Summary
o-Benzynes (arynes) are among the most versatile of all reactive (short-lived) intermediates in organic chemistry. These species can be trapped to give products that are valuable from the perspective of both fine (pharmaceuticals) and commodity (agrochemicals, dyes, polymers, etc.) chemicals. Here we show a fundamentally new strategy that unites a de novo generation of benzynes, through the title hexadehydro-Diels–Alder (HDDA) reaction, with their in situ elaboration into structurally complex benzenoid products. In the HDDA reaction a 1,3-diyne is engaged in a [4+2] cycloisomerization with a third (pendant) alkyne–the diynophile–to produce the highly reactive benzyne intermediate. The metal- and reagent-free reaction conditions for this simple, thermal transformation are notable. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.
Catalytic assembly of enantiopure aliphatic amines from abundant and readily available precursors has long been recognized as a paramount challenge in synthetic chemistry. Herein, we describe a mild and general copper-catalyzed hydroamination that effectively converts unactivated internal olefins, an important yet unexploited class of abundant feedstock chemicals, into highly enantioenriched α-branched amines (≥ 96% enantiomeric excess) featuring two minimally differentiated aliphatic substituents. This method provides a powerful means to access a broad range of advanced, highly functionalized enantioenriched amines of interest in pharmaceutical research and other areas.
This review covers the use of 2-azaallyl
anions, 2-azaallyl cations,
and 2-azaallyl radicals in organic synthesis up through June 2018.
Particular attention is paid to both foundational studies and recent
advances over the past decade involving semistabilized and nonstabilized
2-azaallyl anions as key intermediates in various carbon–carbon
and carbon–heteroatom bond-forming processes. Both transition-metal-catalyzed
and transition-metal-free transformations are covered. Azomethine
ylides, which have received significant attention elsewhere, are discussed
briefly with the primary focus on critical comparisons with 2-azaallyl
anions in regard to generation and use.
Retrograde vesicle trafficking pathways are responsible for returning membrane-associated components from endosomes to the Golgi apparatus and the endoplasmic reticulum (ER), and they are critical for maintaining organelle identity, lipid homeostasis, and many other cellular functions. The retrograde transport pathway has emerged as an important target for intravacuolar bacterial pathogens. The opportunistic pathogen exploits both the secretory and recycling branches of the vesicle transport pathway for intracellular bacterial proliferation. Its Dot/Icm effector RidL inhibits the activity of the retromer by directly engaging retromer components. However, the mechanism underlying such inhibition remains unknown. Here we present the crystal structure of RidL in complex with VPS29, a subunit of the retromer. Our results demonstrate that RidL binds to a highly conserved hydrophobic pocket of VPS29. This interaction is critical for endosomal recruitment of RidL and for its inhibitory effects. RidL inhibits retromer activity by direct competition, in which it occupies the VPS29-binding site of the essential retromer regulator TBC1d5. The mechanism of retromer inhibition by RidL reveals a hotspot on VPS29 critical for recognition by its regulators that is also exploited by pathogens, and provides a structural basis for the development of small molecule inhibitors against the retromer.
The
CuH-catalyzed hydroamination of alkenes and alkynes using a silane
and an amine transfer reagent represents a simple strategy to access
chiral amine products. We have recently reported methods to prepare
chiral amines with high efficiency and stereoselectivity using this
approach. However, the current technology is limited to the synthesis
of trialkylamines from dialkylamine transfer reagents (R2NOBz). When monoalkylamine transfer reagents [RN(H)OBz] were used
for the synthesis of chiral secondary amines, competitive, nonproductive
consumption of these reagents by the CuH species resulted in poor
yields. In this paper, we report the design of a modified type of
amine transfer reagent that addresses this limitation. This effort
has enabled us to develop a CuH-catalyzed synthesis of chiral secondary
amines using a variety of amine coupling partners, including those
derived from amino acid esters, carbohydrates, and steroids. Mechanistic
investigations indicated that the modified amine transfer reagents
are less susceptible to direct reaction with CuH.
The endosomal trafficking pathways are essential for many cellular activities. They are also important targets by many intracellular pathogens. Key regulators of the endosomal trafficking include the retromer complex and sorting nexins (SNXs). Chlamydia trachomatis effector protein IncE directly targets the retromer components SNX5 and SNX6 and suppresses retromer-mediated transport, but the exact mechanism has remained unclear. We present the crystal structure of the PX domain of SNX5 in complex with IncE, showing that IncE binds to a highly conserved hydrophobic groove of SNX5. The unique helical hairpin of SNX5/6 is essential for binding, explaining the specificity of SNX5/6 for IncE. The SNX5/6–IncE interaction is required for cellular localization of IncE and its inhibitory function. Mechanistically, IncE inhibits the association of CI-MPR cargo with retromer-containing endosomal subdomains. Our study provides new insights into the regulation of retromer-mediated transport and illustrates the intricate competition between host and pathogens in controlling cellular trafficking.
We demonstrate that readily available
and bench-stable α-oxo-vinylsulfones
are competent electrophiles in Ni-catalyzed Suzuki–Miyaura
cross-coupling reactions. The C–sulfone bond in the α-oxo-vinylsulfone
motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These
reactions proceed under mild conditions and tolerate a remarkable
scope of heterocycles and functional groups. Preliminary mechanistic
studies revealed the importance of an α-heteroatom in facilitating
these transformations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.