SP3 rich library synthesis via Photoredox


    A group at Vertex Pharmaceuticals Inc. led by Dr Michael Boyd have shown in a recent publication that flow chemistry can vastly improve the yields of sp3-sp2 cross-coupled compounds, during a library photoredox synthesis using the Vapourtec E-Series, and UV-150 photochemical reactor.

    In 2009, Lovering et al. reported that compounds with a higher proportion of sp3 carbons (Fsp3) are more successful in drug-development programmes than those with a lower proportion. As such, incorporating more sp3 functionality is quite desirable, but traditional cross-coupling methods like the Suzuki-Miyaura coupling form sp2-sp2 bonds. Boyd and the group at Vertex have instead used the single-electron photoredox cross-coupling of alkyl halides and potassium alkyl trifluoroborates to build a library of sp3-sp2 coupled compounds, using an E-Series and a UV-150.

    As is the case with many photochemical processes, the photoredox coupling investigated by the group at Vertex faces a number of challenges as a batch process: oxygen is often able to quench photoexcited states or even participate in reactions so must be excluded; a consequence of the Beer-Lambert law is that light penetration in a batch system is poor, resulting in poor reaction efficiencies, and requiring very dilute reactions. As a result, scale-up is challenging.


    By using flow chemistry and the UV-150 photochemical reactor, Boyd and the Vertex group overcome many of these problems, but a chemical difficulty remains; the cross-coupling is limited to secondary and activated primary potassium alkyl trifluoroborates. Therefore, the group make use of hypervalent catechol silicates to overcome these challenges and, using the UV-150 photochemical reactor, have built a library of compounds from appropriate potassium alkyl trifluoroborates and their own stock solutions of catechol silicates, for which they describe a very useful and broadly applicable preparation protocol. For comparison, the team ran the same chemistry in batch, and found that without exception, the flow method resulted in significantly higher conversions with much greater throughput. Finally, the team took one of the more modest-yielding catechol silicate couplings and, after an investigation of temperature, solvent, nickel catalyst loading and photocatalyst choice, were able to improve the yield from 53 – 85%.

    In the text, the group conclude that their “procedure widens the substrate scope of the coupling reaction and is efficient for producing a greater range of analogues bearing a high Fsp3”. Dr Ryan Skilton, research scientist at Vapourtec comments “showing such a straightforward method for sp3 to sp2 coupling is going to be of enormous interest in medicinal chemistry groups, and showing how an E-Series and UV-150 can be used as tool to build a library like this is really exciting”. We look forward to seeing what’s next for Vertex and the group led by Dr Boyd.

    To go to the paper click here

    To read about the E-Series click here

    To read about the UV-150 click here

    To view the poster highlighting complementary work click here

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