Stephen D. Lindell

Combinatorial chemistry in the agrosciences

Combinatorial chemistry and high throughput screening have had a profound effect upon the way in which agrochemical companies conduct their lead discovery research. The article reviews recent applications of combinatorial synthesis in the lead discovery process for new fungicides, herbicides and insecticides. The role and importance of bioavailability guidelines, natural products, privileged structures, virtual screening and X-ray crystallographic protein structures on the design of solid- and solution-phase compound libraries is discussed and illustrated.

Polyfunctionalisation of imidazole via sequential imidazolyl anion formation

Abstract A method for achieving the sequential functionalisation of the imidazole ring in the order C-5→C-4→C-2 is described. The chemistry proceeds via the regioselective formation of positionally stable imidazolyl anions which are reacted with electrophiles (aldehydes, alkyl halides, azides, formamides, isocyanates) to afford substituted imidazoles in 31–90% yield.

Synthesis of potential inhibitors of the enzyme aspartate transcarbamoylase

Two difluoromethylenephosphonates, 7 and 8, and the phosphinylmethylenephosphonate 9 were prepared as potential inhibitors of aspartate transcarbamoylase (ATCase). The synthesis of compound 8 was facilitated by development of a new direct method for converting nitroalkanes to alkanoic acids. Of the three phosphonates, the amide 27 proved to be a good inhibitor of mung bean ATCase (I50n 5μM).

Synthesis of inhibitors of imidazole glycerol phosphate dehydratase

Abstract Novel inhibitors of the newly discovered herbicide target enzyme imidazole glycerol phosphate dehydratase are described. The most potent inhibitor, compound 6 (IC50

Synthesis of potent inhibitors of histidinol dehydrogenase

Abstract Novel inhibitors of histidinol dehydrogenase are described. The most potent inhibitors, compounds 18 ( F i ∗ = 4.4 nM) and 19 ( K i ∗ = 2.9 nM) exploit a hitherto unreported lipophilic binding pocket adjoining the active site. Preliminary SAR data for this pocket are detailed. The electrophilic ketone 6 designed to bind to an active site nucleophile was a considerably weaker inhibitor (IC 50 ∼20μM).

Synthesis of C-ribosyl imidazo[2,1-f][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

The 3-β-D-ribofuranoside 6 of the new imidazo[2,1-f][1,2,4]triazine 27 is isomeric and isoelectronic with the nucleoside deaminoformycin 1 which is a good inhibitor of adenosine deaminase (ADA) while its 5′-monophosphate 2 is a good inhibitor of adenosine 5′-monophosphate deaminase (AMPDA). The 6-methylsulfanyl derivative 7 of 6 is synthesized by condensation of the monocyclic 1,2,4-triazine 9 with bromo aldehyde 10, which is accompanied by cyclization to give the protected C-nucleoside 21; the 8-methylsulfanyl group of 21 is removed by replacement by hydrazine and oxidation. The 1,2,4-triazine 9 cyclizes similarly with chloroacetaldehyde or its dimethyl acetal to give 6,8-bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine 17, which is converted into the parent heterocycle 27 by two routes, and into mono- and di-substituted derivatives (19, 20, 24, 25, 28–30) of the new ring system. Riboside 7 is an inhibitor of mammalian ADA (IC50 40 µM).

Total synthesis of (±)-aspercyclide A and its C19 methyl ether

The total syntheses of (+/-)-aspercyclide A (1) and its C19 methyl ether (15a) featuring Heck-Mizoroki macrocyclisation to form the 11-membered (E)-styrenyl biaryl ether lactone core are described.

Total synthesis of carbocyclic analogues of coformycin

Abstract Four carbocyclic analogues of the ribonucleoside coformycin, including the recently isolated natural product 2, have been synthesised in racemic form. The syntheses were achieved in a convergent and direct manner via palladium(0) catalysed coupling between diazepinones 15 and 16 and the allylic acetate 5.

Recent advances in microwave-assisted combinatorial synthesis and library generation.

Progress and developments made in microwave-assisted combinatorial synthesis and library production since 2002 are reviewed. The use of microwave technology in both solution and solid phase synthesis is discussed with special reference to agrochemical applications where appropriate.

Synthesis of (±)-2′,3′-didehydro-2′,3′-dideoxy nucleosides via a modified Prins reaction and palladium(0) catalysed coupling

Cyclopentenyl allylic acetates have been prepared in diastereoisomerically enriched form by modification of the Prins reaction. Palladium(0) catalysed coupling between these allylic acetates and a heteroaromatic base provides a highly convergent and direct route for synthesising carbocyclic 2′,3′-didehydro-2′,3′-dideoxy nucleosides. The method is exemplified by the coupling reaction with adenine which yields (±)-2′,3′-didehydro-2′,3′-dideoxyaristeromycin 5′-O-acetate 22 in 50% yield. This has been converted in two steps into (±)-aristeromycin triacetate 5.