David Alker

The direct synthesis of the cyclic sulphamidate of (S)-prolinol: SimultaneousN-protection and activation towards nucleophilic displacement of oxygen.

Abstract The preparation of the cyclic sulphamidate of (S)-prolinol has been achieved by reaction with sulphuryl chloride at low temperature. This material has been shown to be susceptible to acid catalysed nucleophilic attack to furnish 2-(NN-dialkylamino)methyl- and 2-(methoxymethy]pyrrolidines after hydrolysis of the intermediate sulphamic acid derivatives.

Application of enantiopure templated azomethine ylids to β-hydroxy-α-amino acid synthesis

Abstract Chiral stabilised azomethine ylids derived from the reaction of (5S)-5-phenylmorpholin-2-one (1) with aldehydes undergo efficient and highly diastereocontrolled cycloaddition with a second molecule of aldehyde to furnish products (2) which may be converted into enantiomerically pure threo (2S,3R) β-hydroxy-α-amino acids (3) in excellent yield.

Long-acting dihydropyridine calcium antagonists. 9. structure activity relationships around amlodipine

Abstract The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated. Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor. Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituent and the DHP receptor. Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity.

CYCLOADDITIONS OF AROMATIC IMINES TO ENANTIOMERICALLY PURE STABILIZED AZOMETHINE YLIDS : CONSTRUCTION OF THREO (2S, 3R)-3-ARYL-2,3-DIAMINO ACIDS

Abstract Chiral stabilized azomethine ylids derived from reaction of (5 S )-phenylmorpholin-2-one ( 1 ) with aromatic imines undergo efficient and highly diastereocontrolled cycloaddition with a second molecule of imine to furnish products which may be converted into enantiomerically pure threo (2 S , 3 R )-3-aryl-2,3-diamino acids.

Synthesis of homochiral trisubstituted γ-butyrolactones

Abstract Efficient syntheses of homochiral, trisubstituted γ-butyrolactones via the highly stereoselective alkylation of a carbohydrate-derived γ-lactone are described.

Formation, synthetic utility and structure elucidation of a 2-bromomethyl 1,4-dihydropyridine

Abstract The structure of the product obtained by reacting the 1,4-dihydropyridine 6 with pyridinium bromide perbromide has been confirmed by NMR spectroscopy as the 2-bromomethyl derivative 7 and its reaction with a range of nucleophiles has been studied.

Carbamate derived stable precursors for generating chiral azomethine ylids under mild conditions

Abstract We describe the evolution of stable azomethine ylid precursors which avoid the need for an aldehyde in the ylid generation step. tert -Butyl carbamate derivative ( 16 ) demonstrates comparable efficiency to the standard method of ylid generation and trapping, but permits use of milder conditions.

The synthesis of 2-substituted-1,4-dihydropyridines

Reaction of the 2-hydroxymethyl-1,4-dihydropyridines 7 and 13 with SO2Cl2limidazole followed by treatment with nucleophiles affords 2-substituted-l,4-dihydropyridines via the intermediacy of the 2-chloromethyl compounds 14 and 18, respectively.

The ‘off-template’ problem: towards a general solution

Wittig reaction of the t-butyldimethylsilylated C-3 ketone methyl 4,6-O-benzylidene-2-O-(t-butyldimethylsilyl)-α-D-ribo-hexopyranosid-3-uloside leads exclusively to C-2 alkenes, providing an efficient synthesis of these potentially useful intermediates. Alternatively, the corresponding t-butyldiphenylsilyl ether, prepared with complete regiospecificity from methyl 4,6-O-benzylidene-α-D-glucopyranoside, gives a C-3 alkene on oxidation and Wittig reaction. Deprotection, hydrogenation and cyclization of this product leads to the cis-fused butyrolactone, methyl 4,6-O-benzylidene-3-deoxy-3-(ethoxycarbonyl)-2,3-butyrolacto-α-D-allopyranoside, which is alkylated stereospecifically to give methyl 4,6-O-benzylidene-3-deoxy-3-(prop-2- yloxycarbonyl)-2,3-butyrolacto-α-D-allopyranoside. This procedure provides a general solution to the ‘off-template’ problem of carbohydrate-based natural product synthesis.

Long-acting dihydropyridine calcium antagonists. 7. Compounds containing unsaturation in the 2-substituent on the 1,4-dihydropyridine ring

Abstract To evaluate the effect of introducing unsaturation into the 2-substituent of 1,4-dihydropyridines related to amlodipine ( 1 ), a number of alkene and alkyne analogues were prepared and their calcium antagonist activity was assessed. For several series of compounds, in vitro potency increased in the order alkane