Modified Metalloenzymes for Stereoselective ATRA Reactions

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Solution Overview

Problem

Conventional small-molecule catalysts face challenges in achieving enantiocontrol and diastereocontrol in atom transfer radical addition (ATRA) and cyclization (ATRC) reactions due to the difficulty in maintaining tight association with radical intermediates, leading to low selectivity and limited substrate scope.

Innovation Solution

Modified metalloenzymes, such as heme and non-heme enzymes, are engineered to perform stereoselective ATRA/ATRC reactions by modifying enzymes like cytochromes P450 and Bacillus megaterium P450 with specific mutations, enabling enantio- and diastereocontrol over a broad range of substrates through intimate interaction with radical intermediates.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If conventional small-molecule catalysts are used in ATRA/ATRC reactions, then the reaction can proceed, but enantiocontrol and diastereocontrol are poor due to difficulty in maintaining tight association with radical intermediates

Engineering Contradiction:

Improveenantiocontrol and diastereocontrolVSAvoidassociation with radical intermediates

Core Design Contradiction:

Manufacturing precisionVSReliability

Solution Approach 1:

The patent employs modified metalloenzymes as intermediary catalysts that provide a chiral environment for radical intermediate stabilization. The enzyme active site acts as a mediator between the radical precursor and substrate, enabling tight association through non-covalent interactions while maintaining enantiocontrol and diastereocontrol during the ATRA/ATRC reaction.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the catalytic properties of metalloenzymes by changing amino acid residues in the active site through site-directed mutagenesis. These parameter changes in the enzyme structure alter the electronic and steric environment, enhancing the ability to stabilize radical intermediates and control stereochemistry while maintaining catalytic activity.

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If natural enzymes are used for catalysis, then excellent stereoselectivity is achieved, but the catalytic repertoire is limited to reactions found in nature

Engineering Contradiction:

ImprovestereoselectivityVSAvoidcatalytic repertoire

Core Design Contradiction:

Manufacturing precisionVSAdaptability or versatility

Solution Approach 1:

The patent creates multi-functional metalloenzyme catalysts that can perform both their native biological functions and new-to-nature ATRA/ATRC reactions. By modifying enzymes like cytochrome P450 and Bacillus megaterium P450, the catalysts gain universal applicability across different substrate types while retaining their inherent stereoselective capabilities.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The patent expands the catalytic repertoire by modifying enzyme parameters through amino acid substitutions that enable new reaction types. The modified metalloenzymes exhibit altered reactivity profiles, allowing them to catalyze ATRA and ATRC reactions with diverse substrates including alkyl halides, aryl halides, and unsaturated compounds that are not substrates for the wild-type enzymes.

Inventive Principle:

Principle #35Parameter changes

3Manufacturing precision

If modified metalloenzymes are engineered for stereoselective ATRA/ATRC, then high enantio- and diastereoselectivity is achieved, but the device complexity increases

Engineering Contradiction:

Improveenantio- and diastereoselectivityVSAvoidenzyme modification complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent applies local quality changes by modifying only specific amino acid residues in the enzyme active site rather than the entire protein structure. This localized approach to enzyme engineering achieves the desired stereoselectivity enhancement while minimizing overall structural complexity and maintaining the enzyme's natural fold and stability.

Inventive Principle:

Principle #3Local quality

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The modified metalloenzymes achieve high enantio- and diastereoselectivity in ATRA/ATRC reactions, producing a diverse array of enantioenriched products with excellent yields and stereopurity, overcoming the limitations of natural enzymes and conventional catalysts.

Implementation Method 1

atom transfer radical addition (ATRA) or atom transfer radical cyclization (ATRC) reaction

Methodology Applied

Scientific EffectAtom transfer radical addition:

Implementation Method 2

difficulty in maintaining tight association with radical intermediates

Methodology Applied

Scientific EffectRadical intermediate formation:

Implementation Method 3

Modified metalloenzymes are utilized to perform enantioselective and/or diastereoselective atom transfer radical addition chemistry

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 4

a metalloenzyme catalyst that exerts enantiocontrol or diastereocontrol over the first and the second substrates

Methodology Applied

Scientific EffectStereoselective catalysis: Catalysis

Data Source

PatentUS20240336943A1Compositions, Systems and Methods for Atom Transfer Radical Addition Reaction

Publication Date: 2024.10.10 RGT UNIV OF CALIFORNIA

AI summary

Biocatalysts and methods for performing atom transfer radical addition chemistry are described. Generally, modified metalloenzymes are utilized to perform enantioselective and/or diastereoselective atom transfer radical addition chemistry on a broad range of substrates.