Article | Published:

Diverting non-haem iron catalysed aliphatic C–H hydroxylations towards desaturations

Nature Chemistry volume 3, pages 216222 (2011) | Download Citation

Subjects

Abstract

Carboxylate-ligated, non-haem iron enzymes demonstrate the capacity for catalysing such remarkable processes as hydroxylations, chlorinations and desaturations of inert, aliphatic C–H bonds. A key to functional diversity is the enzymes' ability to divert fleeting radicals towards different types of functionalization using active site and/or substrate modifications. We report that a non-haem iron hydroxylase catalyst [Fe(PDP)] can also be diverted to catalytic, mixed hydroxylase/desaturase activity with aliphatic C–H bonds. Using a taxane-based radical trap that rearranges under Fe(PDP) oxidation to furnish a nortaxane skeleton, we provide the first direct evidence for a substrate radical using this class of stereoretentive hydroxylation catalysts. Hydroxylation and desaturation proceed by means of a short-lived radical that diverges in a substrate-dependent manner in the presence of carboxylic acids. The novel biomimetic reactivity displayed by this small molecule catalyst is harnessed to diversify natural product derivatives as well as interrogate their biosynthetic pathways.

  • Compound C24H32F12FeN6Sb2

    (2S,2'S-(-)-[N,N'-Bis(2-pyridylmethyl)]-2,2'-bipyrrolidine(acetonitrile)iron(II)hexafluoroantimonate

  • Compound C10H16O3

    (±)-(1R*,2R*)-2-Isopropyl-5-oxocyclohexanecarboxylic acid

  • Compound C10H14O3

    (±)-(3aR*,7aR*)-3,3-Dimethylhexahydroisobenzofuran-1,6-dione

  • Compound C10H14O4

    (±)-(3aR*,7aR*)-3-(Hydroxymethyl)-3-methylhexahydroisobenzofuran-1,6-dione

  • Compound C9H16O2

    (±)-(1R*,2R*)-2-Isopropylcyclopentanecarboxylic acid

  • Compound C9H14O2

    (±)-(3aR*,6aS*)-3,3-Dimethylhexahydrocyclopenta[c]furan-1-one

  • Compound C9H14O3

    (±)-(3aR*,6aS*)-3-(Hydroxymethyl-3-methylhexahydrocyclopenta[c]furan-1-one

  • Compound C6H12O2

    4-Methylpentanoic acid

  • Compound C6H10O3

    5-(Hydroxymethyl)-5-methyldihydrofuran-2-one

  • Compound C6H10O2

    4-Methylpent-4-enoic acid

  • Compound C11H22O2

    4-Methylpentyl pivalate

  • Compound C11H22O3

    4-Hydroxy-4-methylpentyl pivalate

  • Compound C11H20O2

    4-Methylpent-4-en-1-yl pivalate

  • Compound C11H20O3

    3-(2-Methyloxiran-2-yl)propyl pivalate

  • Compound C8H14O2

    3-Cyclopentylpropanoic acid

  • Compound C8H12O2

    1-Oxaspiro[4,4]nonan-2-one

  • Compound C8H10O3

    1-Oxaspiro[4,4]nonane-2,6-dione

  • Compound C8H12O3

    (5R*,6S*)-6-Hydroxy-1-oxaspiro[4,4]nonan-2-one

  • Compound C8H14O3

    3-(1-Hydroxycyclopentyl)propanoic acid

  • Compound C29H40O11

    (3S,4S,4aS,6R,8S,11R,12R,12aR)-9,12a,13,13-Tetramethyl-2'-oxo-2,3,4a,5,6,7,8,11,12,12a-decahydro-1H-spiro[6,10-methanobenzo[10]annulene-4,4'-[1,3]dioxolane]-3,8,11,12-tetrayl tetraacetate

  • Compound C29H40O12

    (2S,3aS,4aS,4'S,6S,8aR,9R,10R)-3a-(2-Hydroxypropan-2-yl)-1,8a-dimethyl-2'-oxo-3,3a,4,4a,6,7,8,8a,9,10-decahydro-2H-spiro[benzo[f]azulene-5,4'-[1,3]dioxolane]-2,6,9,10-tetrayl tetraacetate

  • Compound C29H40O12

    (3S,4S,4aS,6S,8S,11R,12R,12aR)-6-Hydroxy-9,12a,13,13-tetramethyl-2'-oxo-2,3,4a,5,6,7,8,11,12,12a-decahydro-1H-spiro[6,10-methanobenzo[10]annulene-4,4'-[1,3]dioxolane]-3,8,11,12-tetrayl tetraacetate

  • Compound C7H14O2

    (S)-4-Methylhexanoic acid

  • Compound C7H12O2

    (R)-5-Ethyl-5-methyldihydrofuran-2-one

  • Compound C12H20O4

    ((±)-4-trans-2-(tert-Butoxycarbonyl)cyclopropyl)butanoic acid

  • Compound C12H18O5

    ((±)-4-trans-2-(tert-Butoxycarbonyl)cyclopropyl)-4-oxobutanoic acid

  • Compound C12H18O4

    (±)-tert-Butyl 2-(5-oxotetrahydrofuran-2-yl)cyclopropanecarboxylate

  • Compound C17H24O7

    (2aS,2a1R,4aR,5S,6S,7R,7aS)-7-Acetoxy-4a-hydroxy-6-isopropyl-2a1-methyl-2-oxodecahydroindeno[7,1-bc]furan-5-carboxylic acid

  • Compound C17H22O7

    (2aS,2a1R,4aS,5R,5aS,8aS,8bR)-8b-Hydroxy-2a1,6,6-trimethyl-3,8-dioxododecahydroindeno[4,3-bc:6,7-c']difuran-5-yl acetate

  • Compound C17H22O8

    (2aS,2a1R,4aS,5R,5aS,6S,8aS,8bR)-8b-Hydroxy-6-(hydroxymethyl)-2a1,6-dimethyl-3,8-dioxododecahydroindeno[4,3-bc:6,7-c']difuran-5-yl acetate

  • Compound C17H22O8

    (2aS,2a1R,4aS,5R,5aS,6R,8aS,8bR)-8b-Hydroxy-6-(hydroxymethyl)-2a1,6-dimethyl-3,8-dioxododecahydroindeno[4,3-bc:6,7-c']difuran-5-yl acetate

  • Compound C18H26O7

    (2aS,2a1R,4aR,5S,6S,7R,7aS)-Methyl 7-acetoxy-4a-hydroxy-6-isopropyl-2a1-methyl-2-oxodecahydroindeno[7,1-bc]furan-5-carboxylate

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Dehydrogenation as a substrate-activating strategy in homogeneous transition-metal catalysis. Chem. Rev. 110, 681–703 (2010).

  2. 2.

    & Selective catalytic dehydrogenation of alkanes to alkenes. J. Am. Chem. Soc. 109, 8025–8032 (1987).

  3. 3.

    , , , & Dehydrogenation of n-alkanes catalyzed by iridium ‘pincer’ complexes: regioselective formation of α-olefins. J. Am. Chem. Soc. 121, 4086–4087 (1999).

  4. 4.

    et al. Catalytic alkane metathesis by tandem alkane dehydrogenation–olefin metathesis. Science 312, 257–261 (2006).

  5. 5.

    & Dioxygen activation by enzymes containing binuclear non-heme iron clusters. Chem. Rev. 96, 2625–2657 (1996).

  6. 6.

    , , & Dioxygen activation at mononuclear nonheme iron active sites: enzymes, models, and intermediates. Chem. Rev. 104, 939–986 (2004).

  7. 7.

    , & Mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad: recent developments in enzymology and modeling studies. Chem. Soc. Rev. 37, 2716–2744 (2008).

  8. 8.

    Fatty acid desaturases: selecting the dehydrogenation channel. Nat. Prod. Rep. 21, 249–262 (2004).

  9. 9.

    , , , & Nature's inventory of halogenation catalysts: oxidative strategies predominate. Chem. Rev. 106, 3364–3378 (2006).

  10. 10.

    , & Purification and characterization of clavaminate synthase from Streptomyces clavuligerus: an unusual oxidative enzyme in natural product biosynthesis. Biochemistry 29, 6499–6508 (1990).

  11. 11.

    et al. Spectroscopic studies of substrate interactions with clavaminate synthase 2, a multifunctional α-KG-dependent non-heme iron enzyme: correlation with mechanisms and reactivities. J. Am. Chem. Soc. 123, 7388–7398 (2001).

  12. 12.

    , & Oxygen economy of cytochrome p450: what is the origin of the mixed functionality as a dehydrogenase–oxidase enzyme compared with its normal function? J. Am. Chem. Soc. 126, 5072–5073 (2004) and references therein.

  13. 13.

    , , , & Shape-selective interception by hydrocarbons of the O2-derived oxidant of a biomimetic nonheme iron complex. Angew. Chem. Int. Ed. 48, 1780–1783 (2009).

  14. 14.

    , , , & A diiron(IV) complex that cleaves strong C–H and O–H bonds. Nature Chem. 1, 145–150 (2009).

  15. 15.

    , & Modeling nonheme diiron enzymes: hydrocarbon hydroxylation and desaturation by a high-valent Fe2O2 diamond core. J. Am. Chem. Soc. 119, 3635–3636 (1997).

  16. 16.

    et al. Manganese catalysts for C–H activation: an experimental/theoretical study identifies the stereoelectronic factor that controls the switch between hydroxylation and desaturation pathways. J. Am. Chem. Soc. 132, 7605–7616 (2010).

  17. 17.

    & A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

  18. 18.

    , & The Fe(PDP)-catalyzed aliphatic C–H oxidation: a slow addition protocol. Tetrahedron 65, 3078–3084 (2009).

  19. 19.

    & Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010).

  20. 20.

    , & A synthetically useful, self-assembling MMO mimic system for catalytic alkene epoxidation with aqueous H2O2. J. Am. Chem. Soc. 123, 7194–7195 (2001).

  21. 21.

    & In situ formation of peracetic acid in iron-catalyzed epoxidations by hydrogen peroxide in the presence of acetic acid. Adv. Synth. Catal. 346, 190–194 (2004).

  22. 22.

    & Iron-catalyzed olefin epoxidation in the presence of acetic acid: insights into the nature of the metal-based oxidant. J. Am Chem. Soc. 129, 15964–15972 (2007).

  23. 23.

    , & A novel approach to the efficient oxygenation of hydrocarbons under mild conditions. Superior oxo transfer selectivity using dioxiranes. Acc. Chem. Res. 39, 1–9 (2006).

  24. 24.

    & Hypersensitive radical probes and the mechanisms of cytochrome P450-catalyzed hydroxylation reactions. Acc. Chem. Res. 33, 449–455 (2000) and references therein.

  25. 25.

    , , , & The chemistry of taxanes: skeletal rearrangements of baccatin derivatives via radical intermediates. J. Org. Chem. 59, 1475–1484 (1994).

  26. 26.

    , & Highly regio- and stereospecific hydroxylation of C-1 position of 2-deacetoxytaxinine J derivative with DMDO. Tetrahedron Lett. 41, 3907–3910 (2000).

  27. 27.

    & The taxane diterpenoids. J. Nat. Prod. 62, 1448–1472 (1999).

  28. 28.

    et al. Structure and stereochemistry of taxuchin A, a new 11(15→1) abeotaxane type diterpene from taxus chinensis. Chem. Commun. 1561–1562 (1994).

  29. 29.

    , , & Selective microbial hydroxylation and biological rearrangment of taxoids. Tetrahedron Lett. 38, 2721–2724 (1997).

  30. 30.

    & Stereospecific alkane hydroxylation by non-heme iron catalysts: mechanistic evidence for an FeV=O active species. J. Am. Chem. Soc. 123, 6327–6337 (2001).

  31. 31.

    , , , & The stereochemistry of 9-decalyl free radicals. J. Am. Chem. Soc. 87, 2590–2596 (1965).

  32. 32.

    & Picosecond radical kinetics. Alkoxycarbonyl accelerated cyclopropylcarbinyl radical ring openings. Tetrahedron 51, 657–664 (1995).

  33. 33.

    & Picrotoxinin binding sites in brain, in Brain Receptor Methodologies Part B Amino Acids. Peptides. Psychoactive drugs (eds Marangos, P.J., Campbell, I.C. & Cohen, R.M.) 211–229 (Academic Press, 1984).

  34. 34.

    , , , & Non-heme iron oxygenases generate natural structural diversity in carbapenem antibiotics. J. Am. Chem. Soc. 132, 12–13 (2010).

Download references

Acknowledgements

The authors are grateful to Pfizer, Bristol-Myers Squibb and UIUC for financial support. M.A.B. is supported by an Illinois Distinguished Fellowship (2007-2010) and a Harold R. Snyder Fellowship (2010-2011). S.A.R. is supported by the National Science Foundation under the Center for Chemical Innovation in Stereoselective C–H Functionalization (CHE-0943980) and by an Ullyot Graduate Fellowship (2009-2010). J. Guerra and R.M. Williams are thanked for providing the (+)-taxusin used in the radical trap experiments.

Author information

Affiliations

  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, Illinois 61801, USA

    • Marinus A. Bigi
    • , Sean A. Reed
    •  & M. Christina White

Authors

  1. Search for Marinus A. Bigi in:

  2. Search for Sean A. Reed in:

  3. Search for M. Christina White in:

Contributions

M.A.B. and M.C.W. conceived and designed the experiments outlined in Figs 1 3,4b, and M.A.B. performed these experiments. S.A.R. and M.C.W. conceived and designed the experiments outlined in Figs 4a,5 and S.A.R. performed these experiments. M.A.B and M.C.W co-wrote the paper, with assistance from S.A.R.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to M. Christina White.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.967