Multiple strategies (see SI) to access fragment B (8) were evaluated via a structure such as lactone 20 (Scheme 1B). Similar molecules have been prepared in the past through laborintensive chiral pool strategies. For instance, a derivative of 20 bearing a Cbz instead of a benzenesulfonyl (Bs) group was previously accessed in either 9 steps 8c or 6 steps 8h from (S)citronellal, with 2 additional steps required to exchange the PG as the sulfonamide protecting group has proven to be essential for late-stage manipulations (see SI for discussion). A concise 4-step route to 20 was thus developed through an unusual sequence relying on the C5-selective asymmetric allylic alkylation (AAA) of siloxyfuran 10 as reported by Arseniyadis et al. This key precedent was improved for the synthesis of γbutenolide 17 through the addition of NH4OAc (as per suggested by the Arseniyadis group in our correspondence) which further boosted reaction efficiency and regioselectivity (favoring C5 allylation over C3), delivering 17 in 75% isolated yield and 97% ee (see SI for details). Subsequent aza-Michael addition to 17 required substantial screening (see SI) that eventually led to the identification of BsNHOBn (Nbenzenesulfonyl-O-benzylhydroxylamine) as the optimal nucleophile. X-ray analysis confirmed that addition occurred exclusively trans to the existing γ substituent on the butenolide. In its fully optimized form, this reaction involved directly treating the aza-Michael adduct with Zn 0 /NH4Cl in the same reaction vessel to effect N-O bond cleavage and furnish the sulfonamide 18 as a single diastereomer in 71% isolated yield. Racemization of 18 (71% ee) was observed but could be rectified by a single round of recrystallization from DCM/Et2O (1:1), which restored its enantiopurity (>97% ee). With gram quantities of 18 at hand, the key halocyclization step to construct the strained trans-6,5 EF bicycle was investigated. Due to the extreme strain that would be incurred through a 5exo-trig cyclization to deliver a trans-5,5 ring system, it was rationalized that an unusual 6-endo-trig cyclization would be preferred. After the initial hit with NIS/K2CO3 verified this hypothesis, further screening was performed (see SI for details) that eventually led to the most reproducible and scalable protocol with KOtBu/I2. In its fully optimized form, the halocyclization step furnished the tertiary iodide 19 in 51% yield as a 20:1 mixture of diastereomers, which were subjected to a tin hydride-mediated dehalogenation reaction to afford the desired lactone 20 in 71% yield as a single diastereomer. This stereochemical outcome could be rationalized as a combination of thermodynamic preference (methyl group prefers to be equatorial) and steric bulk of the benzenesulfonyl group (which disfavors hydride approach from top face of the tertiary radical). It is worth noting that the ring-opening side product 18 was consistently observed on larger scale (>100 mg) and could be isolated in 21% yield. Attempts to suppress this process by running the reaction at ambient temperature instead of 100 °C (see SI) surprisingly exacerbated ring-opening (20:18 = 1:1, vs. 3:1 with AIBN at 100 °C). Besides this piece of evidence, we also observed that 1) the halocyclization reaction exhibited certain degrees of reversibility over prolonged reaction times (see SI), and 2) addition of TEMPO to the halocyclization reaction inhibited product formation. These clues led us to speculate that the halocylization might proceed through a oneelectron pathway involving formation and homolysis of an N-I species (see SI). Methylation of 20 by enolate alkylation proceeded smoothly to deliver the key lactone 21 as a single diastereomer, the structure of which was confirmed by X-ray analysis. Finally, addition of isopropenyllithium to lactone 21, followed by simultaneous ring-chain tautomerization of the resulting hemiketal and TES protection of the secondary alcohol, furnished enone 8 in 65% yield over this one-pot sequence. With both fragments (7 and 8) in hand, the endgame sequence (Scheme 2) commenced with union of the two fragments by 1,2-addition, wherein the primary iodide 7 first underwent lithium halogen exchange with tBuLi, and then the resulting alkyllithium species added into enone 8. Addition of LaCl3•2LiCl proved to be crucial (see SI for additive screening) for the exclusive 1,2-regioselectivity observed in this reaction 13 , yielding tertiary alcohol 22 as a single diastereomer (confirmed by X-ray) possibly due to Felkin-Ahn selectivity. This success set the stage for the final D/E ring double cyclization sequence, which entailed formation of the E ring through an alkoxide Tsuji-Trost cyclization followed by formation of the D ring by ring-closing metathesis (RCM). The challenging Tsuji-Trost cyclization turned out to be an immense undertaking that required considerable optimization (see SI). To our delight, Boc carbonate 23 (prepared from 22 in two steps) emerged as the singularly successful substrate, delivering the desired THFcontaining RCM precursor 24 in 73% yield with perfect net stereoretention from tertiary alcohol 22. This diastereochemical outcome was in line with previous observations in similar THFforming Tsuji-Trost cyclizations. The RCM reaction to form the tetrasubstituted olefin, which was the final hurdle in this synthesis, was initially met with expected difficulties (see SI for details): conventional metathesis catalysts such as Hoveyda-Grubbs 2 nd generation catalyst (Ru-1) gave low conversions even at elevated temperatures, and the less sterically encumbering o-tolyl variant Ru-2 only led to slightly improved results. Fortunately, the indenylidene catalyst Ru-3 was reported to be an extremely effective metathesis catalyst for sterically demanding substrates. 15 Indeed, a significant improvement in yield was observed with Ru-3, which, when combined with perfluorotoluene 15b as solvent, led to the optimal condition that afforded bis-protected cyclopamine 25 in 85% yield, the structure of which was confirmed by X-ray analysis. The prior approach of Giannis necessitated two distinct reductive deprotection conditions to excise Bn and sulfonamide groups. 7h Instead, removal of both groups could be accomplished with freshly prepared LiDBB , yielding (-)cyclopamine in 78% yield. It is worth noting that we observed significant concentration dependence when acquiring the NMR spectra of cyclopamine in CD2Cl2, a solvent that was used in multiple previous reports (see SI for discussion).