Oxidation-Active Flavin Models: Oxidation of α-Hydroxy Acids by Benzo-dipteridine Bearing Metal-Binding Site in the Presence of Divalent Metal Ion and Base in Organic Solvents

• Published in: Journal of the American Chemical Society 2001-03, Vol.123 (11), p.2478-2486
• Main Authors: Ohshiro, Hideaki, Mitsui, Keita, Ando, Nobuyuki, Ohsawa, Yoichi, Koinuma, Wataru, Takahashi, Hirobumi, Kondo, Shin-ichi, Nabeshima, Tatsuya, Yano, Yumihiko
• Format: Article
• Language: English
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0009121

The oxidizing ability of benzo-dipteridine bearing a bipyridin-6-ylmethyl moiety (4) was found to be increased with Zn2+ by ∼103-fold for sulfite addition in MeOH and ∼102-fold for oxidation of an NADH model in MeCN. It was found for the first time that 4 is able to oxidize α-hydroxy acids to α-keto acids in the presence of a divalent metal ion such as Zn2+, Co2+, and Ni2+ and an amine base in MeCN or t-BuOH, whereas benzo-dipteridine having a bipyridin-5-ylmethyl moiety (3) is unable to oxidize them under the same conditions. The oxidation reaction was kinetically investigated including the kinetic isotope effect for deuterated mandelic acids (k H/k D = 2.1−3.7) and the Hammett plots for substituted mandelic acids (V-shaped plots). In the reaction of α-substituted α-hydroxy acids such as α-methyl mandelic and benzylic acids with 4, novel oxidative decarboxylation was found to take place, giving acetophenone and benzophenone, respectively. The oxidation mechanism for mandelic acid was proposed to proceed via a ternary complex of 4·Zn2+·PhCH(OH)CO2 -, in which α-oxyanion of mandelate attacks C(4a)-position of 4 to form an adduct followed by 1,2-elimination to afford benzoyl formate and 2e-reduced 4. The roles of the metal ion were proposed as follows; (i) activation of 4, (ii) substrate-binding site, and (iii) activation of the bound α-hydroxy acid by lowering pK a's of α-OH and α-CH. This is a first example that a flavin model oxidizes α-hydroxy acids in the presence of a metal ion.