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MRS Advances © 2019 Materials Research Society DOI: 10.1557/adv.2019.308

Thiol Michael-Type Reactions of Optically Active Mercapto-Acids in Aqueous Medium Makafui Y. Folikumah1,2, Axel T. Neffe1,#, Marc Behl1, Andreas Lendlein1, 2* 1 Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies, HelmholtzZentrum Geesthacht, Teltow, Germany

2

Institute of Chemistry, University of Potsdam, Potsdam-Golm, Germany

# Present address: Institute for Technical and Macromolecular Chemistry, University of Hamburg, Hamburg, Germany

*Correspondence to: Prof. Andreas Lendlein Institute of Biomaterial Science, Helmholtz-Zentrum Geesthacht, Kantstr. 55, 14513, Teltow, Germany Email: [email protected] Phone: +49 (0)3328 352-235

Abstract

Defined chemical reactions in a physiological environment are a prerequisite for the in situ synthesis of implant materials potentially serving as matrix for drug delivery systems, tissue fillers or surgical glues. ‘Click’ reactions like thiol Michael-type reactions have been successfully employed as bioorthogonal reaction. However, due to the individual stereoelectronic and physical properties of specific substrates, an exact understanding their chemical reactivity is required if they are to be used for in-situ biomaterial synthesis. The chiral (S)-2-mercapto-carboxylic acid analogues of L-phenylalanine (SH-Phe) and L-leucine (SH-Leu) which are subunits of certain collagenase sensitive synthetic peptides, were explored for their potential for in-situ biomaterial formation via the thiol Michael-type reaction.

In model reactions were investigated the kinetics, the specificity and influence of stereochemistry of this reaction. We could show that only reactions involving SH-Leu yielded

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the expected thiol-Michael product. The inability of SH-Phe to react was attributed to the steric hindrance of the bulky phenyl group. In aqueous media, successful reaction using SHLeu is thought to proceed via the sodium salt formed in-situ by the addition of NaOH solution, which was intented to aid the solubility of the mercapto-acid in water. Fast reaction rates and complete acrylate/maleimide conversion were only realized at pH 7.2 or higher suggesting the possible use of SH-Leu under physiological conditions for thiol Michael-type reactions. This method of in-situ formed alkali salts could be used as a fast approach to screen mercaptoacids for thio Michael-type reactions without the synthesis of their corresponding esters.

INTRODUCTION Generally, the term “thiol−Michael click chemistry” describes the reaction of thiol containing compounds with α,β conjugated carbonyls with high conversion rates [1]. The capability of thiol Michael-type reactions to proceed rapidly at conditions compatible tissue and the facile characterization of