[novel kinetic resolutions | parallel catalysis | biocatalysis for desymmetrizations]

Kinetic Resolution Route of Exocyclic Alkenes

Several kinetic resolutions of varying effectiveness have been reported using Sharpless' asymemtric dihydroxylation chemistry.[1,2] As a route to novel chiral diols, and also as a mechanistic study, we considered AD of systems which possess large substituents close to an exocyclic alkene which are unusual substartes that may challenge the AD mechanism.[2]

We have found that kinetic resolution of the alkenes 1 provides a route to novel chiral diols (3 or 4) in high optical purity. From the four possible diastereomers, achiral dihydroxylation provides only a single diastereomer derived from only one of the two enantiomeric pairs of alkenes (i.e. alkene 2 is completely unreactive!), and the same diastereomer is obtained by AD reactions. AD using (DHQ)2PHAL provides a single enantiomeric diol (ee>97%) at up to 40% conversion - only one of the eight possible enantiomers shown that could arise from this reaction is obtained! AD using (DHQD)2PHAL is also effective, providing diols of up to 86% ee, and using a double resolution strategy, this diol is also obtained optically pure.[4]

This provides the most efficient kinetic resolution yet reported using the AD ligand series.

NMR experiments on derivatives of these diols, and also of several related compounds have allowed assignment of the diastereomeric structure of the diol, and an X-ray structure has been solved for the diol itself, confirming these stereochemical assignments.

We have also now (2005) shown some valubale conversions of these novel diols towards complex multi-chiral targets,[5] and aim to exploit this further.

1. VanNieuwenhze, M. S.; Sharpless, K. B. J. Am. Chem. Soc., 1993, 115, 7864.

2. (a) Hawkins, J. M.; Meyer, A. Science, 1993, 260, 1918. (b) Lohray, B. B.; Bhusan, V. Tetrahedron Lett., 1993, 34, 3911. (b) Jefford, C. W.; Timári, G. J. Chem. Soc., Chem. Commun., 1995, 1501. (c) Corey, E. J.; Noe, M. C.; Guzman-Perez, A. J. Am. Chem. Soc., 1995, 117, 10817. (d) F. J. A. D. Bakkeren, A. J. H. Klunder and B. Zwanberg, Tetrahedron , 1996, 52, 7901.

3. (a) Symmetric 'binding cleft' model involving quinoline face-to-face p-interactions: Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc., 1995, 117, 10805. (b) quinoline 'active site' floor and a quinoline 'wall' available for face-to-edge stabilisation: Norrby, P.-O.; Becker, H.; Sharpless, K. B. J. Am. Chem. Soc., 1996, 118, 35 and refs therein.

4. (a) Gardiner, J. M.; Nørret, M.; Sadler, I. H. Tetrahedron Lett. 1996, 37, 8447. (b) Gardiner, J. M.; Nørret, M.; Sadler, I. H. J. Chem. Soc., Chem. Commun., 1996, 2709.


5. Gardiner, J. M.; Nayd, M. unpublished 2005.
Parallel Catalyst Discovery
Research sponsored by GlaxoSmithKline
This research has been developing methodology to generate novel chiral ligand libraries from inexpensive chiral natural products sources.

Parallel synthesis has generate novel ligands, and initial catalyst activity screening has identified nove ligands which can catalyze an asymmetric C-C bond forming reaction in up to 95% enantiomeric selectivity.

 

J. M. Gardiner, P. D. Crewe, G. E. Smith, K. T. Veal. Novel Isomenthone-derived 1,3-diol ligands identified through parallel synthesis and screening catalyse an asymmetric aldol reaction " Chem. Commun. 2003, 618-619.

J. M. Gardiner, P. D. Crewe, G. E. Smith, K. T. Veal, R. G. Pritchard, J. E. Warren. Synthesis, stereostructure and conformations of novel bi- and trifunctional (+)-isomenthone derivatives. Organic Lett. 2003, 5, 467-470.
Novel Enzyme Catalyzed Desymmetrizations
The synthesis of enantio-enriched materials can be achieved by some enzyme classes by desymmetrizing meso or prochiural compounds. These compounds all have two identical functional groups, but if ONE is selectively transformed, the symmetry is 'broken' and a chiral compound is obtained. This is a fast way to chiral metrials, but chemical methods are almost without exception unable to bring about such reactions. Some types of enzymes, however, can do this. They do however have substrate structure limiations.


We have been using parallel enzyme screening and have identified enzymes and conditions to effect desymmetrizations on a category of hindered quaternary substrate. These have not been transformed previously, and we now have conditions to provide high yields of enantiomerically enriched materials of >99% e.e. This provides not only an unusually valuable potential biotransformation, but the opportunity to try to understand why our substrates are so selectively ransformed as there is crystal strcuture informaiton on the enzymes allowing us in future to do some detailed modelling.

We are now applying this to synthesis of novel chiral building blocks (amino acids, target N-heterocycles) as well as evaluating the full scope of the desymmetrizations on related substrates (all novel). Some molecular modelling has also been udnertaken to rationalize the extraordinary selectivity observed with our substrates.