The PGA Research Group

Byron Peters

Asymmetric hydrogenation of sulfones (Figure 1-A): A variety of cyclic and acyclic unsaturated sulfones were hydrogenated in excellent enantioselectivity and yield (up to 99% ee and 98 % yield). High enantioselectivity was achieved regardless of the position of the olefin (vinylic, allylic or homoallylic); even challenging aliphatic substitutions were tolerated. Furthermore, the saturated nearly optically pure sulfones were treated under the conditions of the Chan modified Ramberg-Bäcklund reaction to generate the corresponding olefin. High E selectivity was obtained for acyclic derivatives and pure Z for cyclic derivatives, producing both cyclic and acyclic unfunctionalised molecules with a-, b- and g-stereogenenic centres to the olefin. ,

sulfone
Figure 1 : Asymmetric Hydrogenation (AH) and Transfer Hydrogenation (ATH); A) AH of unsaturated sulfones combined Ramberg-Bäcklund reaction - methodology. B) AH of heterocyclic substrates.


Asymmetric Hydrogenation of Heterocycles (Figure 1-B): Five-, six- and seven-membered aza-, oxo- and carbocycles, lactones and cyclic ketones were hydrogenated with fantastic enantioselectivity. Many substitution patterns are tolerated including aliphatic groups, generating the saturated derivatives in high enantiomeric excesses (up to 99 % ee). Post hydrogenation modification afforded piperidines and 1,3-substituted lactones in high yields while retaining the optical purity installed in the hydrogenation.

Asymmetric Isomerisation: An Enantioselective Transposition (Figure 2): A highly enantioselective and general protocol for the asymmetric isomerisation reaction has been developed. Only a few rhodium and iridium catalysts are available that are capable of very selectively transforming E-allylic alcohols to the corresponding saturated aldehyde, however, these catalysts often suffer from low selectivity and reactivity on Z- and aliphatic allylic alcohol substrates. In light of this, we have developed a catalyst that is capable of isomerizing E-, Z- and aliphatic allylic alcohols in >99 % ee and respectable yields.

allylic alcohol
Figure 2 : Iridium catalysed asymmetric isomerisation of allylic alcohols


From Allylic Alcohols to Aliskiren (Figure 3): Aliskiren, a widely sought after Renin inhibitor drug is prepared in high yield from a key intermediate. Our synthesis utilised two allylic alcohol fragments, prepared using highly selective protocols to control the geometry about the olefin. These allylic alcohols are subjected to the iridium catalysed asymmetric hydrogenation, furnishing the saturated alcohols in >93 % ee and >91 % yield, providing the necessary chirality at the 2- and 7- position of Aliskiren. These chiral alcohols were then modified and these two fragments joined using an optimised Julia-Kocienski protocol to yield the key intermediate with >99 % E purity about the double bond.   

aliskiren
Figure 3 : Formal synthesis of Aliskiren.


Asymmetric Hydrogenation and the Birch Reduction (Figure 4): In earlier work, we have shown that combining the Birch reduction with the iridium-catalysed asymmetric hydrogenation provides a powerful methodology to prepare minimally functionalised molecules in high enantiomeric excess (up to 99 % ee), an otherwise, extremely challenging task using other existing strategies.
Our current interests are on the functional group tolerance of this methodology, and to use this strategy to prepare commercially useful molecules, that are currently prepared using less elegant, less efficient and more costly protocols.

Previous work

bird

Current work

dvsd

Figure 4 : The Birch reduction as a source of substrates for asymmetric hydrogenation.

References:

1. Zhou, T.; Peters, B. K.; Maldonado, M. F.; Govender, T.; Andersson, P. G. Journal of the American Chemical Society, 2012, 134, 13592-13595.
2. Peters, B. K.; Zhou, T; Rujirawanich, J.; Cadu, A.; Singh, T.; Rabten, W.; Kerdphon; S.; Andersson, P. G. Journal of the American Chemical Society, 2014, 136, 16557–16562.
3. Verendel, J. J.; Li, J.; Quan, X.; Peters, B. K.; Zhou, T.; Gautun, O. R.; Govender, T.; Andersson, P. G. Chemistry-A European Journal, 2012, 18, 6507-6513.
4. Li, J.; Peters, B. K.; Andersson, P. G. Chemistry-A European Journal, 2011, 17, 11143-11145.

5.Peters, B. K.; Liu, J.; Margarita, C.; Andersson, P. G. Chemistry-A European Journal (early view), 2015.