School of Chemistry (ETDs)

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Browsing School of Chemistry (ETDs) by Keyword "Amino alcohols"

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    Use of transaminases for the biosynthesis of enantiopure building blocks of two essential medicines: Ethambutol and Dolutegravir
    (University of the Witwatersrand, Johannesburg, 2023) Maboya, Josephine; Pienaar, Daniel
    (S)-2-Amino butan-1-ol and (R)-3–amino butan-1-ol play an important role as intermediates in the synthesis of the anti-tuberculosis drug ethambutol and HIV integrase inhibitor drug dolutegravir respectively. The current industrial preparation of these enantioenriched amino alcohols is quite a challenging process; it typically involves the use of harsh chemicals, results in low yields, and generates hazardous waste materials. Consequently, these methods tend to be expensive, and it has been demonstrated that the cost of these intermediates has a significant impact on the overall costs of the synthesis of the entire drug. Therefore, it is not surprising that the convenient, cost–effective, and environmentally benign production of these optically pure amino alcohols is still the subject of ongoing investigations. The chemo-enzymatic approach holds great potential to replace the conventional routes for the synthesis of enantiopure amines. Transaminase enzymes (ATAs), in particular, have gained much attention over time due to their remarkable capability to transform inexpensive ketone starting materials into valuable enantiopure amino alcohols. Through the utilization of the isopropyl amine donor system, pro-chiral ketone starting materials were effectively transformed into the desired (S)-isopropyl 2-aminobutanoate and (R)-isopropyl 3-aminobutanoate using transaminase biocatalysis. These reactions proceeded well under milder conditions such as ambient temperature and pressure conditions, and impressively under an aqueous environment. Three (S)-enantiomer selective “hit “enzymes were discovered (ATA-189, ATA-194, and ATA-254) for the biotransformation of alpha-keto ester substrate into an enantio-enriched amino ester product, with enantiomeric excess ranging between 95-99% and the yield was 15-73% depending on the enzyme and reaction conditions. However, when it came to dolutegravir intermediate, a different scenario unfolded. In this case, the majority of the ATA enzymes in our enzyme library fortuitously exhibited selectivity for the (R)-enantiomer. In particular, four highly enantioselective enzymes (ATA-254, ATA-261, ATA-262, and ATA-234) were discovered, demonstrating % e.e ranging from 93% to 99.99%, with corresponding yields from 38% to 45%. The successful biotransformation of an inexpensive pro-chiral starting material into highly valuable enantioenriched amino ester intermediates represents a significant achievement. Coupled with an effective reduction method to convert these intermediates into the corresponding amino alcohols, this biotransformation process holds immense potential for enabling the sustainable and cost- effective production of both of the valuable ethambutol and dolutegravir amine intermediates