Skip to main content
NCBI home page
ACS Organic & Inorganic Au logoLink to ACS Organic & Inorganic Au
. 2026 Jan 23;6(1):47–52. doi: 10.1021/acsorginorgau.5c00121

Fluorinated Solvents for Chemoselective Oxidations: A Strategy toward Synthetic Ideality in Natural Product Synthesis

Victor C S Santana †, Lucas D P Gonçalves †, Yasmin N Salmazo †, Julian C S Pavan ‡, Deborah de A Simoni †, Vladimir C G Heleno ‡, Emilio C de Lucca Jr †,*
PMCID: PMC12879165  PMID: 41658994

Abstract

Late-stage catalytic oxidations of complex natural products have been shown to exhibit dramatically improved chemoselectivity through the crucial use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), even in the presence of oxidatively sensitive groups, such as hydroxyls and diols. This strategy reduced the need for protecting groups, effectively mimicking enzymatic pathways, and substantially enhancing synthetic ideality in the preparation of ent-beyerane and ent-kaurane metabolites.

Keywords: chemoselectivity, metal-catalysis, oxidation, synthetic ideality, fluorinated solvents, diterpenes, natural products

graphic file with name gg5c00121_0007.jpg

graphic file with name gg5c00121_0006.jpg

The increasing demand in the past decades for the invention of even more selective transformations has become critical, and chemoselectivity and synthetic ideality are now part of the lexicon of our scientific community. While the discovery of new reactions and methodologies using concepts such as step economy, redox economy, and the minimization of protecting group use has greatly expanded the chemistry toolkit, the use of solvents as key agents in achieving chemoselectivity remains underappreciated.

The choice of solvents in organic chemistry plays an essential role in the development of new reactions, as they not only are responsible for dissolving the species in the reaction medium, but also exert a significant influence on reactivity and selectivity.

On the other hand, it was only recently that fluorinated solvents such as nonafluoro-tert-butyl alcohol (NFTBA), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 2,2,2-trifluoroethanol (TFE), which exhibit noteworthy properties such as high polarity, high Brønsted acidity, low nucleophilicity, and strong hydrogen bond donating (HBD) ability, became widespread. These interesting features enable activation of hydrogen peroxide (H2O2) and organic functionalities, and have attracted attention for applications in a variety of organic reactions, including oxidations, ring openings, and cycloadditions.

Fluorinated solvents were also applied for chemoselective CH bond oxidations in hydroxyl-containing substrates (Scheme A). The activation of the carbinolic CH bond via hyperconjugation with the adjacent oxygen atom can result in overoxidation products. However, hydrogen-bonding interactions promoted by HFIP and TFE have been shown to mitigate this issue by reversing the polarity of the substrate. This effect deactivates carbinolic CH bonds, thereby enabling selective oxidation at remote sites. Compared with the sole use of acetonitrile (MeCN), fluorinated alcohols consistently afford higher selectivities and yields for hydroxylated products.

1. A) Effects and Applications of Fluorinated Solvents and B) Our Studies on Complex Molecules.

1

Open in a new tab

While these beneficial effects are easily recognized in simple molecules, the lack of complex substrate examples in these studies tends to undermine their use in natural product synthesis. Such transformations, especially when applied at a late-stage, allow rapid access to molecules, expediting structural diversification and broadening the chemical space.

By combining the deactivation of functional groups with the prevalent formation of alcohols, fluorinated solvents enhance the biomimetic character of metal-oxo species by modulating their reactivity to more closely resemble that of enzymatic systems, particularly the P450 superfamily. The ability of small molecules to imitate the selectivity of enzymes enables new reactivity patterns and more chemoselective transformations, affording synthetic routes in higher yields and fewer reaction steps by reducing or even eliminating the need for protecting groups.

We envisioned that the use of HFIP and TFE in late-stage, nondirected CH oxidations could be challenged by complex diterpenes in the presence of White–Gormisky–Zhao catalyst Mn­(CF3–PDP) and H2O2 (Scheme B). When compared to our previous report, the use of fluorinated solvents could prevent overoxidation of the C2 position affording higher selectivities and yields for alcohol 2. Moreover, the polarity reversal effect could assist in the tolerance for a preinstalled C17-hydroxy group, eliminating the need for protecting groups, which hampered our synthetic ideality in the first synthesis. These outcomes would facilitate a more chemoselective and optimal synthesis of ent-beyerane 3 and would further advance the investigation of ent-kaurane metabolite synthesis.

Initially, we investigated the chemoselective CH bond oxidation of isosteviol methyl ester (4) to alcohol 5 employing HFIP and TFE along with CH2Cl2, and compared these results with the MeCN/CH2Cl2 media (Table ). Using MeCN/CH2Cl2 1:1 at 0 °C and 10 equiv of H2O2, we obtained 50% isolated yield in a ratio of 80:20 ketone/alcohol (Entry 1). When acetonitrile was replaced with TFE (TFE/CH2Cl2 1:1), the yield was slightly improved, while the selectivity for ketone 6 remained the same (Entry 2). The use of HFIP/CH2Cl2 1:1 led to a dramatic inversion in selectivity and the formation of alcohol 5 was favored (25:75, Entry 3) with a decrease in yield. Lowering the temperature to −36 °C increased the yield to 62% and the selectivity for alcohol remained the same (Entry 4). While decreasing the amount of H2O2 to 2 equiv proved unproductive (Entry 5), increasing the HFIP/CH2Cl2 ratio to 4:1 afforded alcohol 5 as the sole product in 61% yield (Entry 6). In these experiments, solely the starting material and products 5 and 6 were detected and successfully isolated.

1. CH Bond Oxidation of Compound 4 with (R,R)-Mn­(CF3–PDP) .

graphic file with name gg5c00121_0005.jpg

Entry T (°C) H2O2 (equiv) Solvent/CH2Cl2 (ratio) Total yield Selectivity (5:6) RSM (%)
1 0 10 MeCN (1:1) 50 20:80 15
2 0 10 TFE (1:1) 56 22:78 0
3 0 10 HFIP (1:1) 49 75:25 0
4 –36 10 HFIP (1:1) 62 82:18 0
5 –36 2 HFIP (1:1) 58 83:17 26
6 –36 10 HFIP (4:1) 61 100:0 0
Open in a new tab
a

Reaction conditions: 4 (0.20 mmol), (R,R)-Mn­(CF3–PDP) (10 mol %), ClAcOH (15 equiv), H2O2 (10 or 2 equiv), solvent:CH2Cl2, 0 or −36 °C, 3 h. Isolated yields, selectivity, and recovery of starting material (RSM) are averages of two runs.

b

The yield corresponds to the total yield of products 5 and 6.

Notably, the bulky Mn­(CF3–PDP) catalyst strongly favors sterically accessible sites over electron-rich ones, resulting in exclusive oxidation at C2, the only position flanked by two methylenes, even in the presence of more electron-rich sites such as C1. This same factor underlies the preferential equatorial C2 oxidation: the axial C2 CH bond is sterically shielded by axial ester and methyl groups, leaving the equatorial C2 hydrogen significantly more exposed.

The chemoselective synthesis of alcohol 5 in good yield promoted by HFIP enabled us to realize a second-generation synthesis for metabolite 3, isolated from Streptomyces griseus ATCC 10137, in a route that would not require any use of protecting groups (Scheme ). In addition, due to the strong ability of HFIP in interacting with polar moieties, we proposed a synthesis without the need to protect the C19 carboxylic acid as the corresponding methyl ester.

2. Second-Generation Synthesis of 2β,17-Dihydroxy-16-oxo-ent-beyeran-19-oic Acid (3).

2

Open in a new tab

Then, we submitted oxime 7 (obtained in one step from isosteviol) to Sanford acetoxylation followed by acid hydrolysis to furnish 17-hydroxy-16-oxo-ent-beyeran-19-oic acid (8) in 74% yield over two steps. Subsequent CH oxidation of compound 8 catalyzed by (R,R)-Mn­(CF3–PDP) in HFIP/CH2Cl2 proceeded smoothly to afford 2β,17-dihydroxy-16-oxo-ent-beyeran-19-oic acid (3) as the only product in 56% yield.

The control experiment conducted in MeCN/CH2Cl2 resulted in no substrate conversion (see Supporting Information for experimental details), which we hypothesize is due to a nonanticipated chelation between the manganese center and the β-hydroxy ketone, leading to catalyst deactivation and preventing the desired oxidation. Although not observed in our experiments, we expect that an extensive screening of different carboxylic acids could enable lactone formation from compound 8.

The synthesis of metabolite 3 was accomplished in four steps from isosteviol in 26% overall yield, representing a substantial improvement facilitated by using HFIP. Compared to the previous synthetic route, this approach not only increased the overall yield and synthetic ideality but also reduced the number of steps by half. Most notably, this application demonstrated the effectiveness of fluorinated alcohols as important agents to increase ideality in remote late-stage CH bond functionalization, emulating the ambitious selectivity of enzymes by leaving all other sites and functional groups of the molecule unaltered.

Since the oxidation of an ent-beyerane was smoothly achieved in a hydroxyl-containing intermediate, we envisioned performing the same approach to oxidize the C2 position in the more challenging ent-kaurane 10. The first step consisted of a syn-dihydroxylation reaction with aqueous OsO4 and NMO to obtain 16α,17-dihydroxy-ent-kauran-18-oic acid (10) in 60% yield (Scheme ). This intermediate was submitted to the same CH bond oxidation conditions highlighted in the previous synthesis, furnishing natural product 11 in 40% yield, with no formation of byproducts. A control experiment conducted in MeCN/CH2Cl2 resulted in no substrate conversion, with complete recovery of the starting material.

3. Synthesis of 2β,16α,17-Trihydroxy-ent-kauran-19-oic Acid (11) and 2β-Hydroxy-16-oxo-ent-17-norkauran-19-oic Acid (12).

3

Open in a new tab

This two-step procedure enabled the first synthesis of 2β,16α,17-trihydroxy-ent-kauran-19-oic acid (11) with no overoxidation of the diol moiety, in 24% overall yield and 100% of synthetic ideality, providing a practical and concise exhibition of how fluorinated solvents can improve the chemoselectivity in nondirected CH bond oxidations. The oxidative cleavage of diol 11 with NaIO4 afforded 2β-hydroxy-16-oxo-ent-17-norkauran-19-oic acid (12) in 56% yield, the first reported synthesis of this natural product.

The syntheses of 11 and 12 were both accomplished in 100% ideality from kaurenoic acid (9), providing 24% and 13% overall yield, respectively. By taking advantage of oxidized natural product intermediate 11, we avoided an alternative dedicated route to 12, which would require oxidative cleavage of 9, followed by C2 functionalization. Instead, by performing a three-reaction route, we achieved improved step economy and ideality compared to two fully independent syntheses, thereby expanding the chemical space with higher efficiency.

With the preparation of the ent-kauranes 11 and 12 ensured, we decided to expand the beneficial use of HFIP in oxidations of terpenes using (S,S)-Fe­(PDP) to prepare tricalysiolide B (14) (Scheme ). After a (S,S)-Fe­(PDP)-catalyzed epoxidation followed by a Pinnick oxidation, natural product 14 was delivered in 55% yield from the ent-kaurene cafestol (13).

4. Synthesis of Tricalysiolide B (14).

4

Open in a new tab

Notably, the control experiment of 13 replacing HFIP with MeCN delivered the natural product 14 in 54% yield, indicating that the epoxidation occurs faster than the oxidation of the diol moiety regardless of the solvent used. Although fluorinated alcohols did not show a significant improvement for this reaction, we report a straightforward method to synthesize tricalysiolide B (14) without the need for protecting groups, achieving higher synthetic ideality compared to the previously report.

In summary, we reported that the use of HFIP can be beneficial for chemoselective nondirected CH bond oxidations, preventing both overoxidation of alcohols and diols and deactivation of the catalyst in complex natural products. We have shown this efficacy in the synthesis of ent-beyerane and ent-kaurane natural products in four steps or less from available starting materials. Through these syntheses, HFIP played a crucial role, in combination with the Mn­(CF3–PDP) catalyst, in delivering hydroxylated products in a late-stage scenario.

Supplementary Material

gg5c00121_si_001.pdf (19.5MB, pdf)

Acknowledgments

We are grateful to the São Paulo Research Foundation (FAPESP) for financial support of this work (grant numbers 2018/04837-6 and 2024/11730-4) and fellowships to V. C. S. Santana, L. D. P. Gonçalves and Y. N. Salmazo (grants 2019/27528-1, 2023/13162-0 and 2024/22319-3, respectively). We also thank CNPq, CAPES, and FAEPEX-UNICAMP (grant number 2369/23). We thank LIRMN (RRID: SCR_027247, NMR equipment EMU-FAPESP 2022/11152-5), LIEM (RRID: SCR_027240), LIRX (RRID: SCR_027392), and LISpec (RRID: SCR_027391) from CEMUIQ-UNICAMP for technical support. The authors thank F. A. Saito for checking the experimental procedures, and Padaria Alemã (Campinas/SP, Brazil) for donating the spent coffee grounds that were used to extract cafestol.

The data underlying this study are available in the published article and its Supporting Information. Raw NMR data files can be found online at DOI: 10.5281/zenodo.18270798.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.5c00121.

  • Additional experimental details and spectra data for all compounds (1H and 13C NMR, optical rotation, HRMS, and crystallographic data) (PDF)

§.

V.C.S.S. and L.D.P.G. contributed equally. CRediT: Victor Camargo Stork Santana conceptualization, formal analysis, investigation, writing - original draft; Lucas Dias Pires Gonçalves conceptualization, formal analysis, investigation, writing - original draft; Yasmin Nascimento Salmazo formal analysis, investigation, writing - review & editing; Julian Carlos Silva Pavan resources, writing - review & editing; Déborah de Alencar Simoni resources; Vladimir Constantino Gomes Heleno resources, writing - review & editing; Emilio Carlos de Lucca Jr. conceptualization, formal analysis, funding acquisition, project administration, resources, supervision, writing - original draft.

The Article Processing Charge for the publication of this research was funded by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil (ROR identifier: 00x0ma614).

The authors declare no competing financial interest.

References

  1. a Trost B. M.. Selectivity: A Key to Synthetic Efficiency. Science. 1983;219(4582):245–250. doi: 10.1126/science.219.4582.245. [DOI] [PubMed] [Google Scholar]; b Shenvi R. A., O’Malley D. P., Baran P. S.. Chemoselectivity: The Mother of Invention in Total Synthesis. Acc. Chem. Res. 2009;42(4):530–541. doi: 10.1021/ar800182r. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. a Hendrickson J. B.. Systematic Synthesis Design. IV. Numerical Codification of Construction Reactions. J. Am. Chem. Soc. 1975;97(20):5784–5800. doi: 10.1021/ja00853a023. [DOI] [Google Scholar]; b Gaich T., Baran P. S.. Aiming for the Ideal Synthesis. J. Org. Chem. 2010;75(14):4657–4673. doi: 10.1021/jo1006812. [DOI] [PubMed] [Google Scholar]
  3. a Wender P. A., Croatt M. P., Witulski B.. New reactions and step economy: the total synthesis of (±)-salsolene oxide based on the type II transition metal-catalyzed intramolecular [4 + 4] cycloaddition. Tetrahedron. 2006;62(32):7505–7511. doi: 10.1016/j.tet.2006.02.085. [DOI] [Google Scholar]; b Wender P. A., Verma V. A., Paxton T. J., Pillow T. H.. Function-Oriented Synthesis, Step Economy, and Drug Design. Acc. Chem. Res. 2008;41(1):40–49. doi: 10.1021/ar700155p. [DOI] [PubMed] [Google Scholar]; c Wender P. A., Miller B. L.. Synthesis at the Molecular Frontier. Nature. 2009;460:197–201. doi: 10.1038/460197a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. a Richter J. M., Ishihara Y., Masuda T., Whitefield B. W., Llamas T., Pohjakallio A., Baran P. S.. Enantiospecific Total Synthesis of Hapalindoles, Fischerindoles, and Welwitindolinones via Redox Economic Approach. J. Am. Chem. Soc. 2008;130(52):17938–17954. doi: 10.1021/ja806981k. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Burns N. Z., Baran P. S., Hoffmann R. W.. Redox Economy in Organic Synthesis. Angew. Chem., Int. Ed. 2009;48(16):2854–2867. doi: 10.1002/anie.200806086. [DOI] [PubMed] [Google Scholar]
  5. a Hoffmann R.. Protecting-Group-Free Synthesis. Synthesis 2006. 2006;2006(21):3531–3541. doi: 10.1055/s-2006-950311. [DOI] [Google Scholar]; b Young I. S., Baran P. S.. Protecting-Group-Free Synthesis as an Opportunity for Invention. Nat. Chem. 2009;1:193–205. doi: 10.1038/nchem.216. [DOI] [PubMed] [Google Scholar]; c Hui C., Chen F., Pu F., Xu J.. Innovation in Protecting-Group-Free Natural Product Synthesis. Nat. Rev. Chem. 2019;3:85–107. doi: 10.1038/s41570-018-0071-1. [DOI] [Google Scholar]
  6. Newhouse T., Baran P. S., Hoffmann R. W.. The Economies of Synthesis. Chem. Soc. Rev. 2009;38(11):3010–3021. doi: 10.1039/b821200g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Reichardt, C. ; Welton, T. . Solvents and Solvent Effects in Organic Chemistry, 4th ed.; Wiley, 2010. 10.1002/9783527632220. [DOI] [Google Scholar]
  8. a Bégué J.-P., Bonnet-Delpon D., Crousse B.. Fluorinated Alcohols: A New Medium for Selective and Clean Reaction. Synlett. 2004;1:18–29. doi: 10.1055/s-2003-44973. [DOI] [Google Scholar]; b Leboeuf D.. The Rise and Future of Hexafluoroisopropanol as a Solvent. Trends Chem. 2025;7(5):205–207. doi: 10.1016/j.trechm.2025.04.001. [DOI] [Google Scholar]
  9. Colomer I., Chamberlain A. E. R., Haughey M. B., Donohoe T. J.. Hexafluoroisopropanol as a Highly Versatile Solvent. Nat. Rev. Chem. 2017;1:0088. doi: 10.1038/s41570-017-0088. [DOI] [Google Scholar]
  10. Motiwala H. F., Armaly A. M., Cacioppo J. G., Coombs T. C., Koehn K. R. K., Norwood V. M. IV, Aubé J.. HFIP in Organic Synthesis. Chem. Rev. 2022;122(15):12544–12747. doi: 10.1021/acs.chemrev.1c00749. [DOI] [PubMed] [Google Scholar]
  11. a Dantignana V., Milan M., Cussó O., Company A., Bietti M., Costas M.. Chemoselective Aliphatic C–H Bond Oxidation Enabled by Polarity Reversal. ACS Cent. Sci. 2017;3(12):1350–1358. doi: 10.1021/acscentsci.7b00532. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Borrell M., Gil-Caballero S., Bietti M., Costas M.. Site-Selective and Product Chemoselective Aliphatic C–H Bond Hydroxylation of Polyhydroxylated Substrates. ACS Catal. 2020;10(8):4702–4709. doi: 10.1021/acscatal.9b05423. [DOI] [Google Scholar]; c Sisti S., Galeotti M., Scarchilli F., Salamone M., Costas M., Bietti M.. Highly Selective C­(sp3)–H Bond Oxygenation at Remote Methylenic Sites Enabled by Polarity Enhancement. J. Am. Chem. Soc. 2023;145(40):22086–22096. doi: 10.1021/jacs.3c07658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Newhouse T., Baran P. S.. If C–H Bonds Could Talk: Selective CH Bond Oxidation. Angew. Chem., Int. Ed. 2011;50(15):3362–3374. doi: 10.1002/anie.201006368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. a Bietti M.. Activation and Deactivation Strategies Promoted by Medium Effects for Selective Aliphatic C–H Bond Functionalization. Angew. Chem., Int. Ed. 2018;57(51):16618–16637. doi: 10.1002/anie.201804929. [DOI] [PubMed] [Google Scholar]; b Hahn P. L., Lowe J. M., Xu Y., Burns K. L., Hilinski M. K.. Amine Organocatalysis of Remote, Chemoselective C­(sp3)–H Hydroxylation. ACS Catal. 2022;12(8):4302–4309. doi: 10.1021/acscatal.2c00392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. a Shugrue C. R., Miller S. J.. Applications of Nonenzymatic Catalysts to the Alteration of Natural Products. Chem. Rev. 2017;117(18):11894–11951. doi: 10.1021/acs.chemrev.7b00022. [DOI] [PMC free article] [PubMed] [Google Scholar]; b White M. C., Zhao J.. Aliphatic C–H Oxidations for Late-Stage Functionalization. J. Am. Chem. Soc. 2018;140(43):13988–14009. doi: 10.1021/jacs.8b05195. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Hong B., Luo T., Lei X.. Late-Stage Diversification of Natural Products. ACS Cent. Sci. 2020;6(5):622–635. doi: 10.1021/acscentsci.9b00916. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Wein L. A., Wurst K., Magauer T.. Total Synthesis and Late-Stage C–H Oxidations of ent-Trachylobane Natural Products. Angew. Chem., Int. Ed. 2022;61(3):e202113829. doi: 10.1002/anie.202113829. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Santana V. C. S., Fernandes M. C. V., Cappuccelli I., Richieri A. C. G., de Lucca E. C. Jr.. Metal-Catalyzed C–H Bond Oxidation in the Total Synthesis of Natural and Unnatural Products. Synthesis. 2022;54(24):5337–5359. doi: 10.1055/a-1918-4338. [DOI] [Google Scholar]; f Rocha E. C. S., Salmazo Y. N., Hayashi M., Zaragoza C. A. D., de Lucca E. C. Jr.. Funcionalização de Ligações CH em Estágio Tardio em Síntese Orgânica. Quim. Nova. 2023;46(1):43–76. doi: 10.21577/0100-4042.20170949. [DOI] [Google Scholar]; g Ottenbacher R. V., Samsonenko D. G., Bryliakova A. A., Nefedov A. A., Bryliakov K. P.. Manganese Catalyzed Direct Regio- and Stereoselective Hydroxylation of 5α- and 5β-Androstane Derivatives. J. Catal. 2023;425:32–39. doi: 10.1016/j.jcat.2023.06.003. [DOI] [Google Scholar]; h Ahn C., Gomez A., Hartmann M. A., White M. C.. Selective Methylene Oxidation in α,β-Unsaturated Carbonyl Natural Products. Nature. 2025;648:607–615. doi: 10.1038/s41586-025-09742-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. a Wencel-Delord J., Glorius F.. C–H Bond Activation Enables the Rapid Construction and Late-Stage Diversification of Functional Molecules. Nat. Chem. 2013;5:369–375. doi: 10.1038/nchem.1607. [DOI] [PubMed] [Google Scholar]; b Cernak T., Dykstra K. D., Tyagarajan S., Vachal P., Krska S. W.. The Medicinal Chemist’s Toolbox for Late Stage Functionalization of Drug-like Molecules. Chem. Soc. Rev. 2016;45(3):546–576. doi: 10.1039/C5CS00628G. [DOI] [PubMed] [Google Scholar]; c Kim K. E., Adams A. M., Chiappini N. D., Du Bois J., Stoltz B. M.. Cyanthiwigin Natural Product Core as a Complex Molecular Scaffold for Comparative Late-Stage C–H Functionalization Studies. J. Org. Chem. 2018;83(6):3023–3033. doi: 10.1021/acs.joc.7b03291. [DOI] [PubMed] [Google Scholar]; d Ma X., Kucera R., Goethe O. F., Murphy S. K., Herzon S. B.. Directed C–H Bond Oxidation of (+)-Pleuromutilin. J. Org. Chem. 2018;83(13):6843–6892. doi: 10.1021/acs.joc.8b00462. [DOI] [PubMed] [Google Scholar]; e Kim K. E., Kim A. N., McCormick C. J., Stoltz B. M.. Late-Stage Diversification: A Motivating Force in Organic Synthesis. J. Am. Chem. Soc. 2021;143(41):16890–16901. doi: 10.1021/jacs.1c08920. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Bakanas I., Lusi R. F., Wiesler S., Hayward Cooke J., Sarpong R.. Strategic Application of C–H Oxidation in Natural Product Total Synthesis. Nat. Rev. Chem. 2023;7:783–799. doi: 10.1038/s41570-023-00534-6. [DOI] [PubMed] [Google Scholar]
  16. a Meunier B., de Visser S. P., Shaik S.. Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes. Chem. Rev. 2004;104(9):3947–3980. doi: 10.1021/cr020443g. [DOI] [PubMed] [Google Scholar]; b Ortiz de Montellano P. R.. Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes. Chem. Rev. 2010;110(2):932–948. doi: 10.1021/cr9002193. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Guengerich F. P., Waterman M. R., Egli M.. Recent Structural Insights into Cytochrome P450 Function. Trends Pharmacol. Sci. 2016;37(8):625–640. doi: 10.1016/j.tips.2016.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. a Breslow R.. Centenary Lecture. Biomimetic Chemistry. Chem. Soc. Rev. 1972;1(4):553–580. doi: 10.1039/cs9720100553. [DOI] [Google Scholar]; b Biomimetic Organic Synthesis, 1. Auflage.; Poupon, E. , Poupon, E. , Nay, B. , Eds.; Wiley-VCH: Weinheim, 2011. 10.1002/9783527634606. [DOI] [Google Scholar]
  18. Zhao J., Nanjo T., de Lucca E. C. Jr., White M. C.. Chemoselective Methylene Oxidation in Aromatic Molecules. Nat. Chem. 2019;11:213–221. doi: 10.1038/s41557-018-0175-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Santana V. C. S., Rocha E. C. S., Pavan J. C. S., Heleno V. C. G., de Lucca E. C. Jr. Selective Oxidations in the Synthesis of Complex Natural ent-Kauranes and ent-Beyeranes. J. Org. Chem. 2022;87(15):10462–10466. doi: 10.1021/acs.joc.2c01051. [DOI] [PubMed] [Google Scholar]
  20. a Cianfanelli M., Olivo G., Milan M., Klein Gebbink R. J. M., Ribas X., Bietti M., Costas M.. Enantioselective C–H Lactonization of Unactivated Methylenes Directed by Carboxylic Acids. J. Am. Chem. Soc. 2020;142(3):1584–1593. doi: 10.1021/jacs.9b12239. [DOI] [PubMed] [Google Scholar]; b Call A., Capocasa G., Palone A., Vicens L., Aparicio E., Choukairi Afailal N., Siakavaras N., López Saló M. E., Bietti M., Costas M.. Highly Enantioselective Catalytic Lactonization at Nonactivated Primary and Secondary γ-C–H Bonds. J. Am. Chem. Soc. 2023;145(32):18094–18103. doi: 10.1021/jacs.3c06231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. a Chen M. S., White M. C.. A Predictably Selective Aliphatic C–H Oxidation Reaction for Complex Molecule Synthesis. Science. 2007;318(5851):783–787. doi: 10.1126/science.1148597. [DOI] [PubMed] [Google Scholar]; b Chen M. S., White M. C.. Combined Effects on Selectivity in Fe-Catalyzed Methylene Oxidation. Science. 2010;327(5965):566–571. doi: 10.1126/science.1183602. [DOI] [PubMed] [Google Scholar]; c Gormisky P. E., White M. C.. Catalyst-Controlled Aliphatic C–H Oxidations with a Predictive Model for Site-Selectivity. J. Am. Chem. Soc. 2013;135(38):14052–14055. doi: 10.1021/ja407388y. [DOI] [PubMed] [Google Scholar]
  22. Chang S.-F., Yang L.-M., Hsu F.-L., Hsu J.-Y., Liaw J.-H., Lin S.-J.. Transformation of Steviol-16α,17-Epoxide by Streptomyces griseus and Cunninghamella bainieri . J. Nat. Prod. 2006;69(10):1450–1455. doi: 10.1021/np0602564. [DOI] [PubMed] [Google Scholar]
  23. a Desai L. V., Hull K. L., Sanford M. S.. Palladium-Catalyzed Oxygenation of Unactivated sp3 C–H Bonds. J. Am. Chem. Soc. 2004;126(31):9542–9543. doi: 10.1021/ja046831c. [DOI] [PubMed] [Google Scholar]; b Neufeldt S. R., Sanford M. S.. O-Acetyl Oximes as Transformable Directing Groups for Pd-Catalyzed C–H Bond Functionalization. Org. Lett. 2010;12(3):532–535. doi: 10.1021/ol902720d. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Borrell M., Costas M.. Mechanistically Driven Development of an Iron Catalyst for Selective Syn-Dihydroxylation of Alkenes with Aqueous Hydrogen Peroxide. J. Am. Chem. Soc. 2017;139(36):12821–12829. doi: 10.1021/jacs.7b07909. [DOI] [PubMed] [Google Scholar]
  25. Ohkoshi E., Kamo S., Makino M., Fujimoto Y.. ent-Kaurenoic Acids from Mikania hirsutissima (Compositae) Phytochemistry. 2004;65(7):885–890. doi: 10.1016/j.phytochem.2004.02.020. [DOI] [PubMed] [Google Scholar]
  26. Rocha A. D., Santos G. C., Fernandes N. G., Pfenning L. H., Takahashi J. A., Boaventura M. A. D.. Hydroxylation at Carbon-2 of ent-16-Oxo-17-norkauran-19-oic Acid by Fusarium proliferatum . J. Nat. Prod. 2010;73(8):1431–1433. doi: 10.1021/np100134f. [DOI] [PubMed] [Google Scholar]
  27. Nishimura K., Hitotsuyanagi Y., Sugeta N., Sakakura K., Fujita K., Fukaya H., Aoyagi Y., Hasuda T., Kinoshita T., He D.-H., Otsuka H., Takeda Y., Takeya K.. Tricalysiolides A-F, New Rearranged ent-Kaurane Diterpenes from Tricalysia dubia . Tetrahedron. 2006;62(7):1512–1519. doi: 10.1016/j.tet.2005.11.024. [DOI] [Google Scholar]
  28. Bigi M. A., Liu P., Zou L., Houk K. N., White M. C.. Cafestol to Tricalysiolide B and Oxidized Analogues: Biosynthetic and Derivatization Studies Using Non-Heme Iron Catalyst Fe­(PDP) Synlett. 2012;23(19):2768–2772. doi: 10.1055/s-0032-1317708. Tricalysiolide B was previously synthesized using Fe(PDP) as the catalyst, starting from cafestol protected as its diacetate derivative: [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

gg5c00121_si_001.pdf (19.5MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information. Raw NMR data files can be found online at DOI: 10.5281/zenodo.18270798.

Articles from ACS Organic & Inorganic Au are provided here courtesy of American Chemical Society

RESOURCES