Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases.

The nitroaldol (Henry) reaction is an important carbonyl addition process that affords products that may be transformed into valuable building blocks. 1 Therefore, it is not surprising that recent efforts have focused on the development of catalytic enantioselective reaction variants. The current contributions to this area have been highlighted by the recent studies of Shibasaki and Trost. [2][3][4][5] The purpose of this Communication is to report a new catalyst system for the nitroaldol reaction (eqs 1,2; M ) Cu, X ) OAc). The basis for the current study was to identify a weakly Lewis acidic metal complex bearing moderately basic charged ligands (X) that would facilitate the deprotonation of nitroalkanes (eq 1) as a prelude to the aldol addition process (eq 2). It was felt that divalent metal acetate-ligand complexes of the general structure A might meet these requirements because acetate has been employed as a Brønsted base in the racemic nitroaldol reaction. 1 A series of divalent metal acetates in combination with chiral bidentate ligands were screened as enantioselective catalysts for the nitroaldol process. 6,7 From this survey, bis(oxazoline) 8 (box) complexes derived from Cu(OAc) 2 emerged as promising catalyst candidates. The results from the ligand survey with this metal acetate are summarized in Table 1. The five box ligands (1a-d, 2) with the illustrated absolute configurations that were evaluated with Cu(OAc) 2 ‚H 2 O afforded promising levels of enantioselection (entries 1-5). 8,9 In each instance, the reactions carried out at ambient temperature were complete within 24 h. From this comparison, the indabox ligand 2 proved to be the ligand of choice, 9 providing the nitro alcohol product in 74% ee (Table 1, entry 5). With ethanol as the solvent (Table 1, entry 6), the nitro alcohol product was isolated in 81% ee. Further optimization of this process showed that the reaction may be performed with lower catalyst loadings (1-5 mol %), while the use of 10 equiv of nitromethane was found to be sufficient for the reaction to proceed to completion. Reaction concentrations could also be increased to as high as 1.0 M with no change in enantioselectivity. Cu(II) carboxylate structure was also evaluated with ligand 2, and it was concluded that this catalyst variable is subordinate to ligand architecture. 10 In all instances, the only side reaction observed in these reactions was the accompanying dehydration product.With optimized conditions in hand, the scope of the reaction was explored (Table 2). In general, high enantiomeric excesses (87-94% ee) are observed at room temperature for aromatic aldehydes bearing either electron-withdrawing or electron-donating groups (entries 1-9). 11 Aliphatic branched and unbranched aldehydes are also acceptable substrates, affording nitro alcohol adducts in good yields and enantioselectivities (entries 10-15, 90-94% ee).Reaction enantioselectivity can be further improved by lowering the temperature at the accompanying expense of increasing the reaction time. In one insta...

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