Divergent Syntheses of (-)-Chicanine, (+)-Fragransin A2, (+)-Galbelgin, (+)-Talaumidin, and (+)-Galbacin via One-Pot Homologative γ-Butyrolactonization.

In this study, the divergent syntheses of (-)-chicanine, (+)-fragransin A2, (+)-galbelgin, (+)-talaumidin, and (+)-galbacin are detailed. In this approach, an early-stage modified Kowalski one-carbon homologation reaction is utilized to construct the central γ-butyrolactone framework with the two necessary ß,γ-vicinal stereogenic centers. The two common chiral γ-butyrolactone intermediates were designed to be capable for assembling five different optically active tetrahydrofuran lignans from commercially available materials in a concise and effective divergent manner in five to eight steps. These five syntheses are among the shortest and highest-yielding syntheses reported to date.

Divergent Total Syntheses of Gymnothelignan N, Beilschmin A, and Eupomatilones 1, 3, 4, and 7.

A seven-step asymmetric total synthesis of gymnothelignan N is detailed in the current report. The approach is based on an early-stage one-carbon homologative lactonization reaction, which we recently revisited and modified to construct the core γ-butyrolactone motif with the requisite ß,γ-vicinal stereogenic centers. By design, the utilization of the same chiral γ-butyrolactone intermediate permitted the rapid and effective divergent assembly of optically active eupomatilones 1, 3, 4, and 7 in five or six steps from commercially available materials. This represents one of the shortest and highest-yielding syntheses reported to date.

Stereoselective Synthesis of Oxazolidin-2-Ones via an Asymmetric Aldol/Curtius Reaction: Concise Total Synthesis of (-)-Cytoxazone.

Herein, we are reporting an efficient approach toward the synthesis of 4,5-disubstituted oxazolidin-2-one scaffolds. The developed approach is based on a combination of an asymmetric aldol and a modified Curtius protocol, which uses an effective intramolecular ring closure to rapidly access a range of oxazolidin-2-one building blocks. This strategy also permits a straightforward and concise asymmetric total synthesis of (-)-cytoxazone. Consisting of three steps, this is one of the shortest syntheses reported to date. Ultimately, this convenient platform would provide a promising method for the early phases of drug discovery.

Discrimination between Human Colorectal Neoplasms with a Dual-Recognitive Two-Photon Probe.

Colorectal cancer is a major cause of cancer-related deaths worldwide. Histologic diagnosis using biopsy samples of colorectal neoplasms is the most important step in determining the treatment methods, but these methods have limitations in accuracy and effectiveness. Herein, we report a dual-recognition two-photon probe and its application in the discrimination between human colorectal neoplasms. The probe is composed of two monosaccharides, d-glucosamine and ß-d-galactopyranoside, in a fluorophore for the monitoring of both glucose uptake and ß-gal hydrolysis. In vitro/cell imaging studies revealed the excellent selectivity and sensitivity of the probe for glucose transporter-mediated glucose uptake and ß-gal activity. Cancer-specific uptake was monitored by increased fluorescence intensity, and additional screening of cancer cells was achieved by changes in emission ratio owing to the higher activity of ß-gal. Using human colon tissues and two-photon microscopy, we found that the plot of intensity versus ratio can accurately discriminate between colorectal neoplasms in the order of cancer progression (normal, adenoma, and carcinoma).

Ratiometric Detection of γ-Glutamyltransferase in Human Colon Cancer Tissues Using a Two-Photon Probe.

γ-Glutamyltransferase (GGT) plays a role in cleaving the γ-glutamyl bond of glutathione. The GGT is known to be overexpressed in some tumors and has been recognized as a potential biomarker for malignant tumors. Colon cancer is one of the most common cancers worldwide; however, there is no quantitative method for detecting cancer cells in human colon tissues. In this study, we report a ratiometric two-photon probe for GGT that can be applied in human colon tissues. The probe (Probe 2) showed high fluorescence efficiency, marked fluorescence changes, excellent kinetics, and selectivity for the GGT in live colon cells. Additionally, we obtained ratiometric two-photon microscopy images of GGT activity in human colon tissue. We used this method to compare normal and cancer tissues based on their ratio values; the ratio value was higher in cancer tissue than in normal tissue. This study provides a method for quantitative analysis of GGT, particularly in human colon cancer, which will be useful for studying GGT-related diseases and diagnosing colon cancer.

Synthetic efforts towards the stereoselective synthesis of NF00659B1.

NF00659B1 is a novel α-pyrone diterpenoid natural product with potent anti-colon cancer activity. A stereoselective approach to the 2,2-dimethyl oxepanol core of NF00659B1 is described enlisting a sequence of olefinic ester ring-closing metathesis, epoxidation, and Grignard addition. This strategy paves the way to a total synthesis of NF00659B1 for further biological studies.

Advances in the synthesis of glycosidic macrolides: clavosolides A-D and cyanolide A.

Covering: 2005 to 2016Clavosolides A-D and cyanolide A are glycosidic macrolides and represent a new family of marine natural products. They possess a number of unusual structural features and have attracted considerable interest from the synthetic community. This review presents a comprehensive survey of all aspects of the clavosolides A-D and cyanolide A. Specific topics include isolation, structure determination, biological activity, and synthetic approaches.

Total synthesis of (-)-kopsinine and ent-(+)-kopsinine.

The total synthesis of (-)-kopsinine and its unnatural enantiomer is detailed, enlisting a late-stage SmI2-mediated transannular free radical conjugate addition reaction for construction of the core bicyclo[2.2.2]octane ring system with strategic C21-C2 bond formation. Key to the approach is assemblage of the underlying skeleton by an intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the precursor C21 functionalized pentacyclic ring system 1 in a single step in which the C3 methyl ester found in the natural product 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 synthesis of dihydrolysergic acid and dihydrolysergol: development of a divergent synthetic strategy applicable to rapid assembly of D-ring analogs.

The total syntheses of dihydrolysergic acid and dihydrolysergol are detailed based on a Pd(0)-catalyzed intramolecular Larock indole cyclization for the preparation of the embedded tricyclic indole (ABC ring system) and a subsequent powerful inverse electron demand Diels-Alder reaction of 5-carbomethoxy-1,2,3-triazine with a ketone-derived enamine for the introduction of a functionalized pyridine, serving as the precursor for a remarkably diastereoselective reduction to the N-methylpiperidine D-ring. By design, the use of the same ketone-derived enamine and a set of related complementary heterocyclic azadiene [4 + 2] cycloaddition reactions permitted the late stage divergent preparation of a series of alternative heterocyclic derivatives not readily accessible by more conventional approaches.

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 15, 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 15 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 Synthesis of Gymnothelignan K via a One-Pot Homologative γ-Butyrolactonization.

The first total synthesis of tetrahydrofuran dilignan gymnothelignan K is disclosed. The approach is based on implementing an early stage one-carbon homologative lactonization, which we recently disclosed, for constructing the γ-butyrolactone scaffold with the requisite ß,γ-trans-vicinal stereocenters. Other salient features of the synthesis include the acid-promoted dimerization and the Suzuki-Miyaura cross-coupling reaction to install the challenging diaryl skeleton that permits the effective assembly of the optically active gymnothelignan K in 8 steps from commercially available materials.

Nickel Carbene-Mediated One-Carbon Homologative γ-Butyrolactonization.

In this report, we present a highly efficient approach for the synthesis of ß,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.

Synthesis of γ-Lactones via the Kowalski Homologation Reaction: Protecting-Group-Free Divergent Total Syntheses of Eupomatilones-2,5,6, and 3-epi-Eupomatilone-6.

A highly efficient synthesis of functionalized chiral γ-butyrolactone scaffolds has been described. The basis of the approach is the Kowalski ester homologation that is modified for our proposed transformation. The newly developed methodology combines a divergent synthetic strategy to permit a straightforward protecting-group-free asymmetric total syntheses of eupomatilones-2,5,6, and 3-epi-eupomatilone-6 in five or six steps from commercial starting materials, making it one of the shortest syntheses reported to date.

Chemical logic of MraY inhibition by antibacterial nucleoside natural products.

Novel antibacterial agents are needed to address the emergence of global antibiotic resistance. MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles. An incomplete understanding of the structural and mechanistic basis of MraY inhibition has hindered the translation of these compounds to the clinic. Here we present crystal structures of MraY in complex with representative members of the liposidomycin/caprazamycin, capuramycin, and mureidomycin classes of nucleoside inhibitors. Our structures reveal cryptic druggable hot spots in the shallow inhibitor binding site of MraY that were not previously appreciated. Structural analyses of nucleoside inhibitor binding provide insights into the chemical logic of MraY inhibition, which can guide novel approaches to MraY-targeted antibiotic design.

Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters.

Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively.

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.

A stereoselective formal synthesis of leucascandrolide A.

A stereoselective formal synthesis of leucascandrolide A was accomplished through the tandem and organocatalytic oxa-Michael reactions, which were promoted by the gem-disubstituent effect, in conjunction with the dithiane coupling reaction.

A facile and efficient synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans via tandem cross-metathesis/thermal S(N)2' reaction: protecting-group-free synthesis of (+/-)-diospongin A.

The tandem cross-metathesis/thermal S(N)2' reaction was explored for the facile and efficient synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans. The mildness of the thermal conditions allowed for the synthesis of 4-hydroxy-2,6-cis-tetrahydropyrans from base-sensitive substrates without the use of protecting groups. The tandem reaction enabled a protecting-group-free synthesis of (+/-)-diospongin A.