No abstract

The catalytic hydrogenation of alkenes, ketones, and imines is arguably one of the most important transformations in chemistry. Powerful asymmetric versions have been realized that require metal catalysts or the use of a stoichiometric amount of metal hydrides [Eq. (1)]. [1] Although effective and industrially relevant catalytic asymmetric hydrogenations and transfer hydrogenations of olefins and ketones have been developed, the corresponding imine reductions, although potentially highly useful for the synthesis of enantiomerically pure amines, are less advanced.[2] Living organisms employ organic dihydropyridine cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with enzyme catalysts for the reduction of imines.[3] Chemical transition metal catalyzed asymmetric imine reductions have also been developed, [4] and are used, in at least one case, on an industrial scale. [5] However, with the exception of interesting Lewis base catalyzed asymmetric imine hydrosilylations, [6] organocatalytic and metal-free variants were not known. Recently, we and MacMillan and co-workers developed an asymmetric transfer hydrogenation of a,b-unsaturated aldehydes catalyzed by a chiral ammonium salt by using Hantzsch esters as a biomimetic hydrogen source. [7] Rueping et al. [8] very recently reported the development of a novel and elegant approach using Hantzsch esters as the reducing reagent for the catalytic asymmetric reduction of imines using a chiral Brønsted acid catalyst previously developed by Akiyama et al.

In Xenopus oocytes, the spindle assembly checkpoint (SAC) kinase Bub1 is required for cytostatic factor (CSF)-induced metaphase arrest in meiosis II. To investigate whether matured mouse oocytes are kept in metaphase by a SAC-mediated inhibition of the anaphase-promoting complex/cyclosome (APC/C) complex, we injected a dominant-negative Bub1 mutant (Bub1dn) into mouse oocytes undergoing meiosis in vitro. Passage through meiosis I was accelerated, but even though the SAC was disrupted, injected oocytes still arrested at metaphase II. Bub1dn-injected oocytes released from CSF and treated with nocodazole to disrupt the second meiotic spindle proceeded into interphase, whereas noninjected control oocytes remained arrested at metaphase. Similar results were obtained using dominant-negative forms of Mad2 and BubR1, as well as checkpoint resistant dominant APC/C activating forms of Cdc20. Thus, SAC proteins are required for checkpoint functions in meiosis I and II, but, in contrast to frog eggs, the SAC is not required for establishing or maintaining the CSF arrest in mouse oocytes.

A novel organocatalytic asymmetric reductive amination of aldehydes has been developed. Treating racemic alpha-branched aldehydes with p-anisidine and a Hantzsch ester in the presence of our previously developed phosphoric acid catalyst, TRIP, gave beta-branched secondary amines in excellent yields and enantioselectivities via an efficient dynamic kinetic resolution. The process is applicable to several different aromatic aldehydes and amines but gives slightly reduced enantiomeric ratios with aliphatic aldehydes.

The cancer cell secretome has emerged as an attractive subproteome for discovery of candidate blood-based biomarkers. To choose the best performing workflow, we assessed the performance of three first-dimension separation strategies prior to nanoLC-MS/MS analysis: (1) 1D gel electrophoresis (1DGE), (2) peptide SCX chromatography, and (3) tC2 protein reversed phase chromatography. 1DGE using 4-12% gradient gels outperformed the SCX and tC2 methods with respect to number of identified proteins (1092 vs 979 and 580, respectively), reproducibility of protein identification (80% vs 70% and 72%, respectively, assessed in biological N = 3). Reproducibility of protein quantitation based on spectral counting was similar for all 3 methods (CV: 26% vs 24% and 24%, respectively). As a proof-of-concept of secretome proteomics for blood-based biomarker discovery, the gradient 1DGE workflow was subsequently applied to identify IGF1R-signaling related proteins in the secretome of mouse embryonic fibroblasts transformed with human IGF1R (MEF/Toff/IGF1R). VEGF and osteopontin were differentially detected by LC-MS/MS and verified in secretomes by ELISA. Follow-up in serum of mice bearing MEF/Toff/IGF1R-induced tumors showed an increase of osteopontin levels paralleling tumor growth, and reduction in the serum of mice in which IGF1R expression was shut off and tumor regressed.

The chiral phosphoric acid TRIP, a useful Brønsted acid catalyst, easily becomes contaminated with metal impurities in the form of phosphate salts during synthesis. This significantly reduces the content of free acid in the product which can hamper the catalytic activity. Methods to easily judge whether TRIP contains mainly the free acid or phosphate salts are presented, using 1 H NMR spectroscopy or a simple pH test. An improved synthetic protocol for TRIP was established that reliably produces the free acid.In recent years, relatively strong chiral Brønsted acids have emerged as powerful catalysts for many asymmetric transformations. 1 Particularly effective are phosphoric acids 1 with an axially chiral binaphthyl backbone bearing sterically demanding substituents in the 3-positions, first introduced as catalysts by Akiyama and Terada 2 ( Figure 1). Among the many differently substituted binaphthyl-phosphoric acids, 3,3¢-bis(2,4,6-triisopropylphenyl)-1,1¢-binaphthyl-2,2¢-diyl hydrogenphosphate (2, abbreviated TRIP), emerged as a particularly powerful one in terms of activity and stereoselectivity. 3 Figure 1 Chiral binaphthyl phosphoric acids: general structure 1 and TRIP 2TRIP was first introduced for the asymmetric transfer hydrogenation of imines. 4 Other notable applications in which TRIP turned out to be the best asymmetric Brøn-sted acid catalyst include the reductive amination of abranched aldehydes, 5 an aldol conjugate reduction-reductive amination cascade, 6 Friedel-Crafts and PictetSpengler reactions 7 and cycloadditions. 8In the aforementioned reactions, asymmetry was introduced by the conjugate base of TRIP 2. The chiral phosphate can also effect stereoselectivity if employed in the form of salts in reactions with cationic intermediates, 9 a strategy also termed asymmetric counteranion directed catalysis (ACDC). 10 The TRIP anion has proven to induce high levels of stereoselectivity in combination with organic counterions, for example, in the transfer hydrogenation and epoxidation of a,b-unsatured aldehydes 10,11 and ketones, 12 respectively. The use of the TRIP anion in otherwise achiral transition-metal complexes enabled asymmetric gold-catalyzed allene cyclizations 13 and palladium-catalyzed allylic alkylations 14 with high levels of stereoselectivity. Furthermore, TRIP was also the catalyst of choice in combinations of Brønsted acid and transitionmetal catalysis. 15 Interestingly, alkali or alkaline earth salts of chiral phosphates 1 can also be efficient catalysts. 16 Feng and coworkers reported the use of sodium salts of 1 in an enantioselective Strecker reaction 16b and Ishihara and coworkers reported the use of alkali or alkaline earth salts for an enantioselective cyanosilylation of ketones 16a and a Mannich reaction. 16c In all these cases, the chiral induction was dependent on the metal counterion and the mode of preparation of the salts.Lately, Ishihara pointed out the possible salt formation and contamination of BINOL-derived phosphoric acids 1 during purification on silica gel and...

The catalytic hydrogenation of alkenes, ketones, and imines is arguably one of the most important transformations in chemistry. Powerful asymmetric versions have been realized that require metal catalysts or the use of a stoichiometric amount of metal hydrides [Eq. (1)]. [1] Although effective and industrially relevant catalytic asymmetric hydrogenations and transfer hydrogenations of olefins and ketones have been developed, the corresponding imine reductions, although potentially highly useful for the synthesis of enantiomerically pure amines, are less advanced.[2] Living organisms employ organic dihydropyridine cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with enzyme catalysts for the reduction of imines.[3] Chemical transition metal catalyzed asymmetric imine reductions have also been developed, [4] and are used, in at least one case, on an industrial scale. [5] However, with the exception of interesting Lewis base catalyzed asymmetric imine hydrosilylations, [6] organocatalytic and metal-free variants were not known. Recently, we and MacMillan and co-workers developed an asymmetric transfer hydrogenation of a,b-unsaturated aldehydes catalyzed by a chiral ammonium salt by using Hantzsch esters as a biomimetic hydrogen source. [7] Rueping et al. [8] very recently reported the development of a novel and elegant approach using Hantzsch esters as the reducing reagent for the catalytic asymmetric reduction of imines using a chiral Brønsted acid catalyst previously developed by Akiyama et al.

Branching out: An organocatalytic reductive amination of α‐branched ketones using dynamic kinetic resolution is reported. The cis‐2‐substituted cyclohexyl amines were obtained in high diastereoselectivity and enantioselectivity from the corresponding ketones.