Rhodium DuPhos

In the case of cyclopentenyl carbamate in which a directive group is present at the homoallyl position, the cationic rhodium [Rh(diphos-4)]+ or iridium [Ir(PCy3)(py)(nbd)]+ catalyst cannot interact with the carbamate carbonyl, and thus approaches the double bond from the less-hindered side. This affords a cis-product preferentially, whereas with the chiral rhodium-duphos catalyst, directivity of the carbamate unit is observed (Table 21.7, entry 7). The presence of a hydroxyl group at the allyl position induced hydroxy-directive hydrogenation, and higher diastereoselectivity was obtained (entry 8) [44]. 

This strategy also gives access to a variety of non-natural a-amino acids. Furthermore, rhodium-DuPHOS complexes catalyse the asymmetric reduction of enol esters of the type PhCH = CH — C(OCOCH3) = CH2 to give (R)-2-acetoxy-4-phenylbut-3-ene (94% ee)[64]. 

Chiral rhodium-DuPHOS complexes are highly efficient catalyst for the enantioselective hydrogenation of enamides. One drawback of these catalysts is that they are easily oxidised and inert conditions are required for optimal results. The methyl- and ethyl substituted Rh-DuPHOS compounds, 3a and 3b, have been successfully applied in the reduction of a-acetamidocinnamic acids in [C4Ciim][PF6], Scheme 3.7.[7,39] While activities and selectivities are slightly lower compared to the homogeneous reaction in 2-propanol, the ionic liquid-immobilised catalyst is less prone to oxidation and recycling is feasible at least three times. 

A class of catalyst that has proven to be valuable for industrial processes is the rhodium DuPHOS family [1] an example of which, as its precatalyst [(R,R)-Me-DuPHOS Rh-COD]BF4 1, is illustrated in Fig. 1. 

Fig. 2 Examples of hydrogenation substrates for which rhodium DuPHOS catalysts are suitable.

In order for these rhodium DuPHOS catalysts to achieve the desired reactivity and selectivity, the hydrogenation substrate must contain certain features to facilitate the highly diastereoselective transition state required for the reaction. All the substrates to which rhodium DuPHOS hydrogenation catalysts have been successfully applied thus far possess a donor atom y to the olefin (Fig. 2). Within the constraint of this geometric requirement a wide array of prochiral olefins have been demonstrated as suitable substrates for asymmetric hydrogenation with rhodium DuPHOS catalysts. Examples include enamides 2 [1, 2], vinylacetic acid derivatives 3 [3], and enol acetates 4 [4]. 

Work on the candoxatril precursor 11 [16] gave an insight into the importance of substrate purity for efficient hydrogenation using rhodium DuPHOS catalyst systems. The asymmetric hydrogenation of 11 with rhodium Me-DuPHOS furnished the desired intermediate 12 in excellent enantiomeric excess and yield (Fig. 9). 

There have been many other independent reports of excellent S/C ratios using rhodium DuPHOS systems. For the synthesis of an (R)-metalaxyl intermediate 19 [21], a turnover number of 50000 has been demonstrated using Me-DuPHOS-Rh. Hoffmann la Roche have reported the Et-DuPHOS-Rh-catalyzed hydrogenation at S/C 10000-20000 of a cyclic enol acetate 21 to provide an intermediate 22 to Zeaxanthin in 98% ee [22] (Fig. 12). 

The rhodium DuPHOS precatalysts are very sensitive to oxygen when in solution and should be handled under an inert atmosphere, but the crystalline complexes are stable for long periods of time under nitrogen and can be weighed and... 

Asymmetric Hydrogenation of Prochiral Olefins by Rhodium-DuPhos Catalysts... 

Scheme 203 Mechanism for olefin hydrogenation with rhodium-DuPhos catalysts.

Scheme 20.5 Industrial applications of rhodium-DuPhos catalysts...

Scheme 20.6 Application of a rhodium-DuPhos catalyst for 3-methylsuccinamic acid.

The mechanism of the catalysis (Scheme 20.8) is quite unlike that of the rhodium-DuPhos catalysis of prochiral olefins described above, since the ketone substrate does not bind to the metal (ruthenium) atom. When a substrate binds the metal, as in the rho-dium-DuPhos systems, there are opportnnities for unwanted pathways that terminate the catalysis. On the other hand, a conseqnence of the metal being protected by its ligands in the Noyori-Ikariya catalysis in principle rednces the likelihood of catalyst deactivation and increases the expectation for achieving very high catalyst utilization (substrate/catalyst ratios). Thus, in the asymmetric hydrogenation of acetophenone to (i )-l-phenylethanol, Noyori et al. reported an astounding molar snbstrate/catalyst ratio of 2,400,000 1. ... 

Examples of commercial syntheses of a-amino acids by hydrogenation catalyzed by rhodium-DuPhos complexes, including data on the activities and selectivities, are shown in Figure 15.10. Notice that several of these processes occur with high enantioselectivities and turnover numbers ranging from 1000 to 50,000. " ° In general, turnover numbers of 1000 or 5000 are needed for the cost of the catalyst to become a minor contributor to the cost of the overall process. 

Examples of a-amino acid precursors that have been reduced by asymmetric hydrogenation with a rhodium-DuPhos catalyst in commercial processes. Data from references 224-226. 

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