Mark G. Moloney

Excitatory amino acids

Covering: January 1999–December 2001. Previous review: Nat. Prod. Rep., 1999, 16, 485.Recent developments in the understanding of the molecular function of memory and other CNS-mediated processes have arisen from the multidisciplinary interplay of excitatory amino acid synthesis and medicinal chemistry, X-ray crystallographic structural protein analysis, molecular biology, pharmacology and physiology. This review seeks to place recent synthetic developments of EAA analogues in the wider pharmacological setting, illustrating the need for and importance of these compounds.

Amino acid synthesis using (L)-pyroglutamic acid as a chiral starting material

Abstract Deprotonation of protected pyroglutamates 1(c), 1(d), 1(e) with lithium di-isopropylamide (LDA) or lithium hexamethyldisilazide (LiHMDS) in THF, followed by reaction with electrophiles, leads to the formation of 4-substituted pyroglutamates in good yield. This approach has been used for the synthesis of the novel amino acid (4).

New photolabile phosphate protecting group

Abstract The synthesis of phosphate, protected with various photolabile protecting groups, is described. Upon laser photolysis at 355 nm, inorganic phosphate is released, in yields of up to 85%.

(L)-PYROGLUTAMIC ACID AS A CHIRAL STARTING MATERIAL FOR ASYMMETRIC SYNTHESIS

Abstract Elaboration of lactam (1), readily available from ( L )-pyroglutamic acid, provides access to a range of 2,4- and 2,3,4-substituted pyrrolidinones.

Non-proteinogenic amino acid synthesis. The β-anion derived from aspartic acid, and its application to α-amino acid synthesis.

Abstract Treatment of α- t -Butyl β-methyl N -Z-(S)-aspartate (2) with lithium amide bases generates the corresponding β-ester enolate, which can be alkylated with suitable electrophiles. The application of this strategy for synthesis of optically active amino acids has been investigated.

Non-proteinogenic amino acid synthesis: Synthesis of β,γ-unsaturated α-amino acids from asparic acid

Abstract A general, stereospecific, synthesis of β,γ-unsaturated α-amino acids using the β-anion derived from aspartic acid is described.

Functionalised pyrrolidinones derived from (S)-pyroglutamic acid

Abstract The generation of the lactam enolate derived from bicyclic lactams 2a-c, prepared from (S)-pyroglutamic acid 1a, and subsequent reaction with a range of electrophiles, is reported. Exo-diastereoselectivity is generally favoured. The deprotection of some of these adducts to give functionalised hydroxymethylpyrrolidinones is readily achieved by simple hemiaminal ether cleavage under acidic conditions.

Chemical functionalization of diamond surfaces by reaction with diaryl carbenes.

A rapid route to the chemical functionalization of hydrogen-terminated diamond surfaces deposited by chemical vapor deposition involving their reaction with substituted diaryl carbenes has been investigated. To avoid difficulties in the handling of highly reactive compounds, the carbene is generated in situ from the thermal decomposition at 400 K of a thin film of the corresponding diaryl diazomethane precursor deposited at the diamond interface. X-ray photoelectron spectroscopy (XPS) has been used to verify that surface functionalization using two starting compounds, bis(4-iodophenyl) diazomethane and bis(4-nitrophenyl) diazomethane, can be achieved using this approach in agreement with recent theoretical studies. The surface grafting density is measured to be around 10(14) cm(-2) in each case. The chemistry observed is found to be insensitive to the detailed properties of the diamond film and to the presence of oxygen contamination at the hydrogen-terminated diamond surface. We further demonstrate the utility of the approach, in the case of the bound nitrophenyl compound, by its reduction to the corresponding primary amine followed by reaction with fluorescein isothiocyanate to achieve fluorescent tagging of the diamond interface.

Natural Products as a Source for Novel Antibiotics

Natural products have historically been of crucial importance in the identification and development of antibacterial agents. Interest in these systems has waned in recent years, but the rapid emergence of resistant bacterial strains has forced their re-evaluation as a route to identify novel chemical skeletons with antibacterial activity for elaboration in drug development. This overview examines the current situation, highlights new natural product systems which have been found, together with re-examination of some old ones, and new technologies for their identification. While natural products certainly have the potential to re-emerge as a key start-point in antibacterial drug discovery, reports of new or reinvestigated structures need to be supported with sufficient quality chemical (solubility, stability), biochemical (including toxicity in particular, along with target information) and microbiological [minimum inhibitory concentration (MIC) and resistance frequency] validation data to assist in the identification of promising hit structures and to avoid wasted effort from trawling over already cultivated territory. This is particularly important in a resource-limited research environment.

Enantioselective kainoid synthesis by cobalt-mediated cyclisation of an amino acid derivative

Abstract A new synthesis of (-)-kainic acid is described based on a cobalt mediated cyclisation reaction of an appropriately modified serine precursor.