Following the neutralization of the reaction mixture, the desire d product precipitated, allowing for straightforw ard separat i o n via filtration. This workup efficiently removed impurities an d byproducts, including dimethylated 2-acetyl phloroglucino l , which stayed in solution. Consequently, we obtaine d trimethylated acetyl phloroglucinol 11 with a yield of 69%. Th e obtained trimethylated acetyl phloroglucinol 11 was then coupled with commercially available geranyl acetate (10) in a Tsuji-Trost allylic alkylation. Using Pd2dba3 as a Pd(0) source an d testing multiple ligands, XPhos proved superior, yielding the geranylated phloroglucinol 13 with an excellent yield of 92%. Rendering the coupling reaction enantioselective would be highly desirable. The single stereocenter formed in the Tsuj i -Trost reaction ultimately dictates whether (+)-or (-)cleistocaltone A ( ) is synthesized due to the diastereoselectivity of subsequent steps. Unfortunat e l y, despite rigorous screening, we could not identify a chiral ligan d that induced significant enantiomeric excess. Consequently, we proceeded with the synthesis using a racemic mixture of geranylated acetyl phloroglucinol 13. In the subsequent aldol condensation, 13 was reacted with benzaldehyde under basic conditions. Due to a competi n g Cannizzaro reaction consuming benzaldehyde (yielding benzyl alcohol and benzoic acid), a portion-wise addition of 6 equivalents of aldehyde was crucial for complete conversio n . Then the high solubility of 6 in cyclohexane was exploited fo r extraction, leaving benzoic acid and much of the benzyl alcoho l in the aqueous phase. Unreacted benzaldehyde was remove d under high vacuum, greatly streamlining the purificati o n process. This yielded geranyl champanone B 6 in 94% yield. The terminus of the geranyl moiety in 6 was selectivel y chlorinated using trichloroisocyanuric acid (TCCA) in CH2Cl2, with careful temperature control being crucial. While the reaction proceeded smoothly on a milligram scale (85% yield of 14, simple filtration), scaling up to gram quantities significan t l y decreased the yield to 50% and complicated the colum n chromatograp hy purification due to increased side -prod u c t formation. In the subsequent step, the allylic chloride in 14 was eliminate d via a palladium-catal yze d β-hydride elimination to afford diene 9 in 76% yield. The combination of sodium hydroxide and the phase-transfer catalyst tetrabutylammoniu m chloride ensure d efficient removal the liberated hydrochloric acid (HCl). With the required structural elements assembled, a thermal IMDA was performed in a biphasic mixture of water an d toluene. This process afforded diastereomers 15 and 8 in 20% and 26% yields, respectively. Crystallization proved to be the most efficient purification method. Treatment of the crude product with a pentane followed by cyclohexane preferential l y dissolved the undesired IMDA diastereomer 15, leaving the desired diastereomer 8 as a solid. While this purification was extremely convenient, some amount of 8 also dissolve d , resulting in a reduced yield of only 26% (compared to a possibl e 32% as determined by 1 H-NMR). The absolute configurations of 8 and 15 were confirmed by XRD analysis. In exploring the impact of various solvents on the IMD A reaction's diastereomeric ratio, a 3:1 excess of the undesir e d diastereomer 15 was observed in both pyridine and n-butano l . Unfortunately, no other tested solvent yielded an excess of the desired diastereomer 8. Consequently, a toluene/water mixtur e was chosen, allowing the reaction to proceed at a lower temperature (80 °C), which minimized side product format i o n and simplified purification. The epoxidation of 8 presented a challenge, as its two trisubstituted double bonds appeared electronically similar. We speculated that strain-release in the transition state woul d render the macrocyclic double bond significantly more reactive . The facial preference was predicted from the X-ray crystal structure of the starting material. Treatment of 8 with peroxyacetic acid in a biphasic sodium acetate/dichl o r omethane mixture selectively furnished epoxide 16 as a singl e diastereomer in 66% yield. Various conditions for opening epoxide 16 were investigat e d . Lewis acidic conditions generally led to decomposition. Basi c conditions, even using strong bases such as n-butyl lithium at room temperature, resulted in no conversion. This lack of reactivity is attributed to steric hindrance, with the macrocyc l e shielding the acidic α-position adjacent to the epoxide . Fortunately, Brønsted acidic conditions proved successfu l . Treatment with HCl at 50 °C opened the epoxide, yielding the allylic alcohol and, ultimately, cleistocaltone A (1) in a 33% yield. Additionally, the acid-mediated opening of the epoxide in 16 resulted in an intriguing side product 17, characterized by an unusual tetracyclic structure that includes an eight-membe r e d cyclic ether. The structure was confirmed through XRD analysi s. It is proposed that this product originates from a nucleophili c attack by the enol-oxygen on the tertiary carbon center, a process initiated by the protonation of the epoxide (Scheme 3).