After confirming the structural misassignment with NMR calculations, we sought to validate the structure prediction through chemical synthesis (Scheme 18). An X-ray diffraction structure of the experimentally obtained sample of xylogranatin F (1-3) was acquired, 2g which clearly showed that we synthesized the proposed structure of xylogranatin F (1-3) with the C3-hydroxyl group on the α-face. In order to invert the stereochemistry at C3, a tosylate (18-1), mesylate (18-2) and phosphate (18-3) were prepared. However, the attempted SN2 displacement with various nucleophiles failed to give the desired stereochemical outcome, and instead the undesired stereochemistry was observed presumably via an SN1 pathway (see Supporting Information Scheme SI8 for more details). Fortunately, modifying the leaving group from acetate to chloride allowed for partial inversion of the C3-stereocenter. When NaOMe or Zn(OAc)2 were utilized as nucleophiles, 1:1 dr was Scheme 16. Computational Investigation of the Regioselective Pyran Formation and Experimental Evidence a a Calculations were performed using ωB97x-D/6-311+G(2d,p)//ωB97x-D/6-31+G (d,p). Free energies (in kcal/mol). a Geometry optimization calculations were performed using B3LYP/6-31+G (d,p) level of theory with the SMD solvation method (chloroform), while NMR single point calculations were conducted using mPW1PW91/6-311+G(2d,p) for all the above calculations. The diversity of C3-substituents in this family sparked our curiosity about their biosynthetic origins. We speculated this diversity may be an artifact of isolation. The principal observation that suggested this hypothesis is that granatumine A (1-2), which possesses a C3-methoxy group, was isolated from MeOH. Whereas hainangranatumin G, which possesses a C3ethoxy unit was isolated from EtOH. 4c Meanwhile xylogranatin G (17-5, C3 = β-OAc) xylogranatin F (17-1, C3 = β-OH) were isolated from EtOH. 4b However, degradation was not observed when xylogranatin F (1-1) or xylogranatin G (17-5) were subjected to various acidic or neutral conditions with MeOH or EtOH as solvent. This study implies that if these were artifacts of isolation, they are not derived from xylograntin F (1-1) or xylogranatin G (17-5), and instead are derived from some other labile natural product that may not have been isolated yet.