Early work focused on the application of pincer palladacycles as catalysts for the asymmetric Michael reaction to give product 1 containing a quaternary stereogenic centre.1 Here palladium activates the nitrile through coordination, and rapid ligand exchange prevents product inhibition of the catalyst such that a low loading may be employed.
Palladacycle activation of alkenes by coordination has been exploited in the allylic imidate rearrangement (also known as the Overman rearrangement).2 Initially as a collaboration with Overman, it was established that a chloride-bridged Cobalt Oxazoline Palladacycle B (COP-Cl) is an excellent catalyst for the synthesis of N-aryl allylic trifluoroacetamides 2 in high ee.3
Later independent work focused on the minimisation of the catalyst loading for the synthesis of allylic trichloroacetamides, with just 0.25 mol% of B providing a practical method for the generation of multigram quantities of enantioenriched product, as exemplified below for 3.4 These rearrangements are also catalysed by silver salt activated Cobalt Amine Palladacycle C (CAP-Cl), this resulting in 3 as essentially a single enantiomer, albeit using a higher catalyst loading.5
A cobalt sandwich complex has also been exploited as the basis of nucleophilic catalyst D, in which the chirality of the 4-pyrrolidino group is relayed through to the pyridine nitrogen, the centre of reactivity. This is an active catalyst for the asymmetric Steglich rearrangement of O-acylated azlactones to give 4 in up to 76% ee.6 This chemistry has been extended for the asymmetric synthesis an oxindole precursor to pyrroloindoline alkaloids such as physostigmine.7 The related C2-symmetric nucleophilic catalyst E has also been synthesised, and with this enantioenriched alcohols and esters such as 5 and 6 were obtained by kinetic resolution.8
Serine derived ligands
A modular approach to oxazoline-based N-O and N-P ligands starts with (R) or (S)-serine, from which R, R’ and R” groups are introduced readily.9 The alcohol containing ligands F have been applied to the generation of (R)-7 by diethylzinc addition to benzaldehyde, and on combination with palladium the phosphinite ligands G give (S)-8 in up to 96% ee by allylic alkylation.10
Asymmetric Catalyst Efficiency (ACE)
This simple formula provides a numerical descriptor of the efficiency of a catalysed asymmetric reaction. It is based on the premise that a catalyst is more efficient if fewer atoms are utilised to give a product in a required enantiomeric excess. It permits the comparison of a diverse range of catalysts, including enzymes, and provides an additional perspective with which to view catalyst utility.11
1. M. A. Stark, G. Jones and C. J. Richards, Organometallics 2000, 19, 1282.
2. Review: H. Nomura and C. J. Richards, Chem. Asian J. 2010, 5, 1726.
3. L. E. Overman, C. E. Owen, M. M. Pavan and C. J. Richards, Org. Lett. 2003, 5, 1809.
4. H. Nomura and C. J. Richards, Chem. Eur. J. 2007, 13, 10216.
5. D. J. Cassar, G. Ilyashenko, M. Ismail, J. Woods, D. L. Hughes and C. J. Richards, Chem. Eur. J. 2013, 19, 17951. [open access]
6. D. C. D. Butler, H. V. Nguyen and C. J. Richards, Org. Lett. 2006, 8, 769.
7. M. Ismail, H. V. Nguyen, G. Ilyashenko, M. Motevalli and C. J. Richards, Tetrahedron Lett. 2009, 50, 6332.
8. H. V. Nguyen, M. Motevalli and C. J. Richards, Synlett 2007, 725.
9. G. Jones and C. J. Richards, Tetrahedron Lett. 2001, 42, 5553.
10. G. Jones and C. J. Richards, Tetrahedron: Asymmetry 2004, 15, 653.
11. S. El-fayyoumy, M. H. Todd and C. J. Richards, Beil. J. Org. Chem. 2009, 5, No. 67. [open access]