Enantioselective Synthesis of Enantioisotopomers with Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy

Abstract

Fundamental to the synthesis of enantioenriched chiral molecules is the ability to assign absolute configuration at each stereogenic center, and to determine the enantiomeric excess for each compound. While determination of enantiomeric excess and absolute configuration is often considered routine in many facets of asymmetric synthesis, the same determinations for enantioisotopomers remains a formidable challenge. Here, we report the first highly enantioselective metal‐catalyzed synthesis of enantioisotopomers that are chiral by virtue of deuterium substitution along with the first general spectroscopic technique for assignment of the absolute configuration and quantitative determination of the enantiomeric excess of isotopically chiral molecules. Chiral tag rotational spectroscopy uses noncovalent chiral derivatization, which eliminates the possibility of racemization during derivatization, to perform the chiral analysis without the need of reference samples of the enantioisotopomer.

Highly selective catalytic transfer hydrodeuteration of cyclic alkenes

“…39,40 More recently, our group reported several Cu-catalyzed alkene transfer hydrodeuteration reactions that precisely incorporate one deuterium atom and one hydrogen atom across a double bond with high fidelity. [41][42][43] The transfer hydrodeuteration was extended to acyclic aryl alkene substrate types to achieve the synthesis of small molecules containing exactly one deuterium atom at the benzylic position (Scheme 1c). 41 Despite the broad alkenyl arene substrate scope, cyclic alkene types were not explored.…”

Assignment of the absolute configuration of molecules that are chiral by virtue of deuterium substitution using chiral tag molecular rotational resonance spectroscopy

“…9 Recently, precision deuteration of small molecules has emerged at the forefront of new reaction discovery. [10][11][12][13][14][15][16][17][18][19][20][21][22] Precision deuteration techniques are used to control the exact placement and quantity of deuterium being installed into an organic molecule. This is challenging from both a synthetic and analytical perspective.…”

“…Recently, we reported the first general and enantioselective protocol for accessing enantioisotopomers that are chiral by virtue of deuterium substitution. 12 To develop this type of precision deuteration reaction, a formal alkene catalytic transfer hydrodeuteration was studied. 24 Chiral analysis of the enantioisotopomers produced in precision deuteration chemistry poses many challenges to analytical chemistry.…”

“…We have used the method of chiral tag molecular rotational resonance (MRR) spectroscopy 12,[49][50][51][52][53] to meet the challenges of providing chiral analysis support for the development of precision deuteration chemistry. This approach gives a single measurement technique that can assign the absolute configuration and measure the ee.…”

Examining the gas-phase homodimers of 3,3,3-trifluoro-1,2-epoxypropane using quantum chemistry and microwave spectroscopy

“…Recently, the phenomenon of chiral recognition, where the manner of interaction of one chiral species with another depends on the relative handedness of the two, 1,2 is being developed into an analytical tool for the determination of not only enantiomeric excess, but also the absolute stereochemistry of a sample. [3][4][5][6][7][8] This method, known as chiral tagging, relies on the conversion of enantiomers, which have identical microwave rotational spectra, into spectroscopically distinct and readily identifiable diastereomers upon complexation via non-covalent interactions to form a heterodimer with a tag molecule of known chirality.…”