Solid phase heterocyclic compounds

For more than two decades, most developments in solid-phase chemistry were focussed on the preparation of biopolymers. Only in recent years has interest in other synthetic targets, including heterocyclic compounds, begun to grow. Today, the field of solid-phase heterocyclic chemistry is rapidly expanding, and numerous preparations have been reported. 

Unloaded silica does not recover HPA from aqueous solution. The surface of silica gel modified with quarternary ammonium salts (QAS) gets anion-exchange properties. The aim of the work is the elaboration of solid-phase reagents on the base of ion associate of HPA with QAS immobilized onto silica surface for the determination of phosphoms and organic reductants. Heterocyclic (safranine and lucigenine) and aliphatic (trinonyloctadecyl ammonium iodide and tetradecyl ammonium nitrate) compounds have been examined as QAS. 

A new solid phase method to synthesize libraries of compounds based on 1,2,5-thiadiazolidine heterocycle was developed (00TL(41)3161). Starting from the coupling of the protected aminoacid to the resine functionalized with p-alkoxybenzylalcohol as the linker, a series of sulfahydantoins 251 could be obtained. The method is applicable to aminoacids with a basic side chain, aliphatic aldehydes or aldehydes with basic functionalities. 

The interstellar dust was shown to contain quinone derivatives as well as oxygen-rich condensed aromatic compounds the quinones were present in both hydrated and carboxylated form. Very little nitrogen was present in the compounds detected. The cometary material, however, contained condensed nitrogen heterocycles. Hardly any oxygen was detected in the solid phase of the cometary dust it possibly evaporates from the tail of the comet in the form of water or oxidized carbon compounds. The authors assume that these analytical results could lead to a reconsideration of the current biogenesis models (Kissel et al 2004 Brownlee, 2004). 

Various heterocyclic structures, among them 3-substituted-hexahydro-277-pyrimido[l,2- ]pyrimidin-2-ones 190, have been prepared by solid-phase synthesis. The acetates 187 were reacted with diaminoalkanes, the resulting diamines 188 cyclized with BrCN to the monocyclic compounds 189, which were cleaved and cyclized with Et3N to give 190 (Scheme 30) <2005TL5289>. 

Chemical libraries of /3-turn mimetics, among them highly saturated pyrazino[l,2-tf]pyrazines, were synthesized and patented as biologically useful compounds <2001W02001/000210>. Solid-phase syntheses starting from substituted a,/3-unsaturated ester templates provided differently substituted saturated heterocyclic systems, among them saturated 2,4,8-trisubstituted-pyrazino[l,2- ]pyrazine-l,6-diones <2003W02003/013740>. 

Due to the importance of this heterocycle in medicinal chemistry, solid-phase synthesis of derivatives based on this condensation reaction have been investigated. The first report in this area uses a sodium benzenesulfinate resin 247 and gives access in five steps and good overall yields to a library of imidazo[l,2- ]pyridines 248 functionalized at C-2 with an enone moiety <2002OL3935>. Later on, the preparation of libraries of compounds related to 250 or 251 from Rink amide resin 249 have been published (Scheme 68) <2003TL6265>. 

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... 

The few thiophene syntheses reported in which the formation of the heterocycle is realized on an insoluble support (Entries 1-3, Table 15.10) are based on the intramolecular addition of C,H-acidic compounds to nitriles (Thorpe-Ziegler reaction), or on the Gewald thiophene synthesis. The mechanism of these cyclizations is outlined in Figure 15.6. In thiophene preparations performed on solid phase, the required a-(cya-... 

Other known oligonucleotide analogs include oligomers in which the heterocyclic bases have been modified [155] or replaced by other types of compound [156], Solid-phase syntheses of hybrids of DNA with peptides [157-163], with carbohydrates [164,165], and with PNA (peptide nucleic acids, see Section 16.4.1.2 [166-168]) have also been reported, and several strategies have been developed that enable the preparation of oligonucleotides with a modified 5 - or 3 -terminus [169-174] or of cyclic oligonucleotides [122,175], Various techniques for the parallel solid-phase synthesis of oligonucleotides have been developed for the preparation of compound libraries [176-181],... 

The first account on the carbonylation of heterocyclic compounds with metallo-dendrimers was recently reported by Lu and Alper using Rh-complexed dendrimers on a resin [207]. The building-block techniques of solid-phase chemistry were used to synthesize dendrimers, followed by phosphonation of the dendrimers with diphenylphosphinomethanol. The resulting phosphonated dendrimers were then reacted with chloro(dicarbonyl)rhodium(I) dimer to give dendritic catalysts A and B (31P NMR, 8 - 25 ppm loading of rhodium A, 0.74 mmol g-1 B, 0.83 mmol g ). As a model study, the reaction of l-ferf-butyl-2-phenylaziridine with carbon monoxide in catalytic presence of A afforded the desired [3-lactam... 

Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. In 1994, Ellman and co-workers24 reported a 192 member library of structurally diverse 1,4-benzodiazepines. These compounds were prepared on Mimotopes pins that were grafted with polyacrylic acid, the surface originally used for antibody epitope elucidation.10 Ellman and co-workers25 subsequently synthesized a 1680-member 1,4-benzodiazepine library on SynPhase Crowns that were grafted with a methacrylic acid/dimethylacrylamide copolymer, one of the first SynPhase surfaces designed for solid-phase synthesis. The synthesis was performed on a preformed linker-template system in order to avoid low aminobenzophenone incorporation in this case the HMP acid-labile linker... 

Here we illustrate selected examples of common derivatization reactions on heterocycles grafted on the solid phase. The aim is to provide a sense of the relevant factors and experimental conditions that allow application of known chemical reactions on solid supported heterocyclic substrates for the preparation of novel compounds. In industry, it is not uncommon to seek and secure novelty in a whole chemical class rather than in single derivatives. A direct route to broad coverage aims at the development of a novel heterocyclic scaffold, which in turn is derivatized with standard reactions in order to create a thematic library. The novel scaffold material may be prepared in bulk, typically in solution. Subsequently it is loaded onto a solid support, which is then appropriately portioned for multiple derivatizations in parallel. The latter may involve common reactions, but the resulting products are novel. 

Solid-Phase Synthesis of Heterocyclic Compounds from Resin-Bound Amino Acids, Short Peptides, and Polyamines... 

Fig. 2. Solid-phase synthesis of heterocyclic compounds from resin-bound amino acids.

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Nefzi A, Ostresh JM, Meyer JP, Houghten RA, Solid phase synthesis of heterocyclic compounds from linear peptides cyclic ureas and thioureas, Tetrahedron Lett., 38 931-934, 1997. 

A solid-phase Ugi-Reissert reaction on chloroformate resin, has been reported. The product, the ot-carbamoylated isoquinoline 230, is released by oxidative cleavage (Scheme 33a). Interestingly, the enamide moiety in the adduct can be exploited to perform this process in tandem with a Povarov MCR [189, 190]. In this way, by interaction of dihydroisoquinoline 231 with aldehydes, anilines and a suitable Lewis acid catalyst, the polyheterocyclic system 232 was prepared (Scheme 33b). The Zhu group devised an innovative approach for the synthesis of this class of compounds. They employed the heterocyclic amine 233, which was oxidized in situ to the dihydroisoquinoline 234 with IBX, to undergo the classic Ugi reaction. Remarkably, all the components are chemically compatible, allowing the sequence to proceed as a true MCR (Scheme 33c) [191]. 

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