Tag Archive | 2-azaallyl anions

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In a recent retraction, Martin has now withdrawn this work “on the basis that the RCM of 24 to give 25… is not reproducible; thus, the reduction of 25 to give 26… is also not reproducible.”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

Hooked on heterocycles

I have a question: How did you get hooked on heterocycles?

I’ll go first:

A failed exam, cocaine, and a crusty chemist:  How I came to love heterocyclic chemistry.

I became an azaphile during my undergraduate days at UNC-Chapel Hill, a process that involved failing a final exam, becoming enraptured by the chemistry of lysergic acid, morphine, and cocaine, then being turned down for undergraduate research.  Well, initially at least.

At some point, anything with a nitrogen atom in it became fascinating, especially if the nitrogen was in a ring.  Everything else started to look… bare.

How did this happen?  I can trace it back to Professor Robert L. McKee, a “heterocyclic chemist’s heterocyclic chemist” at UNC.  He’s no longer with us, but he’s worth a tribute, as you’ll see.

You know those dreams where you’re not prepared for the final exam?

I had Professor McKee for two classes, one that proved traumatic, the other enlightening, both being important to my baptism into heterocyclic chemistry.

First, the trauma.

I walked into the final exam for McKee’s second semester organic chemistry class with a strong A average and a lot of confidence.  I loved the class and had studied hard for the final.  But my confidence quickly faltered as I found out that he had made two final exams, one for those with an A average and one for everyone else.  Huh?

I sat down and looked at it, and there were all these crazy rings with nitrogen atoms sprinkled all over them, none of which I’d never seen.  And the questions were unintelligible.

I walked to the front of the room to ask what was going on, and Professor McKee told me that the “A” students were supposed to have read Chapter 10 on Nucleic Acids on their own, for the exam, which would be entirely on that topic.  I had somehow missed this announcement, despite attending every single lecture.

I sat back down and tried, but I couldn’t answer a single question.  I got maybe ten points.

My “A” became a “B”, which McKee told me was generous.

I still get sweaty thinking about this.

Nonetheless, it exposed me to purines, pyrimidines, nucleosides, and nucleic acids, prime denizens of the world of heterocyclic chemistry.

Ironically, I would end up as VP of a company that specializes in nucleic acids chemistry some twenty-five years later.

I’d like to see that exam again.

Onward to enlightenment…


With my tail between my legs, I enrolled in UNC’s advanced organic chemistry course, taught by none other than my beloved Professor McKee.

Things went much better this time.

We used Noller’s Advanced Organic Chemistry, an old textbook even back then.  I loved it because it had plenty of history and was rather descriptive in its approach.  It was also heavily slanted towards heterocyclic chemistry.

What I remember most were McKee’s lectures on the chemistry of lysergic acid, morphine, and cocaine.  These were beautiful molecules and came with such rich chemistry.  I can’t say I remember much else from the class, but that was enough; I was hooked on heterocycles.

It felt empowering to know something about the drugs that were making the rounds back then.  Even more exciting was the realization that powerful physiologically-active substances can actually be synthesized.  From scratch!

Pearson/Mans synthesis of (+)-cocaine

I remember sitting on the bed in my dorm room at UNC with a ball-and-stick molecule of cocaine, thinking, “I wonder how I might make this?”  Not because I wanted to use it or sell it, mind you; just because it was beautiful.

Fast forward to 2004, when Douglas Mans, a talented graduate student in my research group at the University of Michigan, synthesized (+)-cocaine, the enantiomer of natural (-)-cocaine.  Full circle.

Do you really want to do undergraduate research with this guy?

Sometime during this period, my budding interest in heterocyclic chemistry led me to stop by McKee’s office.  It was attached to a one-man lab, and since he was getting near retirement, he no longer had graduate students.

I was struck by the dark, archaic lab crowded with hundreds of vials of crystals, each labeled with hand-drawn structures of unique heterocycles.  I could swear there was also a retort containing some bubbling liquid.  I wanted to get in there and make something!

A few things concerned me, though.

First, he smoked a pipe.  In the lab.  Not good.

Second, he tasted all of his compounds.  Even as a neophyte, I knew this couldn’t be a good thing, and I quickly made an association between this practice and the various growths I could see on his skin.  He was old-school though, and taste was part of compound characterization.

Despite my misgivings, I asked this kindly, crusty man if I could work for him.  His response was quick:  “If you want to do research and continue on to graduate school, you need to go work for someone other than me.”

He suggested Ernest Eliel, whose area was stereochemistry, a topic I also loved.  I joined Eliel’s lab, where I managed to get some heterocyclic chemistry in:  We published the first example of neighboring group participation involving a four-membered ring sulfur intermediate, a thietane.

And we used Barry Trost’s method for making the thietane intermediates, relevant in that I ended up getting my Ph.D. with Barry at Wisconsin, working on… things with lots of nitrogens!

So, how did you get hooked on heterocycles?