Helically Structured Peptide Architecture Engineered Using Dimedone as a Rigid Organic Scaffold

Abstract

This communication reports the use of a rigid organic scaffold to attach two unsymmetrical peptide chains on a single carbon atom. The approach describes the step‐by‐step attachment of peptide chains to the rigid dimedone template (5,5‐dimethyl‐1,3‐cyclohexanedione) – a molecular scaffold that directs orientation of the peptide helices in a well‐defined arrangement via intra‐molecular hydrogen bonding. The overall topology of the final molecules was studied using CD spectroscopy which suggested existence of helical architecture.

Dimedone‐Based Rigid Organic Scaffold for Organizing Symmetrical Helical Peptide Chains.

“…Similarly, trithiolane 4 was reacted with octa‐peptide amine 3 c furnishing dimedone‐tethered peptide 5 a . Plausible mechanism of formation of dimedone‐tethered peptide derivatives 5 a‐c has been discussed in our previous report . By utilizing this synthetic strategy further, dimedone‐tethered higher oligopeptides 5 b and 5 c are obtained in excellent yield, as shown in scheme .…”

“…Peptides Boc‐L–Leu‐Aib‐L–Val‐OMe, Boc‐L‐Ala‐L–Leu‐Aib‐L–Val‐OMe and Boc‐L–Leu‐Aib‐L–Val‐L‐Ala‐L–Leu‐Aib‐L–Val‐OMe (Boc=tertbutoxycarbonyl; OMe=methoxy) were synthesized using conventional solution‐phase methods mediated by EDC/HOBt. Boc‐Gly‐L–Leu‐Aib‐L–Val‐L‐Ala‐L–Leu‐Aib‐L–Val‐OMe 3 was synthesized following the procedure from our previous report . We synthesized pentadecapeptide Boc‐Gly‐L–Leu‐Aib‐L–Val‐L‐Ala‐L–Leu‐Aib‐L–Val‐L–Leu‐Aib‐L–Val‐L‐Ala‐L–Leu‐Aib‐L–Val‐OMe 1 in good yield, using solution‐phase methods involving a racemisation‐free coupling of octa‐peptide acid 3 a and hepta‐peptide amine 3 b via a fragment condensation strategy mediated by EDC/HOBt.…”

“…Recently, we reported the preparation of trithiolane 4 as an intermediate to synthesize dimedone‐tethered peptides from peptide amino esters. Similarly, trithiolane 4 was reacted with octa‐peptide amine 3 c furnishing dimedone‐tethered peptide 5 a . Plausible mechanism of formation of dimedone‐tethered peptide derivatives 5 a‐c has been discussed in our previous report .…”

“…Recently, we reported the preparation of trithiolane 4 as an intermediate to synthesize dimedone‐tethered peptides from peptide amino esters. Similarly, trithiolane 4 was reacted with octa‐peptide amine 3 c furnishing dimedone‐tethered peptide 5 a .…”