Quinine analogues

It was found, during a study of synthetic routes leading to quinine analogues, that oxidation of a specific bicydic pyrazoline derivative with mercuric acetate gives an enamine-like pyrazole (87b). 

There are some who have argued that without the use of Cinchona extracts, and later synthetic quinine analogues, world history over the past two centuries would have taken a very different course. It is argued that the use of quinine to treat malaria (and to a lesser extent yellow fever) facilitated colonialisation by western European countries of territories that would have been too hostile for foreigners with little natural resistance to parasitic-induced fevers. For example, the Panama Canal might not have been built without access to quinine. The outcome of the American Civil War has even been speculated upon because the successful blockade of the Confederate ports caused severe shortages of quinine so the Confederate Armies were debilitated by fevers. 

Hutzler JM, Walker GS, Wienkers LC (2003) Inhibition of cytochrome P450 2D6 strueture-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol 16 450-459... 

A Chinese traditional herbal treatment for malaria obtained from the roots of Dichroafebrifuga is called Ch ang Shan and was investigated in the 1940s. Febrifugine (80), the alkaloid responsible for its activity, was isolated and found to be considerably more active than quinine in experimental infections. Unfortunately, the dmg caused nausea and vomiting in humans. Synthesized analogues were generally less effective than the parent. 

The vinyl-free analogues of quinine and quinidine, viz., the 6 -methoxy-ruban-9-ols were also synthesised in 1941 by Rabe and Hagen and further details added by Rabe, Schuler and Voss in 1943. 6 -Methoxy-ruban-9-one, m.p. 89° (Prelog et found m.p. 90-1° and picrate m.p. 211-211-5° the latter was confirmed by Kleiman and Weinhouse on hydrogenation in dilute hydrochloric acid in presence of palladium black gave... 

Quinidine (155) and dihydroquinidine (157) have been used for a long time for the treatment of cardiac antiarrythmia. These cinchona alkaloids (and their analogues in the quinine and cinchonidine family) are metabolized in animals and humans [234,235] to give, among several products, the corresponding (3S)-3-hydroxy derivatives (156,159) [236-240], which were shown to be pharmaco-... 

The same principle applies to other easily made symmetrical dichloro derivatives of these rings and their benzo-analogues. The nitrogen atoms can be related 1,2,1,3, or 1,4 as in the examples alongside. The first two are used to link the quinine-derived ligands required for the Sharpless asymmetric dihydroxylation, which will be described in Chapter 45. 

TTie cinchona tree produces four alkaloids that were, until recently, the prototypical molecules on which most untimu-larial drugs were based. TTiese alkaloids (Fig. 9-2) are the enantiomeric pair quinine and quinidine and their desmeth-oxy analogues, cinchonidine (for quinine) and cinchonine (for quinidine). (Unfortunately, the nomenclature for the two series of alkaloids is inconsistent.) Their numbering system is based on rubane. The stereochemistry differs at positions 8 and 9, with quinine and cinchonidine being S.R and quinidine (cinchonine) being R.S. Historically, quinine was the main treatment for malaria until the advent of World War II, when battle in areas where malaria was endemic led to the search for more effective agents. 

Access to optically active 2-fluoro-l-tetralone 53 was achieved using the same palladium-mediated cascade reaction [30]. The catalytic enantioseiective decarbox-ylative protonation of 2-fluoro benzyl P-keto ester 54 in the presence of 30 mol% of quinine 20 afforded enantioenriched (S)-tetralone 53 in 65% ee (Scheme 7.24). The reaction was very sensitive to the nature of the palladium catalyst used. Furthermore, a minor amount of defluorinated product was observed. Several other cinchona derivatives were tested including analogues of cinchonine described by Brunner in organocatalytic EDP (see Section 7.5.3), but these chiral inductors afforded low selectivities (<30% ee). 

The heterogeneous version of this reaction was quite recently reported by Guo and coworkers [75]. Highly interestingly, in the reaction of the indole with the N-Bs (Bs, benzene sulfonyl) phenyl imine 162, enhanced enantioselectivity (99.2% ee at 40 °C) compared with that (92% ee at 50 °C [74], 93.2% ee at 40 °C [75]) obtained with the homogeneous analogue 40 was achieved using the mesoporous silica (SBA-15) supported epi-quinine thiourea catalyst 161. The increased ee value can be ascribed to the confinement effect [76] of the support (Scheme 8.64). 

Conversion of the natural product quinine into its alkyne analogue 26 was reported at the beginning of the twentieth century [16], but to our surprise, no further work on this potentially interesting and useful class of compounds had come forward since then. Similarly, transformations such as oxidative cleavage or degradation to the ketone functionality at carbon C3 had remained unexplored until the 1990s. 

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