Friday, January 9, 2015

Academia–industry collaboration in the route optimization of taxadienone

In early 2012, we reported the gram-scale synthesis of a non-natural taxane, taxadienone, as well as that of a natural taxane, taxadiene. Now, chemists at Albany Molecular Research Inc. (AMRI) report a route optimization of taxadienone in none other than the process chemistry journal, OPRD.

Before we describe how the story of this collaboration came about, we will take you through the route optimization process. The synthetic route itself is identical, as all the intermediates of our synthesis appear in their synthesis as well, but the reactions have been scaled up and the yields have been improved. 

Reaction scale-up: We made ~2 g of taxadienone whereas AMRI made ~10 g.
Reaction yields: Please see the figure below.

Although the contents of AMRI’s paper will not be reiterated, we will show their concluding paragraph here (almost verbatim from their manuscript):

“The reported route to taxadienone was successfully optimized and scaled-up to decagram quantity. Thermal hazards associated with the production of bromodiene were addressed by employing a continuous flow reactor. The crystallization of a cyclized diketone at the penultimate step proved to be a decisive factor for obtaining taxadienone of high quality.”

Now, as for the behind-the-scenes story. This story started out as an interesting “experiment” in academia-industry collaboration. Our laboratory is engaged in many collaborations with industrial groups, including LEO Pharma, Bristol-Myers Squibb, and Sigma-Aldrich, and in most cases, our industrial partner has a project goal toward which we provide expertise and in-house research findings (industry —> academia outsourcing). This Baran–AMRI collaboration has actually been a “reverse collaboration” in which our initial synthetic route was taken up by an industrial group for scale-up (academia —> industry outsourcing). Through many interactions, by email, by phone and in person, AMRI saved our group much time and effort by generating large amounts of enantioenriched taxadienone. With this extra time in hand, we were able to study the front-line chemistry for longer periods of time, resulting, for example, in the synthesis of taxuyunnanine D. AMRI’s work also validated our synthesis by having an independent group reproduce our results, even when some of the reactions can be tricky. This “field-testing” of chemistry further refined our initial work, when some reactions were difficult to scale up (even though our initial synthesis was performed on a decent scale already). 

Although this sort of “reverse” academia-industry collaboration is rare, we learned a lot from this experience! We understand that there is a time and place for this type of collaboration but we believe that in the near future, such collaborative work will be more commonplace. Finally, this is a wonderful advertisement for the impressive capabilities of the AMRI team and we recommend all our industrial friends that are looking to outsource challenging chemistry to give AMRI a try!

Written by Yoshihiro Ishihara
Uploaded by Nathan Wilde