The use of indirectly bonded ¹³C‐¹H (INCH) shift correlation spectra for ab initio structure elucidation of natural products and other complex organic compounds; A personal and historical perspective

Abstract

This article reviews the use of long-range shift correlation spectra for structure elucidation of natural products and other complex organic compounds from the early 1980's to the present. Much of it is written from the personal viewpoint of someone who has been involved in this area of research since its earliest days. The first section covers the early use of long-range correlation spectra in the 1980's. The second section covers the development of specialized pulse sequences for this type of acquisition. It begins with three 13 C-detected sequences, followed by heteronuclear multiple bond correlation (HMBC) and some modified versions of HMBC and, finally, longer range correlation sequences based on the heteronuclear single quantum multiple bond correlation sequence. The third section covers various sequences designed to distinguish between 2-bond and longer range 13 C-1 H correlations. Unfortunately, none of these can make this distinction for non-protonated carbons. Only the 1,1-ADEQUATE sequence can make this distinction but its very low sensitivity limits its usefulness. The next section focuses on ways of avoiding getting incorrect structures of organic compounds, an ongoing problem in natural product research. The last section includes likely shortterm developments and possible long-term developments in NMR methodology that would be beneficial for small molecule structure elucidation. K E Y W O R D S 1,1-ADEQUATE, constant-time inverse-detection gradient accord rescaled, correlation by long-range coupling constants, FLOCK, heteronuclear 2-bond correlation, heteronuclear multiple bond correlation, heteronuclear single quantum multiple bond correlation, long-range 13 C-1 H correlation spectra, structure elucidation, X-nucleus CORrelation with Fixed Evolution time

Minimizing the risk of deducing wrong natural product structures from NMR data

“…Methyl proton singlets are particularly useful for natural product structure elucidation because the non-protonated carbons to which the methyl groups are bonded often form the junctions between two different rings. Also, during our past investigations of structures of hundreds of natural products, [18] methyl protons have always shown all of the expected two-bond and three-bond HMBC correlations for the final deduced structure and these peaks have consistently been among the strongest peaks in HMBC spectra. On the other hand, four-bond methyl peaks, if observed at all, have always been much weaker.…”

“…[16] A key further development in 1984 was the demonstration that combinations of 1 H-1 H (COSY) spectra [17] and one-bond and n-bond (n = 2 or 3) 1 H- 13 C shift-correlation spectra could be used to determine the skeletal structures of natural products and other complex organic molecules. [18] The same basic approach that was first proposed in 1984 is still widely used today, except that the earlier 13 C-detected sequences have been replaced by more sensitive 1 H-detected sequences. For example, a combination of COSY spectra [17] and HSQC spectra [19] can be used to deduce molecular fragments composed of sequences of protonated carbons.…”

“…In that case, an n-bond 1 H- 13 C shift correlation spectrum (n > 1) can be used to determine possible ways in which to combine the different fragments into a complete skeletal structure. [18] This information is now usually obtained using the HMBC sequence. [20,21] Information about the 3D geometry of a proposed structure can often be deduced by using vicinal 1 H-1 H coupling constant data [22] together with nuclear Overhauser enhancement (nOe) data.…”

“…[83] In Figure 9, the H2BC and HMBC spectra for 2-bromophenol,15, illustrate the complementary nature of these two spectra in this situation. [18] However, because H2BC spectra rely on 1 J CH coupling constants, no correlation peaks are observed for nonprotonated carbons. Thus, H2BC cannot be used in place of HMBC.…”