The world of organocatalysis

Organocatalysis and Photoredox Catalysis

Ξ October 12th, 2008 | → 0 Comments | ∇ Photoredox catalysis, organocatalysis and redox catalysis |

 

Merging Photoredox Catalysis with Organocatalysis: The Direct Asymmetric Alkylation of Aldehydes

David A. Nicewicz and David W. C. MacMillan

Science 322, 77 (2008)

 

Here I report a MacMillan’s paper recently published in Science: the paper regards the asymmetric alkylation of aldehydes by means of both organocatalysis and photoredox catalysis.

Nature’s ability to convert solar energy to chemical energy in photosynthesis has inspired the development of a host of photoredox systems in efforts to mimic this process. The most studied one-electron photoredox catalyst has been Ru(bpy)₃²⁺ : an inorganic complex that has facilitated important advances in the areas of energy storage, hydrogen and oxygen evolution from water, and methane production from carbon dioxide.

 

Over the last years, the organocatalytic methods are grown at a dramatic pace; now chemists are able to make 130 chemical reactions by means of organocatalysis. Recently, MacMillan’s research group introduced the concept of organo– singly occupied molecular orbital (SOMO) catalysis, a one-electron mode of activation that has enabled the development of several useful transformations.

Given the widespread success of both electron transfer catalysis and organocatalysis, MacMillan’s group recently questioned whether it might be possible to merge these two powerful areas, with the goal of solving long-standing, yet elusive problems in chemical synthesis.

They hypothesized that the enantioselective catalytic a-alkylation of aldehydes, could be carried out by the marriage of inorganic electron transfer and organic catalysis.

 

They proposed that two catalytic cycles might be engineered to simultaneously generate an electron-rich enamine (8) from the condensation of an aldehyde and an amine catalyst and an electron-deficient alkyl radical (5) via reduction of an alkyl bromide with a Ru photoredox catalyst. Given that electron-deficient radicals are known to rapidly combine with elettronrich olefins to forge even the most elusive C–C bonds, we hoped that this dual-catalysis mechanism would successfully converge to enable the direct coupling of aldehydes with alpha-bromo ketones or esters.

 

It has long been established that Ru(bpy)₃²⁺ (1) will readily accept a photon from a variety of light sources to populate the *Ru(bpy)₃²⁺(2) metal-to-ligand charge transfer (MLCT) excited state. This high-energy intermediate would efficiently remove a single electron from a sacrificial quantity of enamine, to initiate our first catalytic cycle and provide the electron-rich Ru(bpy)₃⁺ (3). Given that Ru(bpy)₃⁺ (3) has been shown to be a potent reductant, we anticipated that single-electron transfer (SET) to the alpha-bromocarbonyl substrate 4 would rapidly furnish the electron-deficient alkyl radical 5 while returning Ru(bpy)₃²⁺ (1) to the catalytic cycle.
Concurrent with this photoredox pathway, the organocatalytic cycle would begin with condensation of the imidazolidinone catalyst 6 and the aldehyde substrate 7 to form enamine 8. At this stage, we expected the two catalytic cycles to intersect via the addition of the SOMOphilic enamine 8 to the electron-deficient alkyl radical 5, thereby achieving the key alkylation step. This coupling event would concomitantly produce an electron-rich a-amino radical 9, a single-electron species that has a low barrier to oxidation. Once again, convergence of our catalytic cycles should ensure SET from alpha-amino radical 9 to the *Ru(bpy)₃²⁺ (2) excited state to produce the iminium ion 10 and regenerate the active reductant, Ru(bpy)₃⁺ (3), a step that would close the photoredox cycle (24).
Hydrolysis of the resulting iminium 10 would reconstitute the amine catalyst 6 while delivering the requisite enantioenriched alpha-alkyl aldehyde product.

With respect to operational convenience, it is important to consider that this alkylation protocol does not require any heating or cooling, all of the components employed in this study (substrates, catalysts, and solvents) are commercially available and inexpensive, and a simple household 15-W fluorescent light bulb can be employed as a suitable light source.