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
. 2017 Jan 1;8(1):507-514.
doi: 10.1039/C6SC03347D. Epub 2016 Aug 17.

Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade

Robert A Craig 2nd  1 , Jennifer L Roizen  1 , Russell C Smith  1 , Amanda C Jones  1 , Scott C Virgil  1 , Brian M Stoltz  1
Affiliations

Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade

Robert A Craig 2nd et al. Chem Sci. .

Erratum in

Abstract

An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation-Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Isomeric [6,7]- and [7,6]-norcembranoid diterpene natural products (blue and red, respectively).
Scheme 1
Scheme 1. Biomimetic semisynthesis and previous synthetic attempts toward ineleganolide (1).
Scheme 2
Scheme 2. Retrosynthetic analysis of ineleganolide (1).
Scheme 3
Scheme 3. Enantioselective synthesis of 1,3-cis-cyclopentenediol coupling partner ent-17.
Scheme 4
Scheme 4. Convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic core.
Scheme 5
Scheme 5. Synthesis of ent-isoineleganolides A and B.
Scheme 6
Scheme 6. Conformational assessment and relative ground state energies.
Scheme 7
Scheme 7. Redox manipulation of diene 28.
Fig. 2
Fig. 2. Conformational isomers of 2H-ent-ineleganolide.
Fig. 3
Fig. 3. Biological activity of select ineleganoloids.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Duh C.-Y., Wang S.-K., Chia M.-C., Chiang M. Y. Tetrahedron Lett. 1999;40:6033.
    1. Tseng Y.-J., Ahmed A. F., Dai C.-F., Chiang M. Y., Sheu J.-H. Org. Lett. 2005;7:3813. - PubMed
    1. Lillsunde K.-E., Festa C., Adel H., de Marino S., Lombardi V., Tilvi S., Nawrot D., Zampella A., D'Souza L., D'Auria M., Tammela P. Mar. Drugs. 2014;12:4045. - PMC - PubMed
    2. Radhika P., Subba Rao P. V., Anjaneyulu V., Asolkar R. N., Laatsch H. J. Nat. Prod. 2002;65:737. - PubMed
    3. Sheu J.-H., Ahmed A. F., Shiue R.-T., Dai C.-F., Kuo Y.-H. J. Nat. Prod. 2002;65:1904. - PubMed
    4. Iguchi K., Kajiyama K., Yamada Y. Tetrahedron Lett. 1995;36:8807.
    1. Huang C.-Y., Tseng Y.-J., Chokkalingam U., Hwang T.-L., Hsu C.-H., Dai C.-F., Sung P.-J., Sheu J.-H. J. Nat. Prod. 2016;79:1339. - PubMed
    2. Tseng Y.-J., Wang S.-K., Duh C.-Y. Mar. Drugs. 2013;11:3288. - PMC - PubMed
    3. Huang K.-J., Chen Y.-C., El-Shazly M., Du Y.-C., Su J.-H., Tsao C.-W., Yen W.-H., Chang W.-B., Su Y.-D., Yeh Y.-T., Lu M.-C. Molecules. 2013;18:2924. - PMC - PubMed
    4. Kamel H. N., Slattery M. Pharm. Biol. 2005;43:253.
    1. While most synthetic efforts toward the polycyclic norcembranoids have been focused on ineleganolide (1), one attempt was made to synthesize the core of yonarolide (5), see: Ueda Y., Abe H., Iguchi K., Ito H., Tetrahedron Lett., 2011, 52 , 3379 .