The 3,3'-pyrrolidinyl-spirooxindole unit is a privileged heterocyclic motif that forms the core of a large family of alkaloid natural products with strong bioactivity profiles and interesting structural properties. Significant recent advances in the synthesis of this fused heterocyclic system have led to intense interest in the development of related compounds as potential medicinal agents or biological probes.

Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents.

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.

Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.

Asymmetric multicomponent reactions (amcrs): the new frontier

The preparation of urea by Wöhler constituted a landmark achievement in organic chemistry, and it laid the ground for the early days of target-oriented organic synthesis.1 Since then, significant progress has been achieved in this discipline; many powerful single bond forming reactions and asymmetric variants have been developed. These discoveries have paved the way for the stereoselective assembly of complex organic molecules, a task deemed inconceivable by early practitioners. A great many strategies were invented by chemists in order to facilitate the synthesis of complex natural products.2 One avenue in emulating nature’s efficiency would * To whom correspondence should be addressed. E-mail: dennis.hall@ ualberta.ca. † Novartis Institute for Biomedical Research. ‡ Department of Chemistry, University of Alberta. Chem. Rev. 2009, 109, 4439–4486 4439

Natural product synthesis using multicomponent reaction strategies.

Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks

The Asymmetric Total Synthesis of (+)- and (−)-Spirotryprostatin B

Asymmetric, stereocontrolled total synthesis of (+) and (−)-spirotryprostatin B via a diastereoselective azomethine ylide [1,3]-dipolar cycloaddition reaction

Concise, asymmetric total synthesis of spirotryprostatin A.

Concise, asymmetric total synthesis of spirotryprostatin A

The asymmetric [1,3] dipolar cycloaddition reactions of azomethine ylides derived from 5,6-diphenylmorpholin-2-one with various aldehydes and ethyl oxindolylideneacetate are described. Addition of an aldehyde to the morpholin-2-one, under essentially neutral conditions, results in the preferential formation of the E-ylide which then reacts with the dipolarophile to yield spirooxindole pyrrolidine derivatives in moderate to excellent regio- and diastereoselectivities. The resulting cycloadducts were easily separated by column chromatography and converted to the corresponding amino acid methyl esters through catalytic hydrogenolysis.

Paul R. Sebahar

Papers

The Asymmetric Total Synthesis of (+)- and (−)-Spirotryprostatin B

Asymmetric, stereocontrolled total synthesis of (+) and (−)-spirotryprostatin B via a diastereoselective azomethine ylide [1,3]-dipolar cycloaddition reaction

Concise, asymmetric total synthesis of spirotryprostatin A.

Concise, asymmetric total synthesis of spirotryprostatin A

The Synthesis of Spirooxindole Pyrrolidines via an Asymmetric Azomethine Ylide [1,3]-Dipolar Cycloaddition Reaction