Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

Abstract

Here we report a scalable route to the polyhydroxylated steroid ouabagenin with an unusual spin on the age-old practice of steroid semi-synthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 mg of a key precursor towards ouabagenin–and ultimately ouabagenin itself–and the discovery of innovative methods for C–H and C–C activation and C–O bond hemolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules.

Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay

“…On the basis of our studies, the facile repurposing 54 of cardiac glycosides as DDR inhibitors could be pursued. Recent advances in the chemical synthesis of cardiac glycosides, 55 including methods to produce libraries of glycosylated derivatives, 56 provide methods to further optimize their structures and control their polypharmacology.…”

Synthesis of Medicinally Relevant Terpenes: Reducing the Cost and Time of Drug Discovery

“…A similar semi-synthetic strategy was also pursued by Baran and co-workers in their synthesis of ouabagenin ( 30 , Figure 7), whose glycoside, ouabain, is a cardiotonic steroid with a narrow therapeutic window that has resisted expansion despite some effort in medicinal chemistry [34–36]. Therefore, it was envisaged that semi-synthetic conversion of an inexpensive steroid might increase the opportunities for derivatization of the ouabain core and potentially lead to better tolerated treatments of, for instance, congestive heart failure.…”

Scalable C–H Oxidation with Copper: Synthesis of Polyoxypregnanes

“…Given the success of a Norrish reaction in the context of a redox-relay approach to steroid oxidation, the C20 ketone was evaluated under a variety of photochemical conditions. 3b,3c Unfortunately, despite screening numerous solvents and photosensitizers, only undesired photocleavage products resulting from scission of the C17–C20 bond were obtained. Next, Barton’s classic photolysis was evaluated in a variety of different solvents but only the hydrolyzed nitrite ester was detected.…”

“…Next, the Cu-mediated C–H oxidation was employed on gram-scale as discussed above to deliver 12 in 40% yield. Saegusa oxidation (59%) followed by a recently developed olefin isomerization protocol 3a (57%) delivered the diene 21 . Stereo- and chemoselective Mukaiyama hydration took place smoothly to furnish diol 22 in 67% yield as verified by X-ray crystallography.…”

“…Stereo- and chemoselective Mukaiyama hydration took place smoothly to furnish diol 22 in 67% yield as verified by X-ray crystallography. 3a The D ring methyl ketone subunit was then installed using an organolanthanum reagent derived from lithiated ethyl vinyl ether in 51% yield (along with 20% recovered 22 ). 20 At this juncture, the allylic cyclopropane, which remained chemically silent until this point, was cleanly dismantled using HBr to afford the homoallylic bromide.…”