Stereochemistry of Sagittamide A from Residual Dipolar Coupling Enhanced NMR

Schuetz, A.; Junker, J.; Leonov, Andrei; Lange, Oliver; Molinski, Tadeusz F.; Griesinger, Christian

doi:10.1021/ja075876l

Cited by 109 publications

(107 citation statements)

References 18 publications

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“…Although the absolute configuration at C4 and C5 could be derived from the trans-isoa-acid 3 a, the assignment of the neighboring CH 2 moieties in the inherently flexible five-membered rings could not be achieved unambiguously based on conventional scalar coupling analysis, thus leaving the configuration at C1', C2'', and C3' unidentified. To determine the relative chirality of these centers, a number of experiments were performed to measure residual dipolar couplings (RDCs), which recently enabled the successful prochiral assignment [30][31][32][33] and configurational analysis [34][35][36][37][38][39][40] of several organic compounds. Two samples of tricyclocohumol (4 a) were prepared; one was dissolved in [D 6 ]DMSO, and the other one was diffused into a poly(acrylonitrile)/ [D 6 ]DMSO gel, [41][42][43] which was then stretched using the method reported recently [44,45] to obtain partial alignment of the solute.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

Structures of Storage‐Induced Transformation Products of the Beer’s Bitter Principles, Revealed by Sophisticated NMR Spectroscopic and LC–MS Techniques

Intelmann

Kummerlöwe

Haseleu

et al. 2009

Chemistry A European J

108

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Besides undesirable changes in the attractive aroma, a significant decrease in the intensity of the bitterness as well as a change of the taste into a lingering, harsh bitterness has long been known as a shelf-life limiting factor of beer. Multiple studies have demonstrated that the aging of beer induces a decrease of the total amount of cis- and trans-iso-alpha-acids, the well-known bitter principles of beer. Although the trans-iso-alpha-acids exclusively, not the cis-iso-alpha-acids, were found to be degraded upon storage of beer, the key transformation products formed exclusively from the trans isomers in beer are not known. In the present study, suitable model experiments followed by LC-MS/MS and sophisticated NMR spectroscopic experiments, including the measurement of residual dipolar couplings (RDCs) in gel-based alignment media as well as a novel broadband and B(1)-field-compensated incredible natural abundance double-quantum transfer experiment (INADEQUATE) pulse sequence, enabled the identification of a series of previously unknown trans-specific iso-alpha-acid transformation products, namely, tricyclocohumol, tricyclocohumene, isotricyclocohumene, tetracyclocohumol, and epitetracyclocohumol, respectively. HPLC-MS/MS analysis of these compounds, which exhibit the aforementioned harsh lingering bitter taste and have threshold concentrations ranging from 5 to 70 micromol L(-1), confirmed their generation during aging of beer and, for the first time, explained the storage-induced changes of the beer's bitter taste on a molecular level.

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Section: Wwwchemeurjorgmentioning

confidence: 99%

Structures of Storage‐Induced Transformation Products of the Beer’s Bitter Principles, Revealed by Sophisticated NMR Spectroscopic and LC–MS Techniques

Intelmann

Kummerlöwe

Haseleu

et al. 2009

Chemistry A European J

108

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“…The technique involves two steps: residual dipolar coupling (RDC)-enhanced NMR spectroscopy to enable the determination of the conformational ensemble and the relative configuration; [11,12] and subsequent prediction of ORD spectra by DFT calculations to differentiate between enantiomers. Combined, the two steps reveal the absolute configuration of a flexible molecule in solution.…”

Section: Introductionmentioning

confidence: 99%

Bijvoet in Solution Reveals Unexpected Stereoselectivity in a Michael Addition

Sun¹,

d’Auvergne²,

Reinscheid³

et al. 2011

Chemistry A European J

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The absolute configuration of small crystallizable molecules can be determined with anomalous X‐ray diffraction as shown by Bijvoet in 1951. For the majority of compounds that can neither be crystallized nor easily be converted into crystallizable derivatives, stereocontrolled organic synthesis is still required to establish their absolute configuration. In this contribution, a new fundamental methodology for resolving the absolute configuration will be presented that does not require crystallization. With residual dipolar coupling enhanced NMR spectroscopy, ensembles of a limited number of structures are created reflecting the correct conformations and relative configuration. Subsequently, from these ensembles, optical rotation dispersion (ORD) spectra are predicted by DFT calculations and compared to experimental results. The combination of these two steps reveals the absolute configuration of a flexible molecule in solution, which is a big challenge to chiroptical methods and DFT in the absence of NMR spectroscopy. Here the absolute stereochemistry of the product of a new Michael addition, synthesized via a niobium(V) chiral enolate, will be elucidated by using the new methodology.

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“…However, the calculated 15 Table 1). The Δδ( 15 N) of the nonprotonated model (254 ppm) indicated that the positive charge must be compensated.…”

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confidence: 99%

Determining the Absolute Configuration of (+)-Mefloquine HCl, the Side-Effect-Reducing Enantiomer of the Antimalaria Drug Lariam

et al. 2012

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DFG Research Center Molecular Physiology of the Brain (CMPB) and Cluster of Excellence 171 "Microscopy at the Nanometer Range", Goẗtingen, Germany ∥ Department of Pharmaceutical Chemistry, University of Jena, Philosophenweg 14, 07743 Jena, Germany * S Supporting Information ABSTRACT: Even though the important antimalaria drug rac-erythro-mefloquine HCl has been on the market as Lariam for decades, the absolute configurations of its enantiomers have not been determined conclusively. This is needed, since the (−) enantiomer is believed to cause adverse side effects in malaria treatment resulting from binding to the adenosine receptor in the human brain. Since there are conflicting assignments based on enantioselective synthesis and anomalous X-ray diffraction, we determined the absolute configuration using a combination of NMR, optical rotatory dispersion (ORD), and circular dichroism (CD) spectroscopy together with density functional theory calculations. First, structural models of erythro-mefloquine HCl compatible with NMR-derived 3 J HH scalar couplings, 15 N chemical shifts, rotational Overhauser effects, and residual dipolar couplings were constructed. Second, we calculated ORD and CD spectra of the structural models and compared the calculated data with the experimental values. The experimental results for (−)-erythro-mefloquine HCl matched our calculated chiroptical data for the 11R,12S model. Accordingly, we conclude that the assignment of 11R,12S to (−)-erythro-mefloquine HCl is correct.

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Stereochemistry of Sagittamide A from Residual Dipolar Coupling Enhanced NMR

Cited by 109 publications

References 18 publications

Structures of Storage‐Induced Transformation Products of the Beer’s Bitter Principles, Revealed by Sophisticated NMR Spectroscopic and LC–MS Techniques

Structures of Storage‐Induced Transformation Products of the Beer’s Bitter Principles, Revealed by Sophisticated NMR Spectroscopic and LC–MS Techniques

Bijvoet in Solution Reveals Unexpected Stereoselectivity in a Michael Addition

Determining the Absolute Configuration of (+)-Mefloquine HCl, the Side-Effect-Reducing Enantiomer of the Antimalaria Drug Lariam

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