Equipping 1,4,7-Triazacyclononane with Substituents via Solid-Phase Synthesis

Area of Science:

• Coordination Chemistry
• Organic Synthesis
• Materials Science

Background:

• Substituted 1,4,7-triazacyclononane (tacn) ligands are crucial in metal ion complex chemistry.
• Tacn scaffolds enable functionalization for tuning metal ion properties and adding features like light-absorbing antennas or bioconjugation groups.
• Directed synthesis of unsymmetrically substituted tacn ligands (NO(R1,R1,R2) and NO(R1,R2,R3)) is needed to fully exploit their potential.

Purpose of the Study:

• To develop a strategy for the directed synthesis of unsymmetrically substituted tacn ligands.
• To enable the preparation of tacn derivatives with two and three different substituents (R).
• To demonstrate the broad applicability of the developed synthetic strategy.

Main Methods:

• Solid-phase synthesis approach utilizing a (4-nitrophenyl carbonate)-resin.
• Loading of tacn onto the resin to form resin-bound (rb)-tacn (NO(Cbz,H,H)).
• Selective functionalization of rb-tacn with ethyl trifluoroacetate to yield rb-NO(tfAc,H) (NO(Cbz,tfAc,H)).
• Subsequent diverse reactions on the resin-bound intermediates to introduce various substituents (R1, R2, R3).

Main Results:

• A robust solid-phase synthesis strategy for assembling NO(R1,R1,H) and NO(R1,R2,H) precursors was established.
• The method demonstrated high selectivity in forming key intermediates like NO(Cbz,tfAc,H).
• A wide range of substituents were successfully introduced via nucleophilic substitution, reductive amination, aza-Michael addition, epoxide opening, and acylation reactions.
• The study identified limitations and areas for future improvement in the synthetic strategy.

Conclusions:

• The developed solid-phase synthesis strategy provides efficient access to diversely substituted tacn ligands.
• This approach facilitates the creation of complex metal ion coordination spheres with tailored functionalities.
• The methodology holds promise for advancing the design of novel metal complexes for various applications.