Dirhodium Method Research Articles

Optimizing dirhodium(ii) tetrakiscarboxylates as chiral NMR auxiliaries

Thirteen enantiopure paddlewheel-shaped dirhodium(II) tetrakiscarboxylate complexes have been checked for their efficiency in the dirhodium method (differentiation of enantiomers by NMR spectroscopy); six of them are new. Their diastereomeric dispersion effects were studied and compared via so-called key numbers KN. Adducts of each complex were tested with five different test ligands representing all relevant donor properties from strong (phosphane) to very weak (ether). Only one of them, the dirhodium complex with four axial (S)-N-2,3-naphthalenedicarboxyl-tert-leucinate groups (N23tL), showed results significantly better for all ligands than the conventional complex Rh* [Rh(II)(2)[(R)-(+)-MTPA](4); MTPA = methoxytrifluoromethylphenylacetate]. On the basis of (1)H{(1)H} NOE spectroscopy and X-ray diffraction, a combination of favourable anisotropic group orientation and conformational flexibility is held responsible for the high efficiency of N23tL in enantiodifferentiation. Both complexes, Rh* and N23tL, are recommended as chiral auxiliaries for the dirhodium experiment.

Comparing various chiral dirhodium tetracarboxylates in the dirhodium method

Three enantiopure dirhodium tetracarboxylates are compared in their NMR properties to differentiate chiral ligands of various kinds (dirhodium method). The complex with four (S)-2-methoxy-2-(1-naphthyl) propionate (MalphaNP) residues (Rh2) is slightly better for strong donors than the complex with four Mosher acid anions (Rh1), but it is inferior for weak donors. On the other hand, the dirhodium tetracarboxylate complex with four (S)-N-phthaloyl-(S)-tert.-leucinate residues (Rh3) is generally more effective than Rh1. These results are explained by the estimated conformational behavior of the substituents within the equatorial acid residues and the anisotropy (ring-current) effect of aryl groups.

A new method proposed for the determination of absolute configurations of α‐amino acids

Enantiopure alpha-amino acids were converted to 4-substituted 2-aryl- and 2-alkyl-5(4H)-oxazolones under partial racemization. These nonracemic mixtures were dissolved in CDCl(3), an equimolar amount of the chiral dirhodium complex Rh(II)(2)[(R)-(+)-MTPA](4) (MTPA-H = Mosher's acid) was added, and the (1)H NMR spectra of the resulting samples were recorded (dirhodium method). The relative intensities of (1)H signals dispersed by the formation of diastereomeric adducts allow to determine the absolute configuration (AC) of the starting alpha-amino acids. Binding atoms in the adducts were identified by comparing the (1)H and (13)C chemical shifts of the oxazolones in the absence and presence of Rh(II)(2)[(R)-(+)-MTPA](4). Thereby, information about the scope and limits of this method can be extracted. A protocol how to use this method is presented.

Enantiodifferentiation by 1H and 13C NMR Spectroscopy (Dirhodium Method) – Selectivity of Oxygen Functionalities

Chiral carbonyl compounds can easily be enantiodifferentiated by the dirhodium method. The rhodium atoms reveal a remarkable selectivity in binding to oxygen atoms, which is of great advantage for discriminating chiral polyoxygenated natural products. Amides are the strongest ligands followed by ketones and esters; ethers and alcohols/phenols are even less effective. This sequence is rationalized by electronic charges at the oxygen atoms, as obtained from density functional calculations.

Enantiodifferentiation of polyethers by the dirhodium method. Part 2: Cyclotriveratrylenes and cryptophanes

Cycloveratrylenes and cryptophanes 1– 12 are chiral compounds and were studied in their racemic form. Although most of them are non-polar oligocyclic ethers, their enantiomers can be easily differentiated by 1H and 13C NMR spectroscopy in the presence of an equimolar amount of Rh 2[( R)-(+)-MTPA] 4 (the standard protocol for the dirhodium method). Coordination mechanisms were studied. Various functionalities (sulfide, various ethers, olefin and phenol) were also sequenced according to their donor properties.

Atropisomeric 3‐aryl‐2‐oxo‐4‐oxazolidinones and some thione analogues—Enantiodifferentiation and ligand competition in applying the dirhodium method

The atropisomeric 2-oxo-4-oxazolidinones 1Z bind weakly to the rhodium atoms in the complex Rh(II)2 [(R)-(+)-MTPA]4 (Rh*, MTPA-H = methoxytrifluoromethylphenylacetic acid identical with Mosher's acid), presumably via the C-2 carbonyl oxygen atom. There are some 1H and 13C NMR signals in these compounds which show small dispersion effects suitable for enantiodifferentiation. In contrast, the thiocarbonyl sulfur atoms in 2Z and 3Z bind strongly so that significant complexation shifts (Delta delta) and diastereomeric dispersion effects (Delta nu) can be observed, and chiral discrimination and the determination of enantiomeric ratios of these thiocarbonyl compounds is easy. So, it is shown that--as expected--C=S is a much better binding site when competing with C=O. In compounds of Series 2 a "syn-methyl effect" was discovered which describes the dependence of dispersion effects of syn-oriented methyl groups 6 on the nature of the substituents Z. A mechanism of combined steric and electronic interaction influencing the conformational equilibria inside the adducts is proposed. Determination of absolute configurations by correlation fails, at least on the basis of the data available.

Chiral recognition of the Schiff bases by NMR spectroscopy in the presence of a chiral dirhodium complex. Deuterium isotope effect on 13C chemical shift of the optically active Schiff bases and their dirhodium adducts

The dirhodium method has been successfully applied in chiral recognition of the optically active Schiff bases, derivatives of ortho-hydroxyaldehydes existing in the NH-form. or at tautomeric equilibrium. The position of the equilibrium of Schiff bases as well as their adducts has been established on the basis of measurements of deuterium isotope effects on 13C chemical shifts. The presence of the proton transfer equilibrium or NH-tautomer has promoted the adduct formation. At the equilibrium state, formation of the adducts has shifted the proton transfer equilibrium towards the NH-form. The binding site was the oxygen atom of the proton donor group.

Chalcogen Atom Competition in the Coordination of Bicyclic β-Lactam Derivatives to a Dirhodium Tetracarboxylate Complex

NMR spectra of five enantiopure β-lactam derivatives with varying oxygen and sulfur atoms (1 to 5) have been recorded in the presence of an equimolar amount of a 2:1-mixture of (R)-Rh* and (S)-Rh* [(R/S)-Rh*]. No carboxylate ligand exchange between the two enantiomeric dirhodium complexes was observed. In general, sulfur is a much better donor than oxygen in axial coordination to rhodium. If both chalcogen atoms are equal (S in 1 and O in 4) the doubly bonded atom is the prefered binding site (C 9 =X). In the compounds with mixed chalcogen atoms, sulfur prevails as donor regardless of its bond order. This behaviour can be rationalized by comparing calculated molecular orbital energies and electronic charges. Olefinic groups do not contribute to binding significantly. All β-lactam derivatives were enantiopure so that it was possible to monitor significant chemical shift differences of the 1 H, 13 C and 19 F NMR resonances for the two Rh* enantiomers. An experiment with racemic 4-vinyloxyazetidin-2-one (6) and (R)-Rh* suggests that the dirhodium method is effective for enantiodifferentiation of β-lactams.

Rh 2[( R)-(+)-MTPA] 4 as an NMR auxiliary for the enantiodifferentiation of chiral secondary and tertiary phosphine–borane complexes

The direct chiral recognition of secondary and tertiary phosphine–borane complexes is made possible by applying the dirhodium method (NMR in the presence of Rh 2[( R)-(+)-MTPA] 4, Rh ∗). Due to the acid lability of the phosphine–borane complexes, it is advisable to use deuterated benzene as solvent rather than deuterated chloroform. The decomposition of the phosphine–borane complexes and the resulting Rh ∗–phosphine adducts are also studied.

Enantiodifferentiation of a silane and the analogous hydrocarbon by the dirhodium method—silane⋯dirhodium complex interaction

Chiral silane 1 was enantiodifferentiated by recording NMR spectra in the presence of the chiral dirhodium complex Rh 2 ( II ) [ ( R ) - ( + ) - MTPA 4 ] ( Rh ∗). This is the first report of direct chiral recognition by spectroscopic methods with this class of compounds. A comparison with the carba-analogue 2 shows that 1 is a soft Lewis-base ligand and that the Si–H hydrogen is the binding site, presumably by forming an adduct with a (3c-2e) silicon–hydrogen–rhodium contact (end-on), which exists in equilibrium with the free ligands.

Enantiodifferentiation of Aliphatic Ethers by the Dirhodium Method

AbstractThe enantiomers of chiral aliphatic ethers can easily bedifferentiated by the dirhodium method, i.e. by 1H and13C NMR spectroscopy in the presence of the chiral auxiliary Rh2[(+)‐MTPA]4. This is the first direct chiral recognitionby spectroscopic methods in this class of ligand compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

N-(Chloroacetyl)- and N-(dichloroacetyl)- N-(xylyl)alanine esters: assignment of the absolute configurations and enantiodifferentiation by the dirhodium method

Four chlorinated N-acylalanine methylesters (metalaxyl ® derivatives) containing either stereogenic centres alone as in 1 and 3 or stereogenic centres plus chiral axes as in 2 and 4 were investigated. The latter have been examined in terms of the absolute configurations of the diastereomers in unresolvable mixtures, which were determined by evaluating NOE contacts in preferred conformations. Although these ligands are weak donors in Rh* adducts, it is easily possible to monitor their enantiomeric purity by the ‘dirhodium method’. Surprisingly, only the monochloro derivatives 1 and 2 gave satisfactory results in chirality recognition experiments under standard dirhodium method conditions (including one drop of acetone- d 6 for enhancing the solubility of Rh*). The dichloro derivatives 3 and 4 failed. However, they developed significant dispersion effects in the absence of acetone- d 6. It turns out that the preferred complexation site in the monochloro derivatives 1 and 2 is primarily the amide carbonyl oxygen, whereas this group is hardly available in the case of the dichloro derivatives 3 and 4 so that the ester group appears to be the complexation site.

Dirhodium tetraacetate as an auxiliary chromophore in a circular dichroic study on vic-amino alcohols

The dirhodium method proposed herein, involves the in situ formation of chiral complexes of optically active vic-amino alcohols with the achiral dirhodium tetraacetate [Rh 2(OAc) 4] acting as an auxiliary chromophore. The resulting CD spectra are suitable for stereochemical studies, since the observed sign of Cotton effects arising within the d–d absorption bands of the metal core is determined by the chirality of the amino alcohol ligand. It has been demonstrated that in acetonitrile and chloroform solutions, chiral complexes are formed by axial ligation of the ligand to the metal atom(s) of the dirhodium core. This axial binding occurs through the nitrogen atom of the 1,2-amino alcohol unit independently of the ligand-to-metal molar ratio, as shown from the 15N and low-temperature NMR experiments. In agreement with NMR results, ESI MS experiments indicate that in solution, a mixture of chiral complexes with ligand-to-metal molar ratios 1:1 and 2:1 is present. An empirically based rule correlating the sign of Cotton effect occurring above 600 nm with the stereochemistry of ligand has been formulated.

Chirality Recognition of Selenium Compounds by NMR Spectroscopy in the Presence of a Chiral Dirhodium Complex

Diastereomeric adducts of chiral soft-base selenium ligands with the enantiopure dirhodium complex Rh* allows stereodifferentiation by NMR spectroscopy of various nuclei (dirhodium method). The individual adduct species can be identified by low-temperature NMR spectroscopy.

Effective enantiodifferentiation of spirochalcogenuranes by the dirhodium method: Towards the determination of absolute configurations?

The properties of chiral spirochalcogenuranes acting as ligands in adducts with a chiral dirhodium tetracarboxylate complex is explored, and the individual adduct species are characterized by low-temperature NMR spectroscopy. Chiral recognition and the determination of enantiomeric composition of the chiral spirochalcogenuranes is easy by evaluating NMR signal dispersions both at low and at room- or slightly elevated temperatures. The uniformity in the signs of 1H dispersion effects and taking reference to the spiroselenurane with known absolute configuration [(S)-(-)-2] indicates that a convenient rule for the determination of absolute configuration in the spirochalcogenurane system can be established on the basis of 1H chemical shift dispersions.

Rh2[MTPA]4, a dirhodium complex as NMR auxiliary for chiral recognition

The dirhodium complex Rh(+II)2[(+)-MTPA]4 is introduced as an NMR auxiliary for enantiodifferentiation. As a soft Lewis acid, it is particularly useful for the recognition of soft Lewis base molecules. The donor properties of ligands can be divided into several categories and are exemplified by various classes of phosphorus-containing functionalities. In addition, the thermodynamics of the underlying ligand-complex equilibria are discussed and stereochemical implications demonstrated. The extension of the dirhodium method to absolute configuration determination is evaluated. The outlook for future applications with further non-phosphorus ligands is presented.

Chiral atropisomeric diiodobiphenyls––enantiodifferentiation by the dirhodium method

Enantiodifferentiation of atropisomeric biphenyl diiodides can easily be accomplished by adding the enantiopure dirhodium complex Rh* as an NMR auxiliary, although iodine is only a weak donor in forming adducts with Rh*. Further Lewis-base substituents X/X′ (e.g., NH 2 or SH) may dominate the adduct formation equilibria whereas others are hardly involved (e.g., Cl, OCH 3, NMe 2, and OH).

Phosphine-Rh2[(R)-MTPA]4 Adducts in Solution: Characterization by NMR Spectroscopy and Chiral Discrimination

The adducts of dirhodium tetraacylates and phosphines are characterized in solution by 1H and 31P NMR spectroscopy at room temperature. A differentiation of the enantiomers of chiral phosphine ligands is easily performed by NMR signal integration after adduct formation with the enantiopure Rh2[(R)-(+)-MTPA]4 complex (Rh*). Stereochemical aspects are discussed in terms of chiral discrimination and adduct diastereomerism. A second type of chiral recognition was discovered, namely, that between two ligand molecules in 2:1 adducts across the Rh2[(R)-(+)-MTPA]4 building block. Conditions for optimizing the experiment for the determination of enantiomeric composition of chiral phosphines by the “dirhodium method” are presented. The possibility of determining absolute configurations of chiral phosphines is briefly discussed.

Multinuclear magnetic resonance study of chiral mesoionic oxa‐ and thiatriazole and tetrazole derivatives: adducts with dirhodium complexes and chiral recognition

AbstractMesoionic compounds 1–8 were synthesized and their 1H, 13C, 14N, 15N and 17O NMR spectra recorded in the absence and presence of the chiral dirhodium complex Rh*. It is shown that the enantiomers of the mesoionic compounds could be differentiated satisfactorily (‘dirhodium method’). Copyright © 2003 John Wiley & Sons, Ltd.

Phenylselenenylmenthane derivatives and their enantiomeric discrimination by 1H and 13C NMR spectroscopy in the presence of a chiral dirhodium complex

AbstractThe phenylselenenylmenthane and ‐menthene derivatives 1–4 were studied in terms of 1H and 13C signal assignments, conformational analysis and also complexation shifts (Δδ) and dispersion effects (Δν) observed when non‐racemic (ca 2 : 1) mixtures of the chiral selenides were exposed to an equimolar amount of the chiral dirhodium complex Rh*. The complexation site is the selenium atom exclusively. Whereas Δδ values are moderate or small, dispersed signals (split into two owing to the existence of diastereomeric adducts) can be observed, many of which are large enough for a facile determination of enantiomeric ratios of the selenides irregardless of the conformational behaviour of the selenides and the adduct composition. Thus, the ‘dirhodium method’ is simple and reliable for chiral recognition in the class of organoselenium compounds which is gaining increasing importance in developing new techniques of asymmetric synthesis. Copyright © 2002 John Wiley & Sons, Ltd.