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Yes—radical chemistry can make many unusual alpha-amino acids in a short, modular sequence. A nickel-promoted asymmetric coupling joins radicals generated from ordinary carboxylic acids to chiral sulfinimines. The sulfinimine controls the new stereocenter, while the acid supplies the side chain. In a 2018 study, the strategy was tested on more than 85 compounds and produced building blocks that are difficult to reach with conventional amino-acid chemistry.
The method is best viewed as a powerful complement to, rather than a universal replacement for, the 168-year-old Strecker synthesis. It avoids cyanide-based aminonitrile formation, can compress some multistep routes into one key coupling, and delivered milligram quantities for biological testing. It still relies on a redox activator and a chiral auxiliary, and some substrates—including benzoic acid—resisted the reaction.
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What the radical method actually does
Protein-making organisms mainly use about 20 standard amino acids, but medicinal chemists often need side chains that nature does not encode. Replacing a methyl group with a cyclopropane, adding a highly strained polycyclic fragment, or installing a side chain that resembles part of atorvastatin can alter a peptide’s shape, stability, permeability, or binding surface. Those changes create chemical space for molecular probes, peptide therapeutics, and inhibitors of protein–protein interactions.
The 2018 nickel-catalyzed strategy starts with a carboxylic acid rather than an aldehyde. The acid is converted into a tetrachlorophthalimide redox-active ester (often abbreviated a redox-active ester). Under the reaction conditions, that ester accepts an electron and fragments to release carbon dioxide and an alkyl radical. Nickel then captures and reorganizes that radical so it can add to a chiral sulfinimine, forming a carbon–carbon bond at the future amino-acid alpha carbon.
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After the coupling, routine deprotection converts the sulfinimine-derived nitrogen group into the free amine. The carboxyl group is represented by the sulfinimine partner’s carbon framework, so the product is an alpha-amino acid whose side chain came directly from the starting acid. In practical terms, a chemist can swap one carboxylic acid for another and explore a new side chain without redesigning the entire route.
Why a radical is useful here
Radicals have one unpaired electron and often tolerate steric congestion that slows polar two-electron reactions. They can be generated from many aliphatic acids, including acids bearing rings and other three-dimensional motifs. Nickel serves as a single-electron and bond-forming catalyst: it engages the radical, coordinates to the imine, and promotes reductive elimination to forge the new carbon–carbon bond. The exact elementary sequence can depend on the substrate, but the operational result is consistent—a side-chain fragment is attached to a stereodefined amino-acid framework.
How stereochemistry is controlled
The sulfinimine contains a chiral sulfur center. When the carbon radical adds, the two possible diastereomeric products are not equivalent; one is favored because the auxiliary shields one face of the imine. The auxiliary is removed after coupling to reveal the amine. If the reaction gives an imperfect diastereomeric ratio, the two forms can often be separated because they are diastereomers, not mirror-image enantiomers. That separation option is one reason the developers considered the auxiliary acceptable for medicinal-chemistry work.
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How chemists run the sequence
The published chemistry is a platform rather than a single recipe. Exact solvents, catalyst loading, light or reductant requirements, temperature, and purification vary with the acid and sulfinimine. The conceptual workflow is nevertheless clear:
- Select a carboxylic acid. Choose the side chain you want in the final amino acid. Aliphatic acids are the demonstrated strength of the method; aromatic acids are more challenging.
- Prepare the redox-active ester. Convert the acid into a tetrachlorophthalimide ester. This activation makes single-electron reduction and radical release possible while the carboxyl carbon leaves as carbon dioxide.
- Combine the radical precursor with the chiral sulfinimine. The sulfinimine supplies the nitrogen-bearing carbon and the stereochemical environment. A nickel catalyst and the reaction’s reducing system mediate the coupling.
- Form the carbon–carbon bond. Reduction of the activated ester generates the side-chain radical. Nickel captures it and delivers the radical-derived fragment to the imine carbon, producing the protected alpha-amino-acid skeleton.
- Separate diastereomers if necessary. Chromatographic or crystallization-based separation can remove the minor diastereomer when stereoselectivity is not complete.
- Remove the chiral auxiliary and protecting groups. Standard acidic or other substrate-appropriate conditions release the free amine and furnish the unusual amino acid for downstream chemistry or testing.
This sequence has two practical consequences. First, the difficult carbon–carbon bond is made late, so the same sulfinimine partner can be paired with many different acid-derived radicals. Second, the acid-to-radical conversion is decoupled from the stereochemical step: changing the side chain does not require finding a new chiral catalyst for every substrate.
What the 2018 study demonstrated
The breadth was tested rather than inferred from a handful of examples. More than 85 compounds — the Baran research team, 2018 report were examined across the reaction scope. The examples included compact rings, sterically demanding structures, and side chains resembling a portion of the cholesterol-lowering drug atorvastatin. The set also reached highly strained propellane-derived structures, showing that the chemistry can accommodate unusual three-dimensional fragments instead of only simple linear alkyl groups.
One especially useful demonstration involved a cyclopropane amino acid. A conventional route required seven steps; the radical strategy shortened the synthesis to one key step from the corresponding acid-derived precursor. “It would be very hard to find a simpler way to put them together,” said Phil Baran, whose team developed the method.
The chemistry was also tested in an applied medicinal-chemistry setting rather than only at discovery scale. Four medicinal-chemistry teams assembled a 30-compound amino-acid array. Twenty-five of 30 reactions yielded at least 1 mg — medicinal-chemistry teams reported by Chemistry World, 2018. A milligram is enough for many initial binding, cellular, or analytical assays, so the result indicates that the method can supply material for biological decision-making, not merely prove that a structure is theoretically accessible. The study did not provide a single percentage-yield summary for the whole array; the useful statistic is the number of reactions that reached the milligram threshold.
| Demonstration | What was shown | Why it matters |
|---|---|---|
| Overall scope | More than 85 compounds | Shows broad substrate exploration rather than a single showcase molecule. |
| Cyclopropane example | Seven steps reduced to one key coupling | Illustrates route compression for a strained-ring amino acid. |
| Side-chain types | Atorvastatin-like fragment and propellane structures included | Demonstrates tolerance of medicinally relevant and highly strained motifs. |
| Array production | 25 of 30 reactions produced at least 1 mg | Provides material suitable for early bioactivity testing; no overall array yield percentage was stated. |
Radical coupling versus the Strecker synthesis
Strecker chemistry remains a foundational way to make alpha-amino acids. It reacts an aldehyde with an amine source and cyanide to form an aminonitrile, then hydrolyses the nitrile to the carboxylic acid. Its age is not a defect: the reaction is familiar, inexpensive in many settings, and adaptable to numerous aldehydes. The question is where the radical route offers a better starting point or a safer, shorter operation.
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| Decision factor | Nickel-promoted radical coupling | Strecker synthesis |
|---|---|---|
| Starting fragment | Carboxylic acid converted to a tetrachlorophthalimide redox-active ester | Aldehyde converted to an aminonitrile, then hydrolysed |
| Functional-group tolerance | Demonstrated breadth with many aliphatic and strained side chains; benzoic acid was among the resistant substrates | Some functional groups are incompatible with the aldehyde, cyanide, or hydrolysis conditions |
| Number of steps | Can make a key bond in one coupling; a cyclopropane example replaced a seven-step route | At least aminonitrile formation and nitrile hydrolysis, with protection or manipulation as needed |
| Stereochemical control | Chiral sulfinimine directs diastereoselective addition; diastereomers can be separated | Can be asymmetric with specialized variants, but a basic Strecker reaction does not inherently provide the same auxiliary-controlled outcome |
| Hazard profile | Uses a redox activator, nickel catalyst, and chiral auxiliary | Frequently uses toxic cyanide reagents |
| Side-chain scope | More than 85 tested compounds, including strained and drug-like fragments | Governed largely by which suitable aldehydes can be prepared and survive the conditions |
| Material for assays | 25 of 30 array reactions reached at least 1 mg | Depends on the individual route; no corresponding array statistic was reported for this comparison |
The comparison does not establish that radicals supersede Strecker chemistry everywhere. If a readily available aldehyde gives a clean Strecker reaction, that route may remain the simplest choice. The radical platform becomes attractive when the desired side chain is easiest to obtain as a carboxylic acid, when cyanide compatibility is a concern, or when a long sequence can be replaced by late-stage coupling.
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Aromatic acids are difficult
Benzoic acid was one of the building blocks that resisted the reaction. The authors identified reduction of aryl carboxylic acids as an important mechanistic challenge. An aromatic acid-derived radical is not automatically generated under the same conditions that work for aliphatic acids, so a scope claim should not be extended from alkyl examples to every benzoic-acid derivative.
Activation adds operations and waste
The carboxylic acid is not used directly; it must first be converted into a redox-active ester. That activation consumes reagents and creates additional purification and waste streams. The process also uses a chiral auxiliary that must be installed and removed. For a medicinal-chemistry library, the time saved in the carbon–carbon bond-forming step can outweigh those costs. For very large-scale manufacturing, solvent use, metal recovery, auxiliary recycling, and waste treatment would require a separate process assessment.
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Stereoselectivity is strong but not universal
The auxiliary biases the addition, yet some substrates can give mixtures. Separation of diastereomers is practical at small scale but can become expensive or slow when repeated across hundreds of compounds. Chemists should measure the diastereomeric ratio for each new substrate rather than assume that the selectivity of one example transfers unchanged to another.
Nickel and redox conditions need compatibility checks
Nickel catalysis and single-electron reduction introduce their own compatibility questions. Functional groups that bind nickel, undergo reduction, or react with radicals may require protecting groups or a different substrate design. The published scope demonstrates what worked in that study; it is not a guarantee for every peptide fragment, heterocycle, or oxidation-sensitive substituent.
How to decide whether to use it for a drug-discovery building block
- Start from the available feedstock. If the desired side chain is commercially available or readily prepared as a carboxylic acid, the radical route has a strong logistical advantage.
- Look for a late-stage shortcut. Compare the number of protecting-group, oxidation, and functional-group-manipulation steps in a conventional route with acid activation plus coupling.
- Check the substrate class. Aliphatic, cyclic, and strained examples are supported by the demonstrated scope. Treat aryl acids, especially benzoic-acid-like substrates, as a development question.
- Define the stereochemical requirement. If one amino-acid stereoisomer is required, plan for diastereomer analysis and possible separation after coupling.
- Budget for auxiliary handling. Include installation, removal, purification, and disposal or recovery in the process comparison.
- Set a material target early. The array study shows that milligram production is realistic for many examples, but each new substrate still needs an experimental route and isolated-material check.
- Compare hazards, not just step counts. Avoiding frequently used toxic cyanide reagents may simplify risk management, but redox activators, nickel salts, and radical-generating conditions still require appropriate controls.
What this changes for medicinal chemistry
Medicinal chemistry often stalls not because a target lacks ideas, but because a promising side chain is too difficult to make in enough variants. A modular acid-to-amino-acid coupling changes that economics of experimentation. One team can prepare a panel of acids, run a common coupling logic, and test how each three-dimensional appendage affects potency, selectivity, permeability, or stability. The 30-member array is important for that reason: it connects reaction scope to actual compound triage.
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A free scan shows the junk files, broken settings and background clutter dragging Windows down - then fixes them in one click.Free scan · Windows 10 & 11Unnatural amino acids are also useful outside linear peptides. They can be incorporated into constrained peptides, macrocycles, covalent probes, and conformationally biased fragments. Cyclopropanes and propellanes alter shape and lipophilicity without simply adding bulk, while atorvastatin-like fragments illustrate how a complex, recognizable side chain can be transplanted into an amino-acid framework. The method therefore expands the menu of building blocks available at the point where biological hypotheses are being tested.
The defensible conclusion is measured: the nickel-promoted radical coupling materially improves access to a broad set of unusual alpha-amino acids and can shorten individual syntheses dramatically. It is not a universal replacement for Strecker chemistry, and the 2018 evidence does not establish how later catalyst systems or scale-up processes perform. For researchers choosing a route today, it is a high-value option when a carboxylic acid is the natural side-chain precursor, stereochemical control is needed, and a conventional aldehyde/cyanide sequence is unattractive.
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