Total Syntheses of (−)-Kopsifoline D and (−)-Deoxoapodine: Divergent Total Synthesis via Late-Stage Key Strategic Bond Formation

Divergent total syntheses of (−)-kopsifoline D and (−)-deoxoapodine are detailed from a common pentacyclic intermediate <b>15</b>, enlisting the late-stage formation of two different key strategic bonds (C21–C3 and C21–O–C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21–C2 bond formation) and (+)-fendleridine (C21–O–C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21–C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system <b>15</b> in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole

Total Syntheses of (−)-Kopsifoline D and (−)-Deoxoapodine: Divergent Total Synthesis via Late-Stage Key Strategic Bond Formation

Divergent total syntheses of (−)-kopsifoline D and (−)-deoxoapodine are detailed from a common pentacyclic intermediate <b>15</b>, enlisting the late-stage formation of two different key strategic bonds (C21–C3 and C21–O–C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21–C2 bond formation) and (+)-fendleridine (C21–O–C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21–C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system <b>15</b> in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole

Nickel Carbene-Mediated One-Carbon Homologative γ‑Butyrolactonization

In this report, we present a highly efficient approach for the synthesis of β,γ-disubstituted γ-butyrolactone motifs. This newly developed strategy is based on the combination of a diastereoselective aldol and a nickel carbene-mediated γ-butyrolactonization and uses an effective intramolecular ring closure to rapidly access a range of functionalized chiral γ-butyrolactones. This single-step approach was applied to produce straightforward asymmetric syntheses of (−)-talaumidin methyl ether, (+)-veraguensin, and (+)-dubiusamine A and a formal synthesis of (+)-phaseolinic acid as one of the shortest syntheses disclosed to date

Manipulating JNK Signaling with (−)-Zuonin A

Recently, in a virtual screening strategy to identify new compounds targeting the D-recruitment site (DRS) of the c-Jun N-terminal kinases (JNKs), we identified the natural product (−)-zuonin A. Here we report the asymmetric synthesis of (−)-zuonin A and its enantiomer (+)-zuonin A. A kinetic analysis for the inhibition of c-Jun phosphorylation by (−)-zuonin A revealed a mechanism of partial competitive inhibition. Its binding is proposed to weaken the interaction of c-Jun to JNK by approximately 5-fold, without affecting the efficiency of phosphorylation within the complex. (−)-Zuonin A inhibits the ability of both MKK4 and MKK7 to phosphorylate and activate JNK. The binding site of (−)-zuonin A is predicted by docking and molecular dynamics simulation to be located in the DRS of JNK. (+)-Zuonin A also binds JNK but barely impedes the binding of c-Jun. (−)-Zuonin A inhibits the activation of JNK, as well as the phosphorylation of c-Jun in anisomycin-treated HEK293 cells, with the inhibition of JNK activation being more pronounced. (−)-Zuonin A also inhibits events associated with constitutive JNK2 activity, including c-Jun phosphorylation, basal Akt activation, and MDA-MB-231 cell migration. Mutations in the predicted binding site for (−)-zuonin A can render it significantly more or less sensitive to inhibition than wild type JNK2, allowing for the design of potential chemical genetic experiments. These studies suggest that the biological activity reported for other lignans, such as saucerneol F and zuonin B, may be the result of their ability to impede protein–protein interactions within MAPK cascades

Manipulating JNK Signaling with (−)-Zuonin A

Recently, in a virtual screening strategy to identify new compounds targeting the D-recruitment site (DRS) of the c-Jun N-terminal kinases (JNKs), we identified the natural product (−)-zuonin A. Here we report the asymmetric synthesis of (−)-zuonin A and its enantiomer (+)-zuonin A. A kinetic analysis for the inhibition of c-Jun phosphorylation by (−)-zuonin A revealed a mechanism of partial competitive inhibition. Its binding is proposed to weaken the interaction of c-Jun to JNK by approximately 5-fold, without affecting the efficiency of phosphorylation within the complex. (−)-Zuonin A inhibits the ability of both MKK4 and MKK7 to phosphorylate and activate JNK. The binding site of (−)-zuonin A is predicted by docking and molecular dynamics simulation to be located in the DRS of JNK. (+)-Zuonin A also binds JNK but barely impedes the binding of c-Jun. (−)-Zuonin A inhibits the activation of JNK, as well as the phosphorylation of c-Jun in anisomycin-treated HEK293 cells, with the inhibition of JNK activation being more pronounced. (−)-Zuonin A also inhibits events associated with constitutive JNK2 activity, including c-Jun phosphorylation, basal Akt activation, and MDA-MB-231 cell migration. Mutations in the predicted binding site for (−)-zuonin A can render it significantly more or less sensitive to inhibition than wild type JNK2, allowing for the design of potential chemical genetic experiments. These studies suggest that the biological activity reported for other lignans, such as saucerneol F and zuonin B, may be the result of their ability to impede protein–protein interactions within MAPK cascades