Application Of Residual Dipolar Couplings To The Structural Analysis Of Organic Molecule And Enantiodiscrimination In NMR Spectroscopy

Structural elucidation of natural and synthetic molecules,in particular,the stereochemical problems remains a challenging task in the field of bio-organic and medicinal chemistry.Although the constitution and spatial structure of most organic molecules can be determined using a combination of three well-established classical NMR parameters,such as chemical shift(?),nuclear Overhauser enhancement(NOE)and 3J-coupling constants,the conventional NMR experiments cannot always provide a perfect solution for the chemist due to several limitations.As a valuable and complementary NMR structural parameter,residual dipolar coupling(RDC)has recently become increasingly important in organic structure determination due to their unique information content.However,the application of RDC analysis to small molecules has developed much more slowly compared to the widespread use in biological macromolecular NMR spectroscopy,in large part due to the absence of appropriate alignment media that are compatible with organic solvents.In this context,the major goal of our research in the field was the development of simple and practical aligned solutes as alignment media.The ongoing study has been enriched the kinds of alignment media and play an important role in expanding upon the applications of RDC analysis for organic molecules and have significant values in theory and application.The main contents include the following parts:Part ?:This review focuses on the measurement and application of RDC on small organic molecule.We discuss the different ways of partially orienting molecules and how to scale their alignment properties in order to get ideal measurement conditions.Finally,we complete the overview of the recent developments in the use of RDC for the simultaneous determination of 3D structure of natural products.Part ?:We have synthesized and examined the propensity of designed helical polyisocyanopeptides to form lyotropic liquid crystalline(LLC)phases in apolar organic solvents.To our delight.the tunable concentration of L,L-PIAF-OBn LC assemblies thus formed could be kept even at low concentrations in CDCl3.The applications for the determination one-bond RDCs in strychnine and triptolide have been demonstrated.The plots of experimental versus back-calculated RDC of X-ray structure show excellent correlations.Remarkably,significant RDC differences in the enantiomeric pair of isopinocampheol(IPC)revealed it as a promising candidate as an enantio-differentiating alignment medium.This work represents the first example of a polymeric LLC which is stable at extremely low critical concentration.Importantly,the excellent solubility and intrinsic low viscosity allowed us to acquire good quality NMR spectra with narrow lines.Part III:The enantiodiscrimination of small organic molecules remains an arduous task by RDC-based strategy in non-racemic oriented medium.The new isocyanide-based helical polymers poly-L-4 and its opposite-handed poly-D-4 were developed as complementary alignment media for measurement of RDCs in chloroform.The enantiodiscriminating properties of poly-L-4/poly-D-4 alignment media have been investigated by employing enantiomeric pairs of IPC,single enantiomer of natural products(+)-artemisinin and(-)-dendrobine.The remarkable RDC differences in chiral molecule revealed the enantiomer-differentiating property of the LLC alignment medium.The desired sizes of the measured RDC of chiral molecules were observed.The faster data collection and better measurement accuracy will make the determination and the application of RDC to solve stereochemical aspects in small molecules more efficiently.Part IV:NMR spectroscopy has proven to be a powerful and versatile tool for the discrimination of chiral molecules and the precise measurement of enantiomeric contents.In this chapter,we have developed the proline-derived diphenylprolinols and tested their efficacy as chiral solvating agents(CSAs)in1 H NMR spectroscopy to discriminate carboxylic acids.A linear relationship has been observed between the experimental and observed values of ee indicating the possible use of these compounds for quick and reliable analysis of enantiomerically enriched samples of mandelic acid.Therefore,this result provides a new insight to refining and expanding the applications of the existing chiral solvating agents for pharmaceutical analysis.