Indolizidine (octahydroindolizine) alkaloids are a prominent group of secondary metabolites, many of which have important medicinal, or pharmacological activity. Non-natural structures based around the indolizidine ring have also featured in traditional medicinal chemistry programs. For example, King has described the use of 7-amino-indolizidine derivatives, such as those based around octahydro-5,5-dimethylindolizin-7-amine 1, as gastric prokinetic agents. We have also developed an interest in the application of compound 1, and have described its use within a series of protein kinase C theta (PKCq) ligands, a serine-threonine kinase whose inhibition may be useful against a number of immunological disorders. As part of an effort to prepare compounds for advanced preclinical testing, we required access to decagram quantities of (7R, 8aS)-octahydro-5,5-dimethylindolizin-7-amine 2. In this paper, we disclose an efficient synthesis of compound 2 and (7S,8aS)-octahydro-5,5-dimethylindolizin-7-ol 3, using a Novozym 435-mediated kinetic resolution of a racemic alcohol precursor, undertaken on up to 100g-scale. Subsequent reaction of compound 3, using a series of standard functional group interconversions undertaken in a telescoped fashion, provided the desired amine 2 in good yield and with excellent enantio-enrichment (e.r. &gt; 99:1; e.e. &gt;98%).

Synthesis of (7R,8aS)-octahydro-5,5-dimethylindolizin-7-amine and (7S,8aS)-octahydro-5,5-dimethylindolizin-7-ol using an enzymatic resolution approach

253rd National Meeting (2017)

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