This Review describes singlet oxygen (1O2) in the organic synthesis of targets on possible 1O2 biosynthetic routes. The visible-light sensitized production of 1O2 is not only useful for synthesis; it is extremely common in nature. This Review is intended to draw a logical link between flow and batch reactions—a combination that leads to the current state of 1O2 in synthesis.

Using Singlet Oxygen to Synthesize Natural Products and Drugs

The native chemical ligation reaction (NCL) involves reacting a C-terminal peptide thioester with an N-terminal cysteinyl peptide to produce a native peptide bond between the two fragments. This reaction has considerably extended the size of polypeptides and proteins that can be produced by total synthesis and has also numerous applications in bioconjugation, polymer synthesis, material science, and micro- and nanotechnology research. The aim of the present review is to provide a thorough mechanistic overview of NCL and extended methods. The most relevant properties of peptide thioesters, Cys peptides, and common solvents, reagents, additives, and catalysts used for these ligations are presented. Mechanisms, selectivity and reactivity are, whenever possible, discussed through the insights of computational and physical chemistry studies. The inherent limitations of NCL are discussed with insights from the mechanistic standpoint. This review also presents a palette of O, S-, N, S-, or N, Se-acyl shift systems as thioester or selenoester surrogates and discusses the special molecular features that govern reactivity in each case. Finally, the various thiol-based auxiliaries and thiol or selenol amino acid surrogates that have been developed so far are discussed with a special focus on the mechanism of long-range N, S-acyl migrations and selective dechalcogenation reactions.

Native Chemical Ligation and Extended Methods: Mechanisms, Catalysis, Scope, and Limitations

The late-stage modification of structurally complex peptides bears great potential for drug discovery, crop protection, and the pharmaceutical industry, among others. Whereas traditional approaches largely rely on prefunctionalizations, C-H activation catalysis has in recent years emerged as an increasingly powerful tool for post-translational peptide modifications in a step-economic manner. Herein, we summarize recent progress in organometallic C-H activation on peptides until June 2018, including position- and chemoselective palladium-, ruthenium-, and manganese-catalyzed processes.

Late-Stage Peptide Diversification by Position-Selective C-H Activation.

The first catalytic formal [5+4] cycloaddition to prepare nine-membered heterocycles is presented. Under palladium catalysis, the reaction of N-tosyl azadienes and substituted vinylethylene carbonates (VECs) proceeds smoothly to produce benzofuran-fused heterocycles in uniformly high efficiency. Highly diastereoselective functionalization of the nine-membered heterocycles through peripheral attack is also demonstrated.

Construction of Nine-Membered Heterocycles through Palladium-Catalyzed Formal [5+4] Cycloaddition

The first enantioselective formal [5+4] cycloaddition is realized under palladium catalysis to deliver benzofuran-fused nine-membered rings. These medium-sized heterocycles and derivatives undergo unique rearrangements induced by transannular bond formation, resulting in the production of two classes of densely substituted polycyclic heterocycles in excellent efficiency and stereoselectivity.

Nine-Membered Benzofuran-Fused Heterocycles: Enantioselective Synthesis by Pd-Catalysis and Rearrangement via Transannular Bond Formation

Financial support of the Spanish Ministry of Science and
Innovation (CTQ2012-38543-C03) and Generalitat Valenciana
(PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the
Spanish Ministry of Science and Education for a predoctoral
fellowship (FPU AP2007-02562) and Generalitat Valenciana for
a VALi+d postdoctoral fellowship (APOSTD/2013/041).
M.D.P. thanks the Spanish Ministry of Education for a
postdoctoral fellowship and UGC India for a Startup Grant.

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

A pseudopeptidic compound comprising a central C2 symmetric bis(aminoamide) moiety derived from the amino acid serine and two pyrene groups at the ends, Et(SerPyr)2, has been efficiently prepared. In aqueous solution, it displays fluorescence bands typical of both monomer and excimer pyrene emission. In particular, the emission at 490 nm, due to the excimer, is strongly pH-dependent, with a linear 4.7-fold increase from pH 6.0 to pH 4.2. This feature makes Et(SerPyr)2 suitable for intracellular pH sensing in the acidic range. A fluorescence microscopy study revealed that Et(SerPyr)2 allows the visualization of acidic organelles in human lung adenocarcinoma A549 cells, as well as their pH changes over time. Other advantages of this probe include its easy and modular synthesis, good photostability, high quantum yield, fast optical response, large Stokes shift (ca. 145 nm) and low cytotoxicity.

Mrituanjay D. Pandey

Papers

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

Pseudopeptidic fluorescent on-off pH sensor based on pyrene excimer emission: Imaging of acidic cellular organelles

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template‐Induced Preorganization