Using iterative lithiation-borylation homologations, the mycolactone toxin core has been synthesized in 13 steps and 17 %o verall yield. The rapid build-up of molecular complexity,h igh convergencea nd high stereoselectivitya re noteworthy features of this synthesis.The third most common Mycobacterium infection( after M. tuberculosis and M. leprae)i sthat of M. ulcerans,t he pathogen responsible for the severeu lcerative skin disease,B uruli ulcer. [1] Endemic in tropical Africa, it infects over 5000 patients per annum with 48 %o fc ases being aged under 15. [1a, 2] Transmission is thought to occur by an aquatic organism bite, [3] with initial manifestation occurring as ap ainless skin nodule. If diagnosed early, simple antibiotic chemotherapyi seffective (80 %), [4] however, if untreated, propagation of the infection results in large skin lesions of necrotic tissue and bone loss which are only treatable througha ggressive surgery,r esulting in scarring and loss of limb function. [2,5] The serious morbidity due to the socio-economic burden of ay oung disabled workforce in rural communities [6,7] resulted in the World Health Organizationi dentifyingB uruli ulcer as one of seventeen neglected tropical diseases requiring research. [7] M. ulcerans secretes au niquep olyketide-derived virulence factor,a ne quilibrating mixtureo fm ycolactones Aa nd B, 1 (Scheme1,3:2 trans/cis)w hich inhibits the immune response and causes necrosis of the infected tissue. [1a, c] Small and coworkers [8] successfully isolated milligram quantities of 1 allowing structure elucidation by NMR [9] and confirmationo fm ycolactones A/B as the causativet oxin through studies in vivo. [10] An umbero fc ongers (C-F) have since been isolated containing the common lactone 2,v aryingo nly by the appended acyl side chain. [11] The absolutes tereochemistry of firstlyt he lactone core 2 [12] and then mycolactonesA /B 1 [13] was determined throught otal synthesis by Kishi and co-workers.M ultiple synthetic studies have since followed including a3 rd generation( 1.3 g) [14] synthesiso fp rotected core 2 by Kishi, in additiont oo ther accomplisheds yntheses by the groups of Negishi, [15] Blanchard, [16] and Altmann. [17] These efforts have enabled furtherr esearch into the pathogenesis of Buruli ulcer, [18] aid the invention of new/simplerd iagnostic techniques [19] and allowed structural activity relationships of the core. [16, 17, 20] These SAR investigations have shown that while the northern fragment can be augmented, ac omplete side chain is critical for the potency of 1. [20a] The side chain of 1 has alreadyb een synthesized by the groups of Kishi, [21] Negishi [22] and Feringa/Minnaard, [23] so we therefore focused our efforts towardst he synthesis of the lactone core 2.W ew ere particularly keen on applying our recently developed lithiation-borylation methodology, [24] whichi s highlye ffective in not only controlling stereochemistry but also simultaneously creatingC ÀCb onds. Whilsts uch methodology has already been applied ...