Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry

Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed “CyClick” chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019 , 58, 19073–19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in “CyClick” of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre-organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the “CyClick” of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses “CyClick” reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.     

Peptide‐Coated Platinum Nanoparticles with Selective Toxicity against Liver Cancer Cells

Peptide‐stabilized platinum nanoparticles (PtNPs) were developed that have significantly greater toxicity against hepatic cancer cells (HepG2) than against other cancer cells and non‐cancerous liver cells. The peptide H‐Lys‐Pro‐Gly‐d Lys‐NH₂ was identified by a combinatorial screening and further optimized to enable the formation of water‐soluble, monodisperse PtNPs with average diameters of 2.5 nm that are stable for years. In comparison to cisplatin, the peptide‐coated PtNPs are not only more toxic against hepatic cancer cells but have a significantly higher tumor cell selectivity. Cell viability and uptake studies revealed that high cellular uptake and an oxidative environment are key for the selective cytotoxicity of the peptide‐coated PtNPs.     

Hydrogen‐Bond‐Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Non‐biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion‐mediated O‐alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O?H???NCO hydrogen bond. Upon O‐alkylation of the H‐bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H‐bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol^?1, thereby facilitating the observed dynamic kinetic resolution.     

NHC‐Catalyzed Chemoselective Reactions of Enals and Aminobenzaldehydes for Access to Chiral Dihydroquinolines

An N‐heterocyclic carbene (NHC)‐catalyzed reaction between α‐bromoenals and 2‐aminoaldehydes has been developed. Key steps include chemoselective reaction of the NHC catalyst with one of the aldehyde substrates (the bromoenal) to eventually generate an α,β‐unsaturated acylazolium intermediate. Addition of the nitrogen atom of aminoaldehyde to the unsaturated azolium ester intermediate followed by intramolecular aldol reaction, β‐lactone formation, and decarboxylation leads to chiral dihydroquinolines with high optical purity. The dihydroquinoline products, which are quickly prepared by using this method, can be readily transformed into a diverse set of functional molecules such as pyridines and chiral piperidines.     

Engineered Peptide Macrocycles Can Inhibit Matrix Metalloproteinases with High Selectivity

Matrix metalloproteinases (MMPs) are zinc‐dependent endopeptidases at the intersection of health and disease due to their involvement in processes such as tissue repair and immunity as well as cancer and inflammation. Because of the high structural conservation in the catalytic domains and shallow substrate binding sites, selective, small‐molecule inhibitors of MMPs have remained elusive. In a tour‐de‐force peptide engineering approach combining phage‐display selections, rational design of enhanced zinc chelation, and d ‐amino acid screening, we succeeded in developing a first synthetic MMP‐2 inhibitor that combines high potency (K_i=1.9±0.5 nm ), high target selectivity, and proteolytic stability, and thus fulfills all the required qualities for in cell culture and in vivo application. Our work suggests that selective MMP inhibition is achievable with peptide macrocycles and paves the way for developing specific inhibitors for application as chemical probes and potentially therapeutics.     

Peptide [4]Catenane by Folding and Assembly

A topologically complex peptide [4]catenane with the crossing number of 12 was synthesized by a folding and assembly strategy wherein the folding and metal‐directed self‐assembly of a short peptide fragment occur simultaneously. The latent Ω‐looped conformation of the Pro‐Gly‐Pro sequence was found only when pyridines at the C‐ and N‐termini coordinatively bind metal ions (Ag^I or Au^I). Crystallographic studies revealed that the Ω‐looped motifs formed four M₃L₃ macrocycles that were intermolecularly entwined to generate an unprecedented peptide [4]catenane topology.     

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

The first enantioselective total synthesis of (−)‐cycloclavine was accomplished in 8 steps and 7.1 % overall yield. Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by the dirhodium catalyst Rh₂(S‐TBPTTL)₄, and the enone 1,2‐addition of a new TEMPO carbamate methyl carbanion. An intramolecular strain‐promoted Diels–Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate with more than 99 % ee after crystallization. The synthesis of (−)‐ 1 was completed by a late‐stage intramolecular Diels–Alder furan (IMDAF) cycloaddition to install the indole.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

Access to a Stereoisomer Library of Solomonamide Macrocycles

In an attempt towards understanding stereo‐structure activity relationships (SSARs), we have prepared eight possible stereoisomers of solomonamide macrocycles, in particular, by changing the stereochemical pattern of non‐peptide fragment AHMOA. Here, we have demonstrated different ways to construct three contiguous chiral centers present in solomonamide B macrocycle using substrate/reagent‐controlled methods. These methods involve Brown crotylation, NHK reaction and Evans aldol addition as key steps to synthesize key non‐peptide fragment. Further, these non‐peptide fragments were converted to their corresponding macrocycles via ligand‐free intramolecular Heck reaction.     

Skeletal Rearrangement of Twisted Thia‐Norhexaphyrin: Multiply Annulated Polypyrrolic Aromatic Macrocycles

A hybrid thia‐norhexaphyrin comprising a directly linked N‐confused pyrrole and thiophene unit ( 1 ) revealed unique macrocycle transformations to afford multiply inner‐annulated aromatic macrocycles. Oxidation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone triggered a cleavage of the C?S bond of the thiophene unit, accompanied with skeletal rearrangement to afford unique π‐conjugated products: a thiopyrrolo‐pentaphyrin embedded with a pyrrolo[1,2]isothiazole ( 2 ), a sulfur‐free pentaphyrin incorporating an indolizine moiety ( 3 ), and a thiopyranyltriphyrinoid containing a 2H‐thiopyran unit ( 4 ). Furthermore, 2 underwent desulfurization reactions to afford a fused pentaphyrin containing a pyrrolizine moiety ( 5 ) under mild conditions. Using expanded porphyrin scaffolds, oxidative thiophene cleavage and desulfurization of the hitherto unknown N‐confused core‐modified macrocycles would be a practical approach for developing unique polypyrrolic aromatic macrocycles.     

An In‐tether Chiral Center Modulates the Helicity,Cell Permeability,and Target Binding Affinity of a Peptide

The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X‐ray diffraction analysis suggests that the absolute configuration of the in‐tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation.     

Asymmetric Strecker Reaction Arising from the Molecular Orientation of an Achiral Imine at the Single‐Crystal Face: Enantioenriched l‐ and d‐Amino Acids

Strecker synthesis has long been considered one of the prebiotic reactions for the synthesis of α‐amino acids. However, the correlation between the origin of chirality and highly enantioenriched α‐amino acids through this method remains a puzzle. In the reaction, it may be conceivable that the handedness of amino acids has been determined at the formation stage of the chiral intermediate α‐aminonitrile, that is, the enantioselective addition of hydrogen cyanide to an imine. Herein, an enantiotopic crystal surface of an achiral imine acted as an origin of chirality for the enantioselective formation of α‐aminonitriles by the addition of HCN. In conjunction with the amplification of the enantiomeric excess and multiplication of enantioenriched aminonitrile, a large amount of near enantiopure α‐amino acids, with the l ‐ and d ‐handedness corresponding to the molecular orientation of the imine, is reported.     

Targeting the Genome‐Stability Hub Ctf4 by Stapled‐Peptide Design

The exploitation of synthetic lethality by small‐molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND‐1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double‐click stapled peptides encoding the Ctf4‐interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNA polymerase α from the replisome in yeast extracts. Our study provides proof‐of‐principle evidence for the development of small‐molecule inhibitors of the human CTF4 orthologue AND‐1.     

Regioselective Insertion of o‐Carborynes into the α‐C?H Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Pyridine‐Fused Bis(Norcorrole) through Hantzsch‐Type Cyclization: Enhancement of Antiaromaticity by an Aromatic Bridge

A non‐catalytic condensation of Ni^II β‐aminonorcorrole with aryl aldehydes is shown to produce a family of pyrromethane dimers that undergo deaminative cyclization to yield pyridine‐fused bis(norcorrole)s comprising two antiaromatic macrocycles communicating by an aromatic moiety. The new compounds were characterized by spectroscopic, structural, and electrochemical methods supported by DFT calculations, all of which revealed unexpected antiaromaticity enhancement in the fused system.     

Gold‐Catalyzed Asymmetric Intramolecular Cyclization of N‐Allenamides for the Synthesis of Chiral Tetrahydrocarbolines

Highly enantioselective gold‐catalyzed intramolecular cyclization of N‐allenamides was implemented by utilizing a designed chiral sulfinamide phosphine ligand (PC‐Phos). This represents the first example of highly enantioselective intramolecular cyclization of N‐allenamides. The practicality of this reaction was validated in the total synthesis of (R )‐desbromoarborescidine A and formal synthesis of (R )‐desbromoarborescidine C and (R )‐deplancheine. Moreover, the catalyst system PC‐Phos/AuNTf₂ proved to be specifically efficient to promote the desymmetrization of N‐allenamides in excellent yields with satisfactory ee values.     

“Helix‐in‐Helix” Superstructure Formation through Encapsulation of Fullerene‐Bound Helical Peptides within a Helical Poly(methyl methacrylate) Cavity

A one‐handed 3₁₀‐helical hexapeptide is efficiently encapsulated within the helical cavity of st‐PMMA when a fullerene (C₆₀) derivative is introduced at the C‐terminal end of the peptide. The encapsulation is accompanied by induction of a preferred‐handed helical conformation in the st‐PMMA backbone with the same‐handedness as that of the hexapeptide to form a crystalline st‐PMMA/peptide‐C₆₀ inclusion complex with a unique optically active helix‐in‐helix structure. Although the st‐PMMA is unable to encapsulate the 3₁₀‐helical peptide without the terminal C₆₀ unit, the helical hollow space of the st‐PMMA is almost filled by the C₆₀‐bound peptides. This result suggests that the C₆₀ moiety can serve as a versatile molecular carrier of specific molecules and polymers in the helical cavity of the st‐PMMA for the formation of an inclusion complex, thus producing unique supramolecular soft materials that cannot be prepared by other methods.     

One‐Pot N‐Deprotection and Catalytic Intramolecular Asymmetric Reductive Amination for the Synthesis of Tetrahydroisoquinolines

A one‐pot N‐Boc deprotection and catalytic intramolecular reductive amination protocol for the preparation of enantiomerically pure tetrahydroisoquinoline alkaloids is described. The iodine‐bridged dimeric iridium complexes displayed superb stereoselectivity to give tetrahydroisoquinolines, including several key pharmaceutical drug intermediates, in excellent yields under mild reaction conditions. Three additives played important roles in this reaction: Titanium(IV) isopropoxide and molecular iodine accelerated the transformation of the intermediate imine to the tetrahydroisoquinoline product; p ‐toluenesulfonic acid contributed to the stereocontrol.     

Biomimetic Synchronized Motion of Two Interacting Macrocycles in [3]Rotaxane‐Based Molecular Shuttles

Noncovalent interactions between all the neighboring components in biomolecular machines are responsible for their synchronized motion and thus complex functions. This strategy has rarely been used in multicomponent molecular machines. Here, we report four [3]rotaxane‐based molecular shuttles. Noncovalent interactions among the three components (two interacting macrocycles and one axle) not only cause a “systems‐level” effect on the relative positions of the two macrocycles along the axle, but also result in a synchronized motion of the two macrocycles when adding partial amount of stimuli. Moreover, the intermediate state with one shuttled macrocycle even exist predominantly in the solution during the titration of stimuli, which is theoretically unexpected for the [3]rotaxane with two non‐interacting rings. This biomimetic strategy may provide a method for constructing highly complex molecular machines.     

Intramolecular Singlet Fission in an Antiaromatic Polycyclic Hydrocarbon

Singlet fission (SF), in which one singlet exciton (S₁) splits into two triplets (T₁) on adjacent molecules through a correlated triplet‐pair ¹(TT) state, requires precise but difficult tuning of exciton energetics and intermolecular electronic couplings in the solid state. Antiaromatic 4nπ dibenzopentalenes (DPs) are demonstrated as a new class of single‐chromophore‐based intramolecular SF materials that exhibit an optically allowed S₂ state with E(S₂)>2×E(T₁) and an optically forbidden S₁ state. Ultrafast population transfer from a high‐lying S₂ state to a ¹(TT) state was observed in monomeric solution of styryl‐substituted DP (SDP) on a sub‐picosecond timescale. There is evidence of exciton diffusion (ED) of the ¹(TT) state to yield two individual long‐lived triplets in SDP thin film. The overall triplet yield via intramolecular SF and subsequent triplet‐pair diffusion can be as high as 142±10 % in thin film.