Cinchona quinoline moiety

The Park-Jew group proposed a possible transition state in which the chalcone is located between the two cinchona units in the catalyst 66, and the (1-phenyl moiety of chalcone has a k-k stacking interaction with one of the quinoline moieties in 66. 

There are recognized at present three naturally occurring members of this group, cinchonamine, quinamine, and conquinamine, all minor alkaloids of certain Cinchona and Memijia species. The elucidation of their structures led to the suggestion that the quinoline moiety of the major bases, e.g., cinchonine and quinine, of these plants was probably derived from tryptophan via an indolic precursor. It has since been demonstrated from the results of feeding experiments with isotopically labeled tryptophan that this amino acid really can serve as a precursor of various indole alkaloids (1) as well as of quinine (2). The details of these processes are not yet known but probably involve an intermediate(s) related to cinchonamine (2, 3, 6). 

Pyridine is an aromatic 6n electron heterocycle, which is isoelectronic with benzene, but electron deficient. Nucleophiles thus add almost invariably to carbon C2 of the imine-like C=N double bond. Perhaps the best known nucleophilic addition is the Chichibabin reaction with sodium amide in liquid ammonia, giving 2-aminopyr-idine. Reactions of the quinoline moiety of cinchona alkaloids can be more complex. Although expected 2 -addition can be achieved easily with organolithium reagents to yield 13 (Scheme 12.6) [9], LiAlH4, for example, has been shown to attack C4 en route to quincorine and quincoridine (Schemes 12.4 and 12.5). C4 selectivity is due to chelation of aluminum by the C9 OH oxygen. 

Scheme 12.9 Synthesis of novel cinchona alkaloid organocatalysts with modified quinoline moiety. Reagents and conditions (a) Dt-BuAD, CH2CI2, rt, 2 h, 93% (b) PhNTf2, DMAP, CH2CI2 (c) 1. Pd(OAc)2, BINAP, Cs2C03, THF, Ph2C=NH, 2. citric acid, THF, H20 (d) 3,5-(CF3)2PhNCS, THF.

The simplest cinchona alkaloids, cinchonidine and its 10,11-dihydro-derivative, have been shown by D-tracer studies and by NEXAFS and ATR-IR spectroscopy to adsorb by interaction of the quinoline moiety with the platinum surface. Mechanistic studies have established that a site exists adjacent to the open-3 conformation of adsorbed cinchonidine at which pyruvate ester can undergo selective enantioface adsorption. Hydrogenation of the preferred enantioface results in preferential formation of one enantiomer of the product, methyl lactate, MeC H(OH)COOMe. Pt modified by cinchonidine provides R-lactate preferentially, whereas the near enantiomer cinchonine provides 5-lactate in excess. Values of the enantiomeric excess of 75% can be obtained without optimisation, and of 98% under special conditions. In solution, conditions that achieve enantioselectivity normally promote the reaction rate by a factor of 2 to 100 depending on conditions. ... 

Quinine and related alkaloids isolated from the bark and other parts of Cinchona plants, such as Cinchona ledgeriana and Cinchona succimbra (Rubia-ceae), can be classified as quinoline alkaloids because these alkaloids also possess a quinoline moiety. However, the biosynthetic origin of the chro-mophore of these alkaloids is tryptophan rather than anthranilic acid. Namely, the quinoline moiety is formed by the oxidative transformation of the indole nucleus during biosynthesis, as described in Section 2.17. 

Cupreines and cupreidines are pseudoenantiomers of Cinchona alkaloids with the replacement of quinoline C(6 )-OCH3 with an OH-group. The result is availability of an additional hydrogen-bonding moiety. 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

From corynantheal onwards the pathways diverge completely. The generation of the skeleton of the Cinchona bases requires not only a further reorganization of the terpenoid moiety but also a fundamental rearrangement of the indolic portion of the molecule to generate the quinoline residue. The currently favoured working hypothesis for this transformation is shown in Scheme 2 (13) — (14) — (15)— (16)—>(17) and (18). With the required skeleton in hand, only relatively trivial biochemical reactions are required to produce the known Cinchona alkaloids (21), (22), and (23). 

Several new syntheses of quinoline and indole Cinchona alkaloids were reported in the last few years. In these synthetic routes the quinuclidine moiety of the alkaloids was derived from various synthetic meroquinene derivatives 18. These new syntheses all proceed through intermediates of general formula 19 which are characterized by a properly positioned functional group (t.e., X) which facilitates the formation of quinuclidine ring 20. 

Besides quinine (1), quinidine (2), cinchonidine (3), and cinchonine (4), a considerable number of their close derivatives have been found in the bark or in the leaves of Cinchona species (occasionally also in other species, see Table 21.2), differing mainly with the type of substituents (vinyl or ethyl group) at C-3 of quinuclidine moiety, methoxyl, hydroxyl, or hydrogen in the quinoline ring or in configuration at C-9 (Table 21.1) [23, 36]. 

Quinoline-type Cinchona alkaloids (1-4) ccmsist of an aromatic quinoline (or 6 -methoxyquinoline) ring joined to the bulky bicyclic quinuclidine moiety by a carbinol linker C-9. Each Cinchona alkaloid contains five stereogenic centers at C-9, C-8, C-4, C-3, and N-1 (Fig. 21.2). 

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