https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

In studying the evolution of organic chemistry and grasping its essence, one comes quickly to the conclusion that no other type of reaction plays as large a role in shaping this domain of science than carbon-carbon bond-forming reactions. The Grignard, Diels-Alder, and Wittig reactions are but three prominent examples of such processes, and are among those which have undeniably exercised decisive roles in the last century in the emergence of chemical synthesis as we know it today. In the last quarter of the 20th century, a new family of carbon-carbon bond-forming reactions based on transition-metal catalysts evolved as powerful tools in synthesis. Among them, the palladium-catalyzed cross-coupling reactions are the most prominent. In this Review, highlights of a number of selected syntheses are discussed. The examples chosen demonstrate the enormous power of these processes in the art of total synthesis and underscore their future potential in chemical synthesis.

Palladium-catalyzed cross-coupling reactions in total synthesis.

4.2.8. Reductive Coupling 3109 5. Reaction of Aromatic Compounds 3110 5.1. Electrophilic Substitutions 3110 5.2. Radical Substitution 3111 5.3. Oxidative Coupling 3111 5.4. Photochemical Reactions 3111 6. Reaction of Carbonyl Compounds 3111 6.1. Nucleophilic Additions 3111 6.1.1. Allylation 3111 6.1.2. Propargylation 3120 6.1.3. Benzylation 3121 6.1.4. Arylation/Vinylation 3121 6.1.5. Alkynylation 3121 6.1.6. Alkylation 3121 6.1.7. Reformatsky-Type Reaction 3122 6.1.8. Direct Aldol Reaction 3122 6.1.9. Mukaiyama Aldol Reaction 3124 6.1.10. Hydrogen Cyanide Addition 3125 6.2. Pinacol Coupling 3126 6.3. Wittig Reactions 3126 7. Reaction of R,â-Unsaturated Carbonyl Compounds 3127

Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond Formations: A Decade Update

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.

An account of two synthetic approaches to the pentagonal dodecahedrane based upon the “pincer” Diels-Alder reaction of 9,10-dihydrofulvalene and dimethyl acetylenedicarboxylate is given. In both schemes, the strategem calls for the maintenance of symmetry in all intermediates as a means of minimizing the total number of requisite synthetic manipulations and permitting maximum utilization of l3C NMR spectroscopy.

Quest for the pentagonal dodecahedrane

Gas-Phase Basicities of Cubane, Dodecahedrane, and Methyl- and 1,16-Dimethyldodecahedrane as Measured by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry.

A series of homologous α-sulfonamidyl radicals has been generated by reaction of α-halomethyl precursors with tri-n-butyltin hydride under AIBN catalysis. The intramolecular cyclization capability of these highly reactive intermediates has been evaluated. Where possible, five-membered sultams are formed by 5-exo transition states. The longer C−SO2 and SO2−NR2 bonds have little demonstrable effect on this pathway. In larger systems, however, the 7-endo option predominates over the 6-exo alternative. A preparatively useful route to sultams has emerged from this investigation.

Intramolecular Cyclization of Radicals Generated from α-Halomethylsulfonamides.

A useful method is presented for controlling whether linear or angular triquinanes are formed during a reaction cascade initiated by the 2-fold addition of alkenyl anions to diisopropyl squarate. The key feature of the process involves the incorporation of a leaving group into one of the original nucleophilic reagents. Placement of the nucleofuge within a cyclic anion leads ultimately to formation of a linear product. Extracyclic and intracyclic options are possible, with preference given to the better leaving group when a competitive situation exists. When the leaving group is incorporated into an acyclic component, angular triquinanes result instead. Several other aspects of this impressive scaffolding scheme are detailed.

Realization of Complete Regiochemical Control During the Conversion of Squarate Esters into Complex Linear and Angular Polyquinanes. The Consequences of Incorporating a Leaving Group into One of the Alkenyllithium Reactants.

The tandem addition of an alkenyllithium reagent and a 2-lithioallylamine to squarate esters has been systematically examined. The effect of the sequencing of this twofold addition has been investigated. The extent to which the amino group is eliminated was found to be dependent on the structural features of the companion nucleophile. Also assessed was the comparative ease with which the amino and methoxy groups experience competitive β-elimination from the highly reactive, medium-ring dianionic intermediates. Attempts were made to curtail the level of competing 1,4-addition, and success was achieved by increasing the effective size of the O-alkyl groups in the squarate ester. The highly stereocontrolled transformations described represent a notably direct means for producing highly fused polycyclic compounds. Mechanistic considerations surrounding these reactions, which are characterized by an impressive enhancement of molecular scaffolding, are discussed.

Evaluation of Amino Substituents as Nucleofugal Controllers of Regioselectivity and as Chelate Modulators of Stereoselectivity in Squarate Ester Cascades.

Leo A. Paquette

Papers

Quest for the pentagonal dodecahedrane

Gas-Phase Basicities of Cubane, Dodecahedrane, and Methyl- and 1,16-Dimethyldodecahedrane as Measured by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry.

Intramolecular Cyclization of Radicals Generated from α-Halomethylsulfonamides.

Realization of Complete Regiochemical Control During the Conversion of Squarate Esters into Complex Linear and Angular Polyquinanes. The Consequences of Incorporating a Leaving Group into One of the Alkenyllithium Reactants.

Evaluation of Amino Substituents as Nucleofugal Controllers of Regioselectivity and as Chelate Modulators of Stereoselectivity in Squarate Ester Cascades.