The final retrosynthetic depiction shown in Figure benefitted from the learnings of multiple generations of unsuccessful routes, most of which were based on the convergent union of ABC and EF fragments followed by D-ring formation post-coupling (see SI for details). Learnings from those studies led to the current approach wherein a fully formed ABC tricycle (Fragment A, 7) was coupled to an EF bicycle The synthesis of 7 (Scheme 1A) commenced from the decalin 11, previously prepared in 6 steps from (S)-Wieland-Miescher ketone (9). 8k A convenient, scalable 3-step protocol was thus developed involving enone isomerization/reduction of acetal protected 9 (see SI for details). A cyclopentenone annulation sequence was subsequently carried out using the known phosphonate reagent 12 9 : the lithium enolate of 11 was first alkylated with 12 to afford intermediate 13 as a 1:1 mixture of C9 epimers (after hydrolysis of the enol ether), which upon treatment with Cs2CO3 underwent an intramolecular Horner-Wadsworth-Emmons reaction to forge the cyclopentenone motif with concomitant equilibration to a 9:1 mixture of C9 epimers favoring the desired diastereomer, as confirmed by Xray crystallographic analysis. Further enrichment of 14 to >20:1 dr was achieved after a single round of recrystallization from hexanes/DCM (ca. 10:1). With gram quantities of 14 at hand, a second enolate alkylation at C13 with tert-butyl bromoacetate proceeded smoothly to yield 15 as a single diastereomer. The conjugate reduction of enone 15 required judicious choice of reagents (see SI for the full optimization table). Whereas Stryker's reagent and SmI2 gave no reaction and Shenvi's HAT reduction conditions 10 resulted in decomposition, a reactive CuH species reported by proved to be the optimal choice, furnishing the desired 1,4-reduction product 16 in 86% yield as a single diastereomer without any undesired 1,2-reduction. Ketone 16 was ultimately transformed to the 1,2addition precursor 7 by Wittig olefination, DIBAL-H reduction of the tBu ester, and finally an Appel reaction to convert the resulting primary alcohol to iodide.