High‐Throughput Assay for Enantiomeric Excess Determination in 1,2‐ and 1,3‐Diols and Direct Asymmetric Reaction Screening

Abstract

A simple and efficient method for determination of the yield, enantiomeric/diasteriomeric excess (ee/de), and absolute configuration of crude chiral diols without the need of work-up and product isolation in a high throughput setting is described. This approach utilizes a self-assembled iminoboronate ester formed as a product by dynamic covalent self-assembly of a chiral diol with an enantiopure fluorescent amine such as tryptophan methyl ester or tryptophanol and 2-formylphenylboronic acid. The resulting diastereomeric boronates display different photophysical properties and allow for fluorescence-based ee determination of molecules containing a 1,2- or 1,3-diol moiety. This method has been utilized for the screening of ee in a number of chiral diols including atorvastatin, a statin used for the treatment of hypercholesterolemia. Noyori asymmetric hydrogenation of benzil was performed in a highly parallel fashion with errors <1 % ee confirming the feasibility of the systematic examination of crude products from the parallel asymmetric synthesis in real time and in a high-throughput screening (HTS) fashion.

Click chemistry enables quantitative chiroptical sensing of chiral compounds in protic media and complex mixtures

“…Optical methods are compatible with parallel data acquisition, miniaturization, and multiwell plate formats and offer a new path to real high-throughput analysis of chiral samples 4–7 . Few examples of asymmetric reaction analysis with sensors operating on the principles of dynamic covalent chemistry 8–11 , metal complex coordination 12 , and supramolecular chemistry 13–15 to recognize a chiral target compound and to generate quantifiable ultraviolet (UV), fluorescence, and circular dichroism (CD) signals have been reported 16–18 . Comprehensive chirality sensing (CCS), i.e., determination of the absolute configuration, yield, and enantiomeric excess ( ee ), of crude asymmetric reaction mixtures via irreversible covalent product fixation has been largely neglected to date 19 .…”

Accelerated Asymmetric Reaction Screening with Optical Assays

“…Anzenbacher and colleagues analyzed the ruthenium-catalyzed asymmetric Noyori hydrogenation of benzil ( 17 ) using a dynamic covalent assembly that was obtained by mixing the reaction product hydrobenzoin ( 19 ), 2-formylphenylboronic acid ( 20 ), and tryptophanol ( 21 ) (Scheme 4 ). 12 Multivariate data analysis of the fluorescence emission changes of the boron complex 22 allowed calculation of the enantiomeric excess and concentration of 19 . The practicality of this fluorimetric assay is quite remarkable and it impresses with several attractive features: it is very fast, generates accurate data with less than 1 mg of crude reaction mixtures, and it requires only commercially available reagents.…”

Advancement in Organic Synthesis Through High Throughput Experimentation

“…To circumvent the time‐consuming nature of chiral HPLC or NMR for evaluating asymmetric reactions, UV/Circular Dichroism based methodology was developed to monitor 54 asymmetric allylations of isatin with chiral boron reagents [34] (Scheme 2f). Efforts were also devoted to the analysis of high throughput data obtained from asymmetric reactions to identify the enantiomeric or diastereomeric excess via chemometrics, [35] or artificial neural network [36] approaches; these methods are still in early stages of development. For example, a 2D‐LC/MS analytical method was developed by Genentech using achiral separation in the 1 st dimension and chiral separation in the 2 nd dimension to determine the yield and stereoselectivity.…”