Tag Archive | RCM

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In a recent retraction, Martin has now withdrawn this work “on the basis that the RCM of 24 to give 25… is not reproducible; thus, the reduction of 25 to give 26… is also not reproducible.”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.


A beautiful synthesis of (+)-pseudococaine

You might recall my fascination with cocaine (no, not for that reason), which culminated in a total synthesis of its enantiomer, (+)-cocaine, using our 2-azaallyl anion chemistry (Mans and Pearson, 2004, blog post here).  Davies and co-workers at Oxford have now published a short and elegant synthesis of (+)-pseudococaine, a diastereomer of natural (-)-cocaine.

The key step is a highly diastereoselective transannular iodoamination with concomitant N-debenzylation by iodide ion to produce the tropane skeleton:

It’s worth pointing out that intramolecular iodoamination reactions of simple primary and secondary amines can be problematic due to N-iodoamine formation and subsequent shenanigans, including potential post-cyclization aziridinium ion formation.  Davies’ reaction is well-behaved, since transannular iodoaminations are especially favorable, the amine is tertiary, and the product is not susceptible to aziridinium ion formation.

The cyclization precursor is made by a very nice sequence involving conjugate addition of a chiral lithium amide to an enoate with subsequent in situ trapping of the enolate by a diasteroselective aldol condensation (7% of the other aldol diastereomer is not shown).

Nice work!