Asymmetric Catalysis in C-C Bond Formation

Palladium chemistry is pre-eminent in catalytic C-C bond formation, as a result of its early applictions in both cross-coupling reactions and allylic alkylation. The development of asymmetric synthesis in this area is much newer, with recent breakthroughs from the research group of Hayashi in Japan being pre-eminent.

Almost single-handedly, Trost made catalytic allylic alkylation part of the essential repertoire of synthetic organic chemistry (2). His reaction sequence is illustrated in Figure 1, and it should be noted that the key step involves reaction between a cationic palladium allyl and a soft nucleophile such as malonate ion. With an optically active biphosphine such as CHIRAPHOS, asymmetric synthesis can occur. Because the new bond is formed some distance from the metal and its chiral ligand, optical yields were modest in most early studies. Bosnich and co-workers found that diphenylallyl derivatives were better (Figure 2(a)) because their bulkiness elicited a stronger interaction with the ligand, so that one of the two possible intermediates was strongly favoured (3). The best examples to date are due to Hayashi’s group (4). They use a rather unusual ferrocenyl-phosphine, with a polar side-arm. This acts so as to bias the reaction towards one end of a symmetrical or near-symmetrical intermediate. Although the details are not properly understood the effect is dramatic, leading to allylic products with high optical purity, as shown in Figure 2(b).

Cross-coupling is the enigma of asymmetric catalysis. This straightforward reaction, whereby a carbon-carbon bond is assembled within the co-ordination sphere, seems a perfect arrangement for stereochemical control (5), see Figure 3. The intrinsic limitations of existing procedures, particularly incompatibility towards polar substituents, have yet to be overcome and few good examples of asymmetric synthesis with high enantiomer excess are available. Again the best work comes from Hayashi’s group, and makes optically active allylsilanes available (6), as illustrated below in Figure 4. A feature of their approach is the clever use of ferrocene as a template for designing asymmetric ligands. The allylsilanes have a well-developed organic chemistry and can be converted into many other chiral products.

Asymmetric Catalysis in C-H Bond Formation

Wilkinson’s classic work on rhodium catalysed homogeneous hydrogenation encouraged many other groups to make optically active phosphines; hydrogenation is widely utilised in synthesis, and the potential for introducing optical activity seemed highly attractive. Progress only became rapid when Kagan showed that the important step was to employ biphosphines, and now there are upwards of fifty ligands which give good results in asymmetric hydrogenation (7). Application tends to be limited to dehydroamino acids and related compounds where a substituent on the olefin provided the necessary “bite” by occupying a co-ordination site throughout the catalytic cycle. The source of chiral recognition is still not fully understood, despite much effort (8), but the role of the biphosphine has been clarified by X-ray studies on a rigid biphosphine rhodium complex, see Figure 5. The asymmetric centres enforce a chiral conformation on aryl groups bound to phosphorus. This permits a discrimination between the reaction channels leading to “left-hand” and “right-hand” products because of the way that the catalytic reactant is bound to rhodium during the catalytic cycle. For dehydroamino acids, it appears that the interactions involving the −CO₂H group are the most critical. By analogy with enzymology, asymmetric hydrogenation works because this substituent operates as a key on the arylphosphine lock, but only when one prochiral face of the olefin is bound to rhodium. For the other face, there is a mismatch which makes the addition of hydrogen energetically unfavourable.

One recent development widens the scope of asymmetric hydrogenation (9). When the olefin being reduced includes a neighbouring chiral centre there can be two possible isomeric products, depending on which face accepts hydrogen. For example, the β -hydroxyacrylate of Figure 6 can give rise to syn- and anti -hydrogenation products, and it turns out that the latter is strongly predominant. With a simple chelate rhodium catalyst both enantiomers of racemic starting material are reduced with equal facility; the most interesting experiment involves an optically active catalyst such as DIPAMP-Rh⁺. Here the reactivity of the two enantiomeric forms of starting material is quite different, and one is efficiently drained off in a fast hydrogenation. This leads to kinetic resolution of the slow reacting enantiomer. It may be recovered in 90 to 95 per cent optical purity at ⩾65 per cent reaction. In similar manner, β -carboxyacrylates and acylaminoacrylates can be subjected to kinetic resolution. The sequence of two hydrogenation steps, one with an optically active catalyst and the second with a simple chelate rhodium catalyst leads to β -hydroxyesters and β -aminoesters or to 2,3-dialkylsuccinic acid derivatives in a state of high optical purity. This represents the first case of a catalytic kinetic resolution which does not require enzymes or micro organisms, as is shown in Figure 7.

The secret of success is to find reactants possessing a functional group in proximity to the olefin which can bind to the metal and control the stereochemical course of hydrogenation. In a cyclic compound, this can lead to face-selectivity, where the functionality directs hydrogen to the double bond in a constrained way. Some of the best examples involve iridium catalysts, which work well for cyclic systems. It is of interest that the alcohol or amide group which controls reaction stereochemistry can be quite remote from the double bond undergoing hydrogenation, see Figure 8. The stereo-selectivity can exceed the limits of conventional measurement by g.c. or h.p.l.c. techniques, and product discrimination of >1000:1 has been reported (9).

Over a period of twenty years, rhodium catalysts have dominated homogeneous hydrogenation, so it was natural for asymmetric catalysts to be closely related. Their dominance has been challenged in recent Japanese work, particularly that emanating from Noyori’s laboratory. He developed the binaphthyl-derived ligand, BINAP, which made a useful but not outstanding contribution to the asymmetric hydrogenation of dehydroamino acids (10a). When the corresponding ruthenium complexes were prepared, they were also found to be active in hydrogenation, but in the opposite stereochemical sense to their rhodium counterparts. More recent applications to the production of enantiomerically pure isoquinoline alkaloids are impressive (10b). Even more so is the hydrogenation of trisubstituted allylic alcohols, for it solves a long-standing problem in organic chemistry and provides a route to enantiomerically pure compounds in the Vitamin E series (10c) shown in Figure 9. This takes the field of asymmetric hydrogenation one stage further, and closer to being a completely general method for the asymmetric synthesis of tertiary centres.

The final example again comes from Noyori’s group and involves catalytic isomerisation in the generation of a new asymmetric centre (11). This brings the discussion full circle, since the reactive intermediate in the catalytic cycle is presumably an allylrhodium hydride, quite closely related to the allylpalladium intermediates in allylic alkylation. The rhodium complex is prepared from BINAP and is an efficient catalyst for olefin isomerisation in the absence of hydrogen around 40°C; olefin isomerisation has long been known as a competing side-reaction in some homogeneous hydrogenations. The most successful case (Figure 10) is with dimethylgeranylamine and dimethylnerylamine, which were converted into opposite enantiomers of the same enamine, with high optical purity. The product can be hydrolysed in acid to citronellol, providing an elegant and commercially viable route to this important perfumery intermediate.

Summary and Future Trends

These examples demonstrate that asymmetric catalysis has become a significant contributor to the “chiral economy” over the last ten years and promises to provide further developments. There is a conspicuous gap in our knowledge at the present time. Most industrial chemists think first of hydroformylation or hydrocarboxylation in the context of homogeneous catalysis, but here the problems associated with the asymmetric induction have not been satisfactorily solved. Optical yields in rhodium hydroformylation have been uniformly low; platinum-tin complexes give better results, but under rather forcing conditions (12). Clearly much work remains to be done but the future of platinum metal complexes as asymmetric catalysts looks most encouraging, for both industrial and academic applications.