Metallocene ligands

Most of our work in this area is based on the diastereoselective lithiation of ferrocenyloxazoline 1, and using this methodology we were the first to report1 (just!)2a,b the synthesis of phosphinoferrocenyloxazoline 2. This ligand has been exploited widely in asymmetric catalysis and is commercially available. Related C2-symmetric planar chiral ferrocene derivatives are available from (S,S)-3 using similar methodology.3

CJR6a

Available from (S)-1 in three steps (86% overall yield) is planar chiral building block (Sp)-4. This has been used for the synthesis of a number of chiral phosphine ligands including C3-symmetric TomPhos (Sp,Sp,Sp)-5.4

CJR7a

Chirality pairing and ligand epimer synthesis
The objective when generating a new element of chirality is to achieve high stereoselectivity, as illustrated above by the almost exclusive generation of (S,Sp)-2. As a consequence of this selectivity, its epimer, (S,Rp)-2, is essentially unexplored as a ligand for asymmetric catalysis. This difference in availability and utilisation applies to most ligands containing two or more chirality elements,  such that matched and mismatched pairings are rarely identified, and the potential of the better ligand may be missed.

Epimeric (S,Rp)-2 has been generated by use of a TMS blocking group which is readily removed following a second lithiation and introduction of the phosphine.5

CJR8

Many commercially available ferrocene ligands are derived from Ugi’s amine which undergoes highly diastereoselective lithiation leading to products of general structure (R,Sp)-6. Epimers are now available from key building block (Sp)-4 following oxidation and Grignard addition to the resultant aldehyde. The starting planar chirality controls the formation of the new stereogenic centre with high selectivity, and stereospecific introduction of dimethylamine provides epimeric (S,Sp)-6.6

CJR9

Overall these methods enable the synthesis of numerous ligands with a full exploration of stereochemical space. This will aid ligand optimisation for numerous metal catalysed reactions, and help in the understanding of the relationships between reactivity and selectivity with catalyst structure.

1. C. J. Richards, T. Damalidis, D. E. Hibbs and M. B. Hursthouse, Synlett 1995, 74.
2. (a) Y. Nishibayashi and S. Uemura, Synlett 1995, 79. (b) T. Sammakia and H. A. Latham, J. Org. Chem. 1995, 60, 10.
3. A. J. Locke, T. E. Pickett and C. J. Richards, Synlett 2001, 141.
4. T. E. Picket, F. X. Roca and C. J. Richards, J. Org. Chem. 2003, 68, 2592.
5. C. J. Richards and A. W. Mulvaney, Tetrahedron: Asymmetry 1996, 7, 1419.
6. C. J. Taylor, F. X. Roca and C. J. Richards, Synlett 2005, 2159.