Kinetics Study Of Mitsunobu Reaction On Resin Supports

Combinatorial chemistry was widely implemented in drug discovery and other research disciplines in the 90s of last century.It is a technique by which large numbers of structurally distinct molecules may be synthesized in a time and submitted for pharmacological assay.The combinatorial strategies have also been utilized in other scientific areas such as material science,catalysts,and biosynthesis.The application of new techniques has promoted the development in future.Both solid phase and solution phase synthetic methods are used for combinatorial chemistry.To date nearly the half of combinatorial libraries have been assembled by solid phase organic synthesis(SPOS).Solid phase organic synthesis(SPOS) has advantages in several key aspects such as the realization of true combinatorial synthesis(such as split synthesis),the ease of reaction workup and automation,and the use of a large excess of reagent to drive a reaction nearly to completion without the requirement of purification.To realize this advantage,the reactions should go to completion in each step,preferably at a high rate.It is important to consider the efficiency and kinetics of the intended reaction on the resin support when selecting a resin for library synthesis.A better understanding of the effect on reaction kinetics by the currently used solid supports would aid in their applications in SPOS and combinatorial chemistry.In solution,the Mitsunobu reaction has gained wide acceptance in organic synthesis because of its effectiveness and versatility.This mild reaction converts a hydroxyl group into a potent leaving group that is able to be displaced by a wide variety of nucleophiles.However,the purification of reaction products from reagents and byproducts remains a major challenge.Solid phase Mitsunobu reaction has also been applied in libraries synthesis.We noticed that the reaction conditions employed in those syntheses are not consistent and the kinetics and mechanism of solid-phase Mitsunobu reaction have not been reported.As part of our efforts to optimize SPOS,we set to investigate solid-phase Mitsunobu reaction kinetics and optimize the reaction.We aimed to investigate the effects of various reaction conditions on the reaction kinetics, intermediates,and side reactions,not focus on cleaving the final products in the current study.To simplify the procedures,we skipped the linker step and directly used Wang resin as an alcohol reactant for such investigations. Thirteen solid-phase Mitsunobu esterification reactions proceeded at rates between 2.5×10^-3 and 19×10^-3 s^-1,while five etherification reactions at generally slower rates between 3.3×10^-3 and 8.9×10^-3s^-1.We discovered that reaction rates,as in solution phase Mitsunobu reactions,linearly correlated to pKa values of acids and phenols used in the reaction.By studying side reactions and intermediates,we found that the solid-phase reaction mechanism also bears remarkable similarities to that of solution phase Mitsunobu reaction.It is the first study of kinetics and mechanism of Mitsunobu reaction on solid supports.The optimized reaction conditions and the better understanding of the reaction kinetics and mechanisms have provided valuable information for organic synthesis and combinatorial or diversity-oriented synthesis on resin supports.