Monocyclic Precursors Research Articles

Synthesis and Bioactivity of Ophiofuranones A and B.

Ophiofuranones A and B, metabolites of the fungus Ophiosphaerella korrae, were synthesized in 16 steps and 12%/22% yield. The stereogenic centers were established by Sharpless dihydroxylations and epoxidation, the 1,3-dienes via Wittig or HWE olefinations. The rings were closed through Knoevenagel-type condensation and lactonization. The ophiofuranones proved nontoxic at relevant concentrations against tumor cells, fibroblasts, and various bacteria and fungi. Ophiofuranone A and the monocyclic precursors 4 were weakly active against microbial biofilms.

FlICk (fluorescent isoindole crosslinking) for peptide stapling.

The rigidification of peptide secondary structure via stapling is an important and enduring goal in the development of functional peptides for biochemical and pharmaceutical applications. In addition, the incorporation of fluorophores and chromophores has been a sought-after application for creating peptidic probes of cellular function and localization. The combined application of peptide stapling and fluorescent-readout is featured by the reaction of ortho-phthalaldehydes to create isoindole staples, thus transforming inactive linear and monocyclic precursors into fluorescent or visibly colored monocyclic and bicyclic products with noted biological activity. Given its user-friendliness, we have termed this approach FlICk (fluorescent isoindole crosslink) chemistry and we have featured this application on an array of high-affinity macrocyclic α-MSH derivatives as well as for late-stage intra-annular isoindole stapling furnished a bicyclic peptide mimic of α-amanitin that is cytotoxic to CHO cells. The synthetic methods for preparing substituted ortho-phthalaldehydes along with subsequent applications to FlICk stapling are detailed herein.

Fluorescent Isoindole Crosslink (FlICk) Chemistry: A Rapid, User-friendly Stapling Reaction.

The stabilization of peptide secondary structure via stapling is a ubiquitous goal for creating new probes, imaging agents, and drugs. Inspired by indole-derived crosslinks found in natural peptide toxins, we employed ortho-phthalaldehydes to create isoindole staples, thus transforming inactive linear and monocyclic precursors into bioactive monocyclic and bicyclic products. Mild, metal-free conditions give an array of macrocyclic α-melanocyte-stimulating hormone (α-MSH) derivatives, of which several isoindole-stapled α-MSH analogues (Ki ≈1 nm) are found to be as potent as α-MSH. Analogously, late-stage intra-annular isoindole stapling furnished a bicyclic peptide mimic of α-amanitin that is cytotoxic to CHO cells (IC50 =70 μm). Given its user-friendliness, we have termed this approach FlICk (fluorescent isoindole crosslink) chemistry.

Fluorescent Isoindole Crosslink (FlICk) Chemistry: A Rapid, User‐friendly Stapling Reaction

AbstractThe stabilization of peptide secondary structure via stapling is a ubiquitous goal for creating new probes, imaging agents, and drugs. Inspired by indole‐derived crosslinks found in natural peptide toxins, we employed ortho‐phthalaldehydes to create isoindole staples, thus transforming inactive linear and monocyclic precursors into bioactive monocyclic and bicyclic products. Mild, metal‐free conditions give an array of macrocyclic α‐melanocyte‐stimulating hormone (α‐MSH) derivatives, of which several isoindole‐stapled α‐MSH analogues (Ki≈1 nm) are found to be as potent as α‐MSH. Analogously, late‐stage intra‐annular isoindole stapling furnished a bicyclic peptide mimic of α‐amanitin that is cytotoxic to CHO cells (IC50=70 μm). Given its user‐friendliness, we have termed this approach FlICk (fluorescent isoindole crosslink) chemistry.

Concise Syntheses of Meridianins and Meriolins Using a Catalytic Domino Amino-Palladation Reaction

A synthesis of natural and synthetic members of the meridianin family of kinase inhibitory natural products has been developed. The sequence utilizes a variation of the Cacchi palladium-catalyzed domino reaction to efficiently construct the heterocyclic framework of the meridianins and meriolins from monocyclic precursors.

ChemInform Abstract: Synthesis of Indolizidinone Analogues of Cytotoxic Alkaloids: Monocyclic Precursors Are also Active.

AbstractA two‐step route is reported for the transformation of readily available hydroxyproline N‐amides into indolizidinone derivatives of type (V) and (VI).

Synthesis of indolizidinone analogues of cytotoxic alkaloids: Monocyclic precursors are also active

Readily available proline derivatives can be transformed in just two steps into analogues of cytotoxic phenanthroindolizidine alkaloids. The key step uses a sequential radical scission−oxidation−alkylation process, which yields 2-substituted pyrrolidine amides. A second process effects the cyclization to give the desired alkaloid analogues, which possess an indolizidine core. The major and minor isomers (dr 3:2 to 3:1) can be easily separated, allowing their use to study structure–activity relationships (SAR). The process is versatile and allows the introduction of aryl and heteroaryl groups (including biphenyl, halogenated phenyl, and pyrrole rings). Some of these alkaloid analogues displayed a selective cytotoxic activity against tumorogenic human neuronal and mammary cancer cells, and one derivative caused around 80% cell death in both tumor lines at micromolar doses. The cytotoxicity of some monocyclic precursors was also studied, being comparable or superior to the bicyclic derivatives.

Variations of solvent and substitution pattern in Pb(OAc)4 mediated domino reactions

The effect of solvent on oxidative cleavage of the Hajos–Parrish ketone derived hydrindene–diols 1, and Wieland–Miescher ketone derived octaline–diols 2 with Pb(OAc)4 is presented. Various solvents were screened and compared for these domino reactions. Changing the solvent influenced the reaction rate, product distribution, and chemical yield in the octalin–diol series, while no-effect was detected in the lower homologue hydrindene–diol series. The use of a cheap, readily available chiral carboxylic acid, such as (S)-2-acetoxypropionic acid gave diastereomeric mixtures when performed in the racemic series, offering the potential of a chemical resolution. The influence of the substitution pattern on the substrate was also investigated on variously substituted derivatives of 1. Diols 38 failed to give any detectable amount of IMDA type ring closure, leading only to dialdehyde 39. For the compounds studied, alkyl or carboxyalkyl substituents on the olefin 41 and 44 led to incomplete cascade transformation due to steric interference caused by the alkyl or acyl groups. The oxidative cleavage of unsaturated diols 46 and 48 derived from monocyclic precursors, used as templates to determine whether any unsaturated 1,2-diol could be regarded as a substrate, is also described.

Relationship of Stereochemical and Skeletal Diversity of Small Molecules to Cellular Measurement Space

Systematic and quantitative measurements of the roles of stereochemistry and skeleton-dependent conformational restriction were made using multidimensional screening. We first used diversity-oriented synthesis to synthesize the same number (122) of [10.4.0] bicyclic products (B) and their corresponding monocyclic precursors (M). We measured the ability of these compounds to modulate a broad swath of biology using 40 parallel cell-based assays. We analyzed the results using statistical methods that revealed illuminating relationships between stereochemistry, ring number, and assay outcomes. Conformational restriction by ring-closing metathesis increased the specificity of responses among active compounds and was the dominant factor in global activity patterns. Hierarchical clustering also revealed that stereochemistry was a second dominant factor; whereas the stereochemistry of macrocyclic appendages was a determinant for bicyclic compounds, the stereochemistry of the carbohydrates was a determinant for the monocyclic compounds of global activity patterns. These studies illustrate a quantitative method for measuring stereochemical and skeletal diversity of small molecules and their cellular consequences.

Regioselective Spiroannulations of α-Acetyl Lactones.

For Abstract see ChemInform Abstract in Full Text.

Computational Studies of the Growth Mechanism of Small Fullerenes: A Ring‐Stacking Model

AbstractA ring‐stacking model for the fullerene growth mechanism has been analyzed using the semiempirical AM1 scheme. Following different routes, small fullerenes C28 (Td and D2), C26 (D3h) and C24 (D6d) have been constructed from monocyclic/polycyclic precursors and circumscribing them with appropriate carbon belts. The deformation energies (DE) and the average bond lengths <R> of the precursors have been computed. The DE values suggest that there is a chance of bond cleavage of the polycyclic precursors as the growth process proceeds towards the cage formation. On the other hand, the monocyclic precursors are found to have significantly lower deformation energies than the polycyclic precursors. Further analyzing <R> values of the polycyclic and monocyclic cases at different stages, it is observed that the <R> values of the polycyclic cases decrease gradually, depicting a shrink in the precursors which may be detrimental to the growth process, whereas monocyclic precursors tend to swell, corroborating the tendency of the system to grow, which may be conducive for the growth process.

Pb(OAc) 4 mediated hetero-domino transformations: can any unsaturated 1,2-diol be regarded as a substrate?

We report the oxidative cleavage of unsaturated diols 6 and 7 derived from monocyclic precursors, used as substrates to determine the limits of the olefin as a source of diversity.

ChemInform Abstract: Synthesis of Thiabicyclic Heterocycles Through Free Radical Cyclization of β-Thioacrylates.

Abstract 8-Aza-3-thiabicyclo[4.3.0]nonanes 7 and 8, 3-thiabicyclo[4.4.0]decanes 18, and 8-thiabicyclo[4.3.0]nonanes 31 were obtained from monocyclic precursors through free radical cyclizations involving a β-thioacrylate system as radical acceptor and a thionocarbonate as radical precursor. Oxidative sulfur extrusion in 3-thiabicyclo[4.4.0]decanes 18 afforded methyl (2-isopropenyl-5-methylcyclohexyl)-2-propenoates 35.

Synthesis of Thiabicyclic Heterocycles Through Free Radical Cyclization of β-Thioacrylates

8-Aza-3-thiabicyclo[4.3.0]nonanes 7 and 8, 3-thiabicyclo[4.4.0]decanes 18, and 8-thiabicyclo[4.3.0]nonanes 31 were obtained from monocyclic precursors through free radical cyclizations involving a β-thioacrylate system as radical acceptor and a thionocarbonate as radical precursor. Oxidative sulfur extrusion in 3-thiabicyclo[4.4.0]decanes 18 afforded methyl (2-isopropenyl-5-methylcyclohexyl)-2-propenoates 35.

Theoretical studies of the fullerene growth mechanism: Ring-collapse model to C28 and cascade bond formation

The ring-collapse mechanism that suggests the reactions among the mono- to polycyclic carbon clusters has been analyzed using semiempirical AM1 and HF/6-31G* methods. The two cage structures D2 (chiral) and Td (achiral) for the C28 clusters are considered. Basing on the ring-stacking/circumscribing model and the ring-collapse mechanism various precursors are selected along with some appropriate carbon belts. Reactions between the precursors and the belts are found to be endoergic and lead to stable intermediates. All these stacking processes follow gradual and sequential paths. Various possible transition states structures (TSs) have been located and the barrier heights are found to be well within the earlier prescribed limits. Further, stacking the stable intermediates by suitable carbon belts generate the desired cage structures. The second step of the stacking resembles the annealing mechanism for the formation of the cage structures that is essentially an exoergic process. In this annealing process cascade-type bond formation is visualized. Finally, basing on the deformation energies of the precursors and the barrier heights, it is observed that monocyclic precursors are more suitable for the fullerene growth mechanism.

Quantum Chemical AM1 Treatment of the Circumscribing Algorithm: Fullerene Growth Mechanism

A graph theoretically formulated circumscribing algorithm for the fullerene growth mechanism has been analyzed using the quantum chemical AM1 method. Following different routes, two small fullerenes C28 (Td and D2) and C26 (D3h) have been constructed from monocyclic/polycyclic precursors and circumscribed with appropriate carbon belts. The deformation energies (DE) and the average bond lengths 〈R〉 of the precursors have been computed. The DE values suggest that there is a chance of bond cleavage of the polycyclic precursors as the growth process proceeds toward the cage formation. On the other hand, the monocyclic precursors are found to have significantly lower deformation energies than the polycyclic precursors. Further, with analysis of 〈R〉 values of the polycyclic and monocyclic cases at different stages, it is observed that the 〈R〉 values of the polycyclic cases decrease gradually, depicting a shrinkage in the precursors which may be detrimental to the growth process, whereas monocyclic precursors te...

Revised Structure of Tolyporphin A.

Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.

Total Synthesis of the Proposed Structure of (+)-Tolyporphin A O,O-Diacetate.

Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.

Synthesis of Bridgehead Nitrogen Heterocycles via Cyclization of alpha-Ammonio 5-Hexenyl Radicals.

Ring-closure of the 2,2-dimethyl-2-azonia-5-hexenyl radical (4) proceeds smoothly and efficiently to give the 5-exo isomer essentially quantitatively, in accordance with predictions based on MP4SDTQ/6-31G ab initio calculations on the thermodynamic stability of alpha-ammonio radicals. The corresponding 5-hexynyl radical species 15 and its 6-phenyl derivative 19 display similar behavior affording the analogous 5-exo-3-methylenepyrrolidinium salts in high yield. In none of these cases were the products of reduction were detected. All of the radical intermediates were generated conveniently by treatment of the iodomethyl and/or phenylselenomethyl salts with tributyltin hydride. Application of this procedure to monocyclic precursors such as 1-methyl-1-iodomethyl-4-methylene-1-azoniacyclohexyl iodide (31) provided an attractive entry into quaternary derivatives of the 1-azabicyclo[2.2.1]heptyl system in good yield via a three-step sequence from 1-methylpiperidone. Dequaternization of the bicyclic salts so obtained unexpectedly leads to rupture of one of the rings rather than loss of the N-methyl group. The 1-azabicyclo[2.2.1]heptane could be accessed readily via tin hydride-induced cyclization of the corresponding N-phenylethylammonium salt 54, followed by Hofmann elimination with potassium tert-butoxide.

A Concise Synthesis of Coronafacic Acid via Ring Closing Olefin Metathesis

The synthesis of coronafacic acid using ring closing olefin metathesis is described. Cyclisation of monocyclic precursors was attempted with both ruthenium and molybdenum catalysts. A smooth reaction was achieved with molybdenum catalyst.