Automated solid-phase synthesis

DeWitt SH, Schroeder MC, Stankovic CJ, Czarnik AW, Diversomer technology solid phase synthesis, automation, and integration for the generation of chemical diversity, Drug. Dev. Res., 33 116-124, 1994. 

Combinatorial chemistry Library Microarray Solid-phase synthesis Automated synthesis Polymer-supported solution synthesis Tag-assisted solution synthesis High-throughput synthesis... 

One widely used method involving protected compounds is solid-phase synthesis (polymer-supponed reagents). This method has the advantage of requiring only a simple workup by filtration such as in automated syntheses, especially of polypeptides, oligonucleotides, and oligosaccharides. 

Substituted 4-aryl-1 -oxo-1,2-dihydropyrazino[l, 2-i]isoquinolinium salts 402 were obtained when 3-substituted isoquinolines 401 were cleaved from a polymer by treatment 25% TFA (00MIP5). c/i-3,lla-H-3-Phenyl-1,2,3,4,11,11 fl-hexahydropyrazino[l, 2-i]isoquinoline-1,4-dione (404) formed when isoquinoline derivative 403 was cleaved from a resin with 25% TFA during an automated solid-phase synthesis (98BMCL2369). 

Fig. 10 Liberty (CEM Corporation), the first automated microwave solid-phase peptide synthesizer, is shown on the left-, the available reaction vessel setup for solid-phase synthesis is depicted on the right...

The techniques for automated solid phase synthesis were first highly developed for polypeptides and the method is abbreviated as SPPS. Polypeptide synthesis requires the sequential coupling of the individual amino acids. After each unit is added, it must be deprotected for use in the next coupling step. 

Synthetic oligonucleotides are very important tools in the study and manipulation of DNA, including such techniques as site-directed mutagenesis and DNA amplification by the polymerase chain reaction. The techniques for chemical synthesis of oligonucleotides are highly developed. Very efficient automated methodologies based on solid phase synthesis are used extensively in fields that depend on the availability of defined DNA sequences.52... 

Scheme 13.79. Protocol for Automated Solid-Phase Synthesis of Oligonucleotides5...

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

The application of solid-phase synthesis and automation has revolutionized much of the chemical and biochemical research related to peptides and nucleic acids.5 Thus, it is likely that successful methods to synthesize oligosaccharides and glycoconjugates... 

Other fields using short monolithic units are solid phase synthesis and combinatorial chemistry. Hird et al. [102] predicted that having a single polymer particulate block of porous polymer or monolith would allow the optimization of automation in the field of solid phase (combinatorial) synthesis. They have developed a method for the preparation of monolithic rods, which were then cut into discs of 1.0 to 2.5 mm thickness and used for solid phase synthesis. They... 

In general, solid-phase synthesis, rather than solution-phase synthesis, can be the preferred method for the generation of combinatorial libraries because of the greater abihty to automate a solid-phase protocol, primarily due to the use of excess reagents in solution to effect cleaner reactions and to the ease of workup by simple filtration. The solid-phase method of peptide synthesis has had many notable successes. However, the preparation of peptides containing more than 20 amino acids in length using the solid-phase technique often causes major problems in that very extensive purification of the final product is needed. 

The techniques for automated solid-phase synthesis were first highly developed for polypeptides. Polypeptide synthesis requires the sequential coupling of the individual amino acids. 

Scheme 13.55. Automated Solid-Phase Synthesis at Oligonucleotides ...

The utility of solid-phase synthesis for rapid generation of libraries of small molecules is unquestionable and this technique is particularly amenable to automation. It is not surprising then that the 1,3-dipolar cycloaddition reactions of nitrones have been applied to solid-phase synthesis, either through a supported... 

Plante, O.J. Palmacci, E.R. Seebo-go-, P.H. (2001) Automated solid-phase synthesis of oligosaccharides. Science, 291, 1523-7. 

Several synthetic methods are available for the preparation of Fc peptide conjugates, of which the active ester method is most compatible with biological environments.41 This method works under mild conditions with an isolable FcCO-active ester, in which reactive heterocyclic isolable esters are formed. These can be isolated or reacted in situ with suitable peptides to give the desired Fc-peptide conjugate. These active esters can be used as stoichiometric Fc delivery reagents, which make them suitable for automated solid-phase synthesis of Fc-peptide conjugates. 

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