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Synthesis 2009(2): 318-324  
DOI: 10.1055/s-0028-1083296
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Aspects of the Synthesis of an Exceptionally Preorganized Self-Immolative Spacer-Phenolate Unit

Michael Waibel, Xiao-Bing Zhang, Jens Hasserodt*
Laboratoire de Chimie, UMR CNRS 5182, Université de Lyon-ENS, 46 allée d’Italie, 69364 Lyon cedex 07, France
Fax: +33(4)72728860; e-Mail: Jens.Hasserodt@ens-lyon.fr;
Further Information

Publication History

Received 13 September 2008
Publication Date:
19 December 2008 (online)

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Abstract

This study introduces a highly preorganized self-immolative spacer that is coupled to a nonfluorescent leaving group. The water-soluble compound can rapidly liberate a water-insoluble fluorescent precipitate by intramolecular attack of a free amine on a phenolic ester group via a six-membered transition state. One of the crucial steps in the synthesis of this molecule was a sterically very unfavored nucleophilic substitution to create a tertiary ether; this was optimized using model compounds. Another key challenge was deprotection by catalytic hydrogenation at low temperatures in order to furnish the hydroacetate of the free amine without further fragmentation. LC-MS and fluorescence studies showed that this compound collapsed instantaneously in methanol, as well as within a wide pH range in buffered aqueous media.

Key words

self-immolative spacer - preorganization - tertiary ether formation - low temperature hydrogenation - fluorescence

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Permanent address: State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry & Chemical Engineering, Hunan University, Changsha 410082, P.R. of China.