Halogenated alkaloid synthesis

Gribble GW (2008) Structure and Biosynthesis of Halogenated Alkaloids. In Fattorusso E, Taglialatela-Scafati O (eds) Modem Alkaloids Structure, Isolation, Synthesis and Biology. Wiley, Weinheim, p 591... 

Addition to cyclic iminium salts has been utilized in alkaloid synthesis. A zinc-promoted reductive coupling reaction of iminium salts and alkyl halides has been reported by Shono et al. (Scheme 8). Evidence delineating the mechanistic course (organozinc addition or electron transfer reaction) of the addition has not been established. In contrast to organolithium or Grignard additions, aromatic halogen and alkoxycarbonyl substituents are compatible with this methodology. The intramolecular version of this reaction has been employed for the synthesis of tricyclic amines (53 equation 9). 

A molecular dissection of the alkaloid vasicine (52) ultimately resulted in the expectorant and mucolytic agent bromhexine (54). The synthesis starts with displacement of halogen on 2-nitrobenzyl-bromide (53) by N-methyl cyclohexylamine, followed by Raney nickel and hydrazine reduction of the nitro group. Bromination in acetic acid then affords bromhexine. 

Cyclization arising from the intramolecular photoelimination of HC1, HBr, and HI has been extensively used in the synthesis of heterocycles and alkaloids. The mechanisms of these transformations have not in many cases been thoroughly investigated. Some undoubtedly are initiated by simple homolysis of the carbon-halogen bond whereas others involve photocycliza-tion and subsequent elimination of HX. 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

Morphine alkaloids. 113. Synthesis of C-3 halogen-substituted apocodeines and apomorphines... 

Intramolecular photoelimination of HCl, HBr, and HI, often initiated by carbon-halogen bond homolysis, has again been widely used in the synthesis of heterocycles and alkaloids. 6-Acetyl-l,2-dimethoxy-4//-5,6,6a,7-tetrahydrobenzo-[rf ]thieno[2,3-g]quinoline (197), for example, has been obtained in this way by irradiation of the bromothiophen (198). " Analogous photocyclizations have been employed in the synthesis of ( + )-oliveroline, ( )-domesticine, ... 

Combination of the Pummerer ((212) -> (213)) and Bischler-Napieralsky ((214) -> (215)) reactions, with an intermediate reductive removal of both the halogen and the methylthio group has allowed the synthesis of protoberberine alkaloids from benzyl phenylethyl amines <87TL2399>, as shown in Scheme 40. 

Still, there remain many open problems. It would be efficient to be able to prenylate or ferf-prenylate indole regioselectively at the benzene positions 4, 5 and 6 without having to rely on pre-functionalisation such as halogenation or hydroxylation. Here, deeper investigation of prenyl shifts and of CH functionalisation on indole is required. Enantioselective catalysis has to be explored further towards the synthesis of optically pure 3-prenylated or -tert-prenylated alkaloids. A chiral version of NBS would be helpful. In the case of conformationally flexible starting materials, the diastereoselectivity of oxidative cyclisations of tryptophan-derived diketopiperazines is still not convincing. In the area of chemoenzymatic synthesis, the number and availability of enzymes has to be enhanced and their substrate tolerance has to be elucidated in more detail. 

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