Site-selective and stereoselective transformations on p-quinols & p-quinamines.

The intermolecular transformation of simple substrates into highly functionalized scaffolds with multiple stereogenic centers is an attractive strategy in modern organic synthesis. Prochiral 2,5-cyclohexadienones, being stable and easily accessible, are privileged key building blocks for the synthesis of complex molecules and bioactive natural products. In particular, p-quinols and p-quinamines are important subclasses of cyclohexadienones, having both nucleophilic and electrophilic sites, and can undergo various intermolecular cascade annulations via formal cycloadditions and other transformations. This article highlights the recent developments of intermolecular transformations on p-quinols and p-quinamines along with plausible reaction mechanisms. We hope that this review will inspire the readers to explore the new potential applications of these unique prochiral molecules.

CuH-Catalyzed Enantioselective Desymmetrization of Cyclic 1,3-Diketones.

Herein, we report a CuH-catalyzed asymmetric desymmetrization of prochiral cyclopentane-1,3-diones to access cyclic 3-hydroxy ketones having an all-carbon quaternary center with high diastereoselectivity via hydrosilylation using PMHS as an inexpensive hydride source. This reaction displays high functional group tolerance including reducible alkyne, alkene, and ester groups with a broad substrate scope. The importance of chiral cyclic 3-hydroxy ketone building blocks was also demonstrated through the synthesis of (-)-estrone, the toxicodenane E core, and fused indoles.

Metal-free oxidative formal C(sp2)-H arylation of cyclopentene-1,3-diones with ß-naphthols.

An efficient, mild, and transition-metal free formal C(sp2)-H arylation of prochiral 2,2-disubstituted cyclopentene-1,3-diones is reported. This oxidative arylation with ß-naphthols proceeds via base-mediated C-Michael addition followed by aerial oxygen insertion and a subsequent α-hydroperoxy elimination sequence. This operationally simple and environmentally benign transformation is highly scalable and does not require any pre-functionalization. Moreover, this reaction affords excellent yields of α-substituted ß-naphthols bearing all-carbon quaternary centers.

Enantioselective Cu(I)-catalyzed borylative cyclization of enone-tethered cyclohexadienones and mechanistic insights.

The catalytic asymmetric borylation of conjugated carbonyls followed by stereoselective intramolecular cascade cyclizations with in situ generated chiral enolates are extremely rare. Herein, we report the enantioselective Cu(I)-catalyzed ß-borylation/Michael addition on prochiral enone-tethered 2,5-cyclohexadienones. This asymmetric desymmetrization strategy has a broad range of substrate scope to generate densely functionalized bicyclic enones bearing four contiguous stereocenters with excellent yield, enantioselectivity, and diastereoselectivity. One-pot borylation/cyclization/oxidation via the sequential addition of sodium perborate reagent affords the corresponding alcohols without affecting yield and enantioselectivity. The synthetic potential of this reaction is explored through gram-scale reactions and further chemoselective transformations on products. DFT calculations explain the requirement of the base in an equimolar ratio in the reaction, as it leads to the formation of a lithium-enolate complex to undergo C-C bond formation via a chair-like transition state, with a barrier that is 22.5 kcal/mol more favourable than that of the copper-enolate complex.

Rh(III)-catalyzed diastereoselective cascade annulation of enone-tethered cyclohexadienones via C(sp2)-H bond activation.

Herein, we report highly diastereoselective arylative cyclization of enone-tethered cyclohexadienones via Rh(III)-catalyzed C-H activation of N-methoxybenzamides. This reaction proceeds through the formation of a five-membered rhodacycle followed by bis-Michael cascade annulation to access functionalized bicyclic scaffolds with four contiguous stereocenters with a broad substrate scope. These products have excellent functional handles, allowing further synthetic transformation to increase the structural complexity. Furthermore, mechanistic studies of arylative cyclization and a gram-scale experiment are also presented.

Bachem - Insights into Innovative and Sustainable Peptide Chemistry and Technology by the Leading Independent Manufacturer of TIDES.

Since its foundation in 1971, Bachem has grown sustainably over the last 50 years and is excellently positioned as the leading company for the development and production of TIDES i.e. peptides and oligonucleotides. Bachem's success relies on its commitment to manufacturing high-quality active pharmaceutical ingredients (APIs) alongside its continual passion for innovative chemistry and technologies. This review aims at summarizing improvements in high-quality peptide manufacturing as well as recent advances towards sustainable and innovative technology in peptide chemistry, thereby reducing the environmental footprint.

Self-assembling tetrameric peptides allow in situ 3D bioprinting under physiological conditions.

We have developed an in situ bioprinting method that allows the printing of cells under true physiological conditions by applying self-assembling ultrashort peptides as bioinks. This method avoids cell stressing methods, such as UV-treatment, chemical crosslinking and viscous bioink printing methods. We further demonstrate that different nanomaterials can easily be synthesized or incorporated in the 3D bioprinted peptide scaffolds which opens up the possibility of functionalized 3D scaffolds.

Diastereoselective Desymmetrization of p-Quinamines through Regioselective Ring Opening of Epoxides and Aziridines.

A highly diastereoselective desymmetrization of p-quinamines via regioselective ring opening of epoxides and aziridines under mild conditions has been developed. A chairlike six-membered transition state with minimized 1,3-diaxial interactions explains the relative stereoselectivity of the cyclization reaction. This transition-metal free [3 + 3] annulation reaction provides rapid access to fused bicyclic morpholines and piperazines with a tetrasubstituted carbon center in high yields. In addition, it also allows the synthesis of enantioenriched products by using easily accessible chiral nonracemic epoxides and aziridines.

Rh-Catalyzed diastereoselective desymmetrization of enone tethered-cyclohexadienones via tandem arylative cyclization.

The rhodium-catalyzed arylative cyclization of enone tethered-cyclohexadienones has been developed with high efficiency, thus providing cis-fused bicyclic enones in good yields and with excellent diastereoselectivities. Furthermore, this mild transformation has a broad range of substrate scope and excellent functional group tolerance. In addition, bicyclic products have an enone functionality, which can be a synthetically valuable handle for further transformations.

Remarkable Modulation of Self-Assembly in Short γ-Peptides by Neighboring Ions and Orthogonal H-Bonding.

Gabapentin, an antiepileptic drug, is known to form stable helical structures in short peptides. Distinctly, we report on the newly synthesized γ-analogue of gabapentin, that is, γ-gabapentin (γ-Gpn), which manifests ß-sheet character at molecular and nanofibrous hydrogels at the supramolecular level. We investigated the influence of proximally immobilized cationic amino acids (lysine and arginine) on the self-assembly of backbone-expanded tripeptide motif. Interestingly, arginine was found to be superior, both physically and mechanically, over lysine in driving hydrogelation. We have concluded that intrinsic and biochemically distinct properties of the guanidinium ion of arginine (compared to ammonium ion of lysine) have contributed towards this effect. Furthermore, similar to pyroglutamyl (pGlu) modified amyloid ß peptides, N-pGlu modification of our self-assembling tripeptide motif exerts a dramatic influence on aggregation and exhibits enhanced ß-sheet character, accelerated self-assembly kinetics, improved optical transparency and provides higher mechanical stiffness to the peptide hydrogel.

Foldamers to nanotubes: influence of amino acid side chains in the hierarchical assembly of α,γ(4)-hybrid peptide helices.

Supramolecular assembly of various artificially folded 12-helical architectures composed of γ(4) -Val, γ(4) -Leu and γ(4) -Phe residues is investigated. In contrast to the 12-helices composed of γ(4) -Val and γ(4) -Leu residues, the helices with γ(4) -Phe residues displayed unique elongated nanotubular architectures. The elongated nanotube assembly was further explored as a template for biomineralization of silver ions to silver nanowires. A comparative study using an analogous α-peptide helix reveals the importance of the spatial arrangement of aromatic side chains along the helical cylinder in a 12-helix. These results suggested that the proteolytically and structurally stable α,γ(4) -hybrid peptide 12-helices may serve as a new generation of potential templates in the design of functional biomaterials.

γ-Amino acid mutated α-coiled coils as mild thermal triggers for liposome delivery.

The stability and compatibility of designed coiled coil peptides towards the selective incorporation of γ(4)-amino acids at the hydrophobic positions of the heptad repeat are studied. Investigations reveal that the low thermal denaturation temperature of γ(4)-residue mutated coiled coils can be utilized as a mild hyperthermia trigger in liposomes.

Efficient access to enantiopure γ4-amino acids with proteinogenic side-chains and structural investigation of γ4-Asn and γ4-Ser in hybrid peptide helices.

Hybrid peptides composed of α- and ß-amino acids have recently emerged as new class of peptide foldamers. Comparatively, γ- and hybrid γ-peptides composed of γ(4) -amino acids are less studied than their ß-counterparts. However, recent investigations reveal that γ(4)-amino acids have a higher propensity to fold into ordered helical structures. As amino acid side-chain functional groups play a crucial role in the biological context, the objective of this study was to investigate efficient synthesis of γ(4)-residues with functional proteinogenic side-chains and their structural analysis in hybrid-peptide sequences. Here, the efficient and enantiopure synthesis of various N- and C-terminal free-γ(4)-residues, starting from the benzyl esters (COOBzl) of N-Cbz-protected (E)-α,ß-unsaturated γ-amino acids through multiple hydrogenolysis and double-bond reduction in a single-pot catalytic hydrogenation is reported. The crystal conformations of eight unprotected γ(4)-amino acids (γ(4)-Val, γ(4)-Leu, γ(4)-Ile, γ(4)-Thr(OtBu), γ(4)-Tyr, γ(4)-Asp(OtBu), γ(4)-Glu(OtBu), and γ-Aib) reveals that these amino acids adopted a helix favoring gauche conformations along the central C(γ) -C(ß) bond. To study the behavior of γ(4)-residues with functional side chains in peptide sequences, two short hybrid γ-peptides P1 (Ac-Aib-γ(4)-Asn-Aib-γ(4)-Leu-Aib-γ(4)-Leu-CONH2 ) and P2 (Ac-Aib-γ(4)-Ser-Aib-γ(4)-Val-Aib-γ(4)-Val-CONH2 ) were designed, synthesized on solid phase, and their 12-helical conformation in single crystals were studied. Remarkably, the γ(4) -Asn residue in P1 facilitates the tetrameric helical aggregations through interhelical H bonding between the side-chain amide groups. Furthermore, the hydroxyl side-chain of γ(4)-Ser in P2 is involved in the interhelical H bonding with the backbone amide group. In addition, the analysis of 87 γ(4)-residues in peptide single-crystals reveal that the γ(4)-residues in 12-helices are more ordered as compared with the 10/12- and 12/14-helices.

Remarkable thermoresponsive nanofibers from γ-peptides.

Conformational analysis of γ-peptides composed of 4,4-gem-dimethyl γ-amino acids, their spontaneous self-assembly into nanofibrillar superstructures and remarkable thermoreversible gelation properties in various organic solvents are studied. This new generation of γ-peptides may serve as potential templates to design advanced biomaterials.

Protein secondary structure mimetics: crystal conformations of α/γ4-hybrid peptide12-helices with proteinogenic side chains and their analogy with α- and ß-peptide helices.

Numerous strategies have been developed to mimic the α-helical secondary structure using hybrid peptides containing non-natural amino acids. In contrast to the ß- and α/ß-hybrid peptides, very little is known about the folding patterns of hybrid peptides containing γ(4)-amino acids. Here we report the solid phase synthesis and crystallographic insight into the secondary structures formed by 1 : 1 alternating α/γ(4)-hybrid peptides. The crystal conformations suggest that heptapeptides P1, P2 and P3 adopted the 12-helix conformation with backward consecutive 1←4 H-bonds [C=O(i)···H-N (i + 3)]. In comparison with α-, ß- and γ-peptides, the distinct projection of side-chains was observed along the helical cylinder. In contrast to the peptide containing stereochemically constrained α-amino acid Aib (P1), the peptide with complete proteinogenic side-chains (P3) displayed organized side chain-side chain interactions between the antiparallel helices in crystal packing. The analogy of the α/γ(4)-hybrid peptides with 3(10)-helix, α-helix and ß-peptide 12-helix suggests that the internal H-bonding pattern and macrodipole were analogous to the α- and ß-peptide helices. In addition, helical parameters were found to be very similar to that of ß-peptide 12-helices.

Copper(II) mediated facile and ultra fast peptide synthesis in methanol.

A novel, ultrafast, mild and scalable amide bond formation strategy in methanol using simple thioacids and amines is described. The mechanism suggests that the coupling reactions are initially mediated by CuSO(4)·5H(2)O and subsequently catalyzed by in situ generated copper sulfide. The pure peptides were isolated in satisfactory yields in less than 5 minutes.

α/γ(4)-Hybrid peptide helices: synthesis, crystal conformations and analogy with the α-helix.

Synthesis, crystal conformations of α/γ(4)-hybrid peptide helices containing proteinogenic amino acid side-chains, and the analogy with the α-helix are reported. Results suggest that α/γ(4)-hybrid peptides adopted helical conformations with 12-membered H-bond pseudocycles in single crystals.

Synthesis of α, ß-unsaturated γ-amino esters with unprecedented high (E)-stereoselectivity and their conformational analysis in peptides.

Mild, efficient and racemization-free synthesis of N-protected α, ß-unsaturated γ-amino esters with unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-, Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous γ-amino esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous homo-dipeptide showed a ß-sheet conformation, while mixed α- and α,ß-unsaturated γ-hybrid dipeptide adapted an irregular structure in single crystals.

A facile synthesis and crystallographic analysis of N-protected ß-amino alcohols and short peptaibols.

A facile, efficient and racemization-free method for the synthesis of N-protected ß-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of ß-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III ß-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.