Strategy Robinson approach

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The stereoselective construction of nitrogen heterocycles remains a topic of intense synthetic interest [39]. Evans and Robinson described the combination of the stereospecific aUylic amination with ring-closing metathesis as a strategy for the constmction of mono- and disubstituted azacycles, which they demonstrated with the stereospecific construction of cis- and tra s-2,5-disubstituted pyrrolines [40]. Furthermore, this approach provided an ideal system for the determination of whether the enantiospecific rhodium-catalyzed aUyhc amination with an enantiomerically enriched nucleophile experiences a matched and a mismatched reaction manifold. 

In the synthesis of occidentalol (ref. 13), a eudesmane-type compound consisting of a cis-fused decalin containing a homoannular 1,3-diene system, dihydrocarvone was converted by a typical Robinson annellation reaction to the basic reguired bicyclic structural unit. (It is of interest that a related bicyclic methyldecalenone structure, the Wieland-Miescher ketone, has been employed for the synthesis of longifolene (ref.14), copaene (ref.15) and sativene (ref.16) by three totally different strategies outside the present concept of the semi-synthetic approach). 

The same strategy, but with the opposite polarity, along with other enone approaches is illustrated by the bicyclic enone 84 needed for the synthesis of the terpene cadinene. Aldol disconnection gives the 1,5-diketone 85 which we expect to make by a Michael addition.18 Hence we require a specific enol equivalent of cyclohexanone to add to the enone 86, and we have rediscovered the Robinson annelation.19... 

Huffman and Mole have published full details of their synthetic approach to the basic eudesmane skeleton. In the past the synthetic strategy for the construction of this bicyclic ring system has been largely restricted to standard reaction sequences involving at some stage a Robinson annelation procedure. Schwartz et have now developed a new approach to this problem, culminating in the synthesis of ( )-junenol (251) as outlined in Scheme 24. From the... 

In the implementation step, researchers must decide whether the data is to be collected sequentially or concurrently. There should be a clear rationale for choosing a specific strategy that is tied to the overall goal of the study. For example, in a sequential design where the qualitative data are collected and analyzed first, the emergent understandings may be explored with a wider audience in a second quantitative phase. That was the implementation approach used in the Mulford and Robinson study (2) described above. The qualitative phase took place first and was used to develop the survey implemented in the quantitative phase of the study. 

Flavonoids are a class of widely distributed naturally occurring phenolic compounds, the most abundant being the flavones. Members of this class display a wide variety of phannacological activities and have been useful in the treatment of various diseases. Flavones have been prepared by a variety of methods such as Allan-Robinson synthesis and synthesis from hydroxychalcones via an intramolecular Wittig strategy. The most popular approach, however, involves the Baker-... 

Herein, three syntheses of morphine or related alkaloids are discussed in detail, which utilize completely different protocols for the coupling of the ring motifs of the alkaloid. Rice published a biomimetic approach with an acid-mediated electrophilic cyclization strategy as key step [144]. Mulzer employed a Friedel-Crafts acylation and a Robinson annulation to construct the phenanthrenone ring system [145]. The D ring of the alkaloid was elaborated with a 1,4-cuprate addition as key step. In his most recent contribution to morphine research, Hudlicky employed a Diels-Alder cycloaddition reaction to construct the ABCE ring system of the natural product. The requisite diene was obtained after oxidative dearomatization of the A ring precursor [146]. 

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