Within the rich history of steroid synthesis, one extremely popular chapter involves approaches to the CD-ring system, a deceptively simple looking fused bicycle (Figure ). This thermodynamically unfavored trans-hydrindane (6,5-trans-fused) core is inherently strained, rendering syntheses of this bicycle challenging. The most popular general strategies are summarized in Figure . Amongst all the total synthetic efforts towards the CD ring fragment (>100!), few examples can deliver this structure within ten steps. In the vast majority of cases, the starting materials for the key ring constructing step either required lengthy routes or extensive concession steps (redundant redox manipulations and functional group interconversions) were employed after the ring system had been constructed. For the specific purpose of synthesizing VitD, key intermediate 11 with oxygenation at C-8 was targeted. Many of the routes that are used to access a CD-ring precursor for steroids are not easily adapted for VitD. For example, the elegant 3-component coupling between 2-methylcyclopentenone, a vinylsilyl methyl ketone, and an optically active iodo-olefin 34 (4-step synthesis from leucine) reported by Tsuji and co-workers arrived at 35 and was shown by others to require additional steps to forge the trans-hydrindrane (Path A). Wilson's intramolecular Diels-Alder approach to a minimally functionalized ring system required a lengthy sequence (racemic) to the unsaturated precursor and resulted in poor diastereocontrol (Path B). Johnson's classic cation-olefin cyclization approach (Path C) successfully forged the trans-6-5 ring system (87:13 d.r., 82% isolated yield) however precursor 36 was arduous to prepare (8 steps and an expensive non-recyclable chiral auxiliary) and the resulting allene required several additional steps to install the side-chain functionality. The Mourino group utilized a Pauson-Khand cyclization (Path D) to form the CD-ring skeleton and a Si-assisted allylic substitution to set the challenging pivotal quaternary methyl group at the fusedring junction of the CD-trans-hydrindane core followed by an additional 9 steps to install the side chain . Takahashi reported a radical cyclization of 37 (10-step preparation), provided the transring fusion after anionic ring cyclization (Path E). The C-ring could also be installed first followed by cyclization of ring-D as exemplified by Stork's classic approach (Path F). As with the other routes, this indirect path required multiple steps. As mentioned above, the six examples shown here are not a comprehensive summary, but rather a selection of strategically diverse synthetic blueprints to this ring system known at the outset of these studies. Ultimately, the Hajos-Parrish ketone ( ) is historically one of the most popular starting materials for total synthesis approaches when the CD ring system is retained. By far, the most practical approach to CD fragments remains semi-synthesis via vitamin D2 degradation (to the Lythgoe-Inhoffen diol, 12). Indeed, LEO Pharma employed this starting material for their in-house medicinal chemistry efforts (Figure ). In contemplating a new approach to this strained 6,5-fused bicyclic system in 38, two strategies emerged to the forefront (Figure ). Late-stage stereocontrolled hydrogenation of olefin 39 or semi-pinacol rearrangement of protected diol 40. For the former approach, numerous concise routes were designed (see SI for examples). In order to de-risk the path, 39 could be prepared from VitD2 semisynthetically. Unfortunately, despite screening dozens of reduction conditions, the coveted trans-stereochemistry could never be obtained. Efforts then shifted completely to the latter semi-pinacol approach. The advantage of this design was that the trans-stereochemistry could be pre-programmed by virtue of the diol precursor 40. In turn, this isopropylidene-protected diol served as a rigid scaffold (cis-6,5 bicycle) that could potentially control the stereochemical outcome of an intramolecular reductive HAT-based olefin coupling 32 on substrate 23. Such a disconnection was ambitious since it would need to controllably form a key quaternary center and two contiguous tertiary stereocenters in one step. From modeling studies there was confidence that the key C13-C17 bond would form in the desired fashion, although the stereochemical outcome at C20 was uncertain. HAT-precursor 23 could be traced back to inexpensive 2-cyclohexenone and an acrylate. Our initial entry towards the enantioselective synthesis of advanced CD-ring 38 commenced by targeting enoate 40 (Figure ). Baylis-Hillman reaction on 2-cyclohexenone with t-butyl acrylate in the presence of catalytic DBU delivered enone 41 in 81% yield on multi-gram scale. Although various disconnections and conditions were employed to deliver the diol in 42 (see SI), an asymmetric dihydroxylation of such an olefin would appear the most appealing choice. Although using NMO as the co-oxidant and citric acid in the presence of catalytic OsO4 efficiently delivered the dihydroxy product in a racemic fashion, the asymmetric version proved more challenging. Indeed, dihydroxylation on electron deficient alkenes suffers from poor enantioselectivity, especially in endocyclic systems. Moreover, alkyl α-substitutions further exacerbate this issue, and is known to interfere with the coordination between the osmium catalyst and alkene. Supported by the fact that there are only a few examples on asymmetric dihydroxylation of cyclopentenone or cyclohexenone with α-substitutions, dihydroxylation on such systems still prove challenging today. In the initial optimization, potassium ferrocyanide(III) was able to achieve the desired dihydroxy ketone 42 in 66% ee. Consistent with Sharpless's original study on dihydroxylation of α,βunsaturated ketones, 35b the reaction utilizing AD-mix only gave trace amount of 42, requiring extra osmium due to the less reactive olefin as well as additional base to buffer the reaction. After screening a variety of additives, ligands and various solvent combinations (see SI), diol 42 was obtained with 67% conversion and 74% ee. In its most optimized form, diol 42 could be obtained in 42% yield with 82% ee on gram scale. The desired enantiomer could be enantioenriched through recrystallization (gram scale). With ample quantities of diol 42 in protection with 2-methoxypropene gave the corresponding acetonide which served to rigidify the system. Subsequent methylenation required an extensive optimization as standard olefination conditions (Wittig, salt-free Wittig, Peterson olefination) gave low conversion or low yields on scale, while most Ti-based reagents (Takai-Utimoto, Lambardo, Petasis) proved similarly unsuccessful. The use of the Ti-based Nysted reagent ultimately delivered olefin 43 in respectable yields. After further optimization (see SI), the use of Nysted reagent, in conjunction with Ti(O i Pr)2Cl2, delivered the desired olefin 43 in 61% (2 steps from diol 42, gram-scale). Saponification of tert-butyl ester 43 delivered acid 44 in quantitative yield, which then set the stage for a key C-C bond forming step (44 to 40). A number of approaches were evaluated for achieving this conversion on 44 and related intermediates; ultimately, the newly developed electrochemical reductive cross-coupling proved to be successful in accessing advanced intermediate 40. Thus, in-situ activation of acid 44 with NHPI, followed by reductive coupling with vinyl iodide 45, enabled by Ag-nanoparticle functionalized electrochemical cross-coupling , delivered HAT precursor 40 in 48% yield on small-scale. Gratifyingly, a correlation of yield and reaction concentration was observed, providing 40 in 63% yield (gram-scale). With enoate 40 in hand, attention turned towards establishing the CD-ring core via an intramolecular HAT-mediated annulation (Figure ). During the course of extensive optimization (see SI for full details), the utilization of PhSi(O i Pr)H2 was found to be crucial, whereas phenyl silane failed to give 46. In general, the solvent choice had very little effect on the reaction conversion (entries 1-4), although ethyl acetate/ i PrOH proved detrimental (entry 5). A survey of catalysts revealed that manganese(III)-based catalysts only led to unsatisfactory yields (entry 7), while use of Fe-based catalysts (Fe(dpm)3, Fe(acac)3) delivered the desired annulated product in appreciable yields (entries 1,6). After a thorough screening of conditions, the use of Fe(dpm)3 and PhSi(O i Pr)H2, in DCE/(CH2OH)2 delivered the desired stereoisomer 46 in 54% isolated yield. It is noteworthy that this HAT-mediated cyclization installs 3 contiguous stereocenters with the major diastereomer being the correct C20 stereochemistry belonging to the VitD family. the direct coupling could be practically achieved only under newly established electrochemical conditions, with vinylbromide 50A being the most suitable choice for this transformation (see SI). In the event, RAE 49 and 50A were subjected to Ag-nanoparticle based electrochemical conditions in delivering 51 in 48% NMR yield (carried crude to the next step) as a 1:1 mixture of diastereomers (ca. 75 mg scale). The endgame sequence involved tandem semihydrogenation/isomerization followed by global deprotection to furnish calcipotriol in 38% isolated yield over 3 steps from 49.