Unveiling the Secrets of Asymmetric Hydrogenation in Amino Acid Synthesis

Asymmetric hydrogenation has emerged as a pivotal reaction in the synthesis of chiral compounds, particularly in the manufacture of amino acids. This process involves the use of a highly reactive catalyst to facilitate the hydrogenation of dehydro precursors at low temperatures, such as –40 ˚C, where significant results have been reported. For example, the hydrogenation of a precursor to Merck's HIV protease inhibitor Crixivan yielded an impressive enantiomeric excess (ee) of 86%. When utilizing more advanced conditions, such as working at 70 atmospheres with RhBINAP, the process achieved a remarkable 99% ee.

The revival of interest in enamide hydrogenation is largely driven by the demand for diverse amino acids in combinatorial chemistry. Researchers aim to create extensive libraries for the assembly of small peptides with maximum variability in side chains. This can be accomplished through direct asymmetric hydrogenation of dehydro precursors or from bromoaryl dehydro precursors, followed by reactions such as Heck coupling or cross-coupling. The latter approach allows the generation of a substantial library from a relatively small number of reductions, underscoring the efficiency of these methodologies.

A key aspect of the asymmetric hydrogenation process is the ability of specific catalysts to influence the stereochemistry of the reaction. For instance, the introduction of a pendant tertiary amine in the ligand structure can significantly enhance diastereoselectivity, reaching levels of up to 95%. This highlights the importance of molecular design in optimizing the stereochemical outcomes of hydrogenation reactions. In cases where an achiral catalyst is used, the stereochemical control tends to be quite limited, stressing the need for careful catalyst selection.

Moreover, the hydrogenation of dehydrodipeptides can be executed over heterogeneous catalysts with high diastereoselectivity. Recent studies have shown effective reductions of prolinyldehydrodipeptides and diketopiperazines, achieving stereospecific results. A novel approach to asymmetric deuteration has also been explored, employing enzymatic dehydrogenation followed by re-reduction with deuterium, yielding diastereomer ratios greater than 99:1.

Interestingly, the functionality of the substrate plays a crucial role in the hydrogenation process. In the case of dehydroamino acids, the carbonyl group of the amide serves as a binding site, while the carboxyl group remains inert until the transition state. This behavior is also observed in related compounds, such as alkylidenesuccinic acids and esters, which have historically been used to evaluate new ligands for Rh asymmetric hydrogenation. Current research efforts focus on optimizing these reactions by systematically varying the aryl residues of established ligand analogues, leading to increased enantioselectivity in synthesis.