Stereoselective Synthesis of Non-Canonical Amino Acids via Photobiocatalytic Oxidative Coupling

Core Concepts

Photobiocatalysis enables the stereoselective synthesis of a range of α-tri- and tetrasubstituted non-canonical amino acids through cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts, and an oxidizing agent.

Abstract

The content describes a novel photobiocatalytic approach for the stereoselective synthesis of non-canonical amino acids. Photobiocatalysis, where light is used to expand the reactivity of an enzyme, has emerged as a powerful strategy to develop chemistries that are new to nature.

The key highlights are:

• The researchers repurposed a family of pyridoxal-5'-phosphate-dependent enzymes, threonine aldolases, for the α-C–H functionalization of glycine and α-branched amino acid substrates by a radical mechanism.
• This allowed the synthesis of a range of α-tri- and tetrasubstituted non-canonical amino acids possessing up to two contiguous stereocenters.
• Directed evolution of pyridoxal radical enzymes enabled the coupling of primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, in an enantio- and diastereocontrolled fashion.
• The cooperative use of photoredox catalysts and an oxidizing agent was crucial for this photobiocatalytic sp3–sp3 oxidative coupling reaction, which is unknown to chemistry or biology.
• This work provides a platform for stereoselective, intermolecular free-radical transformations that were previously inaccessible.

Stats

The reaction allows the synthesis of a range of α-tri- and tetrasubstituted non-canonical amino acids possessing up to two contiguous stereocenters.
Directed evolution of pyridoxal radical enzymes enabled the coupling of primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents.

Quotes

"Photobiocatalysis—where light is used to expand the reactivity of an enzyme—has recently emerged as a powerful strategy to develop chemistries that are new to nature."
"Cooperative photoredox–pyridoxal biocatalysis provides a platform for sp3–sp3 oxidative coupling, permitting the stereoselective, intermolecular free-radical transformations that are unknown to chemistry or biology."

Key Insights Distilled From

Stereoselective amino acid synthesis by photobiocatalytic oxidative coupling - Nature

by Tian-Ci Wang... at www.nature.com 05-01-2024

https://www.nature.com/articles/s41586-024-07284-5

Deeper Inquiries

How can the scope of this photobiocatalytic approach be further expanded to synthesize an even broader range of non-canonical amino acids?

To expand the scope of this photobiocatalytic approach for synthesizing a broader range of non-canonical amino acids, several strategies can be employed. Firstly, exploring the use of different organoboron reagents with varying functional groups can lead to the synthesis of diverse non-canonical amino acids. By optimizing the reaction conditions and substrate specificity of the engineered pyridoxal biocatalysts, a wider range of amino acid derivatives can be accessed. Additionally, incorporating different oxidizing agents and fine-tuning the photoredox catalysts can enhance the selectivity and efficiency of the oxidative coupling reactions, enabling the synthesis of novel non-canonical amino acids with unique structural features.

What are the potential limitations or challenges in scaling up this technology for industrial-scale production of stereoselective non-canonical amino acids?

Scaling up the photobiocatalytic technology for industrial-scale production of stereoselective non-canonical amino acids may face several limitations and challenges. One major challenge is the stability and activity of the engineered pyridoxal biocatalysts under large-scale reaction conditions. Ensuring the reproducibility and robustness of the enzymatic system at a commercial scale is crucial for maintaining high yields and selectivity. Another limitation could be the cost and availability of the required photocatalysts and oxidizing agents, which may impact the economic feasibility of the process. Furthermore, optimizing the reaction parameters, such as light intensity, temperature, and reaction time, for large-scale production while maintaining stereoselectivity can be a complex task that requires extensive process development and optimization.

What other types of biocatalysts or photocatalysts could be explored to further diversify the types of radical precursors that can be coupled in a stereoselective manner?

To diversify the types of radical precursors that can be coupled in a stereoselective manner, exploring alternative biocatalysts and photocatalysts can be beneficial. For biocatalysts, enzymes such as flavin-dependent monooxygenases or heme-containing proteins could be investigated for their potential in mediating oxidative coupling reactions. These enzymes may offer different selectivity profiles and reactivity towards a broader range of substrates, thus expanding the scope of non-canonical amino acid synthesis. In terms of photocatalysts, transition metal complexes or organic dyes with unique photophysical properties could be explored to enable the activation of different types of radical precursors under mild reaction conditions. By combining diverse biocatalysts and photocatalysts, new catalytic systems can be developed to achieve the stereoselective coupling of a wide variety of radical precursors for the synthesis of novel non-canonical amino acids.