Alkaloids aryl radical

The plan for a tandem cyclization as the key step in the synthesis of morphine alkaloids has been successfully performed [95]. Three examples are given in Scheme 7.10. Specifically, the initially formed aryl radical, generated by bromine abstraction from compound 74, underwent a tandem cyclization to construct the desired carbocyclic skeleton. Depending on the nature of the Z substituent to the double bond, the product radicals either abstracted hydrogen from silane (Z = C02Me or CN) or eliminated thiyl radical (Z = SPh). 

Reversed regioselectivity in aryl radical additions to enamides and enamines can also be observed with aryl substituents on the alkene [86]. This cyclization type has been successfully applied in the synthesis of protoberberines and the pavine alkaloids. Argemonine (39) was obtained from a 6-exo cyclization of 40 passing through a well-stabilized benzylic radical (Scheme 15). 

As an extension of the known radical additions to isonitriles [87], aryl radical cyclizations to /V-acyl cyanamides provide new access to pyrrolo-quinazolines (Scheme 16) [88]. In a tandem process, the iminyl radical 41 resulting from the 5-exo cyclization onto the nitrile was used for a second cyclization step. In this way, the alkaloid luotonin A (42) was synthesized from cyanamide 43 in a single reaction. 

Cyclization of aryl radicals on to either 2- or 3-carbonyl substituted pyrroles occurs preferentially at the 2-position. In the case of the former cyclizations, the yields are poor but this could represent a rapid approach to a range of indole alkaloids. Thus, cyclization of 2-substituted pyrroles 929 by treatment with Bu3SnH (0.02 M) and AIBN (catalytic amounts) as initiator in refluxing toluene for 12 h gave the -exo cyclization products 931 and 932 as the major products judging by H NMR of the crude product (Scheme 181) <1995TL6743>. 

The addition of an aryl radical intermediate to a pyridine featured as a key step in a total synthesis of the alkaloid toddaquinoline by Harrowven and Nunn <98TL5875, 00TL6681, 01T4447>. Thus, cyclisation of azastilbene 148 using tributyltin hydride and AIBN, led to both the desired product, toddaquinoline methyl ether 149, and an unwanted regioisomer 150 (Scheme 41). 

The Ziegler group has described a creative approach to mitomycin derivatives and the related alkaloid FR-900482 that involves use of indoles as radical acceptors (Eq. 28) [62]. The key step involves cyclization of aziridinyl bromide 98 to 99 which was carried on to (+)-desmethoxymitomycin A. This reaction surely illustrates the unusual bond constructions that can be accomplished using free-radical chemistry. Interesting approaches to other indole alkaloid substructures have been reported as illustrated in Eqs. (29) [63] and (30) [64]. The former was developed in an approach to lysergic acid while the later is a model study for the synthesis of aspidosperma alkaloids. Neither of these interesting approaches has been brought to fruition. A synthesis of carbazomycin that involves an aryl radical cyclization for construction of the C3-C3a bond of an indole has also been described [65]. 

Some examples of intermolecular addition of carbon-centred radicals, followed by -elimination of tin or sulfur radicals were provided in Schemes 4.38-4.43 and this strategy is effective in intramolecular processes. Thus, in a synthesis of the antitumor agent CC-1065, the aryl radical generated from the bromide 66 underwent cyclization and subsequent p-ehmination to give the indoline 67 (4.59). An advantage of this type of elimination procedure is that it provides a new alkene in a defined position that is suitable for further elaboration. The p-elimination of a sulfur radical has found other applications, such as in syntheses of the alkaloid morphine and the neuroexcitatory amino-acid kainic acid. ... 

Another elegant example that shows the synthetic valne of this type of reaction is the synthesis of the stmctnrally unique alkaloid (+)-scholarisine A precursor 63 (Eq. 9.14) [49]. This synthetic seqnence involves the formation of aryl radical from 61, followed by 1,5-H atom transfer to generate regioselectively the tertiary alkyl radical 62, which then adds onto the aryl group. This proposed mechanism is represented in a general way in Scheme 9.3 path C ... 

It was postulated [152, 153] that the aryl amine is oxidized by direct oxygen transfer from Compound I to the substrate. In contrast, for the oxidation of alkaloids, e.g. morphine, codeine and thebaine (Eq. 12), to the corresponding N-oxi-des by hydrogen peroxide in the presence of HRP or crude enzyme preparation from poppy seedlings, a radical mechanism was proposed [154]. 

A further alternative involved the homolytic cleavage of an aliphatic C(sp )— halide bond, for example in a-chloroacetamides, rather than an aryl C(sp )—halide bond. The radical thus formed was exploited for the synthesis of a potential precursor to vinblastine-type dimeric indole alkaloids such as 20-de-ethylcatharanthine through a radical cyclization step onto an indole skeleton [70]. 

---