Unequivocal identification of two-bond heteronuclear correlations in natural products at nanomole scale by i-HMBC

• Published in: Nature communications Vol. 14; no. 1; pp. 1842 - 11
• Main Authors: Wang, Yunyi, Fan, Aili, Cohen, Ryan D., Dal Poggetto, Guilherme, Huang, Zheng, Yang, Haifeng, Martin, Gary E., Sherer, Edward C., Reibarkh, Mikhail, Wang, Xiao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 140/131; 639/638/11/878/1263; 639/638/403/936; Correlation; Humanities and Social Sciences; multidisciplinary; Natural products; NMR; Nuclear magnetic resonance; Organic chemistry; Science; Science (multidisciplinary); Sensitivity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37289-z

HMBC is an essential NMR experiment for determining multiple bond heteronuclear correlations in small to medium-sized organic molecules, including natural products, yet its major limitation is the inability to differentiate two-bond from longer-range correlations. There have been several attempts to address this issue, but all reported approaches suffer various drawbacks, such as restricted utility and poor sensitivity. Here we present a sensitive and universal methodology to identify two-bond HMBC correlations using isotope shifts, referred to as i-HMBC (isotope shift detection HMBC). Experimental utility was demonstrated at the sub-milligram / nanomole scale with only a few hours of acquisition time required for structure elucidation of several complex proton-deficient natural products, which could not be fully elucidated by conventional 2D NMR experiments. Because i-HMBC overcomes the key limitation of HMBC without significant reduction in sensitivity or performance, i-HMBC can be used as a complement to HMBC when unambiguous identifications of two-bond correlations are needed. The inability to distinguish two-bond from long-range HMBC correlation has historically impeded NMR structure elucidation. Here the authors developed a practical iHMBC methodology utilizing accurate isotope shift measurement to overcome this limitation.