To incorporate a TCO-anchored TDG, we hypothesized that an axial OH func=onality installed in the 5'-posi=on of a cleavable TCO could assist proton migra=on, leveraging its proximity to the bridgehead hydrogen in 4'-posi=on (distance O … H = 2.2 Å) to direct post-click tautomeriza=on to the releasing 1,4-DHP (Fig. ), a mechanism that resonates with prior observa=ons of facilitated tautomeriza=on of DHPs to accelerate the forma=on of fluorescent click products . To leverage this effect addi=onal architectural features are required (Fig. ). First, axially configured cleavable TCO-carbamates are significantly more reac=ve than their equatorial isomers, making an axial configura=on for the leaving group in allylic posi=on essen=al for fastest kine=cs. As the direc=ng OH can only assist tautomeriza=on in axial configura=on, we thus aimed for a TCO with two hydroxyl groups in axial posi=on, and thus a fixed trans stereochemical rela=onship of these func=onali=es throughout the synthesis. Finally, in addi=on to the OH func=onality in the allylic release posi=on, which is commonly used to abach the cargo via a carbamate linkage, the TCO scaffold needs to provide a modifiable moiety to serve as a cleavable linker .