A feasible and enantioselective total synthesis of (-)-trans-dihydronarciclasine [(-)-1], a highly biologically active alkaloid, was devised starting from vanillin (8). The key step of this new synthesis was an asymmetric, organocatalytic Michael addition, in which an optically active nitropentanone [(-)-13] was obtained from a butenone derivative (12). Excellent enantioselectivity (>99% ee) was achieved using the (8S,9S)-9-amino(9-deoxy)epiquinine (16) organocatalyst. The target molecule can be prepared in 13 steps from compound (-)-13. The total synthesis has provided a facile and first access to the ent-form of naturally occurring (+)-trans-dihydronarciclasine, a highly potent cytostatic alkaloid.
Some new trans-dihydronarciclasine derivatives containing a 1,4-benzodioxane moiety were stereoselectively synthesised using our feasible and efficient method developed recently. These new phenanthridone alkaloid analogues were obtained in both racemic and optically active forms. High enantioselectivities (up to 99% ee) were achieved by applying (8S,9S)-9amino(9-deoxy)epiquinine as an organocatalyst. Due to a side reaction, various methoxyphenanthridine regioisomers were also prepared which afforded further synthetic trans-dihydronarciclasine analogues modified in the ring A of the phenanthridone scaffold.
Graphical abstract
The
discovery and characterization of novel naphthyridine derivatives
with selective α5-GABAAR negative allosteric modulator
(NAM) activity are disclosed. Utilizing a scaffold-hopping strategy,
fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among
these, 1,6-naphthyridinones were identified as potent and selective
α5-GABAAR NAMs with metabolic stability, cardiac
safety, and beneficial intellectual property (IP) issues. Relocation
of the oxo acceptor function and subsequent modulation of the physicochemical
properties resulted in novel 1,6-naphthyridines with improved profile,
combining good potency, selectivity, ADME, and safety properties.
Besides this, compound 20, having the most balanced profile,
provided in vivo proof of concept (POC) for the new scaffold in two
animal models of cognitive impairment associated with schizophrenia
(CIAS).
Several new trans-dihydronarciclasine analogues were stereoselectively synthesised by applying our feasible and efficient process developed recently. These new phenanthridone alkaloid derivatives were obtained in both racemic and optically active forms. During their enantioselective syntheses, high selectivities (up to 99% ee) were achieved by using (8S,9S)-9-amino(9-deoxy)epiquinine as an organocatalyst. The modifications, the introduction of ethoxy or methoxy groups, were made in ring A of the phenanthridone scaffold.
An efficient stereoselective synthesis of a pivotal intermediate, a cyclic allyl alcohol derivative containing two methoxy groups [(±)-22], using for the preparation of (±)-trans-dihydronarciclasine analogues was elaborated starting from easily available and inexpensive methyl gallate. This new synthetic route consists of 17 reaction steps, and provides an opportunity to obtain the wanted alkaloid derivative containing an additional methoxy group at position 11, in the ring A of the phenanthridone scaffold.
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