At the outset of this work, certain criteria needed to be met from the standpoint of starting material and reagent cost so as to be competitive with the semi-synthetic approach on scale. Aside from keeping the step count low, a fully stereocontrolled route was needed to avoid tedious separations on scale. Ideally, a process-friendly blueprint that would feature crystalline intermediates, no cryogenic reaction conditions, and inexpensive reagents was targeted. The classic strategy of cyclohexadienone desymmetrization was strategically appealing due to the low cost of the aromatic starting materials and the multitude of options for functional group installation. To be sure, enyne 22 could conceivably be accessed through the stepwise difunctionalization of a symmetrical pro-chiral dienone 23 (Figure ). As such, two parallel pathways leading to the same advanced intermediate 24 can be envisaged, which could be transformed to the final A-ring enyne 22 following diastereoselective ketone reduction and subsequent dehydration. Specifically, access to enantiopure 24 could potentially be achieved through either an enantioselective alkynylation or hydroxylation or a formal equivalent thereof. The ability to interchangeably employ either path with multiple tactics proved appealing from a route-scouting standpoint. For either route the initial desymmetrization requires both high regio-and facial selectivity to control the ee and de, respectively (see Figure ). The fact that the C-5/C-10 stereocenters are eventually ablated after dehydration provided additional flexibility in the design. Such logic has been shown to be a powerful strategy to create multisubstituted cyclohexane scaffolds in a stereocontrolled fashion. Finally, since A-ring building block 22 shares the same formal oxidation state as benzene, all reactions need to be carefully orchestrated to avoid potential re-aromatization/decomposition. Some initial forays to deconvolute this maze of options are outlined in Figure . Path A, which involves an initial conjugate addition followed by formal b-oxygenation was evaluated first. In a racemic approach, initial conjugate addition worked smoothly followed by diastereoselective epoxidation and global reduction to open the epoxide and access the correct alcohol stereochemistry in 22. Unfortunately, this concise route could not be rendered enantioselective despite extensive efforts (see SI for a summary). The route was nevertheless instructive in that it set an important precedent for the diastereoselective installation of the critical C-1/C-3 hydroxyl groups in 22. Concurrent with this approach, an ambitious proposal to enlist the Zard-alkyne synthesis was pursued wherein an isoxazolone serves as a surrogate for the unveiling of an alkyne. Although isoxazolone engaged in a Michael addition to deliver 25, such an adduct could not be unraveled to provide the requisite alkyne. Turning to Path B, the most intuitive approach of enantioselective epoxidation was surveyed. However, as with the aborted route described above, the racemic pathway delivered the desired diastereomeric diol 24 but could not be rendered enantioselective in a practical fashion. Finally, an approach inspired by You's work on desymmetrization of cyclohexadienones via Brønsted acid-catalyzed enantioselective oxa-Michael reaction was pursued by targeting tartrate-derived dienone 26. The tartrate was expected to act as an auxiliary to introduce the chirality, however, this target proved to be inaccessible in synthetically useful yields (3-5% observed after screening multiple conditions for oxidative dearomatization). It is postulated that p-cresol oligomerization was faster than the nucleophilic attack resulting in the low yield of 27.