Abstract: “The building block-based approach is increasingly being recognized as a highly flexible and efficient method for the automated construction of molecules. For biomolecules such as polypeptides, oligosaccharides, and oligonucleotides the common linkages between building blocks is easy to recognize. This has led to the development of automated platforms which have broadly enabled both experts and non-experts to explore biomolecule chemistry. If a similar strategy could be applied to small organic molecules, the societal impact would be tremendous as it would address a key bottleneck in the development and discovery of new drugs, fragrances, fertilizers, and materials. Toward the objective of creating a building block-based platform for small molecule synthesis, we have developed a novel method of forming carbon-carbon bonds in near perfect selectivity using carbenoid-boronate building blocks. We are now demonstrating how the saturated and unsaturated portions of small molecules can be installed using this platform, thereby paving the way to the automated construction of small molecules. To further demonstrate the utility of our new method, we plan to complete the synthesis of a natural product, sch 725674, an antifungal macrolide.”
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Nice talk Sriya! I’m not super knowledgeable about boron chemistry – are there acid-labile protecting groups for boronic acids that could potentially widen the applicability of this approach? Or do you simply not need them if you can make your base-sensitive functional groups later in the synthesis, like you’ve shown here?
Hi Philip, Thank you!
MIDA, an analog of TIDA that has protons in the place of gem dimethyl groups can undergo an acid promoted cleavage reaction. So it is probable that TIDA, the boron protecting group used in this project could undergo a similar pathway. And as you pointed out, this pathway would be useful to use in the presence of functional groups that are base sensitive! However, we haven’t explored acid promoted cleavage of TIDA as the functional groups needed for the total syntheses are tolerant of the mild basic conditions needed to cleave TIDA. I hope that answers your question! Please let me know if you have any more 🙂
Hi Sriya! Great presentation!
I have a couple of general questions: How many steps do you save, on average/in general, using the building block approach to synthesis of natural products vs. traditional synthetic methods? Second, are there differences in final yields of a natural product (just an example, or a genralization would suffice here for my curiosity) using the building block synthetic method vs. traditional methods?
Hi! The longest linear sequence in the synthesis is 9 steps which is close to the other syntheses of the macrolide that has been published. Regarding the yields, I have not looked much into this. In general, our goal is to be able to use building block based synthesis for the purposes of drug discovery, meaning we are not very focused on the yields, but rather on how quick or how efficient we can make enough of a natural product and its derivatives to test for biological activity. Since making derivatives and various analogs of a natural product can be extremely important in the process of drug discovery, approaching the synthesis of natural products through building block based construction allows easy access to derivatives as a block can simply be switched out to put a different functional group in or different stereochemistry, instead of having to make a molecule again from scratch that is only slightly different from the others.
And thank you! 🙂 Please let me know if this helps or if you have any other questions!
Thanks Sriya!
Very nice job and good significant chemistry. Did you determine stereochemical integrity in your sp3 coupling reactions? Also can you forsee any limitations on your carbenoid homologation reactions, in terms of the borate ester component (as all most of your examples were devoid of other functional groups)? Finally, would there be an issue in matching/mismatching if you tried the 1st coupling reaction towards samrioyotmcyin with the S-configuration at the Methyl bearing carbon?
Hi! I apologize for the late response! We have not yet determined the stereochemical integrity of the sp3 coupling reactions. However, the Aggarwal group has shown that these reactions are highly stereospecific and we foresee high dr and er ratios.
We have recently shown that a primary chloride, an azide, an OTBS and a tert butyl ester can survive the carbenoid homologation reactions. Functional groups that would not survive would be those that could readily react with a grignard. I would foresee a primary bromide or primary iodide not compatible with this methodology. I would also say that some heteroaryl rings might not work with an ortho position boronic ester, as the boronate complex forming will not be as stable. Also functional groups with enolizable protons could possibly not work. Although we have shown that a tert butyl ester works, I would think a methyl ester would possibly not work as the protons are much easily enolizable.
I would not think their would be an issue with mismatching according to the established reaction mechanism. The boronate complex formation followed by the 1,2 migration is completely stereospecific. The sigma bond of the boron-migrating group and the sigma star of the boron-leaving group must be aligned in order for the reaction to occur.
Thank you! 🙂 Please let me know if this helps and if you have any other questions!