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Just look at the structure of this alkaloid!

Sometimes you just have to step back and marvel at the structures that are found in nature.  Check out zamamiphidin A, a new manzamine alkaloid isolated from an Okinawan sponge by J. Kobayashi and co-workers (Organic Letters).  Heptacyclic.  Quaternary ammonium.  Massively bridged.  Well done, sponges!

Zamamiphidin A

Synthesis of Kopsia lapidilecta alkaloids – The RCM approach takes a hit (retraction)

Let’s take a moment to appreciate the challenges of synthetic organic chemistry.  Not exactly stamping out widgets, is it?  Witness the recent retraction of an approach to the lundurine alkaloids from Steve Martin’s group (original Organic Letters paper here, retraction here).  Since the early days of RCM, Martin’s group has recognized its potential for the construction of alkaloids, but the presence of nitrogen atoms in RCM precursors can lead to problems.  Such may be the case here.

The Kopsia lapidilecta alkaloids

The Kopsia lapidilecta species of Asian flowering plants produces numerous alkaloids that bear the novel 5,6,12,13-tetrahydro-11a,13a-ethano-3H-pyrrolo[1′,2′:1,8]azocino[5,4-b]indole ring system.  Representative examples include lapidilectine B and lundurine B.

Synthetic efforts

Back at the University of Michigan, we became interested in making these alkaloids using our 2-azaallyl anion cycloaddition chemistry.  It was a war, but postdoc Ill Young Lee and Ph.D. student Patrick Stoy were up to the task.  The key step was the cycloaddition of the 2-azaallylanion shown with phenyl vinyl sulfide.  The resultant pyrrolidine cycloadduct was then converted on to lapidilectine B, completing the first total synthesis of any of the Kopsia lapidilecta alkaloids (JACS, JOC).

Martin’s group at Texas (link) and Sarpong’s group at Berkeley (link) have published approaches to the lundurines and lapidilectines, respectively, the former using RCM to make the central azocine core and the latter using an intramolecular electrophilic aromatic substitution approach.

Trouble with the RCM approach

Martin and co-workers reported a potentially simple way to access these alkaloids.  They carried out an RCM reaction on 24, which itself was made by an RCM assembly of the pyrroline ring.  The closure of the eight-membered ring was reported in 26% yield, producing 1.4 mg of 25.  A larger amount (12.9 mg) of 25 was then hydrogenated selectively to produce 26.  Their plan was to use this approach to make lundurine B. (Edit: Corrected yield of RCM.)

 

In a recent retraction, Martin has now withdrawn this work “on the basis that the RCM of 24 to give 25… is not reproducible; thus, the reduction of 25 to give 26… is also not reproducible.”  The wording of this sentence is curious to me, since the reproducibility of the reduction should not depend on the reproducibility of the RCM (the RCM product was used after purification), but nonetheless, this is a setback for this potentially powerful approach.

I hope the situation can be remedied.  Our synthesis of lapidilectine B was linear and involved a lot of steps, and I’d like to see the Martin or Sarpong approaches succeed; they have the potential to be considerably shorter.  I imagine there are other groups working on these alkaloids; they’re too beautiful to resist.  In my opinion.