*2.3. Quateraryl Assembly*

In order to establish the conditions for the assembly of the quateraryls, we used commercial 3,30 ,5,50 -tetramethyl-4,40 -biphenol (**25**) as a model core fragment (Scheme 3). With its two ortho-substituents, it represents a sterically and electronically challenging pattern for subsequent cross-coupling reactions. The methyl substituents are representative of Ala-side chains, giving rise to test compounds, which could serve as control compounds in biological assays following the strategy of an alanine scan widely used in the biochemistry of proteins [35]. Despite considerable effort in optimization, we never succeeded in using the bistriflate of **25** in Pd-catalyzed cross-coupling reactions. We faced considerable side reactions in the form of hydrolysis of the triflate by any type of inorganic base used in the Suzuki-coupling reactions. Therefore, we chose nonaflates as leaving groups, which have been described as a more stable and convenient substrate in Pd-catalyzed cross-coupling reactions [36]. Nonaflation of **25** with nonafluorobutanesulfonylfluoride (NfF) in DCM delivered bisnonaflate **26** in a 62% yield. Suzuki-coupling with 5-methyl-3-pyridine boronic acid ester (**27**) with Pd(dppf)Cl<sup>2</sup> as catalyst and K2CO<sup>3</sup> as base produced the Ala-Ala-Ala-Ala-quateraryl **28** in a 63% yield. For the synthesis of the asymmetrically substituted Arg-Ala-Ala-Ile quateraryl **30**, Pd(OAc)2/SPhos was chosen as the catalyst. Bisnonaflate **26** was coupled first with Ile-building block **16** and then—after isolation of the teraryl—with the cyanoethyl-building block **23**, using the same catalyst system. As the selectivity of the reaction for the heterocoupling product was only moderate, desired product **29** could only be isolated in a 16% yield. The cyanoethyl group could be converted into the arginine-side chain by first reducing the nitrile to a primary amine with Raney-Ni, followed by reaction with guanylating reagent **24**, producing Arg-Ala-Ala-Ile-quateraryl **30** in a 16% yield over two steps.

*Catalysts* **2020**, *10*, x FOR PEER REVIEW 6 of 10

**Scheme 3.** Synthesis of the quateraryls in the form of Ala-controls. **Scheme 3.** Synthesis of the quateraryls in the form of Ala-controls.

#### *2.4. Synthesis of Quateraryls as Bcl9-Mimetics 2.4. Synthesis of Quateraryls as Bcl9-Mimetics*

decent yields.

With the productive nonaflate strategy for quateraryl assembly at hand, we could take on the challenge of preparing quateraryls with four different aryl building blocks. As a first target, we selected the Ile-Leu-Leu-Arg\*-quateraryl **33** (Scheme 4). Starting from heterocoupling product **13** nonaflation produced **31** in a 19% yield. From the two nonaflate groups in **31**, we expected the With the productive nonaflate strategy for quateraryl assembly at hand, we could take on the challenge of preparing quateraryls with four different aryl building blocks. As a first target, we selected

with Ile-pyridine boronic acid ester **19**, leaving the top ring nonaflate intact for a second Suzukicoupling with cyanoethyl building block **23**, furnishing target Ile-Leu-Leu-Arg\*-quateraryl **33** in the Ile-Leu-Leu-Arg\*-quateraryl **33** (Scheme 4). Starting from heterocoupling product **13** nonaflation produced **31** in a 19% yield. From the two nonaflate groups in **31**, we expected the nonaflate at the bottom ring for steric and electronic reasons to be more reactive than the one at the top ring, which is flanked by two ortho-substituents, among which one is a strongly electron-donating methoxy group. As expected, the bottom ring nonaflate reacted first in a Suzuki-coupling with Ile-pyridine boronic acid ester **19**, leaving the top ring nonaflate intact for a second Suzuki-coupling with cyanoethyl building block **23**, furnishing target Ile-Leu-Leu-Arg\*-quateraryl **33** in decent yields. *Catalysts* **2020**, *10*, x FOR PEER REVIEW 7 of 10

**Scheme 4.** Synthesis of the Ile-Leu-Leu-Arg\*-quateraryl **33**. **Scheme 4.** Synthesis of the Ile-Leu-Leu-Arg\*-quateraryl **33**. **Scheme 4.** Synthesis of the Ile-Leu-Leu-Arg\*-quateraryl **33**.

Similarly, the Leu-Ile-"MeO"-Leu-quateraryl **36** could be assembled in an impressive 47% overall yield from the bisphenol **11** (Scheme 5). For the coupling of the second nonaflate, again the SPhos Pd G3 catalyst [37] turned out to be very efficient. Similarly, the Leu-Ile-"MeO"-Leu-quateraryl **36** could be assembled in an impressive 47% overall yield from the bisphenol **11** (Scheme 5). For the coupling of the second nonaflate, again the SPhos Pd G3 catalyst [37] turned out to be very efficient. Similarly, the Leu-Ile-"MeO"-Leu-quateraryl **36** could be assembled in an impressive 47% overall yield from the bisphenol **11** (Scheme 5). For the coupling of the second nonaflate, again the SPhos Pd G3 catalyst [37] turned out to be very efficient. **Scheme 4.** Synthesis of the Ile-Leu-Leu-Arg\*-quateraryl **33**. Similarly, the Leu-Ile-"MeO"-Leu-quateraryl **36** could be assembled in an impressive 47% overall yield from the bisphenol **11** (Scheme 5). For the coupling of the second nonaflate, again the

SPhos Pd G3 catalyst [37] turned out to be very efficient.

**Scheme 5.** Synthesis of the Leu-Ile-"MeO"-Leu-quateraryl **36**. **Scheme 5.** Synthesis of the Leu-Ile-"MeO"-Leu-quateraryl **36**. **Scheme 5.** Synthesis of the Leu-Ile-"MeO"-Leu-quateraryl **36**. **Scheme 5.** Synthesis of the Leu-Ile-"MeO"-Leu-quateraryl **36**.

The same precursor also served as the starting material for the synthesis of Ile-Leu-"MeO"-Arg\*-

quateraryl **39**, which could be synthesized in a 33% overall yield (Scheme 6). The same precursor also served as the starting material for the synthesis of Ile-Leu-"MeO"-Arg\* quateraryl **39**, which could be synthesized in a 33% overall yield (Scheme 6). The same precursor also served as the starting material for the synthesis of Ile-Leu-"MeO"-Arg\*-quateraryl **39**, which could be synthesized in a 33% overall yield (Scheme 6). The same precursor also served as the starting material for the synthesis of Ile-Leu-"MeO"-Arg\* quateraryl **39**, which could be synthesized in a 33% overall yield (Scheme 6).

**3. Materials and Methods Scheme 6.** Synthesis of the Ile-Leu-"MeO"-Arg\*-quateraryl **39**. **Scheme 6.** Synthesis of the Ile-Leu-"MeO"-Arg\*-quateraryl **39**. **Scheme 6.** Synthesis of the Ile-Leu-"MeO"-Arg\*-quateraryl **39**.

**3. Materials and Methods** 

**3. Materials and Methods** 

*Electrochemical Anodic Dehydrogenative Cross-Coupling Reactions* 

Reaction parameter optimization of anodic cross-coupling reactions was carried out in undivided 5 mL Teflon cells (self-made by the mechanical workshop at JGU Mainz, Germany; or commercially available from IKA, Staufen, Germany as the IKA Screening System), equipped with a

Reaction parameter optimization of anodic cross-coupling reactions was carried out in undivided 5 mL Teflon cells (self-made by the mechanical workshop at JGU Mainz, Germany; or commercially available from IKA, Staufen, Germany as the IKA Screening System), equipped with a

Reaction parameter optimization of anodic cross-coupling reactions was carried out in undivided 5 mL Teflon cells (self-made by the mechanical workshop at JGU Mainz, Germany; or commercially available from IKA, Staufen, Germany as the IKA Screening System), equipped with a
