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Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases
KTH, School of Biotechnology (BIO), Industrial Biotechnology.
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2018 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 360, no 11, p. 2157-2165Article in journal (Refereed) Published
Abstract [en]

Abstract Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1‐acetonaphthone yielded an enantiopure (R)‐amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)‐alcohol, which was easily converted into the previous (R)‐amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co‐immobilized on the same porous surface. This self‐sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA‐based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018. Vol. 360, no 11, p. 2157-2165
Keywords [en]
Cinacalcet, Transaminases, Ketoreductases, Asymmetric synthesis, Biocatalysis
National Category
Biocatalysis and Enzyme Technology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-224455DOI: 10.1002/adsc.201701485ISI: 000434349400014Scopus ID: 2-s2.0-85042563096OAI: oai:DiVA.org:kth-224455DiVA, id: diva2:1191332
Projects
Biocascades
Funder
EU, Horizon 2020, 634200
Note

QC 20180326

Available from: 2018-03-18 Created: 2018-03-18 Last updated: 2019-09-04Bibliographically approved
In thesis
1. Chemo-enzymatic cascades for the synthesis of chiral high-value chemicals
Open this publication in new window or tab >>Chemo-enzymatic cascades for the synthesis of chiral high-value chemicals
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chiral amines are frequent in today´s top selling pharmaceuticals. Classical organic synthesis of pharmaceuticals is often work intensive involving many synthesis steps, the use of protection group chemistry, heavy metal catalysts and chiral crystallization techniques. In recent years biocatalysts have proven their outstanding ability to synthesize chiral compounds. In this work the possibility of employing biocatalysts as alternative catalysts for API (active pharmaceutical ingredient) synthesis was explored. Three compounds currently on the market were selected as viable case studies: Cinacalcet (a hyperparathyroidism drug), Vyvanse (an ADHD-drug) and Sertraline (an antidepressant). Two enzyme classes were investigated to directly provide the chiral amines - transaminases and imine reductases. Ketoreductases were also investigated to provide the chiral amine via the chiral alcohol. Laccases and hydrolases were employed to complete the synthesis pathways to the final API. In the case of Vyvanse a true one-pot, two-step enzymatic cascade was achieved by a transaminase and hydrolase. For Cinacalcet a chemo-enzymatic cascade could be demonstrated. Both transaminase and ketoreductase gave excellent enantioselectivities and high yield for the key intermediates, which could then be chemically converted into the final API with good yield. For Sertraline the best yield of one diastereomer precursor could be achieved by a ketoreductase, followed by further enzymatic and chemical steps to the final API. Transaminases and imine reductases both have potential in synthesizing the key amine precursors or the APIs themselves. But to date selectivity and yield are insufficient for industrial application in a lot of cases. This work demonstrates the potential of enzymes to serve as viable alternatives to organo-metallic synthesis. Furthermore enzymes have the potential to simplify work-up because of their excellent enantioselectivity. Finally, a scale-up of a one-step transamination to the key chiral precursor of Cinacalcet demonstrated the enzyme´s applicability in larger volume and at higher substrate concentration.

Abstract [sv]

Kirala aminer är ofta förekommande i de mest sålda läkemedlen. Deras framställning med klassisk organisk syntes är ofta komplicerad på grund av många syntessteg, användning av skyddsgrupper, tungmetall-katalysatorer och kirala kristallisationstekniker. Under de senaste åren har biokatalysatorer visat sin framstående förmåga att syntetisera kirala aminer. I det här arbetet visas möjligheten att använda biokatalysatorer som alternativa katalysatorer för läkemedelssyntes. Tre substanser som finns idag på marknaden har valts som exempel: Cinacalcet- ett hyperparatyroidism-botemedel, Vyvanse- ett ADHD-botemedel och Sertraline- ett antidpressivt läkemedel. Två enyzmklasser har undersökts som kan syntetisera kirala aminer direkt-transaminaser och iminreduktaser. Ketoreduktaser har också undersökts för att de kan syntetisera kirala alkoholer, vilka kan omvandlas till kirala aminer. Laccaser och hydrolaser har använts för att komplettera hela syntesen till den aktiva läkemedelssubstansen. För Vyvanse kunde en två-stegssyntes i samma reaktionskärl utvecklas med ett transaminas och ett hydrolas. För Cinacalcet kunde en kombinerad kemisk-enyzmatisk katalyserad syntes utvecklas. Både transaminaser och ketoreduktaser uppvisade en enastående enantioselektivitet och hög omsättning för framställningen av nyckelintermediärer som kunde omvandlas till målsubstanserna med organisk kemiska metoder med bra utbyte. För Sertraline kunde den bästa omsättningen med bra selektivitet för en diastereomer erhållas med ett ketoreduktas. Den aktiva substansen Sertraline kunde erhållas med vidare enzymatiska och kemiska steg. Både transaminaser och iminreduktaser har potential för att användas till själva syntesen men tills nu inte med tillräckligt selektivitet och omsättning. Detta arbete visar att enyzmer har ett framtid som möjliga alternativ till organisk-metalliska katalysatorer. Framöver finns möjlighet att de kan minska behovet av upparbetnings-steg på grund av deras enastående selektivitet. Slutligen gjordes en uppskalning av en transaminasreaktion för framställning av en kiral nyckel-byggsten till Cinacalcet. Denna uppskalning visade enzymets tilllämpbarhet att hantera större volymer och högre substratkoncentrationer.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2019. p. 59
Series
TRITA-CBH-FOU ; 42
National Category
Industrial Biotechnology
Identifiers
urn:nbn:se:kth:diva-257769 (URN)978-91-7873-275-3 (ISBN)
Public defence
2019-09-30, Kollegiesalen, Brinellvägen 8, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
EU, Horizon 2020, 634200
Note

QC 2019-09-05

Available from: 2019-09-05 Created: 2019-09-04 Last updated: 2019-09-05Bibliographically approved

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