Biocatalysis enantioselective synthesis

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

Hudlicky T, Reed JW (2009) Celebrating 20 years of SYNLETT - special account on the merits of biocatalysis and the impact of arene cis-dihydrodiols on enantioselective synthesis. Synlett 2009 685-703... 

In Chapter 2, the two methods of enantioselective biocatalysis have been introduced Asymmetric synthesis and kinetic resolution. 

Brussee, J., Van der Gen, A. Biocatalysis in the Enantioselective Formation of Chiral Cyanhydrins, Valuable Building Blocks in Organic Synthesis. In Stereoselective Biocatalysis, Patel, R. N. Ed., Dekker New York, 2000, p. 289. 

Microreactor technology offers the possibility to combine synthesis and analysis on one microfluidic chip. A combination of enantioselective biocatalysis and on-chip analysis has recently been reported by Beider et al. [424]. The combination of very fast separations (<1 s) of enantiomers using microchip electrophoresis with enantioselective catalysis allows high-throughput screening of enantioselective catalysts. Various epoxide-hydrolase mutants were screened for the hydrolysis of a specific epoxide to the diol product with direct on-chip analysis of the enantiomeric excess (Scheme 4.112). 

Buchholz, S., and Groger, H. 2006. Enantioselective biocatalytic reduction of ketones for the synthesis of optically active alcohols. In Patel, R. N. (Ed.), Biocatalysis in the Pharmaceutical and Biotechnology Industries (pp. 757-790). Boca Raton FL CRC Press. 

Epoxide formation using biocatalysis is a useful process for the formation of chiral oxiranes (Scheme 29). The synthesis of enantioenriched epoxides using enzymes has been reviewed <1995BCSF769>. Chloroperoxidase has been examined for the oxidation of 2-methyl-l-alkenes, among other alkenes. The yields in some cases can be low, but the enantioselectivities can be high <1995JA6412, 1997JA443>. This enzyme has been used in a synthesis of... 

At present, the resolution of racemates via dassical diastereomer crystallization as a method of chiral target production is somewhat hampered by a rapid development of other methods, mainly asymmetric synthesis, including biocatalysis [9] and enantioselective chromatography [11], Diastereomer crystallization remains, however, an important technique because of its two fundamental advantages, especially attradive for industry. First, process development (practical know-how and accessibility to wide libraries of the resolving agents) is usually fast and easy. Second, the cost is often low compared to other methods. 

Knowles [1] and Homer [2] independently discovered homogeneous asymmetric catalysts based on rhodium complexes bearing a chiral monodentate tertiary phosphine. Continued efforts in this field have produced hundreds of asymmetric catalysts with a plethora of chiral ligands [7], dominated by chelating bisphosphines, that are highly active and enantioselective. These catalysts are beginning to rival biocatalysis in organic synthesis. The evolution of these catalysts has been chronicled in several reviews [8 13]. 

Brusse J, vrm der Gen A (2000) Biocatalysis in the enantioselective formation of chiral cyanohydrins, vrduable building blocks in organic synthesis. In Patel RN (ed) Stereoselective biocatalysis. Marcel Dekker, New York/Basel, pp 289-320... 

These earlier studies on stereochemistry-JH activity relationships indicated that the synthesis of extremely pure enantiomers of JHs would allow us to determine the relationships accurately. We therefore started our enantioselective JH synthesis based on biocatalysis. 

Whereas biocatalysis previously was a last option that was only looked into when all other synthetic methods had failed, it is now a discipline well integrated into classical organic synthesis in the pharma-, agro-, and fine chemical industries [2]. An example from the latter group is laboratory chemicals producer Fluka, which has reported over 100 biocatalytic processes in routine production [3]. Biocatalysis can offer outstanding chemo-, regio- and/or enantioselectivities under mild reaction conditions. It is, hence, often used to create chirality, for example, in the pharma industry [4]. 

While most of the syntheses of hyacinthacines are based on the modification and elaboration of precursors from the chiral pool, less effort has been directed toward the construction of the pyrrolizidine skeleton using non-natural precursors. This chapter summarizes racemic as well as enantioselective total synthesis of hyacinthacines reported to date, which start from nonchiral pool sources. In this context, biocatalysis constitutes the most widely used alternative to the chiral pool approach. Enzymatic kinetic resolution using lipases but also aldolase-mediated reactions have been successfully employed to provide precursors that were later elaborated toward hyacinthacines. Synthetic chiral auxiliaries have also been used successfully in this context. 

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