Controllable incorporation of one or more fluorine atoms into a small organic molecule, such as a drug candidate, is highly desirable. For example, trisubstituted alkenyl fluorides are bioisosteres of secondary amides, the link that connects amino acids in a protein. Amide bonds can be cleaved enzymatically and exist in a lower energy stereoisomeric form. Trisubstituted alkenyl fluorides are their more robust doppelgängers. E-trisubstituted fluoro olefins are surrogates for fleetingly stable cis amide bonds, offering a unique opportunity for studying high-energy peptide analogues.
Figure 1: A trisubstituted alkenyl fluoride mimics Leu-enkephalin’s secondary amide.
We wondered if there would be a way to access a large variety of trisubstituted alkenyl fluorides catalytically and in either stereoisomeric form. The approach could be streamlined if the alkene would have, in addition to a fluorine, another substituent that could be easily and chemoselectively modified in a stereocontrolled manner. This way, a single fluoro-substituted alkene could be transformed to a myriad of other desirable compounds. Our idea was that an attractive way to obtain such trisubstituted fluoro-alkenes would be through cross-metathesis.
Figure 2: The blue print for an all-catalytic approach to stereocontrolled synthesis of trisubstituted alkenyl fluorides.
Olefin metathesis is a central chemical transformation and a main area of investigation in the Hoveyda group. For more than two decades our group has been involved in the development of new Ru, Mo, and W complexes that promote ring-closing, ring-opening, and/or cross-metathesis reactions. Apropos Mo and W systems, the group has worked together with the Schrock group since 1997. The collaboration was born during a lunch conversation at a Gordon Conference in early August of that year, and the first joint paper was submitted in early December of that same year (now close to 100 manuscripts). This partnership has generated a plethora of uniquely effective olefin metathesis catalysts. The latest set, the monoaryloxide pyrrolide (MAP) and monoaryloxide chloride (MAC) complexes, notable for their high reactivity and ability to control stereochemistry, served as the cornerstone of our investigations.
Figure 3: Richard Schrock (left) and Amir Hoveyda (right) at a recent meeting and some of the complexes they have jointly developed.
We started with a few questions: What would be the optimal alkene substrates? What functional group would be amenable to cross-metathesis and sufficiently reactive for the ensuing alterations? If the alkene starting material were to be disubstituted, how might we avoid having them just react with one another (homocoupling) or produce other undesired byproducts? After some thought and debate, the team agreed on a promising cross-partner, one that is commercially available in either isomeric form, namely, 1,2-dichloro-1-fluoroethene (E-1 and Z-1). Alkenyl chlorides are suitable substrates for catalytic cross-coupling (a stereoretentive process), and there was good precedent that the C–F bond would not interfere.
Figure 4: The original plan and some of the expected byproducts.
We were ready to run experiments, and started by probing the reaction between a Z-disubstituted olefin and polyhalogenated Z-1. The initial returns were exciting and reassuring: the desired trisubstituted alkene bearing a fluoro/chloro terminus could indeed be generated. However, considerable amounts of two byproducts were also formed. These were footprints that led us to the possible reason as to what might be going awry in the catalytic cycle. We analyzed the data and reached a consensus regarding what was going wrong and why. The upshot, daunting and yet exciting, was that probably the only solution was to go where no one has been before. That is, we needed to find a way of efficiently and stereoselectively merging two trisubstituted alkenes, entities that are typically perceived to be a safe terminus in a catalytic cross-metathesis. We needed to be a bit more daring.
Figure 5: The initial promising data, the subsequent disappointment, and finding a way to merge two trisubstituted olefins.
Our first tip of the toe into the unknown waters was unpleasant. There was hardly any reaction when we presented Z-1 (or E-1) with a trisubstituted alkene, no matter which Mo complex was used. One thing the group has learned through the years is that, at time, a catalyst needs a bit of encouragement to join the fray. We imagined that we would need something a bit less intimidating than a trisubstituted alkene to lure a well-guarded (to shield it from rapid decomposition) Mo complex out of its shell. So, we added a very small amount of a disubstituted olefin and, indeed the cross-metathesis between two trisubstituted olefins was off and running – and stereoselective too. We had found a door that opened to a room filled with many possibilities. We could catalytically access a lot of different trisubstituted alkenes, E or Z, that had a fluoro and chloro substituent.
Through catalytic cross-metathesis and cross-coupling sequences, we could site-selectively as well as regio- and stereodivergently incorporate one or more fluorine atoms into structures of different bioactive compounds. This included obtaining a stereoisomerically pure alkenyl fluoride used in nematic liquids in LCDs, synthesizing peptide-like structures with trisubstituted alkenyl fluorides as amide bond isosteres, and easily generating all four stereoisomers of difluoro-modified rumenic ester, a promising anticancer agent.
Figure 6: A sampling of applications of the all-catalytic new strategy.
A criticism about Mo complexes is that they are air and moisture sensitive. While true, great progress has been made to render these systems truly practical. Scientists at XiMo, a company founded in 2010 by Hoveyda and Schrock, which has licensed and distributes these catalysts, have developed paraffin pellets that contain Mo complexes that can be handled and used without rigorous precautions (no glovebox or custom glassware). These commercially available paraffin pellets can indeed be used to generate trisubstituted fluoro,chloro-alkenes without any loss in yield or selectivity. In a “real-world” application, one of these catalysts was used to promote a 45–50 metric ton scale process.
Figure 7: The cross-metathesis reactions are easy to perform; commercially available Mo complexes embedded in air-stable paraffin tablets may be used.
We believe this exciting advance will impact drug discovery and investigations in biological chemistry. It also raises new questions. Might we someday be able to synthesize readily modifiable tetrasubstituted alkenyl fluorides? Only time will tell but I would not bet against us.
For the full report please see: Stereodefined alkenes with a fluoro-chloro terminus as a uniquely enabling compound class