The standard experiments, HMQC, HMBC, COSY and TOCSY are frequently not sufficient to solve complex structural problems. An impasse arises because there is no easy way to distinguish the cabons that are 2, 3 and 4 bonds away from the correlated protons in an HMBC spectrum. This problem occurs because the long range CH coupling constant nJCH has no simple relationship with the number of intervening bonds (n) between the carbon and the proton. The best way of mapping the carbon backbone, 2D INADEQUATE is usually impractical because a large amount of material (>1OO mg) is required. INADEQUATE works because 1JCC is much larger than nJCC, and almost all magnetization is transfered between adjacent carbons. There is an alternative technique that is practical for mapping that part of the carbon backbone that is protonated. It is called HMQCTOCSY and combines two very useful experiments. The HMQC part of the experiment correlates protons with their directly bound carbons and the TOCSY part of the experiment then relays the magnetisation around the proton spin system. The extent of the relay is dependent on the length of mixing time in the TOCSY experiment. Transfer between vicinal and geminal protons will almost always occur before protons separated by 4 and 5 bonds and thus neighbouring CH fragments can be unambiguously identified by properly tuning the mixing time. The diagram below illustrates the information that can be gained from the common types of inverse heteronuclear experiments. carbon proton relay diagram

The Problem:

Identify the C11-C11a and C15-C16-C16a fragments in the natural product, drimentine D.

drimentine D spectrum

The Solution:

Each carbon resonance has crosspeaks at the resonance of the directly bonded proton (negative crosspeak) and at the resonances of other protons in the same spin system (positive crosspeaks). The spin systems of C11-C11a and C15-C16-C61a are illustrated by lines connecting the crosspeaks in the spectrum above. A mixing time was chosen in this example to illustrate several relays through the proton spin system. Notice that each spin system is broken by quaternary carbons. HMBC is required to connect the adjacent fragments mapped out by HMQCTOCSY.

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