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Photochemistry In Organic Asymmetric Synthesis: A New Promising Approach

Khoi Van

Advisor: Professor Daniel Romo Monday, October 8, 2012

The importance of light in our human life cannot be overstated. However, the potential

use of light in chemical reaction was suggested only 100 years ago by Ciamician.1 Most photochemical reactions usually occur without any additional reagents, therefore, producing fewer side-products. This aspect makes photochemistry attractive especially for exploring green chemistry. More importantly, due to their different pathways,2,3 photochemical reactions can give access to highly complex compounds or those that are virtually inaccessible by conventional methods.4,5 Nevertheless, the outcomes of photo-catalyzed reactions are usually difficult to control, especially stereoselectively, and until only recently have highly stereoselective photochemical reactions (enantioselective and diastereoselective) been established.5 This seminar will focus on recent advances of photochemistry in the field of stereoselective asymmetric synthesis.

One of the most applied photochemical

processes is the [2+2] photocycloaddition reactions, where two olefins react to form cyclobutane.4-6 In this reaction, two C-C bonds are formed and up to four stereogenic centers can be generated in a single step. As a result, [2+2] photocyclizations are an excellent tool for synthetic chemists to rapidly construct complex structures. The reaction begins with the excitation of partitioning substrates. Different excitation mechanisms are used for various olefins.6 Direct excitation of alkenes usually leads to the lowest excited singlet state (S1), which subsequently forms cyclobutane (Scheme 1, path A). On the other hand, other olefins such as α,β-unsaturated carbonyl compounds usually follow a different pathway in which intersystem crossing (ISC) happens fast to form the triplet excited state (T1). Cyclobutane is then produced from this excited triplet state via 1,4-biradical intermediates (Scheme 1, path B). This triplet state can also be promoted by sensitizers (Scheme 1, path C). Sensitizer-accompanied [2+2] photocycloadditions have been used for some low photochemical-

Scheme 1. Excitation pathways in [2+2] photocycloadditions (Subst=substrate).

Scheme 2. Enantioselective intramolecular [2+2]’s using chiral sensitizer.

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reactive compounds, such as β-alkoxy, or β-amino substituted α,β-unsaturated lactam.7 Recently, an intramolecular [2+2] photocyclization using a chiral sensitizer resulted in excellent enantioselectivity and yield of the desired cyclobutane (Scheme 2).8 This high enantioselectivity is explained by hydrogen-bonding that blocks one face of the reactive olefin.

Another important pathway of light-excited species is electron-transfer reactions.

Excited state species are more easily reduced and oxidized than their corresponding ground states, which make them better electron donors and acceptors.9 Very recently, MacMillan and coworkers applied these properties by merging photoredox catalysis and organocatalysis.10 In this process, the organocatalytic cycle can either accept or donate an electron in order to complete the photoredox catalytic cycle. Utilizing previously developed highly enantioselective organocatalysis via SOMO (Single Occupied Molecular Orbital) activation,11 this dual catalytic process was applied to α-alkylation10(Scheme 3) and α-trifluoromethylation12 of aldehydes, which resulted in excellent enantioselectivities and good yields. By substituting the expensive metals used in the photoredox catalytic cycle with the organic dye eosin Y, Zeitler and coworkers were able to produce comparable results to the MacMillan’s work.13 Different from bothMacMillan and Zeitler’s work, oxidative quenching of the photoredox catalytic cycle has been explored by Yoon and coworkers as well as Stephenson and his group. This direction has resulted in cross intermolecular [2+2] photocyclizations,14 hetero Diels-Alder cycloadditions,15 and halogenation of olefins.16 However, these transformations have not been performed enantioselectively.

More recently, adopting a well-known observation in photochemistry, chemists have been able to alter the enantioselectivity of a reaction by changing the geometry of the catalyst. Upon irradiation at a specific wavelength, olefin configurations of the catalyst can be switched from E to Z configurations and vice versa. In an ingenious design, Feringa and coworkers attached two catalysts on the end of two arms of a supramolecule (Scheme 4).17 These two arms are connected to each other through an olefin axis. In the E-configuration, due to the long distance between the two catalysts, there was no observed enantioselectivity. On the contrary, when the supramolecule is in its Z-configuration, the two catalysts bring the substrates (the deprotonated thiol and cyclohexenone) closer and, therefore, differentiate the side of attack. As a result, different conformations of the supramolecule lead to either a racemic mixture or high enantioselectivity.

α-alkylation

Scheme 3. Enantioselective α-alkylation by visible light photoredox organocatalysis.

NH

NO Me

Me

. TfOH

organocatalysis 6(20 mol%)

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Overall, various methods including chiral sensitizers and dual catalytic photoredox organotransformations demonstrate that asymmetric photosynthesis is plausible with proper designs. A novel idea of switching on/off the stereochemical outcome shows how powerful photochemistry can be in obtaining high enantioselectivities. Compared to other asymmetric chemical transformations, light-initiated reactions still need further development but thus far have shown to be a promising approach in asymmetric synthesis. References: (1) Ciamician, G. Science. 1912, 36, 385-394. (2) Zimmerman, H. E. Angew. Chem. Int. Ed. 1969, 8, 1-11. (3) Anslyn, E. V.; Dougherty, D. A., Modern Physical Organic Chemistry. University

Science Books: 2005. (4) Hoffmann, N. Chem. Rev. 2008, 108, 1052-1103. (5) Bach, T.; Hehn, J. P. Angew. Chem. Int. Ed. 2011, 50, 1000-1045. (6) Bach, T. Synthesis 1998, 1998, 683-703. (7) Basler, B.; Schuster, O.; Bach, T. J. Org. Chem. 2005, 70, 9798-9808. (8) Müller, C.; Bauer, A.; Maturi, M. M.; Cuquerella, M. C.; Miranda, M. A.; Bach, T. J.

Am. Chem. Soc. 2011, 133, 16689-16697. (9) Zeitler, K. Angew. Chem. Int. Ed. 2009, 48, 9785-9789. (10) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77-80. (11) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science

2007, 316, 582-585. (12) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875-

10877. (13) Neumann, M.; Füldner, S.; König, B.; Zeitler, K. Angew. Chem. Int. Ed. 2011, 50, 951-

954. (14) Ischay, M. A.; Ament, M. S.; Yoon, T. P. Chem. Sci. 2012, 3, 2807-2811. (15) Hurtley, A. E.; Cismesia, M. A.; Ischay, M. A.; Yoon, T. P. Tetrahedron 2011, 67, 4442-

4448. (16) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. J. Am. Chem.

Soc. 2011, 133, 4160-4163. (17) Wang, J.; Feringa, B. L. Science 2011, 331, 1429-1432.

Scheme 4. Dynamic control of chirality by Feringa et. al.