with NaN3 at 70 °C delivered azido-imidazole 13 (structure confirmed via X-ray crystallography) in 73% yield (small amount of deprotected product was re-protected in one-pot afterwards). At this juncture the final guanidine unit had to be installed on a preexisting guanidine unit -a challenge with little precedent in the literature. One of the most powerful reagents for installation of this functional group, Turboguan TM , was evaluated but proceeded with low conversion. An analog of this reagent bearing a 1,2,4-triazole leaving group proved successful delivering phenol 14 (structure confirmed via X-ray crystallography) in 64% yield after hydrogenolytic benzyl group removal and azide reduction in a one pot process. All that remained was formation of the C-ring, restoration of the spirocyclic A-ring, global deprotection, and a stereoselective reduction on the Dring. PIDA-mediated dearomatization occurred smoothly to deliver 15 in 76% yield. Subsquent exposure to BCl3 removed the Boc groups and the BOM group along with concomitant equilibration to the correct connectivity expressed in the pentacyclic ring system thereby affording 16 (structure confirmed via X-ray crystallography) in almost quantitative yield. The selective installation of two hydrogen atoms were all that remained to complete the total synthesis of 1. Not surprisingly, this required extensive experimentation due to the highly polar nature of 16, its multiple Lewis-basic sites and its tendency to aromatize via guanidine fragmentation under reductive conditions. Furthermore, the X-ray structure of 16 suggested that the requisite hydrogenation might be favored on the undesired face of the molecule. Indeed, amongst the numerous conditions screened (see inset Table for a small selection and SI for an extensive list), aromatization products and epi-KB343 (2) predominated. Even under radical-based reduction conditions, the undesired diastereomer was formed exclusively. The first glimmer of hope emerged from standard Pd/C-based hydrogenation in MeOH solvent. Whereas screening of chiral ligands had only a detrimental effect on selectivity, careful selection of guanidinium counterions showed some promise. Ultimately, by employing a trifluoromethanesulfonic acid counterion, a 2:1 dr favoring 1 (ca. total 90% yield) was achieved. The spectra of synthetic 1 matched that of the isolation report 1 and its structure was unequivocally confirmed via X-ray crystallography. To assign the absolute stereochemistry of 1, an enantioselective total synthesis was pursued. Initial attempts to render the conjugate addition (Step 3, Scheme 1) asymmetric were met with failure. Thus, a de novo route to enantiopure 6 was developed hinging upon an asymmetric Diels-Alder (DA) reaction as shown in Scheme 2. While a-heteroatom containing dienophiles are known to react with Rawal's diene , there are no examples employing enamide-based systems such as aldehyde 26. Fortunately, assisted by Co-Salen based catalyst , the enantioselective DA proceeded in 65% yield with 95% ee (structure of 27 confirmed via X-ray crystallography).