User:Lupophilus/sandbox/Asymmetric Isomerization of Allylic Amines

The asymmetric isomerization of allylic amines into enamines is a methodology allowing for the establishment of chiral centers in organic molecules. The reaction can be catalyzed by several transition metals, but the most effective conditions utilize cationic rhodium catalyst. This reaction finds industrial application by the Takasago company to produce (–)-menthol.

Cobalt catalysis
First work in the isomerization of allylic amines was conducted with cobalt catalyst. Desired because at the time citronella type molecules were expensive and aliphatic chiral centers are hard. Difficulties involve trisubbed bonds and Reversible reactions were a concern as catalyst would have to distinguish the faces very well. Some previous examples suggested Co might be good at the isomerization.(ref 9 in ref 3)

The reaction was able to produce product but measureable ee, but not enough to be practically useful or without major amounts of byproduct. By using a secondary amine cyclohexylgeranylamine, more reactive and gave the desired imine in good yield and ee. However, still not quite good enough to be practically useful.

Rhodium
It was ultimately decided that Co wouldn't work despite considerable effort. A brief stint with Fe and Ni met the same fate. Ultimately, the team started looking toward Pd and Rh due to increased stability of chiral information. Rh(I) was favored due to existing projects in the Osaka lab.

Cationic rhodium catalyst with BINAP ligand does very well. BINAP works well because they found that alkyl groups were bad, having an amine was bad, and the others were bad too. BINAP could also stay on the metal better and its C2-ness led to good things. The reactions proceed in remarkably high yields and selectivities. The use of geometrically pure starting material is critical.



This reaction has been demonstrated on a wide variety of allylic amines to produce optically active aldehydes. The figure below is going to show some of the large substrate scope.



Mechanistic work
Isotope labeling studies suggests things about kinetics and steps

(Picture of mechanism)

Most importantly, explain why the enantioselectivity is observed. Complicated "3-d" model to explain selectivity

Takasago menthol synthesis
A rhodium catalyzed enantioselective isomerization is the key stereodetermining step in the production of (–)-menthol by Takasago International Corporation. This process represents the world's largest application of homogenous asymmetric catalysis. The enantiomeric purity of (R)-citronellal obtained by this method is greater than the natural product which is 80% ee. The catalyst has approximately 8000 turnovers in 18 hours and can be efficiently recycled.

(add m back into image to make it work again)