Asymmetric Catalysis
Application of Metallacycles
Nucleophilic Catalysis
Ligand Diversity

DMAP (dimethylaminopyridine) 1 is a ubiquitous nucleophilic catalyst that is used to accelerate many common organic transformations. Recently several chiral DMAP equivalents such as 2 and 3 have been reported that enable reactions, such as the kinetic resolution of 4, to be carried out with a high selectivity factor s. However neither these or other the chiral DMAP equivalents are especially accessible (the generation of 2 is complex, and both of these systems require resolution techniques such as semi-preparative HPLC).

Our approach to this problem avoids the issue of catalyst resolution by incorporating readily available sources of chirality into heterocycles where the asymmetric environment of the nucleophilic nitrogen (N) is controlled by attachment to a bulky cobalt metallocene. The basis of this approach was first demonstrated with imidazole 5, for which the conformer revealed in the X-ray crystal structure is also dominant in solution, placing this heterocycle in an environment of virtual planar chirality.1
X-ray crystal structure of 5 (R = t-Bu).
This approach has been extended to DMAP itself, with the synthesis of cobalt metallocene appended derivative 6 in three steps from commercially available (S,S)-2,5-hexanediol.2 The C2-symmetric derivative 7 is similarly available.3 Preliminary investigations have revealed 6 to be an enantioselective catalyst for the Steglich rearrangement (up to 76% ee), and 7 to be applicable to the kinetic resolution of secondary alcohols (s = 6).
[1] G. Jones and C. J. Richards, Organometallics, 2001, 20, 1251. [2] H. V. Nguyen, D. C. D. Butler and C. J. Richards, Org. Lett. 2006, 8, 769. [3] H. V. Nguyen, M. Motevalli and C. J. Richards, Synlett, 2007, 725.