8, 1994) and Richard M. Kellogg #
Abstract.Inversion of configuration at the benzylic hydroxyl group of (lS,2S)-pseudoephedrine (2) to afford (1R,2S)-ephedrine is known to be a difficult process. The Mitsunobu reactions of 1 and 2 might offer a route to achieve such inversions. In fact Mitsunobu reactions on 1 and 2 are known to proceed via aziridines formed on intramolecular S , 2 substitution by the amine functionality. The Mitsunobu reactions of N-methylated and N-benzylated ephedrines have been found to proceed via the corresponding aziridinium ions. These aziridinium ions can be opened (S,2 substitution) by nucleophiles like phthalimide and thiols. Intramolecular participation in 2 can be avoided by use of the tert-butyloxycarbonyl-(BOC) or benzyloxycarbonyl-(CBZ) protected derivatives. Mitsunobu reactions on these derivatives lead to inversion of configuration at the benzylic hydroxyl center. In contrast the BOC and CBZ derivatives of 1 are deprotected under Mitsunobu conditions. The Mitsunobu reactions of threo (lS,2S)-2-amino-l,3-propanediol have also been examined. An attempt to achieve protection by reaction with dimethylformamide dimethyl acetal led to the more substituted 2-oxazoline as established by X-ray crystallography. The desired inversion of configuration of the benzylic hydroxylic group was eventually achieved by protection of the amino substituent as the phthalimide and protection of the primary hydroxyl group as the tosylate.
Introduction aIn seeming contrast to their relative structural simplicity, ephedrine [l, 1R,2S-2-(methylamino)-1-phenylpropanol] and its diastereomer pseudoephedrine [2, (1S,2S)I in organic chemistry have traditionally stood at an important crossroads of practical application, stereochemistry and mechanism'**. In the following discussion we will abide by the traditional approach of referring to 1 as erythro (groups on same side in Fischer projection formula) and to 2 as threo (opposite sides). The best known source of 1 is the Chinese herb, "Ma Huang", in which this material is present in up to 1% bulk weight. The herb also contains 2 as well as other ephedrine alkaloids. These compounds have been used in China for over five thousand years for the treatment of bronchial asthma, hay fever and other allergic conditions.
Abbreviations:Currently very large quantities are used in Western medicine to relieve mucous membrane c o n g e~t i o n~~. For technical purposes it would be useful to have a direct method, i.e. inversion of configuration at tetravalent carbon, of converting 2 into 13b. This seemingly simple operation is, however, usually foiled by stereochemical considerations. Welsh4 was apparently the first to collate the literature and to provide a believable interpretation of the stereochemical course of these and related transformations. The essence of rather confused early observations as summarized by Welsh is given in Scheme 1. In early attempts to discover the structure of acylated ephedrines, that is whether 0-or N-acylation had taken place, it was observed ...
Abstract. Dialkylcarbodiimides in the presence of a Cu' catalyst react cleanly with the hydroxyl group of N-methylated (lR,2S)-ephedrine and (lS,2S)-pseudoephedrine. These adducts react with nucleophiles like alkyl and aryl thiols as well as thioic acids and phthalimide to form the substitution products with overall retention of configuration. It is postulated that intramolecular participation of the amino group via an SN2 reaction leads to aziridium salts, which are subsequently opened by the nucleophiles via a second sN2 reaction. This synthetic approach is also useful for the inversion of simple secondary alcohols; on treatment with dicyclohexylcarbodiimide followed by benzothioic acid and treatment with LiAlH,, menthol was converted in good yield to neomenthane thiol.
Heating 0-methyl (S)-prop-2-ynyl dithiocarbonates la-c with electrophilic alkenes 7a-d containing nucleophilic acetoxy group gives 1,3-dithiol-2-ones 9 by a new carbon-carbon bond forming process.
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