Monday, June 11, 2018

Pyrone Diterpenoids: A Not-So-Boring Journey 4 Years in the Making

Today, our work on the synthesis of natural products from alpha-pyrone diterpene family is out in JACS. While the paper details our final approach to these compounds, I would like to share the behind the scenes journey towards these molecules. Some of you may recognize that this topic was presented by Phil during his DOC lecture last month.
In the summer of 2014, our long time industrial collaborators  at LEO Pharma asked our lab to synthesize subglutinols A and B due to their reported immunosuppressive properties and potential as therapeutics. At that time, Kevin (postdoc in the lab and now a medicinal chemist at Eli Lilly) and I were charged with accessing these natural products in a concise and divergent manner. Assuming that Suzuki cross-couplings are always supposed to work (perhaps naively), we wanted to append the pyrone to the terpene skeleton via a cross-coupling strategy. To cut a long story short, after 8 months of starting the project (see SI for failures to this intermediate), we prepared the substrate to try our key step. However, it won’t be a good story (only in hindsight) without a catastrophe. Although “borono-subglutinol” could be cross-coupled with simple coupling partners like bromobenzene, the coupling never worked with the required bromo-pyrone, and we spent another 9 months trying to install the pyrone. However, all our efforts with met with spectacular failure. 
With the project in shambles, we decided to come up with a boring route (as Phil calls it) to prepare the natural product so that LEO could do the biological studies. We could in fact synthesize subglutinol A in 25 steps (detailed in the SI), and the natural product was delivered to LEO. Based on our “boring” route, we identified the following key limitations; (1) It took 5 steps to install 5 out of the 6 stereocenters on the molecule (including the core and subglutinol A THF ring) but 16 steps to install 1 stereocenter (C4 stereochemistry) as well as the pyrone; (2) While we had a way to access both subglutinol A and B THF rings selectively, the divergence occurred fairly early on in the sequence, and we wanted to delay this as much as possible; (3) We had a material throughput problem – the polyene cyclization required 3 grams of Mn(OAc)3and 1 gram of Cu(OAc)2for every gram of SM which resulted in purification nightmares!!
I won’t go into detail about how we ended up solving each of these problems ,but the key highlights are:
(1)For the polyene cyclization, electrochemistry allowed us to reoxidize Mn(II) to Mn(III) during the course of the reaction, making the reaction catalytic in Mn salts and resulting in a much simpler workup procedure.
(2)To fix the other problems, we came up with a “revised retrosynthesis”. So far, the sterically hindered C18 methyl group and diortho substituted pyrone had been the bane of my existence. We decided to kill two birds with one stone via a more radical disconnection. Disconnecting C4–C20 bond would allow us to use the sterics of C18 methyl group to our advantage (blocking the top face of the molecule). With regards to the late divergence to access both subglutinols A and B, we believed that under radical cross-coupling conditions, the C12 stereochemistry could be inverted through a stereoablative radical intermediate from a more sterically hindered cis THF ring of subglutinol A to a more stable trans THF ring of subglutinol B. However, the core of the molecule that we could easily access had an extra carbon at both the C12 and C4 position. One way to burn off a carbon to generate an alkyl radical was to perform a decarboxylation transform! This was helped by the fact that our lab was working decarboxylation cross-couplings at the same time and therefore, we thought this would be a good opportunity to develop decarboxylative Giese and alkenylation transformations.
To cut a long story short, we went on to develop a general decarboxylative Giese and alkenylation transformations of redox-active esters, and they could be implemented to the synthesis of subglutinols A and B. Eventually, we could also demonstrate our “revised retrosynthesis template” to prepare sesquicillin A and finish the first total synthesis of higginsianin A. We considered this a less-boring route, but not as exciting as this kind of boring. 
I have been on this project for the past 4 years, and while there have been a lot of ups and downs (definitely more downs), we did eventually reach our desitination! I just want to give a shout out to two extremely talented visiting students, Alex Novak and Yutong Lin, as well as thank our collaborators at LEO for their patience. If you have any questions about the chemistry or natural products themselves, please let us know! Thanks for reading!!



  1. your substrate is quite different but I was stuck once in a project with Suzuki reaction on 2-chloro-4-pyrones - they ring-open easily under the standard Suzuki conditions. My solution was to use dried powdered K2CO3 + 4A powdered activated sieves in anhydrous dioxane with Pd(PPh3)4, microwave 130C and then the yield was good.

  2. one more comment about Mn salts mucking up the workup: I had a good experience working up Mn(OAc)3 oxidations with large excess of KF, you get hexafluoromanganate complexes that are very soluble. Likewise, KMnO4 oxidations done in the presence of KF are much less pain. The only issue is fluoride incompatibility with silyl protecting groups but you don't have any in your substrate

  3. Hi Milkshake,

    Thanks for your comments. As far as I recall, we did not try the condition you suggested. With our suzuki coupling the mass balance with regards to the pyrone was accounted for by the dehalogenated pyrone and/or bromo pyrone starting material. The pyrone and boronic acid fragments seemed to be fairly resilient to the conditions we attempted. For instance, pyrone could be coupled with other electrophiles such as phenyl boronic acid in ~70% yields. We believe, the difficulty in getting the coupling to work arose because we were trying to cross-couple two very sterically hindered pieces (diorthosubstituted pyrone + hindered alkyl boronic acid).

    With regards to the Mn work up, we did not try the KF workup. That's an excellent suggestion and something we should try. Apart from improving the workup, one our goals was also to move away from using Mn(OAc)3 itself as a reagent and use the much cheaper Mn(OAc)2 instead.