Solution phase synthesis methods

Kim et al. have developed a solution-phase synthesis method of ultralarge GO sheets involving pre-exfoliation of graphite flakes. Such large GO sheets spontaneously form lyotropic nematic phase at a very low concentration in water [125]. They produced self-assembled brick-Uke GO nanostmctures by simple casting of GO dispersions and drying in ambient conditions. These free-standing GO papers... 

A solution-phase synthesis method to highly active Pt-Co/C electrocatalysts for proton exchange membrane fuel cell. Journal of Power Sources, 195 (9), 2534-2540. 

The environment in the swollen 1% cross-linked bead is substantially like a solution of linear polymer with no evidence for a fundamental resin-caused physical limitation to the solid-phase synthesis method. 

Combinatorial chemistry and parallel synthesis are now the dominant methods of compound synthesis at the lead discovery stage [2]. The method of chemistry synthesis is important because it dictates compound physical form and therefore compound aqueous solubility. As the volume of chemistry synthetic output increases due to combinatorial chemistry and parallel synthesis, there is an increasing probability that resultant chemistry physical form will be amorphous or a neat material of indeterminate solid appearance. There are two major styles of combinatorial chemistry - solid-phase and solution-phase synthesis. There is some uncertainty as to the true relative contribution of each method to chemistry output in the pharmaceutical/biotechnology industry. Published reviews of combinatorial library synthesis suggest that solid-phase synthesis is currently the dominant style contributing to about 80% of combinatorial libraries [3]. In solid-phase synthesis the mode of synthesis dictates that relatively small quantitities of compounds are made. 

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. 

Solution-phase synthesis [5] often needs purification or clean-up procedures after each reaction step to remove excess reagent. These methods include scavenging, extractions and associated plate transfers. All these procedures cause the loss of the desired compound. Although the purity can be improved after treatment, the chemical yield is seriously compromised. In contrast, SPOS has a unique advantage in purifying bound compound without losing compound mass. However, if the reaction is not complete at each step, the side products will form on resin and they cannot be removed while bound to the resin. The final yield and purity wiU both suffer as a result. A 90% yield for a four-step synthesis wiU produce the final product in a disappointing 65% yield. 

Two general methods are used to build a library of compounds by the general techniques of combinatorial chemistry solid-phase synthesis (SPS) and solution-phase synthesis. 

Although it uses an all-liquid environment, like traditional procedures, the methods of solution-phase synthesis (also called parallel synthesis or multiple parallel synthesis ) are distinct. The difference is illustrated below. 

The use of scavenger resins in solution-phase synthesis illustrates a type of procedure that is actually a hybrid between solution-phase and solid-phase methods. The first step of this procedure is clearly a form of solution-phase synthesis since the reactions take place totally within a dissolved state with no solid support provided for any of the reactants. The separation stage of the process occurs only after products have become attached to solid supports—the scavenger resins—from which they may or may not then be removed. 

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. 

Monitoring reaction progress throughout a multistep synthesis is a relatively difficult task.22 Typical methods used for solution-phase synthesis, including thin-layer chromatography (TLC), GC, and most types of mass spectrometry (MS), are less informative for solid-phase methods. However, Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance (NMR) are particularly useful in solid-phase strategies. 

During the early part of this decade, most efforts in high-throughput synthesis utilized solid phase organic synthesis (SPOS) techniques.1-3 SPOS was a natural outgrowth of earlier methods used to synthesize peptides and oligonucleotides.4 This method has several advantages over traditional solution-phase synthesis ... 

Polymer-assisted solution-phase synthesis offers strategies for chemical library construction that complement solid-phase methods. Tools now available include chemoselective sequestering resins, bifunctional solution-phase linking reagents, bifunctional chemically tagged reagents, and an... 

Xu, W. Mohan, R. Morrissey, M. M. Polymer Supported Bases in Solution-Phase Synthesis. 2. A Convenient Method for /V-Alkylation Reactions of Weakly Acidic Heterocycles, Bioorg. Med. Chem. Lett. 1998, 8, 1089. 

One major drawback of the current methods is the low atom economy45 of solid-supported chemistry with conventional resins in comparison to solution-phase synthesis. The low loadings are one important reason for excluding solid-supported methods from many resource-and cost-sensitive applications such as scale-up projects. Furthermore, polystyrene-based resins are restricted by solvent compatibility, thermal and chemical stability, and extensive adsorption of reagents. 

During the past few years, polymer-assisted solution-phase synthesis has become the prevalent method for the parallel synthesis of chemical libraries as confirmed by the increasing number of publications and reviews on the subject.16-29 A key step in the parallel solution-phase combinatorial... 

An alternative procedure for the solution-phase preparation of 1,4-benzodiaze-pine-2,5-diones was reported by Hulme et al. [85]. This method combines the UDC strategy and the use of the convertible 1-isocyano-l-cyclohexene 1. The Ugi-4CR between 1, N-Boc-protected anthranilic acids, amines, and aldehydes afforded the N-Boc-protected Ugi adducts 150 which, on treatment with HCl/MeOH or 10% TFA in DCE underwent N-deprotection, cyclohexenamide cleavage, and cydi-zation to the desired l,4-benzodiazepine-2,5-diones 151 (Scheme 2.55). Hulme and Cherrier [74a] reported another high-yield one-pot solution-phase synthesis of 1,4-benzodiazepine-2,5-diones that used ethyl glyoxylate in a Ugi-4CR to give 152 and then 153 (Scheme 2.55). 

Solution-phase synthesis has both advantages and disadvantages over solid-phase synthesis, and the preferred approach in a particular case will depend on a variety of considerations. Solution-phase expertise is currently the stock-in-trade of most synthetic organic chemists and much of the wealth of developed reactions is potentially available for combinatorial work. Whilst solution-phase reaction development has often been employed prior to transfer to solid phase, it occupies an important position in its own right in the combinatorial armoury. Solution-phase work is free from a number of the chemical constraints which currently limit the general application of solid-phase methods, but has clear disadvantages with respect to purification of products and pool generation. 

The use of supported reagents offers an attractive option for improving the quality of products prepared using solution-phase chemistry. Additionally, liquid-phase synthesis, for example using PEG, provides opportunities to combine some of the benefits of solid-phase approaches with the versatility of solution-phase synthesis. Smart methods such as resin capture for isolating specific compounds from mixtures of products will also help to increase the utility of solution-based approaches. This chapter encompasses developments in each of these areas. 

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