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Actinophyllic Acid   

28 March 2010 16,730 views 14 Comments

Overman, Martin, Rohde. JACS, 2010, ASAP. DOI: 10.1021/ja100178u. Article PDF Supporting Information Group Website

I don’t think there is a single academic whose syntheses I look forward to more than Larry Overman.  I’m not sure exactly why that it, but I think the main reason is the overall standard of his work, as well as his tendency to write fascinating and informing full-papers.  He’s also one of those professors who ‘owns’ a particular type of natural product; ‘Overman molecules’ are of course, alkaloids.

This paper not only discusses a ‘first synthesis’ in a racemic form, but also a second generation, and more interestingly, an asymmetric synthesis, which I’ll be focusing on.  So why all this effort?  Well, Actinophyllic acid was identified in a medium-throughput screen, targeting thrombin-activatable fibrinolysis inhibitors.  These hits interupt the biological processes that control the fine balance between blood clotting and blood thinning – clearly a worthy pursuit.

So to the first piece of exciting chemistry – the transformation of a racemic route into asymmetry.  The key to their route was the synthesis of a chiral 3-hydroxy-piperidine – which may seem simple, but required serious determination.  Initial attempts focused on asymmetric epoxiation (Shi, Jacobsen), but were met with appalling and poor enantioselectivity.  Next the group tried an organocatalytic hydroxylation of an aldehyde.  This solved the enantioselectivity problem (96%), but with poor efficiency, managing about 30% yield.  Latterly, they tried a Noyori reduction of an enone, which when ozonolysed and cyclised, gave the product in an impressive yield and enantioselectivity.  But that is one hell of a catalyst!

The product of this reaction, an acetoxy aminal, was used immediately in a Lewis-acid promoted coupling with an indole.  Their efforts in producing the enantiomerically enriched starting material paid-off here, as the acetoxy group controlled the reaction, allowing the group to achieve both an excellent yield and diastereomeric excess.

Removal of the acetal protecting group (using Dibal-H, which didn’t touch the t-butyl malonate), and oxidation of the revealed hydroxyl group set the group up for the next reaction.

This impressive C-C bond formation works by formation of a pair of enolates (using LDA), and then an oxidative coupling with a rather complex looking iron reagent.  However, Overman explains that it’s rather easily formed by simply combining ferrous chloride with DMF.  Adding this to the di-enolates allowed formation of the tetracyclic products in excellent yield; another reaction I need to add to my tool-kit…

A cerium-chloride mediated addition of vinyl magnesium bromide was somewhat complex, as when a dimethyl-malonate moiety was present further reaction couldn’t be prevented.  However, using a t-butyl malonate was quite successful, allowing construction of the final intermediate after borohydride reduction and hydrolysis of the remaining ester.

The came the final reaction, and coup de grace, an aza-Cope-Mannich cascade which generates the final target in cracking yield.  The reaction works by firstly addition of formaldehyde to the amine, forming an iminium ion.  This then performs a Cope [3+3] rearrangement, generating a enol, which collapses in a Mannich reaction to form a C-C bond and complete the synthesis in it’s enantiomerically enriched form.

There’s a hell of a lot that I haven’t discussed from this paper – two racemic syntheses and a discussion of biosynthesis, and that the aza-Cope-Mannich may be biomimetic.  Add all that to a great discussion, as well as a neat synthesis, and we get what I come to expect from Overman.

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  • joolz says:

    Interesting article – I know it’s a bit late, but… tetravalent phosphorus and nitrogen in the catalyst? And what about the H-BH3 complex? I thought BH3 was a Lewis acid, how come a hydrogen atom can donate electrons? Apologising in advance for either looking like a smartass or just being stupid :P

  • MChem says:

    Apology accepted.

  • European Chemist says:

    Trialkyl or triaryl phosphines are very common ligands. And the catalyst features Ru(II), so the nitrogens bear no formal charge.
    Further, this beast is prepared from NaBH4 and a Ru(II) precursor and its structure was confirmed by X-ray analysis. Sometimes it’s best just to take a look at the reference…

    About the synthesis: Overman belongs to that rare type of chemist who favors quick disclosure of chemistry in communications but follows them by highly useful and honest full papers. This one is simply a mine of valuable information. And the synthesis is beautiful, by the way.

  • MC_Hammer says:

    Why is everyone talking about the “first” total synthesis of actinophyllic acid? It has been synthesized by Overman already back in 2008…

    Beautiful asymmetric version of the old reactions, though…

    A nice paper! – business as usual if we are talking about Larry’s publications!

  • Sergio says:

    That is really awesome

  • ch3mical says:


    agreed, the prep is simple. And a very soluble oxidant relative to CuCl2 or other alternatives which simplifies reaction set-up and purification.

  • HK says:

    Any special precautions for storing it? I’d like to make some and set it aside for a rainy day.

    So they say in the paper that modeling of intermediates found that the overlap of the vinyl and iminium orbitals was pretty poor for the aza-Cope/Mannich, but they went with it anyway. They mention that it was “comparable” to other known aza-Cope/Mannich. Is that common? To say that “objectively, this probably isn’t going to work, but relative to known transformations, it’s downright plausible?”

    Beautiful stuff, and made for a fun literature presentation.

  • mt says:

    Today in ACIE: Two syntheses of Englerin A, both using Au-catalyzed cyclization of a similar substrate, both submitted and published on the same day. One by Echavarren, one by Dawei Ma.

  • fhp says:

    I was impressed with how efficiently they both got to their respective chiral substrates for the gold cat. reaction. ~7 steps in both cases…I must say, I liked Echevarren’s approach better though. Nice work and interesting molecules. Perhaps a blog in the near future?

  • InfMP says:

    Yeah that had to be simultaneous submission, they probably saw each other present the same thing at a conference.

    I’ve never seen the same day be a cooincidence. closest ive seen is like a week (Nozaki-Hiyama-Kishi dicovery of active nickel contaminent)

  • ymu says:

    Check the repetition of the story at ACS publications too!


    What happened to TS guys….?

  • Catharanthus says:

    Off topic question.

    How much a PhD med chem chemist or process chemist right after post-doc can make in the UK? The online offers seem to be quite low compared to the US>