Solid-phase synthesis types

Certain types of molecules, especially polypeptides and polynucleotides, lend themselves to synthesis on solid supports. In such syntheses, the starting material is attached to a small particle (bead) or a surface and the molecule remains attached during the course of the synthetic sequence. Solid phase synthesis also plays a key role in creation of combinatorial libraries, that is, collections of many molecules synthesized by a sequence of reactions in which the subunits are systematically varied to create a range of structures (molecular diversity). 

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... 

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... 

This aldol condensation is assumed to proceed via nucleophilic addition of a ruthenium enolate intermediate to the corresponding carbonyl compound, followed by protonation of the resultant alkoxide with the G-H acidic starting nitrile, hence regenerating the catalyst and releasing the aldol adduct, which can easily dehydrate to afford the desired a,/3-unsaturated nitriles 157 in almost quantitative yields. Another example of this reaction type was reported by Lin and co-workers,352 whereas an application to solid-phase synthesis with polymer-supported nitriles has been published only recently.353... 

Scheme 2.9 Solid-phase synthesis of an H-type 2 blood group determinant.

Scheme 5.2 (a) Monosaccharide building blocks 1-3 selected for solid phase synthesis of heptasaccharide 16 (b) attachment of the first carbohydrate onto phenolic polystyrene through a new photocleavable o-nitrobenzyl-type linker29 (Bn = benzyl, Bz = benzoyl, Fmoc = 9-fluoromethyloxycarbonyl, Ph = phenyl, py = pyridine, TBDPS =t-butyldiphenylsilyl). 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

For such an integrated research activity, differently modified peptides and proteins that carry modifications whose structure can be changed at will through synthesis are invaluable tools. Therefore, the synthesis of the lipidated peptides is an important theme. Lipidated peptides can typically not be accessed via standardized peptide synthesis methods. However, employing the synthetic tools developed and presented here, most types of lipidated peptides can now be synthesized and obtained in pure form. Even though solution-phase approaches still play a significant role in the synthesis of lipidated peptides, the recently developed solid-phase synthesis methods delineate the preferred strategy to access the majority of the required lipidated peptides. 

More recently, the Pam amino acid chimera has also been incorporated into a small j0j0a-motif peptide scaffold [28]. The family of BBA peptides was developed in our laboratory as structured platforms for the design of functional motifs. These motifs are attractive because they are small enough (23 residues) to be easily synthesized by standard solid phase synthesis methods. Additionally, the motifs appear to possess sufficient structural complexity to influence coenzyme properties while still being amenable to structural characterization by standard spectroscopic techniques [3, 29, 30]. The BBA peptides include a -hairpin domain with a type IT turn connected by a loop region to an a-heli-cal domain (Fig. 10). Packing of the sheet and helix against one another is accomplished by hydrophobic contacts created by a hydrophobic core of residues. 

Several different support materials have proven useful for solid-phase organic synthesis, but not all materials are compatible with all types of solvents and reagents. Therefore, for each application the proper type of support has to be selected. Some review articles on supports for solid-phase synthesis have recently appeared [1,9, 12-15]. 

In this section the use of polystyrene and copolymers of styrene with various cross-linking agents as supports for solid-phase organic synthesis is discussed. Copolymers of styrene with divinylbenzene are the most common supports for solid-phase synthesis. Depending on the kind of additives used during the polymerization and on the styrene/divinylbenzene ratio, various different types of polystyrene can be prepared. However, non-cross-linked polystyrene has also been used as a support for organic synthesis [10,16-22], Linear, non-cross-linked polystyrene is soluble in organic solvents such as toluene, pyridine, ethyl acetate, THF, chloroform, or DCM, even at low temperatures, but can be selectively precipitated by the addition of methanol or water. 

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