Just as the medicinal chemistry of steroids largely relies on a rich history of degradation and semisynthesis, explorations of the VitD class rely on such an approach. Thus, semi-synthesis has been employed by a variety of research programs, reported in ca. 90 publications and 90 patents to access thousands of VitD analogs (Figure ). Specifically, VitD2 could be oxidatively degraded to the so-called Inhoffen Lythgoe diol ( ) containing the CD-ring system. Subsequent side-chain installation and reconstitution with a suitably functionalized A-ring surrogate (derived through synthesis) provided a multitude of VitD analogs and natural products (Path A, Figure ). In this way, many commercial medicines such as those outlined in Figure have been discovered. An alternative approach (Path B, Figure ) often involves protection of the configurationally and chemically labile triene system (typically through cycloaddition with SO2, 13), followed by oxidative side-chain removal, reconstitution, and retro-cycloaddition/isomerization to unveil the bioactive VitD analog. Such a route is used by LEO pharma to manufacture calcipotriol (7), and requires a 14 step sequence including a tedious HPLC separation resulting from a lack of stereocontrol in a key reduction and several PG-manipulations. In contrast, the use of totally synthetic routes to access VitD analogs in an industrial setting, to the best of our knowledge, has been unreported. Such efforts have therefore been confined to the academic space where the VitD synthetic challenge has inspired numerous instructive pathways such as the five routes illustrated in Figure . Path A represents an elegant example of how a cyclopropane ( ) could be leveraged to protect the triene moiety yet it relies on diazo chemistry for its preparation which could be prohibitive on scale. 11 Path B is the oldest strategy reported, employing a photochemical ring opening of 7-DHC derivatives (15) to allow for facile seco-Btriene formation. However, numerous redox manipulations to establish the triene core and requisite oxidation at C1 renders this approach less attractive. The most convergent approach that has received widespread adoption for the synthesis of the VitD core has been the Lythgoe-Roche strategy (Path C) between a trans-hydrindrane core 17 and advanced phosphonate 16. The synthesis of 16, initially developed by Baggiolini, was achieved in 13 steps, from (L)-carvone, and is even available commercially from a single vendor (Syncom BV). The coupling of this advanced substrate with 17 (Figure ) or a synthetically prepared trans-hydrindrane moiety (generally accessed through degradation of VitD2) provides the desired derivatives. Another well-adopted strategy is the metal-catalyzed cycloisomerization approach, pioneered by Trost and co-workers as shown in Path D. This clever strategy employs a vinyl halide, typically prefunctionalized with the desired side-chain derivative, together with seco-A-ring synthon enyne 18. As such, this powerful method allows for the direct A-ring and triene formation in a single reaction step, however obtaining the acyclic enyne 18 with high enantiopurity has proven to be a challenge. Finally, Mourino and co-workers initially developed the reduction/isomerization approach to access the requisite triene system found in the Vitamin D scaffold (Path E). This approach relies on a semihydrogenation/thermal isomerization of dienyne 19 to the desired scaffold. Given the ease with which such an approach could potentially be performed on process scale, the convergency it enables, and the hidden symmetry of a building block such as would offer an alternative to semi-synthesis both for the commercial preparation of 7 and analogs thereof. Figure outlines the blueprint that was devised to achieve this goal. Thus, VitD analogs (1) differing at the key side-chain could conceivably be accessed through a late-stage decarboxylative cross-coupling between triene 20 and a suitable coupling partner followed by reduction/isomerization. This modern disconnection could even be employed in a semi-synthetic approach to rapidly access new chemical space while the full total synthesis was developed. The dienyne precursor of 20 could be disconnected into fragments 21 and 22. Since the former fragment could be accessed easily using semisynthesis, it was critical that the route to the latter building block be robust and scalable. Nevertheless, a scalable route to 21 was devised based on the strategic combination of semi-pinacol and HAT annulation tactics from diene 23. This diene could then be accessed through a recently devised electrochemical reductive cross-coupling between enone 24 and vinyl iodide 25. For the A-ring fragment 22, an ambitious desymmetrization approach was targeted by engaging a suitably substituted dienone 26.