Kinetic Study Of Solid Phase Organic Synthesis And Cleavage Reactions

Combinatorial chemistry, as an enabling discovery technology, was widely implemented in drug discovery and other research disciplines in the 90s of last century. Synthesis of diverse organic compound libraries on solid supports has been a key methodology in combinatorial chemistry as applied for drug discovery. One crucial component of solid-phase organic synthesis (SPOS) is the linker strategy. Various linkers, such as acid-, base-, or photo-cleavable linkers, have been developed to accommodate synthesis and the cleavage reactions. Among various linkers and cleavage strategies, the application of acid-labile linkers that are cleaved by trifluoroacetic acid (TFA) is probably the most popular approach. However, TFA is difficult to remove completely in the final products by available evaporation methods. The residual amount TFA in the product can become highly concentrated when the compound is stored as stock solution or dried compound. In the presence of TFA. compounds with acid sensitive scaffolds are degraded with time. Furthermore, TFA at a concentration of 10 to 100 nM reduced cell numbers and some research showed that the toxic effect of TFA is not specific to one cell type or to one species of origin. When the activities of the TFA and HCl were compared in osteoblasts, cell proliferation was consistently less with TFA, resulting in failure to detect a proliferative effect or wrongly attributing an antiproliferative effect. This finding indicated that TFA may cause serious false positive or false negative problems in cell-based high-throughput screening and HC1, on the other hand, is a biologically compatible reagent.In this work, we chose 18 solid phase compounds to explore the feasibility of using HC1 as an alternative in acid cleavage reactions. HC1 is very easy to remove completely from samples and it does not cause toxic effect in cell assays. In this investigation, we studied the cleavage reaction kinetics of an array of diverse compounds using single bead FTIR microspectroscopy. These compounds were linked to 2% PS-DVB resins through three commonly used linkers at different HC1 concentrations. Most compounds studied in this work can be easily cleaved using low concentration of HC1 (0.9-2.3%) and less time (60-90 min). Therefore, our kinetics studies established HC1 as a biocompatible, removable and effective substitute for TFA when final compounds are used for biological screening and drug discovery.Transform of functional groups plays an important role in organic chemistry which we often use in synthetic process. The Mitsunobu reaction is extensively used in organic synthesis under mild conditions for the functionalization of alcohols and related compounds. It is easy to purify the products than the solution-phase reactions because the phosphide can be removed by filtration from the polymer-bound products. Solid phase Mitsunobu ether formation can be used in the design and synthesis of combinatorial libraries in many different ways. However, ether formation via Mitsunobu reaction was complicated by low yields, the need for chromatographic purification made this route impractical for library generation. Besides the conditions they used are varied, it is not surprising that almost all of the solid-phase experimental protocols described to date advocate different optimal reaction conditions. Here we studied the optimized process between Wang resin and a phenol through its yields and kinetic investigation, also we applied it to a set of phenols. Finally we found that most phenols could react with Wang resin except one whose LogP is very big. Moreover we found that spatial hindrance on phenols has no effect.FTIR microspectrscopy technology has been used in monitoring solid phase organic synthesis (SPOS), it is very popular because it is very convenient, fast and simple. It can be used to determination of the presence and the loadings of functional groups and confirm the occurrence and completion of reactions on resins. It can support in shortening the solid-phase synthesis optimization time consuming in combinatorial chemistry. This technique allows the differentiation of functional groups of resin-bound compounds with minor structural differences. In this study, we have applied this technique to the determination of product identity and reaction time course on solid supports by analyzing a single resin bead.