12 research outputs found
Potential Safety Hazards Associated with Using Acetonitrile and a Strong Aqueous Base
Acetonitrile, a common solvent in
organic synthesis, can be hydrolyzed
in the presence of a strong aqueous base, such as NaOH or KOH, which
can propagate into a runaway reaction. For a process recently reviewed
in our laboratory, a possible loss of cooling incident during the
desired reaction was found to have the potential to self-heat to the
onset temperature of this hydrolysis reaction. This base-catalyzed
acetonitrile hydrolysis was determined to potentially escalate into
a runaway reaction, where it could lead to secondary exothermic runaway
reactions of the reaction mixture. The use of acetonitrile was preferred
for the initial cyclization step. Thus, adequate removal of acetonitrile
prior to the following step avoided the process safety hazard posed
by the hydrolysis of the acetonitrile solvent. The findings presented
in this work serve as an alert to chemists and engineers for the potential
safety hazards when scaling up a process in which the solvent becomes
a reactant
Digital NMR Profiles as Building Blocks: Assembling <sup>1</sup>H Fingerprints of Steviol Glycosides
This report describes a fragment-based
approach to the examination
of congeneric organic compounds by NMR spectroscopy. The method combines
the classic interpretation of 1D- and 2D-NMR data sets with contemporary
computer-assisted NMR analysis. Characteristic NMR profiles of key
structural motifs were generated by <sup>1</sup>H iterative full spin
analysis and then joined together as building blocks to recreate the <sup>1</sup>H NMR spectra of increasingly complex molecules. To illustrate
the methodology described, a comprehensive analysis of steviol (<b>1</b>), seven steviol glycosides (<b>2</b>ā<b>8</b>) and two structurally related isosteviol compounds (<b>9</b>, <b>10</b>) was carried out. The study also assessed
the potential impact of this method on relevant aspects of natural
product research including structural verification, chemical dereplication,
and mixture analysis
Digital NMR Profiles as Building Blocks: Assembling <sup>1</sup>H Fingerprints of Steviol Glycosides
This report describes a fragment-based
approach to the examination
of congeneric organic compounds by NMR spectroscopy. The method combines
the classic interpretation of 1D- and 2D-NMR data sets with contemporary
computer-assisted NMR analysis. Characteristic NMR profiles of key
structural motifs were generated by <sup>1</sup>H iterative full spin
analysis and then joined together as building blocks to recreate the <sup>1</sup>H NMR spectra of increasingly complex molecules. To illustrate
the methodology described, a comprehensive analysis of steviol (<b>1</b>), seven steviol glycosides (<b>2</b>ā<b>8</b>) and two structurally related isosteviol compounds (<b>9</b>, <b>10</b>) was carried out. The study also assessed
the potential impact of this method on relevant aspects of natural
product research including structural verification, chemical dereplication,
and mixture analysis
Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed Reactions of Sulfoxonium Ylides with 2āAmino Heterocycles
An
iridium-catalyzed method was developed for the synthesis of imidazo-fused
pyrrolopyrazines. The presence or absence of a nitrogenated ligand
controlled the outcome of the reaction, leading to simple Ī²-keto
amine products in the absence of added ligand and the cyclized 7-
and 8-substituted-imidazoĀ[1,2<i>-a</i>]ĀpyrroloĀ[2,3<i>-e</i>]Āpyrazine products in the presence of ligand. This catalyst
control was conserved across a variety of ylide and amine coupling
partners. The substrate was shown to act as a ligand for the iridium
catalyst in the absence of other ligands via NMR spectroscopy. Kinetic
studies indicated that formation of the Ir-carbene was reversible
and the slow step of the reaction. These mechanistic investigations
suggest that the Ī²-keto amine products form via an intramolecular
carbene NāH insertion, and the imidazopyrrolopyrazines form
via an intermolecular carbene NāH insertion
Belizentrin, a Highly Bioactive Macrocycle from the Dinoflagellate <i>Prorocentrum belizeanum</i>
Belizentrin
(<b>1</b>), a novel 25-membered polyketide-derived
macrocycle, was isolated from cultures of the marine dinoflagellate <i>Prorocentrum belizeanum.</i> This metabolite is the first member
of an unprecedented class of polyunsaturated and polyhydroxylated
macrolactams. The structure of <b>1</b> was primarily determined
by NMR and computational methods. Pharmacological assays with cerebellar
cells showed that <b>1</b> produces important changes in neuronal
network integrity at nanomolar concentrations
Copper-Catalyzed Aerobic Oxidative Amidation of Benzyl Alcohols
A Cu-catalyzed
synthesis of amides from alcohols and secondary
amines using the oxygen in air as the terminal oxidant has been developed.
The methodology is operationally simple requiring no high pressure
equipment or handling of pure oxygen. The commercially available,
nonprecious metal catalyst, CuĀ(phen)ĀCl<sub>2</sub>, in conjunction
with di-<i>tert</i>-butyl hydrazine dicarboxylate and an
inorganic base provides a variety of benzamides in moderate to excellent
yields. The p<i>K</i><sub>a</sub> of amine conjugate acid
and electronics of alcohol were shown to impact the selection of base
for optimal reactivity. A mechanism consistent with the observed reactivity
trends, KIE, and Hammett study is proposed
Importance of Purity Evaluation and the Potential of Quantitative <sup>1</sup>H NMR as a Purity Assay
In any biomedical and chemical context,
a truthful description of chemical constitution requires coverage
of both structure and purity. This qualification affects all drug
molecules, regardless of development stage (early discovery to approved
drug) and source (natural product or synthetic). Purity assessment
is particularly critical in discovery programs and whenever
chemistry is linked with biological and/or therapeutic outcome. Compared
with chromatography and elemental analysis, quantitative NMR (qNMR)
uses nearly universal detection and provides a versatile and orthogonal
means of purity evaluation. Absolute qNMR with flexible calibration
captures analytes that frequently escape detection (water, sorbents).
Widely accepted structural NMR workflows require minimal or no adjustments
to become practical <sup>1</sup>H qNMR (qHNMR) procedures with simultaneous
qualitative and (absolute) quantitative capability. This study reviews
underlying concepts, provides a framework for standard qHNMR purity
assays, and shows how adequate accuracy and precision are achieved
for the intended use of the material
Hytramycins V and I, Anti-<i>Mycobacterium tuberculosis</i> Hexapeptides from a <i>Streptomyces hygroscopicus</i> Strain
Thirty-five thousand actinomycete
extracts were screened for anti-<i>Mycobacterium tuberculosis</i> (<i>M. tb</i>) activity,
followed by C<sub>18</sub> cartridge fractionation of 37 prioritized
extracts. Based on MICs against replicating and nonreplicating <i>M. tb</i>, and IC<sub>50</sub> values against Vero cells to
generate selectivity indices, seven fractions from seven different
strains were selected for further examination. When cultured in G.S.S.
media and extracted with ethyl acetate, the <i>Streptomyces hygroscopicus</i> strain ECUM 14046 yielded an extract with promising anti-<i>M. tb</i> activity and a well-defined chromatographic profile.
Fractionation by preparative HPLC and subsequent structure elucidation
of two active fractions using 1D- and 2D-NMR and MS methods revealed
the presence of two cyclohexapeptides, hytramycins V and I, each containing
three unusual piperazic acid moieties. The use of <sup>1</sup>H iterative
full spin analysis (HiFSA) on both hytramycins confirmed that quantum
mechanics-simulated spectra match the experimental data, and all <i>J</i><sub>H,H</sub> and Ī“<sub>H</sub> values are consistent
with the proposed structures. The absolute configuration of each amino
acid moiety was determined by Marfeyās method. The MICs against
replicating and, more importantly, nonreplicating <i>M. tb</i> fall into the range of some existing second-line anti-TB drugs,
such as streptomycin and capreomycin, respectively. The activities
were maintained against <i>M. tb</i> strains that represent
the major global clades, as well as H<sub>37</sub>Rv-isogenic strains
that are resistant to individual clinical anti-TB drugs
<i>K</i>āTargeted Metabolomic Analysis Extends Chemical Subtraction to DESIGNER Extracts: Selective Depletion of Extracts of Hops (Humulus lupulus)
This study introduces a flexible
and compound targeted approach
to <u>D</u>eplete and <u>E</u>nrich <u>S</u>elect <u>I</u>ngredients to <u>G</u>enerate <u>N</u>ormalized <u>E</u>xtract <u>R</u>esources, generating
DESIGNER extracts, by means of chemical subtraction or augmentation
of metabolites. Targeting metabolites based on their liquidāliquid
partition coefficients (<i>K</i> values), <i>K</i> targeting uses countercurrent separation methodology to remove single
or multiple compounds from a chemically complex mixture, according
to the following equation: DESIGNER extract = total extract Ā±
target compound(s). Expanding the scope of the recently reported depletion
of extracts by immunoaffinity or solid phase liquid chromatography,
the present approach allows a more flexible, single- or multi-targeted
removal of constituents from complex extracts such as botanicals.
Chemical subtraction enables both chemical and biological characterization,
including detection of synergism/antagonism by both the subtracted
targets and the remaining metabolite mixture, as well as definition
of the residual complexity of all fractions. The feasibility of the
DESIGNER concept is shown by <i>K</i>-targeted subtraction
of four bioactive prenylated phenols, isoxanthohumol (<b>1</b>), 8-prenylnaringenin (<b>2</b>), 6-prenylnaringenin (<b>3</b>), and xanthohumol (<b>4</b>), from a standardized
hops (Humulus lupulus L.) extract using
specific solvent systems. Conversely, adding <i>K</i>-targeted
isolates allows enrichment of the original extract and hence provides
an augmented DESIGNER material. Multiple countercurrent separation
steps were used to purify each of the four compounds, and four DESIGNER
extracts with varying depletions were prepared. The DESIGNER approach
innovates the characterization of chemically complex extracts through
integration of enabling technologies such as countercurrent separation, <i>K</i>-by-bioactivity, the residual complexity concepts, as well
as quantitative analysis by <sup>1</sup>H NMR, LC-MS, and HiFSA-based
NMR fingerprinting
Chlorinated Coumarins from the Polypore Mushroom <i>Fomitopsis officinalis</i> and Their Activity against <i>Mycobacterium tuberculosis</i>
An EtOH extract of the polypore mushroom <i>Fomitopsis officinalis</i> afforded two new naturally occurring
chlorinated coumarins, which
were identified as the previously synthesized compounds 6-chloro-4-phenyl-2<i>H</i>-chromen-2-one (<b>1</b>) and ethyl 6-chloro-2-oxo-4-phenyl-2<i>H</i>-chromen-3-carboxylate (<b>2</b>). The structures
of the two isolates were deduced by <i>ab initio</i> spectroscopic
methods and confirmed by chemical synthesis. In addition, an analogue
of each was synthesized as 7-chloro-4-phenyl-2<i>H</i>-chromen-2-one
(<b>3</b>) and ethyl 7-chloro-2-oxo-4-phenyl-2<i>H</i>-chromen-3-carboxylate (<b>4</b>). All four compounds were
characterized physicochemically, and their antimicrobial activity
profiles revealed a narrow spectrum of activity with lowest MICs against
the <i>Mycobacterium tuberculosis</i> complex