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Chiral tricyclic lactams as efficient enantiomeric scaffolds for the synthesis of cis-decahydroquinolines substituted on the carbocyclic ring. Total synthesis of Myrioneuron alkaloids
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[eng] The Myrioneuron alkaloids constitute a family of natural products found in East and South-East Asia. They feature a cis- or trans-decahydroquinoline (DHQ) as a common unit, attached to an oxazine, a diazine, or a cyclohexane ring, forming complex polycyclic ring systems. Despite exhibiting promising biological properties, their study has been hindered by the limited quantities available from natural sources.
This thesis presents our advances on the exploration of new cyclocondensation reactions leading to tricyclic lactams bearing substituents at positions of the carbocyclic ring that were previously inaccessible by the group's established methodology. These studies have culminated in the synthesis of various Myrioneuron alkaloids.
In the first chapter, the synthesis of cis-decahydroquinolines substituted on the carbocyclic ring is explored. Starting from racemic diastereomeric mixtures of dimethyl-2-oxocyclohexanepropionic acids the synthesis of both enantiomers of 7,8-, 6,8-, and 5,8-dimethyl-substituted cis-decahydroquinolines is reported. The procedure involves a dynamic kinetic asymmetric transformation in the cyclocondensation of the ketoacids with (R)-phenylglycinol to give in each case two major oxazoloquinolone lactams, which differ in the absolute configuration of all the stereogenic centers except that of the chiral inductor. A subsequent two-step stereoselective removal of the phenylethanol residue with simultaneous reduction of the lactam carbonyl afforded the enantiopure cis-decahydroquinolines in both enantiomeric series.
The second chapter is centered on the total synthesis of (–)-schoberine B using the previously developed methodology. Firstly, the synthesis of a δ-ketoacid, bearing the appropriate functional groups for the synthesis of the alkaloid, is reported. Subsequently, the application of the aforementioned methodology with this compound allowed the obtention of two major lactams, that differ in the configuration of the four stereocenters on the decahydroquinoline moiety. From the above lactams, the removal of the chiral inductor, the introduction of a 2-piperidone ring, and the closure of the diazine ring completes the first enantioselective total synthesis of the Myrioneuron alkaloid (−)-schoberine B and its enantiomer (+)-schoberine B.
In the third chapter, we assess the scope and limitations in the introduction of substituents at the C-7a and/or C-11 positions of simple (R)-phenylglycinol-derived oxazolo-DHQs. The reaction of this compound with various electrophiles allowed the regio- and stereoselective formation of various C-7a-subsituted oxazolo-DHQs bearing an all-carbon quaternary stereocenter. In a selected example, the regioselectivity of the process has been successfully modulated leading to the obtention of an 11-hydroxymethyl-substituted oxazolo-DHQ. A subsequent two-step stereoselective removal of the phenylethanol moiety afforded various C-4a and C-8 substituted cis-DHQs. Using this methodology, the most efficient enantioselective synthesis of (+)-myrioxazine A has been achieved.
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CALBÓ ZABALA, Arnau. Chiral tricyclic lactams as efficient enantiomeric scaffolds for the synthesis of cis-decahydroquinolines substituted on the carbocyclic ring. Total synthesis of Myrioneuron alkaloids. [consulta: 3 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/215685]