Solid-Support Synthesis

At the time of writing this book, SPOS is in an area of reladve infancy but has considerable potential. One of the main difficulties in SPOS lies in the lack of techniques available to monitor reacdons carried out on polymer supports. Unlike reacdons in solution phase, reactions on solid support cannot be monitored with relative ease and this has hindered the progress as well as the efficacy of solid supported synthesis of small non-peptidic molecules. Despite these difficulties, a large body of studies is available for SPOS. Recent reviews incorporate... 

Solid phase synthesis is a polymer-supported or solid-supported synthesis, i.e., stepwise construction of product molecules attached to an insoluble organic or inorganic polymer. 

The microwave-assisted solid-supported synthesis of 1,3,4-thiadiazoles was described applying from acid and thiosemicarbazide on acidic aliunina... 

Collioud, A., Clemence, J.-F., Sanger, M., and Sigrist, H. (1993) Oriented and covalent immobilization of target molecules to solid supports Synthesis and application of a light-activatable and thiol-reactive cross-linking reagent. Bioconjugate Chem. 4, 528-536. 

In another application, the group of Berteina-Raboin demonstrated the solid-supported synthesis of the indole core of melatonin analogues under microwave irradiation (Scheme 7.6) [26]. A benzoic acid derivative was coupled to Rink amide resin by... 

A very interesting approach toward solid-supported synthesis under microwave heating was introduced by Chandrasekhar and coworkers [64], The authors developed a synthesis of N-alkyl imides on a solid phase under solvent-free conditions employing tantalum(V) chloride-doped silica gel as a Lewis acid catalyst (Scheme 7.53). 

Table 36 Solid-supported synthesis of 1,2,4-triazole derivatives (Scheme 16)... 

William Fraser was born in Hamilton. He studied at the other of the two local universities, Strathclyde, where he obtained a first class B.Sc. honors degree in 1986 and Ph.D. in 1989 under the direction of Professor Colin J. Suckling and Professor Hamish C. S. Wood. He was awarded a Royal Society European Exchange Postdoctoral Fellowship and worked in the laboratories of Professor Albert Eschenmoser at the ETH, Zurich. In 1991, he took up his present position as lecturer in medicinal chemistry at Aston University, Birmingham. His scientific interests include nucleoside and nucleic acid chemistry, solid-supported, synthesis, and study of base-modified antigene oligonucleotides targeted to DNA. 

The Glycal Assembly Method on Solid Supports Synthesis of Oligosaccharides and Glycoconjugates... 

Solid-supported Synthesis and Solution - Solution Manipulation... 

Among the successful linker strategies that are being developed specifically for solid-supported synthesis of small organic molecules, the safety catch principle has become one of the most important approaches. Safety catch linker strategies... 

Scheme 3.37 Solid-supported synthesis of diarylpyridines (291) by Katritzky et al [385],...

Scheme 3.40 Solid-supported synthesis of dihydroimiddazolyidihydroquinoxali-nones (331) by Houghten et al. [452].

Golebiowski A, Jozwik J, Klopfenstein SR, Colson AO, Grieb AL, Russell AF, Rastogi VL, Diven CP, Portlock DE, Chen JJ (2002) Solid-supported synthesis of putative peptide P-tum mimetics via Ugi reaction for diketopiperazine formation. J Comb Chem 4 584—590... 

A bicyclic diketopiperazine 159 as a potential peptide (3-tum mimetic was developed via solid-supported synthesis [51]. The Ugi reaction among the resin... 

Golebiowski A, Klopfenstein SR, Shao X, Chen JJ, Colson A-O, Grieb AL, Russell AF (2000) Solid-supported synthesis of a peptide (3-tum mimetic. Org Lett 2(17) 2615-2617... 

A very interesting approach to the solid-supported synthesis of hydroxamic acids was developed by Golebiowski and Klopfenstein . It employs an oxime resin (Kaiser resin) 171d and, unlike all previouxsly reported methods, allows the use of acid-labile protecting... 

Yun, W. Mohan, R. Heck Reaction on Solid Support Synthesis of Indole Analogs, Tetrahedron Lett. 1996, 37, 7189-7192. 

The Gabriel-Cromwell reaction of amines with chiral c/., 3-unsaturated a-bromo carbonyl compounds was exploited for the synthesis of aziridine-2-carboxylic acid derivatives. 79 This procedure was optimized for a solid support synthesis in which the peptide resin was acylated with 2,3-dibromopropanoic acid active ester in the presence of 3 equivalents of NMM to produce directly on resin the a-bromoacrylamide for the addition of amines to produce the aziridine ring. 80 ... 

The above described methodology was found to be very useful in a solid-supported synthesis of pyrazoles and pyrimidines via propenones developed by Westman and co-workers35 (Scheme 5.19). Merrifield resin was reacted with methylamine in water at 150°C for 10 min to form the solid-supported benzylmethylamine (3) in high yield (86% yield, 1.08 mmol/g based on elemental analysis). After washing, the resin was treated with 5 equiv. DMFDEA and 5 equiv of 4-phenoxyacetophenone at 180°C for 10 min in DMF to form the solid supported benzyl methyl aminopropenones (4). 

Scheme 7.30 High pressure promoted solid-supported synthesis of nitroso acetals (yields quoted are after reductive cleavage).

Further applications for the preparation of jfi-turn mimetics have also been reported by Martens et al. with the synthesis of pipecolic acid derivatives 88 (presumably proceeding via a cyclic Schiff base - not a true post-condensation modification ) [74] and Golebiowski and co-workers who have reported the solid-supported synthesis of bicyclic diketopiperazines with the generic structure 89, via the multi-step synthesis shown in Scheme 11.18 [75]. 

Resins for solid-support synthesis can be obtained from Rapp-Polymere (Germany), Novabiochem (USA), Advanced ChemTech (USA), Chemlmpex, and other suppliers. 

The most important characteristics that make fluorous synthesis superior to solid-supported synthesis is the favorable reaction kinetics associated with the solution-phase reactions. Comparison reactions using fluorous vs. solid-supported thiols to scavenge a bromide are shown in Fig. 1 [16]. Using 1.5equiv of F-thiol 1, more than 95% bromide was quenched in less than 40 min (top line). Under the same conditions and using 1.5 equiv PS-thiol 2, only 50% of the halide was quenched after 80 min (bottom line). By doub-... 

Scheme 9 A solid-supported synthesis via piperazine attachment.

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