Abstract :
For biocatalysis-based processes to be scalable, one has to fulfill at least three requirements: (1) industrially acceptable throughput (volume efficiency); (2) prevention of product inhibition; (3) product separation by partition without recourse to chromatography; and in the case of kinetic resolution, the off-enantiomer needs to be recycled. In the chemoenzymatic synthesis of (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid (BocDMTA) 1 featuring a Klebsiella oxytoca hydrolase, the thermal stability of the enzyme helps to attain an industrially feasible concentration of the substrate, methyl (±)-5,5-dimethyl-1,3-thiazoline-4-carboxylate 6b, at 60 °C: [(±)-6b] = 3.0 M (575 g/L). In the (S)-selective hydrolysis of (±)-3-butyryloxyquinuclidinium butyrate 12 with an Aspergillus melleus protease, Ca(OH)2 serves as so effective a scavenger of butyric acid as to prevent it from impeding the catalytic activity of the protease. This allows the enzymatic hydrolysis to proceed at [(±)-12] = 2.0 M (571 g/L); on extractive separation from the left-over (R)-3-quinuclidinyl butyrate 11a, which is converted to (R)-3-quinuclidinol 2 via methanolysis, the digested (S)-2 can be racemized over Raney Co under hydrogen for another round of the enzymatic resolution. In the synthesis of trans-1-(1,3-dihydroxypropan-2-yl)-4-propylcyclohexane 3, cis-4-propylcyclohexanol 14 is prepared by Galactomyces geotrichum-mediated equatorial hydride delivery to 4-propylcyclohexanone 15; while the microbial reduction fails to go to completion, the unconsumed ketone 15 can be removed via bisulfite adduct formation or by simple distillation after malonate homologation.
