Catalytic asymmetric synthesis of spirooxindoles: recent developments

ConspectusCatalytic asymmetric cycloadditions and cascade cyclizations are a major focus for the enantioselective construction of chiral carbo- and heterocycles. A number of chiral Lewis acids and organocatalysts have been designed for such reactions. The development of broadly applicable catalysts bearing novel chiral backbones to meet the demands of various applications is an ongoing challenge. Approximately 10 years ago, we introduced a group of conformationally flexible C2-symmetric N,N′-dioxide amide compounds, which represent a new class of privileged ligands. The coordination of the four oxygens of a chiral N,N′-dioxide around a central metal generates an octahedral tricyclometalated Lewis acid catalyst that can carry out various enantioselective reactions. In this Account, we summarize our recent studies on asymmetric cycloadditions between various dienophiles and dienes, dipoles and dipolarophiles, and cascade cyclizations catalyzed by chiral N,N′-dioxide–metal complexes. In principle, these uniq...

Asymmetric Cycloaddition and Cyclization Reactions Catalyzed by Chiral N,N′-Dioxide–Metal Complexes

The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.

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New development in the enantioselective synthesis of spiro compounds

The catalytic enantioselective assembly of spirocyclic molecules featuring a spiro quaternary carbon stereocenter is currently of great interest because such privileged 3D structures are widely present in natural products that exhibit a broad spectrum of biological and pharmacological activities. This review summarizes the advances based on six major synthetic strategies and showcases the reaction mechanisms in detail. The advantages and limitations of each synthetic strategy are presented, and the remaining synthetic opportunities are outlined.

Catalytic Enantioselective Construction of Spiro Quaternary Carbon Stereocenters

Recent developments in catalytic asymmetric aldol reactions have been summarized. Enantioselective aldol reactions are important methods to synthesize β-hydroxy carbonyl compounds in optical pure form, and as such, numerous successful chiral catalysts were designed and applied for asymmetric aldol reactions. This review article is organized under the categories of: (1) catalytic enantioselective aldol reactions of preformed enolates, (2) catalytic enantioselective direct-type aldol reactions using chiral metal catalysts, (3) catalytic enantioselective direct-type aldol reactions using organocatalysts, (4) catalytic enantioselective aldol reactions in aqueous media. Examples of the aldol reactions that employ simple carbonyl compounds will be also the focus of this review.

Catalytic enantioselective aldol reactions

A highly efficient enantioselective [2+2] cycloaddition between alkynones and cyclic enol silyl ethers was developed by using a chiral N,N'-dioxide-zinc(II) complex as a catalyst. This method functions well for a variety of terminal alkynes as well as cyclic enol silyl ethers, with good to excellent enantioselectivity (up to 97 % ee). This is also the first successful example for the catalytic enantioselective [2+2] cycloaddition of internal alkynes with cyclic enol silyl ethers to give fully substituted cyclobutenes. Meanwhile, the desired cyclobutene product can easily be transformed into fused cyclobutane derivatives.

A Chiral N,N'-Dioxide-Zn(II) Complex Catalyzes the Enantioselective [2+2] Cycloaddition of Alkynones with Cyclic Enol Silyl Ethers.

Asymmetric Synthesis of Spiro-epoxyoxindoles by the Catalytic Darzens Reaction of Isatins with Phenacyl Bromides

Highly diastereo- and enantioselective synthesis of spirooxindole-cyclohexaneamides through N,N′-dioxide/Ni(II)-catalyzed Diels–Alder reactions

N,N′-Dioxide/nickel(II)-catalyzed asymmetric Diels–Alder reaction of cyclopentadiene with 2,3-dioxopyrrolidines and 2-alkenoyl pyridines

A highly efficient enantioselective inverse-electron-demand hetero-Diels–Alder reaction of dioxopyrrolidines with heterosubstituted alkenes has been realized by using a N,N′-dioxide/Ni(II) complex as the catalyst. A series of chiral bicyclic dihydropyranes were generated in excellent yields, good dr, and excellent ee values. Besides, a catalytic cycle with a possible transition state was proposed.

Yan Lu

Papers

A Chiral N,N'-Dioxide-Zn(II) Complex Catalyzes the Enantioselective [2+2] Cycloaddition of Alkynones with Cyclic Enol Silyl Ethers.

Asymmetric Synthesis of Spiro-epoxyoxindoles by the Catalytic Darzens Reaction of Isatins with Phenacyl Bromides

Highly diastereo- and enantioselective synthesis of spirooxindole-cyclohexaneamides through N,N′-dioxide/Ni(II)-catalyzed Diels–Alder reactions

N,N′-Dioxide/nickel(II)-catalyzed asymmetric Diels–Alder reaction of cyclopentadiene with 2,3-dioxopyrrolidines and 2-alkenoyl pyridines

Catalytic Asymmetric Inverse-Electron-Demand Hetero-Diels–Alder Reaction of Dioxopyrrolidines with Hetero-Substituted Alkenes