Biosynthesis of ML-236C and the hypocholesterolemic agents compactin by Penicillium aurantiogriseum and lovastatin by Aspergillus terreus: determination of the origin of carbon, hydrogen and oxygen atoms by 13C NMR spectrometry and observation of unusual labelling of acetate-derived oxygens by 18O2

Abstract

Sodium [1-¹³C, 2-²H₃]-, [2-¹³C, 2-²H₃]- and [1-¹³C, ¹⁸O₂]-acetate are incorporated in separate experiments into ML-236C 2 and the hypocholesterolemic agent compactin 3 by cultures of Penicillium aurantiogriseum, and the regiochemical distribution of ²H, ¹³C and ¹⁸O is determined by ¹³C NMR spectrometry. In addition, sodium [1-¹³C, ¹⁸O₂]acetate and ¹⁸O₂ are incorporated into lovastatin (mevinolin) 4 by cultures of Aspergillus terreus to re-examine the origin of oxygen atoms. The results show that the main-chain oxygen atoms of 2–4 originate from acetate, and the C-8 oxygen atom of 3 and 4 is derived from molecular oxygen. However, detailed mass spectral analysis shows that significant amounts of aerobic oxygen can be incorporated at sites normally labelled by acetate oxygen, presumably through generation of [¹⁸O]acetate by ω-oxidation of fats. On the basis of labelling results, a mechanism is proposed to account for the formation of the bicyclic ring system in these compounds.