Quinoline continued structure

The hetero-Diels-Alder reaction continues to be a popular method of producing the tetrahydroquinoline ring structure. The generation of o-azaxylylene allows for the subsequent cycloaddition with dienophiles to produce the corresponding quinoline ring structure (Scheme 73) <1998H(48)1103, 1998JHC467>. 

Quinoline forms part of the structure of quinine, the malaria remedy found in cinchona bark and known since the time of the Incas. The quinoline in quinine has a 6-MeO substituent and a side chain attached to C4. In discussing the synthesis of quinolines, we will be particularly interested in this pattern. This is because the search for anti-malarial compounds continues and other quinolines with similar structures are among the available anti-malarial drugs. 

Over decades of sublethal exposure the resistance of all types of malaria has increased to a point where chloroquine no longer offers certain protection (217). With the partial exception of quinine and dihydroquinine (218), resistance to antimalarials had reached the stage at the time of the Vietnam war where more research was required. The development of mefloquine (164) was a continuation of the World War II effort, with a gap of about 20 years. Resistance to chloroquine had developed widely during that period, but surprisingly less so to quinine, given the obvious similarities in structure. This observation stimulated a reappraisal of quinolines, known as quinoline methanols, which bear a hydroxy group on the a-carbon of a substituent at-... 

The quest to tackle malaria with a synthetic drug was the challenge that led William Perkin to the discovery of his aniline purple, or mauve (5), in 1856. Research into antimalarials continued to attract attention, at first to aid colonial expansion, and later because of shortages in time of war. Research was guided by the fact that quinine was found to be an oxygenated quinoline, a 6-methoxyquinoline derivative (84), as established by Zdenko H. Skraup. The structure became available in 1908, through the research of Paul Rabe93. 

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