Tamiflu Synthesis Part 2

We have slightly altered the machine proposed synthesis of Tamiflu that was put up on the 19th of January 2014 to provide an alternative approach to the production of the TM, using the same disconnections.

 

This altered approach would be useful if the original tandem Grubbs CM followed by an RCM does not work, and also if the coordination and chelation models were incorrect and a mixture of isomers is obtained - and - a chiral resolution proves too costly or low yielding to utilize. 

 

This changes the longest linear sequence from 3 to 5, but still completes the synthesis of Tamiflu in 6 steps overall. There have been some questions regarding the need for protection of the ester, but it is likely that altering the order in which that group is installed could also resolve any potential problems that might arise.

 

We like to try to avoid protecting groups where necessary. If reactivity, or conditions can be utilized to avoid unwanted reactions then we opt to try for that first, and in the case of syntheses this small, we would suggest proceeding without protecting groups on the first run.

 

This proposed synthesis still utilizes the original disconnections, but it's also important to note that the desired COOR substituted oxo-cyclohexadiene intermediate can easily be reached in a similar number of steps from other known oxo-cyclohexadiene derivatives.

 

And this showcases the strength of our software, as it continues to improve in the selection of highly efficient disconnection points. This is an area that we have worked very dilligently on over the past few months, and so we have thus far produced a software package where in the majority of the cases, the disconnections are flexible enough that even if the originally proposed reactions do not work, similar reactions or the alteration of the synthetic order can often produce the desired TM in the same or a similar number of steps.

 

This also makes the majority of our synthetic methods highly customizable...

 

In addition to the syntheses put up on figshare, the software has also produced other, slightly longer methods that are problem free and would still reach the TM in less steps than have currently been published in literature.

 

However, despite that fact, we find the Jan 19th synthesis, as well as some of the others derived directly from it, more interesting for the following reasons:

As we are focusing mostly on the generic pattern recognition of our software, we are more interested in the exotic syntheses with the more efficient disconnections than we are in the syntheses that would be considered more traditional and therefore more "safe".

 

The ultimate goal is to design a system that can accurately balance the risk vs reward in these situations, and provide synthetic strategies, reaction conditions, predictions, etc, that are situation specific, and that accomplish the task in the most efficient means possible.

 

That is to say, if you are attempting a risky or novel reaction, but your overall synthesis is only 7 steps vs 30, you can afford to take a risk on a novel reaction. Even more so if that synthesis can be altered slightly and still produce your TM at 7 or slightly more (say 8 to 10) steps with more traditional methods that are more guaranteed to work. 

 

What's interesting about these syntheses to us is therefore the fact that they showcase how the software is starting to improve in its selection of intermediates, disconnection points, and - though we haven't presented any of that data yet - the prediction of novel chemical reactions, reaction success, etc.

 

We've still got a long way to go with stereochemistry (depending on the disconnections proposed) but overall, even that area of the software's performance has been steadily improving over time... 

 

Summary:

Access to the source code and other project data requires the signing of a non-disclosure, as well the status of collaborator (which has additional requirements).

 

For more questions or comments about this project, please send an email to: Jamie@ITSMolecularDesign.com. 

 

Please note that we are always looking for the submission of negative data. You can contact us at the email address provided for more information.