The akuammiline alkaloids are a family of intricate natural products which have received considerable attention from scientists worldwide. Despite the fact that many members of this alkaloid class were discovered over 50 years ago, synthetic chemistry has been unable to address their architectures until recently. This minireview provides a brief overview of the rich history of the akuammiline alkaloids, including their isolation, structural features, biological activity, and proposed biosyntheses. Furthermore, several recently completed total syntheses are discussed in detail. These examples not only serve to highlight modern achievements in alkaloid total synthesis, but also demonstrate how the molecular scaffolds of the akuammilines have provided inspiration for the discovery and implementation of innovative cascade reactions for the rapid assembly of complex structures.
The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methanoquinolizidine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (−)-2(S)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described.
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.
We report the non-decarbonylative Mizoroki–Heck reactions of amide derivatives. The transformation relies on the use of nickel catalysis and proceeds using sterically hindered tri- and tetrasubstituted olefins to give products containing quaternary centers. The resulting polycyclic or spirocyclic products can be obtained in good yields. Moreover, a diastereoselective variant of this methodology demonstrates its value for accessing adducts bearing vicinal, highly substituted sp3 stereocenters. Our results demonstrate that amide derivatives can be used as building blocks for the assembly of complex scaffolds.
We report the first total synthesis
of the complex akuammiline
alkaloid picrinine, which was first isolated nearly five decades ago.
Our synthetic approach features a concise assembly of the [3.3.1]-azabicyclic
core, a key Fischer indolization reaction to forge the natural product’s
carbon framework, and a series of delicate late-stage transformations
to complete the synthesis. Our synthesis of picrinine also constitutes
a formal synthesis of the related polycyclic alkaloid strictamine.
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.
Picrinine, which is a member of the akuammiline family of alkaloids, was first isolated in 1965 from the leaves of Alstonia scholaris. The natural product possesses a daunting polycyclic skeleton that contains a furanoindoline, a bridged [3.3.1]azabicycle, two N,O-acetal linkages, and six stereogenic centers. These structural features render picrinine a challenging and attractive target for total synthesis. This paper provides a full account of our synthetic forays toward picrinine, which culminates in the first total synthesis of this long-standing target. Central to the success of our approach is the use of the Fischer indolization reaction to introduce the C7 quaternary stereocenter and the indoline nucleus of the natural product's scaffold. We probe some of the subtleties of this classic transformation by examining some of the most complex Fischer indolization substrates to date. Additionally, we describe various roadblocks encountered in our experimental efforts, which were successfully overcome to complete the total synthesis of picrinine.
Die Akuammilin‐Alkaloide bilden eine Klasse faszinierender Naturstoffe, die vielfach Beachtung gefunden haben. Obwohl viele Akuammiline schon vor über 50 Jahren entdeckt wurden, ist es erst vor kurzem gelungen, diese Strukturen zu synthetisieren. Dieser Kurzaufsatz gibt einen Überblick über die Geschichte der Akuammilin‐Alkaloide, einschließlich ihrer Isolierung, Strukturaufklärung, biologischen Aktivität und vorgeschlagenen Biosynthesen. Darüber hinaus werden kürzlich abgeschlossene Totalsynthesen vorgestellt. Diese Beispiele veranschaulichen nicht nur die Leistungsfähigkeit der Totalsynthese zum Aufbau von Alkaloiden, sie zeigen außerdem, wie die Molekülgerüste der Akuammiline die Entdeckung und Realisierung von innovativen Kaskadenreaktionen zum schnellen Aufbau komplexer Strukturen angeregt haben.
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