In light of our previous work in the synthesis of a-pyrone meroterpenoids from 7, a route involving enzymatic C3 oxidation of 7 with variants of P450BM3, followed by epimerization at C9 was initially considered. However, preliminary forays into this route showed that the C3 alcohol is incompatible with strong acids, even in its protected form. As a workaround, we decided to investigate the feasibility of performing enzymatic C-H oxidation on lactones 9 and 12, which was prepared in seven steps from 9 (vide infra). Despite the high structural similarities of 9 and 12 to 7, it is widely accepted that even minor alterations in substrate structure could result in dramatic changes in reactivity in enzymatic transformations. Gratifyingly, initial screening of a subset of our P450BM3 library revealed a few variants with C3 hydroxylation activity on 9 (Figure ). Variant KSA15, previously developed by Reetz and co-workers for steroid hydroxylation, showed the highest conversion (54%) among all the library members tested. Following an analogous screening with lactone 12, variant MERO1 L75A, previously developed in our laboratory for the synthesis of oxidized meroditerpenoids, was identified to be the optimal enzyme to hydroxylate 12 at C3 (Figure ). While variant KSA15 provided higher conversion (95%) in its reaction with 12, additional product regioisomers could be detected. Thus, we elected to perform subsequent C-H oxidation scale-up with MERO1 L75A.