We move from benzo-fused pyrroles to benzo-fused pyridines and meet quinoline and isoquinoline. Isoquinolines will feature as benzylisoquinoline alkaloids in Chapter 51 and their synthesis will mostly be discussed there. In this section we shall concentrate on the quinolines. 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. We shall also be very interested in quinolones, analogous to pyridones, with carbonyl groups at positions 2 and 4 as these are useful antibiotics. A simple example is pefloxacin which has a typical 6-F and 7-piperazine substituents.

Quinolines and Isoquinolines

Emetine, the active principle of ipecac, is isolated from the roots of Cephaelis ipecacuanha, a small plant indigenous to the tropical rain forests of Brazil and countries immediately to the north. The medicinal properties of ipecac in the treatment of dysentery have long been known to the natives of Brazil (Purchas, 1625). The drug was introduced into Europe during the latter part of the 17th Century and sold by a Paris physician, Helvetius, as a secret remedy for dysentery. By 1688, ipecac had achieved such fame that the formula was purchased by Louis XIV and placed in the public domain (Lloyd, 1921; Staub, 1927).

Emetine and Related Alkaloids

The broad presence of azaarene moieties in natural products has promoted the development of new functionalization reactions, giving access to larger libraries of bioactive compounds. The light promoted [2 + 2] photocycloaddition reaction to generate cyclobutanes has been extensively studied in photochemistry. In particular, De Mayo reported the [2 + 2] cycloaddition followed by retroaldol condensation between enols of 1,3-dicarbonyls and double bonds to synthesize 1,5-dicarbonyls. Herein, we describe the [2 + 2] photocycloaddition followed by a ring-opening rearomatization reaction between electron-deficient 2-methylene-azaarenes and double bonds, taking advantage of the ability of these heterocyclic derivatives to form the corresponding pseudo-enamine intermediate. The procedure shows a high functional group tolerance either on the double bond or the heteroarene side and allows the presence of different electron-withdrawing groups. In addition, the wide applicability of this reaction has been demonstrated through the late-stage derivatization of several natural products. Photochemical studies, together with theoretical calculations, support a mechanism involving the photosensitization of the pseudo-enamine intermediate. The visible light-promoted [2 + 2] cycloaddition is a useful and extended route to prepare cyclobutanes and their derivatives. Here, we present an aza variant, in which heterocycles and olefins undergo a cycloaddition-ring opening rearomatization sequence, providing access to functionalised nitrogen heterocycles.

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Visible light mediated photocatalytic [2 + 2] cycloaddition/ring-opening rearomatization cascade of electron-deficient azaarenes and vinylarenes

Publisher Summary This chapter discusses the ipecac alkaloids. Ipecac root has been used in therapy since the beginning of the XVIIth century as an emetic and expectorant; its use against dysentery, already recommended by Helvetius in the eighteenth century, was found to be therapeutically correct in 1912, when emetine, the most important of its alkaloids, was successfully used by L. Rogers in the treatment of amebic dysentery. This very important application has stimulated many investigations of Ipecac root and has shown emetine to be an almost indispensable alkaloid. Two kinds of Ipecac from which the alkaloids, and in particular emetine, can be extracted are important in commerce, namely. Trading in Ipecac has practically become a monopoly of Brazil, and since there are many adulterations on the market it is important to use only authentic raw materials, with a guaranteed content of alkaloids, not less than 2%, which is demanded by most pharmacopoeias.

M. Pailer

Papers

ber Brechwurzelalkaloide: IV. Mitteilung: Die Konstitution des Emetins