Desymmetrisations of 1‐Alkylbicyclo[3.3.0]octane‐2,8‐diones by Enzymatic Retro‐Claisen Reaction Yield Optically Enriched 2,3‐Substituted Cyclopentanones

On the Resolution of Chiral Substrates by a retro‐Claisenase Enzyme: Biotransformations of Heteroannular Bicyclic β‐Diketones by 6‐Oxocamphor Hydrolase

“…[2] This would allow for the attack of a water molecule activated by histidine 145 at the carbonyl carbon of the five-membered ring as previously suggested. Transformation of this favoured enantiomer would result in a mixture of the (2S,3S)-trans-and (2R,3S)-cis-keto acid product enantiomers of 15.…”

“…[2] In this arrangement, the methyl group of the substrate points toward the entrance to the active site marked by the gate residue phenylalanine 79, analogous to the proposed binding of the symmetrical…”

“…This outcome would be consistent with the stereochemical outcome of the biotransformations of the bicycloA C H T U N G T R E N N U N G [3.3.0] series of ketones as suggested by both modelling studies and optical rotation measurements. [2] The poor E values recorded for the resolutions indicate that the disfavoured enantiomer is also recog- nised by OCH. In order to explain the recognition of the (1S,6R)-enantiomer in the active site, it would need to be accommodated in a significantly different conformation to allow attack at the carbonyl carbon of the five-membered ring.…”

“…[4] With a view to examining the wider substrate specificity of OCH, we decided to synthesise a series of asymmetric, heteroannular bicyclic b-diketones that would test the ability of the enzyme to catalyse the resolution of racemic substrates. As the substrate specificity of OCH had proven to be quite narrow, accepting only mono-or bicyclic diketones that were non-enolisable, either through restrictions imposed by Bredts rule (in the case of bicycloA C H T U N G T R E N N U N G [2.2.2]octane-2,6-dione) or by alkylation at the carbon atom between the carbonyl groups (as in the series of 1-alkylbicyclo- [2] it was decided to synthesise compounds based around bicyclo A general route to this class of bicyclic b-diketones was recently published. [5] In this report we detail studies into the biotransformation of compounds 9, 10 and 12 by OCH, and describe some characteristics of the kinetic resolution exhibited by the enzyme.…”

“…[1] The transformation catalysed by OCH in nature is the cleavage, by a retro-Claisen reaction, of the bicyclic diketone 6-oxocamphor (1), to a-campholinic acid (2), a reaction that proceeds with high diastereoselectivity and enantioselectivity in favour of the (2R,4S)-enantiomer of the product (Figure 1). This represented an unusual enzymatic desymmetrisation reaction, and we have since applied the enzyme to the desymmetrisation of a series of symmetrical bicyclic b-diketones of the [2.2.1], [1] [2.2.2] [1] (3) and [3.3.0] [2] (5) series, and demonstrated that, in each case, it is possible to obtain quantitative yields of optically enriched keto acid products (4 and 6) from these biotransformations. We have also obtained an X-ray crystal structure of both native OCH [3] and a low activity mutant, in which one of the natural products of reaction was observed.…”