Catalytic length-controlled oligomerization with synthetic programmable templates

Abstract

Nature uses templated length-controlled oligomerization to process genetic information. Templates that are DNA and RNA based and fully synthetic have also been developed for preparing unnatural oligomers. However, these reactions require stoichiometric amounts of the template for product formation. Here we report a catalytic macrocyclic template that promotes the oligomerization of a small-molecule substrate with a remarkable degree of length control. The design of the template is based on rigid oligoproline moieties decorated with catalytic sites in a defined spatial arrangement. The dimension of the macrocycle and the number of catalytic moieties determine the number of monomers that are incorporated into the growing oligomer, thus allowing access to specific products with lengths preprogrammed by the template.

Catalytic templated length-controlled oligomerization

“…Building on our catalytic length-controlled oligomerization with macrocyclic templates 21 and expertise with conjugate addition reactions using nitroolefins, [24][25][26] we started to explore addition reactions between -ketoesters and functionalized nitroolefins with p-(carboxy)-nitrostyrene (I) as initiator and p-(β-diketoester)-nitrostyrene (P) as propagator (Fig. 4a).…”

“…In our previous studies with the macrocyclic template, the interaction between the template and the substrate was significantly weaker (K a ~20 M -1 ), which agrees with other interactions observed in organocatalytic reactions. 21,28 Thus, the observed association constant is rather high and likely too strong to allow for catalytic turnover in the templated oligomerization reaction. ‡ ‡ In a methanol/water mixture, the binding is, as expected weaker, K a = 1187 ± 36 M -1 , as revealed by titration monitored with 1 H NMR spectroscopy (CD 3 OD/D 2 O = 9:1).…”

“…Templates T L 1 and T L 2 were prepared by SPPS using established procedures. 21 Initiator I was prepared from 4-carboxybenzaldehyde via a Henry reaction followed by dehydration. Propagator P was also readily available from the same starting material in 5 steps.…”

“…The peptides were prepared following previously reported procedures 21 using Fmoc-Pro-OH, Fmoc-Azp-OH (Azp) 29 and Fmoc-di-(Boc)-Gup-OH (Gup) 30,31 as individual amino-acid building blocks. Propagator P (Fig.…”

“…20 Recently, we reported the first catalytic length-controlled oligomerization. 21 Macrocyclic templates T1-T3 catalyzed the formation of oligomers through aldol-type reactions of bifunctional substrate 1 bearing aldehyde and malonic acid half thioester moieties (Fig. 1b).…”