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.

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Advances in transition metal (Pd, Ni, Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners.

The development of new palladium catalysts for the arylation of amines and alcohols with aryl halides and sulfonates is reviewed. Initial systems as well as mechanistic issues are discussed briefly, while subsequent generations of catalysts are described in greater detail. For these later generations of catalysts, substrate scope and limitations are also discussed. The review is organized by substrate class. Modifications and improvements in technical aspects of reaction development are described where appropriate. In addition, applications of this technology toward natural product synthesis, new synthetic methodology, and medicinal chemistry are chronicled. This review is organized in a manner that is designed to be useful to the synthetic organic chemist.

Practical Palladium Catalysts for C-N and C-O Bond Formation

Palladium-catalyzed amination of aryl halides and sulfonates

Die Entwicklung und Umsetzung von Kaskadenreaktionen hat zu beachtlichen neuartigen, eleganten und effizienten Synthesestrategien gefuhrt. Als besonders anspruchsvoll erwies sich die Anwendung von Kaskadenreaktionen in der Naturstoffsynthese, doch gerade hier winken verbluffende und zugleich aufschlussreiche Ergebnisse als Belohnung. In diesem Aufsatz werden ausgewahlte Kaskadenreaktionen in der Totalsynthese erlautert, wobei neuere Anwendungen besonders hervorgehoben werden. Die erorterten Beispiele sollen die Leistungsfahigkeit dieser Prozesse beim Aufbau von komplexen Molekulstrukturen veranschaulichen und ihr Potenzial fur zukunftige chemische Synthesen verdeutlichen.

Kaskadenreaktionen in der Totalsynthese

A convergent biomimetic synthesis of hemibrevetoxin B from d-glucal and d-arabinose utilizes an electrophile-promoted cascade anti-Baldwin cyclization of an epoxy alcohol. The epoxy alcohol arises from a palladium-catalyzed coupling of a highly functionalized organozinc compound and an alkenyl iodide, which serve as two chiral building blocks of similar size and complexity. This first successful implementation of a cascade epoxy alcohol cyclization for the synthesis of marine polycyclic ether toxins proceeds in 39 steps and 4% overall yield.

A Convergent Total Synthesis of Hemibrevetoxin B

Ortho-Directed Metalation of 3-Carboxy-beta-carbolines: Use of the SmI(2)-Cleavable 9-N-(N',N'-Dimethylsulfamoyl) Blocking Group for the Preparation of 9-N-Deprotected 4-Amino Derivatives via Azide Introduction or a Palladium-Catalyzed Cross-Coupling Reaction.

ortho-Directed Metalation of 3-Carboxy-β-carbolines: Use of the SmI2-Cleavable 9-N-(N′,N′-Dimethylsulfamoyl) Blocking Group for the Preparation of 9-N-Deprotected 4-Amino Derivatives via Azide Introduction or a Palladium-Catalyzed Cross-Coupling Reaction.

A Convergent Total Synthesis of Hemibrevetoxin B.

Preparation of 4-Iodo-β-carboline-3-carboxamide via ortho-Metalation and Its Use in Palladium-Catalyzed Carbon—Carbon Bond Forming Reactions with Unsaturated Substrates.

Alexandre Batch

Papers

A Convergent Total Synthesis of Hemibrevetoxin B

Ortho-Directed Metalation of 3-Carboxy-beta-carbolines: Use of the SmI(2)-Cleavable 9-N-(N',N'-Dimethylsulfamoyl) Blocking Group for the Preparation of 9-N-Deprotected 4-Amino Derivatives via Azide Introduction or a Palladium-Catalyzed Cross-Coupling Reaction.

ortho-Directed Metalation of 3-Carboxy-β-carbolines: Use of the SmI2-Cleavable 9-N-(N′,N′-Dimethylsulfamoyl) Blocking Group for the Preparation of 9-N-Deprotected 4-Amino Derivatives via Azide Introduction or a Palladium-Catalyzed Cross-Coupling Reaction.

A Convergent Total Synthesis of Hemibrevetoxin B.

Preparation of 4-Iodo-β-carboline-3-carboxamide via ortho-Metalation and Its Use in Palladium-Catalyzed Carbon—Carbon Bond Forming Reactions with Unsaturated Substrates.