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Vicinal diarylphosphinites derived from carbohydrates are excellent ligands for the Rh(I)-catalyzed enantioselective asymmetric hydrogenation of dehydroamino acid derivatives, producing the highest enantioselectivity of any ligands directly prepared from natural products. The enantioselectivity can be enhanced by the appropriate choice of substituents on the aromatic rings of the phosphinites. For example, the use of phosphinites with electron-donating bis(3,5-dimethylphenyl) groups on phosphorus provides ee's up to 99% for a wide range of amino acids including some with easily removable N-protecting groups. Electron-withdrawing aryl substituents, on the other hand, decrease the enantioselectivity. Sense of chiral induction in the amino acid product depends on the relative juxtaposition of the vicinal diphosphinites on a given sugar backbone. When readily available d-glucopyranosides are used as the starting sugars, 2,3-phosphinites give the S-amino acids and 3,4-phosphinites give the R-amino acids. In the case of aromatic and heteroaromatic amino acids, enantioselectivities > 95% are consistently obtained. Practical considerations such as the ease of ligand synthesis, rates of reactions, catalyst turnover, and scope and limitations in terms of substrates are discussed. A possible explanation for the enhancement of enantioselectivity by electron-rich phosphinites is offered.

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.

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.

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As part of a program to prepare new antithrombotic agents, we discovered that unprotected -amino esters can be exclusively C-alkylated. We sought to optimize this process by studying the structures and reactivities of -amino ester enolates. 1 Determining the aggregation state of an enolate, however, is especially difficult due to the high symmetry of the possible aggregatessmonomers, dimers, tetramers, and hexamerssand the spectroscopically opaque Li-O linkage. 2 Herein we describe a spectroscopic method used to assign -amino ester enolates (1) as hexamers in solution.To understand these studies we must briefly digress by describing the dynamic phenomena that are commonly observed for organolithium aggregates but may seem surprising to the nonspecialist. 3 At the lowest attainable NMR probe temperatures (<-100°C), fast processes including solvent exchange, 4 conformational equilibria, 5 and chelate isomerizations 6 can become observable on NMR spectroscopic time scales, with concomitant spectral complexity. The spectra typically simplify on warming above -100°C due to time averaging. Further warming of the probe often leads to a particularly odd effect in which intra-aggregate exchanges of 6 Li nuclei become fast, whereas inter-aggregate exchanges are still slow. 7 Consequently, aggregates that differ by virtue of their aggregation numbers (dimers versus hexamers) or subunit composition (4:2 versus 3:3 mixed hexamers) appear as separate species by 6 Li NMR spectroscopy, but each aggregate manifests a single 6 Li resonance. This combination of rapid intra-aggregate exchange in conjunction with slow inter-aggregate exchange proves critical to the structural assignments.The 6 Li NMR spectrum recorded on [ 6 Li](R)-1 in 9.0 M THF/ toluene at -100°C shows a single resonance, consistent with almost any aggregation state of high symmetry. The 6 Li NMR spectrum recorded on [ 6 Li]rac-1 affords a single resonance at a markedly different chemical shift than ( Figure 1A) show both resonances along with considerable "noise" in the baseline. Additionally, 6 Li spectra recorded on [ 6 -Li, 15 N](S)-1 and [ 6 Li, 15 N]rac-1 show 6 Li-15 N coupling (d, J Li-N ) 3.4 and 3.6 Hz, respectively), confirming chelation as drawn. 8 Varying the probe temperature from -100 to -50°C afforded a single sharp resonance for Figure 1B). The data are consistent with deep-seated structural complexities that simplify by rapid intra-aggregate exchange at elevated temperatures. Furthermore, the relative intensities are independent of the enolate concentration (0.04-0.40 M) and the THF concentration (2.0-9.0 M), indicating that the four species are at the same aggregation and solvation state.We considered models based on homochiral aggregates (R N or S N ) and heterochiral aggregates (R n S N-n ). R n S N-n /R N-n S n and R N / S N refer to pairs of spectroscopically indistinguishable enantiomers. Dimers (R 1 S 1 and R 2 /S 2 ) and tetramers (R 4 /S 4 , R 1 S 3 /R 3 S 1 , and R 2 S 2 ) afford only two and three 6 Li resonances, respectively. ...

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