Fluorinated natural products, although extremely rare, are highly prized, as fluorine atoms can impart unique physicochemical and biological properties to molecules. Alfa Chemistry has selected a number of fluorinated natural products for drug discovery, biochemical research, and advanced materials applications. Please browse our list of products below and choose the right fluorinated natural product that meets your research needs.
Why Are Fluorinated Natural Products So Scarce?
Fluorine is the 13th most abundant element in the Earth's crust, yet it is rarely used in biological systems. Compared to known organohalogen natural products such as chlorine, bromine, or iodine, only a few dozen biologically derived organofluorine compounds exist. Two major obstacles contribute to this scarcity:
Chemical and physical challenges of the C-F bond
The C-F bond is the strongest single bond in organic chemistry (~480 kJ/mol, typical bond energy). The fluoride anion (F-) is small, strongly solvated, and a "hard base," so it is both kinetically and thermodynamically challenging to desolvate and insert the fluoride ion into carbon centers. Therefore, in order for efficient C-F bond formation to occur in a biological context (enzyme), biological systems must be able to surmount large activation energy barriers and bring together the reactants in close proximity with great precision.
Fig.1 Abundance of chemical bonds containing halogens (F, Cl, Br, I) and biogenic elements (C, O, N, S, P) in natural products. The abundance of natural products containing S–F, N–F, P–F, and O–F bonds is strictly zero[1].
Biological and Evolutionary Constraints
Fluoride is toxic to many enzymes because fluoride ions can inhibit metalloenzymes by coordinating with magnesium, manganese, or other metal centers. Life tends to avoid relying on rare or intractable chemical motifs; in the long run, natural selection pressures favor more manageable functional groups. The scarcity of known fluorinated metabolites makes new discoveries particularly difficult, while contamination by anthropogenic fluorinated compounds makes attribution to bona fide biosynthesis challenging.
However, despite these obstacles, a small number of fascinating fluorinated natural products have been identified. The challenge—and opportunity—lies in understanding how nature (rarely) achieves fluorination and how we can harness or engineer these capabilities.
Fig.2 Developed metalloenzymes that catalyze the cleavage of chemically challenging C-F bonds[2].
Known Fluorinated Natural Products: Structural Motifs and Sources
The following is a concise summary of the major classes of identified fluorinated natural products from Alfa Chemistry for your reference.
| No. | Name | Source / Producing Organism | Key Structural / Mechanistic Features | Notes |
| 1 | Fluoroacetate | Various tropical plants (e.g. Dichapetalum) and Streptomyces spp. | Simple monofluoroacetic acid; converted via metabolic pathways to fluoroacetyl-CoA, then to fluorocitrate | Classical example; poisoning mechanism via TCA cycle inhibition |
| 2 | (2R,3R)-Fluorocitrate | same organisms (metabolic downstream) | Fluorine-substituted analog of citrate; the fluorine blocks normal enzymatic progression | The key toxic species that inhibits aconitase/lipolate-dependent steps |
| 3 | 4-Fluoro-L-threonine (4-FT) | Streptomyces cattleya and related strains | A fluorinated amino acid; formed by transaldolase-type reaction from fluoroacetaldehyde + L-threonine | Only known biologically derived fluorinated amino acid |
| 4 | ω-Fluorooleic acid (e.g. o-fluoro oleic acid) | Marine microalgae / marine microbes | Long-chain unsaturated fatty acid with a terminal (ω) fluorine substituent | Rare example of a fluorinated fatty acid; limited mechanistic data in literature |
| 5 | Nucleocidin (4′-fluoro-5′-O-sulfamoyladenosine) | Streptomyces spp. (e.g. NRRL 3051) | Unusual nucleoside bearing a 4′-fluoro substitution; includes an O-sulfamoyl group | One of the more complex F-natural products, illustrating that nucleoside scaffolds can accept fluorine |
| 6 | 5-Fluoro-5′-deoxy-D-ribose (5-FDRul) | Microbial metabolism | A fluorinated sugar moiety derived from modified nucleoside metabolism | Less well studied than nucleocidin itself |
| 7 | 4′-Fluoro-3′-O-β-glucosides (F-Mets I & II) | Microbial sources | Fluorinated sugar conjugates (glycosides) | Demonstrate that fluorine incorporation can extend to sugar moieties |
| 8 | 4-Fluoronucleosides | Microbes | More general class of nucleoside analogs bearing F substitutions on sugar ring | May overlap mechanistically with nucleocidin derivatives |
| 9 | Fluoroalinosporamide | Marine actinomycetes | Fluorine incorporated into amide-containing natural product scaffold | Reflects the possibility of fluorine in more complex macrocycles or peptide-like frameworks |
| 10 | Other less-certain reports | Various | Weak or tentative structures (e.g. fluorinated aldehydes, minor metabolites) | Some reported candidates have later been disputed due to contamination or structural misassignment |
Of these, fluoroacetates and 4-fluoro-fluoro-isopropylbenzene have remained the best studied "benchmark" systems. Some of the more esoteric classes (fluorofatty acids, glycosylated fluorinated compounds and amide-containing fluorinated nanoparticles) are rare and often without fully defined biosynthetic routes.
Some reported "fluorinated natural products" have been more recently doubted due to contamination or misidentification, especially in marine extracts. The challenge is therefore as much in finding new fluorinated natural products as in showing that they are derived from true enzymatic fluorination reactions and not from industrial pollutants.
Fig.3 Mechanism of fluorocitrate inhibition of citrate synthase[3].
Engineering and Synthetic Biology: How Can We Harness or Expand Fluorine Biochemistry?
Given the scarcity of naturally occurring fluorides, synthetic biology and enzyme engineering are crucial for expanding nature's limited resources into practical applications (e.g., drug leads, imaging agents, and fluorinated polymers). Key strategies include:
Heterologous Expression and Pathway Reengineering
The fluoridase genes of S. cartilamya have been heterologously expressed in Salinispora tropica and other hosts, allowing for the biosynthesis of fluorinated metabolites from sodium fluoride (NaF) in engineered systems. Entire or partial fluoride metabolism gene clusters (including sodium fluoride, dehydrogenases, transaldolases, and custom enzymes) can be transferred and recombined to generate novel fluorinated natural product analogs.
Fig.4 Biosynthesis of C-F bonds. The first identified natural fluorinase is the nucleophilic halogenase flA from Streptomyces cartylya. This fluorinase catalyzes the formation of C-F bonds from inorganic fluoride ions[1].
Enzyme Engineering and Directed Evolution
Mutagenesis or rational redesign of the fluoridase ring, active site residues, or substrate-binding regions can improve catalytic efficiency (k), lower the KM for fluoride, or expand substrate range (e.g., to accept SAM analogs). Recent advances include structure-guided redesign of halide pockets or ring dynamics to fine-tune transition state stability. Combining enzyme catalysis with photochemistry (photoenzymatic reactions) offers a hybrid approach: for example, in 2024, a flavin-dependent enzyme mediated a light-driven asymmetric hydrofluoroalkylation of alkenes.
Modular Integration and Expanded Substrate Scope
Engineering acceptor enzymes (e.g., glycosyltransferases, oxidases, methyltransferases) to tolerate fluorinated intermediates broadens the repertoire of fluorine-modified scaffolds that can be constructed.
Using fluorinated building blocks (e.g., fluorosugars, fluoroaliphatic units) in modular polyketide or nonribosomal peptide synthase (PKS/NRPS) pathways can generate fluorinated "semisynthetic natural products." Integrating the fluorination step into later stages of complex molecular assembly can minimize interference with core metabolic machinery or toxicity.
Addressing Fluoride Toxicity and Export Issues
Fluoride toxicity is a recurring obstacle: intracellular fluoride levels must be controlled; otherwise, enzymes and cofactors are inhibited. Several strategies are currently being explored:
- Co-expressing fluoride exporters (e.g., the CrcB transporter) to maintain low intracellular fluoride concentrations.
- Compartmentalization: Targeting the fluoride transport machinery to subcellular or microcompartments to sequester fluoride flux.
- Manipulating expression levels and flux balance so that fluoride utilization (by fluoridase) exceeds its accumulation.
Pharmaceutical Applications
Because approximately 15-20% of newly approved small molecule drugs contain at least one fluorine atom, there is significant interest in biosynthetic site-specific fluorination. Fluorinated natural product analogs or derivatives may have improved metabolic stability, lipophilicity, or binding affinity (via C-F dipole interactions) compared to non-fluorinated natural product analogs or derivatives.
Fig.5 (a) Fluorinated drugs approved by the FDA in 2021; (b) Fluorinated biologics approved by the FDA in 2019; (c) Fluorinated drugs approved by the FDA for PET imaging in 2021 and 2020; (d) 19F tracers for MRI[4].
In summary, while nature's toolkit is limited, synthetic biology holds the promise of expanding it to a richer range of fluorinated chemistries.
Frequently Asked Questions (FAQ)
1. What makes fluorine insertion so rare in natural products?
The chemical challenge of inserting F into carbon (strong C–F bond, low nucleophilicity of fluoride) combined with biological constraints (fluoride toxicity, limited evolutionary selection) disfavors natural fluorination.
2. How many fluorinated natural products are known to date?
Only a few dozen have been validated with confidence. The core set includes fluoroacetate, fluorocitrate, 4-fluorothreonine, nucleocidin, and some sugar and lipid derivatives.
3. What is the enzyme fluorinase, and why is it central?
Fluorinase (FlA) is the only well-characterized enzyme known to catalyze C–F bond formation under mild conditions by converting SAM + F⁻ into 5′-fluoro-5′-deoxyadenosine.
4. Can we engineer organisms to make fluorinated drugs?
Yes, in principle. By transferring fluorinase and related pathway genes into suitable chassis and optimizing enzyme kinetics and fluxes, one can biosynthesize fluorinated analogs of natural products or drug scaffolds.
5. What obstacles remain in expanding fluorine biochemistry?
Key challenges include low catalytic efficiency, poor tolerance of downstream enzymes to fluorinated substrates, fluoride toxicity, and the difficulty of achieving multi-fluorination.
References
- Petkowski JJ., et al. (2024). "Reasons why life on Earth rarely makes fluorine-containing compounds and their implications for the search for life beyond Earth." Scientific Reports. 14, 15575.
- Wang Y, et al. (2020). "Carbon–fluorine bond cleavage mediated by metalloenzymes." Chem. Soc. Rev. 49, 4906-4925.
- Hagan D, et al. (1999). "Fluorine-containing natural products." Journal of Fluorine Chemistry. 100(1-2), 127-133.
- Chandra G, et al. (2023). "Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs." Chemical Papers. 77, 4085-4106.
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