An innovative route for the production of atorvastatin side-chain precursor by DERA-catalysed double aldol addition

Biocatalysis making waves in organic chemistry

“…Recently this has been coupled to an ADH-catalysed oxidation yielding the desired lactone (Scheme 7). 99,100 A more elaborate industrial cascade involving DERA is discussed below.…”

Recent Advances in the Substrate Selectivity of Aldolases

“…DERAs from thermophilic species proved to be more stable than enzymes of mesophilic origin but were compromised by their lower intrinsic activity at the ambient reaction temperature as well as their lower level of heterologous expression . Therefore, efforts are currently focused on implementation of mathematical models to optimize the process, which have enabled a chlorolactol concentration of 78 g L –1 to be reached, with a productivity of 56 g L day –1 using DERA enzyme from Thermotoga maritima (DERA Tma ) in a fed-batch reactor (Scheme Aa), or a final concentration of 94 g L –1 along with a 229 g L day –1 productivity with phenylacetamide aminoprotected propanal as the electrophile (Scheme Ab) . In these examples, cascade reactions have been implemented involving lactol production followed by its oxidation with the NAD-dependent aldehyde dehydrogenase (ADH) or ketoreductase (KRED), NADH oxidase (NOX) being employed for coenzyme regeneration, yielding a lactonized precursor of statin side chain (Scheme Aa,b) …”

Shortening Synthetic Routes to Small Molecule Active Pharmaceutical Ingredients Employing Biocatalytic Methods

“…A landmark represents the biocatalytic synthesis of statin side chains catalyzed by 2-deoxyribose-5-phosphate aldolase (DERA) from cheap nonchiral starting materials opening a new strategy . It is based on two sequential stereoselective aldol additions of acetaldehyde (serving as donor) onto chloroacetaldehyde (as acceptor) to yield an intermediate 3,5-dihydroxyhexanal intermediate, which spontaneously cyclizes by forming a 6-membered lactol, which interrupts the aldol chain elongation reaction (Scheme A shows the process with acetoxyacetaldehyde instead of chloracetaldehyde). − Although conceptually brilliant, the initial protocol employed reaction conditions not suitable for scale-up due to high enzyme loading, long reaction time (6 days), and the need for Br 2 for lactol oxidation to obtain the lactone. A novel DERA, resistant to process conditions, was obtained by screening of genomic libraries from environmental samples by Diversa Corporation, which reduced enzyme loadings by a factor of 10 (20 to 2 wt %) .…”