terms of its applicability to structurally related pyranones (Scheme 4). Gratifyingly, a set of cycloalkanol-derived substrates (1b-1e) performed more or less equally well and provided high butenolide selectivities of >88% while maintaining good to excellent enantiomeric purity of the products. The geminal diethyl-derivative 7f and the aromatic 7g were best obtained with an alternative single-enzyme option, in which the alcohol dehydrogenase P2-B02 acts both as ketoreductase and as dehydrogenation catalyst for the hemiacetal-to-butenolide conversion. In both cases, high enantioselectivities were achieved but selectivities for the five-membered Oheterocyclic products remained lower, and significant amounts of the d-lactone side products were observed. As previously mentioned, g-butenolides are highly attractive synthesis targets and the structural motif is widespread in natural bioactive secondary metabolites. Obviously, we were eager to also test the applicability of the ring contraction approach as tool in natural product synthesis. The methyl-substituted pyranone 1h was easily obtained via oxidative ring expansion of the corresponding furfural-derived optically pure secondary alcohol, and we were very pleased to find that the P2-G03/evo030 couple mediated the redox isomerization under ring contraction. Hence, the new methodology was successfully applied for the stereoselective synthesis the plant-derived butenolide 7h that was previously isolated from several Osmunda species, albeit at only moderate yield. On the other hand, attempts to perform ring contractions of 1i and 1j remained unsuccessful and the isomerization of 1j to musacin D (7j), a fungal metabolite found in Sepedonium chrysospermum, stalled instead on the hemiacetal stage (>99% conv. of 1j). Even though the process is believed to rely on a substrate-selective dehydrogenation catalyst with preference for the oxidation of the furanose intermediate (Supplementary Table ), we were uncertain whether the general thermodynamic bias for one hemiacetal over another may play a critical role in statistically disfavouring the ring contraction as in for example the case of 1i or 1j. In absence of detailed spectroscopic data on the furanose-pyranose mixtures, we turned to computational tools to gain insights. DLPNO-CCSD(T) ab initio energy calculations on DFT optimized structures revealed that in the comparative study involving the reduced intermediates of the pyranone substrates 1a, 1h, and 1i, the ring-contracted furanose (6) would be favoured in all cases over the pyranose ( ), yet with no clear or decisive bias (Scheme 5). It seems therefore more plausible that not energetics or a lack of selectivity of the dehydrogenative enzymes prohibits from effective ring contractions. In all low yielding or non-productive examples, it is worth noting that primary or secondary alcohol groups would be liberated during the ring contraction. These species, however, are no longer innocent spectators but can engage themselves in ADH-mediated dehydrogenations leading to aldehyde/ketone side products and skewing the overall redox balance (with the accumulation of NAD(P)H). This undesired removal of the oxidizing nicotinamide cofactor would thus prevent hemiacetal dehydrogenation and inhibit the completion of the redox selfsufficient catalysis cycle.