A Two-Catalyst Photochemistry Route to Homochiral Rings

See allHide authors and affiliations

Science  25 Apr 2014:
Vol. 344, Issue 6182, pp. 368-369
DOI: 10.1126/science.1252965

Many biologically active compounds used in medicine and agriculture are still produced as a racemic mixture, even though only one isomer is actually active. The presence of the inactive isomer can lead to unwanted side effects. The efficient synthesis of only one stereoisomer—homochiral molecules—is a key goal in organic synthesis (1). Synthesizing homochiral molecules with light and a photocatalyst has been an unmet challenge for many years (2), yet the combination of light and catalysis to create chiral products is a hallmark of photosynthesis. On page 392 of this issue, Du et al. (3) report an efficient chiral selection by combining a transition-metal photocatalyst with a stereocontrolling cocatalyst. They obtained four-membered rings in good yields and with excellent enantioselectivity. This approach avoids the problems associated with the noncatalyzed background reaction, which hampers most photocatalytic processes.

Enantioselective photochemical reactions have attracted the interest of chemists since the pioneering work of Kuhn in the 1930s (4). Visible light is environmentally benign and can be used to overcome the energetic barrier of reaction pathways not accessible by thermal processes. The [2 + 2] cycloaddition is an archetypical photochemical reaction (5) that in one step converts simple achiral starting materials into strained four-membered rings that can contain up to four different asymmetric centers. Part of the activation energy provided by the photon is not dissipated but is stored as ring strain. The products of these reactions are versatile synthetic intermediates.

Coupling light energy to achieve a selective transformation.

In the reaction developed by Du et al., light activates a ruthenium complex (A), which selectively reduces an α,β-unsaturated phenylketone complex. (B) In a radical process, a formal [2 + 2] cycloaddition is achieved with high enantioselectivity (B). Abbreviations: SET, single-electron transfer; MLCT, metal-to-ligand charge transfer; bpy, bipyridyl; i-Pr, isopropyl; OTf, triflate; Me, methyl; Et, ethyl; Ph, phenyl; Eu, europium; and L, the multidentate chiral ligand.


Since the ground-breaking work from the groups of Knowles (6), Sharpless (7), and Noyori (8), organic chemists have focused on the development of efficient catalytic enantioselective transformations that can replace the synthesis of mixtures of isomers requiring wasteful separation procedures. Instead, chiral catalysts bind reactants to favor the formation of one isomer during reaction. Many enantioselective transformations that can be used with a wide range of substrates have been reported, and the scope of this approach has expanded to include radical reactions (9) and transition-metal–free organocatalytic reactions (1012). With this approach, the synthesis on the ton scale of valuable, biologically active compounds in pure form can be performed with just grams of an optically active catalyst (1).

In view of these developments, it was surprising and disappointing that photochemistry did not follow the trend until recently. The reasons for this belated arrival of success in the development of enantioselective photocatalytic processes can be traced back to a lack of knowledge on the energy surface of the activated state and the short lifetime of excited molecules. To obtain high enantioselectivities, non-enantioselective background reactions must be suppressed. In thermal reactions, this problem can sometimes be addressed simply by lowering the reaction temperature and sacrificing a lower rate for greater selectivity. Bach and co-worker have pioneered a photocatalytic approach in which the complex between the catalyst and the substrate has a distinct absorption maximum from the uncomplexed starting material (13). Carefully choosing the wavelength of irradiation allows selective excitation of the complexed substrate, which is then transformed with high enantioselectivity.

The approach chosen by Du et al. totally decouples the photoactivation from the process responsible for the enantioselectivity (see the figure). Irradiating the ruthenium complex with visible light creates a redox-active excited species that reduces the α,β-unsaturated phenylketone only, when activated by an adequately chosen Lewis acid. The complexed radical anion formed by this process then undergoes a stepwise reaction sequence leading to the enantioselective formation of the four-membered ring under the influence of the chiral ligand. Optimizing all the parameters of this photoredox-catalyzed reaction allowed products to be obtained typically in 50 to 80% synthetic yields and with consistently high enantiomeric excess of 85 to >95%. The utility of photoredox-catalyzed reactions has been demonstrated already for C–C bond–forming processes by MacMillan and co-worker (14). The attractiveness of the Du et al. procedure is that the process achieved via a redox sequence is a genuinely photochemical transformation, the [2 + 2] photocycloaddition.

The process reported mimics in its strategy the process of photosynthesis, which decouples the primary photochemical event from the utilization of the harnessed energy for synthetic transformations. The initial photochemical event creates a redox potential. The synthetic part harnesses the photochemical energy in creating energy-rich chemical structures. The results reported are notable because of the synthetic importance of the synthesized structures, but also because they allow studying the coupling of the energy collected from photons to the energy stored in interesting chemical structures.


View Abstract

Stay Connected to Science

Navigate This Article