Studies on Paraherquamide Biosynthesis: Synthesis of Deuterium-Labeled 7-Hydroxy-Pre-Paraherquamide, a Putative Precursor of Paraherquamides A, E & F.

The stereocontrolled, asymmetric synthesis of triply deuterium-labeled 7-hydroxy-pre-paraherquamide (27) was accomplished, employing a diastereoselective intramolecular S(N)2' cyclization strategy. The deuterium-labeled substrate was interrogated in a precursor incorporation experiment in the paraherquamide-producing organism Penicillium fellutanum. The isolated sample of paraherquamide A revealed incorporation of one of the two geminal deuterons of the CD(2)-group at C-12 exclusively. The lack of signals for the second deuteron of the CD(2)-group at C-12 and for the CH(2)D-group (C-22/C-23) suggests that this substrate suffered an unexpectedly selective catabolic degradation and metabolic re-incorporation of deuterium thus casting doubt on the proposed biosynthetic intermediacy of 27. Consideration of alternative biosynthetic pathways, including oxidation of the indole C-6 position prior to hydroxylation at C-7 or oxidative spiro-contraction of pre-paraherquamide prior to construction of the dioxepin is discussed. The synthesis of 27 also provides for a concise, asymmetric stereocontrolled synthesis of an advanced intermediate that will be potentially useful in the synthesis of paraherquamide E & F.