Integrated catalysis opens new arylation pathways via regiodivergent enzymatic C–H activation

Abstract

Despite major recent advances in C–H activation, discrimination between two similar, unactivated C–H positions is beyond the scope of current chemocatalytic methods. Here we demonstrate that integration of regioselective halogenase enzymes with Pd-catalysed cross-coupling chemistry, in one-pot reactions, successfully addresses this problem for the indole heterocycle. The resultant ‘chemobio-transformation' delivers a range of functionally diverse arylated products that are impossible to access using separate enzymatic or chemocatalytic C–H activation, under mild, aqueous conditions. This use of different biocatalysts to select different C–H positions contrasts with the prevailing substrate-control approach to the area, and presents opportunities for new pathways in C–H activation chemistry. The issues of enzyme and transition metal compatibility are overcome through membrane compartmentalization, with the optimized process requiring no intermediate work-up or purification steps.

An Engineered Tryptophan Synthase Opens New Enzymatic Pathways to β‐Methyltryptophan and Derivatives

“…Recently our laboratory and the Sewald group both showed how halogenase enzymes can be integrated with palladium-catalyzed cross-coupling chemistry, in one-pot reactions, to affect the regioselective arylation or alkenylation of C-H positions of aromatic scaffolds. [19] Following this approach, we were able to affect the direct C5-arylation of β-mTrp 1 to give 5-phenyl-β-mTrp 12, in a one-pot reaction with 63 % yield, using the PyrH-CLEA to generate intermediate aryl bromide (11) and sSPhoS and Na2PdCl4 to catalyse cross-coupling with phenyl boronic acid. These results, coupled with our previous studies, [19a] indicate that combination of StTrpS (βL166V), with halogenases and transition metal catalysis can open the way to more highly modified β-mTrp derivatives that would be difficult to prepare directly from a functionalised indole precursor using TrpS.…”

“…Although 5-substitued indoles proved to be poor substrates for StTrpS (βL166V), the halogenase PyrH can be used to generate 5-chloro or 5-bromo-(2S,3S)-β-mTrp, with the more reactive bromo derivative enabling further derivitisation using cross coupling chemistry using a one-pot integrated approach. [19] Finally, the use of LAAO in the presence of a non-selective reductant enables the complete stereoinversion of the (2S,3S)-β-mTrp to the (2R,3S)-diastereomer in near quantitative yields. StTrpS (βL166V) alone or in combination with halogenase or LAAO enzymes provides a convenient biocatalytic route, offering significant advantages over the synthetic procedures, to a range of functionalised β-mTrp derivatives, which have proven useful building blocks for drug synthesis.…”

One-Pot Combination of Metal- and Bio-Catalysis in Water for the Synthesis of Chiral Molecules

“…Thus, it is not surprising to find in the literature several examples that reported the combination of metal-catalyzed C-C coupling reactions in aqueous media with different biotransformations. In this sense, this section covers the combination of: (i) Pd-catalyzed Suzuki coupling with bioreductions [100], bioaminations [101] or enzymatic halogenations [102,103]; and (ii) Pd-catalyzed Heck reaction and bioreduction [104]. Furthermore, and in the final part of this section, we review the combination of indium-mediated Barbier-type coupling [105] or Zn-catalyzed aldol reactions [106] with enzymatic oxidations or bioreductions, respectively.…”

RadH: A Versatile Halogenase for Integration into Synthetic Pathways

“…The halogen substituents installed by these enzymes are often important for the bioactivity of the natural products and can also be used as an orthogonal handle for further synthetic derivatization 2. Tryptophan halogenases (Trp‐Hal) from bacteria are the most well characterized Fl‐Hal enzymes and have been subject to detailed structural and mechanistic investigations 1, 3.…”

“…Previously, we showed how RadH can be integrated into synthetic pathways with chemocatalysts 2. To further demonstrate the versatility of RadH, we sought to integrate this enzyme into an engineered biosynthetic pathway to generate novel halogenated “non‐natural” products in vivo.…”