Long-range Proton-carbon Coupling Constants Research Articles

Long-range proton–carbon coupling constants for the determination of the stereochemical structure of organic compounds.

A new methods for elucidating stereochemistry of organic compounds was developed on the basis of long-range proton–carbon coupling constants (2,3JC,H) and interpreting spin-coupling constants (3JH,H). Reaction of compound containing pyrin ring with nucleophile reagent was done to open the ring. HSQC-TOCSY experiments one of the new NMR spectroscopy method used to measure this values of spin-coupling constants and elucidating the stereochemistry of the product.

How to measure long-range proton-carbon coupling constants from 1 H-selective HSQMBC experiments.

Heteronuclear long-range scalar coupling constants (n JCH ) are a valuable tool for solving problems in organic chemistry and are especially suited for stereochemical and configurational analyses of small molecules and natural products. This tutorial will focus on the step-by-step implementation of several 2D 1 H frequency selective HSQMBC experiments for the easy and accurate measurement of either the magnitude or both the magnitude and the sign of long-range n JCH couplings. The performance of these experiments will be showcased with several scenarios in a range of different experimental conditions.

Synthesis of new cyano-substituted analogues of Tröger's bases from bromo-derivatives. A stereochemical dependence of long-range (n JHH , n=4, 5, and 6) proton-proton and proton-carbon (n JCH , n=1, 2, 3, 4, and 5) coupling constants of these compounds.

A free-catalyst microwave-assisted cyanation of brominated Tröger's base derivatives (2a-f) is reported. The procedure is simple, efficient, and clean affording the nitrile compounds (3a-e, I) in very good yields. Complete assignment of 1 H and 13 C chemical shifts of 2a-f, I and 3a-d, I was achieved using gradient selected 1D nuclear magnetic resonance (NMR) techniques (1D zTOCSY, PSYCHE, DPFGSE NOE, and DEPT), homonuclear 2D NMR techniques (gCOSY and zTOCSY), and heteronuclear 2D NMR techniques (gHSQCAD/or pure-shift gHSQCAD, gHMBCAD, bsHSQCNOESY, and gHSQCAD-TOCSY) with adiabatic pulses. Determination of the long-range proton-proton coupling constants n JHH (n=4, 5, 6) was accomplished by simultaneous irradiation of two protons at appropriate power levels. In turn, determined coupling constants were tested by an iterative simulation program by calculating the 1 H NMR spectrum and comparing it to the experimental spectrum. The excitation-sculptured indirect-detection experiment (EXSIDE) and 1 H-15 N CIGARAD-HMBC (constant time inverse-detection gradient accordion rescaled heteronuclear multiple bond correlation) were applied for determination of long-range carbon-proton coupling constants n JCH (n=2, 3, and 4) and for assignment of 15 N chemical shift at natural abundance, respectively. DFT/B3LYP optimization studies were performed in order to determine the geometry of 2c using 6-31G(d,p), 6-311G(d,p), and 6-311+G(d,p) basis sets. For calculation of 1 H and 13 C chemical shifts, n JHH (n=2, 3, 4, 5, and 6), and n JCH (n=1, 2, 3, and 4) coupling constants, the GIAO method was employed at the B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), B3LYP/6-311+G(d,p), B3LYP/6-311++G(2d,2p), B3LYP/cc-pVTZ), and B3LYP/aug-cc-pVTZ) levels of theory. For the first time, a stereochemical dependence magnitude of the long-range n JHH (n=4, 5, and 6) and n JCH (n=1, 2, 3, 4, and 5) have been found in bromo-substituted analogues of Tröger's bases.

CLIP-HSQMBC: easy measurement of small proton–carbon coupling constants in organic molecules

A user-friendly 2D NMR approach denoted as CLIP-HSQMBC is proposed for the very easy, direct and accurate measurement of long-range proton-carbon coupling constants in organic molecules and natural products. The J value can be extracted directly from the analysis of resolved in-phase (1)H multiplets that show an additional splitting arising from the proton-carbon coupling. In cases of unresolved peaks, a simple fitting analysis using the internal satellite lines as a reference is performed. Addition of a spin-lock period results in a CLIP-HSQMBC-TOCSY experiment that is suitable for the measurement of very small coupling values or to observe correlations from overlapped resonances.

P.E.HSQMBC: Simultaneous measurement of proton–proton and proton–carbon coupling constants

A long-range optimized P.E.HSQC experiment, named P.E.HSQMBC, is proposed for the simultaneous measurement of a complete set of homonuclear and heteronuclear coupling constants from a single 2D cross-peak. The sign and the magnitude of proton–proton coupling constants are measured along the direct dimension from the relative E.COSY-type multiplet pattern displacement due to the passive one-bond coupling constant splitting generated in the indirect dimension. On the other hand, long-range proton–carbon coupling constants are independently determined in the detected dimension from a traditional fitting analysis of antiphase multiplet patterns or, more conveniently, from the IPAP multiplet displacement obtained from extended HSQMBC experiments.

Efficient measurement of the sign and the magnitude of long‐range proton‐carbon coupling constants from a spin‐state‐selective HSQMBC‐COSY experiment

A spin state-selective Heteronuclear Single-Quantum Multiple-Bond Connectivities (HSQMBC-COSY) experiment is proposed to measure the sign and the magnitude of long-range proton-carbon coupling constants ((n)J(CH); n > 1) either for protonated or for non-protonated carbons in small molecules. The simple substitution of the selective 180° (1)H pulse in the original selHSQMBC pulse scheme by a hard one allows the simultaneous evolution of both proton-proton and proton-carbon coupling constants during the refocusing period and enables a final COSY transfer between coupled protons. The successful implementation of the IPAP principle leads to separate mixed-phase α/β cross-peaks from which (n)J(CH) values can be easily measured by analyzing their relative frequency displacements in the detected dimension.

Accurate measurement of small heteronuclear coupling constants from pure-phase α/ β HSQMBC cross-peaks

A simple proton-selective α/ β-HSQMBC experiment is proposed for the accurate measurement of long-range proton–carbon coupling constants ( n J CH) in small molecules without need for an individualized and time-consuming post-processing fitting procedure. The method acquires two pure-phase In-phase (IP) and Anti-phase (AP) multiplets completely free of any phase distortion due to the absence of J HH evolution. Accurate n J CH values can be directly measured analyzing the relative displacement of the resulting IPAP cross-peaks. Discussion about signal intensity dependence and cross-talk is made for a range of experimental conditions. The robustness of the method is evaluated by comparing the n J CH value measured from the analysis of the three available IP, AP and IPAP multiplet patterns. Multiple-frequency and region-selective versions of the method can also be efficiently recorded provided that excited protons are not mutually coupled.

Measurement of long‐range proton–carbon coupling constants from pure in‐phase 1D multiplets

The SELective INverse detection of carbon-proton CORrelation pulse sequence that yields a 1D spectrum of a proton directly bonded to a selected carbon resonance has been converted into a proton and carbon double-selective variant that provides a (1)H spectrum of a selected proton that is long-range coupled to a specific carbon resonance. The resulting 1D proton multiplet exhibits a pure absorptive in-phase lineshape for precise measurement of specific long-range proton-carbon coupling constants in small organic molecules at natural abundance.

Prorocentrol, a Polyoxy Linear Carbon Chain Compound Isolated from the Toxic Dinoflagellate Prorocentrum hoffmannianum

A polyoxy linear carbon chain compound, prorocentrol (1), was isolated from cultured cells of the dinoflagellate Prorocentrum hoffmannianum, which produces a polyether carboxylic acid, okadaic acid. The structure of 1 was elucidated by detailed analyses of 2D NMR spectra. Compound 1 possesses 30 hydroxy groups, 1 ketone, and 8 double bonds on the C65-linear carbon chain. Its partial relative configuration was deduced by the proton-proton and long-range carbon-proton coupling constants, and compound 1 showed moderate cytotoxicity and antidiatom activity.

Improved NMR methods for the direct 13C‐satellite‐selective excitation in overlapped 1H‐NMR spectra

Improved pulsed-field gradient echo methods are presented and discussed for the direct selective excitation of the (13)C-satellite lines in overcrowded (1)H NMR spectra of small molecules. Sensitivity enhancements in (13)C spin-state selection can be achieved by combining multiple-proton-frequency excitation and Hadamard phase encoding. Several satellite-selective (SATSEL) NMR experiments are proposed and exemplified by measuring the sign and the magnitude of small, long-range proton-carbon coupling constants for (1)H resonances showing several levels of signal overlapping.

Optimum spin-state selection for all multiplicities in the acquisition dimension of the HSQC experiment

Most conventional heteronuclear spin-state-selective (S 3) NMR experiments only work for a specific multiplicity, typically IS spin systems. Here, we introduce a general and efficient IPAP strategy to achieve S 3 editing simultaneously for all multiplicities in the acquisition dimension of the HSQC experiment. Complementary in-phase (HSQC-IP) and anti-phase (HSQC-AP) data are separately recorded with a simple phase exchange of two 90° proton pulses involved in the mixing process of the F2-coupled sensitivity-improved HSQC pulse sequence. Additive and subtractive linear combination of these IP/AP data generates simplified F2-α/β-spin-edited HSQC subspectra for all IS, I 2S, and I 3S spin systems and combines enhanced and optimized sensitivity with excellent tolerance to unwanted cross-talk contributions over a considerable range of coupling constants. Practical aspects such as pulse phase settings, transfer efficiency dependence, inter-pulse delay optimization, and percentage of cross-talk are theoretically analyzed and discussed as a function of each I n S multiplicity. Particular emphasis on the features associated to spin-editing in diastereotopic I 2S spin systems and application to the measurement of long-range proton–carbon coupling constants are also provided.

Spin-state-selective excitation in selective 1D inverse NMR experiments.

A general and very simple strategy for achieving clean spin-state-selective excitation with full sensitivity in carbon-selective gradient-enhanced 1D HMQC and HSQC pulse schemes is presented. The incorporation of an additional hard 90 degrees (13)C pulse applied along a specific orthogonal axis just prior to acquisition into the conventional sequences allows us to select a simultaneous coherence transfer pathway which usually is not detected. The superimposition of this resulting antiphase magnetization to the conventional in-phase magnetization gives the exclusive excitation of the directly attached proton showing only the alpha or beta spin state of the passive (13)C nucleus. The propagation of this particular spin state to other protons can be accomplished by adding any homonuclear mixing process just after this supplementary pulse. Such an approach affords a suite of powerful selective 1D (13)C-edited NMR experiments which are helpful for resonance assignment purposes in overcrowded proton spin systems and also for the accurate determination of the magnitude and sign of long-range proton-carbon coupling constants in CH spin sytems for samples at natural abundance. Such measurements are performed by measuring the relative displacement of relayed signals in the corresponding alpha and beta 1D subspectra.

Novel selective 1D experiments based on heteronuclearJ cross-polarization

Selective 1H–13C inverse NMR experiments based on heteronuclear cross-polarization (HCP) are presented. Practical details on the implementation of one-bond [1J(C,H)] optimized and pseudo-3D HCP experiments combined with gradient coherence selection are reported. On the other hand, accurate values for long-range proton–carbon coupling constants [nJ(C,H); n > 1] can be measured from ultra-clean in-phase 1D proton multiplets resulting of long-range optimized experiments. Alternatively, such heteronuclear connectivities can be also clearly elucidated using a 1H-selective 13C-detected version in which signals exclusively arise from selective transfer of a selected proton to all long-range coupled carbon nuclei. Copyright © 1999 John Wiley & Sons, Ltd.

Long-range proton-carbon coupling constants in conformational analysis of oligosaccharides

Long-range heteronuclear coupling constants, 3J(C,H), were measured across glycosidic linkages in β-linked disaccharides and also for vicinally disubstituted trisaccharides. One-dimensional multiple-site 13C excitation experiments using Hadamard spectroscopy and band-selective 1H decoupling during the acquisition period were used in conjunction with pulsed field gradients for coherence selection in the 1H detected experiment. For one dihedral angle the 3J(C,H) value could only be unambiguously determined utilizing the band-selective 1H decoupling. The 2D EXSIDE was also used for the measurement of 3J(C,H) values and the results showed excellent agreement with those of the 1D measurements. The influence of solvent, water and water–dimethyl sulfoxide (7:3), on conformation was investigated, but showed only small changes in 3J(C,H) values. In general, the long-range heteronuclear coupling constants related to the ϕ dihedral angles (3.6–4.3 Hz) were smaller than those of the ψ dihedral angles (4.3–5.3 Hz). A comparison with 3J(C,H) values from Monte Carlo or Langevin dynamics simulations showed better agreement for the ψ dihedral angles than for the ϕ dihedral angles as calculated using a Karplus relationship. © 1998 John Wiley & Sons Ltd.

マイトトキシンの完全構造決定

Maitotoxin (MTX, 1) is the most toxic and largest non-biopolymer known to date. The complete structural determination of MTX including the absolute configuration has been achieved recently. The relative configurations of the four acyclic portions (C1-C15, C35-C39, C63-C68, and C134-C142) were elucidated by (1) the extensive configurational analysis mainly using long-range carbon-proton coupling constants (2, 3JC, H), and (2) the stereoselective synthesis of the eight model compounds (2A-2D, 13, 27A, 27B, and 47) which were furnished with thus assigned relative configurations. The comparison of their 1H and 13C-NMR data with those for the corresponding portion of MTX evidently established the relative configuration from C1 to C138. The absolute configuration of the entire molecule was determined by the enantioselective synthesis and chiral gas chromatographic comparison with a degradated fragment (3, 4-dimethy1-6-hepten-1-o1) derived from the natural product, which involved two chiral centers at C138 and C139.The present results have revealed that the preferred conformation of an appropriately designed model compound with the correct configuration closely mimics that of the corresponding portion of MTX. Thus, we could deduce the overall conformation of MTX by assembling the preferred conformation of each model compound based on the NMR data.

Long-range carbon-proton coupling constants for stereochemical assignment of acyclic structures in natural products: Configuration of the C5C9 portion of maitotoxin

Long-range carbon-proton coupling constants ( 2,3 J C,H) were measured for maitotoxin (MTX), one of the largest natural non-biopolymers, by hetero-half filter experiments and phase-sensitive HMBC with use of 9 mg of a 4% 13C-enriched sample. The necessary coupling constants within the terminal acyclic portions of MTX, where NOE analysis was not successful owing to the presumed coexistence of multiple conformers, were thus obtained for the resultant elucidation of relative configurations for the acyclic stereogenic centers to be 5R ∗, 7R ∗, 8R ∗ , and 9S ∗ .

Accurate Measurement of Heteronuclear Long-Range Coupling Constants from 1D Subspectra in Crowded Spectral Regions

A general review of novel NMR methods to measure heteronuclear long-range proton–carbon coupling constants (nJCH; n > 1) in small molecules is made. NMR experiments are classified in terms of NMR pulse scheme and cross-peak nature. A discussion about simplicity, general applicability and accuracy for each particular NMR experiment is presented and exemplified. Important aspects such as the sign determination and measurement of very small coupling values involving protonated and non-protonated carbons as well as the complementarity between different experiments are also discussed. Finally, a compilation of applications in structural and conformational analysis of different types of molecules since 2000 is surveyed.

Conformational analysis of natural products using long-range carbon-proton coupling constants: Three-dimensional structure of okadaic acid in solution

Long-range carbon-proton coupling constants ( 2,3 J C,H) are known to depend on the dihedral angles as is the well-known case with interproton couplings. The precise measurement of these J values were carried out using hetero half-filtered TOCSY and phase-sensitive HMBC on a marine natural product, okadaic acid. From the obtained values together with 3 J H,H we disclosed the conformations of okadaic acid in organic and aqueous solutions (CD 3OD-CDCl 3 or NaOD/D 2O), which resembled each other and that obtained for its crystalline o-bromobenzyl ester. The successful result in the present conformational study, even though as an exmaple, demonstrated this methodology to be powerful in elucidation of conformations and configurations of acyclic or macrocyclic portions in natural products of this size.

One-Dimensional Inverse-Detected Methods for Measurement of Long-Range Proton-Carbon Coupling Constants. Application to Saccharides

Abstract Several inverse-detected one-dimensional methods for measurement of long-range heteronuclear coupling constants are proposed. A double-INEPT-type polarization transfer is used in these sequences. An initial transfer via one-bond couplings is followed by modulation of the single-quantum carbon magnetization by long-range heteronuclear couplings and a final back-transfer of the carbon magnetization to protons. Multiplets in pure antiphase with respect to the heteronuclear long-range couplings and additional in-phase splitting from proton-proton couplings are observed. Selection of a particular isotopomer, the subspectrum of which is coadded constructively during the course of the experiment, is achieved by a combined use of selective pulses and chemical-shift-selective filters, both applied in the 13C or the 1H frequency domains. Modifications are proposed which remove the undesirable effect of one-bond and passive long-range proton-carbon coupling constants. Signal intensities are analyzed theoretically and compared experimentally for various experimental schemes. The methods are illustrated on a peracetylated β-cyclodextrin (Mr = 2016 g/mol). The emphasis is placed on the measurement of interglycosidic heteronuclear long-range couplings, which proved to be useful in the conformational analysis of saccharides.

Measurement of Long-Range 1H-13C Coupling Constants Using Selective Excitation of Carbon-13

A general review of novel NMR methods to measure heteronuclear long-range proton–carbon coupling constants (nJCH; n > 1) in small molecules is made. NMR experiments are classified in terms of NMR pulse scheme and cross-peak nature. A discussion about simplicity, general applicability and accuracy for each particular NMR experiment is presented and exemplified. Important aspects such as the sign determination and measurement of very small coupling values involving protonated and non-protonated carbons as well as the complementarity between different experiments are also discussed. Finally, a compilation of applications in structural and conformational analysis of different types of molecules since 2000 is surveyed.