Configuration verification via RDCs on the example of a tetra‐substituted pyrrolidine ring

Abstract

The configurational analysis of organic compounds is an important application for high resolution NMR spectroscopy. In the present study, a tetra-substituted pyrrolidine with four chiral carbon atoms is analyzed using classical methods based on (3) J and NOE data in solution and compared and verified with recently introduced alternative approaches via residual dipolar couplings (RDCs) in two weak anisotropic alignment media. The molecule shows sufficient rigidity in the five-membered ring for the configurational characterization with the various techniques. However, the flexibility caused by the many freely rotating bonds potentially poses problems for the interpretation of data. It is shown that RDCs measured in poly-γ-benzyl-l-glutamate and a stretched polydimethylsiloxane gel provide useful information for the distinction of diastereomers, but the success varies with the data interpretation strategy used. Although a general improvement of corresponding correlation factors is observed when limiting data to a subset of dipolar couplings directly connected to the central ring, the distinction power is reduced because of the smaller number of RDCs available for potential model falsification. Singular value decomposition for fitting experimental RDCs is able to distinguish in most cases the correct from incorrect configurations, but the differences in correlation factors can be relatively small. Surprisingly, predicting RDCs using the rod model as implemented in PALES gives best results in distinguishing the eight possible diastereomers. It is also found that the use of proton-phosphorus and carbon-phosphorus RDCs helps with the configurational analysis of the model compound.

Training Schrödinger’s cat: quantum optimal control

“…Early examples are the CLIP-HSQC [386] and P.E.HSQC [387] for the measurement of one-bond and geminal couplings as well as more recent experiments involving homonuclear decoupling [388] and the rapid acquisition of heteronuclear correlation experiments [389]. All these experiments are of special interest as they are recorded in large numbers every day in chemical laboratories and improvements in robustness, accuracy, or acquisition time are of high interest.…”

P.E.HSQMBC: Simultaneous measurement of proton–proton and proton–carbon coupling constants

“…1. They combine the main features of three different older methods in a single experiment: (a) the accurate measurement of 1 J(CH) along the indirect dimension from F1-coupled HSQC schemes [22][23][24][25]; (b) the sign-sensitive measurement of 1 J(CH) and 2 J(HH) in E.COSY multiplets as reported in the P.E.HSQC experiment [17], and (c) the precise measurement of n J(CH) using the IPAP technology in sel-HSQMBC experiments [11]. For the present work, we have chosen the general application of selective 180°1H pulses as a refocusing element in the INEPT block because this affords pure-phase multiplets and completely avoids any signal modulation due to J(HH).…”

“…As described in the original P.E.HSQC experiment [17], instead of the long phase cycling schemes used in classical experiments, a simple small-angle pulse is used to generate the E.COSYlike pattern (Fig. 1A).…”

“…This pathway provides all direct correlations showing antiphase pattern with respect to 1 J(CH) in both dimensions independently of the selective nature of the INEPT block and therefore, the measurement of the sign and the magnitude of all 1 J(CH) and 2 J(HH) couplings can be performed as exactly described for the regular P.E.HSQC experiment [17].…”

“…Several E.COSY-type methods have been proposed for the simultaneous measurement of different scalar and residual dipolar couplings in small molecules. For instance, a simple and sensitive P.E.HSQC experiment, closely related to a fully coupled non-refocused HSQC pulse scheme, has been proposed to determine the sign and the magnitude of one-bond proton-carbon ( 1 J(CH) and 1 D(CH)) and two-bond proton-proton ( 2 J(HH) and 2 D(HH)) coupling constants from a single 2D spectrum [17]. Recently a spin-flip HSQC experiment has also been proposed for the simultaneous measurement of J(HH) and n J(CH) [18].…”