5 research outputs found
Total Synthesis of (Ā±)-Phomoidrideā D
Described herein is a synthetic strategy for the total synthesis of (Ā±)āphomoidrideā
D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular DielsāAlder cycloaddition. A subsequent SmI2āmediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion
Synthetic studies toward the total syntheses of scholarisine A and phomoidride D.
Isolated in 2008 from a leaf extract of an Alstonia scholaris variant, scholarisine
A contains a unique pentacyclic architecture that makes it a challenging target for total
synthesis. Our approach toward the moleculeās polycyclic core consists of a nucleophilic
olefin addition into an activated isonitrile with subsequent addition of an adjacent ester
into the resultant carbocation to produce a polycyclic imine. The feasibility of this
proposed cascade cycloaddition was explored in a model system that presented an
analogous array of functionality within a similar, but not identical, carbon framework.
Although we were delighted to find that the model substrate was capable of undergoing
the desired cyclization process, it occurred in low yield and only when using an acyl
group as an activating agent, the product of which is not suited as an intermediate en
route to scholarisine A. Our efforts to access an advanced isonitrile-containing
intermediate was met with only limited success and concerns regarding overall efficiency
led us to eventually abandon the scholarisine A effort.
Phomoidrides A and B were isolated in 1996 from an unidentified fungus,
believed to be a steril Phoma variant. Phomoidrides C and D were later isolated from the
same fungus and were shown to be epimeric at the C7 stereocenter. The synthetic
challenges inherent to the phomoidrides have inspired many creative synthetic
approaches that have culminated in four completed total syntheses of members of the
phomoidride family. Our unique approach consist of a phenolic oxidation Diels-Alder
sequence and eventual radical cascade cyclization to produce a functionalized isotwistane
intermediate that undergoes a Grob-type fragmentation to produce the
bicyclo[4.3.1]decadiene core of the phomoidrides. Attempts to install the maleic
anhydride and complete the synthesis from a diester precursor failed. Subsequent model
studies determined the maleic anhydride can be accessed from a Ī²-keto ester
functionality. In our current third-generation approach toward phomoidride D, we have
achieved fragmentation to produce the phomoidride core and attempts to install the
maleic anhydride and complete the total synthesis are currently underway
Wharton-Fragmentation-Based Approach to the Carbocyclic Core of the Phomoidrides
The carbocyclic core of the phomoidrides has been synthesized efficiently and in high yield. Key steps include a phenolic oxidation/intramolecular DielsāAlder sequence, tandem radical cyclization, and a late-stage Wharton fragmentation of a densely functionalized isotwistane skeleton
Toward the Synthesis of Phomoidride D
An efficient and highly stereoselective approach toward
the phomoidride
family of natural products is described. The carbocyclic core structure
was assembled using a tandem phenolic oxidation/DielsāAlder
cycloaddition and a tandem 5-<i>exo</i>-<i>trig</i>/5-<i>exo</i>-<i>trig</i> radical cyclization
to deliver an isotwistane intermediate that, upon a late-stage xanthate-initiated
Grob fragmentation, furnishes the requisite bicyclo[4.3.1]Ādecene
Toward the Synthesis of Phomoidride D
An efficient and highly stereoselective approach toward
the phomoidride
family of natural products is described. The carbocyclic core structure
was assembled using a tandem phenolic oxidation/DielsāAlder
cycloaddition and a tandem 5-<i>exo</i>-<i>trig</i>/5-<i>exo</i>-<i>trig</i> radical cyclization
to deliver an isotwistane intermediate that, upon a late-stage xanthate-initiated
Grob fragmentation, furnishes the requisite bicyclo[4.3.1]Ādecene