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.

Palladium-catalyzed amination reactions of aryl halides have undergone rapid development in the last 12 years, largely driven by the implementation of new classes of ligands. Biaryl phosphanes have proven to provide especially active catalysts in this context. This Review discusses the application of these catalysts in C-N cross-coupling reactions in the synthesis of heterocycles and pharmaceuticals, in materials science, and in natural product synthesis.

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Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

: The unpolarized absorption and circular dichroism spectra of the fundamental vibrational transitions of the chiral molecule, 4-methyl-2-oxetanone, are calculated ab initio. Harmonic force fields are obtained using Density Functional Theory (DFT), MP2, and SCF methodologies and a 5S4P2D/3S2P (TZ2P) basis set. DFT calculations use the Local Spin Density Approximation (LSDA), BLYP, and Becke3LYP (B3LYP) density functionals. Mid-IR spectra predicted using LSDA, BLYP, and B3LYP force fields are of significantly different quality, the B3LYP force field yielding spectra in clearly superior, and overall excellent, agreement with experiment. The MP2 force field yields spectra in slightly worse agreement with experiment than the B3LYP force field. The SCF force field yields spectra in poor agreement with experiment.The basis set dependence of B3LYP force fields is also explored: the 6-31G* and TZ2P basis sets give very similar results while the 3-21G basis set yields spectra in substantially worse agreements with experiment. jg

Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields

The Diels-Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels-Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.

https://www.ch.ic.ac.uk/local/organic/pericyclic/DA.pdf

The Diels--Alder reaction in total synthesis.

2.7. Hydroxylation Reactions of Allenes 3282 2.8. Hydroamination Reactions of Allenes 3284 2.9. Hydrothiolation of Allenes 3284 2.10. Hydroalxoxylation of Alkenes and 1,3-Dienes 3286 2.11. Hydroamination of Alkenes and 1,3-Dienes 3287 2.12. Hydrothiolation of Conjugated Olefins 3289 3. Activation of Carbonyl/Imine Groups and Alcohols 3289 3.1. Condensation Reactions 3289 3.2. Addition Reactions 3291 3.3. Aldol Reactions 3294 3.4. Hydroand Carbosilylation Reactions 3295 3.5. Nucleophilic Substitution Reactions of Alcohols 3297 4. Gold-Catalyzed C-H Bond Functionalization 3297 4.1. Csp3-H Bond Functionalization 3298 4.2. Csp2-H Bond Functionalization 3299 4.3. Csp-H Bond Functionalization 3304 5. Gold-Catalyzed Selective Reductions 3305 5.1. Catalytic Hydrogenation of Alkenes 3306 5.2. Selective Reductions of R, -Unsaturated Carbonyl Groups and 1,3-Dienes 3306

Alternative synthetic methods through new developments in catalysis by gold.

Regiospecific alkylation of cyclic .beta.-diketone enol ethers. General synthesis of 4-alkylcyclohexenones

An improved method for the synthesis of .alpha.-diazo ketones

Stereospecific total synthesis of gibberellic acid. A key tricyclic intermediate

New reagents for the intermolecular and intramolecular pinacolic coupling of ketones and aldehydes

A general strategy for the synthesis of highly substituted polycyclic aromatic and heteroaromatic compounds has been developed. The new aromatic annulation is achieved simply by the irradiation of a dichloroethane solution of an acetylene derivative and a vinyl or aryl α-diazo ketone. Mechanistically, the reaction proceeds via the photochemical Wolff rearrangement of the diazo ketone to generate an aryl- or vinylketene, followed by a cascade of three pericyclic reactions. A variety of substituted phenols, naphthalenes, benzofurans, benzothiophenes, indoles, and carbazoles can be prepared by using the method

Rick L. Danheiser

Papers

Regiospecific alkylation of cyclic .beta.-diketone enol ethers. General synthesis of 4-alkylcyclohexenones

An improved method for the synthesis of .alpha.-diazo ketones

Stereospecific total synthesis of gibberellic acid. A key tricyclic intermediate

New reagents for the intermolecular and intramolecular pinacolic coupling of ketones and aldehydes

An annulation method for the synthesis of highly substituted polycyclic aromatic and heteroaromatic compounds