Paul M. Doyle

Stereospecific synthesis of 4-fluoroglutamic acids

Abstract A stereospecific route to 4-fluoroglutamic acids from pyroglutamic acid has been devised and variable temperature 1 H-nmr spectroscopic studies have explained apparent inconsistencies in the stereochemical outcome of steps in a synthesis of 4-fluoroglutamic acids from hydroxyprolines.

Synthesis of non-proteinogenic amino acids with three chiral centres

Abstract Reaction of activated imines with the lactam enolate of the protected pyroglutamic ester ( 1 ) has been used to prepare optically pure derivatives of amino acids containing three chiral centres.

Synthesis of glutamate agonists and anatagonists by a ring switching strategy

Abstract Our ring switching strategy for synthesis of compounds with structural features consistent with activity at glutamate receptors has been modified to prepare L-alanine derivative substituted at the β-carbon atom with six-membered heteroaromatic rings. The pyrimidinone ( 11, R = R 1 = R 2 = H ) has been shown to be a glutamate agonist and the compound ( 13 ) to be an antagonist.

Extension of ring switching strategy to the glutamate antagonist 2-(pyrimidin-2,4-dione-5-ylmethyl)-(2S)-glycine and related compounds with two chiral centres

Abstract 2-(Pyrimidin-2,4-dione-5-ylmethyl)-(2 S )-glycine 8 has been prepared by treatment of the pyroglutamate urea 12 with mild base, followed by deprotection in a modification of our ring switching approach to the synthesis of glutamate antagonists. The product is an isomer of the natural product willardiine 7 . Use of this two step strategy has allowed us to synthesise l -alanine derivatives, which are β-substituted by a reduced pyrimidinedione containing a second chiral centre. There is little difference between the diastereoisomers of one of these compounds as antagonists at metabotropic glutamate receptors.

Synthesis of an external β-turn based on the GLDV motif of cell adhesion proteins

The (3S,6S,10S)-7/5 bicyclic lactam 4, designed as an external turn constraint, was synthesised by a new stereoselective route involving Eschenmoser condensation. Calculated preferred conformations compare well with the preferred solid state conformation, obtained by X-ray crystallography. The lactam 4 was not a turn mimic in its own right but could be used as an external constraint to prepare the cyclic peptide 29 containing the integrin recognition motif GLDV. High-resolution NMR measurements were consistent with this compound having a single backbone conformation.

Synthesis of potential agonists and antagonists for central glutamate receptors by a novel ‘ring switching’ process

Heterocyclic derivatives 6 of (S)-glutamic acid, which are structurally related to key central nervous system (CNS) glutamate receptor agonists, are prepared from the aldehyde 9 using a novel reaction in which the pyroglutamate ring is cleaved in concert with formation of the new heterocyclic ring.

STEREOSELECTIVE SYNTHESIS OF NON-PROTEINOGENIC AMINO ACIDS

Abstract The lactam enolate of the protected pyroglutamic acid ester (1) has been shown to react with activated imines to yield optically pure derivatives of non-proteinogenic amino acids.

An interesting dichotomy in the cyclisation of exocyclic enamines with protected dehydroamino acids leading to different β-turn templates

Abstract Two templates for the preparation of external β-turns have been synthesised. In the course of the synthetic studies an interesting dichotomy was observed in the PCl 3 catalysed reaction of exocyclic enamines such as 6 and 14 with protected dehydroamino acids. When amide protected dehydroamino acids were condensed with 6 and 14 the expected 6/6 and 6/5 fused bicyclic compounds such as 7 and 15 respectively were obtained, whereas when urethane protected dehydroamino acids were used, the 5/6 and 5/5 fused products 9 and 18 were obtained.

Synthesis of agonists and antagonists for central glutamate receptors bya novel ‘ring switching’strategy1

A novel and versatile ring switching strategy has been developed for the synthesis of compounds with structural features consistent with activity at glutamate receptors. A variety of homochiral L-alanine derivatives substituted at the β-carbon atom with planar five and six-membered heteroaromatic rings have been prepared in a one- or two-pot reaction using this strategy and some of the products have been shown to have biological activity at central glutamate receptors.

Synthesis of homochiral amino acid pyrazine and pyrrole analogues of glutamate antagonists

Use of the acid 7 and the aldehydes 23a and 23b in “ring switching” reactions with hydrazines has given β-(1-aminopyrrole)amino acids as kinetic products. The products from the reaction of the aldehyde have been converted into β-(pyrazine)amino acids by an equilibration–dehydration sequence. A variety of homochiral reduced heterocyclic amino acids containing two chiral centres has been prepared in this way. Some of the product amino acids undergo “reverse ring switching” to the corresponding pyroglutamic acid derivatives.