Cycloadditions combinatorial libraries

By combining several click reactions, click chemistry allows for the rapid synthesis of useful new compounds of high complexity and combinatorial libraries. The 2-type reaction of the azide ion with a variety of epoxides to give azido alcohols has been exploited extensively in click chemistry. First of all, azido alcohols can be converted into amino alcohols upon reduction.70 On the other hand, aliphatic azides are quite stable toward a number of other standard organic synthesis conditions (orthogonality), but readily undergo 1,3-dipolar cycloaddition with alkynes. An example of the sequential reactions of... 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

In striking contrast with these two previous examples of 1,3-dipolar cycloaddition catalyzed by encapsulation, the EMs calculated for particular examples of Diels-Alder reactions catalyzed by Rebek s softball [25] or by Sanders [26] cyclophane, which was selected from a dynamic combinatorial library (DCL), are lower than the actual reactant concentration calculated from the volumes of the molecular cavities. Probably, the Diels-Alder reactions have more stringent orientational requirements than the 1,3-dipolar cycloaddition. The reactants of the Diels-Alder reactions, when encapsulated or included, spend a significant amount of time in ternary complexes displaying a non-productive mutual orientation. 

Cross-enyne metathesis has also been applied to solid-phase synthesis by immobilizing either the alkyne or the alkene (498,499). By combination with a Diels-Alder reaction, this process has been used to create a combinatorial library of various six-membered ring structures (500). Within this theme, intermolecular enyne metathesis is the integral synthetic method used to produce novel amino acid derivatives (501, 502). To this end, the aromatic ring of highly substituted phenylalanines was synthesized through enyne crossmetathesis and cycloaddition. 

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. 

A variety of heterocyclic compounds have been derived from the condensation of aldehydes with a-amino acids. Imines 1 (Fig. 3) are often used as intermediates in organic synthesis and are the starting point for chemical reactions such as cycloadditions, condensation reactions, and nucleophilic additions. The formation of imines via condensation of amines with aldehydes was first adopted for the reductive alkylation of resin-bound amino acids [29-31]. Imines have now been used as synthetic intermediates in the generation of a range of heterocyclic combinatorial libraries. 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

To further illustrate the utility of this solid-phase synthesis, a small (32 member) combinatorial library of furans was generated via split synthesis by using the stepwise cycloaddition sequence. From eight carboxylic acids, two malonyl chlorides and two acetylenes, a library of four pools comprising eight compounds each was synthesised. 

The cycloaddition reaction proceeds by heating the 2-azidomethyl-3-cyanopyridines 300 in toluene to 130-140 °C for 90 h. Those structures could serve as a template for combinatorial libraries. 

The transition state of Diels-Alder reaction of diene 56 with dienophile 57 to give the adduct 58 (Scheme 5.14) is a boat-like type. The antibody 39-Al 1, generated to the bicy-clo [2.2.2 ] octane hapten 59 that mimics the transition state of the reaction, efficaciously catalyzed the cycloaddition, selectively giving 58 in buffered aqueous medium (Scheme 5.14). ° Ribozymes are RNA molecules with catalytic properties. Artificial ribozymes, isolated fi om synthetic combinatorial libraries, accelerate a broad range of reactions including the Diels-Alder cycloaddition. These ribozymes generally require that at least one of the reactants be RNA or be covalently tethered to RNA. 

Fig. 5 Combinatorial synthesis of triazolylcoumarin library using Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction. Each letter represents the relative fluorescence intensities H High, M Middle, L Low. The excitation and emission spectra were recorded in DMF. Reproduced with permission from reference [45]... 

A library of fifteen 6,7,9,9a-tetrahydro-57/-pyrazolo[l,2-tf]pyrrolo[3,4-ir]pyrazole-l,3,5(2/7,3a7/)-triones 712 was prepared by combinatorial stereoselective cycloadditions of compounds 320 to A-substituted maleimides. 

Combinatorial solution-phase cycloadditions of (1Z,4R, 5R )-4-benzoylamino-5-phenylpyrazolidin-3-on-l-azomethine imines 320 to 3-keto esters afforded a library of 26 highly pure bicyclic pyrazolidinones 713 in 6-89% yields and in 14-100% de. Most of the products were isolated as mixtures of the major (13, 23, 3/ , 5/ , 6/ )-epimers 713 and the minor (1R, 2A, 3R, 5R, 6R )-epimers 714 (Scheme 113). Epimerization of these cycloadducts at the anomeric position in solution was confirmed by H NMR spectroscopy <2007MI717>. 

Some reactions afford mixtures of products. Mixtures include diastereomers, such as endo and exo products (10.1 and 10.2) of a Diels-Alder cycloaddition, and regioisomers, such as ortho and para products (10.3 and 10.4) from an electrophilic aromatic substitution (Scheme 10.1). Even a reaction that forms products as subtly similar as enantiomers is technically a mixture of products. Isomeric mixtures violate the spirit of one compound, one well in combinatorial chemistry. Isomeric mixtures, however, are often unavoidable and therefore tolerated in compound libraries. Mixtures are also tolerated in libraries of compounds that have been derived from natural sources. Examples include extracts from finely ground vegetation and microbial broths. 

Non-oligomeric and air- or moisture-sensitive chemistries such as cycloadditions, cyclizations, and carbanion condensations have already been successfully enabled on solid support, and some recent examples are discussed below. It is anticipated that these studies will be further extended in combinatorial formats and libraries subjected to HTS in the near future. 

Each isoxazoline subunit is built up starting from a resin-bound olefin submitted to a 1,3-dipolar cycloaddition of a nitrile oxide, followed by a selenide oxidation/elimination reaction to regenerate the olefin functionality [69]. Using different nitroseleno ethers and nitroalkanes, a library of triisoxazolines has been prepared and characterized by mass spectrometry. This flexible method to create heterocyclic oligomers via C-C bond ring closure is then versatile to combinatorial syntheses. 

---