Tuesday, April 21, 2015

Baran’s Semisynthetic Work on Ouabagenin and Related Bioactive Glucocorticoid Derivatives

            Phil Baran’s laboratory at The Scripps Research Institute recently disclosed a full account of their 20-step synthesis of the aglycone of ouabain starting from a derivative of cortisone. Their general strategy for introduction of the dense hydroxylation pattern of the target molecule was to ‘redox-relay’ pre-existing oxidation states that are naturally present within the cortisone framework to neighboring and distal carbon atoms. For example, using Norrish type II photochemistry, the C11 ketone oxidation state was effectively relayed to the angular C19 methyl group through the intermediacy of a cyclobutanol. Oxidative fragmenation of the cyclobutanol then furnishes the C19-functionalized product. Baran’s optimization and extension of the Norrish protocol to the problem of functionalization of the unactivated steroid C19 substituent provides a useful and complementary alternative to more classical tactics, such as those reported years ago by Barton, as well as Meystre and Heusler from Ciba. A more detailed analysis of Baran’s partial synthesis of ouabagenin can be found here.

            Interestingly, Baran’s group describes a foray into the realm of medicinal chemistry in their recent JACS full article. They report the application of the Norrish type II photochemical C-H functionalization methodology to the synthesis of C19-hydroxylated analogues of corticosteroid drugs such as clobetasol propionate. The authors indicate a motivation to minimize the undesired biological effects of glucocorticoid receptor (GR) agonists stemming from off-target mineralocorticoid antagonism. Unfortunately, the novel clobetasol analogue 1, synthesized in eleven steps from cortisone acetate, exhibits binding affinity to GR that is inferior to clobetasol propionate by about an order of magnitude. While selectivity against the mineralocorticoid receptor is not reported, 1 does exhibit moderate anti-inflammatory efficacy in a cellular assay. Baran’s analogues are clearly lacking 9a-halogenation. The 9a-halogenated glucocorticoid series was first described in 1953 and has been shown to provide a >10-fold increase in binding affinity to GR, relative to parent C9-proteo hormones. The synthetic route used to prepare clobetasol analogue 1 is shown below.
            Arguably, the most robust and practical methodology reported by Baran for semisynthetic cardenolide modification with applications to therapeutically relevant corticosteroids was disclosed much earlier. In the Journal of Organic Chemistry, Baran reports a strategy for systematic deoxygenation of ouabain as a means to obtain important 17b-hydroxyacetyl pregnane-type steroids. Ouabain, by virtue of its pre-built oxygenation at the C11 position and latent side chain derivable from the C17 butenolide, is a logical candidate for a synthetic precursor to various glucocorticoids.
            As proof of this principle, ouabagenin 1,19-acetonide was reductively deoxygenated (see below) at the C1 position via the intermediacy of a 3,11-dione. Subsequently, upon exposure of an 11,19-methyl-ketal to thionyl chloride and pyridine at low temperature, the tertiary hydroxyl group at C14 eliminates to generate an olefinic intermediate. Catalytic hydrogenation of this intermediate results in a saturated system with b-hydrogen atoms located at the newly formed stereogenic ring junction positions. Finally, oxidative manipulation of the a,b-unsaturated lactone moiety affords a 20-oxo-14-iso-pregnane that can be considered a 19-hydroxylated congener of cortisone acetate. Most of the synthetic operations described in this manuscript were demonstrated on decagram scale. For example, the hydrogenation depicted below (step 3) was conducted on 73-gram scale and, ultimately, 4 grams of the 14-isopregnane glucocorticoid derivative were generated from a single batch run.
            This latter synthetic work was conducted by John S. Baran (i.e. not Phil) of The Laboratories of G. D. Searle and Co., Chicago, Illinois. The single author manuscript (see excerpt below) was received by JOC on August, 29, 1963. During this time, the post-World War II era race to synthesize cortisone was in full swing. Ouabain and strophanthidin were two cardenolides that were evaluated as feedstock precursors to the newly discovered and highly sought-after corticosteroid wonder drugs of the 1950s – 1960s. G. D. Searle, much like other major players in the cortisone race - Merck, Syntex and Upjohn - figured prominantly in the vitally important steroid research that was ongoing during this time period.

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