Gordon G. Weingarten

Convergent, Regiospecific Synthesis of Quinolines from o-Aminophenylboronates

A direct convergent two-component synthesis of quinolines from alpha,beta-unsaturated ketones and o-aminophenylboronic acid derivatives is reported. The reaction is regiocomplementary to the traditional Skraup-Doebner-Von Miller synthesis and proceeds under basic rather than strongly acidic conditions. Quinolines substituted in the benzenoid ring can be accessed by using substituted o-aminophenylboronates prepared by direct palladium-catalyzed borylation of the corresponding o-bromoanilines.

Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor.

The lead optimisation of the diaminopyrimidine carboxamide series of spleen tyrosine kinase inhibitors is described. The medicinal chemistry strategy was focused on optimising the human whole blood activity whilst achieving a sufficient margin over liability kinases and hERG activity. GSK143 is a potent and highly selective SYK inhibitor showing good efficacy in the rat Arthus model.

The first X-ray crystal structure of the glucocorticoid receptor bound to a non-steroidal agonist

The amino-pyrazole 2,6-dichloro-N-ethyl benzamide 1 is a selective GR agonist with dexamethasone-like in vitro potency. Its X-ray crystal structure in the GR LBD (Glucocorticoid ligand-binding domain) is described and compared to other reported structures of steroidal GR agonists in the GR LBD (3E7C).

Identification of potent and selective oxytocin antagonists. Part 2: further investigation of benzofuran derivatives.

The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.

Predictive models for the overall 5-endo-trig iodocyclisation of homoallylic alcohols

Abstract Iodoetherifications of all isomers of the 3-methylalk-4-en-2-ols [14∼17] proceed with excellent levels of stereoselectivity, leading to tetrasubstituted tetrahydrofurans [18∼22], via overall anti-addition to the alkene function.

Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3: potency and plasma stability

Mechanism-based inhibitors of HCMV protease, which are stable to human plasma (> or = 20 h) and have single-figure potency in the microM range against HCMV protease, have been developed based on the dansylproline alpha-methyl pyrrolidine-5,5-trans-lactam nucleus.

Aryl aminopyrazole benzamides as oral non-steroidal selective glucocorticoid receptor agonists.

Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).

AN EFFICIENT SYNTHESIS OF A CHIRAL CARBOCYCLIC 2'-DEOXYRIBONUCLEOSIDE SYNTHON BY DIRECTED REDUCTION

Abstract Directed reduction of the 1,4 hydroxy-ketone 9 and the 1,4 aldehydo-ketone 12 with NaBH(OAc)3 gave stereoselectively in high yield the 1,4 diol 10, a key intermediate required in our synthesis of chiral carbocyclic 2′-deoxyribonucleosides.

Synthesis from (–)-aristeromycin and X-ray structure of (–)-carbovir

Efficient processes are described for the synthesis of (–)-carbovir 3 and its triphosphate derivative 28 from (–)-aristeromycin 4. The X-ray structure of (–)-carbovir has been determined.

A study of the stereochemical features of 5-endo-trig iodocyclisations of 2-alkenylcycloalkan-1-ols

Overall 5-endo-trig iodocyclisations of all isomers of the 2-alkenylcyclopentan-1-ols and -cyclohexan-1-ols 11, 12, 14 and 16 have been examined. Only in the cases of the trans-alkenylcyclopentanols 11a and 12a are the reactions either unsuccessful or low yielding, by reason of formation of a relatively strained trans-fused 5/5 ring system. In contrast, iodocyclisations of cis-alkenylcyclopentanols work well but only show useful stereoselection in the case of the cis-(Z)-alkenylcyclopentanol 16a. All examples involving the cyclohexanols 14 and 16 are high yielding and generally lead to single isomers of perhydro-3-iodobenzofurans 18, 20, 23 and 26. Transition state conformations are proposed which account for these observations and which should be useful in applying this type of cyclisation to related substrates.