Stereocontrolled Total Synthesis of Bastimolide B Using Iterative Homologation of Boronic Esters

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2022 May 2

PMID 35499478

Authors

Daniele Fiorito

Selbi Keskin

Joseph M Bateman

Malcolm George

Adam Noble

Varinder K Aggarwal

Affiliations

Soon will be listed here.

Abstract

Bastimolide B is a polyhydroxy macrolide isolated from marine cyanobacteria displaying antimalarial activity. It features a dense array of hydroxylated stereogenic centers with 1,5-relationships along a hydrocarbon chain. These 1,5-polyols represent a particularly challenging motif for synthesis, as the remote position of the stereocenters hampers stereocontrol. Herein, we present a strategy for 1,5-polyol stereocontrolled synthesis based on iterative boronic ester homologation with enantiopure magnesium carbenoids. By merging boronic ester homologation and transition-metal-catalyzed alkene hydroboration and diboration, the acyclic backbone of bastimolide B was rapidly assembled from readily available building blocks with full control over the remote stereocenters, enabling the total synthesis to be completed in 16 steps (LLS).

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References

Newman D, Cragg G . Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J Nat Prod. 2020; 83(3):770-803. DOI: 10.1021/acs.jnatprod.9b01285. View

Binanzer M, Fang G, Aggarwal V . Asymmetric synthesis of allylsilanes by the borylation of lithiated carbamates: formal total synthesis of (-)-decarestrictine D. Angew Chem Int Ed Engl. 2010; 49(25):4264-8. DOI: 10.1002/anie.201001223. View

Staunton J, Weissman K . Polyketide biosynthesis: a millennium review. Nat Prod Rep. 2001; 18(4):380-416. DOI: 10.1039/a909079g. View

Liu H, Lin S, Jacobsen K, Poulsen T . Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights. Angew Chem Int Ed Engl. 2019; 58(39):13630-13642. DOI: 10.1002/anie.201812982. View

Fawcett A, Nitsch D, Ali M, Bateman J, Myers E, Aggarwal V . Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and Sch 725674. Angew Chem Int Ed Engl. 2016; 55(47):14663-14667. PMC: 5129522. DOI: 10.1002/anie.201608406. View

Friedrich R, Friestad G . Inspirations from tetrafibricin and related polyketides: new methods and strategies for 1,5-polyol synthesis. Nat Prod Rep. 2020; 37(9):1229-1261. DOI: 10.1039/c9np00070d. View

Larouche-Gauthier R, Fletcher C, Couto I, Aggarwal V . Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation of challenging boronic esters. Chem Commun (Camb). 2011; 47(47):12592-4. DOI: 10.1039/c1cc14469c. View

Zheng K, Xie C, Hong R . Bioinspired iterative synthesis of polyketides. Front Chem. 2015; 3:32. PMC: 4439576. DOI: 10.3389/fchem.2015.00032. View

Doerksen R, Meyer C, Krische M . Feedstock Reagents in Metal-Catalyzed Carbonyl Reductive Coupling: Minimizing Preactivation for Efficiency in Target-Oriented Synthesis. Angew Chem Int Ed Engl. 2019; 58(40):14055-14064. PMC: 6764920. DOI: 10.1002/anie.201905532. View

10.

Blair D, Chitti S, Trobe M, Kostyra D, Haley H, Hansen R . Automated iterative Csp-C bond formation. Nature. 2022; 604(7904):92-97. PMC: 10500635. DOI: 10.1038/s41586-022-04491-w. View

11.

Chen M, Roush W . Enantioselective synthesis of (Z)- and (E)-2-methyl-1,5-anti-pentenediols via an allene hydroboration-double-allylboration reaction sequence. J Am Chem Soc. 2013; 135(25):9512-7. PMC: 3733567. DOI: 10.1021/ja4033633. View

12.

Roseblade S, Pfaltz A . Iridium-catalyzed asymmetric hydrogenation of olefins. Acc Chem Res. 2007; 40(12):1402-11. DOI: 10.1021/ar700113g. View

13.

Friestad G, Sreenilayam G . Versatile configuration-encoded strategy for rapid synthesis of 1,5-polyol stereoisomers. Org Lett. 2010; 12(21):5016-9. DOI: 10.1021/ol1021417. View

14.

Kumpulainen E, Kang B, Krische M . C(21)-C(40) of tetrafibricin via metal catalysis: beyond stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles. Org Lett. 2011; 13(9):2484-7. PMC: 3084888. DOI: 10.1021/ol200735r. View

15.

Mohr P, Halcomb R . Total synthesis of (+)-phomactin a using a B-alkyl Suzuki macrocyclization. J Am Chem Soc. 2003; 125(7):1712-3. DOI: 10.1021/ja0296531. View

16.

Bootwicha T, Feilner J, Myers E, Aggarwal V . Iterative assembly line synthesis of polypropionates with full stereocontrol. Nat Chem. 2017; 9(9):896-902. DOI: 10.1038/nchem.2757. View

17.

ter Horst B, Feringa B, Minnaard A . Iterative strategies for the synthesis of deoxypropionates. Chem Commun (Camb). 2010; 46(15):2535-47. DOI: 10.1039/b926265b. View

18.

Kliman L, Mlynarski S, Ferris G, Morken J . Catalytic enantioselective 1,2-diboration of 1,3-dienes: versatile reagents for stereoselective allylation. Angew Chem Int Ed Engl. 2011; 51(2):521-4. PMC: 3369812. DOI: 10.1002/anie.201105716. View

19.

Gudipati V, Curran D . Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin. Tetrahedron Lett. 2011; 52(17):2254-2257. PMC: 3097483. DOI: 10.1016/j.tetlet.2011.01.086. View

20.

Schrof R, Altmann K . Studies toward the Total Synthesis of the Marine Macrolide Salarin C. Org Lett. 2018; 20(23):7679-7683. DOI: 10.1021/acs.orglett.8b03422. View