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There are increasing environmental pressures to improve the sustainability of reaction processes in synthetic organic chemistry.  In response to these demands, new techniques and strategies are needed in order to accelerate and facilitate the synthesis and purification of organic compounds while minimizing the waste of solvents and chromatographic supports.  Indeed, much of the wastes produced in organic reactions originate from the extensive use of silica gel and solvents employed in the chromatographic purification.  Phase-switching strategies are very attractive as a means to avoid chromatographic purification.  In phase-switch chemistry, reactions take place conveniently under homogeneous conditions, and product separation is facilitated by a liquid partition or a precipitation–filtration operation.  All known phase-switching strategies require two chemically unproductive steps: attachment of the tag to the substrate, and detagging of the product at the end.  The latter operation often leaves an undesired remnant (or "trace") of the phase-switch tag.  We designed a new phase-switching strategy involving the boronic acid functionality as a productively convertible tag (Figure 1).  Rather than cleaving the extraneous tag at the end of a synthetic sequence, as in other phase-switch systems, the boronic acid can be derivatized productively using the wide range of selective transformations known for this class of compounds.  Because of the commercial availability of hundreds of functionalized boronic acids that can serve as potential substrates in many synthetic applications, this phase-switch system can also circumvent the tag attachment step.

We developed a liquid-liquid, water-organic phase-switching system by exploiting the known ability of boronic acids to form strong complexes with polyol additives at high pH (Figure 2).  We sought a polyol additive that would be polar enough to efficiently "phase-switch" hydrophobic boronic acids to an aqueous phase and be completely insoluble in organic solvents so as to avoid contamination of the organic layer.  Toward this end, the ability of different polyol additives to phase-switch the hydrophobic biphenylboronic acid from ethyl acetate to basic water was rapidly evaluated, and the hexol sorbitol, a cheap and non-toxic commodity chemical, was found to be the most efficient at a pH of 10 and over.  Further optimization identified sodium carbonate as a preferred, milder base.  The efficiency of this system was demonstrated in a control experiment whereby a mixture including p-tolylboronic acid and 9 other organic compounds with different functional groups was subjected to the optimal phase-switching conditions.  The comparison of proton NMR spectra between the initial mixture and the pure, recovered boronic acid (88% mass recovery) clearly demonstrates the high chemoselectivity of this phase switch system.  

A phase-switching system employing boronic acids as phase tags must be complemented with a broad repertoire of chemical transformations tolerant of this functionality.  In this regard, we have planned a number of simple transformations of model unprotected boronic acids with a phase-switch purification. Remarkably, we found that alcohol oxidations, carbonyl reductions, carbodiimide-promoted esterification, carbonyl addition reactions with organometallic reagents, and even a sequence of aldehyde alkynylation and alkyne-azide cycloaddition can all be realized in good to high yields and high purify after the phase-switch purification. 

In the planning of a phase-switch synthetic cycle to a desired compound class, the initial substrate is selected from a broad choice of commercial boronic acids, and that functionality is preserved until the last step of productive tag removal. To illustrate the virtues of the boronic acid functionality as a productive tag, we optimized a diversity-oriented chromatography-free synthesis of polysubstituted biaryl-containing isoxazolines involving a variety of common reactions such as Wittig olefination, [3+2] nitrile oxide cycloaddition, and amide couplings. The final productive clevage of the boronic acid tag was effected by a Suzuki cross-coupling reaction. Likewise, to demonstrate the value of this productive phase-switch concept in target-oriented synthesis, we put it to test toward a racemic synthesis of ezetimibe, (Zetia), a commercial b-lactam-containing anti-hypolipidemic drug (Figure 3).  Our synthetic sequence to ezetimibe emphasizes the possibility of using the boronic acid tag as a masked hydroxyl group. Thus, from p-boronobenzaldehyde, condensation with p-fluoroaniline generated a Schiff base, which was then reacted with a ketene to give the desired trans-configured b-lactam product in very good yield after a simple phase-switch purification.  The latter underwent a high-yielding alkene cross-metathesis with an allylic alcohol, followed by hydrogenation.  No chromatographic purification was necessary up to that stage.  The final step of productive tag removal was performed by simple B-C bond oxidation to yield ezetimibe in good yield. Although it was obtained as a mixture of diastereomers resulting from the carbinol center, this short synthesis further demonstrates the suitability of this concept for preparing highly functionalized molecules.