Maurizio Taddei

Traditionally, anilines can be alkylated with reactive alkyl halides but now more safe reagents such as alcohols or even amines can be used. To overcome the limits of homogeneous catalysis for aniline N-alkylation, we have developed a protocol that employs simple Pd/C as a heterogeneous catalyst under microwave dielectric heating. The process, based on the easy Pd-mediated oxidation of primary amines to imines followed by aniline addition, is characterized by a high atom economy as ammonia is the only other product of the reaction. This kind of aniline alkylation with amines has been carried out both in ionic liquid medium using [bmim]PF₆ or in a more traditional solvent such as THF where the catalyst could be successfully recycled more times. The reusability of the catalyst was further confirmed by using material recycled from the amination in a standard alkene hydrogenation without loss of efficiency.

Starting from commercially available 2-(chloromethyl)-allyltrimethylsilane, the corresponding 2-(azidomethyl)allyl­silane was prepared through reaction with NaN₃. The product was stable upon isolation and storage and could be used for thermal ­cycloaddition of the azido group with alkenes to give allylsilane-containing triazolines or aziridines. This reaction was not accelerated by microwave (MW) dielectric heating, however, the azide fragment undergoes MW-assisted Cu(I)-catalyzed cycloaddition with a range of alkynes (including ynamides). Lewis acid mediated ­Hosomi–Sakurai reaction of the allylsilane with aldehydes was also possible. A one-pot transformation into different triazolo-containing homoallyl alcohols was carried out through a sequence of Cu(I)-catalyzed azide cycloaddition under MW dielectric heating and BCl₃-mediated reaction with aromatic aldehydes.

The introduction of a cyclic amino acid in a peptide is one of the best methods to rigidify a strand. A general approach towards a new class of seven‐membered ring amino acids is described starting from (S)‐tribenzyl glutamic acid γ‐aldehyde, which reacts with β‐keto phosphonates to generate the Horner–Wadsworth–Emmons product. In the presence of H₂ and a Pd catalyst, a four‐step process occurs involving double‐bond hydrogenation, hydrogenolysis of three benzyl protecting groups, imine formation, and reductive amination to produce the 7‐substituted azepane carboxylic acid in good overall yield and with good to excellent diastereomeric ratios. An amino function can be introduced in the 7‐position as an additional orthogonal chemical handle for readily generating diversity on the cyclic amino acid scaffold by using a β‐keto phosphonate derived from amino acids. A cyclic RGD (Arg‐Gly‐Asp) pentapeptide analogue containing this new class of noncoded amino acids was also prepared by microwave‐assisted cyclization, showing a promising activity as α_vβ₃ integrin inhibitor.

The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines. In each series, similar structural trends delivered potent compounds with IC₅₀ values in the nanomolar range with respect to the inhibition of the Hh signaling pathway in various cell-based assays and of BODIPY-cyclopamine binding to human Smo. The similarity of their biological activities, in spite of discrete structural differences, may reveal the existence of hydrogen-bonding interactions between the ligands and the receptor pocket. Biological potency of compounds 61, 72, and 86 (MRT-83) were comparable to those of the clinical candidate GDC-0449. These findings suggest that these original molecules will help delineate Smo and Hh functions and can be developed as potential anticancer agents.

Convenient accesses to enantiomerically pure 2-, 2,3-, 2,6-, 2,3,6-substituted piperidines and 1,4-substituted indolizine are described. At first, indium-mediated aminoallylation and -crotylation of aldehydes with (R)-phenylglycinol or (1R,2S)-1-amino-2-indanol gave homoallylamines with high stereocontrol. Then, these products, submitted to a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation, afforded perhydrooxazolo[3,2-a]piridines whose oxazolidines are opened with nucleophiles. Finally, the removal of the chiral auxiliaries delivered the enantiomerically pure piperidines.

Hydroformylation is a powerful reaction that has suffered for some negative prejudices related to the use of gaseous H₂ and CO. Now it is possible to carry out hydroformylation and different cyclohydrocarbonylations, even on complex substrates, using aqueous formalin as H₂ and CO surrogate in few minutes under microwave irradiation. The catalytic system developed by Morimoto (Rh/BINAP for decomposition of formaldehyde and Rh/Xantphos for hydroformylation) is compatible with microwave dielectric heating and with complex substrates containing ligand atoms allowing rapid domino hydroformylation cyclization reactions without using the external supply of gaseous H₂ and CO (gas cylinder) and without any particular safety limitation or device.

α,β‐Unsaturated ketones can be prepared by reaction of differently substituted β‐keto acids and aldehydes. The reaction is carried out under organocatalysis (β‐alanine, 0.5 equiv.) and generates the enones with high E selectivity (>95 %). This version of the Verley–Doebner modification of the Knoevenagel reaction is a practical alternative to the classic Horner–Wadsworth–Emmons (HWE) reaction without the formation of high molecular weight byproducts. The process makes use of simple reagents and can be applied to large‐scale synthesis under conditions compatible with atom‐economy principles. Differently substituted aliphatic, aromatic, or heteroaromatic α,β‐unsaturated ketones can be prepared. An example of a hydroformylation/Verley–Doebner Knoevenagel telescoped process is also described.

It has been shown that chemo-therapeutic agents, such as histone deacetylase inhibitors (HDACi), are able to increase TRAIL-induced apoptosis in many types of cancer. In the present study, we investigated the effects of the novel HDACi LGP1, a new simplified analogue of FR235222, in human leukaemia U937 cells resistant to TRAIL-induced apoptosis. U937 cells were incubated with TRAIL/LGP1 for 24 h and apoptosis was evaluated using flow cytometric assay and cleavage of caspase-3 and (PARP) by Western blot. Western blot analysis was also used to detect the expression of p21, p27, (NF-kappaB), Bcl-2 and the levels of H4 histone acetylation. Finally, flow cytometry was used to monitor the enhancement of TRAIL-receptor levels. Treatment with LGP1 caused accumulation of acetylated histone H4 and G(1) cycle arrest accompanied by increase of p21. The compound was also able to sensitize U937 cells to TRAIL-induced apoptosis through multiple mechanisms: (i) activation of caspase-3 and cleavage of PARP; (ii) induction of p21 and p27; (iii) cleavage of NF-kappaB and down-regulation of Bcl-2. Finally, LGP1 induced up-regulation of TRAIL-R1 receptor expression. These results demonstrate that U937 cells can be effectively killed by a combination treatment of subtoxic doses of LGP1 and TRAIL.