Biotransformation methods

Chiral alcohols are valuable products mainly as building blocks for pharmaceuticals or agro chemicals or as part of chiral catalysts. Cheap biotransformation methods for the selective reduction of particular ketone compounds are known for many years rather catalyzed by fermentation than with isolated enzymes. Products prepared with whole cells such as baker s yeast often lack high enantioselectivity and there were several attemps to use isolated enzymes. Resolution of racemates with hydrolases are known in some cases but very often the reduction of the prochiral ketone using alcohol dehydrogenases are much more attractive. 

Most of the ergot alkaloids used in therapy are semisynthetic derivatives. There exists a continuous search for new, more potent or more selective EA derivatives. Because of alkaloid complexity and the sensitivity of the EA skeleton to harsh conditions, biotransformation methods are more often used for their derivatization [11]. 

Biotransformation Methods for Preparing Chiral Drugs and Drug Intermediates... 

The product class of enantiomerically pure amines is of considerable importance in both pharmaceutical and agrochemical applications. For instance, enantiopure aryl-alkyl amines are utilized for the synthesis of intermediates for pharmaceutically active compounds such as amphetamines and antihistamines. Several chemical as well as biotransformation methods for the asymmetric synthesis/dynamic kinetic resolution [29] or separation of enantiomers of chiral amines have been described. These are illustrated in Scheme 4.5 for (S)-a-methylbenzylamine [30]. 

The pyrazole NH moiety present in 9 represented a synthetic handle which enabled further derivitization to improve potency and modulate ADME properties. Introduction of a methyl group at this position was tolerated (compound 11) and many other substituents were subsequently incorporated in this location. In particular, introduction of a 4-piperidine moiety afforded compound 12 which displayed the most potent biochemical and cellular ICsoS among aU analogs synthesized. The active enantiomer of 12, compound 1 (crizotinib), was later synthesized using a chiral benzyl alcohol obtained from the biotransformation method mentioned previously. Crizotinib displayed improved biochemical LipE compared with compound 8 (6.4 vs. 2.2) and exhibited enhanced human liver microsomal stability relative to the pyrrolindine-containing compound 4 (HLM% remaining at 1 pM 44% vs. 5.7%). 

The demand for SAM is increasing, which leads to the developing of new manufacture methods. To date SAM is prepared by chemical synthesis such as directed by United States Patent US 6,881,837 B2, enzymatic synthesis in vitro and biotransformation methods. Because of the potential reduction in cost biochemical methods have attracted greater interest recently. SAM can be synthesized by methionine adenosyltransferase (MAT, EC 2.5.1.6) from L-Met and adenosine triphosphate (ATP) in a reaction of the form ... 

L. Baratto, M. Porsani, I. Pimentel, A. Pereira Netto, R. Paschke, B. Oliveira, Preparation of betulinic acid derivatives by chemical and biotransformation methods and determination of cytotoxicity against selected cancer cell lines, Eur.. Med. Chem. 2013. 68,121-131. 

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