Substrate Synthesis, Purity and Catalyst Loading

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). 

However, some variability with different batches of sodium salt 11 was observed [16]. The salt was normally made by treatment of the acid with solid NaOH followed by recrystallization [17]. Either residual NaOH or incomplete sodium salt formation 

For this reaction [(S,S)-Et-DuPHOS Rh-COD]BF4 was found to be the best precatalyst, but good results were also obtained with [Me-DuPHOS Rh-COD]BF4, [Et-FerroTANE Rh-COD]BF4 and [i-Pr-FerroTANE Rh-COD]BF4 [11]. 

As well as impurities being deleterious we have also found the judicious introduction of additives can be critical for developing economic catalytic processes. This is demonstrated in the asymmetric hydrogenation of itaconic acid derivatives to give chiral succinates 17 (Fig. 11) [3]. 

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). 

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