Electronic Effects in Asymmetric Catalysis: Structural Studies of Precatalysts and Intermediates in Rh-Catalyzed Hydrogenation of Dimethyl Itaconate and Acetamidocinnamic Acid Derivatives Using C(2)-Symmetric Diarylphosphinite Ligands.

Enantioselectivity of Rh(I)-catalyzed asymmetric hydrogenation of dehydroamino acid derivatives and dimethyl itaconate can be enhanced by the appropriate choice of substituents on the aromatic rings of vicinal diarylphosphinites derived from carbohydrates as well as trans-cyclohexane-1,2-diol. For example, the use of phosphinites with electron-donating bis(3,5-dimethylphenyl) groups at phosphorus provide high ee's in these reactions whereas electron-withdrawing aryl substituents decrease the enantioselectivity. In this paper, an attempt is made to clarify the origin of these remarkable electronic effects at two levels. First, crystal structures of a number of precatalysts ([phosphinite](2)Rh(+)[diolefin]X(-)) were determined and their structures were studied in detail to examine the electronic effects, if any, on the ground-state conformations of these molecules. A study of six of these complexes reveals that the gross conformational features of these precatalysts are largely unaffected by electronic effects, which suggests that other explanations have to be sought for the electronic amplification of enantioselectivity. One possibility is a change in the diastereomeric equilibrium between the initially formed [substrate]Rh(+)[phosphinite] complexes as a function of electronic effect of the ligand. In the Rh-catalyzed hydrogenation of dimethyl itaconate, we have examined this equilibrium between the major and minor complexes by (31)P NMR. There is a clear difference in the ratio of these two diastereomers when 3,5-dimethylphenylphosphinite vis-à-vis the unsubstituted diphenylphosphinite is used. Electron-deficient ligands such as 1,2-bis-3,5-diflurophenylphosphinite and 1,2-bis-3,5-bis-trifluromethylphenylphosphinite appear to form these diastereomers more readily at room temperature, even though the exact ratio of the diastereomers could not be established with any certainty.

Enantiomeric characterization and structure elucidation of Otamixaban.

Otamixaban is a potent (Ki=0.5 nM) fXa inhibitor currently in late-stage clinical development at Sanofi for the management of acute coronary syndrome. Being unproductive in obtaining a suitable crystal of Otamixaban, the required enantiomeric characterization has been accomplished using vibrational circular dichroism (VCD) spectroscopy. Selected by a spectrum similarity index, the calculated spectra of several higher energy conformers were found to match well with the observed spectra. The characteristic IR bands of these conformers were also identified and attributed to the solvation effect. Combined with both the single crystal x-ray diffraction results for an intermediate and the proton NMR study, the absolute configuration of Otamixaban is unambiguously determined to be (R,R).

Diastereoselective alkylation of beta-amino esters: structural and rate studies reveal alkylations of hexameric lithium enolates.

Alkylation of beta-amino ester enolates proceeds with high diastereoselectivity. Single crystal, powder, and solution X-ray diffraction studies of the enolate show that the racemic enolate forms prismatic hexamers. 6Li NMR spectroscopic studies on partially racemic enolates reveal complex mixtures of homo- and heterochiral hexamers. An implicit fit of the aggregate populations to the Boltzmann distribution provides the free energy differences and equilibrium constants for the ensemble. Rate studies show that enolate alkylation occurs directly from the hexamer with participation by THF. A mechanism based on the alkylation of a ladder-like aggregate is proposed.

Characterization of beta-amino ester enolates as hexamers via 6Li NMR spectroscopy.

Low-temperature 6Li NMR spectroscopic studies on a chiral beta-amino ester enolate reveal a complex mixture of homo- and heterochiral aggregates. Subsequent warming of the samples led to rapid intra-aggregate exchange, resulting in four distinct resonances consistent with an ensemble of hexamers. An implicit fit of the aggregate populations to the Boltzmann distribution provided the free energy differences and equilibrium constants. An X-ray crystal structure obtained from the racemic enolate is consistent with the predominant aggregate in solution.