Simultaneous Determination of the Conformation and Relative Configuration of Archazolide A by Using Nuclear Overhauser Effects, J Couplings, and Residual Dipolar Couplings

Abstract

Combine and conquer: Configurational assignment of remote stereogenic centers in the complex polyketide macrolide archazolide A (see structure; red O, blue N, yellow S) was accomplished by a purely NMR‐based approach relying on a combination of nuclear Overhauser effects, J couplings, and residual dipolar couplings (RDCs).

Long‐Range Residual Dipolar Couplings: A Tool for Determining the Configuration of Small Molecules

“…[12][13][14] Additional examples of the determination of the constitution [15] or configuration [4,16] and conformation [17] of molecules by the use of one-bond C-H RDCs ( 1 D CH )extracted from w 1 -or w 2 -coupled HSQC spectra have also been reported. [18] Thea bove-mentioned alignment media lead to an anisotropic orientational order and consequently reintroduce parameters hidden in isotropic solvents,i ncluding RDCs [19] and RCSAs.…”

“…[18] Thea bove-mentioned alignment media lead to an anisotropic orientational order and consequently reintroduce parameters hidden in isotropic solvents,i ncluding RDCs [19] and RCSAs. [20] Theo bservable coupling between ap roton and a 13 Cnucleus located n bonds away is then n T CH = n J CH + n D CH ,i nw hich J is the scalar coupling and D the RDC.T he anisotropic orientational distribution of the compound under alignment conditions is described by the alignment tensor A, [8] which contains five independent elements and therefore requires am inimum of five linearly independent RDCs.I n cases in which too few 1 D CH values can be measured or the CÀHbonds are close to parallel, the five independent RDCs required for the analysis may not be present. As pecial situation may arise in which all diastereoisomers of amolecule with multiple stereogenic centers fit equally well to ap artic- Aspin-flip experiment in aHSQC-based pulse sequence, named SJS-HSQC, [9] was reported for the determination of long-range RDCs for protonated carbon atoms.Although the method is sensitive because of the use of proton excitation and detection, it does not enable the determination of longrange RDCs for non-protonated carbon atoms.H erein, we describe asimple proton-selective 13 C-detected NMR experiment that facilitates the extraction of LR RDCs,i ncluding those of non-protonated carbon atoms.Both methods exhibit doublet splitting in the indirect dimension as n D CH without homonuclear coupling and provide higher accuracy in their measurement.…”

“…Refocusing of the chemical shifts during t 1 results in as imple 2D spectrum with cross-peaks split by the heteronuclear coupling in the indirect dimension. If as ingle proton is selectively excited, the result is adoublet for its longrange coupled 13 Cn uclei centered at w 1 with their respective chemical shifts in w 2 .T he absolute value of the coupling without its sign, j n T CH i j ,ismeasured as the line splitting in the indirect dimension. Since the proton magnetization is transmitted through j n T CH i j to the carbon nuclei, the method enables the measurement of long-range coupling to quaternary and non-protonated carbon atoms.…”

“…Although the proton resonance of H i needs to be selectively inverted, as ignificant advantage is that several protons can be inverted simultaneously,provided that they do not share acommon 13 Ccoupling partner.Multiplexing in this way makes it possible to reduce the number of experiments required. Usually the constitution of am olecule is known before the conformation and configuration are determined.…”

“…Owing to 13 Cd etection, the performance of the method at lower magnetic fields is not significantly affected by decreased spectral resolution and sensitivity.E xperimental errors in the measurement of RDCs are calculated as the standard deviation of 10 separately measured peak positions from the noise-added signals.…”