Palladium-catalyzed synthesis of macrocycles. A total synthesis of (-)-aspochalasin B

Trost, Barry M.; Ohmori, Masayuki; Boyd, Steven A.; Okawara, Hideki; Brickner, Steven J.

doi:10.1021/ja00203a042

Cited by 56 publications

(25 citation statements)

References 3 publications

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“…The chemistry occurs under mild conditions and is amenable to ligand-induced regio-and stereocontrol. It has been applied broadly, including in numerous instances to form large carbocyclic and heterocyclic rings (57)(58)(59)(60). That said, when we simplified our templates to further study the catalysis in the context of cyclic-peptide synthesis, we discovered a combination of scope and functional group tolerance that was remarkable.…”

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confidence: 99%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide-protein interactions are important mediators of cellularsignaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. S ynthetic peptides and peptidomimetics play wide-ranging roles in pharmacology and drug discovery. Interest in these substances continues to grow, particularly as medicinal chemistry pushes further into control of cellular-signaling events mediated by protein-protein interactions (PPIs) (1-3). The subset of socalled "druggable" PPIs includes those mediated by consensus peptides, where binding determinants are localized within defined motifs (4-8). Experimental data as well as computational/ bioinformatic efforts (9-11) to identify "short linear motifs" within signaling proteins suggest that the number of druggable PPIs has been underestimated (12, 13). Considerable opportunity exists for new chemistry in this area (14). Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15-19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).Ring-forming reactions are prominent among alterations found to improve the stability and performance of peptides (24-27). They find broad utility in synthesis and, increasingly, in combination with phage, ribosome, and mRNA display technologies (28-32). Relative to their acyclic counterparts, cyclic peptides have more defined conformations and are less prone to aggregate (33). Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34-36). Internal disulfide bonding is also used (37, 38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40-42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig. 1A) (43, 44). Careful attention must be paid to...

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confidence: 99%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This experiment gave evidence for 3 and 4 being artifacts, as the acetonyl group was added during the extraction procedure, which included crushing the mycelium in acetone. Two other known compounds were identified as aspochalasins D (7) [9] and B (8) [10] by a comparison of their spectroscopic data with the literature values.…”

Section: Structure Elucidationmentioning

confidence: 99%

Spicochalasin A and New Aspochalasins from the Marine‐Derived Fungus Spicaria elegans

et al. 2009

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Different culture conditions directed by the OSMAC (one strain-many compounds) approach drastically modified the metabolites of the fungus Spicaria elegans, which yielded the novel spicochalasin A (1), five new aspochalasins M-Q (2-6), and two known aspochalasins (7 and 8). The gross structures of 1-6 were elucidated by 1D and 2D NMR and MS methods, and their absolute configurations were determined by X-ray

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“…Previous efforts directed toward the synthesis of the cytochalasins fall into two general categories: those that form the sixmembered ring of the isoindolone core and the larger, macrocyclic ring simultaneously in a late-stage intramolecular DielsAlder cyclization (2)(3)(4)(5)(6)(7) and those that form the isoindolone core first by using an intermolecular Diels-Alder reaction and then append the macrocycle in a stepwise fashion (8,9). We planned to pursue a somewhat different implementation of the latter strategy by targeting a different bond pair for Diels-Alder disconnection and by developing much of the stereochemistry of the macrocyclic portion of the molecule before its introduction in a fragment coupling process.…”

Section: Retrosynthetic Analysismentioning

confidence: 99%

“…The transfer of the nitrogen-containing appendage to the ␣-face in structures 4 and 9 was deliberate, providing a strategic device for stereochemical control of a key intramolecular Diels-Alder reaction. Although the Diels-Alder disconnection has been widely used in syntheses of the isoindolone core of the cytochalasins (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), its implementation has almost universally followed the ''natural'' cycloreversion of a cyclohexene such as 6, whereas our synthetic plan invoked a different Diels-Alder disconnection by prior migration of the cyclohexene double bond (Fig. 3).…”

Section: Retrosynthetic Analysismentioning

confidence: 99%

“…he cytochalasins are fungal metabolites with complex and diverse molecular structures and a range of biological effects and thus have been of interest to synthetic chemists (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Many cytochalasins inhibit cell division and are known to induce an apoptotic response, activities that are thought to arise from the ability of these molecules to inhibit the polymerization of actin (13,14).…”

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confidence: 99%

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An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

Haidle

Myers

2004

Proc. Natl. Acad. Sci. U.S.A.

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The cytochalasins are structurally complex natural products with a broad range of apparently unrelated effects in different biological systems. Different members of the family have variously demonstrated inhibitory activity toward the formation of actin filaments, toward the functioning of HIV protease, and toward the process of angiogenesis. The structural series is defined by a largely conserved, rigid bicyclic isoindolone core that is fused to a macrocyclic appendage. The latter structural component varies widely within the cytochalasins and seems to play an important role in the determination of biological activity. In this work, we describe the development of a convergent and enantioselective synthetic route to the cytochalasins that allows for the late-stage introduction of macrocyclic appendages of different sizes and constitutions. We illustrate the route with the synthesis of the 14-membered macrolactone cytochalasin B (1, an inhibitor of the formation of actin filaments) and the 11-membered macrocarbocyclic cytochalasin L-696,474 (2, an inhibitor of HIV protease) by using common precursors.

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Palladium-catalyzed synthesis of macrocycles. A total synthesis of (-)-aspochalasin B

Cited by 56 publications

References 3 publications

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Spicochalasin A and New Aspochalasins from the Marine‐Derived Fungus Spicaria elegans

An enantioselective, modular, and general route to the cytochalasins: Synthesis of L-696,474 and cytochalasin B

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