Using X-ray Crystallography and 1,n-ADEQUATE NMR to Revise the Structures of Highly Substituted Aromatic Natural Products: The Absolute Configuration of Formicamycin Congeners

Abstract

Formicamycins and their biosynthetic precursors, the fasamycins, form part of the phenylnaphthacenoid family of polyketide natural products. A recent atroposelective total synthesis of formicamycin H brought into question our original stereochemical assignment of the axially chiral linkage between C-6 and C-7. To address this, we obtained an X-ray crystal structure for formicamycin H that unambiguously confirmed our original assignment as the S_a atropisomer. X-ray structures for multiple additional fasamycins and formicamycins confirmed that this is common to all congeners. However, these studies identified a compounded error made by us whereby several structures previously reported as para-methoxy were found to have ortho-methoxy groups on the hanging E-ring. To address this for congeners that did not crystallize or gave nondiffracting crystals, we turned to the surprisingly underutilized 1,n-ADEQUATE NMR experiment. In total, we generated X-ray structures for 15 phenylnaphthacenoid metabolites and by combining these results report the corrected structures for three formicamycins, six fasamycins, and three biosynthetic lactone intermediates, noting that several revised fasamycin structures now match previously reported naphthacemycins. Our results highlight the utility of 1,n-ADEQUATE experiments for regiochemical determination in polysubstituted aromatic molecules. Moreover, our investigations uncovered a potential deracemization step during biosynthesis of the formicamycin framework.