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 C-13 NMR SPECTROMETRY AND OBSERVATION OF UNUSUAL LABELING OF ACETATE-DERIVED OXYGENS BY O-18(2)

Sodium [1-C-13,2-H-2(3)]-, [2-C-13, 2-H-2(3)]- and [1-C-13,O-18(2)]-ac etate are incorporated in separate experiments into ML-236C 2 and the hypocholesterolemic agent compactin 3 by cultures of Penicillium auran tiogriseum, and the regiochemical distribution bf H-2, C-13 and O-18 i s determined by C-13 NMR spectrometry. In addition, sodium [1-C-13,O-1 8(2)]acetate and O-18(2) are incorporated: into lovastatin (mevinolin) 4 by cultures of Aspergillus terreus to re-examine the origin of oxyg en atoms. The results show that the main-chain oxygen atoms of 2-4 ori ginate from acetate, and the C-8 oxygen atom of 3 and 4 is derived fro m molecular oxygen. However, detailed mass spectral analysis shows tha t significant amounts of aerobic oxygen can be incorporated at sites n ormally labelled by acetate oxygen, presumably through generation of [ O-18]acetate by omega-oxidation of fats. On the basis of labelling res ults, a mechanism is proposed to account for the formation of the bicy clic ring system in these compounds.