A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 5: A Complete Set of Pyridine Boronic Acid Pinacol Esters Featuring Side Chains of Proteinogenic Amino Acids

Abstract

Teraryl‐based α‐helix mimetics have proven to be useful compounds for the inhibition of protein‐protein interactions (PPI). We have developed a modular and flexible approach for the synthesis of teraryl‐based α‐helix mimetics using pyridine containing boronic acid building blocks to increase the water solubility. Following our initial publication in which we have introduced the methodology in combination with sequential Pd‐catalyzed cross‐coupling for teraryl assembly, we can now report a complete set of pyridine based boronic acid building blocks decorated with side chains of all proteinogenic amino acids relevant for PPI (Ala, Arg, Asn, Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Ser, Thr, Trp, Tyr, Val) to complement the core fragment set. For a representative set of teraryls we have studied the influence of the pyridine rings on the solubility of the assembled oligoarenes.

A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 4: Core Fragments with Two Halide Leaving Groups Featuring Side Chains of Proteinogenic Amino Acids

“…With these general coupling conditions in hand several different side chains with varying polarity could be incorporated into the teraryl scaffold. In the first step, the core fragments Trp ( 38 ), Val ( 7 ), Asn ( 12 ) and “Glu” ( 30 ) were connected to either the Leu or Trp pyridine boronic acid building block [28] via the more reactive iodide leaving group. The reaction occurred chemoselectively and no cross‐coupling with the bromide was detected.…”

“…The corresponding diaryl bromides were isolated in 54–80 % yield (see SI for details). In the second step, coupling of the bromide leaving group with the Met, Leu, “Ser” or Phe pyridine boronic acid building block [28] also proceeded very smoothly, furnishing teraryls 48 – 51 a in 38–62 % total yield. TBDPS deprotection of the pyridine “Ser” building block in 50 already occurred during cross coupling, while teraryl 51 a was saponified to reveal the free Glu side chain, producing Leu‐Glu‐Phe teraryl 51 in 74 % yield.…”

“…With these two approaches we can now provide a practical solution for the synthesis of any core fragment building block featuring the side chains of all proteinogenic amino acid side chains. Together with our similarly comprehensive approach to 5‐substituted 3‐pyridine boronic acids,[ 11 , 28 ] any motif of α‐helix‐hot spots has become accessible.…”

A Modular Synthesis of Teraryl‐Based α‐Helix Mimetics, Part 3: Iodophenyltriflate Core Fragments Featuring Side Chains of Proteinogenic Amino Acids

“…We were again unsuccessful in converting 8 to the corresponding free amide. Therefore, we suggest that the side chains of either building block 5 or 8 should be converted to the natural Asn side chain after Suzuki‐Miyaura coupling to avoid cleavage of the −I or −OTf functionalities present in the building block by methodology we have presented elsewhere [20] …”

Recent Advances in Pd‐Catalyzed Suzuki‐Miyaura Cross‐Coupling Reactions with Triflates or Nonaflates

“…However, despite this advantage the cross‐coupling of triflates has not become as popular as the corresponding reactions with aryl halides for which robust coupling protocols exist which work for many substrates in a predictable way. In our own work we experienced that Suzuki‐Miyaura (SM) couplings of aryltriflates require careful optimization of reaction conditions [6–10] . In addition, the undesired hydrolysis of the triflate moiety to the corresponding phenol is often observed as a side reaction.…”