α‐Boryl Isocyanides Enable Facile Preparation of Bioactive Boropeptides

Zajdlik, Adam; Wang, Zezhou; Hickey, Jennifer L.; Aman, Ahmed; Schimmer, Aaron D.; Yudin, Andrei K.

doi:10.1002/ange.201302818

Cited by 26 publications

(17 citation statements)

References 90 publications

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“…Herein, we report an efficient strategy to synthesize enantioenriched α-aminoboronates via a cascade process in which a single CuH catalyst mediates sequential hydroboration and hydroamination of readily available alkyne substrates. The transformation offers practical value in streamlining access to the important aminoboronates substructure in a manner that complements existing methods [25][26][27][28][29][30][31][32][33][34] . This system takes advantage on in situ formation of the key terminal alkenylBdan intermediate, a process that had only been described for aliphatic alkynes with HBpin (pin = pinacolato) using a Cu•NHC catalyst (NHC = N-heterocyclic carbene) prior to this work [35][36][37] .…”

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confidence: 99%

Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products

Gao

Shao

et al. 2019

Nat Catal

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Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalyzed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centers. In contrast, applying CuH cascade catalysis to achieve reductive 1,1difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboronates via CuH-catalyzed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product in favor of alternative homodifunctionalized, 1,2-heterodifunctionalized, or reductively monofunctionalized byproducts, thereby offering rapid access to these privileged scaffolds with high chemo-, regio-and enantioselectivity. Alkenes and alkynes are ideal starting materials in organic synthesis due to the fact that they can be readily prepared using a variety of convenient synthetic methods and are widely available from commercial suppliers. Catalytic functionalization of the π-bonds in these substrates leads to a valuable array of building blocks and in the case of alkenes offers a Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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confidence: 99%

Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products

Gao

Shao

et al. 2019

Nat Catal

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“…Our studies go much beyond a singleton report on the use of a few free boronic acids in the Ugi reaction as we also investigated the GBB-3CR, UT-4CR, and several different IMCR variations more in an unprecedented breadth of building block combinations ( 35 , 36 ). In other reports, isocyanide-bearing boronic acids are only known in their protected ester form that would need another, often harsh, deprotecting step to yield boronic acids suitable for screening ( 39 , 40 ). Here, we found that IMCR generally runs under such mild conditions that free boronic acids are widely tolerated.…”

Section: Resultsmentioning

confidence: 99%

Rapid approach to complex boronic acids

et al. 2019

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The compatibility of free boronic acid building blocks in multicomponent reactions to readily create large libraries of diverse and complex small molecules was investigated. Traditionally, boronic acid synthesis is sequential, synthetically demanding, and time-consuming, which leads to high target synthesis times and low coverage of the boronic acid chemical space. We have performed the synthesis of large libraries of boronic acid derivatives based on multiple chemistries and building blocks using acoustic dispensing technology. The synthesis was performed on a nanomole scale with high synthesis success rates. The discovery of a protease inhibitor underscores the usefulness of the approach. Our acoustic dispensing–enabled chemistry paves the way to highly accelerated synthesis and miniaturized reaction scouting, allowing access to unprecedented boronic acid libraries.

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“…Inspired by the impact of β-amino acids and β-peptides on contemporary science 17 , 18 , we questioned the potential significance of homology in aminoboronic scaffolds and turned to amphoteric boron-containing compounds as the enabling building blocks. The goal of our work was to build upon facile α-aminoboronic acid synthesis 19 , 20 and the recently demonstrated stability of β-aminoboronic acids 21 .…”

Section: Introductionmentioning

confidence: 99%

Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

et al. 2017

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Heteroatom-rich organoboron compounds have attracted attention as modulators of enzyme function. Driven by the unmet need to develop chemoselective access to boron chemotypes, we report herein the synthesis of α- and β-aminocyano(MIDA)boronates from borylated carbonyl compounds. Activity-based protein profiling of the resulting β-aminoboronic acids furnishes selective and cell-active inhibitors of the (ox)lipid-metabolizing enzyme α/β-hydrolase domain 3 (ABHD3). The most potent compound displays nanomolar in vitro and in situ IC50 values and fully inhibits ABHD3 activity in human cells with no detectable cross-reactivity against other serine hydrolases. These findings demonstrate that synthetic methods that enhance the heteroatom diversity of boron-containing molecules within a limited set of scaffolds accelerate the discovery of chemical probes of human enzymes.

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α‐Boryl Isocyanides Enable Facile Preparation of Bioactive Boropeptides

Cited by 26 publications

References 90 publications

Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products

Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products

Rapid approach to complex boronic acids

Multicomponent mapping of boron chemotypes furnishes selective enzyme inhibitors

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