Synthesis of Robalzotan, Ebalzotan, and Rotigotine Precursors via the Stereoselective Multienzymatic Cascade Reduction of α,β-Unsaturated Aldehydes

Abstract

A stereoselective synthesis of bicyclic primary or secondary amines, based on tetralin or chroman structural moieties, is reported. These amines are precursors of important active pharmaceutical ingredients such as rotigotine (Neupro), robalzotan, and ebalzotan. The key step is based on a multienzymatic reduction of an α,β-unsaturated aldehyde or ketone to give the saturated primary or secondary alcohol, in a high yield and with a high ee. The catalytic system consists of the combination of an ene-reductase (ER; i.e., OYE2 or OYE3 belonging to the Old Yellow Enzyme family) with an alcohol dehydrogenase (ADH), applying the in situ substrate feeding product removal technology. By this system the formation of the allylic alcohol side product and the racemization of the chirally unstable α-substituted aldehyde intermediate are minimized. The primary alcohols were elaborated via a Curtius rearrangement. The combination of OYE2 with a Prelog or an anti-Prelog ADH allowed the preparation of the secondary alcohols with ee > 99% and de > 87%. The absolute configuration of the primary amines was unambiguously assigned by comparison with authentic samples. The stereochemistry of secondary alcohols was assigned by X-ray crystal structure and NMR analysis of Mosher esters.

Systematic methodology for the development of biocatalytic hydrogen-borrowing cascades: application to the synthesis of chiral α-substituted carboxylic acids from α-substituted α,β-unsaturated aldehydes

“…Chemoselectivity varied from good to excellent. 45 The alcohol was recovered with 91% ee, whereas in our study the related carboxylic acid was obtained with 95% ee (Table 5, entry 5). The stereoselectivity was also in general elevated, although there is an urgent demand for stereocomplementary ERs that would lead to the opposite enantiomer with equally high ees.…”

“…[34][35][36][37][38][39][40][41][42] The parameter for this initial screening of the ERs was the stereoselectivity for the reduction of the carboncarbon double bond of the target substrate α-methyl-transcinnamaldehyde (1a) (Chart 1). Surprisingly, although it is known that α-chiral aldehydes are prone to racemization in aqueous solution, 45 the majority of the procedures reported in the literature for this biocatalytic reaction envisage 24 h reaction time. 21,35,43,44 Asymmetric reduction is commonly conducted using NADPH as cofactor that is recycled by glucose dehydrogenase (GDH) at the expense of glucose as the sacrificial co-substrate.…”

Cascade Coupling of Ene‐Reductases and ω‐Transaminases for the Stereoselective Synthesis of Diastereomerically Enriched Amines

“…β‐Substituted cyclic enone 1 b is a very well‐known substrate for OYEs, and it has also been recently used to investigate the coupling of ERs with other enzymatic activities such as ADHs and Baeyer–Villiger monooxygenases, and even ω‐TAs, as mentioned above . Chromanyl derivative 1 c was previously used by our group as a building block to prepare amine (1 R ,3′ S )‐ 3 c , a precursor of analogues of NK‐1 tachykinin receptor antagonists, by an ER/ADH cascade and subsequent chemical modification . The choice of these two additional substrates also required us to use different ERs in the alkene reduction step, and OYE1 from S. pastorianus and OYE2 from S. cerevisiae were reported to be the most stereoselective enzymes for the preparation of ( S )‐ 2 b (>99 % ee ) and ( S )‐ 2 c (98 % ee ), respectively.…”

Ene‐reductases and their Applications

“…Recently, the stereoselective synthesis of bicyclic primary or secondary alcohols was reported by Brenna et al [52]. Again, the combination of an ER with an ADH was used to catalyze reactions on substrates based on tetralin or chroman backbones, which led to precursors of important active pharmaceutical ingredients (rotigotine, robalzotan, and ebalzotan) with optical purities up to >99% (Figure 18.5b) [52].…”

“…Again, the combination of an ER with an ADH was used to catalyze reactions on substrates based on tetralin or chroman backbones, which led to precursors of important active pharmaceutical ingredients (rotigotine, robalzotan, and ebalzotan) with optical purities up to >99% (Figure 18.5b) [52]. In this case, the addition of an ADH allowed for a minimization of the spontaneous chemical racemization of the unstable saturated aldehyde intermediate.…”