The KiloMentor Approach compared with Yoshida’s Tag Strategy

The KiloMentor philosophy or strategy of process development ranks process schemes not only by the number of reaction steps and their anticipated approximate yields but additionally and with higher priority by the anticipated simplicity of the reaction work-ups and purifications expected as part of the process steps.  A proposed ranking system for isolations is provided in an earlier KiloMentor blog. 

A consequence of this selection principle is that process steps which involve phase switching in the isolation/purification, as taught be D. P. Curran, tend to be preferred over steps in which starting materials, by-products, and co-products are not so easily separated.  In its simplest embodiment, intermediates that are carboxylic acids or amines and that can be separated by acid-base extractions are preferred intermediates as contrasted to neutral substances. However, as readers will discover there are many more robust phase switching techniques.

Compare and Contrast: The Yoshida Teaching

The same philosophy is taught by Jun-ichi Yoshida Kenichiro Itami and coworkers in their article, Chem. Rev. 2002, 102, 3693-3716, Tag Strategy for Separation and Recovery.  The key difference is that these authors are thinking about tagging products, reagents or by-products to simplify the separation in a process that has already been chosen and is just being optimized.  In contrast, KiloMentor would be making the choice among different proposed paper syntheses based, to a fundamental extent, upon whether the intermediates in the process steps are easily separable because they are naturally ‘tagged’ by the functional groups they bear. These naturally tagged intermediates are those intermediates containing (most frequently deployed) acidic and basic functional groups which enable simple acid-base extraction separations.  Put another way, KiloMentor uses the concept of phase tags to select a preferred route, while Yoshida teaches the contribution tagging can make to improving the ease of separation in a previously selected route. Also, while Yoshida’s review encompasses phase tags that are contained within or can be attached to, anyone of reagents, co-products and by-products and not just the desired products,  KiloMentor only looks at whether the desired intermediates themselves contain or could contain some tag.

Yoshida sees tags as being similar modus operandi to protecting groups. Typically a protecting group is introduced into a molecule in one step, protects its corresponding functional group during some transformation(s) and then is removed in still another step.  The protecting group protects a function group from undesired reaction. A tag is introduced intentionally before a process step, simplifies the isolation of pure product from the step and is subsequently removed.  The tag is not an inherent part of the process but a functional add-on. Yoshida does not completely ignore the kind of tagging Kilomentor recommends but calls it the masking of tags. To quote:

“Another approach to this issue is masking of tags (Scheme 7). In some cases, tags are masked so that tagged molecules retain their natural phase affinity. Thus reactions can be conducted under homogeneous conditions in organic solvents. After the reaction, however, the tag is converted into its active form to effect separation of the tagged molecule from untagged molecules. A typical example of this case is acid/base extraction. For example, an ammonium ion tag is unmasked by protonation of the corresponding amine tag and the tagged compound is extracted from the organic phase into acidic aqueous phase. Remasking the tag by neutralization enables reextraction of the tagged compound into the organic phase (phase switching). In such a case, the tag is not a simple tag, but a phase–trafficking tag or “phase shuttle” because it facilitates the back and forth movement of molecules from one phase to another.”

This explanation feels contrived because it makes the simple, complex, but if we must make reference to it, using this nomenclature, what KiloMentor is recommending is that, in making the initial route choice, higher consideration should be given to processes containing intermediates that comprise a “phase-switch.”