Solid-phase synthesis protocol

Typical solid phase synthesis protocols were employed to assemble the tripeptide building blocks into C-link AFGP glycopolymers. The method is illustrated in Scheme 3. 

Derivatization of the C-Terminus The derivatization of glycopeptides has been performed with various amines to yield the corresponding amides. An early example is the synthesis of vancomycin propanamide, histamide, and 3-aminopropana-mide with DCC/HOBt. " Solution and solid-phase synthesis protocols were developed to yield similar derivatives as mentioned above, but also C-terminally elongated nonapeptide and decapeptide derivatives have been obtained. The glycopeptide eremomycin was C-terminally converted to the methylester, the hydra-zide, some urea derivatives, and the amide along with the methylamide and the benzylamide. The latter two derivatives were more active than eremomycin. 

Although cyclization can take place in many ways, according to Kallen [11] the most preferred pathway involves imine formation followed by intramolecular cyclization. During the course of cyclization a new chiral center at C-2 is created thereby giving rise to a diastereomeric mixture namely 2R, 4R and 2S, 4R. An interesting situation arises when the reactant aldehyde is also chiral. The stereochemistry at the newly formed center is controlled by the stereochemistry of the aldehyde [12]. In view of the biological importance of thiazolidine, Patek et al. reported a solid-phase synthesis protocol (Scheme 4) [13]. This enables the synthesis of compound libraries for quick lead optimization. 

The Suzuki-Miyaura reaction has proven useful for synthetic chemists in the formation of aryl-aiyl bonds. Benefits include generally mild reaction conditions, compatibility with most functional groups, and the use of readily available boronic acids known for their stability. In the reaction shown below, Meldal and co-workers reported a palladium-catalyzed Suzuki cross-coupling reaction of a bromothiophene using a solid-phase synthesis protocol. ... 

The use of soluble supports to generate combinatorial libraries has been reported in the literature, but complete automation for both synthesis and analysis must be effected to probe such methodology as a viable alternative to solid-phase synthesis protocols. The discussed results indicate that poly(ethylene glycol) samples could be handled under certain operation conditions as standard chemicals and subjected to high-throughput combinatorial analytical process. 

Emergence of combinatorial chemistry and parallel synthesis in early nineties and synthesis of small molecules inspired by the structural architectures of natural products in the beginning of this century called for further developments in the solid-phase synthesis protocols. Synthesis of compound libraries possessing enantiopure molecules embodying a complex framework and decorated with more than one stereocenters in a combinatorial and parallel fashion calls for highly feasible solid-phase synthesis methods." In particular, these efforts must address the stereocontrol of the reaction course in order to minimize isomer... 

Thus, an effective solid phase synthesis of aPNA 21-mers was successfully developed. The resulting SPPS protocols can be applied to aU four nucleoamino acids as well as a variety of ancillary amino acids leading to diverse aPNAs structures. 

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

One of the key steps in combinatorial solid-phase synthesis is clearly the cleavage of the desired product from the solid support. A variety of cleavage protocols have been investigated, depending on the nature of the linker employed. A complete micro-wave-assisted protocol, involving attachment of the starting material to the solid support, scaffold preparation, scaffold decoration, and cleavage of the resin-bound product, would seem desirable. 

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 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... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

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. 

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