Computer Assisted Structure Elucidation (CASE) is a major challenge in and of itself.
We've been working on this for many, many years and we continue to make huge strides in this area. The technology is sound, the software is being used successfully worldwide, and generally a month does not go by where I don't hear of a nice success story of how our software has helped a scientist elucidate a challenging unknown.
I recently had a good conversation with a customer/colleague who was complimenting us on our efforts in automated structure verification (more on our progress in this area, a little later). His comments went something like this:
"The work you are doing in this area is really impressive, but you do realize that this it today's problem, right?
"Please, please do not forget about tomorrow's problem, which is of course fully automated structure elucidation!"
We certainly haven't forgotten about that, but of course it is a challenging problem. And of course the major limitation might just be having access to the most information rich experiments that are available.
One thing is for certain with CASE. The same rules apply to a software as applies with human. If the data is of high quality and information rich, the problem is going to be much easier to solve.
During that discussion above, we happened to be working with scientists at DuPont, evaluating the impact of the 1,1-ADEQUATE experiment for CASE.
The 1,1-ADEQUATE has obvious benefits for interpretation either by a human or software. The challenging part about many of the traditional 2D experiments is that they are fuzzy by nature, meaning that the correlations are unambiguous (2, 3, or 4 bond). The 1,1-ADEQUATE provides unambiguous correlations which allows from a stronger filter. That said, it is most productive to combine information from a 1,1-ADEQUATE with some experiments that reveal ambiguous correlations to reveal longer distance correlations that aid in the process of structure elucidation.
In the study, we evaluated NMR data for two natural products and ran them through ACD/Structure Elucidator in different combinations.
The take home was that, not surprisingly, the 1,1 ADEQUATE experiment had massive impact on the accuracy and speed of structure generation.
For the first natural product, Retrorsine the following was observed:
HMBC alone: No structures generated after 16 hours of generation time
1,1 -ADEQUATE alone: 553 structures generated after 4 hours and 40 minutes. Retrorsine was the top ranked structure after generation.
1,1- ADEQUATE + HMBC: 2 structures in < 1 second
This publication revealed really an outstanding observation for the impact that the 1,1 ADEQUATE experiment can have on efficient CASE.
The article has been published in Magnetic Resonance in Chemistry and can be accessed here:
Going back to the conversation I had, while this article certainly doesn't prove that fully automated structure elucidation is a reality, it does suggest one more step further in the ongoing process.
The key of course, is providing high quality, information rich experiments. However, before methods like this can really become applicable to a general audience these experiments have to become more accessible. Steve Cheatham and Michael Kline from DuPont did some really exceptional work here with some modern technology. NMR Experiments were run on a Bruker Avance 600MHz using a 5-mm TCI cryoprobe. 10 mg of sample yielded the acquisition times of 2.5 hours (16 scans) and 10 hours (64 scans).
Here's looking forward to the day where a chemist no longer asks, "Did I make what I thought I made?" and rather, "What did I make?"