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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