Site-switchable mono-O-allylation of polyols

Site-selective modification of complex molecules allows for rapid accesses to their analogues and derivatives, and, therefore, offers highly valuable opportunities to probe their functions. However, to selectively manipulate one out of many repeatedly occurring functional groups within a substrate represents a grand challenge in chemistry. Yet more demanding is to develop methods in which alterations to the reaction conditions lead to switching of the specific site of reaction. We report herein the development of a Pd/Lewis acid co-catalytic system that achieves not only site-selective, but site-switchable mono-O-allylation of polyols with readily available reagents and catalysts. Through exchanging the Lewis acid additives that recognize specific hydroxyls in a polyol substrate, our system managed to install a versatile allyl group to the target in a site-switchable manner. Our design demonstrates remarkable scope, and is amenable to the direct derivatization of various complex, bioactive natural products.

Modulating Linker Composition of Haptens Resulted in Improved Immunoassay for Histamine

Histamine (HA) is an important food contaminant generated during food fermentation or spoilage. However, an immunoassay for direct (derivatization free) determination of HA has rarely been reported due to its small size to induce the desired antibodies by its current hapten-protein conjugates. In this work, despite violating the classical hapten design criteria which recommend introducing a linear aliphatic (phenyl free) linker into the immunizing hapten, a novel haptens, HA-245 designed and synthesized with a phenyl-contained linker, exhibited significantly enhanced immunological properties. Thus, a quality-improved monoclonal antibody (Mab) against HA was elicited by its hapten-carrier conjugates. Then, as the linear aliphatic linker contained haptens, Hapten B was used as linker-heterologous coating haptens to eliminate the recognition of linker antibodies. Indirect competitive ELISA (ic-ELISA) was developed with a 50% inhibition concentration (IC50) of 0.21 mg/L and a limit of detection (LOD) of 0.06 mg/L in buffer solution. The average recoveries of HA from spiked food samples for this ic-ELISA ranged from 84.1% and 108.5%, and the analysis results agreed well with those of referenced LC-MS/MS. This investigation not only realized derivatization-free immunoassay for HA, but also provided a valuable guidance for hapten design and development of immunoassay for small molecules.

Quantitation of Cannabinoids in Breath Samples Using a Novel Derivatization LC–MS/MS Assay with Ultra-High Sensitivity

As the legalization of medical and recreational marijuana use expands, measurement of tetrahydrocannabinol (THC) in human breath has become an area of interest. The presence and concentration of cannabinoids in breath have been shown to correlate with recent marijuana use and may be correlated with impairment. Given the low concentration of THC in human breath, sensitive analytical methods are required to further evaluate its utility and window of detection. This paper describes a novel derivatization method based on an azo coupling reaction that significantly increases the ionization efficiency of cannabinoids for LC–MS/MS analysis. This derivatization reaction allows for a direct derivatization reaction with neat samples and does not require further sample clean-up after derivatization, thus facilitating an easy and rapid “derivatize & shoot” sample preparation. The derivatization assay allowed for limits of quantitation (LOQ’s) in the sub-pg/mL to pg/mL range for the five cannabinoids in breath samples, i.e., only 5~50 femtograms of an analyte was required for quantitation in a single analysis. This ultrahigh sensitivity allowed for the quantitation of cannabinoids in all breath samples collected within 3 hours of smoking cannabis (n = 180). A linear correlation between THC and cannabinol (CBN) in human breath was observed, supporting the hypothesis that CBN is converted from THC during the combustion of cannabis. The derivatization method was also applied to the analysis of cannabinoids in whole blood samples, achieving LOQ’s at ten-pg/mL to sub-ng/mL level. This azo coupling-based derivatization approach provided the needed analytical sensitivity for the analysis of THC in human breath samples using LC–MS/MS and could be a valuable tool for the analysis of other aromatic compounds in the future.

Unconventional Rose Odorants: Serendipitous Discovery and Unique Olfactory Properties of 2,2-Bis(prenyl)-3-oxobutyronitrile and Its Derivatives

2,2-Bis(3-methylbut-2-enyl)-3-oxobutanenitrile [2,2-bis(prenyl)-3-oxobutyronitrile], an unusual bifunctional nitrile odorant with a fruity rosy, green odor was found to exhibit surprising differences in its detection thresholds (0.25 ng/L air for hyperosmics; 19 ng/L air for hyposmics) and perceived odor characters. To investigate this remarkable phenomenon, 13 derivatives of 2,2-bis(3-methylbut-2-enyl)-3-oxobutanenitrile were synthesized by either monoalkylation of 3-oxo-2-phenylbutanenitrile, or by dialkylation of sodium 1-cyano-2-oxopropan-1-ide or methyl or ethyl cyanoacetate, or by direct derivatization of 2,2-bis(3-methylbut-2-enyl)-3-oxobutanenitrile via its vinyl triflate and Negishi cross coupling. These systematic permutations of the substitution pattern allowed some insight to be gained into the underlying structure–odor relationships and the construction of a simple olfactophore model, albeit no final conclusion could be drawn as to whether the nitrile or carbonyl function acts as the prime osmophore of the bifunctional compounds. Depending on slight genetic variations and the corresponding differences in the receptor morphology both can engage in H-bond interactions with the olfactory receptors, which might explain the observed largely diverging sensitivities. Methyl 2-cyano-2,2-bis(3-methylbut-2-enyl)acetate with a uniform odor threshold of 0.38 ng/L air turned out to be the most interesting floral, rosy odorant of this study, followed by 3-methyl-2,2-bis(3-methylbut-2-enyl)but-3-enenitrile with only a nitrile function and varying odor thresholds (0.40 ng/L air vs. 125 ng/L air).