Design of artificial metabolism/cascades
By creating an artificial cascade, transformations can be established that are not easily realized by using chemical methodology. For instance, the deracemisation of racemic sec-alcohols was accomplished, yielding a single alcohol enantiomer with up to >99% yield and >99% optical purity in one pot via an enantioselective oxidation and a stereoselective reduction (Angew. Chem. Int. Ed. 2008, 47, 741-745; J. Am. Chem. Soc. 2008, 130, 13969–13972):
By biocatalytic formal reductive amination ketones were transformed in an asymmetric fashion to the corresponding optically pure α-chiral primary amines employing three enzymes (Angew. Chem. Int. Ed. 2008, 47, 9337–9340). With this approach various optically pure amines could be prepared which serve as intermediates for the preparation of bioactive compounds (Org. Lett. 2009, 11, 4810-4812; ChemCatChem 2010, 2, 73-77; Adv. Synth. Catal. 2011, 353, 3227-3233; Eur. J. Org. Chem. 2012, 1003–1007).
For the preparation of a non-natural amino-acid – phenyl glycine – from racemic mandelic acid a redox-neutral metabolism was designed employing three different enzymes. The cascade consisted of three steps: a racemisation, an enantioselective oxidation and a stereoselective reductive amination (Adv. Synth. Catal. 2010, 352, 993–997). It has to be noted that although the metabolism involves two redox-steps, the overall transformation is redox-neutral, since the NADH formed in the oxidation step is consumed in the reductive amination; thus no external redox-reagents are required.
Simultaneously combining redox enzymes in artificial metabolism is in most cases easier than combining a redox-active metal catalyst with a redox enzyme. Nevertheless, for the proof of concept an Ir-catalyst was combined with an alcohol dehydrogenase to achieve deracemization of chlorohydrins. A challenge for the system was the identification of a suitable oxidation agent for the oxidation step which could be combined with the ADH without interference (Chem. Commun. 2010, 46, 8046–8048).
- J. H. Schrittwieser, J. Sattler, V. Resch, F. G. Mutti, W. Kroutil, Curr. Opin. Chem. Biol 2011, 15, 249.
- E. Ricca, B. Brucher, J. H. Schrittwieser, Adv. Synth. Catal. 2011, 353;2239.
Enzyme-triggered domino reactions:
Reactions proceeding through more than a single step in a concurrent fashion are generally denoted as domino or cascade reactions. Despite the fact that they may proceed via a highly reactive, unstable intermediate (which often eludes isolation), the final product often can be isolated in good yields. This is due to the fact that decomposition of the intermediate is largely suppressed since it is transformed in the same instant as it appears and is never present in measurable concentrations.
By making use of the stereoselectivity of enzymes, cascade reactions can be rendered asymmetric, if the first reaction step within the cascade is ‘triggered’ by a biocatalyst. Thus, the final product can be obtained in nonracemic form. In an exploratory project we have investigated the possibility to use enzymes for the initiation of asymmetric cascade reactions. In the meantime, we have managed to control a biohydrolysis–rearrangement cascade of haloalkyl- and bis-epoxides. The cascade was triggered by an epoxide hydrolase to furnish the corresponding vic-diol, which spontaneously underwent cyclisation to form an epoxy-alcohol or a tetrahydrofurane in high d.e. and e.e. as the sole product. Depending on the type of substrate, the ‘generation’ of up to four chiral centers could be simultaneously controlled. Traditional methodology can only dream of such highly complex reactions!
Fascinated by the simplicity to generate highly functionalised molecules, we employed this methodology to the chemo-enzymatic asymmetric total synthesis of several bioactive molecules, such as terpenoids and anti-tumor agents, etc. The next goal is the synthesis of the central core of a large group of bioactive agents (termed ‘Annonaceous acetogenins’) from tropical plants.
- S. F. Mayer, W. Kroutil, K. Faber, Chem. Soc. Rev. 2001, 30, 332–339.
- S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, Eur. J. Org. Chem. 2001, 4537–4542.
- S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, Tetrahedron: Asymmetry 2001, 12, 41–43.
- S. F. Mayer, A. Steinreiber, M. Goriup, R. Saf, K. Faber, Tetrahedron: Asymmetry 2002, 13, 523–528.
- S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, J. Org. Chem. 2002, 67, 9115–21.
- S. M. Glueck, W. M. F. Fabian, K. Faber, S. F. Mayer, Chem. Eur. J. 2004, 10, 3467–78.