Wednesday, April 19, 2017

Decarboxylative Alkenylation

Our latest publication in decarboxylative cross-coupling of redox-active esters was published earlier today.  We will let you check out the publication and the SI (>450 comprehensive pages) for the details of our decarboxylative alkenylation, so this blog post will discuss the behind-the-scenes account of how the project developed.

This saga started over one year ago, in December 2015 at Pacifichem in Honolulu, Hawaii.  Inspiried by back to back talks from Prof. Larry Overman from UC-Irvine and TSRI’s very own Prof. Ryan Shenvi towards the synthesis of clerodane diterpene. Our group’s recent experience in cross-coupling and as well as our prior work on natural product synthesis led us to hypothesize that multiple clerodane natural products could be accessed from a common carboxylic acid intermediate in short order via a decarboxylative alkenylation. 

Initial scheme to access clerodane diterpenes

Shortly thereafter, we presented the above scheme to Phil, and he quickly realized that this strategy could be complementary to the tried-and-true sequence of ester reduction/oxidation/olefination (DIBAL/Swern/Wittig, for example).  Our previous decarboxylative cross-coupling methods were targeted towards medicinal chemists, but olefins are prevalent in natural products, and carboxylic acids (from esters) are common synthetic intermediates, so the marriage of these two entities could prove useful for synthetic chemists targeting natural products.

Phil wasn’t satisfied with just targeting a single class of natural products; he tasked us with determining if this disconnection proved strategic for a variety of natural product classes (other than the clerodane diterpenes).

We went back to our office, and within the day we found that many different classes of natural products could benefit from this strategy.  In particular, macrocyclic polyketides (cladospolides) could arise from difunctionalization of widely abundant tartaric acid.  For smaller natural products, this strategy could be employed as an alternative to OsO4 dihydroxylation chemistry, which has been used in the synthesis of these types of natural products.  At this point, Phil declared, “mission is go for launch.”
Natural products synthesized

We were shortly thereafter joined by Dr. Tian Qin and a fellow graduate student, Kyle McClymont. With Tian and Kyle’s help, we started initial investigations on the decarboxylative alkenylation and arrived at optimized conditions shortly thereafter. We found that this transformation works under both Ni and Fe catalysis and is compatible with organometallic reagents derived by a variety of conditions. Additionally, the activation and cross-coupling can be carried out in the same reaction flask.

Although our true interest was in synthesizing natural products, we conducted a substrate scope as a testing platform for the viability of this methodology. The scope is presented in the publication, so we don’t want to go into detail here.  However, we do want to graciously thank our collaborators at Asymchem in Tianjin, China, who tested and showed that our method was viable even on mole scale (ca. 620 grams) without any significant changes to the reaction conditions.  We also want to thank Ben and Scott from Bristol-Myers Squibb, as they found that our methodology could be used to access methyl ketones when traditional methods (such as Weinreb amides) fail.

(Left) Redox-active ester (Center) Mole-scale reaction (Right) Purified product (in a 500 mL flask)

A new graduate student, Kyle Knouse, joined us in the summer of 2016.  His previous work on lyngbic acid and related natural products allowed us to identify these targets as prime examples for this methodology. We were also joined by Dr. Lara Malins, our group’s peptide expert, and she showed yet again that these decarboxylative reactions can be conducted on peptide substrates. With the combined efforts of the team, we were able to access over 60 substrates and 16 natural products. If you are interested in trying out this reaction, please see the following flow chart (also found in the SI) to guide you in the best conditions for your particular coupling partners.

Flow chart user-guide for decarboxylative alkenylation

In addition to being field tested both at BMS and Asymchem, Phil himself wanted to see how this reaction compared to traditional carbonyl olefination methodologies. Undeterred by his recent humiliating defeat, Phil didn't lose his competitive edge and challenged the lab’s resident samurai warrior, Yuzuru Kanda, in a race to install an olefin on a glutamic acid derivative. Yuzuru was given the Wittig-based route and Phil was given the decarboxylative route.   Who won?  Watch the video to find out…

After completing the project, in true chemist fashion, we celebrated by going on a hike at Iron Mountain, which was followed by a beer at Nickel Beer Company in Julian, CA. 

Please let us know if you have any questions or comments regarding the work!  Thanks for reading!

Jacob and Rohan


  1. Great chemistry, really impressive scope! I have a couple of questions:
    Does this reaction work with (N-protected) alpha-aminoacids? I see glutamate side chain reacting but couldn't quickly find terminal carboxylic acid as a substrate in previous papers.
    Is it possible to make sp2-sp2 coupling this way?
    And experiment-unrelated, why is it so common to put NMR spectra without any labels except structure into SI?

    1. Thanks! We do have examples of an alpha amino acid in our Fe-catalyzed negishi arylation (J. Am. Chem. Soc. 2016, 138, 11132−11135); in this case, we use a phthalimide protecting group for the nitrogen of leucine and phenylalanine. We also have many examples of protected-proline derivatives. We haven't thoroughly investigated the ideal conditions for these types of substrates because we would lose the stereochemistry of the starting material (since we believe these reactions have alkyl radical intermediates).

      For sp2-sp2, this is an ongoing topic of study in our lab.

      As far as the NMR spectra are concerned, we include all characterization data in the SI, so we don't include this information on the spectrum itself.

  2. excellent work.

    On a completely unrelated note; I also enjoy how the Baran group can turn anything into a pissing contest. These days dick length is not only inversely proportional to the length of your total synthesis (at the cost of correctly counting steps), but directly proportional to the length of your supporting information.

    1. We appreciate your open and candid comments, but we can assure you that there's no machismo or competition here. We simply want to provide as much material as we can to the community. Regarding SI length, the community is under no obligation to read or download this information. However in the rare case that someone might be interested it is there for perpetuity. We (and phil especially) are ego-less and just want to do useful stuff. Thanks for commenting at OpenFlask.

  3. This is a staggering amount of goodness, so congratulation!

    One question I have - after you found that Ni(acac)2 + bipyridine (1:1) is the best catalytic system, have you tried to isolate the actual catalyst complex that forms from these two? Pretty X-ray never hurts, and sometimes pre-formed and isolated bench stable catalyst can offer some advantages - or not (and then you can show that in a paper that a complex prepared in situ is every bit as good as isolated on).
    One more - please have you considered using dimethylacetamide instead of DMF?

    1. Hi Milkshake,

      Thanks for your kind words! We actually haven't ever tried to isolate the catalyst; we always used it as a stock solution in DMF or MeCN.

      I don't think we tried DMA for this reaction because we quickly found that DMF (and MeCN for some substrates) worked well.

    2. For those who are industrially minded, NMP is a fine alternative to DMF. If the environmental concerns of NMP of troubling, the Armids from Akzo Nobel are useful.

  4. my only complaint about DMF is variable quality of some commercial batches, and its photosensitivity (sunlight produces Me2NH + CO) so thats where DMAc better, especially when you need anhydrous (Aldrich Sure seal DMAc is reliable and reasonably priced) or if you need to make stock solutions for long term use

  5. Someone needs to make PSB an IMDB page

    1. Maybe we can put that on the list of group jobs.

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  7. "For example, tartaric acid is perhaps the cheapest enantiopure chemical that can be purchased (about US$1 per mole)...". Have you considered sucrose?