46 research outputs found
Elimination of TFA-Mediated Cleavage in Distributed Drug Discovery
Distributed Drug Discovery (D3) is a multi-disciplinary approach to the discovery of new drugs, which target neglected diseases or conditions common to developing-world countries. As part of a continuing effort to improve D3 methodology, two approaches for eliminating the final step TFA-mediated resin cleavage are proposed for investigation. Cleavage under basic conditions (saponification) and mild acid conditions (dilute HCl/hexafluoroisopropanol or dilute HCl/trifluoroethanol) represent improvements in safety and convenience to the undergraduate student researcher. Previous studies have shown that saponification provides yields comparable to the traditional TFA cleavage but recovery is not as convenient. Further improvements in the saponification workup will be evaluated by analyzing the effectiveness of simple trituration with acetone compared to use of a strong anion-exchange resin or drying reagents to isolate the free acid from the salt. Different trituration procedural modifications have been made and are being tested. Results have shown that in the presence of methanol, esterification will occur when the acid is liberated from the salt using HCl. To counter this problem, the samples are first evaporated to remove methanol and then the pH is adjusted with HCl. It was shown that using acetic acid did not result in pH levels low enough to guarantee complete protonation of the carboxylate. Through the use of a Bill-Board, an apparatus that holds six reaction vessels, several procedural modifications can be carried out simultaneously. Analysis is conducted by liquid chromatography coupled with a mass spectrometer and with nuclear magnetic resonance spectroscopy. Further studies will be carried out to assess the efficiency and practicality of using mild acidic conditions for cleavage using HCl/hexafluoroisopropanol or dilute HCl/trifluoroethanol. Both saponification and mild acid cleavage would represent improvements in safety and convenience to the undergraduate student researcher
Preparation and Use of a General Solid-Phase Intermediate to Biomimetic Scaffolds and Peptide Condensations
The Distributed Drug Discovery (D3) program develops simple, powerful, and reproducible procedures to enable the distributed synthesis of large numbers of potential drugs for neglected diseases. The synthetic protocols are solid-phase based and inspired by published work. One promising article reported that many biomimetic molecules based on diverse scaffolds with three or more sites of variable substitution can be synthesized in one or two steps from a common key aldehyde intermediate. This intermediate was prepared by the ozonolysis of a precursor functionalized at two variable sites, restricting their presence in the subsequently formed scaffolds to ozone compatible functional groups. To broaden the scope of the groups available at one of these variable sites, we developed a synthetic route to an alternative, orthogonally protected key intermediate that allows the incorporation of ozone sensitive groups after the ozonolysis step. The utility of this orthogonally protected intermediate is demonstrated in the synthesis of several representative biomimetic scaffolds containing ozonolytically labile functional groups. It is compatible with traditional Fmoc peptide chemistry, permitting it to incorporate peptide fragments for use in fragment condensations with peptides containing cysteine at the N-terminus. Overall yields for its synthesis and utilization (as many as 13 steps) indicate good conversions at each step
Discovery of highly insecticidal synthetic spinosyn mimics – CAMD enabled de novo design simplifying a complex natural product
Simplifying complex natural products: Computer modeling‐based design leads to highly insecticidal, chemically simpler synthetic mimics of the spinosyn natural products that are active in the field
VERSATILE FMOC-ACETAL MERRIFIELD RESINS: SYNTHESES OF BICYCLIC LACTAMS & LACTONES
poster abstractThe preparation of Merrifield resins 5, which represent versatile intermediates
in the syntheses of lactones, lactams, and bicyclic, tricyclic, and
tetracyclic scaffolds, is described. The presence of Fmoc and acetal
protecting groups allows for the eventual incorporation of ozone-labile
groups at R2 (as in III) such as alkenes, alkynes, electron-rich aromatics
and pi-excessive heterocycles whereas the previously reported route can
only accommodate ozone-compatible groups.
An extension of the current methodology to include bicyclic lactams,
which features elaboration at each of R1, R2, and R3 of III including
fragment condensation examples 10a-c, is described. In all cases
separation and characterization of two of the four possible diastereomers
was achieved. Using 2-D NMR methods the relative configuration of the two
diastereomers is being established. Structures such as III are of interest
since the thiazabicycloalkane ring system is a known bioactive scaffold that
mimics the beta-turn (reverse turn) in polypeptides and proteins
Saponification of N-Acylated L-Phenylalanine Wang and Merrifield Resins. Assessment of Cleavage Efficiency and Epimerization
poster abstractAs part of a continuing effort to modify Distributed Drug Discovery (D3) synthetic procedures to enhance safety and accommodate the limited resources available to students in developing-world countries, we have recently begun to examine alternatives to trifluoroacetic acid (TFA)-cleavage of amino acid derivatives from polystyrene-based resins. Cleavage of a representative example, N-(4-chlorobenzoyl)-L-phenylalanine, from both Wang and Merrifield resins was accomplished in thirty minutes at room temperature using 0.5M sodium hydroxide in methanol/tetrahydrofuran. In a side-by-side comparison with cleavage using TFA, results indicated that saponification from Wang resin was incomplete after thirty minutes. Experiments designed to examine separately the effect of reaction time, temperature, and concentration were performed and results will be presented. Additionally, investigations were performed to assess the degree of epimerization which had occurred during cleavage of Merrifield-bound L-phenylalanine acylated with both (R)- and (S)-mandelic acid. Results revealed a small but significant amount of epimerization (15:1 to 31:1 diastereomeric ratios) after a thirty-minute cleavage time at room temperature
Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides
Remote amide bonds in simple N-acyl
amino acid amide or peptide
derivatives 1 can be surprisingly unstable hydrolytically,
affording, in solution, variable amounts of 3 under mild
acidic conditions, such as trifluoroacetic acid/water mixtures at
room temperature. This observation has important implications for
the synthesis of this class of compounds, which includes N-terminal-acylated
peptides. We describe the factors contributing to this instability
and how to predict and control it. The instability is a function of
the remote acyl group, R2CO, four bonds away from the site
of hydrolysis. Electron-rich acyl R2 groups accelerate
this reaction. In the case of acyl groups derived from substituted
aromatic carboxylic acids, the acceleration is predictable from the
substituent’s Hammett σ value. N-Acyl dipeptides are
also hydrolyzed under typical cleavage conditions. This suggests that
unwanted peptide truncation may occur during synthesis or prolonged
standing in solution when dipeptides or longer peptides are acylated
on the N-terminus with electron-rich aromatic groups. When amide hydrolysis
is an undesired secondary reaction, as can be the case in the trifluoroacetic
acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize
that hydrolysis
3,4-Dimethyl-1-phenylpyrano[2,3-c]pyrazol-6(1H)-one
In the title compound, C14H12N2O2, the dihedral angle between the phenyl ring and the 3,4-dimethylpyrano[2,3-c]pyrazol-6(1H)-one system is 7.28 (6)°. An intramolecular C—H⋯O interaction generates an S(6) ring. In the crystal, the molecules are linked by C—H⋯O hydrogen bonds, forming C(8) chains. C–H⋯π and π–π interactions [centroid–centroid separation = 3.6374 (12) Å] further consolidate the packing
Ethyl 3-[(6-chloropyridin-3-yl)methyl]-2-oxoimidazolidine-1-carboxylate
In the title compound, C12H14ClN3O3, the imidazole ring adopts a half-chair conformation. The dihedral angle between the pyridine and imidazole rings is 70.0 (1)°. In the crystal, the molecules are linked by C—H⋯O interactions, forming chains parallel to the c axis
Globally Distributed Drug Discovery of New Antibiotics: Design and Combinatorial Synthesis of Amino Acid Derivatives in the Organic Chemistry Laboratory
An experiment for the synthesis of N-acyl derivatives of natural amino acids has been developed as part of the Distributed Drug Discovery (D3) program. Students use solid-phase synthesis techniques to complete a three-step, combinatorial synthesis of six products, which are analyzed using LC–MS and NMR spectroscopy. This protocol is suitable for introductory organic laboratory students and has been successfully implemented at multiple academic sites internationally. Accompanying prelab activities introduce students to SciFinder and to medicinal chemistry design principles. Pairing of these activities with the laboratory work provides students an authentic and cohesive research project experience
Aminolytic Cleavage from Wang Resin. A New Distributed Drug Discovery Laboratory for the Undergraduate Curriculum
poster abstractWhen treated with ammonia or methylamine, unnatural amino acids bound to Wang resin (1) are released as their corresponding amides 2 in good yield and purity. When carried out at room temperature, aminolytic cleavage proceeds slowly with a four-day exposure to ammonia in methanol representing an optimal reaction time. Aminolytic cleavage proceeds well with unhindered primary amines, however, the hindered amine isopropylamine and benzylamines are unacceptably slow to effect cleavage. Use of the secondary amine pyrrolidine led to a complex mixture. Due to the large stoichiometric amine excess required, the scope is currently limited to unhindered, volatile, primary amines. The overall synthesis of 2 from BPI-Gly-Wang resin represents a new Distributed Drug Discovery Laboratory (D3-7) and was rolled out to the spring 2016 Organic II laboratory