Enantioselective Lewis Acid Catalysis of Intramolecular Enone [2+2] Photocycloaddition Reactions

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Science  15 Nov 2013:
Vol. 342, Issue 6160, pp. 840-843
DOI: 10.1126/science.1244809

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[2+2] Asymmetrically

Catalysts in thermal reactions operate by lowering energy barriers of bound substrates, and thereby increasing the proportion of reagents that can proceed to products at a given temperature. In photochemical reactions, light provides the energy to surmount the barrier. It is therefore challenging to alter selectivity through catalysis, because the catalyst may not be bound when a given reagent absorbs the light. Brimioulle and Bach (p. 840) surmounted this problem in the light-induced intramolecular [2+2] cycloaddition of enones by using a catalyst that shifted the absorption wavelength of the bound substrate. The light was thus predominantly absorbed by substrate-catalyst complexes, enabling asymmetric induction by the catalyst to provide enantiomerically enriched products.


Asymmetric catalysis of photochemical cycloadditions has been limited by the challenge of suppressing the unselective background reaction. Here, we report that the high cross-section ππ* transition of 5,6-dihydro-4-pyridones, a versatile class of enone substrates, undergoes a >50 nanometer (nm) bathochromic absorption shift upon Lewis acid coordination. Based on this observation, enantioselective intramolecular [2+2] photocycloaddition reactions (82 to 90% enantiomeric excess) were achieved with these substrates using 0.5 equivalents of a chiral Lewis acid upon irradiation at a wavelength of 366 nm. One of the products was applied as a key intermediate in the total synthesis of (+)-lupinine and the formal synthesis of (+)-thermopsine. Several enones show similar bathochromic shifts in the presence of a Lewis acid, indicating that chiral Lewis acid catalysis may be a general approach toward enantioselective enone [2+2] photocycloadditions.

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