Oxidative generation of synthetically important amidyl radicals from N-H amides is an appealing and yet challenging task. Previous methods require a stoichiometric amount of a strong oxidant and/or a costly noble-metal catalyst. We report herein the first electrocatalytic method that employs ferrocene (Fc), a cheap organometallic reagent, as the redox catalyst to produce amidyl radicals from N-aryl amides. Based on this radical-generating method, an efficient intramolecular olefin hydroamidation reaction has been developed.
The generation of α-imino gold carbenes via gold-catalyzed intermolecular reaction of azides and ynamides is disclosed. This new methodology allows for highly regioselective access to valuable 2-aminoindoles and 3-amino-β-carbolines in generally good to excellent yields. A mechanistic rationale for this tandem reaction, especially for the observed high regioselectivity, is supported by DFT calculations.
The folding mode
of substrate FPP in sesquiterpene cyclases/synthases
is key to the chemo- and stereoselectivity of the ultimate sesquiterpene
products. However, the precise substrate folding modes in most sesquiterpene
cyclases are still elusive, and it is challenging for theoretical
simulations due to the high flexibility of FPP. Herein, by DFT/MM
MD simulations, we obtain the optimal folding mode of FPP in the 1,6-closure
trichodiene synthase and illuminate the whole catalytic mechanism
for the biosynthesis of trichodiene. Furthermore, a simple and practical
rule is proposed to decipher the relationship between the diverse
FPP folding modes and chemical selectivity toward 1,6- and 1,10-ring
closure, which are common pathways in all sesquiterpene cyclases.
An efficient zinc(II)-catalyzed alkyne oxidation/C-H functionalization sequence was developed, thus leading to highly site-selective synthesis of a variety of isoquinolones and β-carbolines. Importantly, in contrast to the well-established gold-catalyzed intermolecular alkyne oxidation, over-oxidation can be completely suppressed in this system and the reaction most likely proceeds by a Friedel-Crafts-type pathway. Mechanistic studies and theoretical calculations are described.
A novel gold-catalyzed intermolecular ynamide amination-initiated aza-Nazarov cyclization has been developed, allowing the facile and efficient synthesis of various 2-aminopyrroles in moderate to good yields. Furthermore, a mechanistic rationale for this tandem sequence, especially for the observed high regioselectivity, is also well supported by DFT (density functional theory) computations. The high flexibility, broad substrate scope, and mild nature of this reaction render it a viable alternative for the construction of 2-aminopyrroles.
Achieving p-CAr–H site selectivity is one of the
major challenges in direct carbon–hydrogen (C–H) functionalization
reactions. Herein, the copper-catalyzed and picolinamide-assisted
remote p-C–H sulfonylation of 1-naphthylamides
was realized. The synthetic utility of this method was further examined
by sequential functionalizations and the efficient synthesis of the
pharmaceutically useful 5-HT6 serotonin receptor ligand.
This approach also provided a general strategy for other p-C–H bond functionalization, such as highly selective constructions
of C–O, C–Br, C–I, C–C, and C–N
bonds. Control experiments and theoretical calculations suggested
that this C–H sulfonylation reaction might proceed through
a single-electron-transfer process.
A novel
enantioselective aminomethylation reaction of diazo compound,
alcohol and α-aminomethyl ether enabled by asymmetric counteranion-directed
catalysis is disclosed that offers an efficient and convenient access
to furnish optically active α-hydroxyl-β-amino acids in
high yield with high to excellent enantioselectivities. Control experiments
and DFT calculations indicate that the transformation proceeds through
trapping the in situ generated enol intermediate with methylene iminium
ion, and the asymmetric induction was enabled by chiral pentacarboxycyclopentadiene
anion via H-bonding and electrostatic interaction.
Prion diseases are caused by the propagation of misfolded cellular prion proteins (PrPs). A completely prion disease-resistant genotype, V127M129, has been identified in Papua New Guinea and verified in transgenic mice. To disclose the structural basis of the disease-resistant effect of the G127V mutant, we determined and compared the structural and dynamic features of the G127V-mutated human PrP (residues 91–231) and the wild-type PrP in solution. HuPrP(G127V) contains α1, α2 and α3 helices and a stretch-strand (SS) pattern comprising residues Tyr128-Gly131 (SS1) and Val161-Arg164 (SS2), with extending atomic distances between the SS1 and SS2 strands, and a structural rearrangement of the Tyr128 side chain due to steric hindrance of the larger hydrophobic side chain of Val127. The extended α1 helix gets closer to the α2 and α3 helices. NMR dynamics analysis revealed that Tyr128, Gly131 and Tyr163 underwent significant conformational exchanges. Molecular dynamics simulations suggest that HuPrP(G127V) prevents the formation of stable β-sheets and dimers. Unique structural and dynamic features potentially inhibit the conformational conversion of the G127V mutant. This work is beneficial for understanding the molecular mechanisms underlying the complete resistance of the G127V mutant to prion disease and for developing new therapeutics for prion disease.
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