A recent review by David L. Hughes summarizes trends and innovations in biocatalysis in the patent literature starting from 2018. [1] At SpinChem, we like to follow the example but to highlight patent examples using immobilized enzymes a little extra.

• Case 1: Due to limited solubilities of amino acids in organic solvents, the direct amidation of them with ammonia has previously not been reported. However, in this work, a group around Thermo Fisher Scientific introduced a strategy for direct conversion of acids and esters to amides by lipase catalysis. Their approach used immobilized CalB in MTBE, 1,4-dioxane, diisopropyl ether, and 2-methyl-2-butanol. [2]

• Case 2: A group from Pfizer described the direct amidation of diester pharmeceutical intermediate. This reaction has a few noteworthy features: (i) The reaction did not work with soluble lipase but worked well with several immobilized formulations— demonstrating the stabilization that is possible by immobilization. This may be especially important for reactions in organic media. (ii) The use of hexamethyldisilazane (HMDS) as a sort of ammonia alternative was reported as a first. (iii) The reaction was carried out up to a scale of 110 kg, demonstrating an example of the increasing use of biocatalysis in pilot and production scale in the pharmaceutical industry. [3]

• Case 3: Biocatalytic carbon-carbon bond forming reactions are still in early development. While lipases were demonstrated to catalyze aldol reactions in 2003, [4] in 2020 a research group developed the concept to involve three-component chromene-forming reactions. Screening of 13 immobilized lipases and 2 control proteins for activity on the system of 4-chlorobenzaldehyde, 4-hydroxycoumarin, and malonitrile ranked Novozyme TLIM as the most active immobilized lipase, giving the product Chromene at 46% yield. With high enzyme loadings, a range of aldehydes gave products in the three-component reaction in the 97-99% range. The enzyme retained high activity for five re-uses. [5]
  

• Case 4: Normally, L-threonine aldolases catalyze the retro-aldol of threonine to glycine and acetaldehyde. Several patents now report on catalysis by engineered L-threonine aldolase (LTA) in the synthesis direction for the production of aryl b-hydroxy-a-amino acids from benzaldehyde and glycine. A remarkable number of uses were demonstrated for the reaction. [6]