A general catalytic allylation of simple ketoimines was developed using 1 mol % of CuF.3PPh(3) as catalyst, 1.5 mol % of La(O(i)Pr)(3) as the cocatalyst, and stable and nontoxic allylboronic acid pinacol ester as the nucleophile. This reaction constituted a good template for developing the first catalytic enantioselective allylation of ketoimines. In this case, using LiO(i)Pr as the cocatalyst produced higher enantioselectivity and reactivity than La(O(i)Pr)(3). Thus, using the CuF-cyclopentyl-DuPHOS complex (10 mol %) and LiO(i)Pr (30 mol %) in the presence of (t)BuOH (1 equiv) produced high enantioselectivity up to 93% ee from a range of aromatic ketoimines. Mechanistic studies indicated that LiO(i)Pr accelerates the reaction by increasing the concentration of an active nucleophile, allylcopper.

We have synthesized ∆lac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an R, -unsaturated γ-lactone ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of ∆lac-acetogenins in more detail, we carried out wide structural modifications of original ∆lac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF rings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original ∆lac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that ∆lac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.

The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate alpha-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)(3) and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu(4)NCl, alpha-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the gamma-position of 4, followed by regio- and enantioselective protonation at the alpha-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu(4)NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF.3PPh(3).2EtOH (10 mol %) in the presence of KO(t)Bu (15 mol %), ZnCl(2) (1 equiv), and Bu(4)PBF(4) (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the alpha-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic alpha-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.