title: 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.
authors.affiliation: Dipartimento di Chimica, Materiali ed Ingegneria Chimica G. Natta, Politecnico di Milano, P.zza Leonardo da Vinci 32, 20133 Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Brenna
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Gatti
authors.forename: Luciana
authors.initials: L
authors.lastname: Malpezzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Monti
authors.forename: Fabio
authors.initials: F
authors.lastname: Parmeggiani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sacchetti
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000447:Aldehydes; D001578:Benzopyrans; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C047508:rotigotine; C108607:robalzotan; C584127:ebalzotan