Chemoenzymatic one-pot synthesis in an aqueous medium: combination of metal-catalysed allylic alcohol isomerisation–asymmetric bioamination

Abstract

The ruthenium-catalysed isomerisation of allylic alcohols was coupled, for the first time, with asymmetric bioamination in a one-pot process in an aqueous medium. In the cases involving prochiral ketones, the ω-TA exhibited excellent enantioselectivity, identical to that observed in the single step. As a result, amines were obtained from allylic alcohols with high overall yields and excellent enantiomeric excesses.

One-Pot Combination of Metal- and Bio-Catalysis in Water for the Synthesis of Chiral Molecules

“…In this case, the compatibility studies unveiled the same catalytic activity for Complex 2 (99% conversion in the desired ketones) in the presence of KREDs and their co-factor NADPH. Similarly and as previously detected with ω-TAs [27], no inhibition was observed in the biocatalytic system when the ruthenium catalyst was present in the reaction media. After both steps (metal-and bio-catalysis) were independently optimized and several issues (such as reaction medium optimization (i.e., percentage of i PrOH, 15% v/v), concentration of co-factor, metal-catalyst loading (5 mol%) and reaction temperature (30 • C)) were addressed (Scheme 2), we were able to develop, for the first time, a genuine one-pot concurrent process where the metal Catalyst 2 and the biocatalyst coexist from the beginning in aqueous medium, giving rise to enantiopure saturated alcohols starting from racemic allylic alcohols.…”

“…Recent years have also seen an impressive advance in multi-enzymatic systems of remarkable complexity [7][8][9][10], which try to emulate Nature, as living organisms use a great number of enzymatic cascades (in different metabolic pathways) employing the same reaction media (i.e., the cytosol). Thus, the in vitro development of these one-pot asymmetric multi-catalytic enzymatic reactions permits the synthesis of valuable target molecules under practical and economic advantages Thus, the starting point of our investigations, devoted to the combination of metal-and biocatalysts in aqueous media, was the design of a one-pot tandem process through the assembly of the Ru(IV)-catalyzed redox isomerization of allylic alcohols with a ω-transaminase (ω-TA)-mediated bioamination reaction [27]. Initially, the catalytic activity of Complexes 1-3 ( Figure 1) was evaluated in the redox isomerization of racemic allylic alcohols into prochiral ketones (Scheme 1), but in the conditions imposed by the second step of the process, namely the employment of a phosphate buffer solution containing i PrNH2 (as a source for the amino group).…”

“…This enzymatic screening of commercially available ω-TAs enabled identifying highly-efficient biocatalysts, which produced both enantiomers of each amine in almost quantitative conversion and excellent enantiomeric excess, even in the company of the ruthenium Catalyst 3. Thus, the starting point of our investigations, devoted to the combination of metal-and biocatalysts in aqueous media, was the design of a one-pot tandem process through the assembly of the Ru(IV)-catalyzed redox isomerization of allylic alcohols with a ω-transaminase (ω-TA)-mediated bioamination reaction [27]. Initially, the catalytic activity of Complexes 1-3 ( Figure 1) was evaluated in the redox isomerization of racemic allylic alcohols into prochiral ketones (Scheme 1), but in the conditions imposed by the second step of the process, namely the employment of a phosphate buffer solution containing i PrNH2 (as a source for the amino group).…”

From a Sequential to a Concurrent Reaction in Aqueous Medium: Ruthenium‐Catalyzed Allylic Alcohol Isomerization and Asymmetric Bioreduction

“…[10] Although the resulting amines were isolated in very high yields and enantiomeric excesses, the process had to be accomplished in as equential fashion because of the inactivation of the metal catalyst by both w-TA and pyridoxal-5'-phosphate (cofactor). [10] Although the resulting amines were isolated in very high yields and enantiomeric excesses, the process had to be accomplished in as equential fashion because of the inactivation of the metal catalyst by both w-TA and pyridoxal-5'-phosphate (cofactor).…”

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“…25 This represents a rare example of using a one-pot metal and biocatalysed reaction process in water. 25 This represents a rare example of using a one-pot metal and biocatalysed reaction process in water.…”