A chiroptical approach for the absolute stereochemical determination of <i>P</i>-stereogenic centers

Chakraborty, Debarshi; Gholami, Hadi; Sarkar, Aritra; Joyce, Leo A.; Jackson, James E.; Borhan, Babak

doi:10.1039/d0sc02940h

“…The two enantiomeric conformers of 15 rapidly interconvert at room temperature via rotation about the pivotal axis and the mixture remains racemic and therefore chiroptically inactive in the absence of a chiral bias. A chiral amine, [119] sulfoxide, [120] cyanohydrin, [121] or phosphine oxide [122] that diffuses into the cleft may undergo either hydrogen bonding with the phenol groups, coordination to the zinc centers or a combination of both. Importantly, the binding event disturbs the racemic equilibrium and shifts the axial chirality of 15 either toward the P or the M ‐conformation, resulting in strong ECCD signals at long wavelengths that allow non‐empirical assignment of the absolute configuration of the guest molecule with rationally developed and computationally verified mnemonics.…”

Section: Absolute Configuration Analysismentioning

confidence: 99%

Circular Dichroism Sensing: Strategies and Applications

Formen,

Howard,

Anslyn

et al. 2024

Angewandte Chemie

0

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The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high‐throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer‐generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi‐well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small‐molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high‐throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

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“…Gratifyingly, complexation of a variety of phosphorus oxide molecules with Zn-MAPOL 82 did not disappoint and resulted in strong and interpretable ECCD signals (Figure 15). 65 Based on the data obtained for binding of various asymmetric phosphorus oxide substrates with Zn-MAPOL 82, a mnemonic is proposed as depicted in Figure 15. The coordination of the polar P−O bond to the zinc center places the substrates in the cavity of the host Zn-MAPOL 82.…”

Section: Determination Of Absolute Configuration Of Chiral Phosphine ...mentioning

confidence: 99%

“…The generality of this system was demonstrated with the analysis of Sofosbuvir 102 , a commercial antiviral agent, widely used for the treatment of hepatitis C virus. , The phosphorus oxide moiety in Sofosbuvir 102 is embedded in a complex setting. The host Zn-MAPOL 82 was able to detect the asymmetry of the P-stereogenic center in the presence of other chiral centers and heteroatoms.…”

Section: Determination Of Absolute Configuration For Molecules With O...mentioning

confidence: 99%

Absolute Stereochemical Determination of Organic Molecules through Induction of Helicity in Host–Guest Complexes

Gholami

¹

,

Chakraborty

²

,

Zhang

³

et al. 2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Stereochemistry is a fundamental molecular property with important ramifications for structure, function, and activity of organic molecules. The basic building blocks of living organisms (amino acids and sugars) exhibit a precisely selected set of molecular handedness that has evolved over millions of years. The absolute stereochemistry of these building blocks is manifested in the structure and function of the cell machinery (e.g., enzymes, proteins, etc.), which are essential components of life. In the many chemical subdisciplines, molecular stereochemistry is exceedingly important and is often a strong determinant of structure and function. Besides its biological implications, the centrally important role of stereochemistry in many disciplines of chemistry and related fields has led to tremendous effort and activity, highlighted by the success in stereoselective syntheses of a host of functionalities. In the present climate, it is often the difficulty of assigning absolute stereochemistry as opposed to synthesis, which has become a nontrivial challenge, requiring the attention of the community. There will not be a general solution to this problem, as each system will have its own unique requirements and challenges; however, the need for rapid, routine, and microscale analysis is apparent. This is especially true with parallel and high-throughput arrays for screening conditions and catalysts, generating a large number of samples that require analysis.In this Account, we summarize our contribution to this field through the development of molecular receptors for sensing molecular asymmetry. These methodologies strive to unambiguously assign the absolute configuration of asymmetric center(s). To accomplish this task, our laboratory has designed a variety of host molecules, bearing various binding elements, to form stable complexes with chiral molecules (guests). During this complexation event, the stereochemistry of a target molecule induces a supramolecular chirality (i.e., helicity) within the host system. The design of the host system is such that the helicity of the host/guest complex can be observed and assigned via Exciton Coupled Circular Dichroism (ECCD), a nonempirical technique for identifying handedness, which is correlated back to the absolute stereochemistry of the bound chiral molecule. Taking advantage of the high sensitivity of chiroptical techniques (in terms of the required amount of sample for analysis) and fast response time, these methodologies offer a microscale, rapid, and nonempirical solution for assignment of absolute stereochemistry.The first part of this Account describes application of porphyrin tweezers as reporters of chirality for the absolute stereochemical determination of various classes of organic molecules. This methodology is suitable to report the absolute configuration of organic molecules that contain two binding elements (nitrogen or oxygen based functionalities). In the second part, host systems that do not require two sit...

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Circular Dichroism Sensing: Strategies and Applications

Formen,

Howard,

Anslyn

et al. 2024

Angew Chem Int Ed

9

0

View full text Add to dashboard Cite

The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high‐throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer‐generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi‐well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small‐molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high‐throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

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A chiroptical approach for the absolute stereochemical determination of P-stereogenic centers

Abstract: A simple chiroptical solution for the absolute stereochemical determination for asymmetric phosphorus V stereocenters is presented.

Cited by 3 publications

References 47 publications

Circular Dichroism Sensing: Strategies and Applications

Circular Dichroism Sensing: Strategies and Applications

Absolute Stereochemical Determination of Organic Molecules through Induction of Helicity in Host–Guest Complexes

Circular Dichroism Sensing: Strategies and Applications

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