Derek Richard Buckle

Non thiazolidinedione antihyperglycaemic agents. 1: α-Heteroatom substituted β-phenylpropanoic acids

The 5-benzylthiazolidine-2,4-dione moiety of insulin sensitising antidiabetic agents can be replaced by a range of α-heteroatom functionalised β-phenylpropanoic acids. α-Oxy-carboxylic acids show potent antidiabetic activity and one compound, the α-ethoxyacid 15 (SB 213068), is one of the most potent antihyperglycaemic agents yet reported.

Non-thiazolidinedione antihyperglycaemic agents. Part 3 : The effects of stereochemistry on the potency of α-methoxy-β-phenylpropanoic acids

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARgamma (peroxisomal proliferator activated receptor gamma), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

Non thiazolidinedione antihyperglycaemic agents. 2: α-Carbon substituted β-phenylpropanoic acids1

The thiazolidine-2,4-dione ring of insulin sensitising antidiabetic agents can be replaced by α-acyl-, α-alkyl- and α-(aralkyl)-carboxylic acids. Inclusion of an additional lipophilic moiety affords compounds 14 and 16, equipotent to BRL 48482.

A hetero Diels-Alder approach to novel thiopyran analogues of aprikalim, A potassium channel activator

Abstract α-Thioketo-ester (6) derived from Bunte salt (5) has been shown to undergo a hetero Diels-Alder reaction with a variety of dienes to form the basis of a concise synthesis of dihydrothiopyran analogues of the potassium channel activator aprikalim.

Hydroxamate-based inhibitors of low affinity IgE receptor (CD23) processing

A series of hydroxamic acids related to the non-selective matrix metalloprotease inhibitor Batimastat is described, which inhibits the proteolytic cleavage of the low affinity IgE receptor from cell membrane preparations. Limited SAR studies suggest that the structural requirements for effective inhibition are distinct from those required for the inhibition of collagenase.

Oxidation Adjacent to C X Bonds by Dehydrogenation

The synthetic versatility of α,β-unsaturated carbonyl compounds has resulted in the development of a wide variety of methods for their synthesis. Many such procedures rely on the construction of the basic carbon framework from simpler fragments, and are typified by reactions of the Wittig, Knoevenagel, aldol and Reformatsky type.1 To be able to introduce regioselective unsaturation into a previously established carbon skeleton is, however, an additional tool in the chemist’s armamentarium. In this review we have attempted to bring together the main literature relating to dehydrogenation methodology. No attempt has been made to include similar reactions that would generate alkynes or reactions that would result in the formation of carbon atoms doubly bonded to heteroatoms. Several of the intermediates described, and especially those involving α-selenenyl or α-thio moieties, offer the opportunity for further elaboration prior to elimination, since such species are able to stabilize adjacent carbanions.2–4 The synthetic applications arising from such intermediates are left to the ingenuity of the reader.

Electrophilic Amination of Ketone Enolates Mediated by the DiTOX Asymmetric Building Block: Enantioselective Formal Synthesis of α-Aminoacids

Abstract Diastereoselective electrophilic amination of enolates derived from 2-acyl-1,3-dithiane 1-oxides is used as the key step for an enantioselective synthesis of two α-hydrazido carboxylic acids, well-known precursors of α-amino acids.

Studies on v-triazoles. Part 4. The 4-methoxybenzyl group, a versatile N-protecting group for the synthesis of N-unsubstituted v-triazoles

A series of readily prepared monocyclic N-(4-methoxybenzyl)-v-triazoles (1) have been converted into their N-unsubstituted derivatives (2) by treatment with trifluoroacetic acid at 65 °C. The procedure allows the synthesis of a range of N-unsubstituted v-triazoles. Its applicability to multicyclic systems is demonstrated by the synthesis of 3,9-dihydro-9-oxobenzopyrano[2,3-d]-v-triazole (5b), one of a series of compounds of interest as potential antiallergic agents.

Synthesis of BRL 55834 - a novel, potent airways-selective potassium channel activator

Abstract An efficient synthesis of the potassium channel activator, BRL 55834 (2), is described and its absolute stereochemistry established as 3S,4R by X-ray crystallographic analysis of the corresponding (S)-α-methylbenzyl carbamate 12. BRL 55834 is the first compound of this pharmacological class to demonstrate selectivity for the smooth muscle of the airways compared with that of the vasculature.

Highly chemoselective osmium-mediated dihydroxylation of 2-vinyl and 2-allyl-1,3-dithiane 1-oxides

Abstract Chemoselective dihydroxylation of the double bonds of alkenyl-substituted 1,3-dithlane 1-oxide derivatives takes place without competing sulfur oxidation using osmium trichloride and potassium ferricyanide.