Article | Published:

Guided desaturation of unactivated aliphatics

Nature Chemistry volume 4, pages 629635 (2012) | Download Citation

Abstract

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This ‘portable desaturase’ (TzoCl) is a bench-stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group.

  • Compound C6H14O2

    2-Hydroperoxyhexane

  • Compound C6H12O

    Hex-5-en-2-ol

  • Compound C6H12O

    (E)-Hex-4-en-2-ol

  • Compound C8H16

    Cyclooctane

  • Compound C6H12

    3,3-Dimethylbut-1-ene

  • Compound C22H40ClIrO2P2

    {[O,O-Bis(di-tert-butylphosphino)resorcin-2-yl]chlorohydridoiridium(III)}

  • Compound C8H14

    (Z)-Cyclooctene

  • Compound C6H14

    2,2-Dimethylbutane

  • Compound C23H26N2O2

    N-(2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-1-phenylcyclopentanecarboxamide

  • Compound C23H24N2O2

    N-(2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-1-phenylcyclopent-2-enecarboxamide

  • Compound C18H30F3NO3

    (1S,2S,4aR,8R,8aS)-8-Hydroxy-2-isopropyl-4a,8-dimethyldecahydronaphthalen-1-yl (2,2,2-trifluoroethyl)carbamate

  • Compound C18H29BrF3NO3

    (1S,2S,4aR,8R,8aS)-8-Hydroxy-2-isopropyl-4a,8-dimethyldecahydronaphthalen-1-yl bromo(2,2,2-trifluoroethyl)carbamate

  • Compound C18H29BrF3NO3

    (1R,2R,4aR,8R,8aS)-2-(2-Bromopropan-2-yl)-8-hydroxy-4a,8-dimethyldecahydronaphthalen-1-yl (2,2,2-trifluoroethyl)carbamate

  • Compound C18H28F3NO3

    (1S,2S,4aR,8R,8aS)-8-Hydroxy-4a,8-dimethyl-2-(prop-1-en-2-yl)decahydronaphthalen-1-yl (2,2,2-trifluoroethyl)carbamate

  • Compound C11H16ClN3O2S

    (E)-2-(3,3-Diethyltriaz-1-en-1-yl)-4-methylbenzene-1-sulfonyl chloride

  • Compound C18H29N3O3S

    (E)-2-Cyclopentylethyl 2-(3,3-diethyltriaz-1-en-1-yl)-4-methylbenzenesulfonate

  • Compound C14H18O3S

    2-(Cyclopent-1-en-1-yl)ethyl 4-methylbenzenesulfonate

  • Compound C14H20O3S

    2-Cyclopentylethyl 4-methylbenzenesulfonate

  • Compound C14H19BrO3S

    2-Cyclopentylethyl 2-bromo-4-methylbenzenesulfonate

  • Compound C16H24O3S

    2,6-Dimethylhept-1-en-4-yl 4-methylbenzenesulfonate

  • Compound C20H24O3S

    5-Methyl-1-phenylhex-5-en-3-yl 4-methylbenzenesulfonate

  • Compound C18H28O3S

    2,8-Dimethylnon-1-en-4-yl 4-methylbenzenesulfonate

  • Compound C17H24O3S

    2-Methylnona-1,8-dien-4-yl 4-methylbenzenesulfonate

  • Compound C17H26O3S

    7-Methyl-3-methyleneoctyl 4-methylbenzenesulfonate

  • Compound C17H26O3S

    3,7-Dimethyloct-3-en-1-yl 4-methylbenzenesulfonate

  • Compound C14H20O3S

    3-Ethylpent-3-en-1-yl 4-methylbenzenesulfonate

  • Compound C15H20O3S

    2-(Cyclohex-1-en-1-yl)ethyl 4-methylbenzenesulfonate

  • Compound C17H24O3S

    (1R,2S,5R)-5-Methyl-2-(prop-1-en-2-yl)cyclohexyl 4-methylbenzenesulfonate

  • Compound C17H25NO2S

    4-Methyl-N-((1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexyl)benzenesulfonamide

  • Compound C16H25NO2S

    N-(2,6-Dimethylhept-1-en-4-yl)-4-methylbenzenesulfonamide

  • Compound C16H25NO2S

    N-(2,6-Dimethylhept-2-en-4-yl)-4-methylbenzenesulfonamide

  • Compound C14H19NO4S

    (S)-Methyl 4-methyl-2-(4-methylphenylsulfonamido)pent-4-enoate

  • Compound C17H25NO4S

    (R)-tert-Butyl 4-methyl-2-(4-methylphenylsulfonamido)pent-4-enoate

  • Compound C13H17NO4S

    (S)-Methyl 3-methyl-2-(4-methylphenylsulfonamido)but-3-enoate

  • Compound C15H21NO2S

    (R)-N-(1-(Cyclohex-1-en-1-yl)ethyl)-4-methylbenzenesulfonamide

  • Compound C26H43N3O3S

    (1S,2S,4aR,8S,8aS)-2-Isopropyl-4a,8-dimethyldecahydronaphthalen-1-yl 2-((E)-3,3-diethyltriaz-1-en-1-yl)-4-methylbenzenesulfonate

  • Compound C22H32O3S

    (1S,2S,4aR,8S,8aS)-4a,8-Dimethyl-2-(prop-1-en-2-yl)decahydronaphthalen-1-yl 4-methylbenzenesulfonate

  • Compound C22H32O3S

    (1S,2S,4aR,8aS)-2-Isopropyl-4a-methyl-8-methylenedecahydronaphthalen-1-yl 4-methylbenzenesulfonate

  • Compound C31H46N4O2S

    2-((E)-3,3-Diethyltriaz-1-en-1-yl)-N-(((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methyl)-4-methylbenzenesulfonamide

  • Compound C27H35NO2S

    (1R,4aS,10aR)-7-Isopropyl-1,10a-dimethyl-11-tosyl-2,3,4,9,10,10a-hexahydro-1H-4a,1-(epiminomethano)phenanthrene

  • Compound C27H35NO2S

    N-(((1R,4aS,10aR)-7-Isopropyl-1,4a-dimethyl-1,4,4a,9,10,10a-hexahydrophenanthren-1-yl)methyl)-4-methylbenzenesulfonamide

  • Compound C42H67N3O2

    (3S,6aR,6bS,8aS,11S,12aR,14bR)-11-(((2-((E)-3,3-Diethyltriaz-1-en-1-yl)-4-methylbenzyl)oxy)methyl)-4,4,6a,6b,8a,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-ol

  • Compound C37H54O4S

    ((2S,4aS,6aS,6bR,10S,12aS)-10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b-octadecahydropicen-2-yl)methyl 4-methylbenzenesulfonate

  • Compound C34H52N8O6S

    (S)-N-((S)-1-(((S)-1-(((S)-1-Amino-1-oxo-3-phenylpropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-((E)-3,3-diethyltriaz-1-en-1-yl)-4-methylphenylsulfonamido)-4-methylpentanamide

  • Compound C30H41N5O6S

    (S)-N-((S)-1-(((S)-1-(((S)-1-Amino-1-oxo-3-phenylpropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)-4-methyl-2-(4-methylphenylsulfonamido)pent-4-enamide

  • Compound C18H28DN3O3S

    (E)-2-(1-Deuterocyclopentyl)ethyl 2-(3,3-diethyltriaz-1-en-1-yl)-4-methylbenzenesulfonate

  • Compound C14H17DO3S

    2-(Cyclopent-1-en-1-yl)ethyl 2-deutero-4-methylbenzenesulfonate

  • Compound C14H17DO3S

    2-(1-Deutero-cyclopent-2-en-yl)ethyl 4-methylbenzenesulfonate

  • Compound C17H25N3O3S

    (E)-5-Methylhex-1-yn-3-yl 2-(3,3-diethyltriaz-1-en-1-yl)benzenesulfonate

  • Compound C14H16O3S

    6-Methyl-3-(2-methylallyl)-4-methylene-3,4-dihydrobenzo[c][1,2]oxathiine 1,1-dioxide

  • Compound C13H19NO3S

    2-Cyclopentylethyl 2-aminobenzenesulfonate

  • Compound C13H16O3S

    2-(Cyclopent-1-en-1-yl)ethyl benzenesulfonate

  • Compound C20H33N3O3S

    (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 2-((E)-3,3-diethyltriaz-1-en-1-yl)benzenesulfonate

  • Compound C16H19F3N2O5S

    2-((2-Cyclopentylethoxy)sulfonyl)-5-methylbenzenediazonium trifluoroacetate

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Acknowledgements

We thank D-H. Huang and L. Pasternack for NMR spectroscopic assistance, A. Rheingold and C. Moore for X-ray crystallographic analysis, M. Wasa for assistance with chiral high performance liquid chromatography and L. Leman for assistance with the peptide synthesis. Financial support for this work was provided by the National Institute of General Medical Sciences, National Institute of Health (GM-097444), Spanish Ministry of Education and Science (MEC)–Fulbright Program (postdoctoral fellowship for A.M.), National Science Foundation (predoctoral fellowship for W.R.G.), the Spanish MEC (predoctoral grant for J.O.F.) and Bristol-Myers Squibb (unrestricted research support).

Author information

Author notes

    • Abraham Mendoza
    •  & Will R. Gutekunst

    These authors contributed equally to this work

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Ana-Florina Voica
    • , Abraham Mendoza
    • , Will R. Gutekunst
    • , Jorge Otero Fraga
    •  & Phil S. Baran

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Contributions

A-F.V. and P.S.B. conceived the original concept for the desaturation reaction, A-F.V., A.M., W.R.G. and J.O.F. conducted the experimental work and analysed the results, A-F.V., W.R.G., A.M. and P.S.B. co-wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Phil S. Baran.

Supplementary information

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    Supplementary information

    Experimental procedures and characterization data

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    Supplementary information

    NMR spectra

Crystallographic information files

  1. 1.

    Supplementary information

    Crystallographic data for compound 21

  2. 2.

    Supplementary information

    Crystallographic data for compound 33

  3. 3.

    Supplementary information

    Crystallographic data for compound 39

  4. 4.

    Supplementary information

    Crystallographic data for compound 41

  5. 5.

    Supplementary information

    Crystallographic data for compound 43

  6. 6.

    Supplementary information

    Crystallographic data for compound 44

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https://doi.org/10.1038/nchem.1385

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