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Raging Hormones – Gram-Scale Synthesis of Prostaglandin PGF2α

“Stereocontrolled organocatalytic synthesis of prostaglandin PGF in seven steps” Coulthard, G.; Erb, W.; Aggarwal, V. K. Nature 2012, online view. DOI: 10.1038/nature11411

In my very un-scientific survey of the green chemistry-branded journals, I see way more new methodologies than I see total syntheses. I hope to single-handedly change this, and show how green a total synthesis can be by writing about the awesome recent synthesis of prostaglandin PGF by Aggarwal and coworkers. First, a few words on the target molecule. Being hormones, prostaglandins such as PGF are involved in tons of biological processes. Interestingly, instead of being synthesized by some important gland and acting in far-off regions of the body as are endocrine hormones, they are autocrine or paracrine hormones and are synthesized “on-site.” The first structural characterizations of prostaglandins came in the 1960s, some 30 years after their initial discovery. Soon after, they became the subject of numerous syntheses, the first of which was achieved by E. J. Corey in 1969. A series of syntheses followed, but even 40 years later, the structurally-related glaucoma drug latanoprost is synthesized in 20 steps using Corey’s 1969 prostaglandin strategy.

That’s right, the prostglandin structural motif is medicinally relevant. So, not only would an improved synthesis be cool from a fundamental science perspective, it might actually be moved into industrial production and have an immediate impact!

Aggarwal and coworkers’ strategy hinges on the conjugate addition of a functionalized vinyl side chain to enal 1. The stereochemistry of the addition would  be controlled by the cis orientation of the bicyclic lactol. This bond disconnection is what distinguishes the Aggarwal strategy from all others. Awesome idea, but first they had to synthesize enal 1. This, rightfully so, seems to have occupied the majority of the authors’ efforts.

After initial failures, a few model systems, and probably lots of bad nights in lab, they developed an efficient asymmetric synthesis of 1 via the proline-catalyzed aldol dimerization of succinaldehyde (2).

The fact that their initial “let’s just try this thing” attempts yielded only succinaldehyde oligomers is no surprise when you look at the crazy-sensitive nature of some of the reaction intermediates and the insane variety of undesired reaction pathways available to them. As shown below, initial aldol reaction of succinaldehyde (2) yields trialdehyde 3, which can only yield 1 if it forms the correct hemiacetal and undergoes a second aldol reaction followed by dehydration without reacting with another succinaldehyde molecule. Quite a tall order.

Model studies suggested that the initial aldol condensation was proceeding without a problem. They then synthesized another model system to investigate the second aldol reaction and dehydration steps. Sure enough, treatment of the lactone shown below with proline yielded only trace amounts of product, suggesting that the final two steps leading to the enal were indeed the problem. They eventually discovered an ammonium catalyst that affects the desired reaction, as shown below. Why this catalyst works is a mystery to me and is not commented on by the authors.

Heading back to the actual system, the authors subjected succinaldehyde to proline and ammonium mixed catalysis. This is where things get a bit crazy. They performed the reaction in the presence of proline for a certain amount of time to affect the initial asymmetric aldol reaction, after which they threw in the ammonium catalyst to affect the second aldol reaction and dehydration.  After optimizing for all sorts of variables (time for proline catalysts, time for mixed catalysis, etc), they came upon these conditions (e.r. determined on the methyl acetal).

Okay, 20% yield sounds bad, but to get to their key intermediate in one step from commercially available starting materials, it’s not bad! I’m really surprised at the high concentrations used here, especially when their problematic step was an intramolecular reaction that was competitive with further intermolecular reaction with more starting material. The authors do state that oligomeric byproducts were indeed formed but could be removed by filtration (awesome!). Also, they stated that the high concentration conditions “greatly facilitated scale-up of the reaction.”

So now that they’ve got their key intermediate in large quantities, I’ll just skip straight to the complete synthesis as shown below. Exactly according to plan, the installation of the vinyl side chain as well as the ketone reduction both proceed with complete stereoselectivity. Huzzah!! Somehow I had never seen a mixed vinyl cuprate like this one used before, but the Bruce Lipshutz group discovered way back in 1984 that the 2-thienyl group in such complexes could act as a “dummy” ligand and not competitively add to electrophiles. Cool! The final step also serves as an example of old chemistry being used and refined in the total synthesis arena, as a similar Wittig olefination was used by Corey way back in 1969.

Notice they were able to make 1.9 grams of this stuff, in seven linear steps. From what I hear, syntheses that can yield grams of product are very likely to be amenable to making kilograms of product. So, I will be on the lookout for this strategy actually being put to use in the large-scale manufacture of latanoprost and other prostaglandin-like drugs.


  1. Julian says:

    Nice post Lee!

    For the benzylammonium catalyzed intramolecular aldol followed by dehydration, did they report yields for smaller ammonium catalysts? Or maybe for monoprotic ones?

    Perhaps the cation forms two hydrogen bonds to the diketone to lower the barrier for the intramolecular reaction, with the two benzyl groups preventing intermolecular reactivity.


    • Lee Bishop says:

      Interesting hypothesis Julian! That seems definitely plausible. Unfortunately they did not report using any smaller ammonium catalysts. They used a pyridinium salt and trifluoroacetic acid, both of which gave no product. Interestingly they did get 5% yield using proline, which can also form two hydrogen bonds with the aldehydes, so you might be onto something!


  2. John H says:

    Why not try a thiourea?


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