Studies on paraherquamide biosynthesis: synthesis of deuterium-labeled 7-hydroxy-pre-paraherquamide, a putative precursor of paraherquamides A, E, and F

摘要

The stereocontrolled, asymmetric synthesis of triply deuteruim-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 CD2-group at C-12 exclusively. The lack of signals for the second deuteron It the CD2-group at C-12 and for the CH2D-group (C-22/C-23) suggests that this substrate Suffered all 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 paraherquamides F and F.