1) A new oxidative cleavage method was developed to access a critical lactone precursor for aplyronine A analogs.
2) This method allows for enhanced selectivity of the termini, granting access to a previously unavailable C28–C34 fragment of C-32-desmethyl aplyronine A.
3) A dihydroxylation/oxidation sequence was able to achieve the desired regioselective termini differentiation, overcoming limitations of previous ozonolysis approaches.
C-terminal Sequencing of Protein : Novel Partial Acid Hydrolysis & Analysis b...Keiji Takamoto
The document describes a novel method for C-terminal sequencing of proteins using partial acid hydrolysis and mass spectrometry analysis. Peptides or proteins are hydrolyzed with vapors of strong organic acids like trifluoroacetic acid or hepta-fluorobutyric acid at high temperatures. This results in successive degradation of the C-terminal residues as seen by mass spectrometry. The degradation is believed to occur via formation of an oxazolone ring at the C-terminal amino acid, followed by removal of the C-terminal residue. Specific cleavages also occur at the peptide bonds preceding aspartic acid and serine residues. This method allows efficient C-terminal sequencing of proteins in small quantities directly from mass
The study investigated the production of sophorolipids (SLs) by Torulopsis bombicola using different lipid precursors such as glucose, hexadecane, and soybean oil. Liquid chromatography-mass spectrometry analysis showed that hexadecane as a precursor produced a cleaner mixture of predominantly diacetylated lactonic SL isomers with palmitate. Soybean oil as a precursor resulted in SLs corresponding to its fatty acid composition. Production of lactonic SLs increased significantly following addition of the lipid precursors and peaked in stationary phase, while acidic SLs increased gradually. Hexadecane provided the highest SL yield and purity compared to soybean oil and glucose precursors.
This document describes a biomimetic approach to synthesizing the tricyclic core structure of xyloketals. The key steps involve an ortho ester Claisen rearrangement of a chromenol to form a rearranged ester, followed by an intramolecular cationic cyclization to form the tricyclic ketal ring system. This strategy was applied to synthesize alboatrin in high yields through a short and stereocontrolled route. During the synthesis, an unexpected epi-to-natural isomerization was observed, further improving the overall yield.
This study used activity-based protein profiling (ABPP) to identify the target enzyme of the mechanism-based inactivator 1,7-octadiyne (17OD) in the ammonia-oxidizing bacterium Nitrosomonas europaea. ABPP involves using a probe that binds and inactivates the target enzyme, allowing for fluorescent labeling. Using 17OD as a probe, ABPP identified a 28 kDa polypeptide that exhibited characteristics of ammonia monooxygenase (AMO), the target enzyme. Further analysis by mass spectrometry confirmed the target enzyme was AmoA, the subunit that contains the active site of AMO. This study demonstrated ABPP can be used to identify bacterial
Synthesis and characterization of resin copolymer derived from cardanol-furfu...ijceronline
International Journal of Computational Engineering Research (IJCER) is dedicated to protecting personal information and will make every reasonable effort to handle collected information appropriately. All information collected, as well as related requests, will be handled as carefully and efficiently as possible in accordance with IJCER standards for integrity and objectivity.
The document describes the carbon nanotube-gold nanohybrid (AuCNT) catalyzed N-formylation of various primary and secondary amines using aqueous formaldehyde. Key findings include:
1) AuCNT catalyzes the room temperature N-formylation of various primary and secondary amines with aqueous formaldehyde, affording formamides in excellent yields.
2) The reaction proceeds with low catalyst loading (0.34 mol%), excellent chemoselectivity, and recyclability of the AuCNT catalyst.
3) Control experiments confirm the AuCNT nanohybrid is the active catalytic species, and the reaction proceeds through a hemiaminal intermediate that is oxidized to the
This document summarizes the background and research experience of Julien Barbion. He has a PhD in Chemistry from RWTH Aachen and has worked on total syntheses of several bioactive natural products, including (+)-discodermolide, (+)-altholactone, and salinosporamide A. His most recent work involved developing methods for the trifluoromethoxylation of heterocycles during his time at BayerCropScience. Barbion has strong skills in multi-step organic synthesis and natural product total synthesis. He is autonomous, communicates well in multiple languages, and works effectively both independently and as part of a team.
C-terminal Sequencing of Protein : Novel Partial Acid Hydrolysis & Analysis b...Keiji Takamoto
The document describes a novel method for C-terminal sequencing of proteins using partial acid hydrolysis and mass spectrometry analysis. Peptides or proteins are hydrolyzed with vapors of strong organic acids like trifluoroacetic acid or hepta-fluorobutyric acid at high temperatures. This results in successive degradation of the C-terminal residues as seen by mass spectrometry. The degradation is believed to occur via formation of an oxazolone ring at the C-terminal amino acid, followed by removal of the C-terminal residue. Specific cleavages also occur at the peptide bonds preceding aspartic acid and serine residues. This method allows efficient C-terminal sequencing of proteins in small quantities directly from mass
The study investigated the production of sophorolipids (SLs) by Torulopsis bombicola using different lipid precursors such as glucose, hexadecane, and soybean oil. Liquid chromatography-mass spectrometry analysis showed that hexadecane as a precursor produced a cleaner mixture of predominantly diacetylated lactonic SL isomers with palmitate. Soybean oil as a precursor resulted in SLs corresponding to its fatty acid composition. Production of lactonic SLs increased significantly following addition of the lipid precursors and peaked in stationary phase, while acidic SLs increased gradually. Hexadecane provided the highest SL yield and purity compared to soybean oil and glucose precursors.
This document describes a biomimetic approach to synthesizing the tricyclic core structure of xyloketals. The key steps involve an ortho ester Claisen rearrangement of a chromenol to form a rearranged ester, followed by an intramolecular cationic cyclization to form the tricyclic ketal ring system. This strategy was applied to synthesize alboatrin in high yields through a short and stereocontrolled route. During the synthesis, an unexpected epi-to-natural isomerization was observed, further improving the overall yield.
This study used activity-based protein profiling (ABPP) to identify the target enzyme of the mechanism-based inactivator 1,7-octadiyne (17OD) in the ammonia-oxidizing bacterium Nitrosomonas europaea. ABPP involves using a probe that binds and inactivates the target enzyme, allowing for fluorescent labeling. Using 17OD as a probe, ABPP identified a 28 kDa polypeptide that exhibited characteristics of ammonia monooxygenase (AMO), the target enzyme. Further analysis by mass spectrometry confirmed the target enzyme was AmoA, the subunit that contains the active site of AMO. This study demonstrated ABPP can be used to identify bacterial
Synthesis and characterization of resin copolymer derived from cardanol-furfu...ijceronline
International Journal of Computational Engineering Research (IJCER) is dedicated to protecting personal information and will make every reasonable effort to handle collected information appropriately. All information collected, as well as related requests, will be handled as carefully and efficiently as possible in accordance with IJCER standards for integrity and objectivity.
The document describes the carbon nanotube-gold nanohybrid (AuCNT) catalyzed N-formylation of various primary and secondary amines using aqueous formaldehyde. Key findings include:
1) AuCNT catalyzes the room temperature N-formylation of various primary and secondary amines with aqueous formaldehyde, affording formamides in excellent yields.
2) The reaction proceeds with low catalyst loading (0.34 mol%), excellent chemoselectivity, and recyclability of the AuCNT catalyst.
3) Control experiments confirm the AuCNT nanohybrid is the active catalytic species, and the reaction proceeds through a hemiaminal intermediate that is oxidized to the
This document summarizes the background and research experience of Julien Barbion. He has a PhD in Chemistry from RWTH Aachen and has worked on total syntheses of several bioactive natural products, including (+)-discodermolide, (+)-altholactone, and salinosporamide A. His most recent work involved developing methods for the trifluoromethoxylation of heterocycles during his time at BayerCropScience. Barbion has strong skills in multi-step organic synthesis and natural product total synthesis. He is autonomous, communicates well in multiple languages, and works effectively both independently and as part of a team.
This document discusses strategies for solid phase peptide synthesis (SPPS) using different protecting groups. It compares the t-Boc and Fmoc protection methods, noting the advantages of Fmoc such as using milder acidic conditions for deprotection and cleavage from the resin. Protocols are provided for various steps in Fmoc SPPS including resin loading, amino acid coupling and deprotection, and final cleavage and deprotection. Potential side reactions are also described such as diketopiperazine formation and aspartimide formation, along with ways to prevent these reactions.
In this work a new prodrug polymer was
prepared with two attachment groups (amid-ester), using di
functional spacer such as ethanol amine, which could react with
polyacrylic acid producing amide group, with remain ethanol
terminal group which could react with captopril acyl chloride,
producing ester group with extended the arm substituted drug to
improve the hydrolysis and to prevent the steric effect of polymer
chains. Many advantages enhanced the prodrug of polymer. The
prepared polymers were characterized by FTIR, 1H –NMR
spectroscopies. Controlled drug release was studied in different
pH values at 37℃, using UV. Spectra with comparing with
calibration curve. The modification percentage test was studied,and swelling percentage was calculated and all physical properties were observed.
The document summarizes the production and characterization of glucose and ethanol from sugarcane bagasse. It discusses:
1) Pretreatment methods for bagasse including physico-chemical, chemical, biological and hydrolysis to separate lignin and increase accessibility of cellulose.
2) Production of glucose by hydrolyzing cellulose and production of ethanol through fermentation processes like SSF, SHF, DMC and SSCF.
3) Characterization methods for analyzing glucose concentration, sugar conversion, crystallinity, and ethanol yield through techniques like HPLC, SEM and UV spectrophotometry.
The conclusion recommends dilute acid pretreatment and enzymatic hydrolysis as they require fewer steps and
Separation of L-Phenylalanine by Solvent Sublation and Solvent Extraction MethodBRNSS Publication Hub
Aims and Objectives: Separation and purification is a series of processes intended to isolate a single type of biomolecule from a complex mixture. Innovations in improvement of biodownstream processing, which is responsible for the separation of about 50–80% of recombinant proteins and other biomolecules, play a very important role in increasing the yield and reducing the cost of biopharmaceutical production. Methods: Biomolecule isolation and purification from a fermentation broth usually involve centrifugation, filtration, adsorption, and chromatography steps. Results and Discussions: Each step contributes to the product cost and product loss. Thus, we consider that solvent extraction and solvent sublation are the more economic processes for the separation of biomolecules. Conclusion: In extraction of phenylalanine, maximum extraction was observed at amino acid: surfactant ratio 1:1, amino acid: extractant ratio 1:1500, and pH at 3.1. The highest value of % recovery percentage and Co/Cw was 76.3 and 10.21, respectively. The main motive of this article is to provide the advantages of study on the solvent sublation and solvent extraction of l-phenylalanine over the other techniques.
The document describes the synthesis and characterization of new imidazole derivatives derived from D-erythroascorbic acid. D-erythroascorbic acid was modified through multi-step reactions to yield Schiff bases containing heterocyclic units like 1,3,4-oxadiazole and 1,3,4-thiadiazole. These Schiff bases were further derivatized to yield N-acyl, thiourea, and imidazole compounds. The structures of the synthesized compounds were characterized using techniques like elemental analysis, FTIR, NMR, and mass spectrometry. The compounds exhibited good antibacterial activity against Escherichia coli and Staphylococcus aureus.
This document provides information on amino acids and the urea cycle. It begins by defining amino acids and describing their basic structure of an amino group, carboxyl group, and unique R group. It then discusses peptide bond formation and how amino acids exist in molecular and zwitterion forms in aqueous solutions. The document classifies amino acids as essential, semi-essential, or nonessential and lists examples of each. It also describes various amino acid reactions and metabolic pathways. Finally, it provides details on the five step urea cycle that occurs in the liver to synthesize urea from ammonia for excretion.
1) The document reports on a computational and NMR study of a camphor-based chiral amino alcohol (2) and related compounds (1 and 3).
2) NMR analysis showed differences in chemical shifts between diastereotopic hydrogens H11a and H11b in compound 2, suggesting conformational restriction from an intramolecular hydrogen bond.
3) DFT calculations confirmed the most stable conformer of 2 features an intramolecular O-H-N hydrogen bond, restricting rotational mobility and accounting for the observed chemical shift differences between H11a and H11b.
The cholesteric liquid-crystal poly[oxycarbonyl-1,4-phenylene-oxy-1,4 terephthaloyl-oxy-1,4-phenylenecarbonyloxy(
1,2-dodecane)] [C34H36O8]n, named PTOBDME, synthesized by polycondensation reaction from
equimolar quantities of TOBC and the racemic mixture of glycol (R-S-1,2 dodecanediol), exhibits unexpected
optical activity and chiral morphology. The structure of racemic-PTOBDME, under different polymerization
kinetics conditions, is analyzed by conventional NMR techniques and compared with those of polymer
enantiomers R-PTOBDME and S-PTOBDME obtained starting R(+)1,2 and S(-)1,2-dodecanediol respectively.
Molecular models based on the NMR signals intensities are proposed. The optical activity of racemic-
PTOBDME is evaluated by measuring the ORD values during kinetics study, and compared to the chiral
polymers. Each enantiomeric polymer seems to present the same stereoregular head-tail, isotactic structure than
the racemic, which we explain by the higher reactivity of the primary hydroxyl than the secondary one in the
glycol through polycondensation. For each enantiomer, two independent sets of signals were observed by NMR,
explained as two diastereomeric helical conformers: gg and gt, related with two possible staggered
conformations, along the copolymer backbone. Chirality in racemic-PTOBDME is proposed to be due to the
kinetic resolution of a preferable helical diastereomer, such as Sgt, with respect to the possible four forms, while
the R/S ratio of asymmetric carbon atoms remained 50:50. Chiral amplification is observed in R-PTOBDME and
S-PTOBDME due to a helical screw sense excess. Optimum yield was obtained for racemic PTOBDME, after
120 minutes polycondensated and decanted in toluene for 24 hours. Two weeks later a second fraction
precipitated from the toluene mother liquor with 67.6% chiral excess. After eight months and two weeks a third
fraction precipitated with 85.2% chiral excess.
This document describes the total synthesis of the natural product (+)-anamarine and its stereoisomers from D-mannitol. It involves the convergent coupling of fragments synthesized from D-mannitol. The synthesis of (+)-anamarine is described in detail involving the stereoselective synthesis of fragments I and II and their coupling. Similarly, the total synthesis of 8-epi-(-)-anamarine and (-)-anamarine is reported. The document also reports the synthesis of β2,2-amino acids and β3-amino acid from D-ribose to understand their effect on helix formation and stability.
Solution And Solid Phase Synthesis Publicationadotse
This document describes the solution- and solid-phase synthesis of peptide-substituted thiazolidinediones as potential ligands for peroxisome proliferator-activated receptors (PPARs). Initial studies focused on the low-yielding solution-phase synthesis of two target compounds. Improved yields were obtained using solid-phase synthesis and protecting the thiazolidinedione nitrogen. A small library of nine resin-bound peptide-substituted thiazolidinediones was then synthesized to examine structural features that facilitate PPAR binding and identify new PPAR activators/inhibitors.
Characterization of the lipid binding properties of otoferlin reveals specifi...Dr. Nicole Hams
This study investigated the calcium and lipid binding properties of the C2 domains of otoferlin, which is a proposed calcium sensor for synaptic vesicle fusion in hair cells. Isothermal titration calorimetry showed that the C2 domains bind calcium with moderate to low affinity, except for C2A. Lipids increased the calcium sensitivity of the domains. The C2C and C2F domains preferentially bound phosphatidylinositol 4,5-bisphosphate. Mutations in C2C weakened this interaction selectively. Fluorescence spectroscopy indicated the C2F domain directly interacts with lipid bilayers in a calcium-independent manner. These results suggest the C2F and C2C domains preferential
Section 7 organic practicals exam questionsMartin Brown
The document contains questions and information about organic chemistry experiments performed in a school laboratory setting, including:
1) The preparation of soap from lard (animal fat) and sodium hydroxide involves refluxing the reactants with ethanol to allow saponification.
2) Ethanal can be prepared by oxidizing ethanol with sodium dichromate and sulfuric acid. Fehling's test confirms the presence of an aldehyde.
3) Chromatography, including paper, thin-layer, and column chromatography, can be used to separate mixtures like indicators based on differences in compounds' polarity and interactions with the mobile and stationary phases.
Switching Off and On the Supramolecular Chiral Memory in PorphyrinAngela Mammana
This document summarizes research on switching the chiral memory in porphyrin assemblies on and off. The researchers designed a system using tetra-cationic and tetra-anionic porphyrins that form chiral supramolecular complexes when mixed in the presence of a chiral template, like an amino acid. This complex retains its chirality even after removing the template. The researchers found they could cycle the complex between "written" and "erased" states by turning the electrostatic interactions on and off via protonation/deprotonation. Protonation induces aggregation and chirality, while raising the pH leads to disassembly and loss of chirality, but chiral "seeds" allow reassembly of the
Chemistry of peptide (BPHARM,MPHARM,MSC,BSC)Shikha Popali
THE PRESENTATION DESCRIBING BOND FORMATION OF AMINO ACIDS AND PROTEINS AND COUPLING REAGENTS IN PEPTIDE SYNTHESIS FOLLOWED BY CARBODIMIDES, PHOSPHONIUM AND AMMONIUM SALTS.
- The document describes efforts to optimize the solid-phase synthesis of peptide nucleic acids (PNAs) for use as tags to encode small molecule libraries. Two solid supports - Rink amide resin and 2-chlorotrityl chloride (CTC) resin - were tested.
- While the Rink amide resin approach yielded poor results due to difficulties cleaving the Fmoc protecting group, the CTC resin approach successfully produced three PNA trimers that were identified using mass spectrometry, demonstrating the potential of this method for producing encoding elements.
- Going forward, the CTC resin approach will be used to generate larger PNA oligomer libraries that can be efficiently coupled to encode and track collections of
This document describes amino derivatives of acrylic and methacrylic acids, including their preparation and properties. Specifically, it provides new amino derivatives of the formula CH2=C-COO-A-NR'R"CN where R is hydrogen or methyl, R' is an alkyl, cycloalkyl, aryl or aralkyl group, and A is a C2-C4 alkylene group having at least two carbon atoms between oxygen and nitrogen. It describes methods of preparing these monomeric compounds and polymers or copolymers made from them. The methods include reacting cyanogen chloride or bromide with compounds having the formula CH2=C(R)COO-A-NHR' in the presence
This document describes amino derivatives of acrylic and methacrylic acids of the formula CH2=C-COO-A-NR'CN, where R is H or CH3, R' is an alkyl, cycloalkyl, aryl, or aralkyl group, and A is a C2-C4 alkylene group with at least two carbons between oxygen and nitrogen. Methods are provided for preparing these monomeric compounds and polymers or copolymers made from them. Illustrative examples show the preparation of various N-cyano-N-alkylaminoalkyl acrylates and methacrylates.
Design and synthesis of a series of novel, cationic liposaccharide derivativesAdel Abdelrahim, PhD
This document describes the design and synthesis of novel cationic liposaccharide derivatives intended as potential penetration enhancers for oral drug delivery. Specifically, it details the synthesis of a series of positively charged compounds derived from D-glucose, aminododecanoic acid, and additional lipophilic amino acids. Each compound was fully characterized and their ability to form micelles in solution was assessed using isothermal titration calorimetry to determine critical aggregate concentration and thermodynamic parameters. One compound, containing two C12 moieties, was found to have a critical aggregate concentration of 0.275 mM and an enthalpy of micellization of -2.60 kcal/mol, indicating an exother
The document discusses biochemistry for medics and provides information on amino acids. It defines that amino acids are the monomer units that make up protein polypeptides and participate in various cellular functions. It classifies amino acids based on structure, side chains, nutritional requirements, and metabolic fate. The document also discusses the structures, properties, reactions and significance of different amino acids. Testing methods to identify specific amino acids are also outlined.
This document describes the synthesis of a novel nucleoside scaffold featuring an all-carbon quaternary stereocenter. An intramolecular silicon-tethered radical cyclization reaction is used to generate the stereocenter without heavy metals or harsh conditions. This reaction produces the scaffold in good yield and with high diastereoselectivity. The scaffold allows for both α- and β-anomers of nucleoside analogs to potentially have biological activity, unlike most natural nucleosides where only the β-anomer is active.
This document describes an unprecedented C-methylation reaction at the 2-position of 4-chromanone-2-carboxylates using the Corey–Chaykovsky reagent (dimethylsulfoxonium methylide, DIMSOY). Treatment of various 4-chromanone-2-carboxylates with DIMSOY results in good yields of the corresponding 2-methylated products, rather than the expected epoxide formation. Computational calculations provide evidence that the reaction proceeds through cisoid addition of DIMSOY to the carbonyl, formation of a betaine intermediate, and methyl transfer to C2 via a transition state, enabled by the basic nature of DIMSO
This document discusses strategies for solid phase peptide synthesis (SPPS) using different protecting groups. It compares the t-Boc and Fmoc protection methods, noting the advantages of Fmoc such as using milder acidic conditions for deprotection and cleavage from the resin. Protocols are provided for various steps in Fmoc SPPS including resin loading, amino acid coupling and deprotection, and final cleavage and deprotection. Potential side reactions are also described such as diketopiperazine formation and aspartimide formation, along with ways to prevent these reactions.
In this work a new prodrug polymer was
prepared with two attachment groups (amid-ester), using di
functional spacer such as ethanol amine, which could react with
polyacrylic acid producing amide group, with remain ethanol
terminal group which could react with captopril acyl chloride,
producing ester group with extended the arm substituted drug to
improve the hydrolysis and to prevent the steric effect of polymer
chains. Many advantages enhanced the prodrug of polymer. The
prepared polymers were characterized by FTIR, 1H –NMR
spectroscopies. Controlled drug release was studied in different
pH values at 37℃, using UV. Spectra with comparing with
calibration curve. The modification percentage test was studied,and swelling percentage was calculated and all physical properties were observed.
The document summarizes the production and characterization of glucose and ethanol from sugarcane bagasse. It discusses:
1) Pretreatment methods for bagasse including physico-chemical, chemical, biological and hydrolysis to separate lignin and increase accessibility of cellulose.
2) Production of glucose by hydrolyzing cellulose and production of ethanol through fermentation processes like SSF, SHF, DMC and SSCF.
3) Characterization methods for analyzing glucose concentration, sugar conversion, crystallinity, and ethanol yield through techniques like HPLC, SEM and UV spectrophotometry.
The conclusion recommends dilute acid pretreatment and enzymatic hydrolysis as they require fewer steps and
Separation of L-Phenylalanine by Solvent Sublation and Solvent Extraction MethodBRNSS Publication Hub
Aims and Objectives: Separation and purification is a series of processes intended to isolate a single type of biomolecule from a complex mixture. Innovations in improvement of biodownstream processing, which is responsible for the separation of about 50–80% of recombinant proteins and other biomolecules, play a very important role in increasing the yield and reducing the cost of biopharmaceutical production. Methods: Biomolecule isolation and purification from a fermentation broth usually involve centrifugation, filtration, adsorption, and chromatography steps. Results and Discussions: Each step contributes to the product cost and product loss. Thus, we consider that solvent extraction and solvent sublation are the more economic processes for the separation of biomolecules. Conclusion: In extraction of phenylalanine, maximum extraction was observed at amino acid: surfactant ratio 1:1, amino acid: extractant ratio 1:1500, and pH at 3.1. The highest value of % recovery percentage and Co/Cw was 76.3 and 10.21, respectively. The main motive of this article is to provide the advantages of study on the solvent sublation and solvent extraction of l-phenylalanine over the other techniques.
The document describes the synthesis and characterization of new imidazole derivatives derived from D-erythroascorbic acid. D-erythroascorbic acid was modified through multi-step reactions to yield Schiff bases containing heterocyclic units like 1,3,4-oxadiazole and 1,3,4-thiadiazole. These Schiff bases were further derivatized to yield N-acyl, thiourea, and imidazole compounds. The structures of the synthesized compounds were characterized using techniques like elemental analysis, FTIR, NMR, and mass spectrometry. The compounds exhibited good antibacterial activity against Escherichia coli and Staphylococcus aureus.
This document provides information on amino acids and the urea cycle. It begins by defining amino acids and describing their basic structure of an amino group, carboxyl group, and unique R group. It then discusses peptide bond formation and how amino acids exist in molecular and zwitterion forms in aqueous solutions. The document classifies amino acids as essential, semi-essential, or nonessential and lists examples of each. It also describes various amino acid reactions and metabolic pathways. Finally, it provides details on the five step urea cycle that occurs in the liver to synthesize urea from ammonia for excretion.
1) The document reports on a computational and NMR study of a camphor-based chiral amino alcohol (2) and related compounds (1 and 3).
2) NMR analysis showed differences in chemical shifts between diastereotopic hydrogens H11a and H11b in compound 2, suggesting conformational restriction from an intramolecular hydrogen bond.
3) DFT calculations confirmed the most stable conformer of 2 features an intramolecular O-H-N hydrogen bond, restricting rotational mobility and accounting for the observed chemical shift differences between H11a and H11b.
The cholesteric liquid-crystal poly[oxycarbonyl-1,4-phenylene-oxy-1,4 terephthaloyl-oxy-1,4-phenylenecarbonyloxy(
1,2-dodecane)] [C34H36O8]n, named PTOBDME, synthesized by polycondensation reaction from
equimolar quantities of TOBC and the racemic mixture of glycol (R-S-1,2 dodecanediol), exhibits unexpected
optical activity and chiral morphology. The structure of racemic-PTOBDME, under different polymerization
kinetics conditions, is analyzed by conventional NMR techniques and compared with those of polymer
enantiomers R-PTOBDME and S-PTOBDME obtained starting R(+)1,2 and S(-)1,2-dodecanediol respectively.
Molecular models based on the NMR signals intensities are proposed. The optical activity of racemic-
PTOBDME is evaluated by measuring the ORD values during kinetics study, and compared to the chiral
polymers. Each enantiomeric polymer seems to present the same stereoregular head-tail, isotactic structure than
the racemic, which we explain by the higher reactivity of the primary hydroxyl than the secondary one in the
glycol through polycondensation. For each enantiomer, two independent sets of signals were observed by NMR,
explained as two diastereomeric helical conformers: gg and gt, related with two possible staggered
conformations, along the copolymer backbone. Chirality in racemic-PTOBDME is proposed to be due to the
kinetic resolution of a preferable helical diastereomer, such as Sgt, with respect to the possible four forms, while
the R/S ratio of asymmetric carbon atoms remained 50:50. Chiral amplification is observed in R-PTOBDME and
S-PTOBDME due to a helical screw sense excess. Optimum yield was obtained for racemic PTOBDME, after
120 minutes polycondensated and decanted in toluene for 24 hours. Two weeks later a second fraction
precipitated from the toluene mother liquor with 67.6% chiral excess. After eight months and two weeks a third
fraction precipitated with 85.2% chiral excess.
This document describes the total synthesis of the natural product (+)-anamarine and its stereoisomers from D-mannitol. It involves the convergent coupling of fragments synthesized from D-mannitol. The synthesis of (+)-anamarine is described in detail involving the stereoselective synthesis of fragments I and II and their coupling. Similarly, the total synthesis of 8-epi-(-)-anamarine and (-)-anamarine is reported. The document also reports the synthesis of β2,2-amino acids and β3-amino acid from D-ribose to understand their effect on helix formation and stability.
Solution And Solid Phase Synthesis Publicationadotse
This document describes the solution- and solid-phase synthesis of peptide-substituted thiazolidinediones as potential ligands for peroxisome proliferator-activated receptors (PPARs). Initial studies focused on the low-yielding solution-phase synthesis of two target compounds. Improved yields were obtained using solid-phase synthesis and protecting the thiazolidinedione nitrogen. A small library of nine resin-bound peptide-substituted thiazolidinediones was then synthesized to examine structural features that facilitate PPAR binding and identify new PPAR activators/inhibitors.
Characterization of the lipid binding properties of otoferlin reveals specifi...Dr. Nicole Hams
This study investigated the calcium and lipid binding properties of the C2 domains of otoferlin, which is a proposed calcium sensor for synaptic vesicle fusion in hair cells. Isothermal titration calorimetry showed that the C2 domains bind calcium with moderate to low affinity, except for C2A. Lipids increased the calcium sensitivity of the domains. The C2C and C2F domains preferentially bound phosphatidylinositol 4,5-bisphosphate. Mutations in C2C weakened this interaction selectively. Fluorescence spectroscopy indicated the C2F domain directly interacts with lipid bilayers in a calcium-independent manner. These results suggest the C2F and C2C domains preferential
Section 7 organic practicals exam questionsMartin Brown
The document contains questions and information about organic chemistry experiments performed in a school laboratory setting, including:
1) The preparation of soap from lard (animal fat) and sodium hydroxide involves refluxing the reactants with ethanol to allow saponification.
2) Ethanal can be prepared by oxidizing ethanol with sodium dichromate and sulfuric acid. Fehling's test confirms the presence of an aldehyde.
3) Chromatography, including paper, thin-layer, and column chromatography, can be used to separate mixtures like indicators based on differences in compounds' polarity and interactions with the mobile and stationary phases.
Switching Off and On the Supramolecular Chiral Memory in PorphyrinAngela Mammana
This document summarizes research on switching the chiral memory in porphyrin assemblies on and off. The researchers designed a system using tetra-cationic and tetra-anionic porphyrins that form chiral supramolecular complexes when mixed in the presence of a chiral template, like an amino acid. This complex retains its chirality even after removing the template. The researchers found they could cycle the complex between "written" and "erased" states by turning the electrostatic interactions on and off via protonation/deprotonation. Protonation induces aggregation and chirality, while raising the pH leads to disassembly and loss of chirality, but chiral "seeds" allow reassembly of the
Chemistry of peptide (BPHARM,MPHARM,MSC,BSC)Shikha Popali
THE PRESENTATION DESCRIBING BOND FORMATION OF AMINO ACIDS AND PROTEINS AND COUPLING REAGENTS IN PEPTIDE SYNTHESIS FOLLOWED BY CARBODIMIDES, PHOSPHONIUM AND AMMONIUM SALTS.
- The document describes efforts to optimize the solid-phase synthesis of peptide nucleic acids (PNAs) for use as tags to encode small molecule libraries. Two solid supports - Rink amide resin and 2-chlorotrityl chloride (CTC) resin - were tested.
- While the Rink amide resin approach yielded poor results due to difficulties cleaving the Fmoc protecting group, the CTC resin approach successfully produced three PNA trimers that were identified using mass spectrometry, demonstrating the potential of this method for producing encoding elements.
- Going forward, the CTC resin approach will be used to generate larger PNA oligomer libraries that can be efficiently coupled to encode and track collections of
This document describes amino derivatives of acrylic and methacrylic acids, including their preparation and properties. Specifically, it provides new amino derivatives of the formula CH2=C-COO-A-NR'R"CN where R is hydrogen or methyl, R' is an alkyl, cycloalkyl, aryl or aralkyl group, and A is a C2-C4 alkylene group having at least two carbon atoms between oxygen and nitrogen. It describes methods of preparing these monomeric compounds and polymers or copolymers made from them. The methods include reacting cyanogen chloride or bromide with compounds having the formula CH2=C(R)COO-A-NHR' in the presence
This document describes amino derivatives of acrylic and methacrylic acids of the formula CH2=C-COO-A-NR'CN, where R is H or CH3, R' is an alkyl, cycloalkyl, aryl, or aralkyl group, and A is a C2-C4 alkylene group with at least two carbons between oxygen and nitrogen. Methods are provided for preparing these monomeric compounds and polymers or copolymers made from them. Illustrative examples show the preparation of various N-cyano-N-alkylaminoalkyl acrylates and methacrylates.
Design and synthesis of a series of novel, cationic liposaccharide derivativesAdel Abdelrahim, PhD
This document describes the design and synthesis of novel cationic liposaccharide derivatives intended as potential penetration enhancers for oral drug delivery. Specifically, it details the synthesis of a series of positively charged compounds derived from D-glucose, aminododecanoic acid, and additional lipophilic amino acids. Each compound was fully characterized and their ability to form micelles in solution was assessed using isothermal titration calorimetry to determine critical aggregate concentration and thermodynamic parameters. One compound, containing two C12 moieties, was found to have a critical aggregate concentration of 0.275 mM and an enthalpy of micellization of -2.60 kcal/mol, indicating an exother
The document discusses biochemistry for medics and provides information on amino acids. It defines that amino acids are the monomer units that make up protein polypeptides and participate in various cellular functions. It classifies amino acids based on structure, side chains, nutritional requirements, and metabolic fate. The document also discusses the structures, properties, reactions and significance of different amino acids. Testing methods to identify specific amino acids are also outlined.
This document describes the synthesis of a novel nucleoside scaffold featuring an all-carbon quaternary stereocenter. An intramolecular silicon-tethered radical cyclization reaction is used to generate the stereocenter without heavy metals or harsh conditions. This reaction produces the scaffold in good yield and with high diastereoselectivity. The scaffold allows for both α- and β-anomers of nucleoside analogs to potentially have biological activity, unlike most natural nucleosides where only the β-anomer is active.
This document describes an unprecedented C-methylation reaction at the 2-position of 4-chromanone-2-carboxylates using the Corey–Chaykovsky reagent (dimethylsulfoxonium methylide, DIMSOY). Treatment of various 4-chromanone-2-carboxylates with DIMSOY results in good yields of the corresponding 2-methylated products, rather than the expected epoxide formation. Computational calculations provide evidence that the reaction proceeds through cisoid addition of DIMSOY to the carbonyl, formation of a betaine intermediate, and methyl transfer to C2 via a transition state, enabled by the basic nature of DIMSO
Carboxy-terminal Degradation of Peptides using Perfluoroacyl Anhydrides : C-T...Keiji Takamoto
This document describes a new method for determining the carboxy-terminal (C-terminal) amino acid sequence of peptides using perfluoroacyl anhydride vapor. Exposure of peptides to the vapor at -20°C for 0.5-1 hours sequentially degrades the peptide from the C-terminus. Analysis of the truncated peptide fragments by fast-atom-bombardment mass spectrometry allows determination of the C-terminal sequence based on mass differences. The method provides C-terminal sequence information as a complement to the common Edman degradation method for amino-terminal sequencing. The perfluoroacyl anhydride vapor method results in more extensive C-terminal degradation than a previous method using perfluoric acid
This document summarizes the total synthesis of the natural product potassium aeshynomate from L-arabinose. The synthesis involves constructing the γ-amino acid subunit starting from L-arabinose, then coupling it to caffeic acid. Initial attempts using D-arabinose were unsuccessful and determined the natural product has the opposite configuration. Successful synthesis was achieved using L-arabinose as the starting material.
This document describes the discovery of the first organocatalytic α,β,γ-trioxygenation of enals. The reaction proceeds through an initial TEMPO-mediated γ-oxygenation, followed by rapid racemization and reversible conjugate addition of water. This sets the stage for a second TEMPO incorporation at the α-position to set all three stereocenters. Using a tryptophan-derived imidazolidinone catalyst in fluorinated aromatic solvents, α,β,γ-trioxyaldehydes were obtained in up to 51% isolated yield and 85:15 er. Substitution at the δ-position was tolerated, but not at the α, β,
This document describes a novel method for synthesizing highly functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) through 1,4-addition of nucleophiles onto pyrimidin-2(1H)-ones. Ceric ammonium nitrate (CAN) is used as a catalyst to promote the 1,4-addition reaction of indoles and other nucleophiles with pyrimidin-2(1H)-ones to form novel DHPMs in good yields. A variety of substituted indoles undergo regioselective 1,4-addition to form functionalized 4-indolyl-DHPMs. Pyrrole and sodium boroh
Protected Primary Amides from Acyl IsocyanatesSteve Hahneman
This document describes a procedure for synthesizing primary amides from carboxylic acid derivatives using acyl isocyanates. Acyl isocyanates are formed in situ from carboxylic acid chlorides and silver cyanate, then reacted with an alcohol to form a carbamate-protected primary amide. Various reaction conditions were tested, with anhydrous diethyl ether at reflux providing the best yield of the protected amide product. Side reactions can also occur under some conditions, forming carboxylic acids, esters, amides, anhydrides, and imides.
This document describes a facile synthetic route for producing the alpha-glucosidase inhibitor 2,6-dideoxy-2,6-imino-7-O-beta-D-glucopyranosyl-D-glycero-L-gulo-heptitol (1) in 26% overall yield from nojirimycin bisulfite adduct (2). Key steps include: (1) appending a nitrile group to (2) to form an intermediate (3), (2) hydrolyzing (3) to the carboxylic acid (6), and (3) condensing (6) with a protected glucose donor to form the glucoside (9), which
Total synthesis of Sterpurenone New, Total Synthesis of (훽)-Cyperolone, Protecting Group-Free Total Synthesis of (−)-Lannotinidine B, Enantiospecific Total Synthesis of the (−)-Presilphiperfolan-8-ol, Enantioselective Total Synthesis of (−)-Pavidolide B, total synthesis of Eupalinilide E
This document summarizes the development of efficient protocols for synthesizing 1,2,3,4-tetrahydroisoquinolin-1-ones. Several methods were developed, including the use of Mitsunobu reactions, copper-catalyzed arylations, and SNAr reactions to install various substituents on the core scaffold. These methods proved to be versatile, efficient, and amenable to parallel synthesis, allowing for SAR exploration across different regions of the molecule.
This document describes methods for preparing and purifying holo-ACP and malonyl-ACP, which are key intermediates in fatty acid biosynthesis, in order to test engineered fatty acid biosynthesis enzymes in vitro. Holo-ACP is expressed in E. coli by co-expressing apo-ACP and holo-ACP synthase, then purified using nickel affinity and ion exchange chromatography. Malonyl-ACP is prepared in vitro by incubating purified holo-ACP with malonyl-CoA and FabD. The purified malonyl-ACP and holo-ACP can be used as substrates for FabH and other fatty acid biosynthesis enzymes in high-throughput fluorescence assays
Synthesis of 3-Substituted Coumarins by the Knoevenagel Condensation Reactionmariam1020
The document summarizes a study on the synthesis of 3-substituted coumarins via the Knoevenagel condensation reaction of various 2-hydroxyaldehydes and malonate esters under solvent-free conditions using silica gel or basic alumina as catalyst. The reaction was carried out using microwave irradiation. Various coumarin products were obtained in moderate to good yields and characterized using techniques such as IR, NMR, and GC-MS. The method provides an improvement over traditional Knoevenagel condensation reactions through the use of solvent-free conditions and microwave activation.
Bond-Specific Chemical Cleavages of Peptides & Proteins with Perfluoric Acid ...Keiji Takamoto
This document describes research on specific chemical cleavages of peptides and proteins using perfluoric acid vapors. The researchers established conditions for novel cleavages of certain peptide bonds, including glycyl-threonine, the amino side of serine residues, and the carboxyl side of aspartic acid residues. Exposure to vapors of various concentrations of heptafluorobutyric acid at different temperatures (30-90°C) resulted in selective cleavage of these bonds. The cleavages were studied using synthetic peptides as well as proteins. Specific conditions were determined that selectively cleaved each bond type without cleaving other bonds. These cleavages were then applied to sequence analysis of several proteins.
This document describes an efficient synthetic route to produce ethyl 2-aryl-4-hydroxy-1,3(2H,4H)-dioxoisoquinoline-4-carboxylates, which are known to inhibit auxin transport in plants and have plant growth regulating properties. The synthesis involves condensing anilines with homophthalic anhydride to form intermediates, which are then modified through various steps including acylation, enolate formation, alcoholysis, and oxygenation to produce the target compounds. Several of the target compounds showed potent auxin transport inhibition and plant growth regulating activity in tests.
more chemistry contents are available
1. pdf file on Termmate: https://www.termmate.com/rabia.aziz
2. YouTube: https://www.youtube.com/channel/UCKxWnNdskGHnZFS0h1QRTEA
3. Facebook: https://web.facebook.com/Chemist.Rabia.Aziz/
4. Blogger: https://chemistry-academy.blogspot.com/
Organic Synthesis:
The Disconnection Approach
One Group C-C Disconnection of Alcohol and Alkene
1. Paracetamol is generally safe at recommended doses but can cause acute liver failure and require transplantation at higher overdose doses due to its intrinsic toxicity.
2. At therapeutic doses, paracetamol is mainly metabolized through non-toxic pathways like sulfation and glucuronidation. However, at overdose levels it is oxidized by cytochrome P450 2E1 to form the toxic metabolite NAPQI.
3. NAPQI is normally detoxified by conjugating with glutathione, but an overdose depletes glutathione reserves allowing NAPQI to accumulate and cause
The document describes using reversible addition-fragmentation chain transfer (RAFT) polymerization to synthesize novel block copolymers containing both a polyolefin block and a poly(styrene-co-maleic anhydride) block. Specifically, it details:
1) Using a commercially available polyolefin (Kraton L-1203) modified with a dithioester group to serve as a macroinitiator for RAFT polymerization and form the polyolefin block.
2) Conducting RAFT polymerizations of styrene and styrene-co-maleic anhydride using this macroinitiator and a small molecule RAFT agent to form the second block and yield polyolefin
This document describes a new method called polymer-aided stereodivergent synthesis (PASS) that allows the simultaneous preparation of both enantiomers of a chiral compound in discrete form. The key steps are: (1) A cyclization reaction on a polymer-supported quasi-meso substrate leads to the formation of quasi-enantiomers, with one immobilized on the polymer and the other free in solution. (2) Treatment with nucleophiles converts the quasi-enantiomers into the desired enantiomers. This new method was demonstrated through the synthesis of optically pure oxazolidinone enantiomers.
Ultra stable lipid system for the study of P450 EnzymesEmek Blair, Ph.D.
A structured lipid system surrounding the enzymes which is stable at high temperature and acidic conditions is used to characterize P450 CYP119. These mimic the natural lipid bilayers that the enzymes naturally are stable in.
This document describes a three-component reaction to synthesize novel 2-(3-chromonyl)-2-acyloxycarboxamide derivatives. 3-Formylchromone, an alkyl isocyanide, and a carboxylic acid react in dichloromethane at room temperature to form these products in good yields. A variety of carboxylic acids and isocyanides were tested in the reaction, producing diverse derivatives. The reaction proceeds via initial formation of an adduct between the chromone and acid, followed by addition of the isocyanide and intramolecular rearrangement to form the final product.
1. Mechanism-specified 5-exo termini differentiation of a
C32-desmethyl C28–C34 aplyronine A analog segment
Thomas P. Bobinski, Philip L. Fuchs ⇑
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States
a r t i c l e i n f o
Article history:
Received 14 April 2015
Accepted 23 April 2015
Available online 29 April 2015
Keywords:
Aplyronine A
Polyketide
Vinyl sulfone
Ozonolysis
Osmium catalysis
a-Hydroxy lactol
a b s t r a c t
A new mild, high yielding oxidative cleavage method allows access to a critical lactone aplyronine A
analog precursor. Enhanced termini selectivity is achieved, granting access to a previously unavailable
C28–C34 C-32-desmethyl actin binding tail fragment via vinyl sulfone polypropionate methodology.
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
Aplyronine A (Fig. 1) is an exceptionally scarce (3 Â 10À7
wt %)
macrolide originally isolated from the sea hare Aplysia kurodai.1
It
has actin binding and depolymerizing properties,2,3
as well as
potent in vivo antitumor activity.1
The initial inquiry into the
mechanism of aplyronine A’s antineoplastic properties strongly
focused upon its interaction with actin. Actin is the most abundant
protein in the eukaryotic cytoskeleton and is essential for the reg-
ulation of various cellular functions, such as muscle contraction,
cell division, and the migration of tumor cells. Various additional
small agents have been discovered that target actin show cytotox-
icity2
at concentrations above 100 nM. For example, ulapualides,4
mycalolides,5
kabiramides,6
sphinxolides/reidispongiolides,7
swin-
holides,7
and bistramides8
are all actin-depolymerizing agents.
Complexes between these macrolides and actin are similar to the
aplyronine A–actin complex.
While aplyronine A’s ability to bind/depolymerize actin is sim-
ilar to other macrolides, its exceptional cytotoxicity is starkly
apparent. For example, jasplakinolide exhibits an IC50 of 100 nM
against HL-60 cells,9,7
Mycalolide B has an IC50 of 4.7 nM; but aply-
ronine A has an IC50 of 0.0029 nM after 72 h of incubation.
Swinholide A depolymerizes actin at 4 nM–1 lM7
while aplyronine
A requires a concentration of 31 lM.10–13
Aplyronine A increases
the lifespan of mice between 201% and 566% in 5 different tumor
models (566%: Lewis lung; 545%: P388 leukemia; 398% Ehrlich car-
cinoma; 255%: Colon 26 carcinoma; and 201%: B16 melanoma).9
These results provide convincing evidence that actin activity is
not the sole determinant of antineoplastic activity.
Recent seminal work by Kigoshi14
and co-workers has provided
definitive mechanistic insight into the antineoplastic properties of
aplyronine A (ApA). These results indicate that the potent cytotox-
icity of ApA is not solely due to its F-actin severing properties.
Photolabelling experiments revealed that the C7 trimethylserine
ester group binds to b-tubulin, leading to the formation of a
1:1:1 tubulin/aplyronine A/actin complex (Fig. 1) that exhibits its
antineoplastic activity at far lower concentrations than that of
the aplyronine A–actin complex. Evidence suggests that the
existence of this ternary complex in the interior of the cell
inhibits tubulin polymerization and enhances microtubule
depolymerization.
Results and discussion
A primary goal of the Fuchs vinyl sulfone program is to access
biorelevant intermediates containing contiguous chiral carbon
centers.15
While the vinyl sulfone strategy has successfully enabled
the construction of key intermediates of a number of natural prod-
ucts,15
the aplyronine A approach has also revealed several limita-
tions. The design for synthesis of the aplyronine A core features
http://dx.doi.org/10.1016/j.tetlet.2015.04.098
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
⇑ Corresponding author. Tel.: +1 765 494 4292.
E-mail addresses: tbobinsk@purdue.edu (T.P. Bobinski), pfuchs@purdue.edu
(P.L. Fuchs).
Tetrahedron Letters 56 (2015) 3868–3871
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2. three key polypropionate arrays: C7–C10, C23–C26 and C29–C32.
Successful assembly of the C7–C10 and C23–C26 and assembly of
the C1–C23 macrolactone has been achieved by El-Awa, Noshi,
and Hong (Fig. 1).15
Synthesis of enantiopure vinyl sulfones 1, 4, and 4-ent featured
catalytic Jacobsen epoxidation of achiral 2-phenylsulfonyl-1,3-cy-
cloheptadiene, which is prepared from cycloheptanone in a single
operation on the kilogram scale (Scheme 1).16
Transformation of
vinyl sulfones 1 and 4 to lactones 2 and 5 and further on to ter-
mini-differentiated segments 3 and 6 was previously reported.17,18
Unfortunately, base-mediated vinyl sulfone chemistry, established
in several isomeric substrates, was uniformly unsuccessful for the
preparation of allylic sulfone 7 from 4-ent.19,20
Faced with a looming program deadline and encouraged by in
silico modeling by Hirst,21
which had previously calculated F-actin
depolymerization ability, predicted pIC50 values of 4.40, 4.08, and
4.05 for aplyronine A, aplyronine A C32 epi-methyl, and aplyronine
A C32 desmethyl respectively. Authentic aplyronine A has a pIC50
value of 4.51 which correlates well with the calculated value of
4.40.22
Based on these calculations, it was decided that synthesis
of C32 desmethyl analog would provide a more expeditious
approach to the desired target.
The new scheme (Scheme 2) returned to 9 the enantiopure
stereodiad precursor of blue fragment 1, thus avoiding preparation
of 4-ent altogether. Epoxidation of diene 9,19
with dimethyldioxi-
rane (DMDO) formed in situ from OxoneÒ
and acetone provides
enantiopure epoxide diastereomer 10.18,19
Nucleophilic addition
of sodium borohydride effects reduction of 10 to provide alcohol
11 in 82% yield. 2-Azido-2-methylpropanoic acid was prepared
from 2-bromo-2-propionic acid and sodium azide using a simplifi-
cation of the existing literature protocol.23
2-Azido-2-methyl-
propanoic acid forms the acid chloride in situ with oxalyl
chloride, dimethylformamide (DMF), dimethylaminopyridine
(DMAP), and triethylamine (TEA), which suffers reaction with alco-
hol 11 to smoothly afford azapivalate ester 12. Cleavage of the sily-
lether of 12 with camphorsulfonic acid or cerium chloride yields
C31 alcohol 13, thus setting the stage for oxidative cleavage of
the vinylsulfone moiety of C32 desmethyl C28–C34 triad 13.
Ozonolysis of 13 generates the Criegee intermediate, thus test-
ing the competitive reactivity of the C34 acyl sulfone and the C28
oxonium carbon with the C31 hydroxyl oxygen. In the event, the
free hydroxyl, which is equidistant from both functions, suffers
regiospecific addition to the C28 carbonyl oxide (pathway a) rather
than the C34 acylsulfone (pathway b) yielding lactol 14 (Fig. 2). The
Figure 1. Actin–aplyronine A analogs–tubulin ternary complex.
Scheme 1. Initial aplyronine A vinyl sulfone polyketide segment strategy.
T. P. Bobinski, P. L. Fuchs / Tetrahedron Letters 56 (2015) 3868–3871 3869
3. complete recovery of trans–anti-trans lactol 14 suggests this sub-
strate is incapable of providing significant equilibrium populations
of aldehyde 15 to furnish adduct 16 from nucleophiles 17,24,25
and
18 under the olefination conditions of Scheme 3.
Since the ozonolysis method was incapable of generating a
reactive termini-differentiated lactol, an alternative oxidative
cleavage was developed. The vinyl sulfone polypropionate strategy
has recently been augmented by a new mild, citric acid assisted
catalytic dihydroxylation reaction.26
In Scheme 4 the transient acy-
loin formed from the dihydroxylation of vinyl sulfone 13 forms
bridged bicyclic a-hydroxy lactol 19 via addition of the C31 alcohol
to the C34 ketone. Finally, Criegee oxidation of lactol 19 smoothly
affords target containing C34 lactone terminus C28 lactone-alde-
hyde 20, thereby achieving regiospecific termini-differentiation
unattainable by ozonolysis (Scheme 4).
Conclusion
This investigation solves an initial limitation of the vinyl sulfone
polyketide strategy. The scope of the polypropionate is also
increased. A previously unattainable positioning of the polyketide
322932293229
5
6
5
69
11
10
9
SO2Ph
OTES
9
11
10
10
O
OTES
SO2Ph
3428
11
HO
OTES
SO2Ph
3428
12
N3
O
O
OTES
SO2Ph
34
28
13
N3
O
O
OH
SO2Ph
a b c d
Scheme 2. Generation of vinylsulfone 13. Reagents and conditions: (a) OxoneÒ
, NaHCO3, acetone–H2O, 0 °C, 87%; (b) NaBH4, MeOH, 82%; (c) 2-azido-2-methylpropanoic acid,
(COCl)2, DMF, DMAP, TEA, 75%; (d) (1S)-(+)-10-CSA, MeOH 78% or CeCl3, MeOH 100%.
34
31
a
13
30 31
32
33
34
28
29
O
O
N3
O
O
OH
S
b
O O
30
31
32 33
3428
29
O
O
O
N3
Criegee Zwitterion
Acylsulfone
28
O
HO
N3
O
O
O O
Lactol Methylester
O
O
OH
S
14
O3, MeOH
NaHCO3
Me2S
5-exo
C28-OH
Figure 2. Ozonolysis of C32 desmethyl cyclic vinylsulfone 13.
16 a, b
28
31
OH
O
OO
N3
O
31
28
HO OMe
N3
O
O
O
O
34
14
31
28
O OMe
N3
O
O
HO
O
34
15
34
R
Ph
2725
N
N
N
N
O
O
S
O
H2C
CH2R1TESO O
a, b , c
d, e
R2
CH2
PPh3I
17
18
a series R1
=
b series R2
= Me
Scheme 3. Attempted in situ olefination of lactol 14. Reagents and conditions: a
LiHMDS (1.2 equiv), THF/HMPA (5:1), À78?0 °C, 30 min; b
LiHMDS (1.2 equiv), THF/DMF/
HMPA (3:9:1), À78?0 °C, 30 min; c
NaH (50 equiv), THF, À78?0 °C, 30 min; d
n-BuLi, THF, À42 °C?25 °C, 20 h; e
DBU, THF, À40 °C?25 °C, 30 min.
201913
31
29
28
34
ON3
O
O
O
OH
S
31
29
28
34
OH
HO
O
N3
O
O
83%
34
31
29
28 O
O
N3
O
O
O100%
a b
HO
31
29
28
34
N3
O
O
OH
O
transient
acyloin
Scheme 4. Osmylation and oxidative cleavage of stereotetrad 14. Reagents and conditions: (a) N-methylmorpholine-N-oxide (NMO) (2.5 equiv), citric acid (3.0 equiv),
K2OsO4 (0.10 equiv), MeCN/H2O (v/v 4:1), rt, 24 h; (b) Pb(OAc)4 (2.5 equiv), MeOH, rt, 5 min.
3870 T. P. Bobinski, P. L. Fuchs / Tetrahedron Letters 56 (2015) 3868–3871
4. on the carbon backbone furnishes a novel isomer. A mechanism-
specified 5-exo termini-differentiation oxidative cleavage of the
cyclic vinyl sulfone intermediate 13 has been achieved. The com-
plementarity of ozonolysis and osmylation has been elucidated.
Access to the C32 desmethyl, actin-binding tail, lactone precursor
(20) of the of the aplyronine A analog has been established.
Acknowledgements
We thank Arlene Rothwell and Dr. Karl Wood from Purdue
University for MS data and Purdue University for support of this
research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.04.
098.
References and notes
1. Ojika, M.; Kigoshi, H.; Yoshida, Y.; Ishigaki, T.; Nisiwaki, M.; Tsukada, I.;
Arakawa, M.; Ekimoto, H.; Yamada, K. Tetrahedron 2007, 63, 3138.
2. Saito, S.; Karaki, H. Clin. Exp. Pharmacol. Physiol. 1996, 23, 743.
3. (a) Yamada, K.; Ojika, M.; Kigoshi, H.; Suenaga, K. Nat. Prod. Rep. 2009, 26, 27;
(b) Kigoshi, H.; Suenaga, K.; Takagi, M.; Akao, A.; Kanematsu, K.; Kamei, N.;
Okugawa, Y.; Yamada, K. Tetrahedron 2002, 58, 1075.
4. Vincent, E.; Saxton, J.; Baker-Glenn, C.; Moal, I.; Hirst, J. D.; Pattenden, G.; Shaw,
P. E. Cell. Mol. Life Sci. 2007, 64, 487–497.
5. Suenaga, K.; Kimura, T.; Kuroda, T.; Matsui, K.; Miya, S.; Kuribayashi, S.;
Sakakura, A.; Kigoshi, H. J. Am. Chem. Soc. 1999, 121, 5605–5606.
6. Paterson, I.; Ashton, K.; Britton, R.; Cecere, G.; Chouraqui, G.; Florence, G. J.;
Stafford, J. Angew. Chem., Int. Ed. 2007, 46, 6167–6171; Perrins, R. D.; Cecere, G.;
Paterson, I.; Marriott, G. Chem. Biol. 2008, 15, 287–294.
7. Kobayashi, M.; Kawazoe, K.; Okamoto, T.; Sasaki, T. Chem. Pharm. Bull. 1994, 42,
19–26.
8. Wrona, I. E.; Lowe, J. T.; Turbyville, T. J.; Johnson, T. R.; Beignet, J.; Beutler, J. A.;
Panek, J. S. J. Org. Chem. 2009, 74, 1897–1916.
9. Saito, S.; Karaki, H. Clin. Exp. Pharmacol. Physiol. 1996, 23, 743–746.
10. Yamada, K.; Ojika, M.; Kigoshi, H.; Suenaga, K. Nat. Prod. Rep. 2009, 26, 27.
11. Saito, S.; Karaki, H. Clin. Exp. Pharmacol. 1996, 23, 743.
12. Yamada, K.; Ojika, M.; Ishigaki, T.; Yoshida, Y.; Ekimoto, H.; Arakawa, M. J. Am.
Chem. Soc. 1993, 115, 11020.
13. Hirata, K.; Muraoka, S.; Suenaga, K.; Kuroda, T.; Kato, K.; Tanaka, H.;
Yamamoto, M.; Takata, M.; Yamada, K.; Kigoshi, H. J. Mol. Biol. 2006, 356, 945.
14. Kita, M.; Hirayama, Y.; Yoneda, K.; Yamagishi, K.; Chinen, T.; Usui, T.; Sumiya,
E.; Uesugi, M.; Kigoshi, H. J. Am. Chem. Soc. 2013, 135, 18089.
15. El-Awa, A.; Noshi, M. N.; du Jourdin, X. M.; Fuchs, P. L. Chem. Rev. 2009, 109,
2315.
16. Park, T.; Torres, E.; Fuchs, P. L. Synthesis 2004, 1895.
17. Hong, W. P.; El-Awa, A.; Fuchs, P. L. J. Am. Chem. Soc. 2009, 131, 9150.
18. Hong, W. P.; Noshi, M. N.; El-Awa, A.; Fuchs, P. L. Org. Lett. 2011, 13, 6342.
19. El-Awa, A., PhD Thesis, Purdue, 2007.
20. Noshi, M., PhD Thesis, Purdue University, 2009.
21. Hussain, A.; Melville, J. L.; Hirst, J. D. J. Comput. Aided Mol. Des. 2010, 24, 1.
22. Calculations provided by Hirst research group via personal communication.
23. (a) Meldal⁄
, M.; Juliano, M. A.; Jansson, A. M. Tetrahedron Lett. 1997, 38, 2531;
(b) Tornøe, C. W.; Davis, P.; Porreca, F.; Meldal, M. J. Pept. Sci. 2000, 6, 594; (c)
Weigelt, S.; Sewald, N. Synlett 2004, 726; (d) Jost, M.; Greie, J.-C.; Stemmer, N.;
Wilking, S. D.; Altendorf, K.; Sewald, N. Angew. Chem., Int. Ed. 2002, 41, 4267.
24. Hong, W. P. Doctoral, Purdue, 2011.
25. Substrate 17 was synthesized in a parallel manner to compound 6 but for the
p-methoxybenzoyl acetonide.
26. Bobinski, T. P.; Fuchs, P. L. Tetrahedron Lett. 2015. previous Letter.
T. P. Bobinski, P. L. Fuchs / Tetrahedron Letters 56 (2015) 3868–3871 3871