Gaik B. Kok

Two-Step Iron(0)-Mediated N-Demethylation of N-Methyl Alkaloids

A mild and simple two-step Fe(0)-mediated N-demethylation of a number of tertiary N-methyl alkaloids is described. The tertiary N-methylamine is first oxidized to the corresponding N-oxide, which is isolated as the hydrochloride salt. Subsequent treatment of the N-oxide hydrochloride with iron powder readily provides the N-demethylated amine. Representative substrates include a number of opiate and tropane alkaloids. Key intermediates in the synthesis of semisynthetic 14-hydroxy pharmaceutical opiates such as oxycodone and oxymorphone are also readily N-demethylated using this method.

N-demethylation of N-methyl alkaloids with ferrocene.

Under Polonovski-type conditions, ferrocene has been found to be a convenient and efficient catalyst for the N-demethylation of a number of N-methyl alkaloids such as opiates and tropanes. By judicious choice of solvent, good yields have been obtained for dextromethorphan, codeine methyl ether, and thebaine. The current methodology is also successful for the N-demethylation of morphine, oripavine, and tropane alkaloids, producing the corresponding N-nor compounds in reasonable yields. Key pharmaceutical intermediates such oxycodone and oxymorphone are also readily N-demethylated using this approach.

Improved synthesis of 14-hydroxy opioid pharmaceuticals and intermediates

Significantly improved reaction conditions for the synthesis of oxycodone (1), via the conventional two-step process involving oxidation of thebaine (3) into 14-hydroxycodeinone (5) and the subsequent reduction of 5via catalytic hydrogenation, are reported. Employing the hydrochloride salt of thebaine (3) in the oxidation step, in place of the more traditionally used free base form of this opiate, now provides 5 in high yield and purity. For the reduction step, aqueous acetic acid has typically been employed as the solvent. However, this was found to generate varying amounts of 14-hydroxydihydrocodeine (16) as the dominant by-product. Instead, using 5% Pd/BaSO4 as the catalyst and MeOH as the solvent completely eliminated the formation of 16, giving oxycodone (1) in high yield and purity, without the need to purify the intermediates. These improved conditions have also proved effective in the synthesis of other 14-hydroxyopiates, such as oxymorphone (2) and N-noroxymorphone (9). In the latter case, a high overall yield was achieved by starting from N-nororipavine (10), without the need to employ protecting groups.

Efficient Iron-Catalyzed N-Demethylation of Tertiary Amine-N-oxides under Oxidative Conditions

An investigation into the influence of oxidative conditions on the efficiency of opiate N-demethylation using iron powder has been carried out under non-classical Polonovski conditions. This approach involves a two-step process of N-oxidation and subsequent treatment of the intermediate N-oxide hydrochloride with the redox catalyst. Significant improvements in rate and yield have been realized for these reactions in the presence of molecular oxygen. In this context, further rate enhancement was achieved by the judicious addition of small amounts of ferric ions, leading to a concomitant reduction in the amount of the zero-valent iron primary catalyst that is required. This has led to a generalized improved methodology for the N-demethylation of oripavine, codeine, morphine, and thebaine. This protocol can also be carried out in one-pot without the need to isolate the intermediate N-oxide.

Synthesis and biological evaluation of sulfur isosters of the potent influenza virus sialidase inhibitors 4-amino-4-deoxy- and 4-deoxy-4-guanidino-Neu5Ac2en

The synthesis of the thioisosters of 4-amino-4-deoxy-Neu5Ac2en (16) and 4-guanidino-Neu5Ac2en (17) has been achieved. These compounds have been found to be as bioactive as the corresponding oxygen alalogues. The preparation of the key intermediate, 7,8,9,-tri-O-acetyl-2,6-anhydro-3,4,5-trideoxy-2′-methyl-6-thio-(methyl D-glycero-D-talo-non-2-enonato)[5,4-d]oxazole 13, has been achieved from 2-acetamido-2-deoxy-5,6-O-isopropylidene-3-thio-α-β-D-mannofuranose 8 in four steps in 43% overall yield.

The synthesis of C-9 modified derivatives of the a-methyl glycoside of KDN Methyl ester

The synthesis of a range of C-9 substituted derivatives of the α-methyl glycoside of KDN methyl ester (2) is reported. 9-Deoxy-9-iodo, 9-deoxy-9-thioacetyl and 9-azido-9-deoxy derivatives (compounds 10, 12 and 13) were all prepared from the corresponding 9-O-tosylate 8. Catalytic hydrogenation of 10 and 13 results in reduction to give the 9-deoxy and 9-amino-9-deoxy derivatives 20 and 15, respectively. Further derivatisation of the amine 15 into compounds 17 and 18 was achieved via standard acylation procedures.

A palladium(>0>)-mediated approach to some novel C-4-substituted Neu5Ac2en derivatives

The preparation of a range of novel C-4-modified 2,3-unsaturated N-acetylneuraminic acid analogues is reported. These compounds have been prepared from the 4-chloro-4-deoxy-N-acetylneuraminic acid derivatives 10 and 12 by using a palladium(>0>)-mediated coupling with organostannanes.

Transmission of polar substituent effects in bicycloalkane systems. Synthesis and nuclear magnetic resonance study (carbon-13 and fluorine-19) of 4-substituted bicyclo[2.2.1]hept-1-yl fluorides

4-Methoxy-bicyclooctan-oxo-carbonsaure (I) liefert durch Abbau das Brom-Derivat (II), das mit KOH zur Carbonsaure (III) reagiert.

A facile and direct entry to functionalised Neu5Ac2En derivatives from the methyl ketoside of Neu5Ac methyl esters

Acetolysis of some methyl ketosides of N-acetylneuraminic acid (Neu5Ac) methyl esters, in a one-pot reaction, provides a rapid and efficient access to the corresponding 2,3-unsaturated Neu5Ac (Neu5Ac2en) derivatives.

A FACILE SYNTHESIS OF NEU5AC2EN DERIVATIVES FROM THE GLYCOSIDES OF N-ACETYLNEURAMINIC ACID

In a one-pot reaction, acetolysis of some functionalised methyl glycosides of N-acetylneuraminic acid (Neu5Ac) methyl ester provides a direct and efficient entry into the corresponding 2,3-unsaturated (Neu5Ac2en) derivatives. Other glycosides of Neu5Ac, such as benzyl and 2-(trimethylsilyl)ethyl glycosides, like their methyl counterpart, are also transformed into the 2,3-unsaturated analogues. This reaction has also been applied to the synthesis of some novel 4-bis-substituted-Neu5Ac2en derivatives, which in turn has led to the synthesis of the C-4 homologue of the per-acetylated methyl ester of Neu5Ac2en, compound 10.