13C NMR-Based Approaches for Solving Challenging Stereochemical

Letter Cite This: Org. Lett. 2019, 21, 4072−4076

pubs.acs.org/OrgLett

13

C NMR-Based Approaches for Solving Challenging Stereochemical Problems

Ikenna E. Ndukwe,† Andrew Brunskill,† Donald R. Gauthier, Jr.,† Yong-Li Zhong,† Gary E. Martin,†,‡ R. Thomas Williamson,†,§ Mikhail Reibarkh,*,† and Yizhou Liu*,†,⊥ †

Analytical Research & Development, Merck & Co. Inc., Rahway, New Jersey 07065, United States

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S Supporting Information *

ABSTRACT: Determining the configuration of proton-deficient molecules is challenging using conventional NMR methods including nuclear Overhauser effect (NOE) and the proton-dependent J-based configuration analysis (JBCA). The problem is exacerbated when only one stereoisomer is available. Alternative methods based on the utilization of 13C NMR chemical shifts, 13C−13C homonuclear couplings measured at natural abundance, and residual chemical shift anisotropy measurements in conjunction with density functional theory calculations are illustrated with a proton-deficient model compound.

N

although progress has been made in recent years by employing statistical approaches.7 The measurement of JCC couplings and comparison with DFT predictions represents another promising route for configuration analysis.8 However, its utility is often limited by the low sensitivity of the NMR experiments required, for example, J-modulated ADEQUATE, at 13C natural abundance. Alternative 13C-based methods with higher sensitivity would thus facilitate stereochemical analysis of proton-deficient molecules. Anisotropic NMR data, in particular, residual dipolar coupling (RDC),9 can provide relative angular information between different interatomic vectors independent of their distance separation and therefore represent a very powerful technique for determining the relative configuration of remote stereocenters. Unfortunately, the most readily measurable onebond 13C−1H RDC (1DCH) requires protonated carbons. Another type of anisotropic NMR data, namely the 13C residual chemical shift anisotropy (RCSA),5,10 has more recently emerged as a highly promising parameter for configuration determination of proton deficient compounds. RCSA provides information on the relative orientations of the chemical shielding tensors of different carbon atoms. This information is available regardless of the distances between the carbon atoms. Experimentally, RCSA is simply determined from 13C chemical shifts measured at two or three different sample conditions, and therefore, the sensitivity of the measurement is comparable to regular 13C chemical shift measurement.

MR spectroscopy is one of the cornerstones for assigning the configuration of natural products and synthetic organic molecules. 3JHH and 3JCH couplings are the essential components of J-based configuration analysis (JBCA).1 These couplings report on the dihedral angle between the coupled nuclei as described by the well-known Karplus equation.2 The 2 JCH coupling reveals the dihedral angle between the proton and an electronegative substituent on the carbon and is also frequently utilized in JBCA.1 In addition, proton−proton proximity information from NOE/ROEs can facilitate stereochemical differentiation.3 There are two major limitations to the traditional NMR approaches described. First, they rely on the presence of 1H (or, less commonly, 19F) nuclei in proximity to the stereocenter(s) of interest.4 Second, the two stereocenters must be connected by only one bond. For distal stereocenters separated by methylenes, a series of JBCA’s can be performed, at least in principle, to stereochemically assign the intervening diastereotopic methylene groups one by one and to eventually determine the relative stereochemistry of both ends−but this can be quite difficult in practice. Determining the configuration of molecules with protondeficient stereocenters5 presents a significant challenge and typically requires 13C-based methods. Carbon chemical shifts are very powerful for constitution determination, especially as empirical predictive methods are being superseded by much more accurate methods based on GIAO−DFT (gaugeindependent atomic orbital-density functional theory).6 However, configuration determination is still challenging in general due to the usually small chemical shift differences between stereoisomers. The situation is even worse in cases where only one stereoisomer is available for NMR analysis, © 2019 American Chemical Society

Received: April 10, 2019 Published: May 22, 2019 4072

DOI: 10.1021/acs.orglett.9b01248 Org. Lett. 2019, 21, 4072−4076

Letter

Organic Letters The isomeric thiazolidinediones11 shown in Figure 1 represent a case where conventional 1H-based NMR methods

Guided by the DFT predictions, we measured the 3JC7−C4 and 3JC11−C4 couplings for configuration assignment. The Jmodulated 1,n-HD-ADEQUATE experiment13 (Figure S8) was utilized with the scaling factor set to 30. The spectral segment in Figure S8 shows doublet for the 3JC11−C4 coupling. The DFT calculated 3JC11−C4 for 1 and 2 was 1.3 and 5.1 Hz, respectively. Experimentally measured 3JC11−C4 value of 5.0 Hz is in excellent agreement with the calculated value for the Eisomer 2, confirming the assignment from the 13C chemical shift analysis. As noted above, the low sensitivity of the J-modulated HDADEQUATE experiment often precludes even considering its utilization as a means of assigning stereochemistry. An attractive alternative for the stereochemical analysis of proton-deficient compounds is provided by the recently developed RCSA methodology.10,14 The NMR experiment necessary for an RCSA study is as simple as acquiring two 13C spectra using either a SAG (strained alignment in gel) polymeric gel,10 or three 13C spectra using a lyotropic liquid crystalline media such as PBLG, as shown in recently reported studies.14 These data can then be utilized to solve chemical constitution or configuration problems.5,10,14 The structure of 2 represents an example that can showcase the utility of RCSA data in stereochemical assignment. 13C−1H RDCs were found to be unsuitable for E/Z isomer differentiation. While one-bond RDCs have clearly no utility in this case, long-range RDCs,15 in particular C4−H7a/b and C4− H11a/b, were considered as potentially capable of such differentiation. Back-calculated RDC values using the effective alignment tensor determined from RCSA data (vide infra) were the following: C4−H11a/b was 2.17 for Z and 2.30 for E; C4−H7a/b was 1.69 Hz for Z and 0.54 Hz for E (see SI for details). Reliably resolving such small coupling differences is challenging even from the 13C dimension, given a line width greater than 2 Hz. In contrast, significant differences in RCSAs are expected between the E and Z isomers because of the diverging relative orientations of carbon chemical shielding tensors between the thiazolidinedione and cyclohexyl rings. Consequently, RCSA provides a much more promising solution to this problem than RDC. Since this compound contains only four sp2-hybridized carbons, whereas at least six data points are needed for any meaningful structural analysis based on singular value decomposition (SVD),16 it is critical to obtain accurate RCSA data for the sp3-hybridized carbons. As sp3-hybridized carbons have small chemical shift anisotropies (CSAs), accurate measurement of their RCSAs requires a strong alignment medium. We, therefore, adopted the recently developed strategy of RCSA measurement in the strongly aligning PBLG mesophase (experimental details in SI).14 DFT geometry optimization for 1 and 2 gave two major conformations for each isomer involving only the flipping of the cyclohexal ring, with an approximately 1:1 population distribution. Generally speaking, analysis of RCSA or RDC data in the presence of conformational flexibility requires an ensemble averaging approach.17 For medium-induced alignment, the single-tensor ensemble analysis17d is frequently used. This approximate method requires reasonably high structural superimposability between different conformers, which is not true in this case. However, here we note that these two conformers, although poorly superimposable, are actually mirror images of each other (Figure 2). This symmetry does not arise by coincidence. The structure (Figure 1) has intrinsic reflection symmetry, and therefore, conformers arising from

Figure 1. Structures of thiazolidinedione Z- (1) and E-isomers (2) showing the numbering scheme employed.

are insufficient to confidently assign the stereochemistry of the alkene. We first undertook a pre-experimental evaluation through DFT calculations to better understand what types of NMR data could facilitate E/Z isomer differentiation. Clearly, available homonuclear JHH couplings are all indifferent to the E/Z configuration. The calculated long-range heteronuclear scalar coupling constants (nJCH, n = 2, 3, 4) do not differ enough to allow a confident J-based configuration analysis either. For example, the calculated 3JCH for H7a/b-C5 and H11a/b-C5 couplings of 1 were 6.3 and 5.1 Hz, respectively, which are similar in size to the corresponding 3JCH for 2 (5.1 and 6.2 Hz, respectively). DFT-calculated 4JCH values for H7a/ b-C4 were also similar at −0.8 and −1.0 Hz, respectively, for the Z- and E-isomers (H11a/b-C4 was also similar; −0.7 Hz for Z and −1.0 Hz for E). Because 1H-based stereochemical methods were not applicable, we evaluated the possibility of differentiation by 13 C-based approaches making use of the DFT results. In general, stereochemical assignment by 13C chemical shifts alone is challenging using NMR data of only one stereoisomer. In this work, DFT-calculated 13C chemical shifts at the mPW1PW91/6-311+G(2d,p)//B3LYP/6-31+G** level of theory did favor the E-isomer (Table S2). The mean absolute error (MAE) of experimental versus DFT computed chemical shifts are 3.4 ppm for Z- and 2.2 ppm for E-isomer. Although the MAE favors the E-isomer, the difference is less than a typical error in 13C chemical shift calculations.12 Considering that only one diastereomer was available, an orthogonal validation was necessary to improve the confidence of assignment. Although employed much less frequently, 1JCC coupling constants have been utilized in several studies for stereochemical assignments.8 The reported studies have demonstrated that 1JCC values can be sensitive to molecular constitution and configuration and thus can be employed in some cases to identify the correct stereoisomer of molecules. DFT-calculated 1JCC coupling constants for 1 and 2 (Table S4), however, did not provide a definitive answer to this problem. In fact, the only quantifiable difference in J couplings suggested by DFT were the 3JC7−C4 and 3JC11−C4 values for 1 and 2 (Table S6), which were expected from the different dihedral angles in the E- and Z-isomers. 4073


Letter

Organic Letters

Eq 2 suggests that during RCSA data analysis, we can proceed as if there was only one conformer associated with an effective alignment tensor Aeff = kAij I + (1 − k)Aij II . The CSA tensor in eq 2 can be obtained from GIAO−DFT calculation with either one of the two conformers. Differently from the single-tensor SVD method,17d this symmetry-based approach does not require any alignment similarity between the two conformers ( AI and AII can be different in a chiral medium) or any information on the population distribution (k is absorbed into Aijeff). Caution should be taken while using a chiral alignment medium if the compound contains a pro-chiral center such as C8 (Figure 1). The two methyl groups (C12 and C13) on C8 have identical chemical shifts in an isotropic solution, as shown in Figure S10, and in fact it is necessarily so in any achiral environment. As shown in Figure 2, C12 in conformer I experiences an equivalent chemical environment to that of C13 in conformer II, while C13 in conformer I experiences an equivalent chemical environment as C12 in conformer II. The chemical shift equivalency of C12 and C13 arises because conformers I and II are equally populated in an achiral environment. In a chiral medium, however, both the environmental and population equivalency can be broken, which may resolve the methyl degeneracy, although such an effect was not observed here in a dilute isotropic PBLG medium (Figure S11). However, the two methyl groups were clearly differentiated in a concentrated PBLG solution (Figure S12), as the chiral mesophase generated differential alignment tensors for conformers I and II ( AI ≠ AII ) and consequently gave rise to different RCSAs of C12 and C13, as formulated in the following equations:

Figure 2. Mirror image conformers of the E-isomer, 2, oriented to show the exchange of the C12 and C13 positions.

structural flexibility must occur in pairs of mirror images. This property can be exploited to simplify RCSA analysis in a rigorous manner. We show below that with proper treatment of pro-chiral groups, we only need to analyze RCSA or RDC with one of the two conformers instead of employing ensemble averaging. First, we define an arbitrary molecular frame relative to conformer I (MFI) with a Boltzmann population of k, and represent the alignment tensor of conformer I by AI . For the symmetry-related conformer II with a Boltzmann population of 1 − k, we can uniquely define an MFII such that an atom ⎯⎯⎯⇀ position vector vII in MFII is related to the corresponding atom ⎯⇀

⎯⎯⎯⇀

⎯⇀

RCSAC12 = k

position vector vI in MFI by vII = − vI , and further define the

Aij ICSAijI + (1 − k)

∑ i,j=x ,y,z

∑

∑ RCSAC13 = k

∑ i,j=x ,y,z

∑ ∑

Aij ICSAijC13 + (1 − k) Aij IICSAijC12 (4)

i,j=x ,y,z

Unfortunately, direct application of eqs 3 and 4 for data analysis is not straightforward because two different alignment tensors are involved. A simple solution is to analyze the average of RCSAC12 and RCSAC13, as shown in eq 5:

Aij IICSAij II

i,j=x ,y,z

1 (RCSA C12 + RCSA C13) 2 1 = ∑ Aijeff (CSAijC12 + CSAijC13) 2 i,j=x ,y,z

RCSA =

(5)

The reduction to a single effective tensor Aeff in eq 5 allows RCSAC12 and RCSAC13 to be analyzed in the same fashion as the other carbons by 2. This approach shares some similarity with the treatment of the two unassigned 13C−1H RDCs in a methylene group, although the fundamental argument is different. By fitting RCSAC12 and RCSAC13 with eq 5 and the other RCSAs with eq 2 in the same SVD procedure, we obtained Q-factors of 0.068 and 0.404 for the E- and Zisomers, respectively (Figure 3). This result provided facile and

(kAij I + (1 − k)Aij II)CSAij

i,j=x ,y,z

=

(3)

i,j=x ,y,z

Here, CSAijI and CSAijII represent the CSA tensor elements of the two conformers in MFI and MFII, respectively. Because ⎯⎯⎯⇀ ⎯⇀ MFI and MFII are constructed such that vII = − vI , we further have CSAijI = CSAijII. This equality holds because the CSA tensor has inversion symmetry, that is, the transformation x → −x, y → −y, and z → −z does not change the tensor’s matrix values. Then eq 1 further simplifies to eq 2:

∑

Aij IICSAijC13

i,j=x ,y,z

(1)

RCSA =

Aij ICSAijC12 + (1 − k)

i,j=x ,y,z

alignment tensor of conformer II in MFII by AII . Note that k is 0.5 in an achiral environment as the two conformers are energetically equivalent but can differ from 0.5 in a chiral environment. More importantly, in an achiral alignment medium, we have AI ≡ AII , whereas in a chiral alignment medium such as PBLG, generally speaking AI ≠ AII . This inequality forms the basis of enantiomer differentiation by chiral alignment media,18 although enantiomer assignment is currently impossible without sufficiently accurate alignment predictive methods.19 By the usual procedure of ensemble averaging, the experimentally expected RCSA is described by RCSA = k

∑

Aij eff CSAij (2) 4074


Letter

Organic Letters ORCID

Donald R. Gauthier, Jr.: 0000-0003-2825-0530 Yong-Li Zhong: 0000-0001-9701-3630 Yizhou Liu: 0000-0002-1396-922X Present Addresses ‡

Figure 3. Plots of back-calculated vs experimentally observed RCSAs for the thiazolidinone Z- (1) and E-isomers (2).

Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Avenue, South Orange, New Jersey 07079, United States. § Department of Chemistry and Biochemistry, University of North Carolina Wilmington, 5600 Marvin K. Moss Lane, Wilmington, North Carolina 28409, United States. ⊥ Analytical Research and Development, Pfizer Worldwide Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, United States.

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C

confident chiral differentiation of the isomers and orthogonally confirms the conclusion derived from comparative 3JCC and 13 C chemical shift measurements vs DFT calculations. In conclusion, complementary 13C NMR-based methods for establishing the stereochemistry of proton-deficient molecules have been explored. 13C Homonuclear coupling 13C−13C correlation experiments, such as the J-modulated ADEQUATE experiment and variants, provide a parameter for stereochemical differentiation of proton-deficient centers. In some cases, like the example shown in this work, the measurement of 3 JCC couplings provided clear diagnosis. Thus, far, however, the utilization of long-range 13C−13C coupling constants in stereochemical assignment strategies has been infrequent, undoubtedly due to the inherently low sensitivity of ADEQUATE-type experiments. One caveat is that there must still be a proton attached to one of the carbons to facilitate the measurement of the 13C−13C coupling constant. Overall, the acquisition of the J-modulated-1,n-HD-ADEQUATE experiment consumed 26 h on a 600 MHz spectrometer equipped with a 5 mm helium-cooled cryogenic inverse-detection NMR probe. In contrast, the three 13C NMR spectra needed for the RCSA analysis were acquired with the same amount of material in ∼1 h in total. With the excellent signal-to-noise ratio observed for the 13C spectra (see SI), the experimental time can be shortened significantly if necessary. The ease of acquiring a set of one-dimensional 13C experiments versus a J-modulated ADEQUATE experiment makes the use of RCSAs a highly viable technique for stereochemical analysis of proton-deficient molecules. Insight has been gained into simplification of analysis of anisotropic NMR parameters for molecules of structural symmetry and how problems of this nature can be addressed to afford unambiguous stereochemical characterization.

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge support from the MRL Postdoctoral Research Program.

(1) (a) Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K. J. Org. Chem. 1999, 64, 866−876. (b) Cimino, P.; Bifulco, G.; Evidente, A.; Abouzeid, M.; Riccio, R.; Gomez-Paloma, L. Org. Lett. 2002, 4, 2779−2782. (2) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870−2871. (3) (a) Pinto, D.; Santos, C.; Silva, A. 8 Advanced NMR techniques for structural characterization of heterocyclic structures; Research Signpost: Kerala, India, 2007; Vol. 37661. (b) Chini, M. G.; Jones, C. R.; Zampella, A.; D’Auria, M. V.; Renga, B.; Fiorucci, S.; Butts, C. P.; Bifulco, G. J. Org. Chem. 2012, 77, 1489−1496. (4) Gustafson, K. R.; Chan, S. T. S.; Liu, Y. Modern NMR Approaches to the Structure Elucidation of Natural Products: Vol. 2. Data Acquisition and Applications to Compound Classes; The Royal Society of Chemistry, 2017; Vol. 2, pp 39−70. (5) Mevers, E.; Saurí, J.; Liu, Y.; Moser, A.; Ramadhar, T. R.; Varlan, M.; Williamson, R. T.; Martin, G. E.; Clardy, J. J. Am. Chem. Soc. 2016, 138, 12324−12327. (6) (a) Schreckenbach, G.; Ziegler, T. Theor. Chem. Acc. 1998, 99, 71−82. (b) Willoughby, P. H.; Jansma, M. J.; Hoye, T. R. Nat. Protoc. 2014, 9, 643−660. (7) (a) Smith, S. G.; Goodman, J. M. J. Am. Chem. Soc. 2010, 132, 12946−12959. (b) Grimblat, N.; Zanardi, M. M.; Sarotti, A. M. J. Org. Chem. 2015, 80, 12526−12534. (8) (a) Bifulco, G.; Riccio, R.; Martin, G. E.; Buevich, A. V.; Williamson, R. T. Org. Lett. 2013, 15, 654−657. (b) Martin, G. E.; Buevich, A. V.; Reibarkh, M.; Singh, S. B.; Ondeyka, J. G.; Williamson, R. T. Magn. Reson. Chem. 2013, 51, 383−390. (c) Powell, J.; Valenti, D.; Bobnar, H.; Drain, E.; Elliott, B.; Frank, S.; McCullough, T.; Moore, S.; Kettering, A.; Iuliucci, R.; Harper, J. K. Magn. Reson. Chem. 2017, 55, 979−989. (9) (a) Bax, A. Protein Sci. 2003, 12, 1−16. (b) Prestegard, J. H.; AlHashimi, H. M.; Tolman, J. R. Q. Rev. Biophys. 2000, 33, 371−424. (c) Kummerlöwe, G.; Luy, B.; Graham, A. W. Annu. Rep. NMR Spectrosc. 2009, 68, 193−232. (d) Gil, R. R.; Navarro-Vázquez, A. Modern NMR Approaches to the Structure Elucidation of Natural Products: Vol. 2. Data Acquisition and Applications to Compound Classes; The Royal Society of Chemistry, 2017; Vol. 2, pp 1−38. (10) (a) Liu, Y.; Saurí, J.; Mevers, E.; Peczuh, M. W.; Hiemstra, H.; Clardy, J.; Martin, G. E.; Williamson, R. T. Science 2017, 356, No. eaam5349. (b) Hallwass, F.; Schmidt, M.; Sun, H.; Mazur, A.; Kummerlöwe, G.; Luy, B.; Navarro-Vázquez, A.; Griesinger, C.; Reinscheid, U. M. Angew. Chem., Int. Ed. 2011, 50, 9487−9490. (c) Nath, N.; Schmidt, M.; Gil, R. R.; Williamson, R. T.; Martin, G.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01248. Sample preparation, NMR data analysis, anisotropic data acquisition and analysis, calculated long-range RDCs, structure coordinates from DFT (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. 4075


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Organic Letters E.; Navarro-Vázquez, A.; Griesinger, C.; Liu, Y. J. Am. Chem. Soc. 2016, 138, 9548−9556. (d) Liu, Y.; Navarro-Vázquez, A.; Gil, R. R.; Griesinger, C.; Martin, G. E.; Williamson, R. T. Nat. Protoc. 2019, 14, 217−247. (e) Milanowski, D. J.; Oku, N.; Cartner, L. K.; Bokesch, H. R.; Williamson, R. T.; Saurí, J.; Liu, Y.; Blinov, K. A.; Ding, Y.; Li, X.C.; Ferreira, D.; Walker, L. A.; Khan, S.; Davies-Coleman, M. T.; Kelley, J. A.; McMahon, J. B.; Martin, G. E.; Gustafson, K. R. Chem. Sci. 2018, 9, 307−314. (11) Zhong, Y.-L.; Wang, H.; Gauthier, D. R., Jr., Synthesis manuscript in preparation. (12) (a) Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. Chem. Rev. 2012, 112, 1839−1862. (b) Bifulco, G.; Dambruoso, P.; GomezPaloma, L.; Riccio, R. Chem. Rev. 2007, 107, 3744−3779. (13) Saurí, J.; Parella, T.; Williamson, R. T.; Martin, G. E. Magn. Reson. Chem. 2017, 55, 191−197. (14) (a) Liu, Y.; Cohen, R. D.; Gustafson, K. R.; Martin, G. E.; Williamson, R. T. Chem. Commun. 2018, 54, 4254−4257. (b) Ndukwe, I. E.; Wang, X.; Pelczer, I.; Reibarkh, M.; Williamson, R. T.; Liu, Y.; Martin, G. E. Chem. Commun. 2019, 55, 4327−4330. (15) (a) Trigo-Mouriño, P.; Navarro-Vázquez, A.; Ying, J.; Gil, R. R.; Bax, A. Angew. Chem. 2011, 123, 7718−7722. (b) Nath, N.; d’Auvergne, E. J.; Griesinger, C. Angew. Chem., Int. Ed. 2015, 54, 12706−12710. (16) Losonczi, J. A.; Andrec, M.; Fischer, M. W. F.; Prestegard, J. H. J. Magn. Reson. 1999, 138, 334−342. (17) (a) Yamamoto, S.; Yamaguchi, T.; Erdélyi, M.; Griesinger, C.; Kato, K. Chem. - Eur. J. 2011, 17, 9280−9282. (b) Erdélyi, M.; d’Auvergne, E.; Navarro-Vázquez, A.; Leonov, A.; Griesinger, C. Chem. - Eur. J. 2011, 17, 9368−9376. (c) Bertini, I.; Gupta, Y. K.; Luchinat, C.; Parigi, G.; Peana, M.; Sgheri, L.; Yuan, J. J. Am. Chem. Soc. 2007, 129, 12786−12794. (d) Sánchez-Pedregal, V. M.; Santamaría-Fernández, R.; Navarro-Vázquez, A. Org. Lett. 2009, 11, 1471−1474. (e) Sun, H.; Reinscheid, U. M.; Whitson, E. L.; d’Auvergne, E.; Ireland, C. M.; Navarro-Vázquez, A.; Griesinger, C. J. Am. Chem. Soc. 2011, 133, 14629−14636. (18) (a) Sarfati, M.; Lesot, P.; Merlet, D.; Courtieu, J. Chem. Commun. 2000, 2069−2081. (b) Meddour, A.; Berdague, P.; Hedli, A.; Courtieu, J.; Lesot, P. J. Am. Chem. Soc. 1997, 119, 4502−4508. (c) Lesot, P.; Merlet, D.; Meddour, A.; Courtieu, J.; Loewenstein, A. J. Chem. Soc., Faraday Trans. 1995, 91, 1371. (19) Berger, R.; Courtieu, J.; Gil, R. R.; Griesinger, C.; Köck, M.; Lesot, P.; Luy, B.; Merlet, D.; Navarro-Vázquez, A.; Reggelin, M.; Reinscheid, U. M.; Thiele, C. M.; Zweckstetter, M. Angew. Chem., Int. Ed. 2012, 51, 8388−8391.

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13C NMR-Based Approaches for Solving Challenging Stereochemical

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