Scope of Enamide Substrates

Although it has some limitations, the Rh-DIPAMP system developed by Knowles has been well studied and this allows for a fair degree of certainty that it can be used with untried substrates. For this reason, it has been used to prepare a range of unnatural amino acid derivatives at scale [7, 11]. A model has been reported that allows others to predict whether Knowles catalyst can be used in a productive manner with their desired enamide. The prediction of the model is based on dividing the enamide substrate into four quadrants (Fig. 2) [7]. 

If we start at the top left-hand corner and work round anti-clockwise, the scope and limitations of the system can be explained. This quadrant has to be hydrogen. Any substitution results in a drop in the reaction rates and a significant lowering of enantioselectivity. Thus, / -branched a-amino acid derivatives cannot be accessed with Knowles catalyst. This limitation has been overcome by the use of other catalyst systems such as Burk s DuPHOS [12]. The need for hydrogen at this position 

The final quadrant, the top right-hand, has to contain an electron withdrawing group. This group activates the carbon-carbon unsaturation. A wide variety of groups are tolerated including a carboxylic acid, ester, amide, nitrile, ketone, and aldehydes [7, 9]. This shows that the catalyst system can be used to prepare a wide range of amino acid derivatives without recourse to a number of transformations on the product unnatural amino acid. 

Many of the ligands that have been advocated for analogous reductions provide high enantioselectivity and some can provide good turnover numbers and frequencies [4, 5], Knowles catalyst often results in an ee of about 94-95% if the reaction mixture is monitored. However, crystallization of the N-acylamino acid product often results in enantioenrichment [10, 11]. In addition, hydrolysis of the amide to provide the amino acid itself also provides an opportunity for enantioenrichment (Fig. 3) [10]. 

The enantioselectivities did not change upon decrease of the catalyst loading (S/ C) from 5 000 to 20000 in the reduction of the 2-naphthyl enamide (2a), but the 

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