Mechanistic investigations on the aldehyde-catalyzed intermolecular hydroamination of allylic amines using N-alkylhydroxylamines are presented. Under the reaction conditions, the presence of a specific aldehyde catalyst allows formation of a mixed aminal intermediate, which permits intramolecular Cope-type hydroamination. The reaction was determined to be first-order in both the aldehyde catalyst (α-benzyloxyacetaldehyde) and the allylic amine. However, the reaction displays an inverse order behavior in benzylhydroxylamine, which reveals a significant off-cycle pathway and highlights the importance of an aldehyde catalyst that promotes a reversible aminal formation. Kinetic isotope effect experiments suggest that hydroamination is the rate-limiting step of this catalytic cycle. Overall, these results enabled the elaboration of a more accurate catalytic cycle and led to the development of a more efficient catalytic system for alkene hydroamination. The use of 5-10 mol % of paraformaldehyde proved more effective than the use of 20 mol % of α-benzyloxyacetaldehyde, leading to high yields of intermolecular hydroamination products within 24 h at 30 °C.
The lower risk of coronary artery disease in premenopausal women than in men and postmenopausal women implicates sex steroids in cardioprotective processes. β‐Estradiol upregulates liver low‐density lipoprotein receptor (LDLR), which, in turn, decreases circulating levels of low‐density lipoprotein, which is a risk factor for coronary artery disease. Conversely, LDLR protein is negatively regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). Herein, we investigated PCSK9 regulation by β‐estradiol and its impact on LDLR in human hepatocarcinoma HuH7 cells grown in the presence or absence of β‐estradiol. Immunoblot analysis showed upregulation of LDLR at 3 μm β‐estradiol (140%), and the upregulation reached 220% at 10 μm β‐estradiol; only at the latter dose was an increase in LDLR
mRNA detected by qPCR, suggesting post‐translational regulation of LDLR. No changes in PCSK9 mRNA or secreted protein levels were detected by qPCR or ELISA, respectively. β‐estradiol‐conditioned medium devoid of PCSK9 failed to upregulate LDLR. Similarly, PCSK9 knockdown cells showed no upregulation of LDLR by β‐estradiol. Together, these results indicate a requirement for PCSK9 in the β‐estradiol‐induced upregulation of LDLR. A radiolabeling assay showed a significant, dose‐dependent decrease in the ratio of secreted phosphoPCSK9 to total secreted PCSK9 with increasing β‐estradiol levels, suggesting a change in the functional state of PCSK9 in the presence of β‐estradiol. Our results indicate that the protein upregulation of LDLR at subtranscriptionally effective doses of β‐estradiol, and its supratranscriptional upregulation at 10 μm β‐estradiol, occur through an extracellular PCSK9‐dependent mechanism.
Intermolecular hydroamination of unactivated alkenes represents a significant synthetic challenge. An efficient Cope-type hydroamination is achieved under mild conditions for reactions of N-alkylhydroxylamines with allylic amines, using hydrogen bonding to achieve increased reactivity and high regioselectivity. This approach provides a number of highly functionalized vicinal diamine motifs as Markovnikov addition products.
Hydrogen Bonding Directed Intermolecular Cope-Type Hydroamination of Alkenes. -The reaction of unactivated alkenes proceeds under mild conditions with a high Markovnikov selectivity and a series of vicinal diamine units is available. Amine substrates which are substituted at the allylic position are converted into a single diastereomer [cf.(XVI) and (XVIII)]. -(ZHAO, S.-B.; BILODEAU, E.; LEMIEUX, V.; BEAUCHEMIN*, A. M.; Org. Lett. 14 (2012) 19, 5082-5085, http://dx.doi.org/10.1021/ol3023177 ; Dep. Chem., Univ. Ottawa, Ottawa, Ont. K1N 6N5, Can.; Eng.) -R. Simon 09-071
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