In collaboration with researchers from the University of California, Los Angeles, the Forbes Group published in JACS how the solution photochemistry of bis(phenylpyrrolidinonyl)ketones (R,R)-1b and (S,S)-1b exhibited a remarkably high memory of chirality. Stereospecific decarbonylation to products (R,R)-3b and (S,S)-3b, respectively, occurred with an ee of circa 80%. The reaction is thought to occur along the single state manifold by sequential Norrish type-I α-cleavage, decarbonylation, and radical−radical combination in a time scale that is comparable to that required for the radical intermediate to expose its other enantiotopic face by rotation about an axis perpendicular to that of the p orbital (ca. 3−7 ps).
The absolute configuration of a key intermediate and that of ketone (R,R)-1b were determined by single-crystal X-ray diffraction and the ee values of the photochemical products with the help of chiral shift reagent (+)-Eu(tfc)3 and chiral LC-MS/MS. On the basis of the ee and de values at 25 ℃, it could be determined that ca. 70% of the bond forming events occur with double memory of chirality, ca. 21% occur after rotation of one radical to form the meso product (R,S)-3b, and only 9% occur after double rotation to form the opposite enantiomer. This report represents the first example of a doubly enantiospecific Norrish type-I and decarbonylation reaction in solution and illustrates potentially efficient ways to obtain compounds with adjacent stereogenic quaternary centers.
As reported in Organic & Biomolecular Chemistry, researchers with the Forbes Group, in collaboration with researchers in Russia, have studied the thermal degradation reactions of kynurenine (KN), 3-hydroxykynurenine (3OHKN), and several adducts of KN, to amino acids and reduced glutathione (GSH) at physiological temperature. These compounds are all implicated in age-related mammalian eye lens cataract formation at the molecular level. The main reaction pathway for both KN and 3OHKN is deamination via β-elimination to carboxyketoalkenes CKA and 3OHCKA.
These reactions show a weak pH dependence below pH values of ∼8, and a strong pH dependence above this value. The 3OHKN structure deaminates at a faster rate than KN. A mechanism for the deamination reaction is proposed, involving an aryl carbonyl enol/enolate ion, that is strongly supported by the structural, kinetic, and pH data. The degradation of Lys, His, Cys and GSH adducts of the CKA moieties was also studied. The Lys adduct was found to be relatively stable over 200 h at 37 ℃, while significant degradation was observed for the other adducts. The results are discussed in terms of known post-translational modification reactions of the lens proteins and compared to incubation studies involving KN and related compounds in the presence of proteins.