The kinetic resolution [1] of chiral trans-cycloalkane-1,2-diols (1) presents a formidable challenge [2] and a rare case where chemical methods are superior to enzymatic approaches. Taking the kinetic resolution of trans-cyclohexane-1,2-diol (1 a, n = 2) through monoacylation as the delineating test reaction, it was shown that various Pseudomonas lipases display both low activities (reaction times typically within the range of days) and low selectivities.[3] Purely chemical transformations utilizing benzoyl transfer in Cu II -catalyzed reactions with C 2 -symmetric bisoxazoline ligands give good ee values for the monobenzoylated product (around 80 %) and good conversions (37-46 %; selectivity factor s = 14-22) within hours; [4,5] Diol 1 a is resolved with up to 66 % ee.[4]
Utilizing bromine‐free, direct C–H bond amidations we have synthesized a large variety of adamantane amides. Depending on the precursors used these amides directly yield pharmaceutically active aminoadamantanes or γ‐aminoadamantanecarboxylic acids after hydrolytic cleavage. Theserigid analogues of γ‐aminobutyric acid (GABA) were protected at the C‐ and N‐termini and we synthesized a number of peptides incorporating γ‐aminoadamantanecarboxylicacids in solution as well as via solid phase peptide synthesis. These peptides are promising scaffolds for applications in medicinal chemistry as well as in organocatalysis.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.
In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occurred before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146-156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.
Inspired by the extraordinary selectivities of acylases, we envisioned the use of lipophilic oligopeptidic organocatalysts for the acylative kinetic resolution/desymmetrization of rac- and meso-cycloalkane-1,2-diols. Here we describe in a full account the discovery and development process from the theoretical concept to the final catalyst, including scope and limitations. Competition experiments with various alcohols and electrophiles show the full potential of the employed oligopeptides. Additionally, we utilized NMR and IR-spectroscopic methods as well as computations to shed light on the factors responsible for the selectivity. The catalyst system can be readily modified to a multicatalyst by adding other catalytically active amino acids to the peptide backbone, enabling the stereoselective one-pot synthesis of complex molecules from simple starting materials.
Multicatalysts consisting of non-natural oligopeptides with distinctly different catalytic moieties create molecular complexity in a multistep one-pot sequence starting from simple alkenes yielding highly enantiomerically enriched trans-diols.
Die kinetische Racematspaltung [1] von chiralen trans-Cycloalkan-1,2-diolen (1) ist eine anspruchsvolle Aufgabe [2] und einer der wenigen Fälle, in denen chemische Methoden enzymatischen Varianten überlegen sind. So verläuft die kinetische Racematspaltung von trans-Cyclohexan-1,2-diol (1 a, n = 2) zum monoacylierten Produkt mit einer Reihe von Pseudomonas-Lipasen sehr langsam (Reaktionszeiten betragen typischerweise mehrere Tage) und mit geringer Selektivität.[3] Die wenigen chemischen Verfahren erzielen über einen Cu II -katalysierten Benzoyltransfer mit C 2 -symmetrischen Bisoxazolinliganden innerhalb von Stunden hingegen gute ee-Werte für das monobenzoylierte Produkt (um 80 %) und gute Umsätze (37-46 %; Selektivitätsfaktor s = 14-22); [4,5] 1 a kann dabei mit einem ee-Wert von bis zu 66 % isoliert werden.[4] Aus diesem Grund ist ein praktikabler chemischer Zugang zu enantiomerenreinen Diolen 1 über eine katalytische enantioselektive kinetische Racematspaltung wünschenswert.Wir präsentieren hier einen Ansatz auf Basis eines lipophilen chiralen Tetrapeptids (2; Boc = tert-Butoxycarbonyl, A Gly = g-Aminoadamantancarbonsäure; unsere Abkürzung A Gly betont die Verwandtschaft zur entsprechenden a-Aminosäure Gly), das mit einer nucleophilen N-p-MethylhistidinEinheit für den enantioselektiven Acyltransfer ausgestattet ist.[6] Miller et al. waren sehr erfolgreich [7,8] bei der Racematspaltung einfach geschützter Diole, Aminoalkohole [9] und Polyole über Acyltransfer.[8] Die bei einigen dieser Reaktionen verwendeten Tetrapeptidkatalysatoren 3 waren bei unseren Versuchen zur Racematspaltung von (AE )-1 jedoch nicht sehr effizient (Abbildung 1 und Hintergrundinformationen, HI). Toniolo et al. verbesserten die Effizienz von 3 durch Einführung von lipophilem a-Methylvalin.[10]Unsere Strategie für die Entwicklung einer praktikablen chemischen Methode zur Racematspaltung von (AE )-1 beruhte auf der Synthese und Verwendung von lipophilen Oligopeptiden mit wenig flexibler Struktur; die Hoffnung war, dass eine geringere Katalysatorselbstassoziation (Dimerisierung oder Faltung) niedrige Katalysatorbeladungen und die Verwendung unpolarer organischer Lösungsmittel ermögli-chen sollte. Erst kürzlich konnte gezeigt werden, dass wenig polare organische Lösungsmittel eine Schlüsselrolle bei der effizienten Katalysatorregeneration einnehmen, sodass bei 4-Dimethylaminopyridin(DMAP)-katalysierten Acylierungen sogar auf die Hilfsbase verzichtet werden kann, [11] was die Aufarbeitung vereinfacht. [9] Abbildung 1. Katalysator-Screening (2) für die gezeigte enantioselektive Acylierungstestreaktion bei niedrigem Umsatz (< 10 %) zur Bestimmung der maximalen Aktivitäten; Enantiomerenverhältnis (e.r.) angegeben für 4 a. Kasten: 2 i erwies sich als der effizienteste Katalysator.[
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