Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.

An efficient chemoenzymatic synthesis of both enantiomers of fagomine, as well as of cis and trans‐4‐hydroxypipecolic acid is reported. The synthesis starts from commercial δ‐valerolactam which, after a Pd‐catalyzed methoxycarbonylation of the corresponding vinyl phosphate, is subjected to allylic oxidation to give a racemic 4‐hydroxytetrahydropyridine derivative in 57 % overall yield. This product is resolved by an enzyme‐catalyzed esterification using immobilized lipases from Candida antarctica (Novozym 435) and Burkholderia cepacia (lipase PS Amano IM). The latter provides the corresponding R esters and the S alcohol in 95 and 94 % ee, respectively. The S alcohol is then converted into L‐fagomine by a stereoselective hydroboration/oxidation as key steps and the cis‐(2R,4S)‐4‐hydroxypipecolic acid by stereoselective hydrogenation. The corresponding D‐fagomine and cis‐(2S,4R)‐4‐hydroxypipecolic acid, as well as trans‐(2R,4R)‐4‐hydroxypipecolic acid can be prepared by the same strategy after hydrolysis of the R ester obtained by kinetic resolution.

We describe two complementary and stereodivergent routes, from commercially available and inexpensive starting materials, for the synthesis of 4,5‐dihydroxy‐ and 5‐hydroxypipecolic acids based on the chemistry of lactam‐derived enol phosphates. The synthesis of the 4,5‐cis‐4,5‐dihydroxypipecolic acids required the preparation from 2‐deoxy‐D‐ and ‐L‐ribose of the enantiopure cis‐(4S,5R)‐ and ‐(4R,5S)‐4,5‐dihydroxy‐δ‐valerolactam, respectively. These new chiral synthons are potentially useful for the synthesis of other natural products. The key step is the Pd‐catalyzed methoxycarbonylation reaction of the enol phosphates generated from these lactams. This reaction provided enecarbamate esters that were easily converted by stereoselective reduction to the target compounds. The synthesis of the 4,5‐trans‐4,5‐dihydroxypipecolic acid, as well as of 5‐hydroxypipecolic acids, was realized from a known (S)‐5‐hydroxy‐δ‐valerolactam derivative and, for the dihydroxylated compound, required a highly stereoselective allylic bromination reaction of the enecarbamate ester obtained by methoxycarbonylation of the enol phosphate. The preparation of the (4R,5S) enantiomer of the cis‐4,5‐dihydroxy‐δ‐valerolactam from 2‐deoxy‐L‐ribose, alongside the fact that (R)‐5‐hydroxy‐δ‐valerolactam can be prepared from (R)‐(–)‐γ‐hydroxymethyl‐γ‐butyrolactone, means our approach allows for the synthesis of all stereoisomers of these compounds, which can be employed as conformationally constrained scaffolds in drug discovery.

A set of raw industrial materials, that is, pure quartz and quartz-rich mixtures, were investigated through electron paramagnetic resonance and electron spin echo-envelope modulation spectroscopies, with the aim of evaluating the effective role played by defect centres and of assessing whether they can be used to monitor changes in the physical properties of quartz powders with reference to their health effects. The obtained results point to two interactions of the Al defect centres with H+, hosted in sites within the channels parallel and perpendicular to the c axis of quartz, respectively. These two Al/H+ (hAl) centres exhibit a weak chemical bond, and their relative amounts appear to be modified/controlled by the thermo-mechanical processes underwent by powders. Indeed, a mechanically promoted inter-conversion between the two kinds of site is suggested. As a consequence, the hAl centres are effective in monitoring even modest activations of powders, through thermal or mechanical processes, and they are also supposed to play a specific, relevant role in quartz reactivity during the considered industrial processes

A thorough study of the carbonylative Suzuki–Miyaura cross‐coupling reaction of enol triflates with alkenylboronic acids for the synthesis of unsymmetrical dienones is reported. Conditions were found that enabled the coupling of structurally different enol triflates derived from lactams, lactones, and thiolactones (i.e., cyclic ketene aminal, acetal, and thioacetal triflates, respectively) with various alkenylboronic acids at room temperature under 1 atm of CO pressure with 1–5 % palladium catalyst; the carbonylated products were obtained in 50–86 % overall yields. The methodology allows for a convergent and rapid preparation of substrates useful in conjugate additions and Nazarov reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)