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Non-native Intramolecular Radical Cyclization Catalyzed by a B12 -Dependent Enzyme
Jianbin Li1, Amardeep Kumar1, Jared C Lewis1
1Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Angewandte Chemie (International Ed. in English)
|October 24, 2023
Summary
Researchers repurposed a vitamin B12-dependent enzyme, CarH, for novel radical cyclization reactions. The engineered enzyme CarH* efficiently forms lactams and unique spirocycles, expanding biocatalysis applications.
Area of Science:
- Biocatalysis
- Enzyme Engineering
- Organic Synthesis
Background:
- Vitamin B12 (cobalamin) and its derivatives possess unique reactivity.
- B12-dependent enzymes are currently underutilized in biocatalysis.
- Transcription factors offer potential protein scaffolds for enzyme engineering.
Purpose of the Study:
- To repurpose the B12-dependent transcription factor CarH for non-native radical cyclization reactions.
- To engineer a variant, CarH*, with enhanced reactivity and selectivity for B12-catalyzed transformations.
- To explore the synthetic utility of engineered B12-dependent enzymes in forming complex cyclic structures.
Main Methods:
- Engineering of the B12-dependent transcription factor CarH into CarH*.
- Utilizing CarH* to catalyze radical cyclization reactions.
- Mechanistic studies to elucidate reaction pathways and cofactor control.
Main Results:
- CarH* successfully catalyzed the formation of gamma- and delta-lactams via redox-neutral or reductive ring closure.
- Engineered enzyme demonstrated enhanced reactivity and selectivity compared to free B12 cofactor.
- CarH* achieved unusual spirocyclization via dearomatization of pendant arenes, yielding bicyclic 1,3-dienes.
- Demonstrated a novel synthetic route to 1,3-dienes, distinct from existing 1,4-diene methods.
Conclusions:
- Protein scaffolds are crucial for controlling the reactivity of vitamin B12 cofactors.
- Repurposed B12-dependent enzymes like CarH* significantly expand the synthetic toolbox for biocatalysis.
- This work highlights the potential for engineering B12-dependent enzymes for novel chemical transformations.
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