Residual Dipolar Couplings as a Powerful Tool for Constitutional Analysis: The Unexpected Formation of Tricyclic Compounds

Kummerlöwe, Grit; Crone, Benedikt; Kretschmer, Manuel; Kirsch, Stefan F.; Luy, Burkhard

doi:10.1002/anie.201007305

Cited by 84 publications

(78 citation statements)

References 40 publications

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“…[7][8][9] The break-through in this field was the concept of using an alignment medium to transfer weak molecular ordering to arbitrary molecules of interest. Indeed, development of weak alignment media and measurement methods over nearly two decades has led to a boom in the utilization of anisotropic NMR data, particularly RDCs, as a generally applicable NMR parameter for small molecule applications [10][11][12][13][14][15] and for structural and dynamics studies of bio-molecules. 3,[16][17][18][19] As noted above, a critical component of the RDC/RCSA technology is the alignment medium used for molecular ordering.…”

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confidence: 99%

“…13 C RCSAs obtained with stretching and compression devices. Stretching device: Panels a-d show three resonances extracted from the 13 C-{ 1 H} 150 MHz NMR spectra of estrone in the narrow (blue color)) and wide ( red) sections.…”

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confidence: 99%

“…44 Then a new quality factor, QCSA, is calculated by scaling both experimental and back-calculated ΔRCSAs by corresponding atom's chemical shift anisotropies, using the formula given below, where CSAi,ax equals 33-(22+11)/2 and the chemical shielding Eigen-values σ11-33 are obtained from DFT.As an initial proof of concept, we collected RCSA and RDC data for strychnine using both the stretching and compression devices. Twenty 13 C RCSAs were measured from the stretching device through chemical shift differences in 1D13 C-{ 1 H} 150 MHz spectra collected under two alignment conditions (Figure. S1).…”

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Determination of Relative Configuration from Residual Chemical Shift Anisotropy

et al. 2016

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Determination of relative configuration is frequently a rate-limiting step in the characterization of small organic molecules. Solution NMR-based nuclear Overhauser effect and scalar J-coupling constants can provide useful spatial information but often fail when stereocenters are separated by more than 4-5 Å. Residual dipolar couplings (RDCs) can provide a means of assigning relative configuration without limits of distance between stereocenters. However, sensitivity limits their application. Chemical shift is the most readily measured NMR parameter, and partial molecular alignment can reveal the anisotropic component of the chemical shift tensor, manifested as residual chemical shift anisotropy (RCSA). Hence, (13)C RCSAs provide information on the relative orientations of specific structural moieties including nonprotonated carbons and can be used for stereochemical assignment. Herein, we present two robust and sensitive methods to accurately measure and apply (13)C RCSAs for stereochemical assignment. The complementary techniques are demonstrated with five molecules representing differing structural classes.

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Determination of Relative Configuration from Residual Chemical Shift Anisotropy

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“…[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.…”

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

2015

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Together with NOE and Jcoupling,o ne-bond residual dipolar coupling (RDC), whichr eports on the threedimensional orientation of an internuclear vector in the molecular frame,plays an important role in the conformation and configuration analysis of small molecules in solution by NMR spectroscopy. When the molecule has few C À Hbonds,or too many bonds are in parallel, the available RDCs may not be sufficient to obtain the alignment tensor used for structure elucidation. Long-range RDCs that connect nuclei over multiple bonds are normally not parallel to the single bonds and therefore complement one-bond RDCs.H erein we present am ethod for extracting the long-range RDC of ac hosen proton or group of protons to all remotely connected carbon atoms,i ncluding non-protonated carbon atoms.A lignment tensors fitted directly to the total long-range couplings (T = J + D) enabled straightforwardanalysis of both the long-range and one-bond RDCs for strychnine.

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“…23 Particularly, the iodocyclization of enyne derivatives (and related compounds such as o-(alkynyl)styrenes) has received very little attention. The work of S. F. Kirsch and co-workers on the 6-endo iodocyclization of 1,5-enynes [24][25][26][27] and 5-and 6-exo iodocyclization of 1,6-enynes 26,28 should be remarked upon at this point. In this context, we have recently reported pioneering preliminary results regarding the 5-endo iodocyclization reaction proposed in Scheme 1b for the synthesis of 1H-indenes.…”

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Synthesis of Functionalized 1H-Indenes and Benzofulvenes through Iodocyclization of o-(Alkynyl)styrenes

et al. 2016

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ABSTRACT:A convenient method for the preparation of synthetically useful 3-iodoindene derivatives has been developed. This protocol, based on the 5-endo iodocyclization reaction of o-(alkynyl)styrenes, represents one of the scarce examples of halocyclizations using olefins as nucleophilic counterparts, and allows the synthesis of both 3-iodo-1H-indenes (from β-alkyl-β-alkyl/aryl o-(alkynyl)styrenes) and 3-iodobenzofulvenes (from β,β-diaryl o-(alkynyl)styrenes) in good yields under mild reaction conditions. Besides, related alkoxyiodocyclization processes are described, which are particularly interesting in their intramolecular version because they allow the synthesis of heteropolycyclic structures containing the indene core. Finally, the usefulness of the prepared 3-iodoindenes has been demonstrated by the synthesis of several polysubstituted indene derivatives through conventional palladium−catalyzed cross-coupling reactions and iodine−lithium exchange processes.

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Residual Dipolar Couplings as a Powerful Tool for Constitutional Analysis: The Unexpected Formation of Tricyclic Compounds

Cited by 84 publications

References 40 publications

Determination of Relative Configuration from Residual Chemical Shift Anisotropy

Determination of Relative Configuration from Residual Chemical Shift Anisotropy

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

Synthesis of Functionalized 1H-Indenes and Benzofulvenes through Iodocyclization of o-(Alkynyl)styrenes

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