Unconventional Macrocyclizations in Natural Product Synthesis

Abstract

Over the past several decades, macrocyclic compounds have emerged as increasingly significant therapeutic candidates in drug discovery. Their pharmacological activity hinges on their rotationally restricted three-dimensional orientation, resulting in a unique conformational preorganization and a high enthalpic gain as a consequence of high-affinity macrocycle-protein binding interactions. Synthetic access to macrocyclic drug candidates is therefore crucial. From a synthetic point of view, the efficiency of macrocyclization events commonly suffers from entropic penalties as well as undesired intermolecular couplings (oligomerization). Although over the past several decades ring-closing metathesis, macrolactonization, or macrolactamization have become strategies of choice, the toolbox of organic synthesis provides a great number of versatile transformations beyond the aforementioned. This Outlook focuses on a selection of examples employing what we term unconventional macrocyclizations toward the synthesis of natural products or analogues.

Scheme 1. (a) Selected Examples of Common Macrocyclizations in Natural Product Synthesis and (b) Employment of Various Ring-Closing Techniques for the Construction of the Bis-Macrocyclic Natural Product Diazonamide A

Scheme 2. Nicolaou’s “Stitching” Technique en Route to the First Total Synthesis of Rapamycin

Scheme 3. Intramolecular Stille Couplings in the Syntheses of (a) Macrolactin A and (b) Sarain A

Scheme 4. Heck Coupling toward the Synthesis of Etnangien by Menche

Scheme 5. Stereoselective Macrocyclizations in the Syntheses of (a) Biselyngbyolide B and (b) Isoplagiochin D

Scheme 6. Suzuki–Miyaura Couplings en Route to the Syntheses of (a) Phomactin A and (b) Isocomplestatin

Scheme 7. Domino Suzuki–Miyaura/4π-Electrocyclic Ring Opening Developed by Maulide for the Syntheses of FR252921, FR252922, and FR256523

Scheme 8. Tsuji–Trost Macrocyclizations in the Syntheses of (a) Humulene by Yamamoto, (b) Roseophilin by Fürstner, and (c) Macquarimicin A by Tadano

Scheme 9. (a) Cascade Sonogashira Macrocyclization and Transannular Diels–Alder in the Synthesis of the Dynemicin A Core by Schreiber and (b) Hirama’s Development of a Kedarcidin Chromophore Fragment

Scheme 10. (a) Palladium-Catalyzed Macrocyclization Developed by Trost en Route to Bryostatin 16 and (b) Boger’s Palladium-Mediated Transannular Larock Macrocyclization in the Synthesis of Streptide

Scheme 11. (a) Wittig Macrocyclization by Nógrádi toward Garuganin III and (b) Double Wittig Olefination for the Syntheses of Trienomycins A and F by Smith

Scheme 12. Ring-Closing Horner–Wadsworth–Emmons Olefination for in the Synthesis of Lasonolide A by Kang

Scheme 13. HWE Macrocyclizations in the Syntheses of (a) Dactylolide by Keck and (b) Archazolid A by Menche

Scheme 14. Aryl–Aryl Couplings Developed for the Syntheses of (a) Vancomycin Aglycon by Evans and (b) Arylomycin Core (72) by Baran

Scheme 15. (a) Sorensen’s Diastereoselective Intramolecular Diels–Alder Reaction en Route to Abyssomicin C and (b) Corey’s Enantioselective Syntheses of Palominol and Dolabellatrienone

Scheme 16. (a) Baran’s Diels–Alder/Retro-Diels–Alder Approach for the Synthesis of Haouamine A’s Bent Aromatic Ring and (b) Hetero-Diels–Alder Reaction Enabling Nicolaou’s Synthesis of Sporolide B

Scheme 17. Macrolactonization/Diels–Alder Cyclization Sequence to Form the Core of a Dynemicin A Derivative

Scheme 18. Evans’ Synthesis of Miyakolide via 1,3-Dipolar Cycloaddition

Scheme 19. Hsung’s oxa-[3 + 3] Cycloaddition to Build the Phomactin A Core

Scheme 20. Enantioselective, Rh-Catalyzed Synthesis of the Cylindrocyclophane Core by Davies

Scheme 21. (a) Incomplete McMurry Reaction Affording Crassin-Intermediate 99, (b) SmI₂-Induced Pinacol Coupling, as Applied by Corey, and (c) Nicolaou’s Heteropinacol-Macrocyclization en Route to Diazonamide A

Scheme 22. Witkop-Cyclization Approaches to Diazonamide A by (a) Harran and (b) Nicolaou

Scheme 23. Wurtz-Type Coupling Enabled Nógrádi’s Synthesis of Garugamblin-1

Scheme 24. Temporary Addition of a Thiyl Radical Promotes a Giese Macrocyclization, Forming the Brefeldin A and C Core Structure

Scheme 25. (a) Base- and (b) Lewis-Acid-Promoted Macroaldolization Reaction for the Syntheses of Epothilone A and Diazonamide A

Scheme 26. Synthesis of an Advanced Intermediate of Calicheamicinone by Means of a Thiophenolate-Promoted Macroaldolization

Scheme 27. Use of a Samarium-Mediated Reformatsky Reaction in the Synthesis of Cebulactam A1

Scheme 28. Hosomi–Sakurai Reactions Led to the Desired Macrocyclizations in the Syntheses of (a) Bryostatin 1 by Wender and (b) the Cyanolide A Aglycon by Rychnovsky

Scheme 29. (a) Romo’s Room-Temperature Barbier Reaction en Route to Gymnodimine and (b) Danishefsky’s Acetylide Addition for the Synthesis of Calicheamicinone

Scheme 30. Nozaki–Hiyama–Kishi Approaches toward Phomactin A

Scheme 31. Loh-Type Allylation Employed by Banwell in the Syntheses of Paecilomycin F and Cochliomycin C

Scheme 32. Nickel-Catalyzed Alkyne-Aldehyde Reductive Coupling in the Synthesis of Amphidinolide T1 by Jamison

Scheme 33. Hoveyda’s Synthesis of Chloropeptin I through a Chan–Evans–Lam Coupling

Scheme 34. Ullmann-Type Etherification for the Macrocyclization of Hirsutellone B Developed by Uchiro

Scheme 35. Biphasic Conditions Allow Glaser–Hay Coupling in Continuous Flow at High Concentrations for the Formal Synthesis of Ivorenolide A

Scheme 36. Harrowven’s Corey–Seebach Reaction Enabled the Synthesis of Riccardin C