Approaches to Amino Acid Building Blocks via Catalytic Asymmetric Reduction

Work previously conducted within the Jones group on the asymmetric reduction of ketimines and β-enamino esters employed trichlorosilane and an imidazole based organocatalyst (S)-49. This methodology was investigated in relation to imines and enamine based on amino acids. Firstly, naturally available amino acids, glycine and valine, were investigated as N-substituents to synthesise α-methylbenzyl substituted amino acids. By-product formation limited the use of glycine. A poor yield of 11% for the major diastereoisomer was obtained during the trichlorosilane mediated reduction of the valine ketimine with a good diastereoselectivity of 85:15 dr. Due to time limitation brought on by Covid-19 safety procedures, these substrates were not investigated further.
Constrained amino acids based on 2,5-disubstituted pyrrolidines and 2,3-disubstituted piperidines were investigated in a trichlorosilane mediated reduction and a hydrogenation using a H-cube® flow reactor, respectively. Excellent diastereoselectivities of up to 98:2 dr and >99:1 dr were obtained for each method. Difficulties with the determination of the enantioselectivities of the pyrrolidines prevented further optimisation of the reaction and investigation into a kinetic resolution. Hydrogenation using the H-cube® was expanded to 2,3-disubstituted pyrrolidines and azepines, obtaining excellent diastereoselectivities of >99:1 dr.
Amino acid analogues, β-amino phosphonates, were reduced in a trichlorosilane mediated reduction. These compounds were found reduce significantly faster than their carbon counterparts, giving an uncontrollable background reaction. This was investigated and some self-catalysis was occurring but not to the extent that it would be the only factor encouraging the fast reduction without a catalyst.