Triplet NOAH supersequences optimised for small molecule structure characterisation

Abstract

A series of NMR supersequences are presented for the time‐efficient structure characterisation of small molecules in the solution state. These triplet sequences provide HMBC, HSQC, and one homonuclear correlation experiment of choice according to the NMR by Ordered Acquisition using 1H detection principle. The experiments are demonstrated to be compatible with non‐uniform sampling schemes and may be acquired and processed under full automation.

New NOAH modules for structure elucidation at natural isotopic abundance

“…Whilst the MBSC configuration of the NOAH modules is possible, it is advantageous to start the NOAH supersequences with the least sensitive experiment. Although the 15 N HMQC is by a factor of ~3 less sensitive as compared to an equivalent 13 C experiment, the…”

“…The basic set of experiments that are generally employed for structure elucidation of small organic molecules include 13 C-1 H HSQC, 13 C-1 H HMBC and 1 H-1 H COSY. Therefore, the NOAH-3 SBC and the favoured BSC supersequences can be used for structure elucidation in a single measurement.…”

“…Typically, one-bond correlation techniques provide direct connectivity information, long-range correlations connect molecular fragments and through-space dipolar couplings provide supplementary stereochemical (3D) information [5][6][7]. Three basic NMR experiments -HSQC, HMBC and COSY are usually employed to obtain information about one-bond X-H (HSQC), long range X-H (HMBC) and three-bond H-H (COSY) connectivities (X = 13 C and 15 N). Additional experiments, such as NOESY, ROESY, TOCSY, DQF-COSY, HMQC, H2BC, HSQC-TOCSY and occasionally 1,1-ADEQUATE (or its variants) are also used to obtain complementary information when the basic experiments prove to be insufficient for structure elucidation purposes.…”

“…While the INADEQUATE experiment in the PANACEA pulse scheme is one of the most powerful techniques for structure elucidation of small molecules, at natural isotopic abundance it is also one of the least sensitive small molecule NMR experiments. Alternatively, the NOAH (NMR by Ordered Acquisition using 1 H detection) supersequences [11][12][13][14] are constructed from the basic and more sensitive 1 H-detected experiments (modules) that are typically used for small molecule analysis and structure elucidation. Such supersequences not only provide significant time savings and often a superior sensitivity per unit time, but they also ensure that all spectra are recorded under identical experimental conditions thus eliminating inter-experiment variability and associated signal assignment ambiguities.…”

Software for reconstruction of nonuniformly sampled NMR data

“…First, the level of sparsity is crucial as spectra with different dynamic ranges often require different sampling density. For spectra with low dynamic range of intensities as spectra of small molecules 44,45 and triple resonance experiments for protein backbone assignment where the peaks typically are of similar intensity and the peak positions are of higher importance, less points are required, and assertive sample schemes covering only 30% for a 2D spectrum and 10% for a 3D spectrum can be utilized without greatly compromising the spectral quality. For higher dynamic range spectra, such as the NOESY experiment or relaxation measurements, where the intensities of the peaks are crucial, more points are to be sampled.…”