The absolute stereochemistry of fostriecin (1, CI-920), a potent antitumor antibiotic presently in Phase I clinical trials at NCI, was determined to be 5R,8R,9R,11R. 2D 1 H-1 H NMR NOE experiments conducted on the cyclic phosphate derivative 2 and acetonide 4 revealed a syn-diol stereochemical relationship between C8 and C9 and an anti-diol stereochemical relationship between C9 and C11, respectively. The 5R absolute configuration assignment was confirmed by synthesis of the degradation product 8 previously disclosed. Additional degradation studies of 1 to provide 7 and chiral-phase HPLC comparison with a sample of known chirality established the absolute stereochemistry of C11 to be R. This, along with the relative stereochemical assignments established the full set of absolute stereochemistry assignments for 1.
A concise total synthesis of phomazarin (1) is detailed enlisting a heterocyclic azadiene inverse
electron demand Diels−Alder reaction (1,2,4-triazine → pyridine) for preparation of the fully substituted and
appropriately functionalized pyridine C-ring. Thus, [4 + 2] cycloaddition (85%) of triethyl 1,2,4-triazine-3,5,6-tricarboxylate (2) with trimethoxyethylene (3) followed by conversion of the cycloadduct 11 to the cyclic
anhydride 13 provided the phomazarin C-ring with the three carboxylates suitably differentiated. Linkage of
the A- and C-rings through selective nucleophilic addition of the aryllithium reagent 9 to the least hindered
anhydride carbonyl of 13 followed by Friedel−Crafts closure of the B-ring provided the fully functionalized
phomazarin skeleton. The successful structural correlation of synthetic 1 with natural material and its derivatives
confirmed the latest structural assignment for the natural product.
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