Computational Prediction of<sup>1</sup>H and<sup>13</sup>C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry

Lodewyk, Michael W.; Siebert, Matthew R.; Tantillo, Dean J.

doi:10.1021/cr200106v

Cited by 1,044 publications

(1,308 citation statements)

References 236 publications

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“…2C). Additional quantum chemical calculations (23,24) of 1 H and 13 C NMR chemical shifts for several pseudolaratriene isomers and diastereomers of each verified the structure shown in Fig. 2C (Dataset S1) and were consistent with all available NMR data (chemical shifts, coupling constants, and NOE experiments).…”

Section: Significancesupporting

confidence: 76%

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

Mafu

Karunanithi

Palazzo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P. amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono-and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene. diterpene biosynthesis | Pseudolarix amabilis | plant natural products | pseudolaric acid | chemotherapeutic drug

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Section: Significancesupporting

confidence: 76%

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

Mafu

Karunanithi

Palazzo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This protocol has been shown to achieve an RMS error of better than 3 ppm for cellulose Ib and Ia (Kubicki et al 2013;Toukach and Ananikov 2013;Wang et al 2016b). The modified Perdue-Wang exchange-correlation functional mPW1PW91 (Adamo and Barone 1998) with the 6-31G(d) basis set (Rassolov et al 2001) and gauge-independent atomic orbitals (GIAO) (Bühl et al 1999;Cheeseman et al 1996;Karadakov 2006;Lodewyk et al 2011;Schreckenbach and Ziegler 1995;Wiitala et al 2006;Wolinski et al 1990) method in Gaussian 09 were used. Chemical shifts were calculated using the multi-reference method.…”

Section: Methodsmentioning

confidence: 99%

Structural factors affecting 13C NMR chemical shifts of cellulose: a computational study

et al. 2017

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The doublet C4 peaks at * 85 and * 89 ppm in solid-state 13 C NMR spectra of native cellulose have been attributed to signals of C4 atoms on the surface (solvent-exposed) and in the interior of microfibrils, designated as sC4 and iC4, respectively. The relative intensity ratios of sC4 and iC4 observed in NMR spectra of cellulose have been used to estimate the degree of crystallinity of cellulose and the number of glucan chains in cellulose microfibrils. However, the molecular structures of cellulose responsible for the specific surface and interior C4 peaks have not been positively confirmed. Using density functional theory (DFT) methods and structures produced from classical molecular dynamics simulations, we investigated how the following four factors affect 13 C NMR chemical shifts in cellulose: conformations of exocyclic groups at C6 (tg, gt and gg), H 2 O molecules H-bonded on the surface of the microfibril, glycosidic bond angles (U, W) and the distances between H4 and HO3 atoms. We focus on changes in the d 13 C4 value because it is the most significant observable for the same C atom within the cellulose structure. DFT results indicate that different conformations of the exocyclic groups at C6 have the greatest influence on d 13 C4 peak separation, while the other three factors have secondary effects that increase the spread of the calculated C4 interior and surface peaks.

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“…This has the effect of reducing some of the systematic error inherent in the theory used for the computation. After the use of scaling factors, the computed NMR shielding tensors are converted into referenced chemical shifts as defined by equation (2) below, where δ is the referenced chemical shift and σ is the computed NMR shielding tensor 5 .…”

Section: Operation III Nmr Shielding Tensor Calculations and Conversmentioning

confidence: 99%

“…The goal of this tutorial is to break down this barrier by describing protocols for computing chemical shifts of a set of candidate structures and then comparing the resulting set of theoretical values for each of those structures with the experimental data in question. Many excellent reviews 5,6 exist that critically assess various theoretical aspects of the computation of NMR chemical shifts (e.g., improved functionals, improved basis sets, correction and scaling routines, multiple referencing); it is not our intent here to offer an in-depth discussion of those features. Instead, we aim to provide the typical experimentalist (who is, frequently, an inexperienced computationalist) with the guidance required to initiate such a study.…”

Section: Introductionmentioning

confidence: 99%

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

2014

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this protocol is intended to provide chemists who discover or make new organic compounds with a valuable tool for validating the structural assignments of those new chemical entities. experimental 1 H and/or 13 c nMr spectral data and its proper interpretation for the compound of interest is required as a starting point. the approach involves the following steps: (i) using molecular mechanics calculations (with, e.g., MacroModel) to generate a library of conformers; (ii) using density functional theory (DFt) calculations (with, e.g., Gaussian 09) to determine optimal geometry, free energies and chemical shifts for each conformer; (iii) determining Boltzmann-weighted proton and carbon chemical shifts; and (iv) comparing the computed chemical shifts for two or more candidate structures with experimental data to determine the best fit. For a typical structure assignment of a small organic molecule (e.g., fewer than ~10 non-H atoms or up to ~180 a.m.u. and ~20 conformers), this protocol can be completed in ~2 h of active effort over a 2-d period; for more complex molecules (e.g., fewer than ~30 non-H atoms or up to ~500 a.m.u. and ~50 conformers), the protocol requires ~3-6 h of active effort over a 2-week period. to demonstrate the method, we have chosen the analysis of the cis-versus the trans-diastereoisomers of 3-methylcyclohexanol (1-cis versus 1-trans). the protocol is written in a manner that makes the computation of chemical shifts tractable for chemists who may otherwise have only rudimentary computational experience. this method certainly has value, the example described next shows that when one moves to the consideration of molecules bearing more than one stereocenter, this approach is no longer adequate.Consider the case of the trans-versus the cis-diastereomers of 3-methylcyclohexanol (1-trans and 1-cis, respectively). The experimental 1 H NMR spectra for 1-trans and 1-cis are shown in Figure 1a,b (see Supplementary Data 1 for a full listing of actual chemical shift values). There are substantial differences in these two spectra, especially within the upfield 0.7-2.1 p.p.m. range. Clearly, it would be valuable if computational approaches could reproduce these sorts of differences sufficiently well to allow confident assignment of structure.Common software packages that use empirical (often increment-based) compilations of chemical shift information (e.g., tabulated shift increments or databases of known spectral data) allow users to predict the chemical shifts of a given input structure. These include 'ChemNMR' within ChemBioDraw (also known as ChemDraw) and 'C+H NMR Predictor and DB' within the ACD/Labs software suite. These methods sometimes can be sufficient for the task of resolving constitutional structural assignments. However, when issues associated with relative configuration are considered, increment-based methods are decidedly ill-equipped. Analysis of structures 1-trans and 1-cis by each of these programs quickly reveals these limitations, even for these simple structures. Namely, because Che...

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Computational Prediction of¹H and¹³C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry

Cited by 1,044 publications

References 236 publications

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

Structural factors affecting 13C NMR chemical shifts of cellulose: a computational study

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

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Computational Prediction of1H and13C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry

Cited by 1,044 publications

References 236 publications

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase

Structural factors affecting 13C NMR chemical shifts of cellulose: a computational study

A guide to small-molecule structure assignment through computation of (1H and 13C) NMR chemical shifts

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Product

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Computational Prediction of¹H and¹³C Chemical Shifts: A Useful Tool for Natural Product, Mechanistic, and Synthetic Organic Chemistry