Total synthesis of Cinchona alkaloids. 4. Syntheses via quinuclidine precursors

Recent applications of Cinchona alkaloids and their derivatives as catalysts in metal-free asymmetric synthesis

“…6), namely an aromatic quinoline ring and an aliphatic quinuclidine ring linked by two carbonecarbon single bonds. They contain five stereocentres, C-(3), C-(4), N-(1), C- (8) and C- (9), but they occur in pairs that differ in configuration only at N-(1) and the two connecting single-bond carbons, C- (8) and C- (9). The absolute configuration at C-(3) and C-(4) is identical in both pairs and is the same in all naturally occurring Cinchona alkaloids.…”

“…This mode of catalysis simultaneously utilises the quinuclidine nitrogen to activate the nucleophile via general base catalysis and the hydroxyl group at C- (9) to activate the electrophile via hydrogen bond interactions. In other words, the two functional groups provide specific enzyme-like interactions that pre-organise and orient the reactants in an optimum position for reaction and also stabilise the transition-state structure.…”

“…1,2 The isolation of quinine was first accomplished in 1820 by Pelletier and Caventou 3 and was the result of intensive research during the early 19th century, fuelled by the increasing demand for malaria cures coupled with the difficulties created by two world wars in obtaining sufficient raw Cinchona bark. Although a total of about 30 Cinchona alkaloids were eventually isolated from Cinchona species, the four best known being quinine, cinchonidine, quinidine and cinchonine, further research focused mainly on quinine 4,5 leading to its molecular structure determination by Rabe (1907), 6 partial total synthesis in 1945 by Woodward and Doering,7 definite confirmation of its structure by X-ray crystallography (1967), 8 various approaches to its total synthesis 4,9 and, finally, its full synthesis with the correct configuration by Stork in 2001. 10 Although the chiral application of the Cinchona alkaloids dates back to 1853 11 they have been rediscovered outside their medicinal uses as efficient chiral reagents, chiral auxiliaries and privileged catalysts in asymmetric synthesis mainly over the past 30 years.…”

Formation and Structure of Cinchona Alkaloid (Bis-2,3-naphthalenediyl)orthoborate Salts

“…The structure was solved with direct methods using the SHELXS-86 program [8] and refined by full-matrix least-squares method with SHELXL-93 [9], The choice of the correct enantiom er was based on the chemical information about the cat ion [10][11][12]. The large residual electron density was interpreted as the solvent molecule (acetone) with a site occupancy factor of 0.5, and this mole cule was restrained to keep an idealized geometry and was isotropically refined as rigid body.…”

Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine

“…First, the 6-methoxyquinoline would need to be introduced during a later stage in the synthesis, perhaps using an organometallic reagent prepared from 4-bromo-6-methoxyquinoline, 28 Second, the original late-stage C6–C7 bond cleavage tactic (e.g., alkene ozonolysis) was changed to oxidative cleavage of a vicinal diol, which would require oxidation of the C6–C7 alkene prior to the radical addition.…”