Methods of synthesizing alpha acids and substantially enantiomerically pure compositions thereof

摘要

Methods of synthesizing a cis 3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one (“KDT500”) derivative are provided. Such methods may be used to synthesize any desired KDT derivative. In one embodiment, the KDT500 derivative is KDT501.

主权项

1. A method of synthesizing a cis 3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one (“KDT500”) derivative comprising:
a) acylating a starting material comprising phloroglucinol (1) in the presence of a Friedel Crafts catalyst to produce a product A comprising an acylphloroglucinol; b) prenylating the product A in the presence of a strong aqueous base to produce a mixture of beta acids; c) performing an acidic hydrogenation on the mixture of beta-acids to produce tetrahydrodeoxyhumulone (7) and reacting the tetrahydrodeoxyhumulone (7) with strong an oxidation condition to produce a product B comprising tetrahydrohumulone (8); d) performing an isomerization of the product B comprising tetrahydrohumulone (8) to produce one or more diastereomers of tetrahydroisohumulone (9) comprising trans 3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one; e) performing a thermal epimerization of trans 3,4-dihydroxy-2-(3methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one in the presence of an alkaline earth metal; and f purifying the KDT500 and trans 3,4-dihydroxy-2-(3-methylbutanoyl)-5-(3-methylbutyl)-4-(4-methylpentanoyl)cyclopent-2-en-1-one respectively from step (e) by one or more of a salt crystallization, counter-current chromatography (CCC) purification, and chiral chromatography.