A Unified Strategy for the Total Syntheses of Eribulin and a Macrolactam Analogue of Halichondrin B

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Aug 5

PMID 35930662

Authors

K C Nicolaou

Saiyong Pan

Yogesh Shelke

Stephan Rigol

Ruiyang Bao

Dipendu Das

Qiuji Ye

Affiliations

Soon will be listed here.

Abstract

A unified synthetic route for the total syntheses of eribulin and a macrolactam analog of halichondrin B is described. The key to the success of the current synthetic approach includes the employment of our reverse approach for the construction of cyclic ether structural motifs and a modified intramolecular cyclization reaction between alkyl iodide and aldehyde functionalities to establish the all-carbon macrocyclic framework of eribulin. These syntheses, together with our previous work on the total syntheses of halichondrin B and norhalichondrin B, demonstrate and validate the powerful reverse approach in the construction of cyclic ether structural motifs. On the other hand, the unified synthetic strategy for the synthesis of the related macrolactam analog provides inspiration and opportunities in the halichondrin field and related polycyclic ether areas.

Citing Articles

Advanced Technologies for Large Scale Supply of Marine Drugs.

Martinez H, Santos M, Pedraza L, Testera A Mar Drugs. 2025; 23(2).

PMID: 39997193 PMC: 11857447. DOI: 10.3390/md23020069.

Immunomodulatory Effects of Halichondrin Isolated from Marine Sponges and Its Synthetic Analogs in Oncological Applications.

Dissanayake D, Nagahawatta D, Lee J, Jeon Y Mar Drugs. 2024; 22(9).

PMID: 39330307 PMC: 11432918. DOI: 10.3390/md22090426.

An α-chloroaldehyde-based formal synthesis of eribulin.

Kaghad A, Panagopoulos D, Caballero-Garcia G, Zhai H, Britton R Nat Commun. 2023; 14(1):1904.

PMID: 37019928 PMC: 10076431. DOI: 10.1038/s41467-023-37346-7.

References

Pattenden G, Ashweek N, Baker-Glenn C, Kempson J, Walker G, Yee J . Total synthesis of (-)-ulapualide A, a novel tris-oxazole macrolide from marine nudibranchs, based on some biosynthesis speculation. Org Biomol Chem. 2008; 6(8):1478-97. DOI: 10.1039/b801036f. View

Zhang Z, Huang J, Ma B, Kishi Y . Further improvement on sulfonamide-based ligand for catalytic asymmetric 2-haloallylation and allylation. Org Lett. 2008; 10(14):3073-6. DOI: 10.1021/ol801093p. View

Baxter R, Montgomery J . Mechanistic study of nickel-catalyzed ynal reductive cyclizations through kinetic analysis. J Am Chem Soc. 2011; 133(15):5728-31. PMC: 3083823. DOI: 10.1021/ja200867d. View

Furstner A . Carbonminus signCarbon Bond Formations Involving Organochromium(III) Reagents. Chem Rev. 2002; 99(4):991-1046. DOI: 10.1021/cr9703360. View

Yeoman J, Mak V, Reisman S . A unified strategy to ent-kauranoid natural products: total syntheses of (-)-trichorabdal A and (-)-longikaurin E. J Am Chem Soc. 2013; 135(32):11764-7. DOI: 10.1021/ja406599a. View

Wang Y, Habgood G, Christ W, Kishi Y, Littlefield B, Yu M . Structure-activity relationships of halichondrin B analogues: modifications at C.30-C.38. Bioorg Med Chem Lett. 2000; 10(10):1029-32. DOI: 10.1016/s0960-894x(00)00150-5. View

Mahandru G, Liu G, Montgomery J . Ligand-dependent scope and divergent mechanistic behavior in nickel-catalyzed reductive couplings of aldehydes and alkynes. J Am Chem Soc. 2004; 126(12):3698-9. DOI: 10.1021/ja049644n. View

Zheng W, Seletsky B, Palme M, Lydon P, Singer L, Chase C . Macrocyclic ketone analogues of halichondrin B. Bioorg Med Chem Lett. 2004; 14(22):5551-4. DOI: 10.1016/j.bmcl.2004.08.069. View

Narayan S, Carlson E, Cheng H, Condon K, Du H, Eckley S . Novel second generation analogs of eribulin. Part II: Orally available and active against resistant tumors in vivo. Bioorg Med Chem Lett. 2011; 21(6):1634-8. DOI: 10.1016/j.bmcl.2011.01.097. View

10.

Jackson K, Henderson J, Motoyoshi H, Phillips A . A total synthesis of norhalichondrin B. Angew Chem Int Ed Engl. 2009; 48(13):2346-50. PMC: 2901598. DOI: 10.1002/anie.200806111. View

11.

Kawano S, Ito K, Yahata K, Kira K, Abe T, Akagi T . A landmark in drug discovery based on complex natural product synthesis. Sci Rep. 2019; 9(1):8656. PMC: 6572832. DOI: 10.1038/s41598-019-45001-9. View

12.

Praveen Kumar V, Kishi Y . Total Synthesis of Halistatins 1 and 2. J Am Chem Soc. 2020; 142(34):14743-14749. DOI: 10.1021/jacs.0c07390. View

13.

Ao J, Sun C, Chen B, Yu N, Liang G . Total Synthesis of Isorosthin L and Isoadenolin I. Angew Chem Int Ed Engl. 2021; 61(10):e202114489. DOI: 10.1002/anie.202114489. View

14.

Nicolaou K, Pan S, Shelke Y, Das D, Ye Q, Lu Y . A Reverse Approach to the Total Synthesis of Halichondrin B. J Am Chem Soc. 2021; 143(24):9267-9276. DOI: 10.1021/jacs.1c05270. View

15.

Towle M, Salvato K, Budrow J, Wels B, Kuznetsov G, Aalfs K . In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res. 2001; 61(3):1013-21. View

16.

McBride A, Butler S . Eribulin mesylate: a novel halichondrin B analogue for the treatment of metastatic breast cancer. Am J Health Syst Pharm. 2012; 69(9):745-55. DOI: 10.2146/ajhp110237. View

17.

Yang Y, Kim D, Kishi Y . Second generation synthesis of C27-C35 building block of E7389, a synthetic halichondrin analogue. Org Lett. 2009; 11(20):4516-9. PMC: 2759418. DOI: 10.1021/ol9016589. View

18.

Cavedon C, Sletten E, Madani A, Niemeyer O, Seeberger P, Pieber B . Visible-Light-Mediated Oxidative Debenzylation Enables the Use of Benzyl Ethers as Temporary Protecting Groups. Org Lett. 2021; 23(2):514-518. PMC: 7880570. DOI: 10.1021/acs.orglett.0c04026. View

19.

Nicolaou K, Pan S, Shelke Y, Ye Q, Das D, Rigol S . A Highly Convergent Total Synthesis of Norhalichondrin B. J Am Chem Soc. 2021; 143(49):20970-20979. DOI: 10.1021/jacs.1c10539. View

20.

Jackson K, Henderson J, Phillips A . The halichondrins and E7389. Chem Rev. 2009; 109(7):3044-79. DOI: 10.1021/cr900016w. View