Polycyclic scaffolds

A central focus in modem organic synthesis has been the development of highly efficient catalytic processes for the syntheses of natural and unnatural compounds of medicinal interest or intermediates useful for functional materials. A particularly attractive approach is to apply transition metal catalysed cyclisation reactions for the transformation of simple starting materials into monocyclic, bicyclic and polycyclic scaffolds that can be further elaborated into specific targets. 

Another elimination triggered tetrafold anionic domino process has been reported by Risch and coworkers [301]. These authors synthesized polycyclic bipyridine scaffolds as 2-585 (Scheme 2.132) which are potentially useful as ligands for host-guest systems or interesting building blocks for supramolecular applications [302]. The process combines an amine elimination from 2-584 and a Michael addi-... 

Bisi, A., Gobbi, S., Rampa, A., Belluti, F., Piazzi, L., Valenti, P., Gyemant, N. and Molnar, J. (2006) New potent P-glycoprotein inhibitors carrying a polycyclic scaffold. Journal of Medicinal Chemistry, 49, 3049-3051. 

Scheme 60 Three-component synthesis of polycyclic pyrrolopiperazine scaffolds...

Lieby-Muller F, Constantieux T, Rodriguez J (2007) Highly efficient access to original polycyclic pyrrolopiperazine scaffolds by a three-component reaction with 1,3-dicarbonyls. Synlett 1323-1325... 

Schreiber and co-workers have shown that this approach is useful in the preparation of compound libraries. One of their examples is a diversity-oriented synthesis of polycyclic scaffolds through the Perrier reaction followed by the PKR of a glycal template on solid support (Equation (35)). 

The Dess-Martin periodinane 8 is also able to oxidize aromatic compounds to the corresponding quinones. The presence of water is important and, starting from anilides 42 substituted in the 2-position, the rare class of ortho-imido-quinones 43 is accessible, Scheme 21. It has been shown that compounds of type 43 are interesting building blocks and can lead to polycyclic molecules of diverse molecular architecture [95,96]. They can undergo subsequent Diels-Alder reactions and intramolecular versions have been used for a rapid access to natural products and for synthesis of scaffolds for further manipulation.para-Quinones 45 are also easily accessible, however, only in modest yields by reacting 4-sub-stituted anilines 44 under the same reaction conditions, Scheme 21 [97]. 

Some simple biphenols equipped with methyl groups, e.g., 3,3, 5,5 -tetramethyl-2,2 -biphenol 38, have attracted attention as important components of highly potent ligand systems [75-86]. Remarkably, the sustainable synthesis of such biphenols is rather challenging despite their simple scaffolds. In particular, methyl-substituted phenols are prone to side reactions. This is especially the case when 2,4-dimethyl-phenol (37) is oxidatively treated. Upon anodic conversion 37 is preferably transformed into polycyclic architectures [87]. Direct electrolysis in basic media provided only traces of the desired biphenol 38 and the dominating components of the product mixture consisted of Pu in meter s ketone 39 and the consecutive pentacyclic spiro derivative 40 [88]. For an efficient electrochemical access to 3,3, 5,5 -tetramethyl-2,2,-biphenol (38) we developed a boron-based template strategy [89, 90]. This methods requires a multi-step protocol but can be conducted on a multi-kilogram scale (Scheme 17). 

The carbolithiation of unactivated alkenes has also proven very successful for the synthesis of complex polycyclic systems. This has typically been achieved by reaction sequences utilizing an intramolecular carbolithiation process to generate a variety of carbocycles185 and heterocycles186. To achieve the intermolecular carbolithiation reaction required to initiate a controlled cascade reaction sequence for the generation of indole ring scaffold, Kessler and coworkers44 have expanded the synthetic utility of the styrene... 

Apart from the higher reactivity over their thiazolium counterparts, these triazolium salts allow not only the introduction of a second group of greater steric demand at the former unfunctionalized position of sulfur, but also the integration of the triazolium core within further stabilized bi- or polycyclic scaffolds of enhanced rigidity. Only by application of these types of catalysts ee-values greater than 90% can be... 

With the goal of producing different indoline-based functionalized polycyclic architectures and using such architectures in library generation, we developed a practical, enantio-controlled synthesis of an aminoindoline scaffold, (14) (Figure 17.7) [26]. This scaffold has several attractive features that make it extremely... 

Gan, Z., Reddy, P. T, Quevillon, S., Couve-Bonnaire, S., Arya, P. (2005) StereocontroDed solid-phase synthesis of a 90-member library of indohne-alkaloid-like polycyclics from an enantioriched aminoindoline scaffold. Angewandte Chemie, International Edition, 44, 1366-1368. 

Solution- and solid-phase, modular approaches for obtaining different natural product-hke polycyclic architectures from an aminoindoline scaffold for combinatorial chemistry. Journal of Combinatorial Chemistry, 8, 856-871. 

Cytochromes P450 that decorate cores with oxygen-based functionality are commonly found in biosynthetic pathways. For example, these enzymes hydroxylate the reduced polycyclic scaffold of the diterpene taxol and install functional groups that are required for target binding and increase its hydrophilic-ity (31). 

Polycyclic Scaffolds and Bioactive Compounds Based on Monosaccharides.. 1018... 

The generation of polycyclic systems from a monosaccharide (hybrid scaffolds) is a means of further increasing structural diversity [8,83,84,85,86,87,88,89,90,91,92,93,94,95,96]. Hirschmann, Smith and co-workers, for example, synthesised chimeric scaffolds such as 145 and 146 (O Fig. 12) that are hybrids of -D-glucopyranose and benzodiazepines and... 

Galanthamine is a natural alkaloid and a potent acetylcholinesterase inhibitor. Recognizing the potential to access this rigid polycyclic core through a biomimetic oxidative coupling/Michael addition, Shair and coworkers developed a highly efficient diversity-oriented synthesis based on this scaffold (Scheme 21.16) [96]. A library of 2527 compounds was prepared on the aforementioned macrobeads... 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

Bartlett proposed some early guidelines for library synthesis (a) The sequence should involve a small number of steps, (b) no more than one variable should be introduced in any step, (c) starting materials should be readily obtained with a diverse selection of substituents, and (d) cyclic, nonoligomeric structures represent the most interesting targets [18]. Furthermore, Armstrong did some early work toward libraries composed of multiple scaffolds, derived from common synthetic intermediates [19, 20]. In one case, Ugi multicomponent coupling reaction products were converted to various linear and cyclic derivatives (Fig. 9.1-4(a)). In another, squaric acid was proposed as a precursor that could be converted to multiple cyclic and polycyclic products (Fig. 9.1-4(b)) and several such transformations were demonstrated. 

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