Large-scale stereoselective enzymatic ketone reduction with in situ product removal via polymeric adsorbent resins

Vicenzi, Jeffrey T.; Zmijewski, Milton J.; Reinhard, Matthew R.; Landen, Bryan E.; Muth, William L.; Marler, Paul G.

doi:10.1016/s0141-0229(96)00177-9

Cited by 104 publications

(39 citation statements)

References 16 publications

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“…Further microbial reductions with wild-type organisms comprise the synthesis of a chiral C-13 side-chain intermediate of paclitaxel by BMS researchers utilizing Hansenula fabianii cells, which were produced in a 15l-scale fermentation [77], as well as the synthesis of an N-acylated aminoalcohol with excellent conversion (>99% ee) and enantioselectivity (>98% ee) on a 280 l scale by researchers from Merck & Co. based on the use of Candida sorbophila whole cells [78,79]. A combination of ketone reduction with wild-type organisms and the use of XAD-7 resin to decrease the solubility of a substrate being toxic for the microorganism was reported by Eli Lilly researchers, thus obtaining the desired alcohol product in high yield (96%) and with >99.9% ee, even when operating at a high substrate loading of 80 g/l [80][81][82]. Scalability of this process was demonstrated with a batch process operating on a 300 l (reactorvolume) scale.…”

Section: Wild-type Whole Cellsmentioning

confidence: 99%

Asymmetric Synthesis with Recombinant Whole‐Cell Catalysts

2016

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c h a p t e r 2 3 INTRODUCTIONAsymmetric catalytic transformations play a central role in the field of organic chemistry and are of great interest for applications in the chemical and pharmaceutical industry. Among those, hydrolytic and reverse reactions to form carboxylate deriva tives as well as C─C bond-forming and redox reactions are of particular importance. For a long time this field was dominated by the use of chemocatalysts [1]. For example, numerous chiral heavy-metal complexes have been found to be highly efficient cat alysts, on a technical scale, in particular, for the asymmetric reduction of imines, ketones, and enamides. A representative success story is imine reduction for the man ufacture of metolachlor as one of the largest industrially applied asymmetric chemo catalytic processes to date, and the widely technically applied hydrogenation technology for the reduction of ketones and enamides, for which Noyori and Knowles were awarded the Nobel Prize [2]. An alternative for the production of chiral building blocks, with a continuously increasing number of examples, also on an industrial scale, is biocatalysis. Known for a long time, the use of biocatalytic alternatives has also been limited for a long time, which has been due to-among others-the following two reasons: (i) wild-type whole cells such as baker's yeast require a large amount of biomass (due to the forma tion of the desired enzymes in the cell only in low amounts) and often give unsatisfy ing enantioselectivities (due to the action of more than one enzyme), and (ii) the use of isolated enzymes requires additional costs for cell disruption and enzyme isolation as well as the addition of an external amount of cofactor. Due to impressive progress in the field of molecular biology, these limitations have often been overcome. High overexpression of the desired enzyme in recombinant host organism and high cell density fermentation technology provide efficient and economically attractive access to these microorganisms (so-called designer cells), which contain exclusively the desired biocatalyst (enzyme) in large amounts. Such designer cells can be used directly in organic synthetic reactions without the need to isolate the enzyme in additional downstream operation steps. The presence of the cofactor in the cells requires no addition of an external amount of cofactors or supply thereof in very low amount only. Due to these advantages, recombinant whole cells overexpressing cofactor dependent enzymes have become very attractive catalysts for asymmetric synthesis. This is underlined by an increasing number of recent organic biotransformations based on the use of such "designer cells."

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Section: Wild-type Whole Cellsmentioning

confidence: 99%

Asymmetric Synthesis with Recombinant Whole‐Cell Catalysts

2016

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“…In some cases the potentially complicating effects of the auxiliary phase and the biocatalyst on each other will have to be avoided. Several studies 14,15 have addressed the issue of complete integration such that reaction and the product recovery step can take place in the same vessel at a compromise pH and temperature. However, the product-rich auxiliary phase may require transport to another vessel for regeneration.…”

Section: Process Structurementioning

confidence: 99%

Future directions for in‐situ product removal (ISPR)

Woodley

Bisschops

Straathof

et al. 2007

J of Chemical Tech & Biotech

135

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This paper summarizes the main findings of a round-table discussion held to examine the key bottlenecks in the further application and industrial implementation of in-situ product removal (ISPR) techniques. It is well established that ISPR can yield great benefits for processes limited by inhibitory or toxic products, as well as unstable products or reactions that are thermodynamically unfavorable. However, several issues for industrial implementation were revealed in the discussion. Most notably implementation will be dependent on (1) research into the appropriate process structure, (2) methods to achieve process robustness, (3) systematic selection methods for separation operations and (4) the nature of the product market. Here, these four issues will be discussed as a basis for future work in this area.

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“…This approach allowed the reaction concentration to be increased from 6 to 40 g/L. The reaction was scaled up to 300 L by utilizing a commercially available agitated fi lter as the reactor which allowed the reaction, product isolation, and resin recycle to be accomplished within a single piece of equipment with overall productivity of 75 g/L/day (Vicenzi et al , 1997 ).…”

Section: Enzymatic Resolution Of α -Methyl -13 -Benzodioxole -5 -Ethmentioning

confidence: 99%

Biocatalysis: Synthesis of Chiral Intermediates for Drugs

Patel

2008

Biocatalysis and Bioenergy

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Large-scale stereoselective enzymatic ketone reduction with in situ product removal via polymeric adsorbent resins

Cited by 104 publications

References 16 publications

Asymmetric Synthesis with Recombinant Whole‐Cell Catalysts

Asymmetric Synthesis with Recombinant Whole‐Cell Catalysts

Future directions for in‐situ product removal (ISPR)

Biocatalysis: Synthesis of Chiral Intermediates for Drugs

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