A solid phase synthesis

At this time, a solid phase automatic peptide synthesizer was acquired, so we attempted total synthesis of Sh I. A solid phase synthesis of Ax I (antho-pleurin A) had previously been reported in an abstract (36). The synthetic Ax I possessed only 11% of the toxicity of the natural toxin. 

In aqueous DMF, the reaction can be applied to the formation of C-C bonds in a solid-phase synthesis with resin-bound iodobenzoates (Eq. 6.33).80 The reaction proceeds smoothly and leads to moderate to high yield of product under mild conditions. The optimal conditions involve the use of 9 1 mixture of DMF-water. Parsons investigated the viability of the aqueous Heck reactions under superheated conditions.81 A series of aromatic halides were coupled with styrenes under these conditions. The reaction proceeded to approximately the same degree at 400°C as at 260°C. Some 1,2-substituted alkanes can be used as alkene equivalents for the high-temperature Heck-type reaction in water.82... 

Burke TR Jr, Smyth M, Nomizu M, Otaka A, Roller PP. Preparation of fluoro- and hydroxy-4-(phosphonomethyl)-D,L-phenylalanine suitably protected for a solid-phase synthesis of peptides containing hydrolytically stable analogues of O-phosphotyrosine. J Org Chem 1993 58 1336-1340. 

Recently, a solid-phase synthesis was used iteratively for the synthesis of organic substances like oligocarbamates [13] and oligoureas [14] by repeated coupling to amino-functionalized supports. In this way substance libraries [15] have been developed showing that iterative methods can also be employed in combinatorial chemistry [16]. 

A solid-phase synthesis of pyrroloindolizines has been developed using this cycloaddition methodology, whereby an isoxazolopyrroloindolizine can be removed from the polymeric resin upon treatment with trifluoroacetic acid (TFA). This also results in ring opening of the isoxazole to give the isolated compound 210 (Scheme 58). A library of 96 such derivatives has been prepared in this way <1998TL5869>. 

A novel ring opening reaction of isoxazoles led to the formation of functionalized pyrroles <06S1021>. For example, treatment of isoxazole 52 with DBU led to the formation of pyrrole 53. A solid-phase synthesis of 3-amino-2,5-dicarboxylates was accomplished by transformation of pyrrol-3-one 54 <06JCC177>. The reaction between 54 and secondary amines led to the corresponding resin-bound aminopyrroles after enamine formation and loss... 

A solid-phase synthesis of 3-substituted isoxazoles 31 in good yields and purities was achieved by 1,3-DC of polymer-supported vinyl selenide with in situ generated nitrile oxides treatment of intermediate isoxazolines 30 with an excess of hydrogen peroxide resulted in the release of isoxazoles 31 while the use of Mel/Nal led to 3-substituted 5-iodoisoxazolines... 

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

Acylketenes, derived from Meldrum s acid, add to esters of (R)-4,5-dihydrothiazolin-4-catboxylic acid to give 81 <00OL2065>. A solid-phase synthesis of 2P-methyl substituted penam derivatives utilises a tether through an ester group <99TA3893>. 

A divergent protocol for a solid-phase synthesis of 3-substituted 2,5-biarylfurans was reported. Thus, reaction of furan zincate A with polymer bound aryl bromide or iodide provides resin intermediates 61. Subsequent bromination-Suzuki coupling reaction followed by further transformations gives rise to structurally diverse 2,3,5-trisubstituted furans 68 in good overall yields and chemical purities <00TL5447>. 

A solid-phase synthesis of substituted benzopyranoisoxazoles 356 (I R = H, Me, Et, Pr, Ph, CHMe2 R1 =H, Me, decyl, Ph) has been described (414). The six-step synthesis includes a method of generating nitrile oxides on a polymer support, followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne, for assembly of the benzopyranoisoxazole scaffold. 

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

After isolating the product of a solid phase synthesis, the support (resin + linker) is usually discarded as waste, although successful examples of its reuse in further synthetic cycles are known with trityl type linkers (Frechet and Haque 1975). To reduce both volume of operation and amount of waste, the loading of the resin (quantified as millimoles of functionality per gram) has to be increased. Besides theoretical limitations (for polystyrene this is reached when every phenyl ring is substituted by the linker), there may be practical boundaries for using highly loaded resins in solid-phase supported synthesis. This issue was studied... 

A combination of the SNAr feature and the coordination ability of a copper complex has led to the development of a new O-arylation method that makes use of a triazene as an activating and directing group (Equation (2)).32,33 This protocol, though necessitating a three-step removal sequence of the triazene moiety, has been successfully applied to the total synthesis of vancomycin1 6 and extended to a solid-phase synthesis in which the triazene unit serves as an anchor to the resin.37... 

Nefzi, A., Otresh, J.M., Giulianotti, M.A., and Houghten, R.A. Solid-phase synthesis of trisubstituted 2-imidazo-lidones and 2-imidazolidinethiones. 

The stage is then set for a solid-phase synthesis. The monomer to he used in the synthesis is added to the 96 wells in the polyethylene plate. The protecting Fmoc groups are removed from the ends of the pins, and the pins themselves are inserted into the 96 wells. At this point, the monomer in each well reacts with the exposed carhoxylate group on the end of the pin, producing the monomer-support complex (comparable to that present in the first step of resin-head-hased SPS). The 96-pin plate is then removed from the 96-well plate, and the pins are washed and reinserted into a second 96-well plate that contains the second monomer to be added. The 96-pin plate is removed, washed again, and reinserted into a third 96-well plate for the addition of a third monomer. The process is repeated as often as necessary to produce the polymers to be produced in the synthesis. 

A high yielding synthesis of anthranil from 2-nitrobenZaldehyde makes use of zinc and allyl bromide as the reducing agent. The method has also been used for the preparation of 3-substituted anthranils from 2-nitrophenyl ketones <99H(51)1921>. A solid phase synthesis of 3-aminobenzisoxazoles 15 is based on the displacement of fluoride from 2-fluorobenzonitriles by the Kaiser oxime resin and subsequent hydrolysis of the C=N bond <99JOC4547>. A synthesis of 3-(2-dialkylaminoethyl)benzisoxazoles from oximes of 2-hydroxyphenyl ketones has also been described <99H(51)2139>. ... 

A solid-phase synthesis of furo[3,2-3]pyran derivatives utilizing highly functionalized sugar templates has been reported <2003JOC9406>. After incorporation of alkenes within the sugar template, such as compound 95, the solid support is introduced via formation of the acid amide. This immobilized system then allows a ruthenium-catalyzed ring-closing metathesis that leads to the formation of the fused oxacycles. 

In a solid-phase synthesis of a,a-difluoro-/ -amino acids (equation 38), supported iV-(a-aminoalkyl)benzotriazole 59 is reacted with lc and zinc to give adducts 60 in d.e. values which depended on the steric bulkiness of the R1 group, ranging from 0 (R1 = H)... 

Drewry, D. H. Gerritz, S. W. Linn, J. A. Solid-Phase Synthesis of Trisub-stituted Guanidines, Tetrahedron Lett. 1997, 38, 3377-3380. 

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