Design and synthesis of fluorescent SGLT2 inhibitors.

The design and synthesis of the first fluorophore-conjugated SGLT2 inhibitors is described. The mode of linking the fluorophore to the SGLT2 pharmacophore was found to be crucial in achieving optimum potency. Superior potency to phlorizin was provided by examples containing TAMRA, BODIPY, Cy3B and NBD fluorophores.

Achieving conformational control over C-C, C-N and C-O bonds in biaryls, N,N'-diarylureas and diaryl ethers: advantages of a relay axis.

The orientation of Ar-C, Ar-N and Ar-O bonds in biaryls, N,N'-diarylureas and diaryl ethers (whose conformers are distinguishable by NMR) may be controlled with a selectivity up to >95 : 5 by an adjacent stereogenic centre; the selectivity may be greater when a second stereogenic axis is inserted between the controlling centre and the slowly rotating bond.

Conformational preference in aromatic amides bearing chiral ortho substituents: its origin and application to relayed stereocontrol.

Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.

Kinetic and thermodynamic stereocontrol in the atroposelective formation of sulfoxides by oxidation of 2-sulfanyl-1-naphthamides.

Atropisomeric aromatic amides bearing 2-sulfanyl groups are oxidised by m-CPBA to the corresponding sulfoxides apparently with very high diastereoselectivity. NMR studies and oxidations of chiral benzamides however indicate that the kinetic selectivity of the oxidation is in fact relatively poor, and that the final diastereoisomeric ratio (typically >99:1) is under thermodynamic control, with relatively unhindered Ar-CO rotation readily converting the less stable to the more stable product diastereoisomer. Molecular mechanics indicates that the thermodynamic diastereoselectivity results principally from electrostatic repulsion between the C=O and S-O dipoles.

The Ireland-Claisen rearrangement as a probe for the diastereoselectivity of nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group.

The E- and Z-silyl enol ethers 4 derived from allyl 3-R-3-dimethyl(phenyl)silylpropanoate (R = Me, Pr(i) and Ph) and the Z-silyl enol ethers 7 derived from 4-R-4-dimethyl(phenyl)silylbut-2-enyl acetate (R = Me and Pr(i)) undergo Ireland-Claisen rearrangements largely in the same stereochemical sense, with C-C bond formation taking place anti to the silyl group in the conformations 22, 23 and 24 in which the hydrogen atom on the stereogenic centre is inside, more or less eclipsing the double bond. The E-silyl enol ether E-7a derived from 4-methyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the alternative sense, probably because C-C bond formation takes place anti to the silyl group in the conformation 26 with the methyl group inside, but the silyl enol ether E-7b derived from 4-isopropyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the normal sense. The E- and Z-silyl enol ethers 33 derived from cis-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate and the E-silyl enol ether 39 derived from trans-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate undergo Ireland-Claisen rearrangements largely in the same stereochemical sense as their allyl counterparts, but with moderately high levels of diastereocontrol in setting up the third stereogenic centre following from chair-like transition structures.

Diastereocontrol in open-chain nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group.

The bis[dimethyl(phenyl)silyl]cuprate reagent introduces a silyl group to the beta-position of three alpha,beta-unsaturated esters: methyl Z-4-dimethyl(phenyl)silylpent-2-enoate 11, and methyl Z- and E-(1'-dimethylphenylsilylbenzyl)but-2-enoates 14 and 15, diastereoselectively in the unexpected sense, syn to the silyl group in the conformation in which the hydrogen atom is 'inside'. The selectivity is low (58:42) in the first case 11, where the nucleophilic attack is adjacent to the stereogenic centre carrying the silyl group, and moderate (72:28) for both Z- and E-alpha,beta-unsaturated esters 14 and 15, where the nucleophilic attack is at the other end of the double bond from the stereogenic centre. It is conceivable that nucleophilic attack actually takes place in a conformation in which the donor substituent, the silicon-carbon bond, is out of conjugation with the double bond.