Attrition-enhanced total resolution leads to homochiral families of amino acid derivatives

The total resolution of five structurally similar racemizable amino acid derivatives, three of which have racemic crystal structures, was performed simultaneously. By enantioselective incorporation in an amino acid derivative that forms a conglomerate the other four were deracemized on attrition-induced grinding. The outcome of the resolution was random (R) or (S), but all compounds had the same absolute configuration and high enantiomeric purities.

L'Ecologisme en Allemagne et en France : deux modes différents de construction d'un nouvel acteur politique

SummaryThe N-terminally truncated variant of photoactive yellow protein (Δ25-PYP) undergoes a very similar photocycle as the corresponding wild-type protein (WT-PYP), although the lifetime of its light-illuminated (pB) state is much longer. This has allowed determination of the structure of both its dark- (pG) as well as its pB-state in solution by nuclear magnetic resonance (NMR) spectroscopy. The pG structure shows a well-defined fold, similar to WT-PYP and the X-ray structure of the pG state of Δ25-PYP. In the long-lived photocycle intermediate pB, the central β sheet is still intact, as well as a small part of one α helix. The remainder of pB is unfolded and highly flexible, as evidenced by results from proton-deuterium exchange and NMR relaxation studies. Thus, the partially unfolded nature of the presumed signaling state of PYP in solution, as suggested previously, has now been structurally demonstrated

Application of Enzymes in Industrial Organic Synthesis

Aminopeptidase- and amidase-based methods for the production of enantiomerically pure amino acids, intermediates for pharmaceuticals and agrochemicals, are discussed. Furthermore, enzymatic syntheses of the dipeptide sweetener aspartame and semisynthetic antibiotics (such as ampicillin, amoxicillin, cephalexin, and cefadroxil) are highlighted

Combining incompatible processes for deracemization of Praziquantel derivative under flow conditions

An efficient deracemization method for conversion of the racemate to the desirable (R)-enantiomer of Praziquantel has been developed by coupling incompatible racemization and crystallization processes. By a library approach, a derivative that crystallizes as a conglomerate has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 °C, whereas deracemization is achieved by alternating crystal growth/dissolution steps with temperature cycling between 5–15 °C. These incompatible processes are combined by means of a flow system resulting in complete deracemization of the solid phase to the desired (R)-enantiomer (98 % ee). Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization

Comparative conformational analysis of peptides based on the two Cα-tetrasubstituted, Cβ-branched, chiral α-amino acids (αMe)Dip and (αMe)Val

For the first time a number of terminally protected model peptides (to the pentamer level) of the sterically demanding α-amino acid Cα-methyl,Cα-diphenylmethylglycine, (αMe)Dip, in combination with either Ala or Gly residues, have been synthesized (by solution methods) and fully characterized. In a parallel synthesis the corresponding peptides based on the related α-amino acid Cα-methyl,Cα-isopropylglycine, (αMe)Val, have also been prepared. The results of a comparative conformational analysis, performed by using FTIR absorption, 1H NMR, and X-ray diffraction techniques, favour the conclusion that, in contrast to the potent β-turn and 310-helix promoter (αMe)Val, (αMe)Dip may induce either a folded or a fully extended conformation. These findings indicate that, despite the common Cα-methylated and Cβ-branched features, (αMe)Dip and (αMe)Val are characterized by partially divergent conformational bias.The Padova authors gratefully acknowledge M.U.R.S.T., the Ministry of University and Scientific and Technological Research, and the National Council of Research (C.N.R.) of Italy for their continuous support of this research. The Zaragoza and Padova authors are also grateful to the Spain-Italy exchange program “Accion Integrada” HI 97-20/“Azioni Integrate” 1997/1999.Peer reviewe

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, Cα-methylated α-amino acid l-(αMe)Nva with a short, linear side-chain. A set of terminally protected model peptides to the pentamer level containing either (αMe)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (αMe)Nva peptides were also synthesized using side-chain hydrogenation of the corresponding Cα-methyl, Cα-allylglycine (Mag) peptides. A detailed solution and crystal-state conformational analysis based on FT-IR absorption, 1H NMR and X-ray diffraction techniques allowed us to define that: (i) (αMe)Nva is an effective β-turn and 310-helix former; and (ii) the relationship between (αMe)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. l-(αMe)Nva induces the preferential formation of right-handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on α-amino acids with a Cα-methyl substituent and a Cα-linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures.The Padova authors gratefully acknowledge M.U.R.S.T., the Ministry of University and Scientific and Technological Research, and C.N.R., the National Council of Research of Italy for their continuous support. The Zaragoza authors acknowledge the Direccion General de Investigacion Cientifica y Tecnica (PB94±0998) for financial support. The Zaragoza and Padova authors are also grateful to the Spain-Italy exchange program Accion Integrada HI 97-20/AzioniIntegrate 1997/99.Peer reviewe

Selective C-Rel Activation via Malt1 Controls Anti-Fungal TH-17 Immunity by Dectin-1 and Dectin-2

C-type lectins dectin-1 and dectin-2 on dendritic cells elicit protective immunity against fungal infections through induction of TH1 and TH-17 cellular responses. Fungal recognition by dectin-1 on human dendritic cells engages the CARD9-Bcl10-Malt1 module to activate NF-κB. Here we demonstrate that Malt1 recruitment is pivotal to TH-17 immunity by selective activation of NF-κB subunit c-Rel, which induces expression of TH-17-polarizing cytokines IL-1β and IL-23p19. Malt1 inhibition abrogates c-Rel activation and TH-17 immunity to Candida species. We found that Malt1-mediated activation of c-Rel is similarly essential to induction of TH-17-polarizing cytokines by dectin-2. Whereas dectin-1 activates all NF-κB subunits, dectin-2 selectively activates c-Rel, signifying a specialized TH-17-enhancing function for dectin-2 in anti-fungal immunity by human dendritic cells. Thus, dectin-1 and dectin-2 control adaptive TH-17 immunity to fungi via Malt1-dependent activation of c-Rel

Macroheterocycles:Synthesis and applications as complexing agents, enzyme mimics and catalysts

Two types of systems are discussed. The first one is derived from lutidine, which either is condensed with two equivalents of a ketone or ketone equivalent or is subjected to nucleophilic substitution by stabilized carbanions via lutidine‐2,6‐dibromide. The resulting non‐macrocyclic systems (podands) on further conversion form derivatives that wrap themselves selectively about metal ions. The Zn2+ complexes mimic the active site zinc of liver alcohol dehydrogenase. The other type of compound is a thiamacrocycle. Excellent synthetic routes to these sulfur analogs of crown ethers have been devised and the chemistry ‐ complexations of metal ions, reaction with BH3 ‐ has been explored