Using HMBC and ADEQUATE NMR Data To Define and Differentiate Long-Range Coupling Pathways: Is the Crews Rule Obsolete?

Abstract

It is well known that as molecules become progressively more proton-deficient, structure elucidation becomes correspondingly more challenging. When the ratio of (1)H to (13)C and the sum of other heavy atoms falls below 2, an axiom that has been dubbed the "Crews rule" comes into play. The general premise of the Crews rule is that highly proton-deficient molecules may have structures that are difficult, and in some cases impossible, to elucidate using conventional suites of NMR experiments that include proton and carbon reference spectra, COSY, multiplicity-edited HSQC, and HMBC (both (1)H-(13)C and (1)H-(15)N). However, with access to modern cryogenic probes and microcyroprobes, experiments that have been less commonly utilized in the past and new experiments such as inverted (1)J(CC) 1,n-ADEQUATE are feasible with modest sized samples. In this light, it may well be time to consider revising the Crews rule. The complex, highly proton-deficient alkaloid staurosporine (1) is used as a model proton-deficient compound for this investigation to highlight the combination of inverted (1)J(CC) 1,n-ADEQUATE with 1.7 mm cryoprobe technology.

Evaluating Nitrogen-Containing Biosynthetic Products Produced by Saltwater Culturing of Several California Littoral Zone Gram-Negative Bacteria

“…The so-called Crews rule 22 is often cited in discussing difficulties in assigning a final structure in such situations based only on 2D NMR data. We first commented on this circumstance in 2007 23 and must now briefly revisit the conclusion that the Crews rule is obsolete 24 in view of new 2D NMR experiments such as the inverted 1 J CC 1, n -ADEQUATE. 25 We disagree with that idea because this and other 2D NMR data on hydrogen-deficient compounds will not always provide an unequivocal outcome and the entries collected in Figure S15 26 provide case examples, especially for counts of H/(C + Z) < 0.45.…”

Application of INADEQUATE NMR techniques for directly tracing out the carbon skeleton of a natural product

“…South African Drimiopsis maculate, proved difficult to elucidate due to absence of correlating protons within the NMR spectra, yet another example where the Crew's rule becomes apparent. 16,60 Consequently, INADEQUATE spectra were used to confirm the structures of these previously unreported xanthones, e.g. drimiopsin A (11) (Figure 3) within the family Hyacinthaceae.…”

Metabolic profiling as a tool for prioritizing antimicrobial compounds

“…This partly arises from the inherent challenges of differentiating two-bond heteronuclear (H ⇢ C, 2 J CH ) correlations from three-bond correlations ( 3 J CH ) in the HMBC spectrum. In addition, as HMBC normally just provides 2 J CH and 3 J CH but rarely 4 J CH correlations, structure elucidation becomes progressively challenging the more molecules become proton-deficient [ 104 ]. To address these problems, many other approaches have been tried such as combined HSQC-TOCSY [ 61 ].…”