarize the recent progress in the multi-metal redox promoted reactions using Al as an electron pool and their applications to organic synthesis.