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
. 2022 Jul 11;61(28):e202204884.
doi: 10.1002/anie.202204884. Epub 2022 May 24.

Total Synthesis of (-)-Bastimolide A: A Showcase for Type I Anion Relay Chemistry

Joshua B Cox  1 , Alex A Kellum  1 , Yiwen Zhang  1 , Bo Li  1 , Amos B Smith 3rd  1
Affiliations

Total Synthesis of (-)-Bastimolide A: A Showcase for Type I Anion Relay Chemistry

Joshua B Cox et al. Angew Chem Int Ed Engl. .

Abstract

A highly convergent total synthesis of (-)-bastimolide A (1), a polyhydroxy antimalarial macrolide, has been achieved via a longest linear sequence of twenty steps from commercially available glycidyl ethers. Type I Anion Relay Chemistry (ARC) coupling tactics enable rapid construction of the molecule's 1,5-polylol backbone. A late-stage B-alkyl Suzuki-Miyaura union and an Evans-modified Mukaiyama macrolactonization generate the forty-membered Z-α,β-unsaturated macrocyclic lactone.

Keywords: Antimalarial Agents; Macrolides; Multicomponent Coupling; Natural Products; Total Synthesis.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
(−)-Bastimolide A (1) and the related 1,5 polylol-based macrolides (−)-Amantelide A (2), (−)-Nuiapolide (3) (+)-Palstimolide A (4), (−)-Bastimolide B (5) and (−)-Caylobolide B (6).
Scheme 1.
Scheme 1.
Utility of Anion Relay Chemistry (ARC) for constructing 1,5-stereodiols and 1,3,5-stereotriols. HMPA = hexamethylphosphoramide
Scheme 2.
Scheme 2.
Retrosynthetic analysis of 1.
Scheme 3.
Scheme 3.
Synthesis of Northern Fragment (−)-15.
Scheme 4.
Scheme 4.
Preparation of iodide (−)-26
Scheme 5.
Scheme 5.
Synthesis of Western Fragment (+)-14.
Scheme 6.
Scheme 6.
Synthesis of the Northwestern Fragment (+)-12. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
Scheme 7.
Scheme 7.
Synthesis of Southwestern Fragment (−)-16.
Scheme 8.
Scheme 8.
Synthesis of Southeastern Fragment (−)-17.
Scheme 9.
Scheme 9.
Synthesis of Southern Fragment (−)-13.
Scheme 10.
Scheme 10.
End game synthesis of (−)-Bastimolide A (1).
See this image and copyright information in PMC

References

    1. Shao C, Linington RG, Balunas MJ, Centeno A, Boudreau P, Zhang C, Engene N, Spadafora C, Mutka TS, Kyle DE, Gerwick L, Wang C, Gerwick WH, J. Org. Chem 2015, 80, 7849–7855; - PubMed
    2. Salvador LA, Sneed J, Paul VJ, Luesch H, J. Nat. Prod 2015, 78, 1957–1962; - PMC - PubMed
    3. Salvador LA, Paul VJ, Luesch H, J. Nat. Prod 2010, 73, 1606–1609; - PMC - PubMed
    4. Mori S, Williams H, Cagle D, Karanovich K, Horgen D, Smith R III, Watanabe CMH, Mar. Drugs 2015, 13, 6274–6290; - PMC - PubMed
    5. Keller L, Siqueira JL, Souza JM, Eribez K, LaMonte GM, Smith JE, Gerwick WH, Molecules 2020, 25, 1604–1613; - PMC - PubMed
    6. Shao C, Mou X, Cao F, Spadafora C, Glukhov E, Gerwick L, Wang C, Gerwick WH, J. Nat. Prod 2018, 81, 211–215. - PubMed

    1. The original structure of caylobolide B reported in ref.1c was incorrect. The geometry of the C2−C3 double bond was revised later by the same group:

    2. Salvador LA, Paul VJ, Luesch H, J. Nat. Prod 2016, 79, 452. - PubMed
    1. Friedrich RM, Friestad GK, Nat. Prod. Rep 2020, 37, 1229–1261.; - PubMed
    2. Quintard A, Sperandio C, Rodriguez J, Org. Lett 2018, 20, 5274–5277; - PubMed
    3. Kumara NS, Ramulua BJ, Ghosh S, Syn Open 2021, 5, 285–290.
    1. Deng Y, Smith AB III, Acc. Chem. Res 2020, 53, 988–1000. - PMC - PubMed
    1. Yeung K, Mykura RC, Aggarwal VK, Nat. Synth 2022, 1, 117–126;
    2. for a synthesis of bastimolide b see: Fiorito D, Keskin S, Bateman JM, George M, Noble A, Aggarwal VK J. Am. Chem. Soc 2022, 10.1021/jacs.2c03192 - DOI - PMC - PubMed

Publication types

LinkOut - more resources