Leveraging Limited Experimental Data with Machine Learning: Differentiating a Methyl from an Ethyl Group in the Corey-Bakshi-Shibata Reduction.

We present a case study on how to improve an existing metal-free catalyst for a particularly difficult reaction, namely, the Corey-Bakshi-Shibata (CBS) reduction of butanone, which constitutes the classic and prototypical challenge of being able to differentiate a methyl from an ethyl group. As there are no known strategies on how to address this challenge, we leveraged the power of machine learning by constructing a realistic (for a typical laboratory) small, albeit high-quality, data set of about 100 reactions (run in triplicate) that we used to train a model in combination with a key-intermediate graph (of substrate and catalyst) to predict the differences in Gibbs activation energies ΔΔ of the enantiomeric reaction paths. With the help of this model, we were able to select and subsequently screen a small selection of catalysts and increase the selectivity for the CBS reduction of butanone to 80% enantiomeric excess (ee), the highest possible value achieved to date for this substrate with a metal-free catalyst, thereby also exceeding the best available enzymatic systems (64% ee) and the selectivity with Corey's original catalyst (60% ee).

Determining Ultra-Low Organic Molecular Odor Thresholds in Air Helps Identify the Most Potent Fungal Aroma Compound.

The determination of odor threshold values can be performed in various matrices, including air, and serves as a parameter to compare the potencies of odorous compounds. Typically, the odor thresholds in air are determined by gas chromatography-olfactory (GC-O) and referenced to an internal standard, most often ()-dec-2-enal. Herein, a direct gas chromatography-flame ionization detector-olfactory analysis method for the determination of odor thresholds in air is reported.

Quantifying Intermolecular Interactions in Asymmetric Peptide Organocatalysis as a Key toward Understanding Selectivity.

The kinetic resolution of -cyclohexane-1,2-diol with a lipophilic oligopeptide catalyst shows extraordinary selectivities. To improve our understanding of the factors governing selectivity, we quantified the Gibbs free energies of interactions of the peptide with both enantiomers of -cyclohexane-1,2-diol using nuclear magnetic resonance (NMR) spectroscopy. For this, we use advanced methods such as transverse relaxation (), diffusion measurements, saturation transfer difference (STD), and chemical shift (δ) analysis of peptide-diol mixtures upon varying their composition (NMR titrations).

Structure Elucidation of Aroma-Active Bicyclic Benzofuran Derivatives Formed by .

Among the monoterpenoid aroma compounds formed by the basidiomycete are highly potent bicyclic benzofuran derivatives. In addition to the dill ethers previously described in a few fungi, two stereoisomers of the rare 3,6-dimethyl-3a,4,5,6,7,7a-hexahydro-3-1-benzofuran-2-one ( and ), also known as dihydromenthofurolactones, and a C3-unsaturated analogue () are formed by . The analysis of synthesized reference standards of the lactones allowed an unambiguous assignment of the stereoisomers formed by the fungus.

Selective Preparation of Phosphorus Mononitride (P≡N) from Phosphinoazide and Reversible Oxidation to Phosphinonitrene.

The interstellar candidate phosphorus mononitride PN, a metastable species, was generated through high-vacuum flash pyrolysis of (o-phenyldioxyl)phosphinoazide in cryogenic matrices. Although the PN stretching band was not directly detected because of its low infrared intensity and possible overlaps with other strong bands, o-benzoquinone, carbon monoxide, and cyclopentadienone as additional fragmentation products were clearly identified. Moreover, an elusive o-benzoquinone-PN complex formed when (o-phenyldioxyl)phosphinoazide was exposed to UV irradiation at λ=254 nm.

Matrix isolation and photorearrangement of - and -1,2-ethenediol to glycolaldehyde.

1,2-Ethenediols are deemed key intermediates in prebiotic and interstellar syntheses of carbohydrates. Here we present the gas-phase synthesis of these enediols, the high-energy tautomers of glycolaldehyde, trapped in cryogenic argon matrices. Importantly, upon photolysis at = 180-254 nm, the enols rearrange to the simplest sugar glycolaldehyde.

Glycine Imine-The Elusive α-Imino Acid Intermediate in the Reductive Amination of Glyoxylic Acid.

Simple unhindered aldimines tend to hydrolyze or oligomerize and are therefore spectroscopically not well characterized. Herein we report the formation and spectroscopic characterization of the simplest imino acid, namely glycine imine, by cryogenic matrix isolation IR and UV/Vis spectroscopy. Glycine imine forms after UV irradiation of 2-azidoacetic acid by N extrusion in anti-(E,E)- and anti-(Z,Z)-conformation that can be photochemically interconverted.

Site-Selective Acylation of Pyranosides with Immobilized Oligopeptide Catalysts in Flow.

We report the site-selective acetylation of partially protected monosaccharides using immobilized oligopeptide catalysts, which are readily accessible via solid-phase peptide synthesis. The catalysts are able to invert the intrinsic selectivity, which was determined using N-methylimidazole, for a variety of pyranosides. We demonstrate that the catalysts are stable for multiple reaction cycles and can be easily reused after separation from the reaction solution.

The Effects of Tetrapeptides Designed to Fit the Androgen Binding Site of ZIP9 on Myogenic and Osteogenic Cells.

ZIP9 is a recently identified membrane-bound androgen receptor of physiological significance that may mediate certain physiological responses to androgens. Using in silico methods, six tetrapeptides with the best docking properties at the testosterone binding site of ZIP9 were synthesized and further investigated. All tetrapeptides displaced T-BSA-FITC, a membrane-impermeable testosterone analog, from the surface of mouse myogenic L6 cells that express ZIP9 but not the classical androgen receptor (AR).

Formation of Diastereomeric Dihydromenthofurolactones by and Aroma Dilution Analysis Based on Dynamic Headspace Extraction.

Submerged cultures of the basidiomycota emit an intensive coconut-like, sweetish, and buttery smell. For identification of the key aroma compounds, an aroma dilution analysis using dynamic headspace was performed by adjusting the split ratio of the GC inlet system. Flavor dilution (FD) factors varied from 2 up to ≥2, whereby the largest class of compounds represented terpenoids, including two rare stereoisomers of 3,6-dimethyl-2,3,3a,4,5,7a-hexahydrobenzofuran (dill ether, ee ≥ 99.

Site-Selective Acylation of Pyranosides with Oligopeptide Catalysts.

Herein, we report the oligopeptide-catalyzed site-selective acylation of partially protected monosaccharides. We identified catalysts that invert site-selectivity compared to -methylimidazole, which was used to determine the intrinsic reactivity, for 4,6--protected glucopyranosides (-diols) as well as 4,6--protected mannopyranosides (-diols). The reaction yields up to 81% of the inherently unfavored 2--acetylated products with selectivities up to 15:1 using mild reaction conditions.

Capture and Reactivity of an Elusive Carbon-Sulfur Centered Biradical.

The initial oxidation product of dimethyl sulfide in the marine boundary layer, the methyl thiomethyl radical, has remained elusive. A structurally analogous biradical with one radical center in the α-position to a sulfur atom could now be obtained by UV irradiation of -nitrobenzaldehyde dithiane isolated in solid dinitrogen (N) or Ar at cryogenic temperatures. A spin-forbidden reaction with triplet dioxygen (O) does not occur.

In Situ Switching of Site-Selectivity with Light in the Acetylation of Sugars with Azopeptide Catalysts.

We present a novel concept for the in situ control of site-selectivity of catalytic acetylations of partially protected sugars using light as external stimulus and oligopeptide catalysts equipped with an azobenzene moiety. The isomerizable azobenzene-peptide backbone defines the size and shape of the catalytic pocket, while the π-methyl-l-histidine (Pmh) moiety transfers the electrophile. Photoisomerization of the - to the -azobenzene catalyst (monitored via NMR) with an LED (λ = 365 nm) drastically changes the chemical environment around the catalytically active Pmh moiety, so that the light-induced change in the catalyst shape alters site-selectivity.

Gas-phase sugar formation using hydroxymethylene as the reactive formaldehyde isomer.

Carbohydrates (CHO) are the formal adducts of carbon (atoms) to water with a repeating unit that structurally resembles H-C̈-OH (hydroxymethylene). Although hydroxymethylene has been suggested as a building block for sugar formation, it is a reactive species that had escaped detection until recently. Here we demonstrate that formaldehyde reacts with its isomer hydroxymethylene to give glycolaldehyde in a nearly barrierless reaction.

1,3-Dioxolane-4-ol Hemiacetal Stores Formaldehyde and Glycolaldehyde in the Gas-Phase.

We report the spontaneous gas-phase formation of 1,3-dioxolane-4-ol, a mixed hemiacetal resulting from the addition of glycolaldehyde to formaldehyde. It was spectroscopically characterized by matching matrix IR spectra with coupled cluster computations. The formation of the hemiacetal must be surface-catalyzed owing to the very high computed reaction barrier of 39.

Total Synthesis and Structural Revision of the Antibiotic Tetrapeptide GE81112A.

The total synthesis of the naturally occurring antibiotic GE81112A, a densely functionalized tetrapeptide, is reported. Comparison of spectral data with those of the natural product and the lack of biological activity of the synthesized compound led us to revise the published configuration of the 3-hydroxypipecolic acid moiety. This hypothesis was fully validated by the synthesis of the corresponding epimer.

London dispersion as important factor for the stabilization of ()-azobenzenes in the presence of hydrogen bonding.

The understanding and control of the light-induced isomerization of azobenzenes as one of the most important classes of molecular switches is crucial for the design of light-responsive materials using this entity. Herein, we present the stabilization of metastable ()-azobenzenes by London dispersion interactions, even in the presence of comparably stronger hydrogen bonds in various solvents. The → isomerization rates of several -substituted 4,4'-bis(4-aminobenzyl)azobenzenes were measured.

Uncovering Key Structural Features of an Enantioselective Peptide-Catalyzed Acylation Utilizing Advanced NMR Techniques.

We report on a detailed NMR spectroscopic study of the catalyst-substrate interaction of a highly enantioselective oligopeptide catalyst that is used for the kinetic resolution of trans-cycloalkane-1,2-diols via monoacylation. The extraordinary selectivity has been rationalized by molecular dynamics as well as density functional theory (DFT) computations. Herein we describe the conformational analysis of the organocatalyst studied by a combination of nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC)-based methods that resulted in an ensemble of four final conformers.

The Enantioselective Dakin-West Reaction.

Here we report the development of the first enantioselective Dakin-West reaction, yielding α-acetamido methylketones with up to 58 % ee with good yields. Two of the obtained products were recrystallized once to achieve up to 84 % ee. The employed methylimidazole-containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation.

Functionality, Effectiveness, and Mechanistic Evaluation of a Multicatalyst-Promoted Reaction Sequence by Electrospray Ionization Mass Spectrometry.

A multicatalytic three-step reaction consisting of epoxidation, hydrolysis, and enantioselective monoacylation of cyclohexene was studied by using mass spectrometry (MS). The reaction sequence was carried out in a one-pot reaction using a multicatalyst. All reaction steps were thoroughly analyzed by electrospray ionization (ESI) MS (and MS/MS), as well as high-resolution MS for structure elucidation.

En route to multicatalysis: kinetic resolution of trans-cycloalkane-1,2-diols via oxidative esterification.

We demonstrate the application of a multicatalyst to the oxidation of a broad variety of aldehydes and subsequent enantioselective esterification of the incipient acids with (±)-trans-cycloalkane-1,2-diols. This reaction operates well with a multicatalyst bearing two independent catalytic moieties that provide monoprotected 1,2-diols in one pot.

Lipophilic oligopeptides for chemo- and enantioselective acyl transfer reactions onto alcohols.

Inspired by the extraordinary selectivities of acylases, we envisioned the use of lipophilic oligopeptidic organocatalysts for the acylative kinetic resolution/desymmetrization of rac- and meso-cycloalkane-1,2-diols. Here we describe in a full account the discovery and development process from the theoretical concept to the final catalyst, including scope and limitations. Competition experiments with various alcohols and electrophiles show the full potential of the employed oligopeptides.

Enantiomerically enriched trans-diols from alkenes in one pot: a multicatalyst approach.

Multicatalysts consisting of non-natural oligopeptides with distinctly different catalytic moieties create molecular complexity in a multistep one-pot sequence starting from simple alkenes yielding highly enantiomerically enriched trans-diols.

Silicon-(thio)urea Lewis acid catalysis.

We present a new class of catalysts based on the combination of N,N'-diaryl(thio)ureas and weak silicon Lewis acids (e.g., SiCl(4)).