Asymmetric hydrogentation of unfunctionalised olefins/enamines/imines
The reaction survey found that the predominant strategy for the introduction of chirality was through classical chemical resolutions as opposed to introductions through biotransformation or transition metal or organometallic catalytic means.
Asymmetric hydrogenation provides an elegant methodology for the introduction of chirality, meeting many of the goals of green chemistry and is finding increasing application in API synthesis.47
The efficiency of this approach is elegantly exemplified by the Merck second generation synthesis of sitagliptin 5 (Scheme ), where an unprecedented final stage asymmetric hydrogenation of the unprotected enamide 6 resulted in an increase in overall yield of almost 50% and produced 100 kg less waste per kg sitagliptin48 when compared with the first generation approach.49
|Scheme The synthesis of sitagliptin.|
There are challenging areas remaining within the field, for example, the hydrogenation of enamides and related substrates in the synthesis of amino acids has numerous examples50 but few examples exist for unsubstitued enamines41 and imines. Some classes of alkene offer additional challenges.51 For the pharmaceutical industry, the limited time for synthetic route identification is an issue and access to catalyst and ligand diversity is required to ensure the application of this approach.52
Some pharmaceutical companies have synthesised their own ligands and have found very effective catalysts.53 The majority of academic asymmetric hydrogenation approaches are based on homogeneous catalysis to overcome issues of activation and mass transfer. For pharmaceutical use, efficient catalyst and ligand recovery, and eliminating heavy metal contamination of the API are significant requirements for the industry.
These controls are often easier to achieve with heterogeneous methodology where there are less examples.50 The demonstration of organocatalytic hydride transfer offers the possibility of future access to metal free asymmetric hydrogenations.54
- 47………V. Farina, J. T. Reeves, C. H. Senanayake and J. J. Song, Chem. Rev., 2006, 106, 2734–2793. See also Asymmetric Catalysis on Industrial Scale Challenges, Approaches and Solutions, ed. H.-U. Blaser and E. Schmidt, Wiley-VCH, Weinheim, 2004 Search PubMed .
- 48………..http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa06.html .
- 49……K. B. Hansen, J. Balsells, S. Dreher, Y. Hsiao, M. Kubryk, M. Palucki, N. Rivera, D. Steinhuebel, J. D. Armstrong III, D. Askin and E. J. J. Grabowski, Org. Process Res. Dev., 2005, 9, 634–639 Search PubMed .
- 50………..M. Studer, H.-U. Blaser and C. Exner, Adv. Synth. Catal., 2003, 345, 45–65 CrossRef CAS Search PubMed .
- 51……..X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272–3296 CrossRef CAS Search PubMed
- 52……….I. C. Lennon and C. J. Pilkington, Synthesis, 2003, 1639–1642 CrossRef CAS Search PubMed .
- 53………G. Hoge, H.-P. Wu, W. S. Kissel, D. A. Plum, D. J. Greene and J. Bao, J. Am. Chem. Soc., 2004, 126, 5966–5967 CrossRef CAS Search PubMed .
- 54……..H. Adolfsson, Angew. Chem., Int. Ed., 2005, 44, 3340–3342 CrossRef CAS Search PubMed .