Synthetic Tactics

Phenylacetylene chemistry allows construction of shape-persistent molecular architectures through structural control and monomer diversity.27 Combination of this method with solid-phase techniques enhances the rate at which compounds can be made, especially because automation is possible. Oligomer libraries may also be accessible using this type of chemistry. 

Catalyst levels necessary for the reactions outlined above usually do not exceed 5 mol %. Bromoiodoaryl monomers can also be used for selective displacements The iodide functionality reacts much faster than bromides.34 

Pd cross-coupling reactions Lewis acids (e.g., A1C13, BC13, TfOH) 

Procedures for the preparation of propylaminomethylated resin and the corresponding tethered monomers are found at the end of this chapter. 

The tt-propylaminomethylated tether is the best identified to date because of its versatility and ease of synthesis. Although yields tend to vary depending on the side chain, the advantage of this route is that the tether is created directly from the desired monomer thus the oligomer does not have an unsubstituted capping monomer. A protocol was developed to test that all the amino sites on the bead are converted to triazenes.15 The diazonium salt was added portionwise to the DMF-resin suspension and an aliquot was removed and quenched with diethylamine to form the 3,3-diethyltriazene. If any excess of the diazonium remained, the corresponding triazene was formed and detected by gas chromatography (GC). The reaction was complete 

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In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

An example highlighting this synthetic tactic is outlined in Scheme 3, where 4a-carbafuranoses 20, 21 and 22, 23 were the chosen target compounds [7b,c]. The opening move was the BF3-assisted vinylogous... 

The oxidative activation of arenes is a powerful and versatile synthetic tactic that enables dearomatization to give useful synthons. Central to this chemistry are hydroxylated arenes or arenols, the phenolic functions of which can be exploited to facilitate the dearomatizing process by two-electron oxidation. Suitably substituted arenols can hence be converted, with the help of oxygen- or carbon-based nucleophiles, into ortho-quinone monoketals and ortho-quinols. These 6-oxocyclohexa-2,4-dienones are ideally functionalized for the construction of many complex and polyoxygenated natural product architectures. Today, the inherent and multiple reactivity of arenol-derived ortho-quinone monoketals and ortho-quinols species is finding numerous and, in many cases, biomimetic applications in modern organic synthesis. 

Experience Matters. In every aspect of SBDD, as in all technical fields, there is no substitute for experience. Given the variety of different techniques that must be incorporated, this means that experience from several different people will be needed for optimal function of a discovery project team. Essential expertise is needed in X-ray crystallographic studies, graphical display of experimental results, initial and iterative design of compounds and synthetic tactics, the creation of databases and database queries, and the analyses of search outputs and of the results of computational simulation experiments. 

The structural dissection of the lavendamycin molecule 40 revealed a quinolinequinone (AB) and p-carboline (CDE) framework. Both these units are historically known and numerous methodologies for them have been formulated. It was therefore, hoped that the synthetic efforts towards 40 would not pose much difficulties. The synthetic tactics towards 40 revolve around the Bischler-Napieralski reaction between p-methyltryptophan and quinaldic acid to construct ring C, and in the process, bridging the two subunits. However, Roger s group preferred to extend the inverse electron demand Diels-Alder reaction, successfully demonstrated for streptonigrin, to the synthesis of lavendamycin. 

Cervinomycins (126 and 127) have captured interest as synthetic targets for organic synthesis. So far two approaches [104, 105] for the synthesis of partial structures and one total synthesis [106] of cervinomycin have been reported. At the outset, the rationale of the synthetic tactics towards these molecules was to secure an appropriate methodology for constructing the oxazolo-[3,2]-benz(o)isoquinoline skeleton. We envisioned that this moiety might be prepared in a single step from the corresponding isocoumarin (137) and ethanolamine. 

Chemical differences between imide and sulfide ligand types, however, are substantive and dictate synthetic tactics. In ionic form, N-anions are considerably more basic than sulfur anions [e.g. in DMSO PhNH2, = 30.6 PhSH, 10.3) and, when coordinated to weak-field iron, the former remain more reactive than the latter. Furthermore, redox transformations coupled to weak-field iron are much more accessible with sulfur than nitrogen. As a result, imide ligation is introduced in Scheme 5.9 by protolysis rather than the salt-metathesis or redox routes typical in Fe-S chemistry. Protolysis requires iron precursors with reactive ligands as latent bases the relative instability of these complexes forces the incorporation of imide (or equivalent N-anions) early in the synthetic sequence. 

While unable to construct successfully the core of the akuammiline scaffold, Dolby did demonstrate usefiil and successful synthetic tactics that would inspire efforts of other groups decades later as will be described below. 

The organization is along the lines of reaction type rather than functional groups. The first nine chapters discuss most of the important reactions presently in use in organic synthesis. Although the emphasis here is on synthesis, the reactions that are discussed in each chapter are usually members of related mechanistic families. Chapter 10 discusses synthetic tactics and strategy in general. Chapter 11 considers some of the special features of macromolecular synthesis. 

The use of boron as an electron-deficient atomic component of extended polycyclic aromatic structures has been realized in several unique molecular contexts. These molecular targets have refined new synthetic tactics and provided new scaffolds for applied and fundamental studies spanning physical organic chemistry and solid-state device engineering. The ability to use sophisticated organic chemistry to create atomically precise molecular fragments of boron-doped graphene... 

SCHEME 1037 Synthetic tactic of 2,7 -cyclolignan class and their correlation. 

Wishing to provide a deeper understanding of the synthetic tactics, which are used on the examples that will follow, some general guidelines on the design of a common synthetic scaffold are provided. These guidelines follow David W.C. MacMillan s tryptophan-derived monoterpene indole alkaloids syntheses as an example [39] ... 

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