Computer Assisted Data Analysis for Small Molecule Structure Verification

Synthetic chemists are constantly seeking ways to simplify how they work. Doing so allows them to maximize their ability to innovate, whether through designing new compounds, identifying reaction pathways, optimizing reaction conditions, or actually synthesizing compounds. In an industry like pharmaceuticals, such innovation is crucial to moving forward the discovery and development of candidate compounds and winning the race to market.

However, innovation must be balanced with validation. For this reason, organic chemists spend a lot of their time verifying synthesis steps. Verifying these steps in a way that’s both robust and efficient promises to decrease the amount of time chemists spend on rote verification steps while increasing the time they can spend innovating new small molecules.

Computer-assisted verification offers an efficient way to verify molecular structures. Bruker’s Complete Molecular Confidence (CMC) software suite implements this concept for chemists characterizing and elucidating small molecule structures. It supports the chemist with the interpretation of routine NMR spectra, providing automated NMR data processing and analysis. The software uses an algorithm that analyses routine NMR spectra with regard to structural consistency, spectral assignment, multiplet analysis, concentration determination, and purity assessment.

Let’s look at how computer-assisted verification might work in the synthesis of alternariol, a mycotoxin produced by the fungi involved in fruit spoilage, and a compound with therapeutic potential as an antimicrobial agent.

Organic synthesis offers one route to synthesize alternariol. It gives the chemist the advantage of being able to verify the synthetic product at each step in the process.

CMC-assist offers a streamlined way to move from acquired data to spectrum analysis to structure verification, giving the chemist a clear set of stop/go checkpoints based on a spectra’s consistency or inconsistency with a given structure. The progress can be tracked on the spectrometer itself, with the analysis results available in IconNMR, as pictured:

In analyzing the raw data, CMC-assist checks the spectra against known structures, providing information about concentration, consistency, multiplicity, and assignment.

Finally, all the analysis results can be reported in standard formats for patents and publication.

Biosynthesis offers a more challenging situation, with multiple products in a mixture requiring separation and verification, and without the ability to check intermediate steps. Therefore, only the final products can be verified.

In biosynthesis of alternariol, products like norlichexanthone closely resemble the desired compound may also be generated, and so must be carefully elucidated as well. CMC-se offers a computer-assisted approach for this task.

In this workflow, the software uses a more robust set of NMR experimental data, with data from 1D and 2D experiments, to populate a table, which is then refined and used to assess correlation with proposed structures. As you can see, this assists the chemist in seeing if a structure is likely, possible, or, as in this case, unlikely:

These two software tools alleviate the chemist’s daily analytical work, one by confirming the small changes that occur in each synthesis step, the other by assembling a fuller data picture to verify a final product or products. Both use the power of computer-assisted intelligent tools to make life in the analytical lab easier, and speed discovery and development.