Automated Synthesis Protocol of Sequence‐Defined Oligo‐Urethane‐Amides Using Thiolactone Chemistry

Abstract

An automated, iterative protocol for the synthesis of multifunctional, sequence‐defined oligo‐urethane‐amides using thiolactone chemistry is reported. Here, sequenced functionalization of the backbone is easily introduced using commercially available primary amines. The chemistry is carried out on solid phase using different supports for better optimization of the synthetic protocol and in order to demonstrate the versatility of the approach. This technique is very effective for iterative synthesis and solid‐phase chemistry and enables the exploration of full automation of this approach using a robotic peptide synthesizer. As a result, this automated protocol allows for the synthesis of a sequence‐defined nonamer of high purity.

Direct comparison of solution and solid phase synthesis of sequence-defined macromolecules

“…It can also be a time or labour-saving approach as the purification can be much faster than, for example, column chromatography and one can, in principle, automate the reactions. 7,51 For the TAD addition step, the high reactivity of TAD molecules required only 2 equivalents (notably low for solid phase synthesis, compared to other reported methods 7,25,31 ) with shaking for 5 minutes at room temperature to ensure 100% conversion, as quantified by LCMS ( Fig. S1 †).…”

“…Automation of this approach could circumvent problems with scale, as the use of a peptide-synthesiser allows up to 72 reactions to be carried out in parallel. 7,19,51 However, the small scale used in this work resulted in a limited range of characterisation techniques available to use, which could be difficult when optimising reaction conditions compared to the solution phase approach. However, as previously reported by Du Prez and coworkers, 7,31 LCMS was used to unambiguously follow the progress of the reaction after each step (see Fig.…”

“…One could potentially attribute this to human error, as it has been reported that automation introduces more consistency into iterative approaches, thus improving purity and reproducibility. 51…”

“…7 Although usually limited in scale, this approach is particularly advantageous because of simple purification by washing and the potential to automate such a method. 7,31,51 The other option is solution phase chemistry. Whilst this more scalable approach facilitates the characterisation and thus optimisation and understanding of each reaction step, purification can be more time-consuming.…”

From Sequence‐Defined Macromolecules to Macromolecular Pin Codes

“…This has resulted in the emergence of the field of sequence‐defined polymers. [ 1–9 ] While until recently, research has been mostly dedicated toward the development of synthesis routes to design sequence‐defined macromolecules, [ 1–3 ] attention is now shifting toward the potential use of these structures and their wider impact on our daily lives. [ 10,11 ] Hence, biomedical and biomimicking applications, [ 12,13 ] (bio)catalysis, [ 14 ] long‐term data storage, [ 6,11,15,16 ] and product labeling for anti‐counterfeiting purposes [ 17 ] are now all emerging.…”