After a break I return to see that Fujita has been applying his superb crystalline sponge x-ray methodology. Three very recent papers again highlight the importance of this technique: 1) The crystalline sponge method updated, 2) Undeniable Confirmation of the syn-Addition Mechanism for Metal-Free Diboration by Using the Crystalline Sponge Method and 3) Structure determination of microbial metabolites by the crystalline sponge method.
Combined with his previous work these new results are tremendous contribution to making the area of structure determination available for all. The first paper re-examines the entire methodology and addresses the “major improvements in the method which have been made in the guest-soaking and data-collection steps“. Fujita acknowledges that “the data quality of the trapped guest compounds was not very high and the use of restraints and constraints based on chemical information was necessary to refine the guest structures. This was not due to insufficient knowledge or techniques of crystallographic analysis but instead due to unoptimized experimental proto- cols throughout the method.” Now he has gone some way to optimisation of the method -“Unoptimized protocols in every step of the method, reported in our original paper, have been thoroughly optimized to be one of an applied technique in X-ray crystallography.” This self-critical paper is definitely worth reading.
The second paper on alkene diboration says “The stereochemical outcome of the recently developed metal-free 1,2-diboration of aliphatic alkenes has, until now, only been elucidated by indirect means (e.g. derivatization). This is because classical conformational analysis of the resulting 1,2-diboranes is not viable; in the 1H NMR spectrum the relevant 1H resonances are broad-ened by 11B, and the occurrence of the products as oily compounds precludes X-ray crystallographic analysis. Herein, the crystalline sponge method is used to display the crystal structures of the diboronic esters formed from internal E and Z olefins, evidencing the stereospecific syn addition mechanism of the reaction, which is fully consis- tent with the prediction from DFT calculations.” Some beautiful pictures
The third and possibly the most exciting paper is the coupling of the x-ray methodology to a HPLC allowing more or less direct x-ray of the fractions. I agree with his abstract “Structures of metabolites produced in microgram quantities by enzymatic reductions with baker’s yeast were analyzed by the crystalline sponge method. The X-ray data provided reliable structures for trace metabolites including their relative and absolute stereochemistries that are not fully addressed by conventional NMR and LC-MS analyses. Technically, combining two or more chromatographic purification techniques is essential because, unlike abundant synthetic compounds, extracted metabolites contain many low level UV-slient inpurities. The crystalline sponge method coupled with HPLC purification (LC-SCD) would thus be a useful method for metabolic analysis and drug discovery.” Another great picture here
Here is one of the key statements in the paper “having successful results in this study, we are more convincing that the crystalline sponge method, coupled with HPLC separation, will innovate the structural analysis of scarce amount of microbial products in natural product chemistry as well as in drug discovery.”
He is absolutely correct. Imagine, a continuous flow reactor system + a HPLC + sponge x-ray machine. I think that over the coming months and years we will see more and more of this X-ray method being applied to all branches of chemistry. I would guess that “industry” is already applying these methods. Think about the advantages in the drug discovery and development process.
It’s not very often that a ground-breaking technique appears, NMR was one recent example, I think this is another. Time will tell but this is Nobel Prize, worthy up there with the best of them.
Congratulations Prof. Fujita and colleagues.
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