Direct biosynthetic cyclization of a distorted paracyclophane highlighted by double isotopic labelling of l-tyrosineElectronic supplementary information (ESI) available: Experimental procedures, characterization data, and 1H and 13C NMR spectra of products. CCDC 1031563. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob00114e

The biosynthesis of pyrrocidines, fungal PK-NRP compounds featuring a strained [9]paracyclophane, was investigated in Acremonium zeae . We used a synthetic l -tyrosine probe, labelled with oxygen 18 as a reporter of phenol reactivity and carbon 13 as a tracer of incorporation of this exogenous precursor. The ( 18 O)phenolic oxygen was incorporated, suggesting that phenol behaves as a nucleophile during the formation of the bent aryl ether. The biosynthesis of pyrrocidines was investigated using a double ( 18 O, 13 C) labelling of l -tyrosine. It shows that the phenolic 18 O is incorporated during aryl ether bond formation.