Primary aminothiourea derivatives are shown to catalyze enantioselective alkylation of α-arylpriopionaldehdyes with diarylbromomethane. Evidence for a stepwise, S N 1 mechanism in the substitution reaction induced by anion binding to the catalyst is provided by catalyst structureactivity studies, kinetic isotope effects, linear free-energy relationship studies, and competition experiments.The anion-binding properties of urea and thiourea derivatives have been exploited recently in enantioselective catalytic reactions involving heteroatom-stabilized carbocations, such as N-acyliminium and oxocarbenium ions. 1,2 Experimental and computational data point to a consistent mechanistic framework wherein the H-bond donor catalysts promote these reactions by anion-abstraction from a neutral organic precursor to generate the more reactive cationic electrophile (Scheme 1). 1b We reasoned that, with the appropriate catalyst and nucleophilic partner, this mode of electrophile activation might also be applicable to catalysis of S N 1 pathways via formation and reactions of carbocations that are not heteroatom-stabilized. 3 Herein we report the successful application of this activation mode to formation of benzhydryl cations in the context of an asymmetric α-alkylation of α-branched aldehydes.The α-alkylation of 2-phenylpropionaldehyde (6a) with bromodiphenylmethane (benzhydryl bromide, 7a) was chosen as a model reaction (Table 1). Classical studies with benzhydryl derivatives have helped to establish much of the conceptual foundations of carbocation reactivity, 4 and these compounds have been especially useful for characterizing the nature and stereochemical properties of ion pairs. 5 The α-alkylation of aldehydes was deemed particularly worthy of investigation because of the high value of chiral aldehydes bearing α-quaternary stereocenters as synthetic intermediates, 6 and the inherent challenges associated with asymmetric catalysis of this type of transformation. 7 A broad screen of potential catalysts in the alkylation of 2-phenylpropionaldehyde with bromodiphenylmethane led to the discovery that primary aminothiourea derivatives were unique in inducing good reactivity and enantioselectivity (Table 1). 8 This class of catalysts has been applied

The oxidative phosphorylation machinery in mitochondria, which generates the main bioenergy pool in cells, includes four enzyme complexes for electron transport and ATP synthase. Among them, the cytochrome c oxidase (COX), which constitutes the fourth complex, has been suggested as the major regulatory site. Recently, abnormalities in COX were linked to tumor progression in several cancers. However, it remains unclear whether COX and its subunits play a role in tumor progression of hepatoma. To search for the key regulatory factor(s) in COX for hepatoma development, in silico analysis using public transcriptomic database followed by validation for postoperative outcome associations using independent in-house patient cohorts was performed. In which, COX5B was highly expressed in hepatoma and associated with unfavorable postoperative prognosis. In addressing the role of COX5B in hepatoma, the loss- and gain-of-function experiments for COX5B were conducted. Consequently, COX5B expression was associated with increased hepatoma cell proliferation, migration and xenograft growth. Downstream effectors searched by cDNA microarray analysis identified UHMK1, an oncogenic protein, which manifested a positively correlated expression level of COX5B. The COX5B-mediated regulatory event on UHMK1 expression was subsequently demonstrated as bioenergetic alteration-dependent activation of AMPK in hepatoma cells. Phosphoproteomic analysis uncovered activation of ERK- and stathmin-mediated pathways downstream of UHMK1. Finally, comprehensive phenotypic assays supported the impacts of COX5B-UHMK1-ERK axis on hepatoma cell growth and migration.

An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond.

An enantioselective, convergent, total synthesis of the antiviral marine natural product (-)-hennoxazole A has been completed in 17 steps, longest linear sequence, from serine methyl ester and in 9 steps from an achiral bisoxazole intermediate. Elaboration of a thiazolidinethione allowed for rapid assembly of the pyran-based ring system. Key late-stage coupling was effected by deprotonation of the bisoxazole methyl group, followed by alkylation with an allylic bromide side chain segment. [structure: see text]

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