Electrophilic Late Metal Catalysts
Metal Initiated Cation-Olefin Reactivity
One important research direction in the Gagné group focuses on new synthetic methods for complex bond construction. The enzyme Squalene-Hopene Cyclase utilizes the cation-olefin reaction to zip up the poly-ene Squalene into the plant steroid Hopene. Although the enzymatic reaction is proton-initiated, Pd(II) or Pt(II) can similarly activate alkenes towards nucleophilic attack. With a focus on alkene nucleophiles, the notion of replacing the enzyme with a metal catalyst has led to several multicyclization reactions. Below are several Pt(II)-catalyzed cation-olefin reactions. Depending on the ligands, the catalysts can turn over by beta-hydride elimination or other more-unusual mechanisms.
Chianese, Lee, Gagné Angew. Chem. Int. Ed. 2007, 46, 4042-4059.
Enantioselective Oxidative Cyclization of Poly-enes
Chiral P2Pt-dications are capable catalysts for initiating cationic polycyclization reactions. Phenols, alcohols, and sulfonamides are all capable traps for the cation and generate multi-cyclic products with good to excellent enantioselectivities. The turnover-limiting step is beta-hydride elimination, which expels product and generates a putative Pt-hydride. The key to turning over these catalysts is the addition of trityl cation to abstract the hydride and regenerate the dication. Refined conditions utilize trityl-methyl ether as the trityl source. The acid byproduct of cyclization liberates trityl cation and enables turnover. Resin-bound versions of the oxidant also work well. This new reaction is currently the subject of a mechanistic study, and additional variants for applications in synthesis are also ongoing.
Mullen, Gagné J. Am. Chem. Soc. 2007, 129, 11880-11881
Mullen, Campbell, Gagné Angew. Chem. Int. Ed. 2008, 47, 6011-6014
Pincer and Pseudo-Pincer Catalysts for Cation-Olefin Chemistry (inhibition of β-H elimination)
When pincer ligands are utilized to coordinate Pd(II) and Pt(II), extremely electrophilic catalysts can be accessed which don’t β-H eliminate (lack of cis coordination sites). This property enables unique cyclopropanative cycloisomerization processes wherein dienes are stereoselectively converted into bicyclopropanes. A recent improvement of the first-generation triphos-based catalysts uses a modular combination of bi and monodentate ligands to yield the dppm/PMe3 catalyst, which is the most active catalyst, and the xyl-BINAP/PMe3 catalyst, which is also enantioselective.
Feducia, Gagné, J. Am. Chem. Soc. 2008, 130, 592-599
Feducia, Campbell, Doherty, Gagné J. Am. Chem. Soc. 2006, 128, 13290-13297
Kerber, Gagné, Org. Lett. 2005, 7, 3379-3381
Gold(I)-Catalyzed Allene Activation Reactions
The above reactivity is made possible by the selective activation of less substituted alkenes over more substituted alkenes by Pt(II) catalysts. This enables the terminus to be activated for nucleophilic attack by the alkene to kick off the cation-olefin reaction. We find that Au(I) can similarly activate allenes in the presence of other forms of unsaturation to initiate similar cation-olefin reactions. Several recent studies have shown that allene-initiated cycloisomerization reactions are possible when the nucleophile is either an alkene or an arene. We think these reactions proceed via ionic intermediates. Current efforts are focused on examining the scope of allene reactions and examining alternative carbon and heteroatom nucleophiles.
Tarselli, Chianese, Lee, Gagné, Angew. Chem. Int. Ed. 2007, 46, 6670-6673
Tarselli, Gagné, J. Org. Chem. 2008, 73, 2439-2441