Natural
products and their derivatives continue to be wellsprings
of nascent therapeutic potential. However, many laboratories have
limited resources for biological evaluation, leaving their previously
isolated or synthesized compounds largely or completely untested.
To address this issue, the Canvass library of natural products was
assembled, in collaboration with academic and industry researchers,
for quantitative high-throughput screening (qHTS) across a diverse
set of cell-based and biochemical assays. Characterization of the
library in terms of physicochemical properties, structural diversity,
and similarity to compounds in publicly available libraries indicates
that the Canvass library contains many structural elements in common
with approved drugs. The assay data generated were analyzed using
a variety of quality control metrics, and the resultant assay profiles
were explored using statistical methods, such as clustering and compound
promiscuity analyses. Individual compounds were then sorted by structural
class and activity profiles. Differential behavior based on these
classifications, as well as noteworthy activities, are outlined herein.
One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the
endoplasmic reticulum. The workflow described here illustrates a pilot
effort to broadly survey the biological potential of natural products
by utilizing the power of automation and high-throughput screening.
The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (−)-2(S)-cathafoline, (+)-akuammiline, and (−)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection–cyclization cascade. The total syntheses of (−)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (−)-10-demethoxyvincorine and a new analogue thereof.
We report synthetic studies pertaining to two heterocyclic aryne intermediates: the 2,3-pyridyne and the 4,5-pyrimidyne. First, a 2,3-pyridyne precursor was readily accessed from 2-pyridone using a known procedure. Subsequently, 2,3-pyridyne generation and trapping were used to access several functionalized pyridines in a regioselective manner. In addition, we report synthetic routes to two isomeric silyltriflates, which were intended to serve as precursors to the 4,5-pyrimidyne. Consecutive 4,5-pyrimidyne generation and trapping experiments were ultimately deemed unfruitful. We expect these findings will promote the use of 2,3-pyridyne and other heterocyclic arynes as building blocks for the synthesis of functionalized heterocycles.
We report the annulation of heterocyclic building blocks to access pi-extended polycyclic aromatic hydrocarbons (PAHs). The method involves the trapping of short-lived hetarynes with catalytically-generated biaryl palladium intermediates and allows...
Organometallic complexes are ubiquitous in chemistry and biology. Whereas their preparation has historically relied on ligand synthesis followed by coordination to metal centers, the ability to efficiently diversify their structures remains a synthetic challenge. A promising yet underdeveloped strategy involves the direct manipulation of ligands that are already bound to a metal center, also known as chemistry-on-the-complex. Herein, we introduce a versatile platform for on-the-complex annulation reactions using transient aryne intermediates. In one variant, organometallic complexes undergo transition metal-catalyzed annulations with in situ generated arynes to form up to six new carbon–carbon bonds. In the other variant, an organometallic complex bearing a free aryne is generated and intercepted in cycloaddition reactions to access unique scaffolds. Our studies, centered around privileged polypyridyl metal complexes, provide an effective strategy to annulate organometallic complexes and access complex metal–ligand scaffolds, while furthering the synthetic utility of strained intermediates in chemical synthesis.
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