Using NMR spectroscopic methods to determine enantiomeric purity and assign absolute stereochemistry

Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

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Progress in Nuclear Magnetic Resonance Spectroscopy journal homepage: www.elsevier.com/locate/pnmrs

Using NMR spectroscopic methods to determine enantiomeric purity and assign absolute stereochemistry Thomas J. Wenzel *, Cora D. Chisholm Department of Chemistry, Bates College, Lewiston, Maine 04240, USA

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 15 June 2010 Accepted 28 July 2010 Available online 1 August 2010

Ó 2010 Elsevier B.V. All rights reserved.

Keywords: Nuclear magnetic resonance spectroscopy Enantiomeric purity Absolute configuration Chiral solvating agents Chiral derivatizing agents

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Chiral derivatizing agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1. Analysis of secondary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.1. Aryl-containing carboxylic acid reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1.2. Glycoside reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.1.3. Phosphorus-containing reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.1.4. Miscellaneous reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.2. Analysis of primary alcohols, tertiary alcohols and phenols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2.1. Aryl-containing carboxylic acid reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2.2. Phosphorus-containing reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.2.3. Miscellaneous reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.3. Analysis of diols and polyols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 2.4. Analysis of primary amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2.5. Analysis of secondary amines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.6. Analysis of amino alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.7. Analysis of carboxylic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.7.1. Amine reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.7.2. Alcohol reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2.7.3. Miscellaneous reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 2.8. Analysis of amino acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.9. Analysis of ketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.10. Analysis of ethers and epoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.11. Analysis of isocyanates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.12. Analysis of alkyl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.13. Analysis of thiols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.14. Analysis of sulfoxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 2.15. Analysis of phosphorus chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

* Corresponding author. E-mail address: [email protected] (T.J. Wenzel). 0079-6565/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.pnmrs.2010.07.003

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

3.

4.

5. 6.

7.

2.16. 2.17. 2.18. Chiral 3.1. 3.2. 3.3. 3.4. 3.5.

Analysis of phosphates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis of alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The use of isotopically chiral probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . solvating agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alcohol reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amine reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphorus-containing reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cavity and receptor compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.1. Native cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.2. Permethylated cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.3. Carbamoylated cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.4. Miscellaneous neutral cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.5. Carboxymethylated cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.6. Sulfated b-cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1.7. Sulfobutylether-b-cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Crown ethers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.3. Calixarenes and calix[4]resorcinarenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.4. Miscellaneous receptor compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metal complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Lanthanide complexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Binuclear lanthanide–silver complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Water-soluble lanthanide complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Palladium complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Platinum complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Rhodium complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Silver complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liquid crystals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Residual dipolar couplings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Micelles and sol–gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Solid-state NMR spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Database methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The utilization of chiral reagents in NMR spectroscopy for determining enantiomeric purity and assigning the absolute configuration of chiral compounds has a long and extensive history. In 1965, Raban and Mislow were the first to show that enantiomers could be distinguished in NMR spectroscopy by preparing derivatives with an optically pure reagent [1]. The derivatization reaction of a pair of enantiomers with an enantiomerically pure reagent produces two diastereomers. Since the diastereomers are no longer enantiomeric, they may exhibit differences in nuclear shielding and thus differences in chemical shifts in their NMR spectrum. If the chiral derivatizing agent is to be used to determine enantiomeric purity, two important features are that no racemization and no kinetic resolution occur in the derivatization step. Kinetic resolution refers to a situation in which one enantiomer reacts faster with the chiral derivatizing agent than the other. Provided no racemication or kinetic resolution occurs, the area of the peaks for the two diastereomers can be used to determine the enantiomeric purity. Chiral derivatizing agents are often used to assign absolute configuration. In most cases, derivatives of the compound with the (R)- and (S)-isomer of the chiral derivatizing agent are prepared and the difference in chemical shifts for specific resonances of the derivative with the (S)-reagent is substracted from that of the (R)reagent to yield DdRS values. One possibility is that the DdRS values show empirical trends that are consistent for a series of compounds with similar structures. In other cases it is known that the diastereomers have a preferred conformation and the chiral derivatizing agent produces specific shielding, usually from an aro-

24 25 26 26 26 28 29 34 38 38 38 40 40 40 41 41 41 41 43 45 48 48 49 50 51 51 52 54 54 57 57 57 58 58 59 59 59

matic group, or deshielding of resonances of the compound under study. In this case, the DdRS values are usually positive for one substituent group of the substrate and negative for the other, which enables the assignment of absolute configuration. Kinetic resolution is rarely an issue when using chiral derivatizing agents to assign absolute configuration, although it may be the case that one enantiomer of the chiral derivatizing agent reacts much more slowly than the other. Some loss of configuration of the chiral derivatizing agent in the reaction may be tolerable provided it is not a complete racemization and is not sufficient to complicate the NMR spectrum to unacceptable levels. One concern is whether or not the derivative actually adopts the preferred conformation that is expected, and it is most reliable when model compounds of similar structure with known configurations are examined as well. Since chiral derivatizing agents require a reaction and are directed toward specific functional groups, the section of this article on chiral derivatizing agents is divided by specific classes of compounds. Soon after Raban and Mislow’s work demonstrating the ability of achieving enantiomeric discrimination in NMR spectroscopy through the use of chiral derivatizing agents, Pirkle demonstrated that is was also possible to use enantiomerically pure chiral solvating agents for the same purpose [2]. In the case of a chiral solvating agent, instead of forming covalent bonds, the chiral reagent and compound of interest associate through van der Waals forces. One advantage of chiral solvating agents relative to chiral derivatizing agents is that the two reagents are simply mixed together in the NMR tube. Another is that there is no concern with kinetic resolution when using chiral solvating agents, and rarely a worry

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about racemization. Hydrogen bonding, dipole–dipole interactions, p–p stacking and steric effects are often important in influencing the magnitude of the association constants between the chiral solvating agent and the enantiomers. With chiral solvating agents, there are two possible causes for the enantiomeric discrimination. Complexes form between the (R)-isomer and (S)-isomer of the substrate (SUB) and the chiral solvating agent (CSA) with respective association constants KR and KS for the equilibria.

ðRÞ-Sub þ CSA ¡ ðRÞ-Sub-CSA KR

ð1Þ

ðSÞ-Sub þ CSA ¡ ðSÞ-Sub-CSA KS

ð2Þ

In most cases the equilibria are in fast exchange on the NMR time scale and the NMR spectrum of the substrate is a time average of the bound and unbound forms. Just like the derivatives with chiral derivatizing agents, the bound complexes of the (R)- and (S)-enantiomers of the substrate with the chiral solvating agent are diastereomers and therefore may have different chemical shifts. If this is the only reason for the enantiomeric discrimination, it is desirable to have the substrate associate with the chiral solvating agent and larger enantiomeric discrimination is observed in solutions where the concentration of chiral solvating agent is high relative to the concentration of substrate. Another possibility is that KR is not equal to KS. Under these circumstances, the enantiomer with the larger association constant spends a higher proportion of time bound to the chiral solvating agent than the enantiomer with the lower association constant. The differences in time-averaged solvation environments caused by the chiral solvating agent and the solvent can lead to differences in chemical shifts between the two enantiomers. Both mechanisms often contribute to some degree with chiral solvating agents. A detailed analysis of the enantiomeric discrimination with chiral solvating agents has been undertaken. When both mechanisms are significant, the spectra can sometimes show exceptionally complex behavior. Under circumstances where a series of spectra are obtained with a fixed concentration of substrate and increasing concentration of the chiral solvating agent, it is possible for enantiomeric signals to split, recoalesce and then reverse their relative positions in the spectra as the concentration of chiral solvating agent is increased. This may happen for some resonances of the substrate and not for others because it depends on the size of the chemical shift differences induced by complex formation [3]. Some important outcomes arise from these experiments. One is that it is best to record a series of spectra with increasing concentrations of the chiral solvating agent relative to the substrate. Using only one concentration could coincidently be at conditions that correspond to a recoalescence point. The second is that it is risky to spike a sample that exhibits enantiomeric discrimination with one of the enantiomers in an attempt to assign signals to the (R)and (S)-isomers, since it is possible that the new substrate-to-chiral solvating agent ratio in the spiked mixture is now at conditions that reverse the relative position in the spectra. Admittedly this behavior is unlikely to be common when using chiral solvating agents in NMR spectroscopy, but the possibility should be considered [3]. Chiral solvating agents are often used to determine enantiomeric purity. Under conditions of fast exchange, an advantage of using chiral solvating agents to determine enantiomeric purity is that the reagent does not need the high degree of enantiomeric purity that is required with a chiral derivatizing agent. The higher the enantiomeric purity of the chiral solvating agent, the more substantial the enantiomeric discrimination in the spectrum of the substrate, but any enantiomeric discrimination should unequivocally represent the enantiomeric purity of the substrate in the integrated areas of the resonances. There are also many instances in which chiral solvating agents can be used to assign absolute configuration. As with

3

chiral derivatizing agents, trends with DdRS values that result either because of predictable shielding/deshielding effects or through empirical observations of compounds with closely related structures are used in making the assignment. Chiral metal complexes with enantiomerically pure ligands can also be used to produce enantiomeric discrimination in the NMR spectra of compounds that act as ligands. The metal is either a hard or soft Lewis acid, which then influences the types of compounds that function as Lewis base donor ligands and represent suitable substrates for analysis. Reactions similar to those represented in Eqs. (1) and (2) can be used to describe the association of a donor substrate with the metal. Depending on the particular metal complex, the exchange may be fast or slow on the NMR time scale, which then influences how the experiment is performed. A final important strategy for chiral NMR discrimination involves the use of chiral liquid crystalline solvents. Chiral liquid crystals orient in an applied magnetic field. Enantiomers will no longer tumble freely in a liquid crystal but will orient as well. Each enantiomer of a pair often has a different orientation relative to the applied magnetic field. This can lead to chemical shift anisotropy comparable to what occurs with chiral derivatizing agents, chiral solvating agents and metal complexes. What is usually more useful is that the different orientations lead to different dipolar 1H–1H and 1 H–13C coupling constants. Alternatively, a quadrupolar nucleus like 2H undergoing isotropic tumbling has no quadrupolar splitting on its 2H signal. With anisotropic tumbling, there is a residual quadrupolar splitting and the 2H signal appears as a doublet. The magnitude of the quadrupolar splitting depends on the orientation with respect to the applied magnetic field, which leads to two doublets for a pair of enantiomers with different orientations. When analyzing the NMR spectra of substrates with chiral derivatizing agents, chiral solvating agents and metal complexes, resonances closer to the chiral center often show the largest degree of enantiomeric discrimination. Also, resonances that show coupling to fewer nuclei often are more convenient to monitor, although the dispersion achieved with the higher field instruments available today often allows the utilization of more complex and highly coupled resonances. A 1H-d-resolved two-dimensional NMR method for the visualization of enantiomers has been developed. The method allows a distinction of subtle chemical shift differences between resonances of enantiomers even if the resonances are coupled to other nuclei. The utility of the method was demonstrated using a chiral lanthanide shift reagent and a chiral liquid crystal [4]. Analysis of the minor enantiomer to levels of 1% is readily achievable in NMR spectroscopy, although NMR methods for analyzing samples to lower percentages of the minor enantiomer have been described. One report describes a method using lanthanide shift reagents that facilitated the analysis of systems in which the minor enantiomer was present at only 0.3% [5]. Another compared the integrated area of 13C satellite bands for a resonance of the major enantiomer to the area of the resonances of the minor enantiomer in order to more accurately determine enantiomeric purity [6]. A book published in early 2007 provides a comprehensive treatment on the use of NMR spectroscopy for chiral discrimination [7]. A comprehensive review on chiral reagents that have been used to enantiomerically discriminate the NMR spectra of ethers and epoxides has been published [8]. A review that thoroughly documents the variety of chiral derivatizing agents and chiral solvating agents that have been used to assign the absolute configurations of sulfoxides has also been published. This article compares different reagents and recommends particular ones that are judged most reliable for assigning the absolute configuration [9]. A comprehensive review that thoroughly describes and evaluates the effectiveness of chiral solvating and derivatizing agents for the analysis of 1- and 2-hydroxy phosphonates and 1- and 2-aminophosphonates has been published [10]. A broad review on the use of chiral

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

reagents for assigning absolute configuration has recently been published [11]. A comprehensive coverage of the use of NMR spectroscopy for chiral discrimination is outside the scope of this article. Instead, the most widely studied and applicable chiral reagents that have been developed over the past 45 years for the measurement of enantiomeric purity and assignment of absolute configuration are described. Also, reagents that represent the range of compounds that have been used for chiral discrimination are presented. In addition, important new studies that have been published since the comprehensive 2007 book are included. While the use of chiral reagents for enantiomeric discrimination is certainly a mature area of inquiry, many new reagents have been described in the past few years. Also, other studies report important applications of existing reagents to new classes of compounds. Concerning future prospects of developments in the area of using NMR spectroscopy for chiral discrimination, it is reasonable to expect that new reagents will continue to be developed. In addition, a procedure in which chiral discrimination can be achieved in NMR spectroscopy without the need of a chiral reagent has been shown to be theoretically possible. The procedure is based on the principle that a rotating nuclear moment induces an electric dipole that has a specific orientation. Following a p/2 pulse, there is a precessing electric polarization. In the presence of an applied electrostatic field, a chirally sensitive magnetization results [12]. One strategy would be to observe a rotating electric polarizability. Another involves using magnetoelectric shielding [13]. These and other articles show that it is theoretically possible to achieve chiral discrimination without the use of chiral reagents. However, they also indicate that the effect is too weak to be measured on existing equipment [14].

OMe F3 C

COOH

1 MeO

COOH

2 COOH F

CN

2. Chiral derivatizing agents 2.1. Analysis of secondary alcohols 2.1.1. Aryl-containing carboxylic acid reagents Aryl-containing carboxylic acids such as a-methoxy-a-trifluoromethylphenylacetic acid (1 – MTPA, Mosher’s reagent), a-methoxyphenylacetic acid (2 – MPA), a-cyano-a-fluoro-p-tolylacetic acid (3 – CFTA), 2-methoxy-2-(1-naphthyl)propionic acid (4 – MaNP) and a-(9-anthryl)-a-methoxyacetic acid (5 – 9-AMA) are effective chiral derivatizing agents for assigning the absolute configuration of secondary alcohols. The utilization of MTPA by Dale and Mosher in 1973 for assigning the absolute configuration of secondary alcohols is a landmark accomplishment in NMR chiral analysis [15]. The assignment of absolute configuration using these aryl-containing carboxylic acids is predicated on the derivative adopting a preferred conformation [16], and that this conformation occurs independent of the substituent groups on the alcohol [17]. Fig. 1 illustrates the preferred syn-periplanar (sp) conformation of the MTPA derivative of a secondary alcohol. A detailed computational investigation of MTPA esters of secondary alcohols indicates that hyperconjugative interactions are responsible for the stabilization of the syn- and anti-periplanar conformations and further explain the preference for the sp conformer [18]. (OMe) Ph

L1

(Ph) OMe

3

OMe COOH

4 MeO

COOH

(R)-MTPA (S)-MTPA

O

L2

CF3 H

O

5 Fig. 1. Conformational model for the (R)- and (S)-MTPA derivatives of a secondary alcohol.

5

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

While MTPA is the most widely known and frequently used of the aryl-containing carboxylic acid reagents, there are several others that actually give larger DdRS values and allow for more reliable assignment of absolute configuration. One that has been widely studied and thoroughly reviewed is MPA (2) [7,20]. The first reports with MPA noticed larger DdRS values than observed with MTPA, but racemization in the derivatization step restricted its use [15,24]. Derivatization schemes that reduce the racemization of MPA have facilitated its use [25]. The larger DdRS values for MPA derivatives of secondary alcohols relative to those with MTPA occur because the MPA derivative has a greater preference for the sp conformation [26,27]. There are two other strategies that can be used with MPA derivatives of secondary alcohols to increase the reliability of configuration assignment. One is to add Ba(II)perchlorate to the sample. The Ba(II) associates with the derivative in a bidentate manner at the methoxy and carbonyl oxygen atoms. This association increases the proportion of the sp conformer and the sign of the DdBa value correlates with the absolute configuration of the secondary alcohol [28]. A second is to record the spectrum at two different temperatures, usually ambient and about 100 °C lower. Lowering the temperature leads to an enhancement of the population of the sp conformer and the DdT1T2 values correlate with absolute configuration [26,29]. A similar process occurs with MTPA derivatives of secondary alcohols on the addition of La(hfa)3 (hfa = 1,1,1,5,5,5-hexafluoro2,4-pentanedionate). The La(III) bonds to the MTPA derivative in a bidentate manner at the methoxy and carbonyl oxygen atoms and alters the conformational preference, in this case reversing the orientation of the phenyl ring. Changes in the DdRS values correlate with the absolute configuration [30]. Reagents with larger aromatic rings such as 9-AMA (5) and MaNP (4) exhibit greater shielding than those with phenyl rings and usually produce larger DdRS values for secondary alcohols than observed with MTPA [7]. CFTA (3) is another reagent that is especially effective for the analysis of secondary alcohols. With MaNP and CFTA, the absence of a hydrogen atom on the stereogenic carbon reduces the likelihood that a loss of configuration occurs in the derivatization step. An analysis of the crystalline state configuration of 22 ester derivatives of MaNP (4) confirmed the preference for the sp conformer used to assign absolute configuration in NMR studies based on DdRS values [31]. A study of the effect of solvent on MaNP derivatives found that the syn–syn conformation was stable in a wide variety of solvents including chloroform-d, cyclohexane-d12, benzene-d6, methanol-d4, acetonitrile-d3, dimethylsulfoxide-d6, pyridine-d5, acetone-d6, dichloromethane-d2 and acetic acid-d4. Hydrogen bonding in methanol and other protic solvents appears to stabilize the syn–syn conformation leading to the largest DdRS values of those studied. While suitable DdRS values are likely to be obtained with MaNP derivatives in chloroform-d, if not, it is recommended to record the spectrum in methanol-d4 [32]. The utility of MaNP for assigning the absolute configuration of non-terminal aliphatic acetylenic alcohols such as (S)-()-17-octatriacontyl-19-ol (8) that have similar chain lengths in the substituent groups has been described [33]. The utility of MaNP for assigning the absolute configuration of secondary alcohols has been thoroughly reviewed [34].

Of special significance is the shielding by the phenyl ring. As seen by the illustration in Fig. 1, the L1 group is shielded by the phenyl ring in the derivative with (R)-MTPA, whereas the L2 group is shielded in the derivative with (S)-MTPA. By preparing the derivative with both the (R)- and (S)-isomer of the aryl-containing carboxylic acid, the sign of the difference in chemical shifts between the two derivatives (DdRS) is negative for L1 and positive for L2 for the structure in the figure and can be used to assign the absolute configuration. The magnitude of the DdRS values depends on the population of the preferred conformer and the degree of shielding of the aromatic ring. When Dale and Mosher’s work was first published, most investigators had access only to low-field NMR spectrometers. Utilization of the 1H NMR spectrum for assigning absolute configuration was often compromised by overlapping resonances. An advantage of MTPA was the presence of the CF3 group and 19F signal. Trends in the relative order of the 19F signals that correlated with absolute configuration were observed, although using only one resonance to make such assignments has its risks. As high-field NMR spectrometers became more widely available, the use of the so-called modified Mosher method was recommended [19]. Using high-field and two-dimensional NMR methods, it is possible to determine the chemical shifts of many more 1H resonances on L1 and L2 and more reliably assign the absolute configuration. Reviews of the use of MTPA esters for assigning absolute configuration have been published [20,21]. These reports detail when aspects of the substrate may influence the preferred conformation in unexpected ways such that DdRS values may lead to improper assignment of the absolute configuration. At times it may be preferable to use other solvents such as benzene-d6, pyridine-d5 or methanol-d4 with MTPA esters, the latter solvent working especially well [21]. A detailed protocol for using MTPA derivatives to assign absolute configurations has been published. This report also highlights the fact that the (R)- and (S)-configurations are different for the acid and acid chloride reagent because of the different prioritization of the substituent groups. Use of the (R)-MTPA acid leads to the (R)-ester, whereas use of the (S)-acid chloride leads to the (R)-ester [22]. Compound 6 represents an achiral secondary alcohol with two identical substituent groups. Resonances of corresponding methylene groups are prochiral and have identical chemical shifts in the absence of a chiral reagent. In the ester derivative with (R)- or (S)MTPA, the corresponding pairs of prochiral methylene groups of 6 show distinct resonances in the 1H NMR spectrum. (S,S)-Petrocortyne A (7) is chiral but has rather similar substituent groups and has local symmetry from C8 to C20 about the secondary hydroxyl group. Instead of performing the standard analysis of calculating DdRS values, it is possible to subtract the chemical shifts of symmetry-related pairs of methylene resonances in a single (R)- or (S)MTPA derivative. The positive or negative values correlate with the absolute configuration about C14. This procedure should apply generally to all aryl-containing carboxylic acid reagents [23].

OH

6

OH

12

OH

7

6

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

HO

H

8 A possible problem that arises with the aryl carboxylic acidcontaining reagents is whether the expected conformer is actually preferred for the substrate under study. If the substrate does have an unusual property that significantly influences the conformational preference, the utilization of DdRS values to determine absolute configuration is potentially flawed. With CFTA (3) esters, the IR spectrum has two different carbonyl stretching frequencies for the two preferred conformations. Examining the IR spectrum and the intensity of these two bands allows a determination of whether or not the conformer preference needed to assign the absolute configuration is met [35]. Using ()-menthol (9) as a test substrate, the magnitude of the DdRS values of derivatives of MPA (2), MTPA (1), MaNP (4) and eight other similar reagents with 1-naphthyl, 2-naphthyl, 2-anthryl and 9-anthryl groups were compared. The DdRS values are comparable for the reagents with anthryl and naphthyl rings and smaller for those with phenyl rings. The reagents with the 1-naphthyl and 9-anthryl groups provide the best discrimination. A more thorough study of MPA, MTPA and a-methoxy-a-(1-naphthyl)acetic acid (1-NMA) to produce long-range discrimination was evaluated for a series of prochiral alcohols (6). The identical substituent groups had 0–15 methylene groups in each. For 6, the methyl and methylene groups are prochiral and become diastereotopic in the derivatives with the methoxy acetic and propionic acids. With 1-NMA, it is possible to discriminate between the prochiral methyl groups in all of the compounds studied. An interesting observation is that the signs of the DdRS values cross over from positive to negative over the region of six to eight methylene groups in the substituent groups of 6. A study of (S)-10-nonadecanol-1,1,2,2-d4 (10), a chiral derivative achieved by selective deuteriation, comfirmed the crossover in the signs of the DdRS values [36].

OH

9 D

OH

D

on chloroform-d, they do not need to be removed from the NMR tube prior to recording the spectrum [37]. 2.1.2. Glycoside reagents Several procedures for assigning the absolute configuration of secondary alcohols in derivatives with glycosides have been developed. Derivatives of secondary alcohols with D-glucose or D-mannose exhibit differences in the C10 resonance of the glucone and a- and b-carbons of the alcohol that correlate with the absolute configuration of the alcohol [38,39]. The method is effective for aliphatic, cyclic [39] allylic and benzylic alcohols [40]. Reaction of a monosaccharide with 2-butanol leads to a number of J-couplings (H1A-H20 A, H5A-H10 A, H1B-H20 B, H5B-H40 B) that have specific values that correlate with the absolute configuration. The method can be used with an enantiomerically pure monosaccharide such as glucose, mannose or rhamnose to assign the configuration of a secondary alcohol. D-Mannose and L-rhamnose are preferable because they favor the a-configuration of their glycosidic bonds [41]. The b-protons of the alcohol in derivatives of secondary alcohols with tetra-O-acetylglucose show perturbations in chemical shifts that can be used to assign absolute stereochemistry. The method works for alcohols with methylene groups at both b-positions as well as alcohols with substituents at the b-positions [42]. Similarly, derivatives of secondary alcohols with tetra-O-benzoyl-b-L-(or D-)pyranosyl bromide exhibit perturbations in the 1H NMR spectra that can be used to assign absolute stereochemistry. Differential shielding from the benzoyl rings of protons syn or anti to the endocyclic glucopyranoside oxygen atoms, as shown in Fig. 2, is used in making the assignment. For the b-D-derivative (Fig. 2a), R1 is shielded by the benzoyl group whereas R2 is deshielded by the oxygen atom. The reverse trends occur in the b-L-derivative (Fig. 2b) [43]. A procedure using either a b-D- and b-L-fuco- or arabinofuranoside (11) as a chiral derivatizing agent to assign the absolute configuration of secondary alcohols has been developed. A derivative of the alcohol with the tetraacetate derivative is prepared and the acetate groups are then removed using an alkaline hydrolysis. The 1H or 13C NMR spectrum in pyridine-d5 is recorded. Solvent induced shifts from the pyridine show a pattern that correlates with the absolute configuration of the alcohol [44,45]. The fuco- or arabinofuranoside derivatives exhibit comparable enantiomeric discrimination in the NMR spectra, although the tetraacetate derivative of the arabinofuranoside needed in the analysis scheme is more easily prepared [46]. OH

H

O

HO 7 D

8

D

10 A procedure to facilitate the preparation of derivatives with MPA, 9-AMA, N-Boc phenylglycine (BPG) and MTPA is to bind them via anhydride linkages to a carboxypolystyrene. These polymeric resins can be used directly in an NMR tube to prepare the derivatives of primary amines, primary and secondary alcohols, cyanohydrins, thiols, diols, triols and amino alcohols. Since the resins float

HO

OH

11 If the absolute configuration of one monosaccharide of a disaccharide and the anomeric configuration joining the two monosaccharides are known, then perturbations of the 13C resonances can be used to assign the configuration of the second mono-

7

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

(a)

(b) OBz O

BzO BzO

R2 O

O R1

BzO

H

H

OBz

O OBz

R1 R2

BzO

OBz H

H

Fig. 2. Configurational models for secondary alcohol derivatives with (a) b-D-glucopyranoside and (b) b-L-glucopyranoside.

saccharide [47]. Consistent behavior was noted among 19 different 1,10 -disaccharides [48]. 2.1.3. Phosphorus-containing reagents A variety of phosphorus-containing reagents have been explored as chiral derivatizing agents for secondary alcohols. Many have P–Cl bonds that undergo a reaction with the secondary alcohol. Often the 31P signal is conveniently monitored for the presence of enantiomeric discrimination and the reagents are useful for determining enantiomeric purity. Derivatization reactions are usually performed directly in the NMR tube. Certain of the reagents exist in either the P(III) or P(V) form. The P(III) reagents often exhibit larger enantiomeric discrimination in the NMR spectrum, although the P(V) reagents are more stable [7,49]. Addition of sulfur to the P(III) derivative in the NMR tube converts it to the phosphorus(V) derivative [7,50]. One caution to note is that the 31P atoms in the two different diastereomers may have different spin-lattice relaxation times. Appropriate delay times are needed between pulses for accurate integration of the signals [51]. One family of phosphorus-containing reagents incorporates optically pure diamine groups with either a chlorine atom (12) or dimethylamine moiety (13) [49]. Reagents of this type are prepared by reaction of the diamine with phosphorus trichloride. Compounds 14–19 are examples of the chiral diamine ligands that have been studied in these chiral derivatizing agents [7]. For secondary alcohols, enantiomeric discrimination in the 31P NMR spectra of the derivative with 18 was larger than that with 14 [52]. In another comparative study of secondary alcohols, enantiomeric discrimination in the reagent with 15 or 19 was larger than observed with other diamine groups [53].

NH

NH

14

NH

NH

15 CF3

Cl P

R1 N

R1 N NH

R2

R2 NH

12

N P

R1 N

R1 N

R2

16

R2

13

CF3

8

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

N

The enantiomeric purity of a-hydroxyphosphonates (20) can be analyzed using the reagent with 17 [51,54]. Furthermore, the P–P and P–H coupling constants show a consistent trend that correlates with the absolute configuration [51]. Similarly, the 31P resonances of a series of phenyl carbinols with the phosphorus derivative of 14 exhibit consistent patterns that correlate with absolute configuration. The absolute configuration of an unknown could be assigned using 31P chemical shifts with the (R,R)- and (S,S)-cyclohexanediamine derivatives [55]. O

N

OH

P

RO RO

R1

20 17

N

N

In recent studies, cyclic secondary alcohols were analyzed using cyclohexane diamine derivatives of 14–16 as either the P(III) or P(V) oxidation state. The cyclohexane derivative (14) produces larger discrimination than the 1,2-diamino-1,2-diphenyl derivative (15). Using chemical shifts with the (R,R)- and (S,S)-diamine reagents, the DdRS values in the 31P spectra show specific trends that can be used to assign the absolute configuration of the alcohol [56]. A second family of phosphorus-containing reagents has optically pure diol ligands (21). These are analogous to the diamine reagents (12) and a variety of diol ligands have been examined [7], three examples of which employ a diethyl or diisopropyl tartrate unit (22) [57], a 2,20 -dihydroxy-1,10 -binaphthalene (BINOL) unit (23) [58,59], and a tartaramide derivative (24) [60]. The derivative with 24 was judged more effective than 22 on a range of alcohols because there are fewer by-products in the derivatization reaction [60]. The BINOL derivative was recently used in one-pot procedures to analyze the products of catalytic asymmetric hydrosilylations and transfer hydrogenations of prochiral ketones [61]. Cl

18

P O

O

R

R

21 OR

NH HO

O

NH O HO OR R = Et, i Pr

19

22

9

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

OH

H OH

O O

H

H O

O

23

P

N HO

Cl

26

O O HO N

24 [5]-Helol phosphate (25) is especially suitable for the analysis of secondary alcohols with remote chiral centers. Secondary alcohols react at the P–Cl group to form the corresponding phosphate, and the chain of the substrate fits into the helical groove of 25. The 31 P NMR spectrum is monitored in chloroform-d or acetonitriled3 [62].

MeO

H

O

O

2.1.4. Miscellaneous reagents (+)-Octahydro-8,9,9-trimethyl-5,8-methano-2H-1-benzopuran2-ol (27), also known as Noe’s reagent, can be used to assign the absolute configuration of alcohols. Fig. 3 shows the reaction that occurs with alcohols. If the substrate has bulky (b) and planar or linear (pl) groups, a stabilizing interaction between the electron lone pair of the oxygen atom and r* orbital of the Csp3–Csp2 bond occurs in the acetal product. This leads to predictable trends in the 1H [64] or 13C [65] chemical shifts that correlate with the absolute configuration.

OMe

OH O OMe

O Cl

P

OMe

MeO O

MeO

MeO

27 2-(Anthracene-2,3-dicarboximido)cyclohexane carboxylic acid (28) is useful for the analysis of secondary alcohols with remotely disposed chiral centers. The configuration of the derivative positions the anthryl ring of 28 adjacent to the chain of the alcohol as shown in Fig. 4. Shielding from the anthryl ring extends over a long distance of the alcohol chain. A secondary alcohol with a chiral carbon at C16 and two alkyl groups differing by one carbon can be discriminated in the derivative with 28 [66]. Furthermore, the DdRS values for secondary alcohols show trends that correlate with absolute configuration [67].

O OMe

25 Secondary alcohols react with 2-chloro-(4R,5R)-bis[(1R,2S,5R)menth-(1-yloxycarbonyl)]-1,3,2-dioxaphospholane (26). Enantiomeric discrimination suitable for determining enantiomeric purity is observed in the 31P NMR spectrum. The reagent can be stored in solution in anhydrous THF for at least 14 days, although an advantage over many other phosphorus-containing reagents is that 26 is stable to air during transfer and other handling [63].

N

O

28

HOOC

10

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

HO b H pl

O

O

b H

H

+

pl

OH

O

HO b H

pl H

O

O

b H

pl

H

Fig. 3. Acetal derivatives formed by the reaction of the two configurations of a secondary alcohol with Noe’s reagent.

O O O

N

O Fig. 4. Shielding by the anthryl ring in derivatives of secondary alcohols with (1R,2R)-2-(anthracene-2,3-dicarboximido)cyclohexane carboxylic acid.

Isocyanates can be used as chiral derivatizing agents for alcohols. Derivatization with 1-phenylethyl isocyanate (29) or 1-(1-naphthyl)ethyl isocyanate (30) results in Z- and E-rotamers for the corresponding cambamate derivative [68]. For the naphthyl derivative, the Z-rotamer is predominant in the derivatives with secondary alcohols. Shielding from the naphthyl ring can be used to assign the absolute configuration. The use of 30 is preferable to 29 because of greater shielding from the naphthyl ring [69].

O C N

O C N

29

30

2-(20 -Methoxy-10 -naphthyl)-3,5-dichlorobenzoic acid (31) and 20 -methoxy-1,10 -binaphthyl-2-carboxylic acid (32) are atropisomeric compounds that can be used to assign the absolute configuration of secondary alcohols. Derivatives with 31 adopt a specific conformation and the shielding by the naphthyl ring produces DdRS values that correlate with absolute stereochemistry. A detailed study of the conformation of 32 found a higher preference for the sp over the ap conformation, but indicated that shielding in

11

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

the ap conformation is largely responsible in producing the DdRS values with a-chiral alkyl alkyl and alkyl aryl alcohols. Using this understanding, it was possible to predict that 1-(10-bromo-1-anthryl)-2 naphthoic acid (33) would be more effective as a chiral derivatizing agent. The utilization of 33 was shown to provide more reliable assignment of absolute configurations of alcohols than 32 [70].

Se

HN

O

Cl

Ph

34

2.2. Analysis of primary alcohols, tertiary alcohols and phenols HOOC

Cl

2.2.1. Aryl-containing carboxylic acid reagents Far fewer studies on the use of aryl-containing carboxylic acids for primary and tertiary alcohols have been undertaken. The DdRS values of the methylene resonance of 14 primary alcohols chiral at the C2 position show trends with the MTPA (1) derivatives that correlate with absolute configuration. Compounds with a conjugated group or chiral center at C3 may lead to unreliable assignments, though [72]. Similarly, the a-methylene resonances of 2-substituted-1-propanols show a consistent trend with absolute configuration in the MTPA derivatives for 17 of 21 substrates. The anomalous behavior of four substrates necessitates caution when assigning absolute configuration of such substrates [73]. In a recent study, the absolute configuration of 1,3-dihydroxyketones (35) was assigned on the basis of their MTPA esters. Reaction with (R)- and (S)-MTPA occurred mostly at the primary hydroxyl group. Trends on compounds with known configurations and findings from prior reports on C2-chiral primary alcohols were used to assign the absolute configuration of the 1,3-dihydroxyketones [74].

MeO

31

HOOC MeO

O R

32

OH

OH

35

Br COOH

33 Secondary alcohols react at the selenium atom of 4-methyl-5phenyloxazolidine-2-selone (34) in the presence of triphenylphosphine to produce the selenide derivative. Enantiomeric discrimination, as evidenced by the presence of two singlets, is observed in the 77Se NMR spectrum. The large chemical shift range in the 77 SE NMR spectrum means that subtle differences in the enantiomers, as occurs in compounds with remote chiral centers, can be distinguished [71].

9-AMA (5) is a better reagent than MTPA to use for assigning the configuration of C2 chiral primary alcohols. Trends in the DdRS values of a series of acyclic b-chiral primary alcohols in derivatives with 9-AMA are much more reliable than those with MPA (2) and MTPA. The conformational preference and larger shielding of the anthryl ring of 9-AMA relative to the phenyl rings of MPA and MTPA account for the greater effectiveness of 9-AMA. Highly hindered compounds or those with the primary hydroxyl group on a cyclic compound require more care in making the assignment [75]. Using a series of model compounds of known configuration, a subsequent study of b-chiral primary alcohols with (R)- and (S)-9-AMA found that only the Cb–H and signals from one of the substituent groups are needed to make a reliable assignment. This allows the analysis of compounds in which one of the substituent groups has no hydrogen atoms. The assignment could be further confirmed by lowering the temperature of the derivative from 300 to 213 K. The change in conformation on lowering the temperature results in larger DdRS values [76]. In recent work, 9-AMA has been used to assign the absolute configuration of myrioneurinol (36), a compound with a b-chiral primary alcohol [77].

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OH

H H OH HO

N H

39

H

O

36 The analysis of tertiary alcohols with aryl-containing carboxylic acids is limited in scope [78,79]. In a study of 11 model alcohols, a-methoxy-a-(2-naphthyl) acetic acid (2-NMA) produced much larger DdRS values than MTPA and MPA. Racemization of 2-NMA in the derivatization step necessitated a column chromatography separation of the diastereomers prior to the NMR analysis [79]. Ketone cyanohydrins such as (E)-2-hydroxy-2-methyl-4phenylbut-3-enenitrile (37) have a tertiary hydroxyl group. A procedure to assign the absolute configuration using (R)- and (S)-MPA esters has been developed. The method was demonstrated on 16 substrates encompassing cyclic and acyclic compounds. Compounds with an aryl ring at the a-position exhibit some anomalies in the DdRS values at the b-position, but there are other hydrogen atoms that can be reliably used to assign the configuration [80].

NC

OH

37 2.2.2. Phosphorus-containing reagents Several of the phosphorus-containing reagents described earlier for the analysis of secondary alcohols can also be used for primary and/or tertiary alcohols. The family of phosphorus-containing reagents with optically pure diamine groups (14–17) has been used with primary and tertiary alcohols [50] and hydroxyl aryls [81]. Comp 16 and 17 are effective for hindered tert-alcohols such as linalool (38). The derivative with 17 is also effective for the analysis of atropisomeric hydroxyl aryls such as 39 [50,82]. Similarly, phosphorus-containing reagents with optically pure diol ligands (21) with a diethyl or diisopropyl tartrate group (22) can be used to determine the enantiomeric purity of primary and tert-alcohols [57]. The reagent with 23 has also been used with primary alcohols [58,59].

OH

38

[5]-Helol phosphate (25) is especially suitable for the analysis of primary alcohols and phenols with remote chiral centers. The alcohol reacts at the P–Cl group and the chain of the substrate fits into the helical groove [62,83]. For phenylmethyl alcohols such as 40, distinct 31P signals were observed for compounds with up to seven methylene groups [83].

OH Ph

40 The use of 26 for determining the enantiomeric purity of secondary alcohols was described earlier (Section 2.1.3). This mildly air stable phosphorus-containing reagent also produces enantiomeric discrimination in the 31P NMR spectra of primary and tertiary alcohols. Reactions are complete in a few minutes with no specialized procedures required to exclude air or moisture [63]. 2.2.3. Miscellaneous reagents Camphanic acid (41) is a particularly useful reagent for the analysis of prochiral methylene groups of a-deuterated primary alcohols. Early reports at low-field strengths often used paramagnetic lanthanide chelates with the camphanic ester to discriminate the pro-(R) and pro-(S) positions [84]. At the higher field strengths commonly available today, suitable discrimination occurs without needing to add a lanthanide species. The stereoselectivity of deuterium substitution in glucose, galactose, and mannitol by enzymes was analyzed using natural abundance 2H NMR of camphanic acid derivatives [85,86]. O

O

COOH

41 2-(Anthracene-2,3-dicarboximido)cyclohexane (28) is useful for the analysis of primary alcohols with remotely disposed chiral centers. The configuration of 28 positions the anthryl ring adjacent to the chain of the alcohol as shown in Fig. 5, enabling shielding over a long distance. Non-equivalence occurs in the 1H NMR spectra of primary alcohols as far as the C9 group [87,88]. In addition, the DdRS values for primary alcohols show trends that correlate with absolute configuration [87]. 20 -Methoxy-1,10 -binaphthalene-8-carboxylic acid (42) is an atropisomeric reagent that is an effective chiral derivatizing agent

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O

O N O

∗ O

Fig. 5. Shielding by the anthryl ring in derivatives of primary alcohols with (1R,2R)-2-(anthracene-2,3-dicarboximido)cyclohexane carboxylic acid.

for assigning the absolute configuration of b-chiral primary alcohols. The derivatives exhibit preferred rotamers that result from a stabilizing CH–p interaction as well as destabilizing steric effects. NOE correlations are then used to assign the absolute configuration of the alcohol [89].

OMe O COOH

42 The use of b-D- and b-L-fuco- or arabinofuranoside (11) was described earlier (Section 2.1.2) for assigning the absolute configuration of secondary alcohols. The same reagent can be used to assign the configuration of tertiary alcohols. Solvent induced shifts in the 1 H or 13C NMR spectrum in pyridine-d5 show a pattern that correlates with the absolute configuration of the alcohol. Tertiary alcohols where the hydroxyl group is either on a five- or sixmembered ring within a steriod can be studied [90]. Primary alcohols react at the selenium atom of 34 to produce the selenide derivative [71]. Because subtle distinctions in chirality can be observed in the 77Se NMR spectrum, the reagent is useful for analyzing compounds like 1-[2H1]-phenylethanol (43), which is chiral by virtue of deuterium substitution, or 4-phenyl-1-pentanol, which has a remotely disposed chiral center [91]. Ph

COOH

D

43

The bis-MPA esters of 1,2-diols [92,93] and the syn and anticonfigurations of 1,2-, 1,3-, 1,4- and 1,5-diols have been thoroughly investigated [94]. A variety of compounds with known configurations exhibit DdRS values that correlate with the absolute configuration. The patterns can be used to assign the configurations of unknowns. For open-chain sec,sec-1,2-diols with the anti-configuration, it is also found that lowering the temperature of the bisMPA derivative from 298 to 183 K leads to consistent changes in the DdT1T2 values that correlate with absolute configuration. For diols with the anti-configuration, this can be used to confirm assignments based on derivatives with both (R)- and (S)-MPA or in a method where only the (R)- or (S)-derivative is prepared [93,95]. Syn-diols did not show enough differential changes with temperature to assign configuration using only a single MPA derivative [93]. The absolute configuration of 1,2-primary,secondary diols can be assigned using the bis esters with (R)- and (S)-9-AMA. The DdRS values are usually larger with the bis-9-AMA derivative than with the bis-MPA derivative and provide a more reliable assignment. The 9-AMA derivatives exist in equilibrium between the sp and ap conformations and the diastereotopic methylene hydrogen atoms exhibit specific patterns of shielding and deshielding that can be used to assign the stereochemistry. The configuration can also be assigned using only a single (R)- or (S)-9-AMA derivative by examining chemical shifts of the Ca–H resonance from 298 to 183 K [94,96]. MPA can also be used to assign the configurations of 1,2,3primary, secondary, secondary-triols. The tris-MPA esters are prepared and specific trends in the shielding of the H2 and H3 resonances can be rationalized in a way that correlates with the absolute configuration. The reliability of the method was demonstrated by analyzing 24 triols of known configuration [97,98]. Menthoxy acetic acid (44 – MAA) is a useful reagent for assigning the absolute stereochemistry of diols formed from the epoxidation of polycyclic aromatic hydrocarbons. The methylene resonances of the bis-MAA esters of compounds such as the 4,5-dihydrodiol of benzo[a]pyrene (45) show distinct patterns that depend on the absolute stereochemistry of the diol [99]. Derivatives of 46 with MTPA or MPA create a mixture of products that are not amenable for NMR analysis. The reaction with MAA is much cleaner and the patterns of the methylene resonances in the bis-MAA esters can be used to assign the absolute configuration [100].

2.3. Analysis of diols and polyols The successful analysis of diols and polyols using aryl-containing carboxylic acids such as MTPA (1), MPA (2) and 9-AMA (5) depends on the proximity of the hydroxyl groups. If the groups are far enough apart, the same scheme used to assign the configuration of monofunctional alcohols can be used for each moiety of the diol or polyol. If the hydroxyl groups are near each other, the shielding or deshielding effects of two or more derivatizing groups may influence a particular hydrogen atom, thereby complicating the analysis.

O

44

COOH

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OH OH

45 MeO

O

OH OH

46 A variety of boron-containing reagents have been employed as chiral NMR derivatizing agents, some of which are particularly useful for the analysis of diols [7]. The optical purity of 1,2- and 1,3diols can be determined with 2-(1-methoxyethyl)phenylboronic acid (47). The reaction of 47 with a 1,2-diol is illustrated in Fig. 6 [101]. For cis-1,2-diols, the products with 47 show consistent trends in the methoxy resonances that correlate with absolute configuration [102]. Another strategy is to react 2-formyphenylboronic acid with an optically pure amine such as 1-phenylethylamine and a diol to determine the enantiomeric purity of 1,2-, 1,3- and 1,4-diols (Fig. 7) [103,104]. Use of 4-fluoro-2-formylphenylboronic acid (48) provides a similar system in which either 1H or 19F NMR signals can be used to determine enantiomeric purity [105]. HO

taneously determine the identity, enantiomeric purity and concentration of threo diols [106]. The use of b-D- and b-L-fuco or arabinofuranoside (11) was described earlier (Section 2.1.2) for single hydroxyl groups. The same reagent can be used to assign the absolute configuration of 1,2-glycols provided one of the groups is a secondary alcohol. For 1,2-glycols with a secondary and tertiary alcohol on a steroid skeleton, the secondary alcohol reacts with the furanoside. The 13C NMR data is consistent with prior observations of the absolute configuration of secondary alcohols [107]. Phosphorus-containing reagents with optically pure diamine groups (12) were described earlier for determining the enantiomeric purity of primary, secondary and tertiary alcohols. The phosphorus-containing reagent with 15 has been used to analyze 1,2and 1,3-diols. Enantiomeric discrimination is observed in the 31P NMR spectrum [82].

2.4. Analysis of primary amines Aryl-containing carboxylic acids such as MTPA (1), MPA (2) and CFTA (3) react with primary amines to produce the corresponding amides. MTPA derivatives of primary amines have a preference for the sp conformer and the DdRS values are usually larger than those in the MPA derivatives [108]. As with MPA derivatives of secondary alcohols, addition of Ba(II) to MPA amides alters the conformational preference allowing DdBa values of a single derivative to be used to confirm the assignment [109]. Comparative studies on the use of N-Boc phenylglycine (49 – BPG), MTPA and MPA for assigning the absolute configuration of primary amines show that DdRS values with BPG are typically two to three times larger than those with MTPA or MPA [110]. The amide derivative with BPG has a preference for the ap conformation. Derivatives of primary amines with 9-AMA (5) show fairly small DdRS values because the conformational preference does not position the anthryl ring in an especially favorable alignment for significant shielding of the substituent groups of the substrate [108].

OH B

H N

OMe

t

47 HO

49 OH

B

COOH

Bu

H

O

F

48 A sensor array for 1,2-secondary,secondary diols of known configuration was prepared using data obtained with three chiral boronic acid receptors and three pH indicators. The array results in a series of patterns. For unknown diols, and particularly threo diols, it is possible to use pattern recognition techniques to simul-

CFTA is also an effective reagent for the analysis of a-chiral primary amines. The C–F bond of CFTA-amides is anti-periplanar to the carbonyl bond, which is the opposite conformation to that found in CFTA esters. The DdRS values for the 1H resonances are larger than those with MTPA. Another advantage is the high reactivity of CFTA chloride, reducing the likelihood that kinetic resolution will compromise the assignment [111,112]. (R)-N-(2-Nitrophenyl)proline (50) is an effective chiral derivatizing agent for a-chiral primary amines. The amide derivative has an intramolecular hydrogen bond between the NH of the amine and oxygen atom of the nitro group that stabilizes the conformation. Shielding from the phenyl ring produces larger DdRS values then MTPA or MPA. Values are largest in chloroform-d, but the intramolecular hydrogen bond remains in pyridine-d5, acetone-d6, methanol-d4, acetonitrile-d3 and dimethylsulfoxide-d6 as well [113].

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HO

R

OH

OH

B

O

OMe

1

B R2

+

R1

O

R 2

OMe

OH

Fig. 6. Reaction of a 1,2-diol with 2-(1-methoxyethyl)phenylboronic acid.

H

R1

N

H

N

H

O B

n HO

OH

O

B OH

OH

+ R1

n

R2

H CHO

+

+

R2 NH 2

H

R1 O B

n O R2 Fig. 7. Borate–imine complex formed by the reaction of a diol, 2-formylphenylboronic acid and 1-phenylethylamine.

NO 2

intramolecular hydrogen bond, which causes larger DdRS values. O-Methylated amides cannot form the intramolecular hydrogen bonds and adopt a staggered conformation. Larger enantiomeric discrimination is observed with 51 than MTPA, MPA and 50 [114].

N Napht

O

F 3C HOOC

50 (1-naphthyl)(trifluoromethyl) O-carboxy anhydride (51) is an effective chiral derivatizing agent for a-chiral primary amines. The reaction of 51 with a primary amine such as 1-phenylethylamine produces the corresponding a-hydroxyamide (52). The a-hydroxy amide has an eclipsed conformation because of an

O

O

O

51

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H

O

H

O N H Napht

Ph

of triphosgene, reaction of 1-phenylethylamine forms the corresponding carbamoyl derivative (55). As seen in 55, the anti-carbonyl arrangement is stabilized by an intramolecular hydrogen bond. Enantiomeric discrimination in the 77Se NMR spectrum was noted in derivatives of compounds with a remote chiral center such as 4-phenyl-1-aminopentane [118].

CF 3

52 The use of camphanic acid (41) for analyzing the pro-(R) and pro-(S) hydrogen atoms of primary alcohols was described earlier (Section 2.2.3). Similar distinction of the pro-(R) and pro-(S) hydrogen atoms of monodeuteriated or tritiated amines is observed in the camphanamide derivative. The mechanism that causes the discrimination of the HR and HS resonances in the camphanamides is explained by differential shielding of the amide carbonyl group so that the pro-(R) and pro-(S) resonances can be assigned [115]. Similarly, the conformational preference of camphanamides of a-arylethyl amines can be used to rationalize the distinction of the pro(R) and pro-(S) hydrogen atoms in the derivatives [116]. The use of Noe’s reagent (27) was described earlier (Section 2.1.4) for assigning the absolute configuration of alcohols. Although most studies with Noe’s reagent have been done on alcohols, similar conformational rules apply to appropriate amine derivatives as well [64]. Atropisomeric 32 and 33, which were described earlier as useful reagents for the analysis of alcohols (Section 2.1.4), are also effective with primary amines. Of the two reagents, 33 provides a more reliable assignment of the absolute configuration of amines [70]. 1-Phenylethyl isothiocyanate (53) and 1-(1-naphthyl)ethyl isothiocyanate (54) are effective chiral derivatizing agents for determining the enantiomeric purity of amines. The isothiocyanates are more water-stable than isocyanates and react rapidly with amines in n-hexane-d14, chloroform-d, methanol-d4, dimethylsulfoxide-d6 and deuterium oxide to form the thiourea derivatives. Enantiomeric discrimination is observed in the 1H and 13C NMR spectra [117].

H Ph

N

Se

O

N

Me

O

Ph

55 The utilization of 2-formyphenylboronic acid with an enantiomerically pure amine to assign the absolute configuration of a diol was described earlier (Fig. 7). If the reaction is run with enantiomerically pure BINOL (23), the system can be used instead to determine the enantiomeric purity of primary amines [119,120]. The system is successful with b-chiral amines as well as compounds 56 and 57, which have stereocenters at remote positions relative to the amine group. With a-arylethylamines, trends in the chemical shifts of the borate–imine complex exhibit patterns consistent with the absolute configuration of the amine [120]. A detailed protocol for using this system to analyze primary amines has been published [121].

O

S C MeO

N

NH3 Cl

56 NH2

53 S C N

57

54 The enantiomeric purity of primary amines can be determined with 4-methyl-5-phenyloxazolidine-2-selone (34). In the presence

Phosphorus-containing reagents with optically pure diamine groups (12) that were described earlier (Section 2.1.3) for the analysis of alcohols can also be used to analyze amines. Derivatives with 17 [122] and 16 [82] have been employed and enantiomeric purity is determined by monitoring the 31P NMR spectrum. The phosphorus reagent with optically pure BINOL (23) is also effective for amines [123]. Recent work has demonstrated the utility of this reagent for determining the enantiomeric purity of aliphatic and aryl-containing amines [61].

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[5]-Helol phosphate (25), described earlier (Section 2.1.3) for the analysis of primary and secondary alcohols with remote chiral centers, can be used with amines as well. Reaction of the alkyl- or aromatic-containing amine at the P–Cl group forms the corresponding phosphoramide. As with alcohols, amine derivatives with remote chiral centers such as 57 and 58 showed enantiomeric discrimination in the 31P NMR spectrum [62,83].

The (4R,8R)-isomer of lactam 61 is a sterically hindered secondary amine and reaction with MTPA at this site did not work that well. The amide derivative with MPA was successfully prepared and two-dimensional NOE experiments and molecular mechanics indicated that the syn-rotamer was preferred, which is different than that of primary amines. The DdRS values could then be used to assign the absolute configuration [128]. H

NH 2 N R

N N H

58

H

O

61

2.5. Analysis of secondary amines MTPA (1) derivatives of secondary amines exhibit exceptionally large DdRS values that can be reliably used to assign the absolute configuration. The presence of two rotamers and a more complex conformational analysis than occurs with MTPA esters needs to be considered when making the assignment. Nevertheless, a set of conformational rules has been established that can be used to assign the absolute configuration of secondary amines. In some cases, the difference in the discrimination is so great that only a single MTPA derivative is needed to assign the configuration. The use of (R)-MTPA acid chloride is recommended for single derivative studies as it often reacts faster with secondary amines [124,125]. While MTPA is the reagent of choice for analyzing secondary amines, caution must be exercised with certain compounds. Application of MTPA to isoanabasine (59) is complicated because the derivative has two stable rotamers. The first step is to distinguish the major and minor rotamers before being able to assign the absolute configuration. The population of the rotamers was different in the (R)- and (S)-MTPA amides, further complicating the analysis [126]. 2-Aryl pyrrolidines (60) show similar complicating effects in the MTPA derivatives. With these compounds, the MTPA forces a preferred conformer on the pyrollidine ring that shows up in the multiplicity of the H2 signal. The affect on the H2 signal of the (R)-substrate and (S)-substrate is different [127].

N

NH

59

NH

60

The use of camphanic acid for distinguishing the prochiral hydrogen atoms of alcohols and amines was described earlier (Sections 2.2.3 and 2.4). After blocking the two primary amines of spermidine (62) with Boc groups, the camphanamide derivative of the secondary amine exhibited distinct resonances for the two prochiral hydrogen atoms at the C10 position [129].

NH2 H 2N

N H

62

2.6. Analysis of amino alcohols The various reagents that have been described previously for alcohols and amines have the potential to be used for amino alcohols. Since many reagents will react with both the amine and alcohol moiety, as with diols, assigning the absolute configuration of an amino alcohol in which the two moieties are in close proximity may be complicated by shielding and deshielding effects from both of the attached chiral reagents. A detailed analysis of the use of MPA (3) to assign the absolute configuration of secondary,primary and primary,secondary-1,2-amino alcohols has been undertaken [130,131]. Straightforward predictions of shielding and deshielding effects are complicated by the two MPA units in the bis-derivatives, especially since MPA esters have a preference for the sp conformer whereas MPA amides have a preference for the ap conformer. However, the methoxy and Ca–H resonances of the MPA units show characteristic trends that correlate with the absolute configuration of the amino alcohol [130]. Using only a single derivative with either (R)- or (S)-MPA, it is possible to confirm the assignment by recording spectra at 298 and 183 K. Conformational changes that occur with temperature cause perturbations in the Ca–H resonance that correlate with absolute configuration [131]. 2-(1-methoxyethyl)phenylboronic acid (47), which was described earlier (Section 2.3) for determining the optical purity of 1,2- and 1,3-diols, can also be used with 2-amino alcohols. 2-Formylphenylboronic acid undergoes reactions with a primary amine and diol to form the corresponding imino-boronate ester (Fig. 7) [101]. This system can also be used to analyze 1,2-amino alcohols by 1H NMR spectroscopy. Enantiopure (syn)-methyl-2,3dihydroxy-3-phenylpropionate (63) is used as the diol in the reaction. The hydroxyl group of the amino alcohol is first silylated with tert-butyldimethylsilyl chloride (TBDMS). The amine group then

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reacts with the aldehyde to generate the imine derivative needed to determine enantiomeric purity [132]. HN

O

H

HO OMe

Ph

O

OH

HN

O

OH

63 O

Uryl-based BINOL-aldehydes, one example of which is (S)-2-hydroxy-20 -(3-phenyluryl-benzyl)-1,10 -binaphthyl-3-carboxaldehyde (64), react with 1,2-amino alcohols to form an imine as shown for the (R)-enantiomer of the amino alcohol (65) [133]. Similarly, BINOL-based receptors with a pyrrole-2-carboxamide moiety, one example of which is (S)-2-hydroxy-20 -(3-(1H-pyrrole2-carboxamido)benzyl)-1,10 -binaphthyl-3-carboxaldehyde (66), form an imine bond with 1,2-amino alcohols as shown for the (R)-enantiomer of the alcohol (67) [134]. Intramolecular hydrogen bonds constrain the motion of the derivatives and account for the selectivity of 64 and 66.

66

OH

H

HN N

H H

HN

O

HN

OH O

HN

O

O OH O

67

64

H

H

R

H H O

N

N

H N

H

O

a-Methylbenzenepropanoic acid amides of pseudoephedrine and ephedrine undergo a stereospecific cyclization in the presence of triflic anhydride-pyridine to form a 4,5-dihydro-3,4-dimethyl-5phenyl-1,3-oxazolium triflate. Fig. 8 illustrates the reaction for the pseudoephedrine amide of (+)-a-methylbenzene propanoic acid. Inversion of the benzylic center occurs in the reaction such that pseudoephedrine amides give cis-4,5-disubstituted oxazolium heterocycles, whereas ephedrine amides give the trans-derivative. In a study of 52 different pseudoephedrine amide alkylation reaction products, there were clear distinctions in the 1H NMR spectrum of the products that allow the diastereomeric composition of the starting amides to be determined [135].

O

2.7. Analysis of carboxylic acids O

Common chiral derivatizing agents for carboxylic acids consist either of an enantiomerically pure amine or alcohol that is used to prepare the corresponding amide or ester, respectively. 65

2.7.1. Amine reagents Phenylglycine methyl ester (68 – PGME) is an especially effective reagent for assigning the absolute configuration of carboxylic

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O

TfO Ti2O, Py

N

O

CH 2Cl2

H

0 °C

nOe

OH

H

N

Fig. 8. Reaction of the a-methylbenzenepropanoic acid amide of pseudoephedrine to form the 4,5-dihydro-3,4-dimethyl-5-phenyl-1,3-oxazolium triflate derivative.

HA

HB

HC O

HZ

HY

(H)

(Ph)

(R)

Ph

H

(S)

HX

Z

PGME plane H

H

O

Fig. 9. Conformational preference of PGME amide derivatives of a-chiral carboxylic acids.

acids [136]. X-ray and NOE data confirm that the amide derivative adopts the conformation shown in Fig. 9 [137]. The expected signs of the DdRS values are predicated on the shielding by the phenyl group in the (R)- and (S)-PGME derivatives. The utilization of PGME for assigning the absolute configuration of carboxylic acids has been reviewed [7,19]. In additioning to assigning the absolute configuration of a-chiral carboxylic acids, PGME has been used to analyze a-aryl [138], a-hydroxy-, a-alkoxy- and a-acyloxy-a,adisubstituted acetic acids [136], as well as b,b-disubstituted propionic acids [136].

(72), which are chiral at the b-position, have been assigned using amides of PEA. Specific shielding from the phenyl ring allowed the assignment of these b-chiral compounds [142]. NH2

O H2 N

69 OMe NH2

68 1-Phenylethylamine (69 – PEA), 1-(1-naphthyl)ethylamine (70 – NEA) and 1-(9-anthryl)ethylamine (71 – AEA) form amide derivatives with carboxylic acids [139–141]. The derivatives adopt a preferred conformation and comparative studies show that the order of enantiomeric discrimination is AEA > NEA > PEA, which is explained by the greater shielding by the larger rings [140]. PEA and NEA are commercially available, whereas AEA is not. These reagents have been extensively used to analyze a-chiral carboxylic acids [7]. The preferred conformation leads to predictable signs in the DdRS values that can be used to assign the absolute configuration of 3-methyl substituted carboxylic acids [140] and carboxylic acids with other substituent groups at the b-position [141]. The amide derivatives have major and minor rotamers that need to be considered when assigning the absolute stereochemistry. The absolute configuration of 2-(2-oxo-3-indolyl)acetic acids

70 NH2

71

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R2

HOOC

COOH N

Ph O

O

O

76

R1

72

HOOC

2.7.2. Alcohol reagents Ethyl-2-(9-anthryl)-2-hydroxyacetate (73) is an excellent chiral derivatizing agent for assigning the absolute configuration of a-chiral carboxylic acids. The derivatives have a preference for the ap conformation and shielding from the anthryl ring causes predictable signs of the DdRS values that correlate with absolute configuration. Comparison of 9-AHA to a series of other aryl alkyl alcohols indicates better results with all but trans-2-phenyl-1-cyclohexanol [143]. O HO OEt

Ph

O

O

77 2-(Anthracene-2,3-dicarboximido)-1-cyclohexanol (78) is noteworthy as a chiral derivatizing agent for determining the enantiomeric purity of chiral carboxylic acids with remotely disposed chiral centers. The geometry of 78 positions the carboxylic acid over the extended anthryl ring, resulting in shielding over a substantial length of the carbon chain of the carboxylic acid. The methyl resonance in 12-methylpentadecanoic acid exhibits enantiomeric discrimination in derivatives with 78 [146]. O

N

73 2,2,2-Trifluoro-1-(9-anthryl)ethanol (74 – TFAE), commonly known as Pirkle’s alcohol, has also been used to assign the absolute configuration of carboxylic acids. For example, with cis-()(2S,3R)-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acid (75) and trans-()-(2S,3R)-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acid (76), the derivative with TFAE has a conformation in which the ester carbonyl group is eclipsed with the hydrogen atom of TFAE and anti-planar with the hydrogen atom of the stereocenter of the lactone. This facilitates the use of DdRS values to assign the absolute configuration. Model lactones of known configuration were analyzed to confirm the assignment [144]. A similar strategy was used to assign the configuration of trans-()-(3S,4S)-4-benzyl5-oxo-3-tetrahydrofurancarboxylic acid (77) [145]. HO

O

HO

78 Methyl mandelate (79) can be used as a chiral derivatizing agent for carboxylic acids. Of particular significance is its utilization in distinguishing the pro-(R) and pro-(S) hydrogen atoms in a-deuterated carboxylic acids [147] such as [2,3-2H2]propanoic [148], octanoic [149] and decanoic acid [150]. For decanoic acid, the pro-(R) position is deshielded relative to that of pro-(S) in the derivative with methyl mandelate. Specific shielding from the phenyl ring in the derivatives can also be used to assign the absolute configuration of a-chiral carboxylic acids.

CF3

O HO OMe

74 HOOC

79 Ph O

75

O

2.7.3. Miscellaneous reagents 4-Methyl-5-phenyloxazolidine-2-selone (34) is an effective chiral derivatizing agent for determining the enantiomeric purity of carboxylic acids. Reaction of the carboxylic acids

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occurs at the NH group of 34 to produce an amide. Using the 77 Se NMR spectrum, which exhibits two singlets when enantiomeric discrimination occurs, the reagent is especially effective for determining the enantiomeric purity of carboxylic acids with remotely disposed chiral centers. This includes 5-methylheptanoic acid, which has a chiral center eight atoms removed from the selenium [91]. The 77Se NMR spectrum of the derivative with lipoic acid (80) also exhibits distinct resonances for the two diastereomers. Conditions for optimizing the derivatization of carboxylic acids and acid chlorides have been determined [151]. S

describe the specific application of new reagents to amino acids and are described herein. The carbonate derivative of (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol (82 – (S)-enantiomer shown) reacts with a-amino acids or a,a-disubstituted amino acids to produce 83. The derivatives have a preferred conformation that was confirmed by NOESY results. Over fifty natural and unnatural amino acids were studied and the carbamate protons of (S)-83 were always at higher frequency than those of (R)-83 for the L-enantiomer of the amino acid [156].

Cl

COOH

S H

O

80

Cl

Cl

O

2-(1-Methoxyethyl)phenylboronic acid (47) can be used to determine the enantiomeric purity of 2-hydroxyacids. Reaction leads to a bidentate association of the hydroxyl and carbonyl oxygen atoms of the hydroxyl acid with the boron atom (Fig. 6) [101]. Similarly, reaction of one equivalent of trimethoxyborane, (R)- or (S)-BINOL (23) and a hydroxy acid in chloroform-d in an NMR tube forms a BINOL–borate system that can be used to assign the absolute configuration of a- and b-hydroxy acids. Molecular sieves are added to remove water. Specific trends of the Ha position of the hydroxy acid moiety are used to assign the absolute configuration. Prochiral methylene protons in an acid like glycolic acid (81) can be distinguished as well with this system [152].

O

N H

O O

Cl

OMe

82 Cl

H

HOOC

H

Cl

H N

Cl O

COOH

HO

R1

81 Phosphorus-containing reagents (12) with optically pure diamine groups (14 and 15) can be used to determine the enantiomeric purity of a-chiral carboxylic acids. The reagent with 14 is usually more effective than that with 15 [153]. Enantiomeric discrimination is smaller with the P(V) derivative, but still sufficient to determine enantiomeric purity. Similar phosphorus reagents with 18 and 19 can be used to determine the enantiomeric purity of a- and b-chiral carboxylic acids by 31P NMR. Spectra are either run on the P(III) species or, if sulfur is added to the NMR tube, the P(V) species. The reagent with 18 is more effective than the one with 19 [154]. The phosphorus-containing reagent (21) with diol ligand 22 has been examined as a chiral derivatizing agent for carboxylic acids. Enantiomeric discrimination in the 31P NMR spectrum is generally larger with 22 than with 14 [155].

R2

H

O

Cl

OMe

83 0

2,2 -Dihydroxybenzophenone (84) is helically chiral, the P-conformation of which is depicted in the structure. Tetramethyl ammonium salts of a-amino acids such as alanine, asparagine, phenylalanine, serine and valine react to form an imine (85 – depiction is for L-alanine) that constrains the conformation of the derivative and leads to two signals in the NMR spectrum in a protic solvent like methanol-d4. The compound is an effective chirality sensor for amino acids [157].

H O

O

H O

2.8. Analysis of amino acids Many of the reagents described previously that are effective for amines and carboxylic acids are also effective for amino acids. Carboxylic acid reagents react at the amine group of the amino acid. Alcohol and amine reagents react at the carboxylic acid. Generally the same rules used to predict the absolute configuration apply to their use with amino acids. A number of recent reports

84

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OOC O

H O

N

H N

OH

CF3

H OR

O

O

O

CF3 OR

85 A series of trans-(1R,2R)-diaminocyclohexane derivatives with either an amide or urea linker have been evaluated as reagents to assign the absolute configuration of N-protected a-amino acids. The compound with a 1,8-naphthoyl moiety (86) is the best of those studied. Reaction of 86 with a-amino acids leads to an amide derivative through the carboxylic acid group. If an N-Boc amino acid is used, specific trends in the tert-butyl resonance and R group of the amino acid correlate with absolute configuration. The anti orientation of the CH–NH–C(O)–CH unit of the amide derivative is used in predicting the trends [158].

O

HO N H

H N

O

88 The absolute configuration of a-substituted N-Cbz-serines (89) can be assigned on the basis of a derivatization scheme with L- and D-phenylalanine methyl ester hydrochloride. The reaction produces a diketopiperazine (90). Shielding by the benzyl group of the phenyl alanine produces substantial DdRS values that show specific trends with the absolute configuration of the serine derivative [160]. H N

Cbz

N

COOH

HO

R

89

O NH2

O

86 The C2 symmetric binaphthyl-based receptor compound with isopropyl groups ((S)-87) forms reversible covalent bonds with a-amino acids as shown in 88 (as represented for L-alanine). The adduct is stabilized by an intramolecular hydrogen that leads to considerable selectivity in the binding. Enantiomeric discrimination is observed in 13C or 19F NMR spectra. Specific trends in the 19 F NMR spectra correlate with absolute configuration [159].

HO

R NH HN

Bn H O

O

90 2.9. Analysis of ketones

N H

OR

O

CF3

OR

O

CF3

H N

O

87

Ketones react with (R)-butane-2,3-diol or butane-2,3-thiol to produce the corresponding ketal or thioketal, respectively (Fig. 10). While most reports have used butane-2,3-diol, in comparative studies, enantiomeric discrimination of the diastereomeric derivatives is often larger with butane-2,3-thiol [161]. Most studies examine differences in the 13C NMR spectrum. The most comprehensive study examined 39 ketones that encompassed 2- and 3-substituted cyclohexanones, 2-alkyltetrahydropyran-4-ones and 2- and 3-alkyltetrahydrothiopyran-4-ones. Perturbations in the 13C spectra for six-membered rings that have a preference for the chair conformation, acyclic ketones, cyclopentanones and cycloheptanones exhibit specific patterns that correlate with absolute configuration [162]. 1,2-diphenyl-1,2-diaminoethane (91) is an effective reagent for determining the enantiomeric purity of 3-substituted cyclohexa-

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

O

OH O

O

+ OH

R

R Fig. 10. Reaction of (R)-butane-2,3-diol with a 3-substituted cyclohexanone to form the ketal derivative.

nones and cyclopentanones. Reaction of 91 with a ketone such as cyclohexanone produces the corresponding aminal (92). Enantiomeric discrimination is observed in the 13C NMR spectrum. This scheme did not work for acyclic ketones and enones [163]. H2 N

NH 2

2.10. Analysis of ethers and epoxides Vinyl ethers of general structure 94 react with isocyanates 29 or 30 under high pressure in a [2 + 2] cycloaddition to form an azetidinone (95). The aryl ether substituent has a preferred conformation in the derivative and the absolute configuration can be assigned based on shielding from the aryl ring [165]. OR

Ph

Ph

91 Ph

94 Ph

Ar O

HN

NH

N

Ar = Ph or Napht

RO n

95

R

92 The phosphorus reagent (21) with BINOL (23) can be used in two schemes to analyze the enantiomeric purity of ketones. One involves an asymmetric hydrosilylation of the ketone. The silyl derivative is then reacted with 21. The second involves a transfer hydrogenation of the ketone to an alcohol. The alcohol then reacts with 21 [61]. A method to assign the absolute configuration of cyclooctanones such as (2S,3R,7S)-2,3,7-trimethylcyclooctanone (93) using MaNP (4) has been reported. The cyclooctanone is converted to the corresponding alcohol and then analyzed as its MaNP esters. Shielding from the naphthyl ring of MaNP causes some dispersion of the resonances. Two-dimensional NMR studies enabled the assignment of the complex spectra [164]

Phosphorus reagents (21) with 22 and 24 can be used to determine the enantiomeric purity of epoxides. The reaction opens the epoxide ring to form an ethoxide with the phosphorus atom. Unsymmetrical epoxides form two regioisomers in the derivatization step, complicating the analysis, although known trends for electrophillic additions can be used to rationalize the preferred projects [166]. 2.11. Analysis of isocyanates 1-Phenylethylamine (69) reacts with isocyanates to form the corresponding urea derivative. The enantiomeric purity of isocyanates of general structure 96 can be determined. The methoxy resonance is especially useful to monitor [167]. O

O C N

R'O R

96 O

2.12. Analysis of alkyl halides

93

Alkyl halides such as 1-bromo-3-phenylbutane react at the selenium atom of 4-methyl-5-phenyloxazolidine-2-selone (34) to

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trends in the DdRS values are used to make the assignment. MPA is preferable to MTPA in the scheme because of a higher preference for the rotamer that leads to shielding from the phenyl ring. The method works reliably for alkyl and phenyl alkyl sulfoxides, cyclic sylfoxides and compounds with nitrogen- and oxygen-containing functionalities on the substituent groups [21,170].

R

Se

Se R-Br

O

HN

O

N

Ph

2.15. Analysis of phosphorus chlorides

Ph

Compounds with a P–Cl bond such as methyl p-nitrophenyl phosphorochloridothionate (98) [171] and O-methyl ethylphosphonochloridothionate (99) [172] react with 1-phenylethylamine (69) to form a phosphoramide. The derivatives exhibit a conformation in which the phenyl ring of 69 causes shielding that can be used to assign the absolute configuration.

Fig. 11. Reaction of an alkyl halide with 4-methyl-5-phenyloxazolidine-2-selone.

produce the selenide derivative (Fig. 11). This represents one of the few reagents suitable for chiral NMR analysis of alkyl bromides. Enantiomeric discrimination in the 77Se NMR spectrum is monitored [168].

O

2.13. Analysis of thiols P

The utility of MPA (2), MTPA (1), BPG (49), 9-AMA (5) and 2tert-butoxy-2-(2-naphthyl)acetic acid (97) for assigning the absolute configuration of secondary thiols has been compared. MPA or 97 are preferable for the analysis, although DdRS values in the derivatives with 97 are about twice as large as those with MPA. For thiol derivatives with MPA or 97, the ap conformer is preferred over the sp conformer. Addition of Ba(II) to the MPA derivatives cause characteristic changes in the conformation and chemical shifts that correlate with absolute configuration [169].

Cl

O

OMe

NO2

COOH

98 tBuO

S P Cl OMe

97

99

The use of Noe’s reagent (27) for assigning the absolute configuration of alcohols was described earlier (Section 2.1.4). Similar conformational rules apply to appropriate thiols as well [64]. Phosphorus-containing reagents (12 and 13) with optically pure diamine groups such as 14 and 17 can be used to enantiomerically discriminate thiols [50,122]. The use of 17 is recommended over 14 because of its improved stability toward hydrolysis and oxidation [122].

2.16. Analysis of phosphates Several reagents have been used to assign the absolute configuration of phosphate or thiophosphate species that are rendered chiral by differences in the oxygen isotopes. The distinction occurs by virtue of the positioning of 16O, 17O or 18O atoms in bridging positions in the derivatives and the different perturbations that they cause in the 31P NMR spectrum. A configurational analysis of (SP)-[16O, 18O]thiophosphate has been performed with cis-2-chloro-3,4-dimethyl-5-phenyl-1,3,2oxazophospholidin-2-one (100), which is prepared from ephedrine [173]. Reaction of the thiophosphate displaces the chlorine atom

2.14. Analysis of sulfoxides A procedure that uses MPA (2) to assign the absolute configuration of sulfoxides has been devised. In a one-pot synthesis, the sulfoxide is first converted to a sulfoximine, then the sulfoximine is reacted with (R)- and (S)-MPA as shown in Fig. 12. Systematic

O

S R1

NH2

O S R2

R1

NH

O

(S)-MPA

S

(S)-MPA O

N

R

1

R2

S R2

R1

R2

(R)-MPA

O

N S

R1 Fig. 12. Reaction sequence for the analysis of absolute configurations of sulfoxides using MPA.

R2

(R)-MPA

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

and the chemical shift of the 31P resonance facilitates an analysis of the original configuration of the thiophosphate [174].

N

O P Cl

O

Ph

Hb

100 Ha

Other systems include adenosine 50 -O-[(2S)-thiotriphosphate] (ST-ATP) [175], a reaction with propane-1,2-diol to form a cyclized product with a phosphate monoester [176], and a reaction with (S)-2-iodo-1-phenyl ethanol (101) to form a cyclized thiophosphate ester [177]. The products have methyl esters on the phosphate groups that are either syn- or anti-to the methyl and phenyl groups, respectively, in the cyclized products with propane-1,2-diol or 101. Perturbation of the 31P signals caused by 18 O atoms allow a determination of whether the phosphate configuration is retained or inverted.

103

H Ph

104

OH HOOC

COOH MeO

I

101 One concern with these methods is that 18O incorporation is usually not 100% and extra peaks appear in the 31P NMR spectrum. Also, there is potential for loss of labeled oxygen or racemization. Compound 101 exhibits less loss of labeled oxygen and racemization than the use of ST-ATP [177].

105

AcO

2.17. Analysis of alkenes

O

20 -Methoxy-1,10 -binaphthalene-2-carbohydroxymoyl chloride (102) is an effective chiral derivatizing agent for assigning the absolute configuration of alkenes. The reagent has been used with kelsoene (103) [178], a- and b-pinene (104) [179], 105 [180] and 106 [181]. The reaction of 102 with an alkene forms a 4,5-dihydroisoxazole derivative as shown in 107 for the product with kelsoene. The aryl unit in 107 refers to the binaphthyl group. In sterically hindered alkenes such as a- and b-pinene, 102 reacts at the less-hindered side of the double bond [179]. The binaphthyl ring adopts a preferred conformation and a combination of shielding effects from the ring and NOE connectivities are used in assigning the absolute configuration of the substrate.

H

HO

H

OAc

OBz OAc

OAc

106 H

OMe H

Cl

H

OH N O N

102

107

Ar

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

2.18. The use of isotopically chiral probes

3. Chiral solvating agents

A strategy that uses deuterium labeling to determine enantiomeric purity has been described. Using alcohol 108, which has an isotopically labeled methylene group, the diastereomeric cyclohexanones (109) obtained through oxidation can be distinguished by the 2H NMR spectrum. The specificity of the asymmetric protonation of silyl enol ether 110 to 109 can then be studied by 2H NMR spectroscopy. Compound 109 can be converted into its corresponding deuterium-labeled cis-diol, epoxide and alcohol, providing probes for studying asymmetric dihydroxylation, epoxidation and hydroboration/oxidation processes [182].

3.1. Alcohol reagents

OH Ph

2,2,2-Trifluorophenylethanol (113 – TFPE) and TFAE (74), otherwise known as Pirkle’s alcohol, are among the most widely used and versatile chiral NMR solvating agents. The two reagents behave similarly as chiral solvating agents and, although many of the earliest studies were done with TFPE, the larger shielding of the anthryl ring relative to that of the phenyl ring recommends the use of TFAE. The hydroxyl group of the reagent is capable of forming hydrogen bonds with substrates. The methine hydrogen atom of TFAE is acidic enough to be involved in hydrogen bonding as well. The aromatic ring can be involved in p-stacking with some substrates and cause shielding that is important in chiral discrimination. The corresponding 2,2,2-trifluoromethyl-1-cyclohexylethanol derivative is not nearly as effective at causing enantiomeric discrimination as TFPE or TFAE, thereby demonstrating the importance of the aromatic ring for shielding and interaction with many substrates [184].

D

F3C

OH

108 O Ph

113

D

109 OTBS Ph

D

110 The work on the deuterium-labeled system was inspired by an earlier study that used 13C enriched nuclei to create an isotopically chiral compound. Using ketone 111 with a 13C labeled methyl group, it was possible to study the enantioselection of the amino alcohol-ruthenium arene-catalyzed asymmetric transfer hydrogenation to 112 [183]. O

Ph

Me Me

13

TFAE is effective in relatively non-polar solvents. Polar solvents can solvate the hydroxyl group of TFAE and dipole groups of the substrate and reduce the interaction needed for enantiomeric discrimination. TFAE is potentially an effective chiral NMR solvating agent for determining the enantiomeric purity of any organic-soluble chiral compound capable of forming dipole–dipole interactions. A recent review describes the extensive range of systems for which TFAE can be used to effect enantiomeric discrimination [7]. In addition to a wide variety of organic compounds, it includes metal complexes with polar groups in the ligands. Of special significance is that the association of TFAE with several classes of substrates including sulfoxides [185], alkyl and aryl sulfinates (114) [186], N,N0 -dialkylaryl amine oxides (115) [187], a-amino acid methyl esters [188], N,Ndimethyl amino acids [189], epoxides [190] oxaziridines (116) [191,192], imines (117) [191], c-lactones (118) [193], a,a-disubstituted and b-substituted b-propiolactones (119) [194] and c-lactams (120) [195] is specific enough in geometry that the changes in chemical shifts with the (R)- and (S)-enantiomers of TFAE can be used to assign the absolute configuration. Fig. 13 shows the geometry of the complex of TFAE with a c-lactone as just one example of the specific association that occurs. The anthryl ring is positioned to shield either R1 or R2 depending on the absolute configuration of the lactone. The signs of the DdRS values are used in a manner analogous to the Mosher method to assign the absolute configuration.

Me

O

111 OH

OH R

Me Me

13

Me

Me

Me

112

13

Me

R2

S 1

X R2 X = N, O, S

114

27

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

H

O

O

H R1

R2

O

O O H

Ar CF3

O

R2

R1

H

Ar CF3

Fig. 13. Association of TFAE with the two configurations of a c-lactone.

O

N

120 N

O

115 Ph R1 R

C

N O

In recent studies, the absolute configuration of fatty acid butanolides, one example of which is homoancepsenolide (121), were assigned using TFAE. The substrates have c-methyl-c-lactone units, and at low temperatures, DdRS values with TFAE of the H5 resonance provide a reliable assignment of the configuration [196]. The absolute configuration of C10 of a c-butenolide unit embedded in a flexible furanocembranolide network (122) was assigned using TFAE. Spectra were recorded at low temperature and model compounds with known configurations were used to confirm the assignment of the unknown [197]. Similarly, the absolute configuration of the C14 site in Malyngamide X (123) was assigned on the basis of 1H NMR data with TFAE. Model lactams with known configurations were used to confirm the reliability of the assignment [198].

116

O

R1

O

Ph

O

N

O

n

R2

117

121 R1 O O

R2

118 O

R1

O

R2

(α)

R3

(β) R4

O

O

119 O

122 TFAE can also be used to determine the enantiomeric purity and to assign the absolute configuration of allenes. The allene is con-

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OMe

O

OH

O

H N N

N

14 OMe

O O

123 verted to a methoxy ether using a methoxy mercuration and the product is analyzed using TFAE. Only one methoxy ether forms if the substituent groups on the two sides of the allenes are the same. Two derivatives are formed when the allene substituent groups are different [199]. BINOL (23) is an atropisomeric compound that is a broadly applicable chiral solvating agent. The hydroxyl groups of BINOL can form hydrogen bonds and the naphthyl rings cause shielding that accounts for the enantiomeric discrimination. Types of compounds that have been examined with BINOL include alkyl and aryl alcohols, sulfoxides, selenoxides and amines [200–202]. Much like TFAE, BINOL has the potential to cause enantiomeric discrimination in the NMR spectrum of any substrate with the ability to form dipole–dipole interactions [7]. With sulfoxides [201,203], amines [201] and amino alcohols [201], association of BINOL occurs in a manner that causes specific perturbations in the chemical shifts that correlate with absolute configuration. Fig. 14 shows the association of BINOL with sulfoxides and illustrates the differential shielding that will occur for the two enantiomers of the substrate. In recent work, BINOL has been shown to be an effective chiral solvating agent for N-sulfinyl aldimines of general structure 124. Enantiomeric discrimination is observed in the 1H NMR spectrum and the best results are in benzene-d6 [204].

ral NMR solvating agent. Using PEA as the solvent, enantiomeric discrimination was observed in the 19F resonance of 2,2,2-trifluoro-1-phenylethanol [2]. The larger aromatic rings in NEA and AEA will produce larger shielding and enantiomeric discrimination than the phenyl ring of PEA and are recommended for NMR applications [205,206]. Much like Pirkle’s alcohol and BINOL, PEA, NEA and AEA associate with many compounds that have the ability to form hydrogen bonds. As such, they often are useful reagents for determining enantiomeric purity and have been employed in NMR applications for a wide range of compounds [7]. An alternative strategy to preparing PEA, NEA or AEA derivatives with carboxylic acids is to mix the reagent with a carboxylic acid. The acid-base neutralization reaction forms diastereomeric salts that often exhibit enantiomeric discrimination in the NMR spectrum. Analysis can be performed in a range of solvents including methanol-d4 [207], carbon tetrachloride, chloroform-d, benzened6 [208], dimethylsulfoxide-d6 and pyridine-d5 [209]. With MTPA [210] and mandelic acid derivatives [211], perturbations in the chemical shifts with NEA correlate with the absolute configuration. NEA forms diastereomeric salts with phosphorus thioacids (125) as well and causes enantiomeric discrimination in the 1H, 13C and 31P NMR spectra [212]. The reagent is also an effective chiral solvating agent for 1-hydroxyalkyl phosphonic acids (126) [213].

O

R1

S S

H

P

OH

R N

125

R2

O

124 R

P

3.2. Amine reagents

OH OH

The utilization of PEA (69), NEA (70) and AEA (71) as chiral derivatizing agents for carboxylic acids was described earlier (Section 2.7.1). These compounds also have utility as chiral solvating agents, and PEA was actually the first compound ever used as a chi-

126

Ph

O OH

OH

S

OH

Ph

O OH

S

OH (S)

Fig. 14. Association of BINOL with the two configurations of methyl phenyl sulfoxide.

(R)

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

OH

OH

OH OH

(a)

OH

OH

OH

(b)

(c)

Fig. 15. Structural motif for (a) two contiguous propionate units, (b) 1,3,5-triol unit and (c) 2-methyl-1,3-diol unit.

Alcohols associate with PEA and NEA through the formation of hydrogen bonds. The geometry has a preferred orientation such that shielding by the aryl ring of the PEA or NEA causes perturbations in the NMR spectra of aryl alkyl alcohols that correlate with absolute configuration [214]. NEA can be used in a scheme to analyze the enantiomeric purity of ketones. The ketone is converted to an acid oxime. A diastereomeric salt forms with NEA in chloroform-d and enantiomeric discrimination occurs in the 1H NMR spectrum [215]. N,a-Dimethylbenzylamine (127 – DMBA) is a useful chiral solvating agent for assigning the configuration of polyol motifs. Using perdeuterated DMBA as the solvent, the 1H or 13C NMR spectrum of each possible diastereomer of a specific structural motif, examples of which are provided in Fig. 15, is recorded. Chemical shift data is then used to construct a database. One example is to subtract the chemical shift for each 13C resonance for a selected diastereomer from the average value of that carbon in all the diastereomers. Another is to calculate DdRS values for each carbon. The resulting values produce a pattern that is different for each diastereomer. The same measurements are then performed on an unknown that contains the same structural motif. The configuration of the unknown is assigned based on which pattern it best matches in the database [216–219].

N

ing the absolute configuration of secondary alcohols. The BMBApMe associates with the alcohol as illustrated in Fig. 16, and perturbations in the adjacent carbon resonances correlate with the absolute configuration. In particular, the DdRS values with (R,R)and (S,S)-BMBA-pMe is used to make the assignment. The hydroxyl groups in 1,4- and 1,5-diols act independent of each other in the presence of BMBA-pMe. This is not the case for 1,2- and 1,3-diols, and these need to be treated as a structural cluster [220]. Analysis of 1,2-diols led to a set of rules that can be used to reliably assign the configuration of syn- and anti-1,2-diols [221]. Similarly, 13C NMR shift data with BMBA-pMe can be used to assign the configuration of cyclic and biaryl secondary alcohols and acyclic tertiary alcohols [222].

H N

H N

128 Chemical shift data of 94 compounds measured in (R,R)- and (S,S)-BMBA-pMe was combined with 1H NMR data on the (R)MTPA (1) derivatives of 80 secondary alcohols to construct a database. This database was then used to accurately predict the sign of the difference in chemical shift of opposite stereoisomers and the difference in chemical shift between the two chiral solvents for 20 new substrates [223]. 3.3. Miscellaneous reagents

127 (R,R)- and (S,S)-bis-1,3-methylbenzylamine-2-methylpropane (128 – BMBA-pMe) is an effective chiral solvating agent for assign-

Ph N H

H

O

N H Ph

Fig. 16. Association of BMBA-pMe with a secondary alcohol.

N-(3,5-dinitrobenzoyl)-1-phenylethylamine (129 – DNB-PEA), N-(3,5-dinitrobenzoyl)-L-leucine (130 – DNB-Leu), N-(3,5-dinitrobenzoyl)-4-amino-3-methyl-1,2,3,4-tetrahydrophenanthrene (131 – Whelk-O-1) and 1-(1-naphthyl)ethyl urea derivatives of amino acids (132 – NEU-AA) are all effective chiral NMR solvating agents that are useful for determining the optical purity of a diverse group of compounds. These reagents or similar analogues were first exploited as liquid chromatographic stationary phases for the separation of enantiomers. Organic-soluble analogues were then evaluated in NMR applications. The extensive results from liquid chromatographic applications provide an idea of the range of compounds for which these reagents are likely to be applicable in NMR applications. It is important to use these reagents in a relatively non-polar solvent such as chloroform, as effective solvation of the chiral solvating agent and substrate in more polar solvents diminishes the association necessary for chiral discrimination. The presence of aromatic rings and hydrogen bonding moieties in the reagents provide sites for dipole–dipole and p–p interactions to stabilize association. There are also steric groups that have the potential to destabilize association.

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

O

Organic-soluble analogues of DNB-Leu (130) cause enantiomeric discrimination in the 1H and 13C NMR spectra of benzodiazepinones (134), lactones, amides and sulfoxides. For those substrates that were studied, the enantiomer that elutes last in liquid chromatographic applications, indicating a higher association constant with DNB-L-leu, consistently has the larger perturbations of chemical shifts in the NMR spectrum [229].

O2N N H

O

H N

NO2

129 R

O

COOH N

Cl

O2N N H

Ph

134

NO2

130 O O2N N H

NO2

131 O

R O

N H

N H O

132 DNB-PEA (129) is an effective reagent for sulfoxides [224], phosphine oxides [225], amides, esters and alcohols [226,227]. For 2-phospholene-1-oxides such as 133, patterns in the relative perturbations in chemical shifts in the 1H and 31P NMR spectra correlate with absolute configuration [228].

P O

Ph

133

Whelk-O-1 (131) is a useful chiral NMR reagent for a wide range of substrates including epoxides, amides, lactones, lactams, alcohols, sulfoxides and primary amines. A cleft between the dinitrobenzoyl and phenanthrene moieties of Whelk-O-1 accounts for it unusual ability to cause high degrees of enantiomeric discrimination in many classes of substrates [230]. NEU-AA derivatives (132) are easily prepared by reacting optically pure 1-(1-napthyl)ethylisocyanate with amino acids such as valine, leucine, tert-leucine and proline. Organic-soluble ethyl esters of NEU-AA are effective chiral solvating agents for amines, sulfoxides, alcohols and carboxylic acids. The valine derivative is recommended for NMR applications among those studied [231,232]. A strategy that can be used to enhance the enantiomeric discrimination with these chiral solvating agents is to add an appropriate organic-soluble lanthanide species such as the europium(III) tris b-diketonate of 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione [H(fod)]. The most useful situation is when the Eu(III) preferentially binds to the substrate in the bulk solution and not to the chiral solvating agent nor to the substrate-chiral solvating agent complex. Under these circumstances, the NMR spectrum of the substrate with the lower association constant with the chiral solvating agent exhibits the larger perturbation in chemical shifts on addition of the paramagnetic lanthanide ion. The lanthanide species is added in small increments from a stock solution and enhancements in enantiomeric discrimination are monitored. If too much lanthanide species is added, association with the lanthanide ion strips the substrate from the chiral solvating agent and eventually diminishes the magnitude of the enantiomeric discrimination. The enhancements in enantiomeric discrimination are quite large, such that obtaining the samples at elevated temperatures (50 °C) reduces exchange broadening that occurs in the presence of the lanthanide ion while still providing higher enantiomeric discrimination. The method potentially works for any substrate that associates with DNB-PEA, DNB-Leu, Whelk-O-1 and NEU-AA [193,231–235]. Chiral lactam 135 has the ability to complex with amides, lactams, quinolones (136) and oxazolidinones (137) through hydrogen-bonding interactions. One example of the association is shown in Fig. 17. The substrate needs a complementary structure to exhibit favorable binding and the differential perturbations in chemical shifts can be used to assign the absolute configuration. Larger discrimination is usually observed in the spectra of five-membered compared to six-membered lactams [236,237].

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

Compounds 99 [238] and 138 [239] with a 10 ,80 -naphthalimide group and cyclohexylamine or pyrrolidine methanol unit are effective chiral solvating agents for carboxylic acids and N-derivatives of a-amino acids. Whereas 99 is only suitable for the analysis of lipophillic substrates, 138 is applicable with both lipophillic and hydrophilic substrates. Enantiomeric discrimination with 138 is greater than that observed with PEA [239].

O

N O

H N

N

OH

H

O

Ph

N

N

O

O

N

O

Fig. 17. Binding interaction of 7-substituted-3-azabicyclo[3.3.1]nonan-2-ones.

138 HN N

O

O

Compound 139, which incorporates the amino acid L-valine into the structure, is an effective chiral solvating agent for aryl alkyl amines [240]. (+)- and ()-N,N,4-Trimethyl-2-{[1-phenylethyl]amino}(1-naphthyl)methyl]aniline (140) are effective chiral solvating agents for carboxylic acids as well as N-tosyl derivatives of a-amino acids. The enantiomeric discrimination is larger than with PEA [241].

COOH

135

O

N

O

O

N H

139

O

Ph

136 O

NMe 2 O

HN

NH

Cl

137

140

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(S)-1-Benzyl-6-methyl piperazine-2,5-dione (141) forms a hydrogen-bonded complex with similar piperazine-2,5-diones and diketopiperazines. Enantiomeric discrimination is observed in the 1H and 13C NMR spectra [242]. The same compound caused enantiomeric discrimination of 13 N-benzoyl derivatives of a-amino acid derivatives in chloroform-d [243].

The chemical shifts of the NH protons of tosyl derivatives of

a-amino acids with a neutral side chain show characteristic patterns in the presence of (S)-2-(5-bromo-2-dimethylaminobenzylamino)1,1,3-triphenyl-propan-1-ol (144) that correlate with absolute configuration [245]. Several N-acyl-L-amino acid derivatives have been evaluated as chiral solvating agents for phosphonates, phosphinates, phosphine oxides, phosphonamidates and phosphates. The reagents interact through hydrogen bonds and Fmoc-Trp(Boc)-OH is the most effective of those studied at causing enantiomeric discrimination in the 1H, 13C and 31P NMR spectra [246].

O

Ph

Ph

NH

Ph N

NH

Ph

OH

O

Br

141

NMe2

144 (2R,3R)-Dibenzoyltartaric acid (145) is an effective chiral solvating agent for 3,30 -disubstituted 2,20 -bis(diphenylphosphino)-1,10 biaryls (146). The methoxy signal shows trends in chemical shifts that are consistent with the absolute configuration [247]. Compound 145 and the corresponding N,N-dimethylamide derivative (147) are effective chiral solvating agents for bis-phosphine and monophosphine oxides similar in structutre to 146. Perturbations in the 31P NMR spectra of substrates with 147 correlate with absolute configuration [248].

N,N0 -Bis[(S)-1-(1-naphthyl)ethyl]thiourea (142) and the corresponding phenyl analogue are effective chiral solvating agents for a-hydroxy- and a-amino carboxylic acids. A pair of hydrogen bonds are involved in the interaction between 142 and the substrate as shown in 143 for (R)- and (S)-phenylglycine. For the (S,S)-(2-naphthyl) derivative of 142, the a-proton of the (R)-isomer of a-amino acids and a-hydroxyacids is consistently at a higher frequency than that of the (S)-isomer [244].

S

O N H

N H

O

COOH

O

COOH

142 O

145 S

Ph

S

N

N

N

N

H

H

H

H

O

O

O

O

H

Ph

Ph

Ph

NH2 Ph

H (S,S,R)

(S,S,S)

143

NH2

Ph

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O MeO

P Ph2

MeO

Ph2 P

N HO

O MeO

146 N

148 O

O

O

OH

N

O

C(O)NMe2

O

OH

COOH

149

O O

OCH3

N

O

147 The variety of functional groups in quinine (148) results in a versatile chiral solvating agent that can be used with many classes of substrates. This includes alkyl aryl alcohols and binaphthyl derivatives [249,250], hemiacetals (149) and methyl acetals (150) [251], b-hydroxy esters [252] hydroxyl alkyl phosphonates (151) and 1-hydroxyphosphinothioic acids [253], and a thiophene-1-oxide substrate (152) [254]. Quinine derivatives with a 1-naphthyl carbamoyl group at the C9 (153) or C11 (154) positions are effective chiral solvating agents for aryl-substituted amines and amino acids. Quinine is not effective at causing enantiomeric discrimination in the spectra of these substrates [255,256]. The C9 carbamate is especially effective for substrates with a dinitrophenyl group, and p–p stacking between the naphthyl ring and dinitrophenyl ring is an important stabilizing interaction [255]. The C11 carbamate is more effective than the C9 carbamate for underivatized substrates [256]. In recent work, several C9 carbamoyl derivatives of quinine have been shown to be effective chiral solvating agents for N-trifluoroacetyl derivatives of a-amino acids. For the N-TFA derivatives, either 1H or 19F NMR spectra are monitored [257]. Several reagents including quinidine (155), NEA, ephedrine, quinine and two quinidine derivatives were evaluated as chiral solvating agents for N-benzyloxycarbonyl derivatives of 1-amino alkane phosphonic and phosphinic acids (156). The 31P NMR spectrum exhibits the largest enantiomeric discrimination with quinidine [258].

OH

150

OH

O P

OEt OEt

151

CH 3

S

O2 N

O

152

D

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Mandelic acid (157), dimethylaminopyridine and cyanohydrins (158) form an associated complex that consists of a mandelatedimethylaminopyridinium ion pair with the cyanohydrins. Aldo cyanohydrins, which have a secondary hydroxyl group, and keto cyanohydrins, which have a tertiary hydroxyl group, can be analyzed. The DdRS values for particular hydrogen resonances of substrates with aromatic, cyclic, acyclic and olefinic substituent groups show trends that can be used to assign the absolute configuration [259].

1- NP H O N

HN O

HO MeO

COOH

N

153

157

H N

O OH

H

1- NPH

O R

N

H

CN

158

HO

N-Phosphonomethyl-L-proline (159) acts as a ligand and binds to the chiral Dawson lanthanide polyoxometalate [a1Yb(H2O)4P2W17O6]7. Two of the phosphono ligands bind to the ytterbium(III). Splitting of the signals of the two enantiomers is observed in the 183W NMR spectrum, providing a means of sensing the chirality of these polyoxometalates [260]

MeO

N

154 COOH

NH

O P HO

N

HO

O

159

H O

As summarized in a recent review article [261], chiral ionic liquids have been increasingly studied and are beginning to be applied for chiral recognition. Increasing numbers of reports have examined whether chiral ionic liquids can create chemical shift anisotropy in NMR experiments. To date, the extent of discrimination with available ionic liquids is exceptionally modest in scope and usually limited to small splitting of the 19F single of MTPA (1). Only a few show a modest splitting of the 1H signal of MTPA [261].

N

155

3.4. Phosphorus-containing reagents

O H N

O

P

OH OH

O

156

R

Phosphinic amides (160) and phosphinothioic acids (161) form hydrogen-bonded dimers in solution (Figs. 18 and 19) that can lead to an enantiomeric self-discrimination in non-racemic mixtures [262]. More important is that optically pure 160 and 161 can function as chiral solvating agents for many classes of hydrogen-bonding substrates. Compound 161 is more versatile than 160 for chiral discrimination in NMR spectroscopy [263]. Compound 161 can be used to examine the optical purity of phosphinic amides

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

Ph O

Ph

H

N

Ph Ph

P

O

Ph

H

N

P

P N

H

P

O

N

Ph

H

Ph

O

Ph

Fig. 18. Dimer formed by the association of (N-phenyl)methylphenyl phosphinic amide.

S

Ph

H

O

R

P O

H

S

H

O

Ph

P

P

R

S

Ph

Ph

R

P O

H

R

S

Fig. 19. Dimer formed by the association of phosphinothioic acids.

[263], thiophosphinic acids [264], phosphinate esters, thiophosphinates [265], phosphonates [266], sulfoxides [267], amine oxides [268], phosphine oxides [269], phosphites [270], alcohols, diols, thiols, mercaptoalcohols, amines, amino alcohols and hydroxy acids [271]. Compound 161 is a likely candidate to try as a general chiral solvating agent for assessing the enantiomeric purity of a compound of interest, since it works for such a diverse variety of substrates. Similarly, (R)- or (S)-tert-butyl(phenyl)phosphine oxide (162) are effective chiral solvating agents for racemic carboxylic acids [272]. (R)-Tert-butylphenyl phosphinoselenoic acid (163) is an analogous chiral solvating agent to the corresponding sulfur analogue (161). Attempts to determine the enantiomeric purity for desbromoarborescidine A (164), which has an indole[2,3-a]quinolizine heterocyclic ring, with 161 were unsuccessful, whereas 163 produced enantiomeric discrimination in the 1H NMR spectrum [273]. Both 161 and 163 cause enantiomeric discrimination of the indole NH proton of 165, a compound with a similar structure to 164 [274]. O Ph

N

N H

H

164

NH

N H

R1

H N

P

Ph

N H

R2

165

160 S P

OH

Ph t

Another useful phosphorus-containing chiral solvating agent is 1,10 -dinaphthyl-2,20 -diylphosphoric acid (166). Addition of 166 to amines leads to the formation of organic-soluble salts that exhibit enantiomeric discrimination in the 1H and 13C NMR spectra [6,275,276].

Bu

161 O P

Ph

O

H

OH P

tBu O

162

O

Se

Ph t Bu

P OH

163

166 Two anionic reagents, tris[tetrachlorobenzene-1,2-bis(olato)phosphate(V) (167 – TRISPHAT) and bis[tetrachlorobenzene-1,2-

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bis(olato)mono([1,10 ]-binaphthalenyl-2, 2-diolato)phosphate(V) (168 – BINPHAT) have been studied extensively as chiral NMR solvating agents for cations. The reagents achieve their chirality because of the propeller arrangement of the three bidentate moieties about the central phosphorus atom. TRISPHAT has D3 symmetry, whereas BINPHAT has C2 symmetry. In many cases, better enantiomeric discrimination occurs if the symmetry of the ionic reagent is matched to the symmetry of the substrate. The use of TRISPHAT and BINPHAT as chiral NMR solvating agents has been thoroughly reviewed [7,277,278]. The variety of metal complexes whose NMR spectra exhibit enantiomeric discrimination in the presence of TRISPHAT confirm the utility of this reagent for the analysis of optical purity of any cationic chiral metal species.

Cl

Cl

Cl

O

O

Cl

O

Cl

Cl

P

O

O

Cl

O

Cl

Cl

Cl

Cl

167

Cl

Cl

Cl

Cl

N R

N

169

A particular family of substrates for which TRISPHAT has been used extensively are cationic metal complexes that have three identical bidentate ligands and D3 symmetry, [Ru(bpy)3]2+ (bpy = 2,20 -bipyridine) and [Ru(phen)3]2+ (phen = 1,10-phenanthroline) being good examples. Analysis of the association geometry indicates that binding of TRISPHAT with the metal complexes involves an alignment of the propellers along their C3 axes [279]. TRISPHAT also produces enantiomeric discrimination in the NMR spectra of similar tris chelates with mixed bidentate ligands. The association is strong enough that enantiomeric discrimination is sometimes observed in polar solvents such as acetone-d6 [280– 282], acetonitrile-d3 [283] and dimethylsulfoxide-d6 [284]. TRISPHAT is also an effective chiral solvating agent for cationic metal complexes with structures and molecular symmetries other than D3. This includes bis(diimine) copper(I) complexes of the form [CuL2]+ that have tetrahedral coordination geometries. These complexes are chiral because of the asymmetry of the substituent groups on the ligands, one example of which is 2-iminopyridine (179) [285]. The kinetics of racemization of [CuL2]+ complexes that have 1,10-phenanthroline, 2,20 -bipyridine and iminopyridine ligands in pseudotetrahedral structures have been studied with the aid of TRISPHAT by studying the NMR spectra at different temperatures [286]. Chiral metal complexes with cyclopentadienyl ligands such as 170 [287] and 171 [288] that are cationic either because of the metal ion or a quaternary amine group in the ligand show enantiomeric discrimination in the 1H NMR spectrum in the presence of TRISPHAT. The use of TRISPHAT extends to cationic metal carbonyl complexes, one example of which is 172 [289], bimetallic systems (173) [290], and supramolecular systems (174) [291]. These are just a few of many examples that were described in a recent review [7].

O

O

O P

O

Cl

O

O

+

Cp*M

O

R

170 Cl

Cl

N

R I R

Cl

R

Cl

168

Fe

171

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

TRISPHAT and BINPHAT also cause enantiomeric discrimination in the NMR spectra of phosphinium salts such as 176 [294] and 177 [295], although BINPHAT generally causes larger distinction. BINPHAT is also effective for the analysis of quaternary amines such as spirobi[dibenzaepinium] (178) [296] and 179 [297], as well as thiioranium ions such as 180 [298]. In recent studies, BINPHAT has been shown to be an effective chiral solvating agent for quaternary ammonium ions derived from Troger Base, of which 181 is one example. Enantiomeric discrimination occurs in the NMR spectrum in chloroform-d, methylenechloride-d2, and acetonitrile-d3 [299].

X (CO)3 Cr R

172 R (depe) 2 Ru

S I Cr(CO) 3

173 Cl

MeO P CD 3

N

Cp*

O

Rh

176 O

Cp*

Rh

O

O

Li O

OR

Ph

O

Ph

N

Tf O

P

I

Bz

Ph

N H

N Cl

Rh

Cl

O

177

Cp*

174 In recent studies, TRISPHAT has facilitated the study of metal cluster compounds of formula [Co4(L)6(BF4)]7+. The bridging ligand contains two N,N-bidentate pyrazolyl-pyridine groups, one example of which is 175. In the presence of TRISPHAT, resonances of the ligand exhibit enantiomeric discrimination. In addition, the cluster creates a cage that has a BF 4 ion trapped inside. In the presence of TRISPHAT, two 19F signals are observed for the BF 4 species trapped within the two enantiomeric forms of 175 [292].

N

178

N N

N

N

N

N

N

N 175

The compound [Mo3S4Cl3(dppe)3]+ (dppe) = 1,2-bis(diphosphinoethane) is a C3 symmetric trinuclear cluster. The configuration is stable at room temperature and enantiomeric discrimination is observed in the presence of TRISPHAT. At elevated temperatures, the configuration is labile [293].

179

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HO

OH

3 tBu

2 4

O

5

S

1

O

6

180

OH Fig. 20. Representation of a cyclodextrin superimposed with one D-glucose subunit.

N N R

181 TRISPHAT analogues in which one of the three ligands is replaced by a mannose-derived sugar have been investigated (182). The reagent is as effective as TRISPHAT for many metallo-organic complexes and better than BINPHAT for organic cations that were studied [300].

Cl Cl

Cl

ses of compounds for which cyclodextrins are effective, since so many compounds have the ability to form the host–guest complexes needed for enantiomeric discrimination. The cavity is made up of six (a), seven (b) or eight (c) D-glucose units and is configured such that the hydroxyl groups at the 6-position of the glucose rings are arranged around one opening, whereas those at the 2- and 3-positions are at the other opening (Fig. 20). The different sizes of a-, b- and c-cyclodextrin enhance the variety of compounds for which cyclodextrins can be employed for chiral discrimination. Usually the best association and enantiomeric discrimination occurs when the cyclodextrin has a cavity size complementary to the size of the substrate. As depicted in Fig. 20, the cavity is tapered and the larger opening has the secondary hydroxyl groups. Chiral discrimination of substrates often involves differences in the interactions of the enantiomers with the secondary hydroxyl groups. The underivatized or native cyclodextrins are water-soluble. Derivatization of the hydroxyl groups can be used to produce cyclodextrins with different solubility and complexation properties. While a wide variety of cyclodextrin derivatives have been used in chiral NMR applications, only those that have been the most extensively studied and show the most utility will be described herein. A recent review has provided a comprehensive discussion of the use of cyclodextrins in NMR applications [7].

Ph Cl

O

O

O

O

O P O O

O

OMe

O

Cl

Cl

Cl Cl

182

3.5.1.1. Native cyclodextrins. The majority of substrates studied with water-soluble native cyclodextrins have aromatic rings. The inside of the cyclodextrin cavity is relatively hydrophobic, which facilitates insertion of the aromatic ring of an organic substrate in water. Phenyl rings have complementary sizes with a- and b-cyclodextrin, whereas naphthyl rings bind better with the larger b- and c-cyclodextrin. The aromatic rings of the substrate can be substituted and a wide variety of functional groups can be incorporated into the compounds. Cyclodextrins are therefore candidates for use in determining the enantiomeric purity of any water-soluble compound with an aromatic ring or hydrophobic group. Native cyclodextrins have also been used to enantiomerically discriminate compounds such as cis-decalin (183) [301], a-pinene (184) [302,303], camphor (185) [304] and abscisic acid (186) [305]. In many of these cases, the substrate is only solubilized in water through formation of a complex with the cyclodextrin.

3.5. Cavity and receptor compounds 3.5.1. Cyclodextrins Cyclodextrins are naturally-occurring cavity compounds comprised of D-glucose units. Cyclodextrins and their derivatives are effective chiral NMR solvating agents for a diverse variety of substrates. It is impossible to designate a specific class or even clas-

183

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

diethylenetriaminepentaacetic acid (DTPA) amide derivative of cyclodextrin was employed. Fig. 21 shows the scheme for attaching DTPA at the 6-position using an ethylenediamine (EN) linkage [306]. Similar derivatives with an ethylenediamine linker at the 2-position [306] and an amine (NH) linker at the 2- and 6-positions were prepared as well [307]. Addition of a lanthanide ion such as dysprosium(III) to the mixture causes significant enhancements in enantiomeric discrimination for a variety of substrates. Spectra are usually run at 50 °C to reduce broadening from the lanthanide ion. The Dy(III) complex with DTPA-EN at the 2-position is more effective than that at the 6-position. Presumably the Dy(III) is closer to the sites where enantiomeric discrimination occurs [306]. The derivative with DTPA-NH at the 6-position is more effective than DTPA-EN at the 6-position, presumably because the shorter linker places the Dy(III) closer to the substrate. The derivative with DTPA-NH at the 2-position is not that effective and evidence suggests that the DTPA unit blocks the substrate from entering the cavity [307]. In a recent study, native a-, b- and c-cyclodextrin and hydroxypropyl c-cyclodextrin (HP-c-CD) have been used as a chiral solvating agent for N-benzyloxycarbonyl-a-aminophosphonates (187). The b-cyclodextrin and HP-c-CD were the most effective of those studied, and the 31P NMR spectrum was monitored [308]. Similarly a-cyclodextrin is an effective chiral solvating agent for a-hydroxyalkanephosphoric acids (188) in which R is an alkyl or phenyl group [309].

184

O

185

OH COOH

O

O

186

H N

O

P OR'

A strategy to enhance the enantiomeric discrimination in the NMR spectra of substrates with cyclodextrins is to couple paramagnetic lanthanide(III) ions to the system. The paramagnetic lanthanide ions induce perturbations in the NMR spectra by a dipolar (e.g., through-space) mechanism. In particular, a mono-substituted

OH

OH O

187

OTs

NH2

N H

O O N H

O OH

OH

H NC

N

N

N

OH

HO O

O

O O

O O N H

R

NH

Ln N

O N N

Fig. 21. Scheme used to couple lanthanide ions to cyclodextrins through a DTPA amide unit.

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

COOH O

HOOC

F3C

O

HO

190

HOOC Fig. 22. Representation of the p–p stacking of an indole and phthalimide ring to form a ternary complex inside the cavity of c-cyclodextrin.

OH

R

O

COOH

OH

COOH

P OH

188 The cavity of c-cyclodextrin is sufficiently large that certain substrates form 2:1 substrate–cyclodextrin complexes. A possible way to exploit this situation as a strategy for enhancing enantiomeric discrimination has been demonstrated. Reaction of tryptophan with phthalic anhydride leads to the formation of N-phthalimido tryptophan (189). The indole and phthalimide rings are capable of p–p stacking to form ternary complexes, one possibility of which is illustrated in Fig. 22. Sizeable enantiomeric discrimination is observed in several resonances of the substrate [310].

191

TM-b-CD is an effective reagent for determining the enantiomeric purity of trisubstituted allenes (192). The allene hydrogen is especially suitable for monitoring. In addition, use of TM-a-CD consistently causes larger deshielding of the allene hydrogen of the (S)-enantiomer, providing an empirical trend that can be used to assign the absolute configuration [314]. R1

R3 C

O

C

R2

C H

192

HN N HOOC O

HOOC

189 3.5.1.2. Permethylated cyclodextrins. Permethylated cyclodextrins are soluble in organic solvents and water. Heptakis(2,3,6-tri-Omethyl-b-cyclodextrin) (TM-b-CD) is actually more water-soluble than native b-cyclodextrin. Compounds 190 [311], 166 [312] and 191 [313] are some examples where hexakis(2,3,6-tri-O-methyla-cyclodextrin) (TM-a-CD) or TM-b-CD produce larger enantiomeric discrimination in the 1H or 13C NMR spectra than the native cyclodextrins.

3.5.1.3. Carbamoylated cyclodextrins. A series of per-carbamoylated (3,5-dimethylphenylcarbamate), mixed carbamoylated-silylated [315] and mixed carbamoylated-methylated cyclodextrins [316] have been evaluated as chiral NMR solvating agents. Of these chloroform-soluble reagents, the per-carbamoyl derivative is the most effective for N-(3,5-dinitrobenzoyl)amino acid methyl esters, carboxylic acids and alcohols, although the enantiomeric discrimination is relatively modest. Substrates associate through dipole– dipole and p–p interactions with the external carbamoyl groups and do not enter the cyclodextrin cavity. 3.5.1.4. Miscellaneous neutral cyclodextrins. Enantiomeric discrimination is observed in the 1H NMR spectra in chloroform of N-protected (3,5-dinitrobenzoyl, acetyl or trifluoroacetyl) a-amino acid derivatives and trisubsituted allenes with heptakis[2,3-di-Omethyl-6-O-(L-valine-tert-butylamide-Na-ylcarbonylmethyl)]-bcyclodextrin. The enantiomeric discrimination is larger than observed in prior work with heptakis[6-O(3,5-dimethylphenylcarbamoyl)-2,3-di-O-methyl]-b-cyclodextrin for these polar and apolar substrates [317]. N-trifluoroacetyl derivatives of a-amino acids associate with heptakis[2,3-di-O-acetyl-6-O-(tert-butyldimethylsilyl)-b-cyclodextrin in chloroform-d. The amide protons split into two signals and

41

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

the resonance for the (S)-enantiomer is consistently at higher frequency than that of the (R)-enantiomer [318].

R N

3.5.1.5. Carboxymethylated cyclodextrins. Anionic carboxymethylated cyclodextrins (CM-CD) have been explored as water-soluble chiral solvating agents for cationic substrates [319,320]. Derivatives of a-, b- and c-cyclodextrin with carboxymethyl groups incorporated either selectively at the 2- or 6-position or indiscriminately at the 2-, 3- and 6-positions have been evaluated [319]. The indiscriminately substituted derivatives are the most effective of those studied, presumably because they also have the highest degrees of substitution [319,320]. The carboxymethylated cyclodextrins are significantly more effective than neutral native cyclodextrins for cationic substrates. The size of the cavity influences the effectiveness for certain substrates. Phenyl-containing aromatic compounds usually show the largest enantiomeric discrimination with the a- or b-CM-CD derivatives [319–321], whereas substrates with bicyclic indoline, indole or naphthyl rings often show the largest discrimination with b- or c-CM-CD [320]. Depending on the particular substrate, either the a-, b- or c-derivative is most preferable. Another feature of the anionic CM-CD is that paramagnetic dysprosium(III), praseodymium(III) or ytterbium(III) can be added to produce substantial enhancements in enantiomeric discrimination. The lanthanide ions bind at the carboxylate groups and the paramagnetism causes perturbations in the chemical shifts of substrates in the cyclodextrin cavity. The Pr(III) or Yb(III) cause a combination of shielding and deshielding effects in the spectra for different hydrogen atoms that lead to a marked improvement in enantiomeric discrimination [320,321]. 3.5.1.6. Sulfated b-cyclodextrin. An indiscriminately sulfated b-cyclodextrin with a degree of substitution of nine is commercially available. Enantiomeric discrimination in the 1H NMR spectra of a variety of cationic substrates is much larger with the sulfated cyclodextrin than with native b-cyclodextrin. Paramagnetic lanthanide ions such as Dy(III) or Yb(III) bind to the sulfated cyclodextrin and produce enhancements in enantiomeric discrimination in the spectra of substrates [322,323]. 3.5.1.7. Sulfobutylether-b-cyclodextrin. Anionic sulfobutyletherb-cyclodextrin (SBE-b-CD) is commercially available as indiscriminately substituted derivatives. Comparisons show that larger enantiomeric discrimination occurs for derivatives with high degrees of substitution of the SBE groups [324]. As with CD-CM, the anionic SBE-b-CD is more effective for cationic substrates than neutral cyclodextrins [324,325]. Enantiomeric discrimination in the 1H NMR spectra of chiral metal complexes such as [Ru(phen)3]2+ (phen = 1,10-phenanthroline) and [Ru(bpy)]3]2+ (bpy = 2,20 -bipyridine) was measured with sulfated, 1-(1-naphthyl)ethyl carbamated, 3,5-dimethyl carbamated and a carboxymethylated cyclodextrin with relatively low degree of substitution of carboxymethyl groups. The SBE-b-CD and 1-(1-naphthyl)ethyl carbamate derivatives were the most effective of those studied [326]. 3.5.2. Crown ethers Many chiral crown ethers have been prepared and evaluated to some extent as chiral NMR solvating agents. The most common crown ethers have the 18-crown-6 unit (193) and form complexes with protonated primary amines. The interaction with primary ammonium ions involves three hydrogen bonds as shown in Fig. 23. Although large numbers of chiral crown ethers have been prepared, the NMR investigations of most of these have been limited to a few substrates.

H O O

O H

H

O

O O

Fig. 23. Interaction of a protonated primary amine with an 18-crown-6 ether.

O O

O

O

O O

193 Among the crown ethers, (18-crown-6)-2,3,11,12-tetracarboxylic acid (194 – 18-C-6-TCA), a derivative of tartaric acid that is commercially available in both isomeric forms, is the reagent of choice. This crown ether has been studied extensively in NMR and liquid chromatographic applications with primary amines. Not only does it produce larger discrimination than other crown ethers that have been studied, it has other attributes that expand its versatility as a chiral NMR solvating agent. O HOOC

O

O

COOH

HOOC

O

O

COOH

O

194 For example, 18-C-6-TCA can be mixed directly with a neutral unprotonated amine in the NMR tube. A neutralization reaction between 18-C-6-TCA and the amine causes the protonated ammonium ion needed for association [327,328]. For underivatized amino acids, the neutralization reaction may not lead to complete solubilization of the amino acid; however addition of an equivalent of DCl solubilizes the amino acid [329,330]. Another attribute of 18C-6-TCA is that it can be used in methanol-d4, deuterium oxide and acetonitrile-d3 [327,331], although enantiomeric discrimination is larger in methanol-d4 and acetonitrile-d3 than deuterium oxide. Addition of ytterbium(III) to mixtures of the neutral form of 18-C-6-TCA with a protonated ammonium salt typically causes enhancements in the enantiomeric discrimination in the 1H NMR spectrum. The Yb(III) binds to the carboxylate groups of the crown ether and the paramagnetism produces substantial perturbations of the chemical shifts of resonances of the substrates [327,328]. 18-C-6-TCA is an effective chiral NMR solvating agent for a- [327,331] and b-amino acids [330]. For a-amino acids, the

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

methine resonance shows characteristic trends that correlate with the absolute configuration [331]. For acyclic b-amino acids (195), both the a-methylene and b-methine resonances typically show sizeable enantiomeric discrimination and exhibit trends that correlate with absolute configuration. The crown is either mixed directly with the neutral b-amino acid in methanol-d4 or one equivalent of DCl is added to solubilize the amino acid [330]. NH2 HOOC R

195 Another unusual observation with 18-C-6-TCA is its ability to associate with secondary amines. The association of secondary amines with 18-crown-6 ethers is usually weak because of steric hindrance of the second substituent group on the amine and because there is only the ability to form two hydrogen bonds. Mixing 18-C-6-TCA with a neutral secondary amine results in a neutralization reaction. In this case, two hydrogen bonds and an ion pair can form as shown in Fig. 24, leading to favorable association [332]. Significant enantiomeric discrimination is observed in the 1H NMR spectra of N-methyl amino acids, secondary alkyl aryl amines [332], pyrollidines [333], piperidines and piperazines [334]. Enantiomeric discrimination is even observed in the spectra of sterically hindered pyrrolidines such as 196 and 197 [333] and piperidines such as 198 [334].

NH

N

198 18-C-6-TCA produces distinction between prochiral groups in primary amines such as the methyl groups of cis-2,6-dimethylpiperazine (199) and 3-aminopentane (200). Also, small but observable enantiomeric discrimination is observed in the 1H NMR spectra of acyclic and cyclic tertiary amines in the presence of 18-C-6-TCA. The neutral crown and tertiary amine are mixed in methanol-d4. The single hydrogen bond and ion pairing interaction with tertiary amines is still sufficient to cause enantiomeric discrimination [335]. H N

N H

199 NH2

200 N H

Crown 201, which is based on a 1,10 -binaphthyl group, was developed by Cram and coworkers and has been used extensively as a liquid chromatographic phase for the separation of primary amines [336]. Comparative NMR spectroscopic studies in solvents such as chloroform-d, acetonitrile-d3 and methanold4 of 201 with 202, the latter of which was also developed for liquid chromatographic applications, show that 202 is more effective at causing enantiomeric discrimination in NMR spectroscopy [337].

HO

196 O NH2

N H

O

197 R

O

O

O

O

R' N O O

HOOC O

O

O H

O

H

O

O

HOOC

COOH

O Fig. 24. Interaction of a protonated secondary amine with the carboxylate ion of 18-C-6-TCA.

201

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O

O

R

H O

O

O

O

O H H O H O

O

OH

202

204

Many crown ethers incorporate glycosides such as b-D-glucopyranoside and b-D-galactopyranoside as the chiral unit [338]. Compound 203, which was prepared from a crown ether with a b-Dgalactopyranoside unit, is an effective chiral discriminating agent in acetonitrile-d3. Another feature of 203 is that the diol moiety will bind to lanthanide ions. Addition of Yb(III) to the solutions in acetonitrile-d3 cause enhancements in enantiomeric discrimination [339].

HO

OH

O

OMe

R

O

O

O OH

O

203 By examining the temperature dependence of a crown–amine system, it was possible to assign the absolute configuration of the substrate. The system must follow a van’t Hoff relationship and have a well-defined structure with anisotropic shielding. Three solutions are needed and the temperature dependence of the chemical shifts is used. This method is potentially applicable to other chiral NMR discriminating agents as well [340]. 3.5.3. Calixarenes and calix[4]resorcinarenes Calix[4]arenes (204) and calix[4]resorcinarenes (205) are cavity compounds formed from the condensation of an aldehyde with phenol and resorcinol, respectively. Calixarenes are prepared exclusively with formaldehyde and depending on the reaction conditions cavities with different numbers of phenol rings are obtained [341]. Calix[4]resorcinarenes can be prepared with virtually any aldehyde, which has the advantage of enabling the preparation of derivatives with a wide range of solubilities. The standard method used to prepare calix[4]resorcinarenes leads to products with four resorcinol rings in the cavity. Chiral derivatives intended for use as chiral discriminating agents are usually prepared by attaching an optically pure chiral moiety to the cavity. As intriguing as calixarenes and calix[4]resorcinarenes are as potential chiral NMR discriminating agents, only one system based on a set of water-soluble calix[4]resorcinarenes has been applied to a wide variety of substrates in NMR studies [342–348]. Studies of other calixarenes and calix[4]resorcinarenes as chiral NMR discriminating agents have been summarized previously and involve examination of only a few substrates [7]. Organic-soluble calixarenes and calix[4]resorcinarenes often do not show especially high association with substrates, presumably because of favorable solvation of the substrates by the organic solvent.

4

205

O

O

OH

4

A water-soluble calix[4]resorcinarene that incorporates anionic sulfonate groups in the bridges between the resorcinol rings and an L-prolinylmethyl group on each resorcinol ring (206) has been extensively studied. Compound 206 adopts a cone conformation in water and is prepared in two steps. In aqueous solution, organic salts or soluble neutral compounds with aromatic rings insert into the cavity of 206. Insertion of the aromatic ring into the cavity is supported by the observed exceptionally large shielding of the aromatic protons of the substrate [342–344]. Aliphatic compounds do not bind as well with 206 and exhibit no or minimal enantiomeric discrimination in the 1H NMR spectrum [342]. COOH

N

HO

HO

OH

R

R

H

H

OH N COOH

HOOC N HO

R

R H

OH

H

HO

OH R=

SO3

N

HOOC

206

Mono- or ortho-substituted phenyl rings bind favorably to 206. Figs. 25a and b show proposed geometries of association for monoand ortho-substituted phenyl rings within the calix[4]resorcinarene cavity. The comparative magnitude of the shielding of different protons of the aromatic ring of the substrate is the basis for these proposed geometries. Those protons that show the most shielding are assumed to be deepest in the cavity [343,344]. Phenyl

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

from that of 207 (Fig. 25d). Perturbations in the chemical shifts indicate that mono-, 2,3-disubstituted and 1,8-disubstituted naphthalene rings associate strongly with 206, whereas 1,4-, 1,5- and 2,6-disubstituted naphthalene rings associate only weakly. Anthryl rings substituted at the 1-position also bind to 206 [347]. Other studies show that ortho-substituted pyridyl rings [343], indole [343], dihydroindole and indane rings [346] devoid of other steric hindrances on the aryl ring also can insert into the cavity of 206.

R R

R

(b)

(a) R

R

O

N H OH

207

(c)

(d)

Subsequent studies of the effectiveness of similar sulfonated calix[4]resorcinarenes with cis-4-hydroxy-L-proline (208a), trans4-hydroxy-L-proline (208b) and trans-3-hydroxy-L-proline (208c) moieties as chiral NMR solvating agents for substrates with phenyl [345,347,348], pyridyl [345,347], naphthyl, indole, dihydroindole and indane rings [346] have been undertaken. While none of the compounds 208a–c consistently produces the largest enantiomeric discrimination, the hydroxyproline derivatives almost always produce larger enantiomeric discrimination than the proline derivative (206). Presumably the hydroxyl group on the proline moiety provides an additional site for interaction with the substrate that aids in the distinction of enantiomers. Of those that were studied, the trans-4- and trans-3-hydroxyproline derivatives often produce the greatest enantiomeric discrimination.

Fig. 25. Geometries of association of substrates with calix[4]resorcinarene 207.

rings with meta-or para-substituent groups only show small perturbations in chemical shifts in the presence of 206, indicating that steric hindrance from the substituents hinders association [344]. A somewhat surprising observation is that compounds with monosubstituted naphthyl rings such as NEA (70) and propranolol (207) also form complexes with 206. In fact, the association constants of bicyclic compounds are greater than for phenyl compounds. The greater hydrophobicity of the bicyclic ring relative to the phenyl ring likely accounts for this observation [343]. What is also interesting is that the relative magnitude of the shielding indicates that the binding geometry for NEA (Fig. 25c) is different R HO

OH

SO3 Na

4

HO

HO

COOH

N

OH

COOH

N CH2

CH2

(a)

CH2

(b) 208

COOH

N

(c)

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In recent studies, a bis[(R)-(ethyl lactate)] derivative of a tertbutyl calix[4]arene (209) is effective as a chloroform-soluble chiral solvating agent for the discrimination of dinitrobenzoyl derivatives of amino acids. The aromatic resonances of the dinitrobenzoyl group are the best for monitoring the presence of enantiomeric discrimination [349]. tBu

tBu

nating a specific target compound or class of compounds [7]. Most of these are not commercially available. Several receptor compounds have been developed specifically for carboxylic acids. Compounds 210 [350], 211 [351] and 212 [352] are guanidinium-based reagents that bind carboxylate species through hydrogen-bonding interactions as illustrated in Fig. 26. An alternative motif for binding carboxylic acids is shown in 213 [353]. The interaction of 213 with carboxylic acids involves three hydrogen bonds as shown in Fig. 27. Phenyl, naphthyl or cyclohexyl groups were examined as the R group in 213 and the largest enantiomeric discrimination was observed with the naphthyl substituent. N

2 OH

Ph

O

O

O

Si

N H

Ph t

N

Ph Si Ph t

Bu

Bu

210 O

O N

209

N H O

N H

O

O

O

3.5.4. Miscellaneous receptor compounds A wide variety of specialized receptor compounds have been used as chiral NMR solvating agents. Most of these have been used in a limited number of studies and many are targeted at discrimi-

H N

N

H H

N

A

+

O

H

O

C

211

C

SO2 Ph

B

Ph

Ph N

Fig. 26. Interaction of carboxylate species with guanidinium-based reagents.

N H

Ph

Ph

212

O

O O

N R

O

N NH

H

H O

HN

R

N R1

N

H O

Fig. 27. Interaction of carboxylic acids with 214.

213

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

Protonated cations of secondary amines form hydrogen bonds to the nitrogen atoms of 2,6-bis(4,5-dihydro-4-phenylozazol-2yl)pyridine (214) and exhibit enantiomeric discrimination in the 1 H NMR spectrum. The reagent is effective for substituted piperidines and proline methyl ester [354].

O

O N NH

HN

O

O N

N

N

N

N

Ph

Ph

Ph

Ph

216

214 A number of recent studies have decribed chiral NMR applications of macrocyclic receptors. These reagents are usually used with carboxylic acids. An aza crown that contains a cis-2-oxymethyl-3-oxy-tetrahydropyran unit (215) produces enantiomeric discrimination in the 1H NMR spectra of a-amino acid methyl esters. Aromatic amino acids such as phenylalanine and tryptophan have a p–CH interaction of the aromatic ring of the amino acid with the hydrogen of the macrocycle. The D-enantiomer of the amino acid methyl ester associates more strongly with 215 [355]. A series of pincer-like receptors, the best of which contains two (1R,2R)-cyclopentanediamine moieties (216), have been evaluated as chiral solvating agents for carboxylic acids. Aryl propionic acids with an aromatic group at the Ca position exhibit the largest enantiomeric discrimination in the 1H NMR spectrum in chloroform-d [356,357]. Compound 217 is a polyamide macrocycle prepared from tartaric acid. Enantiomeric discrimination is observed in the 1H NMR spectrum of mandelic acid and several of its derivatives [358]. The (S,S,S,S,S,S)-enantiomer of macrocycle 218 prepared from (S,S)-1,2-diaminocyclohexane is an effective chiral solvating agent for aliphatic and aromatic-containing carboxylic acids. In all cases, the signals of the (R)-enantiomer of the carboxylic acid is at higher magnetic field than that of the (S)-enantiomer in the presence of 218 [359].

O

O

O

NH

HN

N

Ph

N

Ph

217

NH

O

O

HN

OH

O NH

N O

HN

O HO

OH O

O O

O

H N

H N

O

215 218

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BINOL is often employed as a building block for macrocyclic and open receptor compounds. A series of BINOL-based macrocycles, the best of which is 219, are effective chloroform-soluble chiral solvating agents for determining the enantiomeric purity of a wide range of substrates. This includes compounds with carboxylic acid, oxazolidinone, carbonate, lactone, alcohol, sulfoxide, sulfoximine, sulfonamide, isocyanate and epoxide moieties that can form hydrogen bonds with functionalities in the cavity [360]. A comparable macrocycle without the 3,5-bis(trifluoromethyl)phenyl groups has been used to assign the absolute configuration of (R)-ceriporic acids (220). The compounds were analyzed as their dimethyl esters and methyl succinic acid was used as a model compound to validate the assignment [361].

observed in the 1H NMR spectrum of carboxylic acids in chloroform-d. Considerable broadening is observed in the spectra of the phosphinic, phosphonic and phosphoric acids in chloroform-d with 221. The addition of 5% methanol-d4 to the chloroform-d reduces the broadening such that enantiomeric discrimination can be observed [362].

N O

O

NH

HN

R

3

R

221

3

D3 symmetric trianglamines, one example of which is 222, have been used as chloroform-soluble chiral solvating agents for secondary alcohols, cyanohydrins, propargyl alcohols. Depending on the nature of the substituent group at the alcohol, the a-methine resonance shows certain trends that correlate with absolute configuration [364]. 3

3

NH

HN

NH

HN

NH

HN

2

222

Macrocycle 221 (R = phenyl or 2-naphthyl) is an effective chiral solvating agent for phosphinic, phosphonic, phosphoric [362] and a-chiral carboxylic acids [363]. Enantomeric discrimination is

Higher fullerenes such as C76 are chiral. Compound 223 is a host with a cavity that matches the size of C76. Using rac-223 in toluened8, the NH and N-methyl proton resonances of the host split into

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

two signals upon inclusion of C76, providing a sensor for the chirality of fullerenes [365].

N t

CF 3

HN t Bu

Bu N

N

O

O

O CH 2 6

O

H2 C 6

O

224

O N

t Bu

HN t Bu

M NH

N

223

CF2CF2CF3

4. Metal complexes

O A variety of metal complexes have been used in NMR spectroscopy to determine the enantiomeric purity and absolute configuration of chiral compounds. Only the most widely studied and broadly applicable ones will be described herein. The majority of these systems involve a donor–acceptor complex between a Lewis acidic metal and an organic Lewis base. The nature of the hard–soft Lewis acid properties of the metal determines the types of substrates that form suitable donor–acceptor complexes. Of the most widely studied metal systems, lanthanide(III)-containing reagents are hard Lewis acids that primarily form complexes with oxygen- and nitrogencontaining donors. Metals such as palladium(II), platinum(II), rhodium(I) and silver(I) are soft Lewis acids that form complexes with soft Lewis base moieties such as alkenes, allenes, aromatics and substrates with phosphorus and sulfur donor atoms. 4.1. Lanthanide complexes The utilization of achiral paramagnetic lanthanide tris b-diketonates as organic-soluble NMR shift reagents was a significant event in the overall development of NMR shift reagents [366]. The lanthanide(III) ion in tris b-diketonate complexes can expand its coordination sphere to bind to donor substrates. The magnetic field of the paramagnetic lanthanide ion causes large changes in the chemical shift in the resonances of a bound donor molecule. The magnitude of the perturbation and the direction of the changes in chemical shifts depend on the lanthanide ion. Paramagnetic lanthanide shift reagents were especially useful when NMR spectrometers with lower field strengths were common. Several important chiral lanthanide tris b-diketonates were described soon after the first reports on achiral complexes [366]. Most noteworthy among the wide variety of chiral derivatives that were studied are those with the ligands 3-trifluoroacetyl-D-camphor (224 – H(tfc)) [367], 3-heptafluorobutyryl-D-camphor (225 – H(hfc)) [368] and D,D-dicampholylmethane (226 – H(dcm)) [369]. There is no consistent trend as to whether lanthanide(III) chelates of tfc or hfc are the more effective at causing enantiomeric discrimination in the NMR spectra of substrates. The presence of the electron-withdrawing fluorine atoms in tfc and hfc makes the lanthanide ion a harder Lewis base and strengthens the association with donors.

O

225

O

O

226 While the chelates of tfc and hfc have been used more often because of their early commercial availability, studies that have utilized the Eu(III) chelate of dcm usually report substantially larger enantiomeric discrimination than occurs with tfc and hfc [7,369]. The Eu(III) chelate of dcm is commercially available. While the reason for the effectiveness of Ln(III) chelates of dcm relative to those of tfc and hfc is not known with certainty, a likely explanation involves greater steric crowding in the dcm complexes. Lanthanide tris b-diketonate complexes have a formal coordination number of six; however, the large lanthanide ions can accommodate coordination numbers up to nine through association of additional donor atoms. The complexes are also fluxional and the ligands move to accommodate donors. Steric crowding is expected to create a more specific association of the chiral donor that enhances the discrimination between the enantiomers. A similar argument has been used to justify the effectiveness of achiral Ln(III) chelates with bulky ligands such as 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5octanedione and 2,2,6,6-tetramethyl-3,5-heptanedione over those of 1,1,1,5,5,5-hexafluoro-2,4-pentanedione and 1,1,1-trifluoro2,4-pentanedione [366]. The fluxional nature of the lanthanide tris b-diketonate complexes also means that the association geometry is not known with enough specificity to assign the absolute configuration based on precise geometrical considerations. Instead, there are a number of sets of compounds for which empirical trends in

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

the chemical shifts for closely related structures correlate with absolute configuration. These have been thoroughly described in a recent review [7]. The most significant attribute of the lanthanide complexes is the wide array of substrates that can be studied. These encompass virtually any nitrogen- or oxygen-containing compound. In addition to organic donors compounds, metal complexes that have hard Lewis base groups in the ligand that are available to bind to the lanthanide ion can also be studied. The versatility of the lanthanide tris b-diketonates is likely unmatched among chiral NMR shift reagents. Chiral lanthanide shift reagents have been applied to the analysis of hundreds of compounds and their use has been described in two comprehensive reviews [7,366]. The significant limitation to the use of paramagnetic lanthanide chelates today is the degree of broadening caused by the lanthanide ions. The paramagnetic ions shorten the relaxation times of nuclei of the substrate leading to line broadening. In addition, exchange broadening caused by intermediate rates of exchange of the substrate between its bound and unbound forms can occur. The broadening with paramagnetic lanthanide ions is dependent on field strength and is more severe at higher field strengths. Furthermore, those ions that cause the largest perturbations in chemical shifts also cause the greatest broadening. Often the broadening can obscure both coupling information and the enantiomeric discrimination present in a resonance. Besides running the spectrum at frequencies of 300 MHz or lower, several strategies have been used to reduce broadening to acceptable levels. One is to record proton-decoupled 13C NMR spectra. The effect of exchange broadening of the 13C nucleus is less than on the 1H nucleus at comparable field strengths. In addition, broadening of the sharp 13C singlets will likely have less of an impact on the ability to observe enantiomeric discrimination. As one example, an examination of the perturbations of chemical shifts for the 13C resonances of secondary and tertiary alcohols with (R)- and (S)Pr(hfc)3 showed specific trends for the neighboring carbon atoms that correlate with absolute configuration. The method can also be applied to diols separated by two or more carbon atoms [370]. Using relatively non-polar solvents such as chloroform-d, or lowering the temperature enhances the association of the substrate with the lanthanide ion and generally increases the enantiomeric discrimination. This will also increase the broadening. Several studies have found that the use of a more polar solvent such as acetonitrile-d3 reduces the broadening to acceptable levels while still providing enantiomeric discrimination with the lanthanide tris chelates [371,372]. Others note that warming the sample to 50–75 °C speeds up substrate exchange, thereby reducing broadening to acceptable levels [306,373]. Using a paramagnetic lanthanide ion such as Sm(III) that causes relatively small perturbations in chemical shifts is another strategy to reduce broadening [374]. It has even been shown that chiral tris b-diketonates of diamagnetic lanthanum(III) and lutetium(III) can cause enantiomeric discrimination in the 1H NMR spectra of many substrates at 400 MHz. Perturbations in chemical shifts with La(III) and Lu(III) occur only through complexation effects of the substrate. Enantiomeric discrimination is observed in the spectra of substrates with amine, alcohol, epoxide, sulfoxide and oxazolidine groups. In this study, chelates of tfc, hfc and dcm were evaluated. Whereas prior studies found that enantiomeric discrimination with dcm chelates of paramagnetic lanthanide ions are usually superior to those with tfc and hfc, this is usually not the case with the diamagnetic chelates. Selection of the best lanthanide ion and ligand varies for different substrates. Solvent is also an important factor and enantiomeric discrimination is often larger in benzene-d6 or cyclohexane-d12 than in chloroform-d. The stronger association expected in non-polar benzene-d6 and cyclohexane-d12 relative to that in chloroform-d likely accounts for this observation [375].

One final strategy for reducing line broadening involves the use of Gaussian line narrowing with a baseline correction. This manipulation of the data makes it possible to observe the enantiomeric discrimination in the 1H NMR spectra of b-alkoxy alcohols and diols with Eu(hfc)3 and Yb(hfc)3 at 300 MHz [376]. Even though paramagnetic lanthanide species often produce unacceptable broadening at high-field strengths, there are cases in which lanthanide chelates have been successfully used for chiral discrimination at high field strengths. One recent example is the compound hexamethylenetriperoxide diamine (227). The helical chirality of 227 was unequivocally demonstrated by a doubling of some resonances in the 1H and 13C NMR spectra in the presence of Eu(tfc)3 and Pr(tfc)3 in methylene chloride-d2 on a 600 MHz instrument [377].

O

O

O

N

N

O O

O

227 The Pr(III) complex of tetraphenylimidodiphosphinate (228 – Pr(tpip)3) is effective for determining the enantiomeric purity of chiral carboxylic acids in organic solvents. An interesting aspect of this system is that the complex is achiral, but association of chiral carboxylic acids forms diastereomeric binuclear complexes. The dimers undergo slow exchange on the NMR time scale. Of special merit is the enantiomeric discrimination in the 1H NMR spectrum of 229, which has a remotely disposed chiral center five bonds removed from the carboxylic acid. Another involves the discrimination of 2-2H-12-phenyldodecanoate, which is chiral by virtue of deuterium substitution at the 2-position. In this case, enantiomeric discrimination is facilitated by formation of a mixed dimer involving enantiomerically pure 2-chloropropionate as a ligand [378].

O

O

P

Ph Ph

P N H

Ph Ph

228 COO Pr 2(tpip)4 S

S

2

229 4.1.1. Binuclear lanthanide–silver complexes A method in which lanthanide ions can be used to analyze organic-soluble soft Lewis bases such as alkenes, aromatics, phosphines and halogenated compounds involves mixing together a lanthanide tris b-diketonate [Ln(b-dik)3] with a Ag(I) b-diketonate [Ag(b-dik)]. Evidence suggests that the mixture forms an ion pair between a lanthanide tetrakis chelate anion and the silver cation ([Ln(b-dik)4]Ag+) [379]. The Ag(I) ion binds to the soft Lewis base and the paramagnetic lanthanide ion is largely responsible for causing perturbations in the NMR spectrum. Chiral analogues are formed by using Ln(tfc)3 or Ln(hfc)3 with achiral or chiral Ag(I) b-diketonate complexes, although the silver complex with

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6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedione is the only one commercially available [379–381]. Lanthanide tris b-diketonates with D,D-dicampholylmethane (dcm) are not effective in the binuclear reagents, presumably because the lanthanide ion is too sterically hindered by the bulky dcm ligands to form the tetrakis chelate anion species [382]. Broadening is reduced relative to the use of lanthanide tris b-diketonates with hard Lewis bases because of the greater distance between the paramagnetic lanthanide ion and the substrate caused by the bridging silver ion. Applications of these reagents to acyclic and cyclic alkenes, aromatic, and bromide substituents have been thoroughly reviewed [7]. In some cases, the use of a binuclear lanthanide–silver reagent for a polyfunctional reagent with both hard and soft Lewis base functionalities is more effective than using chiral lanthanide tris b-diketonates [383–386]. The binuclear reagents can also be used to analyze organic cations. Mixing an organo halide salt with [Ln(b-dik)4]Ag+ leads to a precipitate of silver chloride and an ion pair between the organic cation and lanthanide tetrakis b-diketonate anion. Discrimination of chiral isothiouronium (230) [387] and sulfonium (231) [388] salts has been demonstrated.

Br

NH2

S

NH 2

230 R S

N

N

N

N N

N

233 Since broadening with the Eu(III) complex may be unacceptable with these reagents, the use of Ce(III) [392] and Sm(III) [393] complexes of pdta reduce broadening but still cause enantiomeric discrimination in the 1H or 13C NMR spectra of a-amino acids. Pr(pdta) has been used for the quantitative analysis of a-amino acids in water based on enantiomeric discrimination in the 13C NMR spectra [394]. Sm(pdta-d8) has been used to assign the absolute configurations of mixtures of a-amino acids in peptide hydrosylates. The method was demonstrated for the simultaneous analysis of eight different a-amino acids in a hydrosylate [395]. Studies using complexes with pdta are usually performed at basic pH to deprotonate the carboxylic acid and promote association with the lanthanide ion. Analysis of underivatized a-amino acids with chelates of TPPN can be performed at neutral pH. Certain resonances of the amino acids exhibit trends that correlate with the absolute configuration [396]. The use of TPPN complexes with Ce(III) [397] or La(III) [398] reduces broadening in the spectrum, but still provides sufficient enantiomeric discrimination at 400 MHz. The ytterbium(III) complex of (S,S,S)-234 can be used to determine the enantiomeric purity of a-hydroxyacids and a-amino acids at physiological pH. For a-amino acids, the (R)-enantiomer preferentially binds and exhibits the larger perturbations in chemical shifts. Extremely large enantiomeric discrimination of 2–11 ppm is observed for certain 1H resonances at 200 MHz [399].

231 4.1.2. Water-soluble lanthanide complexes A variety of chiral water-soluble lanthanide reagents have been evaluated as NMR discriminating agents. The most widely studied are compounds with the anionic ligand of propylenediaminetetraacetic acid (232 – pdta) and N,N,N0 ,N0 -tetrakis(pyridylmethyl)propylene diamine (233 – TPPN). These reagents are especially effective for the analysis of carboxylic acids and amino acids. The Ha resonance of a-amino acids [389] and a-methyl signal of a-methyl amino acids [390] show trends with Eu(pdta) that correlate with absolute configuration. Eu(pdta) also causes enantiomeric discrimination in the 1H NMR spectra of b-amino acids and perturbations in the chemical shifts of the a- and b-proton resonances correlate with the absolute configuration [391].

HOOC

HN

HN

N O

O N

N

NH

HOOC N

O

COOH

HOOC

HOOC

N

N H

COOH

COOH

232

234

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4.2. Palladium complexes

4.3. Platinum complexes

Bridged palladium dimers containing enantiomerically pure N,N-dimethyl-(1-phenyl)ethylamine or N,N-dimethyl-1-(1-naphthyl)ethylamine (235) undergo reactions with mono- and diphosphines, arsines, bidentate aminophosphines, a- and b-amino acids and diamines to form a monomeric palladium species. The two chiral ligands are commercially available and the palladium complexes are easily prepared and purified. Because a monomeric palladium species is formed in the reaction with the substrate, the presence of the cis- and trans-dimers for 235 does not influence the nature of the products. Comprehensive reviews on the use of these palladium reagents have been published [7,400].

Complex 237 acts analogously to 236 as a chiral discriminating reagent for alkenes, allenes and alkynes. The substrate displaces the ethylene ligand and the 31P NMR spectrum is examined for enantiomeric discrimination. Substrates with cyclic and acyclic alkene bonds or alkyne bonds can be analyzed [405,406].

NMe2

Ph2 P Pt P

Me 2N

Ph2

Cl Pd

Pd

237

Cl

cis

NMe2 Cl Pd

Pd Cl

Me2 N

trans 235 Many of the complexes undergo slow exchange and nuclei of either the substrate or optically pure ligand exhibit differential shielding in the diastereomeric products. Both 1H and 31P NMR spectra can be used in the analysis of phosphines. Because of the slow exchange and fixed structure of the product, it is sometimes possible to use techniques such as NOESY and ROESY to determine the proximity of groups and assign the absolute configuration [401–403]. The naphthyl derivative is usually more effective than the phenyl derivative at causing enantiomeric discrimination in the NMR spectrum. The H8 atom of the naphthyl ring constrains the geometry of the C-methyl group of the five-membered metallocycle, which explains the effective chiral discrimination. Substitution of a bulkier tert-butyl group on the carbon of the alkyl group or an isopropyl group on the nitrogen atom of the ligand generally results in greater enantiomeric discrimination in the 31 P NMR spectra of phosphines [404]. The palladium complex with 2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolan (236) can be used to analyze the enantiomeric purity of alkenes and alkynes. The substrate displaces the ethylene ligand and splitting of the 31P resonance for the two diastereomeric complexes is observed [405].

Complexes with an amine species either covalently attached to the platinum ion (238) or ion-paired to the anionic platinum species (239) are effective for determining the enantiomeric purity of alkenes and allenes. The substrate displaces the ethylene group and splitting of the 195Pt signal is monitored. A complication with this system is that alkene and allene substrates have two prochiral faces. Binding at only one prochiral face by a pair of enantiomers leads to two 195 Pt signals, whereas binding at both faces leads to four signals. An advantage of the ionic platinum complex is that more sterically crowded amines such as (S)-3,5-dihydro-4H-dinaphthyl-[2,1-c:10 ,20 e]azepine (240) can be used, which often leads to greater enantiomeric discrimination of the platinum signals [407]. The choice of a covalent or ionic complex and the binding distinction of the prochiral faces depends on the class of substrates. A comprehensive review article on these systems summarizes the observations and recommended option between the covalent and ionic metal complexes [408].

Ph HN Cl

Pt

Cl

238 Cl

Cl Pt

[AmH]

Cl

239

Ph2 NH

O P M P

O

Ph2

236

240

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4.4. Rhodium complexes Carboxylate compounds like MTPA (1) react with rhodium to form a dimeric species (241 – Rh2(MTPA)4). Rh2(MTPA)4 is an effective chiral discriminating agent for a broad range of compounds, the majority of which are soft Lewis bases. These include alkenes, and compounds with phosphorus, sulfur or iodine atoms. Depending on the substrate, 1H, 13C, 31P, 77Se or 103Rh NMR spectra can be used to monitor for the enantiomeric discrimination. A caution to note when using this reagent is that both 1:1 and 2:1 substrate–rhodium complexes can form as shown in Fig. 28, and the degree of enantiomeric discrimination can vary between the two species. The literature reports that describe the utility of Rh2(MTPA)4 as a chiral NMR discriminating agent provide recommendations on the best concentration ratios to use for particular types of substrates. Comprehensive reviews of the use of Rh2(MTPA)4 for enantiomeric discrimination have been published [7,409].

O

242

R R2

R O

O

O O

R1

MeO

Rh

Rh O

243

RO2 = MTPA

O O

OMe

R2

MeO

O

R R

241 Recent studies have extended the utility of the rhodium dimer to classes of compounds such as amides, ethers, furans and purans that can be considered hard Lewis bases [410,411]. The 13C NMR spectra of 2-butylphenyl ethers, one example of which is 242, exhibit enantiomeric discrimination in the presence of Rh2(MTPA)4 [412,413]. Similarly, the 1H and 13C NMR spectra of cycloveratrylenes (243) and cryptophanes (244) exhibit enantiomeric discrimination in the presence of Rh2(MTPA)4. Compounds 243 and 244 have methoxy groups that bind to the rhodium. A detailed analysis of the binding of ethers indicates that it primarily involves an electrostatic attraction [414]. The analogous thio ethers bind much more strongly to the rhodium through the sulfur atom. For the thio ethers, interaction between the sulfur HOMO and rhodium LUMO accounts for the more favorable association than occurs with oxygen atoms [413,414]. R

n

+L

O

O

R

R2

O

R

Rh

+L L

L

O

R Fig. 28. Binding of substrate ligands to Rh2(MTPA)4.

O O

Rh

O Rh

O

-L

O O

O O

O R

R

O

Rh

-L

O O

R2

O

244

O

Rh

O R

O O

n'

n

R2

R

O

Rh

R1

R

O

O

O

R O

R1

O

R1

O R

O

O

R

L

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

The 1H and 13C NMR spectra of atropisomeric compounds such as 2-iodo-4,40 ,6,60 -tetramethyl-20 -(diphenylphosphoryl- 1,10 - biphenyl) (245) [415] and 2-oxo-4-oxazoidinones (246) [416] exhibit enantiomeric discrimination in the presence of Rh2(MTPA)4. For 245, both the iodine and phosphoryl group may bind to the rhodium, but association of the phosphoryl group is favored [415]. For 246, the analogous thiocarbonyl compound exhibits much stronger binding and larger enantiomeric dispersion in the NMR spectra. The same behavior occurs for carbonyl and thiocarbonyl analogues of bicyclic lactams of structure 247. Both sets of compounds show enantiomeric discrimination in the 1H and 13C NMR spectra with Rh2(MTPA)4; however, binding of the sulfur analogues is much greater [417].

Schiff bases of ortho-hydroxyaldehydes with general structure 248 exhibit enantiomeric discrimination in the 1H and 15N NMR spectra with Rh2(MTPA)4. The R groups in 248 do not have suitable binding moieties and association with rhodium occurs through the hydroxy group [418].

R'

N

OH

Cl R

248 1

I O P Ph Ph Cl

245

13

The H and C NMR spectra of secondary and tertiary phosphine-borane compounds of general structures 249 and 250 exhibit a small degree of enantiomeric discrimination in the presence of Rh2(MTPA)4. The 31P and 11B NMR spectra are too broadened to be of use in enantiomeric analysis. Benzene-d6 is preferable over chloroform-d as a solvent to minimize decomposition of the substrates. Association of the substrate with the rhodium involves the hydrogen atoms on the boron atom [419]. Similarly, the hydrogen atom of methyl-1-naphthylphenylsilane (251), instead of the aromatic rings, is the site of binding to the rhodium in Rh2(MTPA)4. This was definitively demonstrated by analyzing the corresponding carbon-containing compound, which does not exhibit perturbations in chemical shifts or enantiomeric discrimination in the presence of Rh2(MTPA)4. Enantiomeric discrimination is observed in the 1H and 29Si NMR spectra of 251 [420].

O

O

H

O

N

H

B

P

R

X H

H

249 246 H H TBDMS

H

H

O

N

H

B

P

H MeO

O

247

250

R

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

5. Liquid crystals

Si H

251 Rhodium dimers of several ligands in addition to MTPA were evaluated early on and MTPA was judged most effective [421]. More recently, the effectiveness of rhodium dimers prepared with MaNP (4) and (S)-N-phthaloyl-(S)-tert-leucine (252) were compared to Rh2(MTPA)4 on substrates with selenium, sulfur, carbonyl and phenoxide binding moieties. The MaNP derivative is not very effective in causing enantiomeric discrimination in the NMR spectra. In contrast, the rhodium dimer with 252 is especially effective at causing enantiomeric discrimination, presumably because the complex orients the phthaloyl group in an alignment capable of producing substantial shielding in the NMR spectrum of the substrate [422].

O H N

HOOC t

Bu O

252 4.5. Silver complexes The silver complex of N,N0 -bis(mesitylmethyl)-1,2-diphenyl1,2-ethanediamine (253) and the corresponding cyclohexyl-1,2diamine derivative are effective chiral NMR discriminating agents for alkenes with a chiral center a to the double bond. The mesityl rings of the ligand cause shielding of resonances of the alkene. The reagent is prepared directly in the NMR tube by adding silver triflate, the alkene and the amine ligand [423].

N H

N H Ag

253

The utilization of chiral liquid crystals for determining enantiomeric purity has undergone rapid development in recent years. Liquid crystals are unusual in their properties as chiral NMR discriminators, since there is no necessity for a directed interaction between the substrate and liquid crystal. Instead, when placed in a magnetic field, the liquid crystal molecules are partially aligned relative to the field. Substrate molecules subsequently align as well; however a pair of (R)- and (S)-enantiomers will usually align in different orientations relative to the applied magnetic field. Three possibilities then exist for distinguishing the pair of enantiomers. One is that chemical shift differences can occur between the enantiomers, as observed with other chiral discriminating agents. This is often the least useful way of distinguishing enantiomers in chiral liquid crystals because differences in chemical shifts of the two enantiomers are usually quite small. A second is that the dipolar coupling constants between 1H–1H and 1H–13C nuclei can be different in the two enantiomers. For example, a 1H nucleus coupled to only one other 1H nucleus appears as a doublet in the NMR spectrum if the molecules tumble rapidly, as occurs in solution. If the enantiomers are aligned in different orientations relative to the applied magnetic field, the resonance now appears as two doublets, one for each enantiomer. If there are no induced shielding differences present, the two doublets have the same chemical shift, but different coupling constants. The relative area of each doublet corresponds to the proportion of the enantiomers in the mixture. One complication is that the different dipolar coupling constants introduce considerable complexity in the NMR spectrum. The third and most common way of monitoring chiral discrimination in liquid crystals is to record the spectrum of a quadrupolar nucleus such as deuterium. Under conditions of rapid isotropic tumbling, the signal for a deuterium atom exhibits no quadrupolar splitting. In a liquid crystalline sample the tumbling is anisotropic and the 2H resonance appears as a doublet from the partially-averaged quadrupolar interaction. The magnitude of the quadrupolar splitting is dependent on the orientational order parameters of the C–D bond directions (SCD) relative to the applied magnetic field. For a pair of (R)- and (S)-enantiomers with different values of SCD, two doublets occur in the spectrum. Integration of the areas of the two doublets is used to determine the enantiomeric purity. The values of quadrupolar splittings are quite large and usually an order of magnitude larger than other interactions the influence the NMR spectrum. A variety of two-dimensional pulse strategies that result in simpler 1H and 13C NMR spectra have been devised to overcome the complexity in coupled 1H or 13C NMR spectra of enantiomers in liquid crystals. Pulse sequences that allow for selective refocusing excitations (SERF) so that only one coupling evolves have been reviewed. Experiments that allow homonuclear refocusing for 1H nuclei and heteronuclear refocusing for 13C nuclei are discussed in this article [424]. Since that article, other techniques that allow 1 H band selection with shorter experimental measurement times have been developed. These latest techniques can be applied to larger molecules than earlier methods and also provide the signs of the coupling constants [425]. A procedure for obtaining 13C NMR spectra in liquid crystals that involves much shorter acquisition times was recently reported. The method uses an inverse gated 1H decoupling experiment and relies on using a cryoprobe. Spectral acquisition times are reduced to 12 min for 1–5 mg samples [426]. While differential quadrupolar splitting of 2H NMR signals is most commonly used to analyze enantiomers in liquid crystals,

55

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

this is not without complications. Low isotopic abundance restricts the ability to do natural abundance 2H NMR studies. Furthermore, the potential appearance of two doublets for each specific deuterium atom often leads to complicated spectra with overlapping resonances, especially since the quadrupolar splittings in the spectra are quite large. A variety of strategies for obtaining and assigning natural abundance 2H NMR spectra in liquid crystals have been reported and an overview of these methods has been published [427]. A better strategy than natural abundance 2H NMR spectroscopy is to incorporate, when practical, a 2H-enriched substituent group into the substrate. It is important to note that the purpose of the substituent groups is only to provide an intense 2H signal. As such, the deuterated group is achiral, so kinetic resolution is not a concern in the derivatization step. The most common chiral liquid crystal that has been used is poly(c-benzyl-L-glutamate) (PBLG). Poly-c-ethyl-L-glutamate (PELG) and poly-e-carbobenzyloxy-L-lysine (PCBLL) are other chiral liquid crystals that have been used in NMR studies. The liquid crystal system has a co-solvent, the most common of which are methylene chloride, chloroform or dimethyl formamide. The appropriate cosolvent is chosen to insure adequate solubility of the substrate. Because there is no need for specific interactions with the substrate, liquid crystals can be used to analyze essentially any class of chiral compounds, even including aliphatic hydrocarbons. A variety of studies have demonstrated the incredible diversity of compound classes that exhibit enantiomeric discrimination because of different orientational ordering of the enantiomers in a liquid crystal. A comprehensive overview of these studies has been published [7]. Several recent studies on the use of liquid crystals for chiral NMR discrimination have focused on extending their utility to different classes of compounds. A procedure for analyzing amines in PBLG has been developed. Chloroform and methylene chloride were not suitable as solvents for use with amines because of solubility issues. Dimethylformamide was found to be a suitable solvent. Also, perdeuterobenzyl chloride was an excellent derivatizing agent for amines to incorporate three different 2H signals for monitoring quadrupolar splitting. The presence of three signals enhances the likelihood that one will exhibit large differences in the quadrupolar splitting [428]. Other studies examined atropisomers such as 1-bromo-3-2H5-methyl-2-(10 -naphthyl)benzene (254) [429] and 1-(20 ,60 -dideutero-4-methylphenyl)naphthalene (255) [430]. Kinetic and activation parameters of the internal rotational isomerism were investigated in PBLG using variable temperature NMR studies. At low temperatures, signals are observed for the two enantiomers and these eventually coalesce as the temperature is raised.

D

D

255 Tridioxyethylenetriphenylene (256) is an example of a compound with conformational enantiomers. If there is a fast interconversion of the dioxyethylene groups, all of the ethylene hydrogen atoms are equivalent, as occurs for 256 in solution. With 10% selective deuteriation, the pairs of enantiotopic ethylene groups of 256 exhibit large enantiomeric discrimination in the 2H NMR spectrum when ordered in PBLG liquid crystals [431].

O

O

O

O

O

O

256 The crown and saddle isomers of nona-methoxy-cyclotriveratrylene (257 – M-enantiomer depicted for crown isomer) were distinguished using 2H and 13C NMR spectra in PBLG. The 2H spectra were obtained on derivatives deuteriated at methylene and aromatic sites. The 13C distinction was based on chemical shift anisotropy of the compound. Spectra were recorded at natural abundance and on samples enriched with 13C at a ring methylene and one methoxy group [432]. OMe

D

Br

MeO MeO

OMe MeO

OMe

OMe MeO

OMe

257

254

56

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C chemical shift differences between enantiomers were similarly used to determine the enantiomeric purity of triazole fungicides (258) [433]. Enantiomers of [Ru(bpy)3]2+ (bpy = 2,20 -bipyridine) and complexes with other perdeuterated diimine ligands can be distinguished using quadrupolar splitting of the 2 H NMR spectra in PBLG [434]. The enantiotopic sites in prochiral dihalides such as 2,3-dibromonorbornadiene (259) and 1,2-diiodoferrocene (260) can be distinguished in PBLG using natural abundance 2H NMR spectroscopy [435].

Acyclic phosphonium salts with a stereogenic center on the phosphorus atom or substituent group, one example of which is 261, can be enantiomercially distinguished in PBLG-DMF on PCBLL-DMF systems. DMF is needed for sufficient solubility. Quadrupolar splitting in the 2H spectrum or chemical shift differences in the 13C NMR spectrum are used in the analysis [436].

CD 3 I P

R

Cl

OMe HO

tBu

N

N

261

H

Most applications of chiral liquid crystals in NMR spectroscopy involve a determination of enantiomeric purity. However, if similar compounds align the same way, then it should be possible to use empirical trends in the data to assign the absolute configuration. A series of isostructural epoxides with known configurations exhibit consistent trends in the natural abundance 2H NMR data that can be used to assign the absolute configuration of unknowns [437]. Using monodeuterated derivatives of 1,10 -bis(thiophenyl)hexane of known configuration (262), it is possible to assign the 2H signals of the 4-pro-(R)/pro-(S) and 5-pro-(R)/pro-(S) positions in PBLG–chloroform. With this information, it is then possible using PBLG to examine not only the 2H/1H ratio at each methylene group in fatty acids, but to assign the absolute configuration for each deuterium signal [438].

N

258 Br

Br

259 D

H SPh

SPh

SPh H

SPh

H

D

SPh

D

H

D SPh

SPh

SPh

262

I I Fe

260

Optimization of the liquid crystal or orienting medium is sometimes important when using these systems. In some cases, mixtures of PBLG and PCBLL are found to be more effective at causing enantiomeric discrimination than either individual liquid crystal. Varying the proportion of the two provides a way of optimizing the analysis for a particular substrate [439]. Fragmented DNA samples consisting of 100-500 base pairs have been evaluated as water-soluble liquid crystals. The utility of these systems was demonstrated on a mixture of DL-alanine [440].

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5.1. Residual dipolar couplings A method that is in its early stages of development is the use of residual dipolar couplings (RDCs) to assign absolute configurations. RDCs can be measured if a molecule is aligned in a magnetic field using a liquid crystal or other orientating medium. The different RDCs of the (R)- or (S)-enantiomer can be related back to the absolute configuration. In an early proof-of-concept study, the diastereotopic methylene protons at C20 in strychnine (263) were assigned using PBLG–chloroform as an orienting medium [441]. PELG was later used and provided better alignment, thereby enabling the assignment of all of the diastereotopic methylene protons of strychnine [442].

264

N 20

H H O N

H H

H

O O H

O O

263 Distinction of (R)- and (S)-ibuprofen was achieved in PBLG– chloroform using 1H–1H, 1H–13C, and 13C-13C RDCs. The report provides a detailed procedure for determining absolute configuration based on RDCs. Discrimination of the two enantiomers is more readily achieved when they adopt a preferred conformation, which occurs for ibuprofen. Calculated RDCs for the lowest energy conformers are compared with experimental RDCs and used to assign the absolute configuration. Molecules with non-fixed conformations are more complex as the different RDCs from each conformer will broaden the signals. The method is deemed useful for small molecular weight molecules with one or two chiral centers [443]. Further advances in the use of RDCs for assigning absolute configuration will likely require better orienting media. A recent review article summarizes many of the alignment media that have been developed [444]. A stretched poly(dimethylsiloxane) gel has been used as an alignment medium. The utility of this gel was demonstrated by distinguishing the two diastereomers of a spiroindene (264) [445]. A stretched poly(methyl methacrylate) gel with chloroform as a co-colvent is an effective media for measuring RDCs. Natural abundance 1H–13C RDCs were used to assign the diastereotopic protons at the C2, C8 and C9 positions of ludartin (265) [446]. A high molecular weight PBLG with a mixed chloroform– DMSO co-solvent (2:1 ratio) is effective for measuring different RDCs for the two enantiomers of tryptophan ester hydrochloride. The DMSO is needed to solubilize the tryptophan salt [447]. Iota and kappa-carageenan gels have been evaluated as orienting media. The kappa-carageenan gel produced enantiomeric discrimination in DL-alanine and distinction of prochiral hydrogen atoms of glycine. The corresponding iota-carageenan gel resolved the prochiral CD3 groups in dimethylsulfoxide-d6 [448]. Accelerated electrons have been used to covalently crosslink a collagen gel that can be used with water as the solvent. The utility of this system has been shown on DL-alanine. The same media is able to distinguish the prochiral methyl groups in dimethylsulfoxide-d6 when it is used as the solvent [449].

265 6. Miscellaneous methods 6.1. Micelles and sol–gels The diastereomeric chiral interactions within sols and gels of silica were studied by doping them with the chiral surfactant ()-N-dodecyl-N-methylephidrinium bromide (266). Chemical shift differences in the 31P spectra of 1,10 -binaphthalene-2,20 -diyl hydrogenphosphate (166) in the sol–gels provides information about the enantiomerically discriminating interactions [450].

H HO

N

10

H

266 Micellar aggregates of 1,2-diheptanoyl-sn-glycero-3-phosphatidyl choline (267) and other similar compounds produce chiral discrimination in the 1H NMR spectra of tryptophan dipeptides. Discrimination of the LL, LD, DL and DD stereoisomers is achieved [451]. In a subsequent study with N-acyl prolinate micellar aggregates (268), the length of the hydrophobic chain was found to influence the degree of chiral discrimination of the ditryptophan stereoisomers [452]. The same N-acyl prolinate micelles cause a small degree of enantiomeric discrimination in atropisomeric biphenyls, one example of which is 269. A small degree of enantiomeric discrimination is observed in the 1H aromatic resonances [453].

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T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

OH

OH OH

OH

(a)

OAc

(b) OH

OAc

OH

OH

OAc

OAc

AcO OAc

(c)

(d)

(e)

Fig. 29. Structure of (a) two contiguous propionate units, (b) 1,3,5-triol motif, (c) 1,2,3,5-tetraol peracetate motif, (d) 2-methyl-1,3-diol motif and (e) 2-methyl-1,3-diol motif.

O O H

O

P O

O

O

O

N

O

267

6.2. Solid-state NMR spectroscopy

NaOOC

O

H

n

N

H H

268

Utilization of solid state NMR methods for chiral discrimination has been limited in scope. In the solid state, pure enantiomers have different crystal forms and exhibit some NMR signals that are sensitive to the crystal type. The technique of one-dimensional exchange spectroscopy by sideband alteration (ODESSA) can be used to determine enantiomeric purity and potentially assign absolute stereochemistry. The utilization of ODESSA and other solid state NMR techniques for chiral discrimination has recently been reviewed [454]. The ODESSSA method has been recently demonstrated using 13C NMR spectra of valine [455] and leucine [456].

COOH 6.3. Database methods

N R O2 N

OMe

269

A relatively new strategy for assigning the absolute stereochemistry of particular structural motifs is to construct databases using chemical shifts or coupling constants that provide patterns that are different for the different configurations. The data is then measured for a compound with an unknown stereochemistry and compared to the known patterns. The best match provides the identity of the configuration of the unknown. Several database techniques that rely on the use of enantiomerically pure reagents were described in Sections 2.3 and 3.2.

T.J. Wenzel, C.D. Chisholm / Progress in Nuclear Magnetic Resonance Spectroscopy 59 (2011) 1–63

Fig. 29 provides a series of motifs that have been examined in a database strategy that requires no chiral reagent. Instead, all possible stereoisomers of each motif are synthesized and the 1H and 13C NMR spectra recorded. The database is constructed by subtracting the chemical shift of a particular carbon or hydrogen atom from the average value of all the stereoisomers [457–459]. The validity of the method has been demonstrated by assigning the configuration of similar structural motifs in unknown compounds and comparing the results to other established methods [460] or by performing a stereoselective synthesis of the compound with the assigned configuration and observing similar patterns [459]. A procedure for assigning the configurations of tetrads of polypropionates using a 13C NMR database has been described. The database was prepared by performing a statistical analysis of each tetrad subunit followed by a superposition of all predicted relative configurations. An advantage of this method is that it does not require the preparation of all possible derivatives [461]. The eight possible isomers of the tetraol peracetate motif (270) exhibit specific patterns of 3JH–H coupling constants. Using data available from literature reports, it was possible to construct a database that mapped the coupling constant data for the different configurations. It was then possible to assign the stereochemistry of an unknown motif by comparing the coupling constant data for the unknown with the best match among the known compounds. The reliability of the method was demonstrated for known peracetates derived from two heptoses [462].

OAc

R2

OAc

R1

Acknowledgment We thank the National Science Foundation Research at Undergraduate Institutions Program (Grant CHE–0653711) for supporting our work.

References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]

OAc

OAc

270

[28] [29] [30] [31]

7. Future directions New articles describing the development of optically pure reagents suitable for determining enantiomeric purity and absolute configuration by NMR spectroscopy will continue into the future. A key question with any new reagent is whether or not it offers advantages over reagents that have already been reported in the literature, many of which are commercially available. An area of emphasis will likely be the preparation and investigation of cavity and receptor compounds that exhibit highly specific binding of particular substrate molecules. The utilization of liquid crystals for enantiomeric discrimination is expected to grow in importance. Continued exploration of the use of RDCs in orienting media for assigning absolute configuration will certainly occur. Efforts to develop widely applicable chiral ionic liquids that also produce significant chemical shift anisotropy can be anticipated. Additional database techniques that combine new measurements with the wealth of information already available from prior investigations will certainly be developed. Finally, it remains to be seen if instrumentation with the sensitivity necessary to measure an asymmetric rotating electric polarizability or magnetoelectric shielding will be developed. If so, we may eventually be able to analyze chiral compounds by NMR spectroscopy without the use of enantiomerically pure reagents. The addition of new systems and methods with the knowledge developed over the past 45 years will provide investigators with an increasingly comprehensive ability to determine the enantiomeric purity and assign the absolute configuration of organic and inorganic compounds using NMR spectroscopy.

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