Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Dec 31;3(12):17326-17340.
doi: 10.1021/acsomega.8b02994. Epub 2018 Dec 14.

Benefits of Unconventional Methods in the Total Synthesis of Natural Products

Tomas Hudlicky  1
Affiliations
Review

Benefits of Unconventional Methods in the Total Synthesis of Natural Products

Tomas Hudlicky. ACS Omega. .

Abstract

This article provides a survey of four "unconventional" methods employed in the synthesis of natural products in the Hudlicky group. The utility of flash vacuum pyrolysis is highlighted by examples of many natural products attained via vinylcyclopropane-cyclopentene rearrangement and its heterocyclic variants. Preparative organic electrochemistry was used in oxidations and reductions with levels of selectivity unattainable by conventional methods. Yeast reduction of ketoesters was featured in the total synthesis of pyrrolizidine alkaloids. Finally, the use of toluene dioxygenase-mediated dihydroxylations in enantioselective synthesis of natural products concludes this presentation. Recently, synthesized targets in the period 2010-2019 are listed in the accompanying table. The results of research from the Hudlicky group are placed in appropriate context with the work of others, and a detailed guide to the current literature is provided.

PubMed Disclaimer

Conflict of interest statement

The author declares no competing financial interest.

Figures

Figure 1
Figure 1
von Gerichten’s degradation of morphine to phenanthrene and morphol.
Figure 2
Figure 2
Evolution of FVP-based annulation strategies for the synthesis of natural product frameworks containing five-membered rings.
Figure 3
Figure 3
Some of the milestones in the rearrangements of vinylcyclopropanes and their heteroatom analogues.
Figure 4
Figure 4
Vinylcyclopropane–cyclopentene rearrangement in terpene synthesis.
Figure 5
Figure 5
Examples of natural products attained from the heteroatom variants of the vinylcyclopropane–cyclopentene rearrangement.
Figure 6
Figure 6
Little’s syntheses of hirsutene (32) and quadrone (64).
Figure 7
Figure 7
Electrochemical furan annulations by Wright and Moeller.
Figure 8
Figure 8
Anionic hydroxylation of pymetrozine.
Figure 9
Figure 9
Electrochemical oxidation of pymetrozine on a medium scale.
Figure 10
Figure 10
Examples of electrochemical oxidations and reductions.
Figure 11
Figure 11
Selective reductions of cinnamyl over allylic ethers.
Figure 12
Figure 12
Selectivity in reductions of the cinnamyl group from various substrates: halide vs ether and oxygen vs nitrogen selectivity.
Figure 13
Figure 13
Principle of resolution of alkoxides containing a chiral center.
Figure 14
Figure 14
Resolution of ketoesters and ketoamides via baker’s yeast reductions.
Figure 15
Figure 15
Resolution of ketoester 131 and applications to total synthesis of pyrrolizidine alkaloids.
Figure 16
Figure 16
Enzymatic dihydroxylation of aromatic compounds by bacterial dioxygenase(s).
Figure 17
Figure 17
Enzymatic dihydroxylation of aromatic compounds.
Figure 18
Figure 18
Functional content of arene dihydrodiols and access to their enantiomers.
Figure 19
Figure 19
Metabolism of benzoic acids by Ralstonia eutrophus.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. For leading references to some of these topics see:

    2. Puri S.; Kaur B.; Parmar A.; Kumar H. Applications of ultrasound in organic synthesis—a green approach. Curr. Org. Chem. 2013, 17, 1790–1828. 10.2174/13852728113179990018. - DOI
    3. Baig R. B. N.; Varma S. R. Alternative energy input: Mechanochemical, microwave, and ultrasound-assisted organic synthesis. Chem. Soc. Rev. 2012, 41, 1559–1584. 10.1039/C1CS15204A. - DOI - PubMed
    4. Cravotto G.; Cintas P. Power ultrasound in organic synthesis: Moving cavitational chemistry from academia to innovative and large-scale applications. Chem. Soc. Rev. 2006, 35, 180–196. 10.1039/B503848K. - DOI - PubMed
    5. Abdulla R. F. Ultrasound in organic synthesis. Aldrichimica Acta 1988, 21, 31–42.
    6. Jas G.; Kirschning A. Continuous flow techniques in organic synthesis. Chem.- Eur. J. 2003, 9, 5708–5723. 10.1002/chem.200305212. - DOI - PubMed
    7. Ley S. V. Engineering chemistry for the future of organic synthesis. Tetrahedron 2018, 74, 3087–3100. 10.1016/j.tet.2018.05.046. - DOI
    8. Ley S. V. The engineering of chemical synthesis: humans and machines working in harmony. Angew. Chem., Int. Ed. 2018, 57, 5182–5183. 10.1002/anie.201802383. - DOI - PubMed
    9. Movsisyan M.; Delbeke E. I. P.; Berton J. K. E. T.; Battilocchio C.; Ley S. V.; Stevens C. V. Taming hazardous chemistry by continuous flow technology. Chem. Soc. Rev. 2016, 45, 4892–4928. 10.1039/C5CS00902B. - DOI - PubMed
    10. Ley S. V.; Fitzpatrick D. E.; Myers R. M.; Battilocchio C.; Ingham R. J. Machine-assisted organic synthesis. Angew. Chem., Int. Ed. 2015, 54, 10122–10136. 10.1002/anie.201501618. - DOI - PMC - PubMed
    11. Pastre J. C.; Browne D. L.; Ley S. V. Flow chemistry syntheses of natural products. Chem. Soc. Rev. 2013, 42, 8849–8869. 10.1039/c3cs60246j. - DOI - PubMed
    12. Sideri I. K.; Voutyritsa E.; Kokotos C. G. Photoorganocatalysis, small organic molecules and light in the service of organic synthesis: the awakening of a sleeping giant. Org. Biomol. Chem. 2018, 16, 4596–4614. 10.1039/C8OB00725J. - DOI - PubMed
    13. Eivgi O.; Lemcoff N. G. Turning the light on: Recent developments in photoinduced olefin metathesis. Synthesis 2018, 50, 49–63. 10.1055/s-0036-1589113. - DOI
    14. Menigaux D.; Belmont P.; Brachet E. Light on unsaturated hydrocarbons—“Gotta heterofunctionalize them all”. Eur. J. Org. Chem. 2017, 15, 2008–2055. 10.1002/ejoc.201601626. - DOI

    15. [The entire issue 15 is a special issue on Catalysis]

    16. Dallinger D.; Kappe C. O. Microwave-assisted synthesis in water as solvent. Chem. Rev. 2007, 107, 2563–2591. 10.1021/cr0509410. - DOI - PubMed
    17. Stauch T.; Dreuw A. Advances in quantum mechanochemistry: electronic structure methods and force analysis. Chem. Rev. 2016, 116, 14137–14180. 10.1021/acs.chemrev.6b00458. - DOI - PubMed
    18. Tan D.; Friščić T. Mechanochemistry for organic chemists: an update. Eur. J. Org. Chem. 2018, 18–33. 10.1002/ejoc.201700961. - DOI
    19. Chanda T.; Zhao J. C.-G. Recent progress in organocatalytic asymmetric domino transformations. Adv. Synth. Catal. 2018, 360, 2–79. 10.1002/adsc.201701059. - DOI
    1. von Gerichten E.; Schrotter H. Zur Kenntniss des Morphins. Justus Liebigs Ann. Chem. 1881, 210, 396–401. 10.1002/jlac.18812100211. - DOI
    1. Fischer O.; von Gerichten E. Zur Kenntniss des Morphins. Ber. Dtsch. Chem. Ges. 1886, 19, 792–794. 10.1002/cber.188601901180. - DOI

    1. For reviews of pyrolysis methods see for example:

    2. Wenrup C. Flash vacuum pyrolysis of azides, triazoles, and tetrazoles. Chem. Rev. 2017, 117, 4562–4623. 10.1021/acs.chemrev.6b00738. - DOI - PubMed
    3. Wentrup C. Flash vacuum pyrolysis: techniques and reactions. Angew. Chem., Int. Ed. 2017, 56, 14808–14835. 10.1002/anie.201705118. - DOI - PubMed
    4. Wentrup C. Flash (vacuum) pyrolysis apparatus and methods. Aust. J. Chem. 2014, 67, 1150–1165. 10.1071/CH14096. - DOI
    5. McNab H. Synthetic applications of flash vacuum pyrolysis. Contemp. Org. Synth. 1996, 3, 373–396. 10.1039/co9960300373. - DOI
    6. Karpf M. Organic synthesis at high temperatures. Gas-phase flow thermolysis [New synthetic methods (57)]. Angew. Chem., Int. Ed. 1986, 25, 414–430. 10.1002/anie.198604141. - DOI
    1. Hudlicky T.; Rulin F.; Lovelace T. C.; Reed J. W.. Synthesis of Natural Products Containing Five-Membered Rings: An Evolution of General Methodology. In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science, 1989; Vol. 3, (Part B), , pp 3–72;
    2. The Way of Synthesis; Hudlicky T., Reed J. W., Eds.; Wiley-VCH, 2007; pp 361–429.