The Role of Attractive Non-Covalent Interactions in Peptide Macrocyclization.

The efficiency of macrocyclization reactions relies on the appropriate conformational preorganization of a linear precursor, ensuring that reactive ends are in spatial proximity prior to ring closure. Traditional peptide cyclization approaches that reduce the extent of terminal ion pairing often disfavor cyclization-conducive conformations and can lead to undesired cyclodimerization or oligomerization side reactions, particularly when they are performed without high dilution. To address this challenge, synthetic strategies that leverage attractive noncovalent interactions, such as zwitterionic attraction between chain termini during macrocyclization, offer a potential solution by reducing the entropic penalty associated with linear peptides adopting precyclization conformations. In this study, we investigate the role of (N-isocyanoimino)triphenylphosphorane (Pinc) in facilitating the cyclization of linear peptides into conformationally rigid macrocycles. The observed moderate diastereoselectivity is consistent with the preferential Si-facial addition of Pinc, where the isocyanide adds to the E-iminium ion on the same face as the l-proline amide group. The resulting peptide chain reveals that the activated phosphonium ylide of Pinc brings the reactive ends close together, promoting cyclization by enclosing the carboxylate within the interior of the pentapeptide and preventing the formation of byproducts. For shorter peptides with modified peptide backbones, the cyclization mechanism and outcome are redirected, as nucleophilic motifs such as thiazole and imidazole can covalently trap nitrilium intermediates. The isolation of the intermediate in the unproductive macrocyclization pathway, along with nuclear magnetic resonance and density functional theory studies, provides insights into heterocycle-dependent selectivity. The Pinc-driven macrocyclization process has generated diverse collections of cyclic molecules, and our models offer a comprehensive understanding of observed trends, facilitating the development of other heterocycle-forming macrocyclization reactions.

Competition between C-C and C-H Bond Fluorination: A Continuum of Electron Transfer and Hydrogen Atom Transfer Mechanisms.

In 2015, we reported a photochemical method for directed C-C bond cleavage/radical fluorination of relatively unstrained cyclic acetals using Selectfluor and catalytic 9-fluorenone. Herein, we provide a detailed mechanistic study of this reaction, during which it was discovered that the key electron transfer step proceeds through substrate oxidation from a Selectfluor-derived N-centered radical intermediate (rather than through initially suspected photoinduced electron transfer). This finding led to proof of concept for two new methodologies, demonstrating that unstrained C-C bond fluorination can also be achieved under chemical and electrochemical conditions. Moreover, as C-C and C-H bond fluorination reactions are both theoretically possible on 2-aryl-cycloalkanone acetals and would involve the same reactive intermediate, we studied the competition between single-electron transfer (SET) and apparent hydrogen-atom transfer (HAT) pathways in acetal fluorination reactions using density functional theory. Finally, these analyses were applied more broadly to other classes of C-H and C-C bond fluorination reactions developed over the past decade, addressing the feasibility of SET processes masquerading as HAT in C-H fluorination literature.

C-C Bond Activation and Demethylenation of Epoxides by Amine Radical Dications.

In this note, we explore a unique reactivity pattern that involves a rare radical-based C-C bond scission of epoxides followed by demethylenation. The reaction is accomplished by Selecfluor and its radical dication working in tandem; a mechanism supported by experiment and DFT calculations is proposed that involves the generation and identification of a key reactive intermediate. The reaction seems to be fairly general for 1,1-disubstituted epoxides.

N-Heterocyclic Carbene Organocatalyzed Redox-Active/Ring Expansion Reactions: Mechanistic Insights Unveiling Base Cooperativity.

N-Heterocyclic carbene (NHC) organocatalyzed transformations of redox-active chemical manifolds is a powerful strategy for interconverting and expanding the chemical space. This approach in the context of ring expansion holds promise for preparing lactones from plentiful redox active aldehydes, despite a lack of rigorous mechanistic insights into the underlying elements governing this reactivity and with-it relevance to other NHC organocatalyzed transformations. Herein, in investigating this reactivity under the lens of modern day quantum mechanical calculations, we explore the mechanism of redox-active/ring expansion reactions of aldehydes furnishing lactone products by means of NHC organocatalysis. Through this comprehensive study, the underpinning mechanism of Breslow intermediate formation and ensuing downstream processes such as intermolecular C-C bond formation providing benzoin products versus intramolecular redox pathways are outlined. Notably, this study of NHC organocatalysis reveals the diverse role of bases as cooperative agents in directing and selectively routing reactivity, as highlighted here toward ring expanded lactone products.

Cooperative Noncovalent Interactions Lead to a Highly Diastereoselective Sulfonyl-Directed Fluorination of Steroidal α,ß-Unsaturated Hydrazones.

A series of steroidal α,ß-unsaturated hydrazones is presented whose behavior and reactivity are governed by various types of weak C-H hydrogen bonds. Several interesting features in a representative X-ray crystal structure and 1H NMR spectrum are examined that provide evidence for a unique bifurcated intramolecular C-H interaction. Moreover, these steroid derivatives undergo functionalization in the form of a highly regio- and stereoselective fluorination; the sulfonyl oxygen atoms are proposed to direct the fluorinating reagent through C-H hydrogen bonds.

Stereoelectronic and Resonance Effects on the Rate of Ring Opening of N-Cyclopropyl-Based Single Electron Transfer Probes.

N-Cyclopropyl-N-methylaniline (5) is a poor probe for single electron transfer (SET) because the corresponding radical cation undergoes cyclopropane ring opening with a rate constant of only 4.1 × 104 s-1, too slow to compete with other processes such as radical cation deprotonation. The sluggish rate of ring opening can be attributed to either (i) a resonance effect in which the spin and charge of the radical cation in the ring-closed form is delocalized into the phenyl ring, and/or (ii) the lowest energy conformation of the SET product (5•+) does not meet the stereoelectronic requirements for cyclopropane ring opening. To resolve this issue, a new series of N-cyclopropylanilines were designed to lock the cyclopropyl group into the required bisected conformation for ring opening. The results reveal that the rate constant for ring opening of radical cations derived from 1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (6) and 6'-chloro-1'-methyl-3',4'-dihydro-1'H-spiro[cyclopropane-1,2'-quinoline] (7) are 3.5 × 102 s-1 and 4.1 × 102 s-1, effectively ruling out the stereoelectronic argument. In contrast, the radical cation derived from 4-chloro-N-methyl-N-(2-phenylcyclopropyl)aniline (8) undergoes cyclopropane ring opening with a rate constant of 1.7 × 108 s-1, demonstrating that loss of the resonance energy associated with the ring-closed form of these N-cyclopropylanilines can be amply compensated by incorporation of a radical-stabilizing phenyl substituent on the cyclopropyl group. Product studies were performed, including a unique application of EC-ESI/MS (Electrochemistry/ElectroSpray Ionization Mass Spectrometry) in the presence of 18O2 and H218O to elucidate the mechanism of ring opening of 7•+ and trapping of the resulting distonic radical cation.

Site-Selective Photochemical Fluorination of Ketals: Unanticipated Outcomes in Selectivity and Stability.

We report a method for the regioselective photochemical sp3 C-H fluorination of acetonide ketals that presents interesting problems in chemical reactivity. The question of why certain products of the reaction are stable while others are not is addressed, as is the question of why only select α-ethereal hydrogen atoms are targeted in the reaction. We demonstrate that the method can be employed to synthesize unprecedented fluorinated sugars and steroids, and it can also be applied toward the fluorination of carbamates. Though some substrates contain up to eight discrete α-ethereal C-H bonds, we observed site-selectivity in each case, prompting us to investigate potential transition states for the reaction. Finally, a remarkable regiochemical switch upon minor structural modification of a diketal is also analyzed.

Selective Aerobic Oxidation of Benzylic Alcohols Catalyzed by a Dicyclopropenylidene-Ag(I) Complex.

The unprecedented synthesis, single-crystal X-ray structure, and first catalytic application of a dicarbene-Ag(I) complex [Ag(BAC)2][CO2CF3] (BAC = bis(diisopropyl)aminocyclopropenylidene) is reported. This novel complex provides a versatile catalytic platform for selective aerobic oxidation of benzylic alcohols to aldehyde or ketone products in high yields. Ease of experimental execution coupled with the use of abundant atmospheric molecular oxygen as an oxidant and low catalyst loading are inherit strengths of these oxidations.

Azo synthesis meets molecular iodine catalysis.

A metal-free synthetic protocol for azo compound formation by the direct oxidation of hydrazine HN-NH bonds to azo group functionality catalyzed by molecular iodine is disclosed. The strengths of this reactivity include rapid reaction times, low catalyst loadings, use of ambient dioxygen as a stoichiometric oxidant, and ease of experimental set-up and azo product isolation. Mechanistic studies and density functional theory computations offering insight into this reactivity, as well as the events leading to azo group formation are presented. Collectively, this study expands the potential of main-group element iodine as an inexpensive catalyst, while delivering a useful transformation for forming azo compounds.

Diversity-oriented synthesis of glycomimetics.

Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates.