There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Cascade reactions in total synthesis.

C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.

3d Transition Metals for C-H Activation.

Transition metal-catalyzed direct functionalization of C–H bonds is one of the key emerging strategies that is currently attracting tremendous attention with the aim to provide alternative environmentally friendly and efficient ways for the construction of C–C and C–hetero bonds. In particular, the strategy involving regioselective C–H activation assisted by various functional groups shows high potential, and significant achievements have been made in both the development of novel reactions and the mechanistic study. In this review, we attempt to give an overview of the development of utilizing the functionalities as directing groups. The discussion is directed towards the use of different functional groups as directing groups for the construction of C–C and C–hetero bonds via C–H activation using various transition metal catalysts. The synthetic applications and mechanistic features of these transformations will be discussed, and the review is organized on the basis of the type of directing groups and the type of bond being formed or the catalyst.

Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups

Metal-catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or S(N)2'-type allylic substitution, leads to the formation of C-H, -C, -O, -N, -S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.

Metal-catalyzed enantioselective allylation in asymmetric synthesis.

Regioselective syntheses of substituted furans

DFT calculations suggest that the unexpected meta product in the copper-catalyzed arylation of anilide is formed via a Heck-like four-membered-ring transition state involving a CuIII–Ph species. A competitive electrophilic substitution mechanism delivers the ortho product when a methoxy group is present at the meta position of pivanilide. A series of experiments including kinetic studies support the involvement of a CuI catalyst.

Mechanistic understanding of the unexpected meta selectivity in copper-catalyzed anilide C-H bond arylation.

Tributylphosphine was found to be an effective promoting reagent for the ring-opening reaction of various epoxides and aziridines with nucleophile to produce corresponding anti-bifunctional products in moderate to excellent yields in water.

Efficient ring-opening reaction of epoxides and aziridines promoted by tributylphosphine in water.

Ring-opening reactions of aziridines with trimethylsilyl compounds triggered by tetrabutylammonium fluoride give the corresponding products regioselectively in excellent yield. It provides a facile and efficient procedure for the ring-opening reactions of aziridines and affords a practical access to the synthesis of cyano-, azido-, or chloroamines because of its efficiency and simplicity. The products are easily transformed to vicinal diamines or β-amino acids.

Ring-opening of N-tosylaziridines with TMSN^3 and TMSCN Triggered by TBAF: An efficient and convenient route to vicinal diamines and β=aminoacid

The rapid construction of libraries of chiral organic compounds in drug discovery and the efforts to develop highthroughput chiral-catalyst screening techniques demand rapid and sensitive analytical tools for chiral assays. Amongst many of the enantioselective methods under investigation, the use of fluorescence has attracted a sizable interest because it can offer the advantages of real-time analysis, high sensitivity, multiple sensing modes, widely available instrumentation, and remote detection capabilities. During the past several years, there has been a growing interest in the enantioselective recognition of a-hydroxycarboxylic acids, especially using fluorescence spectroscopy, 8] owing to the synthetic utility of this class of molecules and their biological significance. Several fluorescent sensors, including those developed within our group, have been reported to show high enantioselectivity in the recognition of mandelic acid and/or hexahydromandelic acid. However, the enantioselective recognition of other chiral a-hydroxycarboxylic acids is poor, and the normalized ratios of the fluorescence intensity of the sensors when treated with the two enantiomers of these acid substrates, that is IR/IS or IS/IR, are all less than 2. [4f,8]

Xue-Long Hou

Papers

Regioselective syntheses of substituted furans

Mechanistic understanding of the unexpected meta selectivity in copper-catalyzed anilide C-H bond arylation.

Efficient ring-opening reaction of epoxides and aziridines promoted by tributylphosphine in water.

Ring-opening of N-tosylaziridines with TMSN^3 and TMSCN Triggered by TBAF: An efficient and convenient route to vicinal diamines and β=aminoacid

Highly enantioselective recognition of structurally diverse alpha-hydroxycarboxylic acids using a fluorescent sensor.