Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate.

J Org Chem 2013 Apr 1;78(8):3592-615. Epub 2013 Apr 1.

Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./PO BOX 368, Ridgefield, Connecticut 06877-0368, USA.

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.

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Source
http://pubs.acs.org/doi/10.1021/jo400080y
Publisher Site
http://dx.doi.org/10.1021/jo400080yDOI Listing
April 2013
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