ABSTRACT
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.
Subject(s)
Boronic Acids/chemistry , Hydrocarbons, Fluorinated/chemistry , Ketones/chemistry , Pargyline/analogs & derivatives , Pargyline/chemistry , Proline/analogs & derivatives , Proline/chemistry , Zinc/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
A concise preparation of the pheromone secreted by the female longtailed mealybug [viz., 2-(1,5,5-trimethylcyclopent-2-en-1-yl)ethyl acetate] (1) is described. The key step in the synthesis of 1 involves 5-exo-trig ring closure of the vinyllithium derived from (Z)-1-iodo-4,4,5-trimethyl-1,5-hexadiene by lithium-iodine exchange.
