Alf Claesson

Preparation of highly enantiopure stereoisomers of 1-(2,6-dimethylphenoxy)-2-aminopropane (mexiletine)

Abstract Mexiletine [1-(2,6-dimethylphenoxy)-2-aminopropane], an orally effective antiarrhythmic agent, exhibits enantioselective pharmacokinetics and pharmacodynamics during mexiletine therapy. The purpose of this paper is to emphasize the advantage of tetrahydropyranyl-protected mandelic acid (THPMA) in the resolution of mexiletine enantiomers. Both enantiomers of mexiletine were obtained in 99% enantiomeric excess. Judging by the differential shielding effects in the 1 H and 13 C NMR analyses, we have observed the opposite predominant conformation for the mexiletine mandelates in comparison with the O -methylmandelates.

Synthesis of C-(β-D-glycosyl) analogues of 3-deoxy-D-manno-2-octulosonic acid (Kdo) as potential inhibitors of CMP(Kdo synthetase

Eight C-(beta-D-glycosyl) analogues (14-21) of Kdo (3-deoxy-D-manno-2-octulosonic acid) were obtained from isopropylidene-protected ester precursors and tested in vitro for their inhibitory activity on CMP-Kdo synthetase. None had more than minor inhibitory activity.

Competitive NMDA antagonist that base their activity on a unique conformational effect

Abstract The synthesis of two NMDA antagonist, cis -3-(1-oxi-2-phosphonoethyl)-2-piperidine-carboxylic acid and cis -3-(1-hydroxy-2-phosphonoethyl)-2-piperidinecarboxylic acid ( 1 and 2 ), is reported. The enantiomers of 1 were also prepared. NMR analysis showed that 1 prefers a 3 ax , 2 eq chair conformation due to internal hydrogen bonding.

Synthesis of perhydro-1,4-ethano-1,5-naphthyridine and perhydro-4,7-ethanopyrrolo[3,2-b]pyridine derivatives: potential NK1-receptor antagonists. X-Ray molecular structures of (4aR,8S,8aR)-6-oxo-8-phenylperhydro-1,4-ethano-1,5-naphthyridine and (4aR,7R,8R,8aR)-7,8-diphenylperhydro-1,4-ethano-1,5-naphthyridine

Derivatives of perhydro-1,4-ethano-1,5-naphthyridine and 4,7-ethanopyrrolo[3,2-b]pyridine were designed and synthesized as conformationally constrained analogues of the potent NK1-receptor antagonist CP-96,345. 2-Benzylidenequinuclidin-3-one 1 was used as the common starting material: (i) heterocyclizations of compound 1 with N-(carbamoylmethyl)pyridinium chloride gave unsaturated pyridone derivatives which, after catalytic hydrogenation, afforded 1,5-naphthyridines, and (ii) functionalization of compound 1 by nucleophilic 1,4-addition reactions, followed by reductive cyclizations, gave quinuclidine derivatives with fused five- or six-membered rings. The cyclization reactions proceeded stereoselectively and the relative stereochemistries were determined by a combination of molecular mechanics calculations. X-Ray crystallography, and NMR spectroscopy. The biological activities of the synthesized derivatives were evaluated by binding studies to human NK1-receptors in UC11MG cells. The compounds had low to moderate affinity for the NK1-receptor.

Synthesis of 14C‐labelled (R)‐α‐amino‐6,7‐dimethyl‐3‐(phosphonomethyl)‐2‐quinolinepropanoic acid

The NMDA antagonist (R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-quinolinepropanoic acid 1 was [ 14 C]-labelled at the 6-methyl group. The quinoline synthesis started from 4-bromo3-methylaniline and the radiolabel was introduced late in the synthetic scheme. The synthesis was accomplished by a NiCl2(dppp)2-catalyzed coupling of the 6-bromoquinoline derivative 6 with a zinc reagent made from [ 14 C]-methyl iodide.

Conformational analysis of isopropylidene-protected C-glycosyl derivatives of 3-deoxy-d-manno-2-octulosonic acid (Kdo) in the solid state and in solution

Abstract The favoured conformations of a series of C -glycosyl derivatives of 4,5:7,8-di- O -isopropylidene-3-deoxy- d - manno -2-octulosonic acid (Kdo) esters were analyzed by n.m.r. spectroscopy and in one instance by X-ray crystallography. The Kdo derivatives were found to adopt a skew-boat conformation B 3,6 + 0 S 3 ) in solution which corresponds well to the slid-state conformation. The skew-boat conformation of the pyranose ring appeared to be imposed solely by the 4,5-dioxolane ring. Molecular-mechanics calculations [MM2(85)] on a model compound identified two low-energy conformations of equal steric energy, namely a skew-boat conformation almost identical to the experimentally observed conformation, and a chair conformation 5 C 2 ).

Synthesis of a stable analogue of cytidine 5′-monophospho-3-deoxy-d-manno-2-octulosonic acid (CMP-KDO)

Abstract 2,6-Anhydro-2- C -[(5′-cytidylyloxy)methyl]-3-deoxy- d - glycero - d - talo -octonic acid ( 3 ), a stable analogue of CMP-KDO, was synthesized as a potential inhibitor of bacterial lipopolysaccharide (LPS) biosynthesis. A protected C-glycosidic analogue of 3-deoxy- d - manno -2-octulosonic acid (KDO) was condensed with bis(1 H -1,2,4-triazol-1-yl)-phosphonic acid 2-chlorophenyl ester ( 6 ) and N -benzoyl-2′,3′- O -isopropylidenecytidine ( 7 ). Deprotection afforded the stable CMP-KDO analogue in 42% overall yield. The analogue had weak inhibitory activity on the in vitro incorporation of KDO in the lipopolysaccharide.

New heteroaryl-spaced phosphono α-amino acids are competitive NMDA antagonists with analgesic activity

Abstract The synthesis and the NMDA receptor binding affinities of α-amino-3-(phosphonomethyl)-2-naphthalene-propanoic acid, α-amino-3-(phosphonomethyl)-2-benzofuranpropanoic acid, a series of substituted (R)-α-amino-3-(phosphonomethyl)-2-quinolinepropanoic acids, (R)-α-amino-3-(phosphonomethyl)-1,8-naphthyridine-2-propanoic acid and (R)-α-amino-3-(phosphonomethyl)-1,6-naphthyridine-2-propanoic acid are reported.

Synthesis and reactivity of 6-carbamoyl-5-phenyl-2,3,5,6-tetrahydro-1H-1,4-ethanobenzo[f]quinoline. X-Ray molecular structure of (4aR,5S,6R,10bR)-5-phenyl-2,3,4a,5,6,10b-hexahydro-1H-1,4-ethanobenzo[f]quinolin-6-yl acetate

Cyclocondensation of 2-(2-cyano-1,2-diphenylethyl)quinuclidin-3-one 1 in the presence of sulfuric acid gave an intramolecular phenylation instead of lactam formation. The cyclic product was hydrogenated to give 6-carbamoyl-5-phenyl-2,3,4a,5,6,10b-hexahydro-1H-1,4-ethanobenzo-[f]quinoline. On treatment with LiAlH4 the carbamoyl group was stereospecifically replaced by a hydroxy group. The alcohol was acetylated and the structure was confirmed by X-ray crystallography. The hydroxylation reaction is believed to proceed via a carbonitrile intermediate. In the presence of air the nitrile can be converted to a ketone which is then reduced to the alcohol with an overall retention of configuration.