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.

Recent advances in natural product synthesis by using intramolecular Diels-Alder reactions.

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

Stereocontrolled synthesis of tetrasubstituted olefins.

Selective monodeprotection of bis-silyl ethers

The condensation of (+)-7,7-dimethoxynorbornen-2-one with the cerium reagent derived from enantiopure bromide (+)-11 gives rise to an exo carbinol, which readily undergoes highly stereocontrolled anionic oxy-Cope rearrangement. Conversion of the resulting ketone into 20 proceeds with clean epimerization at C-11 (spinosyn numbering) to properly set the absolute configuration at that site. Reduction of 20 with lithium in liquid ammonia serves to introduce two additional stereogenic centers of the perhydro-as-indacene core. In addition, the protocol makes possible the convenient incorporation of a functionalized two-carbon appendage at C-3 and ultimate generation of a cyclohexene double bond after stereochemical inversion at C-7. This scheme leads to 34, a tricyclic compound subsequently shown to be an advanced precursor to the powerful insecticide spinosyn A.

Total Synthesis of Spinosyn A. 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme

Synthetic studies on spinosyn A. Convenient enantioselective construction of a suitably functionalized trans,anti,cis-decahydro-as-indacene intermediate via [3.3] sigmatropy and double configurational inversion

Total Synthesis of Spinosyn A. Part 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme.

An enantioselective route to the decahydro-as-indacene15 is described. Anionic oxy-Cope rearrangement of alcohol 5 initiates the sequence, which capitalizes on thermodynamics to control ultimate elaboration of the four key stereogenic centers resident in the several intermediates.

Synthetic Studies on Spinosyn A. Convenient Enantioselective Construction of a Suitably Functionalized trans,anti,cis-Decahydro-as- indacene Intermediate via (3.3) Sigmatropy and Double Configurational Inversion.

Zhongli Gao

Papers

Total Synthesis of Spinosyn A. 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme

Synthetic studies on spinosyn A. Convenient enantioselective construction of a suitably functionalized trans,anti,cis-decahydro-as-indacene intermediate via [3.3] sigmatropy and double configurational inversion

Total Synthesis of Spinosyn A. Part 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme.

Synthetic Studies on Spinosyn A. Convenient Enantioselective Construction of a Suitably Functionalized trans,anti,cis-Decahydro-as- indacene Intermediate via (3.3) Sigmatropy and Double Configurational Inversion.