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
. 2020 Jul 29;142(30):12937-12941.
doi: 10.1021/jacs.0c05766. Epub 2020 Jul 7.

Synthesis of Anhydroryanodol

Kang Du  1 , Matthew J Kier  1 , Zachary D Stempel  1 , Valer Jeso  1 , Arnold L Rheingold  2 , Glenn C Micalizio  1
Affiliations

Synthesis of Anhydroryanodol

Kang Du et al. J Am Chem Soc. .

Abstract

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Introduction to ryanoids and anhydroryanodol.
Figure 2.
Figure 2.
Initial retrosynthetic analysis of ryanoids featuring an oxidative annulation reaction between an enyne and a 1,3-diketone.
Figure 3.
Figure 3.
Synthesis of the annulation substrate 12.
Figure 4.
Figure 4.
Investigation of an oxidative annulation and observation of an undesired late-stage Payne rearrangement.
Figure 5.
Figure 5.
Preparation of (+/−)-anhydroryanodol from 1,3-diketone 12; formal total synthesis of (+/−)-ryanodol.
See this image and copyright information in PMC

References

    1. Bélanger A; Berney DJF; Borschberg HJ; Brousseau R; Doutheau A; Durand R; Katayama H; Lapalme R; Leturc DM; Liao C-C; Maclachlan FN; Maffrand JP; Marazza F; Martino R; Moreau C; Saintlaurent L; Saintonge R; Soucy P; Ruest L; Deslongchamps P Total Synthesis of Ryanodol. Can. J. Chem 1979, 57, 3348–3354.
    2. Deslongchamps P; Bélanger A; Berney DJF; Borschberg HJ; Brousseau R; Doutheau A; Durand R; Katayama H; Lapalme R; Leturc DM; Liao C-C; Maclachlan FN; Maffrand JP; Marazza F; Martino R; Moreau C; Ruest L; Saintlaurent L; Saintonge R; Soucy P The Total Synthesis of (+)-Ryanodol. 1. General Strategy and Search for a Convenient Diene for the Construction of a Key Tricyclic Intermediate. Can. J. Chem 1990, 68, 115–126.
    3. Deslongchamps P; Bélanger A; Berney DJF; Borschberg HJ; Brousseau R; Doutheau A; Durand R; Katayama H; Lapalme R; Leturc DM; Liao C-C; Maclachlan FN; Maffrand JP; Marazza F; Martino R; Moreau C; Ruest L; Saintlaurent L; Saintonge R; Soucy P The Total Synthesis of (+)-Ryanodol. 2. Model Studies for Ring B and Ring C of (+)-Anhydroryanodol. Preparation of a Key Pentacyclic Intermediate. Can. J. Chem 1990, 68, 127–152.
    4. Deslongchamps P; Bélanger A; Berney DJF; Borschberg HJ; Brousseau R; Doutheau A; Durand R; Katayama H; Lapalme R; Leturc DM; Liao C-C; Maclachlan FN; Maffrand JP; Marazza F; Martino R; Moreau C; Ruest L; Saintlaurent L; Saintonge R; Soucy P The Total Synthesis of (+)-Ryanodol. 3. Preparation of (+)-Anhydroryanodol from a Key Pentacyclic Intermediate. Can. J. Chem 1990, 68, 153–185.
    5. Deslongchamps P; Bélanger A; Berney DJF; Borschberg HJ; Brousseau R; Doutheau A; Durand R; Katayama H; Lapalme R; Leturc DM; Liao C-C; Maclachlan FN; Maffrand JP; Marazza F; Martino R; Moreau C; Ruest L; Saintlaurent L; Saintonge R; Soucy P The Total Synthesis of (+)-Ryanodol. 4. Preparation of (+)-Ryanodol from (+)-Anhydroryanodol. Can. J. Chem 1990, 68, 186–192.
    1. Urabe D; Nagatomo M; Hagiwara K; Masuda K; Inoue M Symmetry-driven synthesis of 9-demethyl-10,15-dideoxyranodol. Chem. Sci 2013, 4, 1615–1619.
    2. Nagatomo M; Koshimizu M; Masuda K; Tabuchi T; Urabe D; Inoue M Total Synthesis of Ryanodol. J. Am. Chem. Soc 2014, 136, 5916–5919. - PubMed
    3. Nagatomo M; Hagiwara K; Masuda K; Koshimizu M; Kawamata T; Matsui Y; Urabe D; Inoue M Symmetry-Driven Strategy for the Assembly of the Core Tetracycle of (+)-Ryanodine: Synthetic Utility of a Cobalt-Catalyzed Olefin-Oxidation and a-Alkoxy Bridgehead Radical Reaction. Chem. Eur. J 2016, 22, 222–229. - PubMed
    4. Masuda K; Koshimizu M; Nagatomo M; Inoue M Asymmetric Total Synthesis of (+)-Ryanodol and (+)-Ryanodine. Chem. Eur. J 2016, 22, 230–236. - PubMed
    1. Chuang KV; Xu C; Reisman SEA 15-step synthesis of (+)-ryanodol. Science, 2016, 353, 912–915. - PMC - PubMed
    2. Xu C; Han A; Virgil SC; Reisman SE Chemical Synthesis of (+)-Ryanodine and (+)-20-Deoxyspiganthine. ACS Central Sci. 2017, 3, 278–282. - PMC - PubMed
    3. Han A; Tao Y; Reisman SEA 16-step synthesis of the isoryanodane diterpene (+)-perseanol. Nature, 2019, 573, 563–568. - PMC - PubMed
    1. Wood JL; Graeber JK; Njardarson JT Application of phenolic oxidation chemistry in synthesis: preparation of the BCE ring system of ryanodine. Tetrahedron 2003, 59, 8855–8858.
    1. Rogers EF; Koniuszy FR; Shavel J; Folkers K Plant Insecticides. 1. Ryanodine, a new alkaloid from Ryania speciose Vahl. J. Am. Chem. Soc 1948, 70, 3086–3088. - PubMed
    2. González-Coloma A; Cabrera R; Socorro Monzón AR; Fraga BM Persea Indica as a Natural Source of the Insecticide Ryanodol. Phytochemistry, 1993, 34, 397–400.

Publication types

MeSH terms