J. Appl. Cryst.の発刊に際して

1,2-Amino Alcohols and Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric Synthesis

Pyrrole, pyrrolidine, pyridine, piperidine and tropane alkaloids

The palladium-catalyzed α-arylation of ketones has become a useful and general synthetic method. In this process, an enolate is generated from a ketone and base in the presence of an aryl halide, and a palladium catalyst couples this enolate with the aryl halide. With the advent of new catalysts composed of sterically hindered, electron-rich alkylphosphine and N-heterocyclic carbene ligands, this process now encompasses a broad range of enolates and related anions, including those derived from amides, esters, aldehydes, nitriles, malonates, cyanoesters, nitroalkanes, sulfones, and lactones. In the proposed mechanism for this reaction, the carbon−carbon bond of the product is formed by reductive elimination from an arylpalladium enolate intermediate. The structures and reactions of arylpalladium complexes of enolate, cyanoalkyl, and malonate ions have been studied to determine how the binding mode and electronic and steric parameters influence the rate and mechanism of reductive elimination.

Palladium-Catalyzed α-Arylation of Carbonyl Compounds and Nitriles

Recoverable Catalysts for Asymmetric Organic Synthesis

A mild and efficient route to Schiff base derivatives of amino acids

Most peptides have not proved useful as neuroactive drugs because they are blocked by the blood-brain barrier and do not reach their receptors within the brain. Intraperitoneally administered L-serinyl beta-D-glucoside analogues of [Met5]enkephalin (glycopeptides) have been shown to be transported across the blood-brain barrier to bind with targeted mu- and delta-opioid receptors in the mouse brain. The opioid nature of the binding has been demonstrated with intracerebroventricularly administered naloxone. Paradoxically, glucosylation decreases the lipophilicity of the peptides while promoting transport across the lipophilic endothelial layer. It is suggested that glucose transporter GLUT-1 is responsible for the transport of the peptide message. Profound and long-lasting analgesia has been observed in mice (tail-flick and hot-plate assays) with two of the glycopeptide analogues when administered intraperitoneally.

https://www.pnas.org/content/pnas/91/15/7114.full.pdf

Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier.

Equilibrium acidities in Me2S0 are reported for six ketimines of the type Ph2C=NCH(R)C02Et and five aldimines, ArCH=NCH(R)C02Et. Changing R in the ketimine from H to Ph increased the pKa by 2.2 units. This surprising acidity decrease for Ph substitution points to a substantial increase in steric effect, as do the increases in pKa of 3.8 and 4.2 units observed for the replacement of hydrogen by Me and PhCH,, respectively. Phase-transfer alkylation of the Ph2C=NCH2C02Et ketimine gave over 90% of monoalkylate whereas, under similar conditions, the aldimine 4-ClC6H4CH=NCH2C02Et gave a mixture of monoand dialkylate. The difference is that the pKa of the monoalkylated aldimine is essentially the same as that of the parent, which leads to rapid equilibration with the parent anion and consequent dialkylation. The rates of alkylation in Me2S0 of these parent and monoalkylated anions did not differ greatly, showing that the relative pKHAs of the parent acid and its monoalkyl derivative, rather than the relative rates of the monoand dialkylation reactions, is the principal factor that determines the extent of the competition between monoalkylation and dialkylation.

Acidities of glycine Schiff bases and alkylation of their conjugate bases

The synthesis of 18 N-alpha-FMOC-amino acid glycosides for solid-phase glycopeptide assembly is reported. The glycosides were synthesized either from the corresponding O'Donnell Schiff bases or from N-alpha-FMOC-amino protected serine or threonine and the appropriate glycosyl bromide using Hanessian's modification of the Koenigs-Knorr reaction. Reaction rates of D-glycosyl bromides (e.g., acetobromoglucose) with the L- and D-forms of serine and threonine are distinctly different and can be rationalized in terms of the steric interactions within the two types of diastereomeric transition states for the D/L and D/D reactant pairs. The N-alpha-FMOC-protected glycosides [monosaccharides Xyl, Glc, Gal, Man, GlcNAc, and GalNAc; disaccharides Gal-beta(1-4)-Glc (lactose), Glc-beta(1-4)-Glc (cellobiose), and Gal-alpha(1-6)-Glc (melibiose)] were incorporated into 22 enkephalin glycopeptide analogues. These peptide opiates bearing the pharmacophore H-Tyr-c[DCys-Gly-Phe-DCys]- were designed to probe the significance of the glycoside moiety and the carbohydrate-peptide linkage region in blood-brain barrier (BBB) transport, opiate receptor binding, and analgesia.

Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin.

Endogenous peptides (e.g. enkephalins) control many aspects of brain function, cognition, and perception. The use of these neuroactive peptides in diverse studies has led to an increased understanding of brain function. Unfortunately, the use of brain-derived peptides as pharmaceutical agents to alter brain chemistry in vivo has lagged because peptides do not readily penetrate the blood−brain barrier. Attachment of simple sugars to enkephalins increases their penetration of the blood−brain barrier and allows the resulting glycopeptide analogues to function effectively as drugs. The δ-selective glycosylated Leu-enkephalin amide 2, H2N-Tyr-d-Thr-Gly-Phe-Leu-Ser(β-d-Glc)-CONH2, produces analgesic effects similar to morphine, even when administered peripherally, yet possesses reduced dependence liability as indicated by naloxone-precipitated withdrawal studies. Similar glycopeptide-based pharmaceuticals hold forth the promise of pain relief with improved side-effect profiles over currently available opioid an...

Robin Polt

Papers

A mild and efficient route to Schiff base derivatives of amino acids

Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier.

Acidities of glycine Schiff bases and alkylation of their conjugate bases

Solid-phase synthesis of O-linked glycopeptide analogues of enkephalin.

Enkephalin Glycopeptide Analogues Produce Analgesia with Reduced Dependence Liability