Pierrick Nun

Preparation of Chiral Amino Esters by Asymmetric Phase‐Transfer Catalyzed Alkylations of Schiff Bases in a Ball Mill

The asymmetric alkylation of Schiff bases under basic conditions in a ball mill was performed. The starting Schiff bases of glycine were prepared beforehand by milling protected glycine hydrochloride and benzophenone imine, in the absence of solvent. The Schiff base was then reacted with a halogenated derivative in a ball mill in the presence of KOH. By adding a chiral ammonium salt derived from cinchonidine, the reaction proceeded asymmetrically under phase-transfer catalysis conditions, giving excellent yields and enantiomeric excesses up to 75 %. Because an equimolar amount of starting material was used, purification was greatly simplified.

Gold(I)-catalyzed synthesis of furans and pyrroles via alkyne hydration

Furans and pyrroles were prepared via the gold(I)-catalyzed alkyne hydration of diynes. The use of [Au(IPr)OH] as precatalyst in a silver-free protocol permits low catalyst loadings and in situ generation of the active cationic gold species. A detailed computational study confirmed the experimental results and supports the proposed mechanism.

Ligand influence in the selective gold-mediated synthesis of allenes

The use of [(IPr)AuOH] permits the generation of gold(i)-amine complexes by a silver-free protocol. These in situ or well-defined complexes are used in a straightforward synthetic route to substituted allenes from propargylic acetates. The catalytic activity can be modulated as a function of the nature of the ligand bound to the gold-NHC moiety.

A retro-biosynthetic approach to the prediction of biosynthetic pathways from position-specific isotope analysis as shown for tramadol

Significance The extraction of tramadol from the roots of Nauclea latifolia excited great interest worldwide. This was the first time that a widely marketed synthetic drug was found as an apparently natural product at high abundance. In this article, we describe the position-specific distribution of 13C in this tramadol. As a conventional approach to study its probable biosynthetic precursors, enzymatic steps, and intermediate metabolites is not currently feasible, we herein propose the concept of a retro-biosynthesis by examining the position-specific isotope distribution within the molecule and rationally interpreting the data in terms of known plant biochemical processes that may be involved in a biosynthesis of tramadol. Thus, clear guidance is given for future labeling studies. Tramadol, previously only known as a synthetic analgesic, has now been found in the bark and wood of roots of the African medicinal tree Nauclea latifolia. At present, no direct evidence is available as to the biosynthetic pathway of its unusual skeleton. To provide guidance as to possible biosynthetic precursors, we have adopted a novel approach of retro-biosynthesis based on the position-specific distribution of isotopes in the extracted compound. Relatively recent developments in isotope ratio monitoring by 13C NMR spectrometry make possible the measurement of the nonstatistical position-specific natural abundance distribution of 13C (δ13Ci) within the molecule with better than 1‰ precision. Very substantial variation in the 13C positional distribution is found: between δ13Ci = −11 and −53‰. Distribution is not random and it is argued that the pattern observed can substantially be interpreted in relation to known causes of isotope fractionation in natural products. Thus, a plausible biosynthetic scheme based on sound biosynthetic principals of precursor–substrate relationships can be proposed. In addition, data obtained from the 18O/16O ratios in the oxygen atoms of the compound add support to the deductions made from the carbon isotope analysis. This paper shows how the use of 13C NMR at natural abundance can help with proposing a biosynthetic route to compounds newly found in nature or those difficult to tackle by conventional means.

Fractionation in position-specific isotope composition during vaporization of environmental pollutants measured with isotope ratio monitoring by 13C nuclear magnetic resonance spectrometry

Isotopic fractionation of pollutants in terrestrial or aqueous environments is a well-recognized means by which to track different processes during remediation. As a complement to the common practice of measuring the change in isotope ratio for the whole molecule using isotope ratio monitoring by mass spectrometry (irm-MS), position-specific isotope analysis (PSIA) can provide further information that can be exploited to investigate source and remediation of soil and water pollutants. Position-specific fractionation originates from either degradative or partitioning processes. We show that isotope ratio monitoring by (13)C NMR (irm-(13)C NMR) spectrometry can be effectively applied to methyl tert-butylether, toluene, ethanol and trichloroethene to obtain this position-specific data for partitioning. It is found that each compound exhibits characteristic position-specific isotope fractionation patterns, and that these are modulated by the type of evaporative process occurring. Such data should help refine models of how remediation is taking place, hence back-tracking to identify pollutant sources.

Position-Specific Isotope Analysis of Xanthines: A 13C Nuclear Magnetic Resonance Method to Determine the 13C Intramolecular Composition at Natural Abundance

The natural xanthines caffeine, theobromine, and theophylline are of major commercial importance as flavor constituents in coffee, cocoa, tea, and a number of other beverages. However, their exploitation for authenticity, a requirement in these commodities that have a large origin-based price-range, by the standard method of isotope ratio monitoring by mass spectrometry (irm-MS) is limited. We have now developed a methodology that overcomes this deficit that exploits the power of isotopic quantitative (13)C nuclear magnetic resonance (NMR) spectrometry combined with chemical modification of the xanthines to enable the determination of positional intramolecular (13)C/(12)C ratios (δ(13)Ci) with high precision. However, only caffeine is amenable to analysis: theobromine and theophylline present substantial difficulties due to their poor solubility. However, their N-methylation to caffeine makes spectral acquisition feasible. The method is confirmed as robust, with good repeatability of the δ(13)Ci values in caffeine appropriate for isotope fractionation measurements at natural abundance. It is shown that there is negligible isotope fractionation during the chemical N-methylation procedure. Thus, the method preserves the original positional δ(13)Ci values. The method has been applied to measure the position-specific variation of the (13)C/(12)C distribution in caffeine. Not only is a clear difference between caffeine isolated from different sources observed, but theobromine from cocoa is found to show a (13)C pattern distinct from that of caffeine.

Insights into Mechanistic Models for Evaporation of Organic Liquids in the Environment Obtained by Position-Specific Carbon Isotope Analysis

Position-specific isotope effects (PSIEs) have been measured by isotope ratio monitoring (13)C nuclear magnetic resonance spectrometry during the evaporation of 10 liquids of different polarities under 4 evaporation modes (passive evaporation, air-vented evaporation, low pressure evaporation, distillation). The observed effects are used to assess the validity of the Craig-Gordon isotope model for organic liquids. For seven liquids the overall isotope effect (IE) includes a vapor-liquid contribution that is strongly position-specific in polar compounds but less so in apolar compounds and a diffusive IE that is not position-specific, except in the alcohols, ethanol and propan-1-ol. The diffusive IE is diminished under forced evaporation. The position-specific isotope pattern created by liquid-vapor IEs is manifest in five liquids, which have an air-side limitation for volatilization. For the alcohols, undefined processes in the liquid phase create additional PSIEs. Three other liquids with limitations on the liquid side have a lower, highly position-specific, bulk diffusive IE. It is concluded that evaporation of organic pollutants creates unique position-specific isotope patterns that may be used to assess the progress of remediation or natural attenuation of pollution and that the Craig-Gordon isotope model is valid for the volatilization of nonpolar organic liquids with air-side limitation of the volatilization rate.

Predicting equilibrium vapour pressure isotope effects by using artificial neural networks or multi-linear regression – A quantitative structure property relationship approach

We aim at predicting the effect of structure and isotopic substitutions on the equilibrium vapour pressure isotope effect of various organic compounds (alcohols, acids, alkanes, alkenes and aromatics) at intermediate temperatures. We attempt to explore quantitative structure property relationships by using artificial neural networks (ANN); the multi-layer perceptron (MLP) and compare the performances of it with multi-linear regression (MLR). These approaches are based on the relationship between the molecular structure (organic chain, polar functions, type of functions, type of isotope involved) of the organic compounds, and their equilibrium vapour pressure. A data set of 130 equilibrium vapour pressure isotope effects was used: 112 were used in the training set and the remaining 18 were used for the test/validation dataset. Two sets of descriptors were tested, a set with all the descriptors: number of(12)C, (13)C, (16)O, (18)O, (1)H, (2)H, OH functions, OD functions, CO functions, Connolly Solvent Accessible Surface Area (CSA) and temperature and a reduced set of descriptors. The dependent variable (the output) is the natural logarithm of the ratios of vapour pressures (ln R), expressed as light/heavy as in classical literature. Since the database is rather small, the leave-one-out procedure was used to validate both models. Considering higher determination coefficients and lower error values, it is concluded that the multi-layer perceptron provided better results compared to multi-linear regression. The stepwise regression procedure is a useful tool to reduce the number of descriptors. To our knowledge, a Quantitative Structure Property Relationship (QSPR) approach for isotopic studies is novel.

Hemisynthesis of 2,3,4-13C3-1,4-Androstadien-3,17-dione: A Key Precursor for the Synthesis of 13C3-Androstanes and 13C3-Estranes

In this contribution, we describe two simple and efficient routes for the preparation of keto-aldehyde 1, a key intermediate for the synthesis of 13C3-androstanes and 13C3-estranes. In the first route, the targeted aldehyde 1 was obtained in 40% overall yield from 1,4-androstadien-3,17-dione (3 mmol scale) via a two-step sequence involving a one-pot, abnormal ozonolysis/sulfur oxidation/retro-Michael/ozonolysis process. Alternatively, a second route from 4-androsten-3,17-dione, using a six-step sequence, was optimized to produce 40 mmol batches of the key intermediate 1 in 42% overall yield. At the final stage, the A-ring was reconstructed through a Wittig reaction with the 1-triphenylphosphoranylidene-13C3-2-propanone 2, followed by an intramolecular condensation assisted by thioacetic acid via a Michael addition/retro-Michael reaction sequence to provide 2,3,4-13C3-1,4-androstadien-3,17-dione.

One-Pot Synthesis of Functionalized Fused Furans via a BODIPY-Catalyzed Domino Photooxygenation

Six-membered ring fused furans containing a tetrasubstituted tertiary carbon were prepared in an unprecedented one-pot BODIPY-catalyzed domino photooxygenation/reduction process. A series of functionalized furans was synthesized from readily available 2-alkenylphenols and mechanistic studies were performed to account for the domino photosensitized oxygenation.