Biocatalytic cascade reactions for the synthesis of optically active compounds

Abstract

Biocatalysis offers tremendous advantages to generate complex chiral compounds in high enantiomeric purity and yield. The exquisite catalytic efficiency, mild conditions, and regenerative production offered by enzymes is enabling the development of new and more step-economical routes that generate less waste than conventional organic synthesis. Moreover, the intrinsically biodegradable and highly selective properties of biocatalysts are combined with the fact that they are compatible with each other and catalysts of different nature, within certain range of operating conditions. Thus, various attempts have been made to develop new multi-catalytic cascade reactions in vitro, by emulating the multi-step synthetic routes built in living organisms. For these reasons, these cascade transformations have emerged as a good alternative in the academic and industrial sectors, for the synthesis of optically active compounds as building blocks for pharmaceuticals. This doctoral thesis is presented as a main introduction and three chapters. Several kinds of catalysts (biocatalysts, organocatalysts and metal catalysts) have been studied in order to perform various chemical reactions, as transamination, reduction, oxidation, nitrile hydration, and nitrile hydrolysis. Then, different multi-catalytic methods in concurrent or sequential fashion have been developed for the synthesis of interesting optically active compounds: 2-hydroxycycloalkanecarboxylic acids, β-hydroxy amides, β-amino alcohol derivatives, amines, alcohols, and diols; that is, compounds that can be used as building blocks for pharmaceuticals. In Chapter 1, purified enzymes as ketoreductases and whole cells of Rhodococcus rhodochrous have been used in a genuine cascade process for the synthesis of optically pure 2-hydroxycycloalkanecarboxylic acids. In all the cases, the final compounds have been obtained in enantiomerically pure form and with excellent diastereomeric ratio and yield. Moreover, a new protocol for the synthesis of optically pure (1R,2S)-2-hydroxycyclohexanecarboxyamide has also been determined, but an incomplete inhibition of the amidase activity of the microorganism resulted in a detraction of the final yield. In order to overcome this limitation, in Chapter 2 we developed a multi-catalytic methodology for the synthesis of optically pure β-hydroxy amides starting from easily accessible and commercially available β-ketonitriles. Thus, the tandem action of a Ru(IV) catalyst and a ketoreductase allowed the synthesis of the desired compounds in excellent yields. Also β-ketonitriles bearing a chiral centre have been investigated and an efficient dynamic reductive kinetic resolution yielded the final compounds with perfect diastereomeric ratios. This contribution represents a valid example of compatibility between metals and enzymes in water, without need of separation or compartmentalization. Finally, in Chapter 3, a new hybrid methodology for the synthesis of interesting amino alcohols, amines, alcohols and diols has been investigated. The core of this project was the development of a highly efficient AZADO-catalyzed oxidation of easily available racemic alcohols using NaOCl in water. Thus, once the prochiral ketone was quantitatively obtained, the subsequent action of a transaminase or a ketoreductase allowed the synthesis of optically active amines or alcohols, respectively, with excellent enantiomeric excesses, yields and diastereomeric ratios (when applicable). A good part of the work presented here has resulted in the following three publications. • E. Liardo, N. Ríos-Lombardía, F. Morís, J. González-Sabín, F. Rebolledo. “Developing a Biocascade Process: Concurrent Ketone Reduction-Nitrile Hydrolysis of 2-Oxocycloalkanecarbonitriles” Org. Lett., 2016, 18, 3366-3369. • E. Liardo, N. Ríos-Lombardía, F. Morís, F. Rebolledo, J. González-Sabín. “Hybrid Organo- and Biocatalytic Process for the Asymmetric Transformation of Alcohols into Amines in Aqueous Medium” ACS Catalysis, 2017, 7, 4768-4774. • E. Liardo, N. Ríos-Lombardía, F. Morís, J. González-Sabín, F. Rebolledo. “A Straightforward Deracemisation of sec-Alcohols Combining Organocatalytic Oxidation and Biocatalytic Reduction” Eur. J. Org. Chem., accepted article. http://dx.doi.org/10.1002/ejoc.201800569.