The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The ...iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters.
Won't you be my neighbor: The first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers has been developed. The iridium‐catalyzed reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles.
The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which ...serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives.
A catalytic, enantioselective formal synthesis of (+)-dichroanone and (+)-taiwaniaquinone H is reported. The all-carbon quaternary stereocenter was constructed by asymmetric conjugate addition ...catalyzed by a palladium(II) (S)-tert-butylpyridinooxazoline complex. The unexpected formation of a 3.2.1 bicyclic intermediate required the identification of a new route. Analysis of the Hammett constants for para-substituted arenes enabled the rational design of a highly enantioselective conjugate addition substrate that led to the completion of the formal synthesis.
Intraductal papillary mucinous neoplasms (IPMN) have the potential to progress to pancreatic ductal adenocarcinoma (PDAC). As with any progression to malignancy, there are a variety of genetic and ...metabolic changes, as well as other disruptions to the cellular microenvironment including immune alterations and inflammation, that can contribute to tumorigenesis. Previous studies further characterized these alterations, revealing changes in lipid and glucose metabolism, and signaling pathways that mediate the progression of IPMN to PDAC. With the increased diagnosis of IPMNs and pancreatic cysts on imaging, the opportunity to attenuate risk with the removal of high-risk lesions is possible with the understanding of what factors accelerate malignant progression and how they can be clinically utilized to determine the level of dysplasia and stratify the risk of progression. Here, we reviewed the genetic, metabolic, inflammatory, and immunologic pathways regulating the progression of IPMN to PDAC.
The first highly enantioselective iridium‐catalyzed allylic alkylation that provides access to products bearing an allylic all‐carbon quaternary stereogenic center has been developed. The reaction ...utilizes a masked acyl cyanide (MAC) reagent, which enables the one‐pot preparation of α‐quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.
Ir‐resistible: An enantioselective iridium‐catalyzed allylic alkylation was developed that provides access to products bearing an allylic all‐carbon quaternary stereogenic center. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one‐pot preparation of α‐quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products was further explored through a series of product transformations.
The polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BP) is thought to bind covalently to DNA, through metabolism by cytochrome P450 1A1 (CYP1A1) and CYP1B1, and other enzymes, to form r7, t8, ...t9-trihydroxy-c-10-(N(2)-deoxyguanosyl)-7,8,9,10-tetrahydro-benzoa-pyrene (BPdG). Evaluation of RNA expression data, to understand the contribution of different metabolic enzymes to BPdG formation, is typically presented as fold-change observed upon BP exposure, leaving the actual number of RNA transcripts unknown. Here, we have quantified RNA copies/ng cDNA (RNA cpn) for CYP1A1 and CYP1B1, as well as
quinone oxidoreductase 1 (NQO1), which may reduce formation of BPdG adducts, using primary normal human mammary epithelial cell (NHMEC) strains, and the MCF-7 breast cancer cell line. In unexposed NHMECs, basal RNA cpn values were 58-836 for CYP1A1, 336-5587 for CYP1B1 and 5943-40112 for NQO1. In cells exposed to 4.0 µM BP for 12h, RNA cpn values were 251-13234 for CYP1A1, 4133-57078 for CYP1B1 and 4456-55887 for NQO1. There were 3.5 (mean, range 0.2-15.8) BPdG adducts/10(8) nucleotides in the NHMECs (n = 16), and 790 in the MCF-7s. In the NHMECs, BP-induced CYP1A1 RNA cpn was highly associated with BPdG (P = 0.002), but CYP1B1 and NQO1 were not. Western blots of four NHMEC strains, chosen for different levels of BPdG adducts, showed a linear correlation between BPdG and CYP1A1, but not CYP1B1 or NQO1. Ethoxyresorufin-O-deethylase (EROD) activity, which measures CYP1A1 and CYP1B1 together, correlated with BPdG, but NQO1 activity did not. Despite more numerous levels of CYP1B1 and NQO1 RNA cpn in unexposed and BP-exposed NHMECs and MCF-7cells, BPdG formation was only correlated with induction of CYP1A1 RNA cpn. The higher level of BPdG in MCF-7 cells, compared to NHMECs, may have been due to a much increased induction of CYP1A1 and EROD. Overall, BPdG correlation was observed with CYP1A1 protein and CYP1A1/1B1 enzyme activity, but not with CYP1B1 or NQO1 protein, or NQO1 enzyme activity.
The development of the first enantio‐, diastereo‐, and regioselective iridium‐catalyzed allylic alkylation reaction of prochiral enolates to form an all‐carbon quaternary stereogenic center with an ...aliphatic‐substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone‐derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all‐carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.
Sponge worthy: The unique combination of crotyl chloride, LiCl, and proton sponge has delivered the first enantio‐, diastereo‐, and regioselective iridium‐catalyzed allylic alkylation reaction to form an all‐carbon quaternary stereocenter with an aliphatic‐substituted electrophile. The reaction proceeds with good to excellent selectivity for a range of substituted tetralones, providing products bearing a newly formed vicinal tertiary and all‐carbon quaternary stereodyad.
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