Influence of the <i>Trans</i>/<i>Cis</i> Conformer Ratio on the Stereoselectivity of Peptidic Catalysts

<i>Trans</i>/<i>cis</i> isomerization of Xaa-Pro bonds is key for the structure and function of several enzymes. In recent years, numerous versatile peptidic catalysts have been developed that bear Xaa-Pro amide bonds. Due to the many degrees of freedom within even short peptides, the design and optimization of peptidic catalysts by rational structural modifications is difficult. We envisioned that control over the <i>trans</i>/<i>cis</i> amide bond ratio may provide a tool to optimize the catalytic performance of peptidic catalysts. Here, we investigated the influence of the amide bond conformation on the stereoselectivity of H-Pro-Pro-Xaa-NH₂-type peptidic catalysts in conjugate addition reactions. The middle Pro residue within the tripeptides was replaced with analogues of varying ring sizes (azetidine carboxylic acid, Aze, and piperidine carboxylic acid, Pip) to produce different <i>trans</i>/<i>cis</i> ratios in different solvents. The studies revealed a direct correlation between the <i>trans</i>/<i>cis</i> amide bond ratio and the enantio- and diastereoselectivity of structurally related peptidic catalysts. These insights led to the identification of H-d-Pro-Pip-Glu-NH₂ as a highly reactive and stereoselective amine-based catalyst that allows C–C bond formations to be performed in the presence of as little as 0.05 mol %, which is the lowest catalyst loading yet achieved for organocatalyzed reactions that rely on an enamine-based mechanism

Effect of Sterically Demanding Substituents on the Conformational Stability of the Collagen Triple Helix

The effect of sterically demanding groups at proline residues on the conformational stability of the collagen triple helix was examined. The thermal stabilities (<i>T</i>_m and Δ<i>G</i>) of eight different triple helices derived from collagen model peptides with (4<i>R</i>)- or (4<i>S</i>)-configured amidoprolines bearing either methyl or bulkier <i>tert</i>-butyl groups in the Xaa or Yaa position were determined and served as a relative measure for the conformational stability of the corresponding collagen triple helices. The results show that sterically demanding substituents are tolerated in the collagen triple helix when they are attached to (4<i>R</i>)-configured amidoprolines in the Xaa position or to (4<i>S</i>)-configured amidoprolines in the Yaa position. Structural studies in which the preferred conformation of (4<i>R</i>)- or (4<i>S</i>)-configured amidoproline were overlaid with the Pro and Hyp residues within a crystal structure of collagen revealed that the sterically demanding groups point to the outside of these two triple helices and thereby do not interfere with the formation of the triple helix. In all of the other examined collagen derivatives with lower stability of the triple helices, the acetyl or pivaloyl residues point toward the inside of the triple helix and clash with a residue of the neighboring strand. The results also revealed that unfavorable steric dispositions affect the conformational stability of the collagen triple helix more than unfavorable ring puckers of the proline residues. The results are useful for the design of functionalized collagen based materials

Stereoselective Synthesis of α‑Fluoro-γ-nitro Thioesters under Organocatalytic Conditions

Fluorinated monothiomalonates (F-MTMs) were used as building blocks for the stereoselective synthesis of organofluorine compounds. We present conjugate addition reactions between F-MTMs with nitroolefins that proceed under mild organocatalytic conditions and provide access to α-fluoro-γ-nitro thioesters with adjacent tetrasubstituted and tertiary stereogenic centers. Only 1 mol % of a cinchona alkaloid–urea catalyst is necessary to obtain the addition products in excellent yields and stereoselectivities. The methodology allowed for the straightforward synthesis of a fluorinated analogue of the PAR-2 agonist AC-264613

Decarboxylative Organocatalyzed Aldol-Type Addition Reaction of Chloroacetate Surrogates

Chlorinated malonic acid half thioesters were established as chloroacetate surrogates and used in stereoselective organocatalyzed decarboxylative aldol-type additions. Enantioenriched α-chloro-β-hydroxy thioesters were obtained under mild reaction conditions in high yields and allowed for diverse derivatization as highlighted by the synthesis of (+)-prebalamide and (+)-norbalasubramide analogs

Stereoselective Synthesis of Indolines via Organocatalytic Thioester Enolate Addition Reactions

A straightforward stereoselective synthesis route to indolin-3-yl acetates has been developed using organocatalytic addition reactions of monothiomalonates to <i>ortho</i>-bromo nitrostyrenes as the key step. The addition products of this highly stereoselective one-pot addition–deprotection–decarboxylation sequence were easily further converted to the target indolin-3-yl acetates, via an intramolecular Buchwald–Hartwig coupling reaction. The route provided indolin-3-yl acetates bearing tertiary and exocyclic quarternary stereogenic centers in excellent stereoselectivities and overall yields of 34–83%

Organocatalytic Stereoselective Synthesis of Acyclic γ‑Nitrothioesters with All-Carbon Quaternary Stereogenic Centers

A method for the stereoselective synthesis of acyclic thioesters bearing adjacent quaternary and tertiary stereogenic centers under mild organocatalytic conditions was developed. α-Substituted monothiomalonates (MTMs) were used as thioester enolate equivalents. They reacted cleanly with nitroolefins in the presence of 1–6 mol % of cinchona alkaloid urea derivatives, and provided access to γ-nitrothioesters with quaternary stereocenters in high yields and diastereo- and enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access to other compounds with quaternary stereogenic centers, such as γ-nitroaldehydes and γ-butyrolactams

A Crystal Structure of an Oligoproline PPII-Helix, at Last

The first crystal structure of an oligoproline adopting an <i>all-trans</i> polyproline II (PPII) helix is presented. The high-resolution structure provides detailed insight into the dimensions and conformational properties of oligoprolines that are important for, e.g., their use as “molecular rulers” and “molecular scaffolds”. The structure also showed that the amides interact with each other within a PPII helix and that water is not necessary for PPII helicity

Correction to “A Crystal Structure of an Oligoproline PPII-Helix, at Last”

Correction to “A Crystal Structure of an Oligoproline PPII-Helix, at Last

Organocatalytic Route to Dihydrocoumarins and Dihydroquinolinones in All Stereochemical Configurations

A straightforward stereodivergent route to dihydrocoumarins and dihydroquinolinones based on cinchona alkaloid catalyzed addition reactions of monothiomalonates (MTMs) to functionalized nitroolefins followed by deprotection and chemoselective cyclization has been developed. The synthesis proceeds under mild conditions and yields heterocycles with adjacent quaternary and tertiary stereogenic centers in very high yields and stereoselectivities. Moreover, full control over the relative and absolute configuration is achieved by the use of (pseudo)­enantiomeric catalysts and the difference in reactivity of thioester versus oxoester moieties

Organocatalytic Route to Dihydrocoumarins and Dihydroquinolinones in All Stereochemical Configurations

A straightforward stereodivergent route to dihydrocoumarins and dihydroquinolinones based on cinchona alkaloid catalyzed addition reactions of monothiomalonates (MTMs) to functionalized nitroolefins followed by deprotection and chemoselective cyclization has been developed. The synthesis proceeds under mild conditions and yields heterocycles with adjacent quaternary and tertiary stereogenic centers in very high yields and stereoselectivities. Moreover, full control over the relative and absolute configuration is achieved by the use of (pseudo)­enantiomeric catalysts and the difference in reactivity of thioester versus oxoester moieties