Nature stays natural: two novel chemo-enzymatic one-pot cascades for the synthesis of fragrance and flavor aldehydes

Abstract

Novel synthetic strategies for the production of high-value chemicals based on the 12 principles of green chemistry are highly desired. Herein, we present a proof of concept for two novel chemo-enzymatic one-pot cascades allowing for the production of valuable fragrance and flavor aldehydes. We utilized renewable phenylpropenes, such as eugenol from cloves or estragole from estragon, as starting materials. For the first strategy, Pd-catalyzed isomerization of the allylic double bond and subsequent enzyme-mediated (aromatic dioxygenase, ADO) alkene cleavage were performed to obtain the desired aldehydes. In the second route, the double bond was oxidized to the corresponding ketone via a copper-free Wacker oxidation protocol followed by enzymatic Baeyer-Villiger oxidation (phenylacetone monooxygenase from Thermobifida fusca), esterase-mediated (esterase from Pseudomonas fluorescens, PfeI) hydrolysis and subsequent oxidation of the primary alcohol (alcohol dehydrogenase from Pseudomonas putida, AlkJ) to the respective aldehyde products. Eight different phenylpropene derivatives were subjected to these reaction sequences, allowing for the synthesis of seven aldehydes in up to 55% yield after 4 reaction steps (86% for each step).

Fig. 1. (A) Estragole 4a can be isolated from estragon. (B) Safrole 6a can be isolated from makulan. Picture: Forest & Kim Starr (CC BY 3.0). (C) Eugenol 7a can be isolated from cloves. The image was adapted from Brian Arthur (CC BY-SA 4.0).

Scheme 1. Two novel chemo-enzymatic sequential one-pot reactions developed in this work. (A) Consists of a two-step cascade based on a Pd-assisted double bond isomerization and a subsequent enzymatic CC double bond cleavage. (B) Cascade B starts with the double bond oxidation to the corresponding ketone and is followed by an enzymatic cascade to yield the desired fragrance and flavour aldehydes.

Scheme 2. Route A. Compound a is isomerized to b and subsequently oxidized to the corresponding aldehyde f.

Scheme 3. Overview of route B. Compound a is oxidized twice to c and then d, respectively. Ester cleavage affords e, which is again oxidized to f.

Fig. 2. Optimization of the chemo-enzymatic cascade (route B) to avoid the production of the unwanted side product, the carboxylic acid. (a) Non-optimized conditions. (b) Optimized conditions – see the text. The “not recovered” label represents the mass difference between the theoretical mass balance and the observed mass recovery.