NH-type of chiral Ni(II) complexes of glycine Schiff base: design, structural evaluation, reactivity and synthetic applications.

The work being reported here deals with the design of a new type of "N-H" Ni(II) complexes of glycine Schiff bases and study general aspects of their reactivity. It was confirmed that the presence of NH function in these Ni(II) complexes does not interfere with the homologation of the glycine residue, rendering these derivatives of high synthetic value for the general synthesis of α-amino acids. In particular, the practical application of these NH-type complexes was demonstrated by asymmetric synthesis of various ß-substituted pyroglutamic acids via Michael addition reactions with chiral Michael acceptors.

trans-(-)-ε-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington Disease.

Huntington disease (HD) is an inherited neurodegenerative disorder caused by an abnormal polyglutamine expansion in the protein Huntingtin (Htt). Currently, no cure is available for HD. The mechanisms by which mutant Htt causes neuronal dysfunction and degeneration remain to be fully elucidated. Nevertheless, mitochondrial dysfunction has been suggested as a key event mediating mutant Htt-induced neurotoxicity because neurons are energy-demanding and particularly susceptible to energy deficits and oxidative stress. SIRT3, a member of sirtuin family, is localized to mitochondria and has been implicated in energy metabolism. Notably, we found that cells expressing mutant Htt displayed reduced SIRT3 levels. trans-(-)-ε-Viniferin (viniferin), a natural product among our 22 collected naturally occurring and semisynthetic stilbenic compounds, significantly attenuated mutant Htt-induced depletion of SIRT3 and protected cells from mutant Htt. We demonstrate that viniferin decreases levels of reactive oxygen species and prevents loss of mitochondrial membrane potential in cells expressing mutant Htt. Expression of mutant Htt results in decreased deacetylase activity of SIRT3 and further leads to reduction in cellular NAD(+) levels and mitochondrial biogenesis in cells. Viniferin activates AMP-activated kinase and enhances mitochondrial biogenesis. Knockdown of SIRT3 significantly inhibited viniferin-mediated AMP-activated kinase activation and diminished the neuroprotective effects of viniferin, suggesting that SIRT3 mediates the neuroprotection of viniferin. In conclusion, we establish a novel role for mitochondrial SIRT3 in HD pathogenesis and discovered a natural product that has potent neuroprotection in HD models. Our results suggest that increasing mitochondrial SIRT3 might be considered as a new therapeutic approach to counteract HD, as well as other neurodegenerative diseases with similar mechanisms.

Chemical approach for interconversion of (S)- and (R)-α-amino acids.

Here we report a general method for the preparation of unnatural (R)-α-amino acids via complexation of α-(phenyl)ethylamine derived chiral reagent (S)- with various (S)-α-amino acids. The reactions proceed with synthetically useful chemical yields and thermodynamically controlled diastereoselectivity. Chiral reagent (S)- can be conveniently recovered and reused without any loss of enantiomeric purity and reactivity.

Reappraising the structures and distribution of metabolites from black aspergilli containing uncommon 2-benzyl-4H-pyran-4-one and 2-benzylpyridin-4(1H)-one systems.

To date, natural products containing 2-benzyl-4H-pyran-4-one and 2-benzylpyridin-4(1H)-one substructures have been encountered in relatively few fungi outside of the black aspergilli clade. While exploring the occurrence of these compounds among Aspergillus spp., it was determined that the structures of the unusual furopyrrols tensidols A and B (5 and 6) and JBIR-86 and JBIR-87 (9 and 10) were incorrect and should be reassigned as 2-benzyl-4H-pyran-4-ones (7, 8, 11e, and 12, respectively). The origin of the unique N-phenyl groups in the 2-benzylpyridin-4(1H)-ones nygerones A and B (1 and 2) were also examined, and it was established that N-phenylamides added to the culture medium were suitable substrates for generating these metabolites; however, this phenomenon remained limited to a single fungus in our collection (Aspergillus niger ATCC 1015). A variety of 2-benzyl-4H-pyran-4-ones and 2-benzylpyridin-4(1H)-ones were detected among the black aspergilli, but only pestalamide B (13) was found in all 11 of the tested strains. These metabolites, as well as a group of synthetic analogues, demonstrated weak antifungal activity against several Candida strains, Aspergillus flavus, and Aspergillus fumigatus.

21-(4-Methyl-phenyl-sulfon-yl)-4,7,13,16-tetra-oxa-1,10,21-triaza-bicyclo-[8.8.5]tricosane-19,23-dione: an N-tosyl-ated macrobicyclic dilactam.

The macrobicyclic title compound, C(23)H(35)N(3)O(8)S, contains two tertiary amide bridgehead N atoms and a toluene-sulfonamide N atom in the center of the five-atom bridging strand. The mol-ecule has a central cavity that is defined by the 18-membered ring identified by the N(2)O(4) donor atom set and two 15-membered rings with N(3)O(2) donor atom sets. The toluene-sulfonamide N atom adopts an exo orientation with respect to the central cavity, and the tosyl group is oriented on one side of the aza-bridging strand that connects the bridgehead N atoms.

Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum.

Chemical epigenetic manipulation of Penicillium citreonigrum led to profound changes in the secondary metabolite profile of its guttate. While guttate from control cultures exhibited a relatively simple assemblage of secondary metabolites, the guttate collected from cultures treated with 50 muM 5-azacytidine (a DNA methyltransferase inhibitor) was highly enriched in compounds representing at least three distinct biosynthetic families. The metabolites obtained from the fungus included six azaphilones (sclerotiorin (1), sclerotioramine (6), ochrephilone (2), dechloroisochromophilone III (3), dechloroisochromophilone IV (4), and 6-((3E,5E)-5,7-dimethyl-2-methylenenona-3,5-dienyl)-2,4-dihydroxy-3-methylbenzaldehyde (5)), pencolide (7), and two new meroterpenes (atlantinones A and B (9 and 10, respectively)). While pencolide was detected in the exudates of both control and 5-azacytidine-treated cultures, all of the other natural products were found exclusively in the guttates of the epigenetically modified fungus. All of the metabolites from the P. citreonigrum guttate were tested for antimicrobial activity in a disk diffusion assay. Both sclerotiorin and sclerotioramine caused modest inhibition of Staphylococcus epidermidis growth; however, only sclerotioramine was active against a panel of Candida strains.

Resolution/deracemization of chiral alpha-amino acids using resolving reagents with flexible stereogenic centers.

This work has demonstrated that a previously unexplored approach to separation of enantiomers via formation of diastereomeric derivatives with three stereogenic centers has obvious practical potential and deserves further systematic study. The design reported here is based on the unusual application of a configurationally unstable stereogenic nitrogen, which plays a key role in setting up the stereochemical match between the three stereogenic centers in the corresponding products.

Design, synthesis, and evaluation of a new generation of modular nucleophilic glycine equivalents for the efficient synthesis of sterically constrained alpha-amino acids.

A new generation of modular achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of tailor-made, sterically constrained alpha-amino acids, which proved to be the most efficient approach developed to date for the synthesis of symmetrical alpha,alpha-disubstituted-alpha-amino acids. Among the new series of achiral glycine equivalents, one was found to be a superior glycine derivative for the Michael additions with various (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained beta-substituted pyroglutamic acids. In particular, the application of these complexes allowed for the preparation of several beta-substituted pyroglutamic acids which include electron-releasing and sterically demanding substituents in the structure thus increasing the synthetic efficiency and expanding the generality of these Michael addition reactions.

Efficient synthesis of 2-aminoindane-2-carboxylic acid via dialkylation of nucleophilic glycine equivalent.

An efficient, easy to scale-up method for preparing 2-aminoindane-2-carboxylic acid via two-step alkylation of a Ni(II)-complex of glycine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PAAP) (2b) with o-dibromoxylylene (3) is reported. The first step, monoalkylation of 2b with 3, conducted under phase-transfer conditions, gave the corresponding complex 6 in excellent chemical yield (97.2%). Without any purification the intermediate 6 was cyclized under homogeneous conditions (DMF, NaO-t-Bu) to give the product 7 in high chemical yield (93.1%). Decomposition of prepared 7 afforded the target amino acid 2-aminoindane-2-carboxylic acid (1) in 97.9% yield, along with recovery of ligand 8, which was converted back to the starting glycine complex 2b. Operationally convenient experimental procedures, mild reaction conditions, as well as high chemical and volume yields render the method practical for preparing amino acid 1 and its analogues.

Efficient synthesis of serically constrained smmetrically alpha,alpha-disubstituted alpha-amino acids under operationally convenient conditions.

Homologation of the nucleophilic glycine equivalent Ni-Gly-PABP [Ni(II) complex of glycine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PABP)] 2 via alkyl halide alkylations and Michael addition reactions was systematically studied as a general method for preparing symmetrically alpha,alpha-disubstituted alpha-amino acids (sym-alpha,alpha-AA). The dialkylation reactions are conducted under operationally convenient conditions without recourse to inert atmosphere, dried solvents, and low temperatures, thus enjoying key advantages of the experimental simplicity and attractive cost structure. The method has been shown to be particularly successful for the dialkylation of complex 2 with activated and nonactivated alkyl halides, including propargyl derivatives, affording a generalized and practical access to the corresponding sym-alpha,alpha-AA. This study has also shown some limitation of the method, as it cannot be extended to alpha- or beta-branched alkyl halides or Michael acceptors to be used for the dialkylation of glycine equivalent 2. High chemical yields of the dialkylated products, combined with the simplicity of the experimental procedure, render this method worth immediate use for multigram scale preparation of the sym-alpha,alpha-AA.

Improved synthesis of proline-derived Ni(II) complexes of glycine: versatile chiral equivalents of nucleophilic glycine for general asymmetric synthesis of alpha-amino acids.

A synthetically practical and operationally convenient method for preparing (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPBP) and hitherto unknown (S)-2-[N-(N'-benzylprolyl)amino]-4-methylbenzophenone (4-Me-BPBP), (S)-2-[N-(N'-benzylprolyl)amino]-5-nitrobenzophenone (5-NO(2)-BPBP), and their corresponding Ni(II) complexes with glycine [GlyNi(II)BPBP], a widely used chiral equivalent of nucleophilic glycine, and new analogues [GlyNi(II)-4-Me-BPBP] and [GlyNi(II)-5- NO(2)-BPBP] is described. The key step of the method is the synthetically efficient amid bond formation between the corresponding o-aminobenzophenones, featuring significant steric shielding and low nucleophilicity of the amino functionality as well as sterically constrained (S)-N-benzylproline (BP).