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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010A Double Heteroatom Mitsunobu Coupling with AminoHydroxybenzoic Acids on Solid Phase: A Novel Application ofthe Mitsunobu Reaction to Form Dendron Building BlocksTzachi Shalit 1,2 , Amnon Albeck 2 , and Gary Gellerman 1*1 Department of Biological Chemistry, Ariel University Center of Samaria, Ariel, Israel;2 Department of Chemistry, Bar-Ilan University, Ramat Gan, IsraelIntroductionA new highly efficient double heteroatom Mitsunobu coupling with amino hydroxybenzoicacids on solid phase is described. We previously reported the synthesis of twotypes of bi-functional dendron building blocks (BB) from phenolic templates via doubleMitsunobu reaction for convergent dendrimer growth on solid support [1]. This work is anovel and extended aspect of double heteroatom Mitsunobu coupling on solid phase forforming dendron building blocks containing an aminohydroxybenzoic acid core. Thesynthetic routes reported in this work are general and applicable for the preparation ofdiverse building blocks, controlling protection, arm length, chirality and peripheralfunctional groups. These novel units can form unusual dendritic architectures by solidphase chemistry, which may be incorporated into specific complex structures expandingthe scope of dendrimer science.Results and DiscussionDendrimers are polymeric molecules with many arms emanating radially from a centralcore. A high degree of structural symmetry and a defined number of terminal groupsrendering at the surface are important features of the dendritic architecture. Depending ontheir generation or order, dendrons not only have an impact on the backbone conformationand flexibility but also introduce a large number of functional groups at the periphery. Thecombination of these features creates an environment within the dendrimer molecule,which facilitates new discoveries in many important research areas such as Material andBiomedical Sciences [2]. However, most dendronized polymers known today areconstructed from symmetrical dendron building blocks and carry only one kind offunctional group, usually either amine or hydroxyl [3], which limits the choices for“surface” engineering. For increasing the options for surface chemical derivatization andbranching capabilities, and therefore of dendrimers, we decided to develop a shortsynthesis for novel heteroatom dendron building blocks "around" a benzoic acid core.Coupling sites other than classical hydroxyl group can provide dendrons with extendedtunable physico-chemical properties of the dendrimers. We did not find in the literatureany direct Mitsunobu coupling to the amine group, most probably due to its insufficientacidity, although Iranpoor et al. reported facile N-alkylation of aromatic amines with 1 oand 2 o alcohols using triphenylphosphine (PPh 3 ) and 2,3-dichloro-5,6-dicyanobenzoquinone(DDQ) [4]. Our key hypothesis is based on the possible sufficient acidity of amineprotons on the aminobenzoic acid core to enable Mitsunobu coupling, due to the presenceof electron withdrawing (EW) carboxyester group on the benzene ring. Solid phasesynthesis was chosen as our synthetic method, being advantageous over solutionchemistry, mostly because of higher yields and avoiding problems associated withpurification. Initially we have reacted Alloc protected 3-aminopropanol with preloaded4-aminobenzoic acid 1 on acid sensitive Cl-Trt resin (Scheme 1), to examine whether theNHAllocClHO2C7= Chlorotrityl resinNH2NMM, DMFOONH 21. HONHAllocHNCO 2 H2a (92%)Scheme 1. Mono-MitsunobuScheme 1: mono-Mitsunobusolid phasesolidsynthesisphase synthesisof 4-aminobenzoicof 4-aminobenzoicacidacid2a.2a1(1) triphenylphosphine,DBAD, DCM, rt;(2) 3% TFA/DCM224