Xianxing Jiang

Highly Enantioselective Synthesis of γ-Nitro Heteroaromatic Ketones in a Doubly Stereocontrolled Manner Catalyzed by Bifunctional Thiourea Catalysts Based on Dehydroabietic Amine: A Doubly Stereocontrolled Approach to Pyrrolidine Carboxylic Acids

A new class of dehydroabietic amine-substituted primary amine-thiourea bifunctional catalysts were designed and synthesized. The doubly stereocontrolled organocatalytic conjugate addition of a variety of heterocycles-bearing ketones to nitroalkenes was investigated for the first time, affording (S)- or (R)-gamma-nitro heteroaromatic ketones with excellent enantioselectivities (up to ee >99%). Furthermore, the nearly optically pure gamma-nitro heteroaromatic ketones can be readily transformed into chiral pyrrolidine carboxylic acids.

Highly Enantioselective Organocatalyzed Vinylogous Michael-Type Reaction for the Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters

The first example of a highly enantioselective vinylogous Michael-type reaction of β,β-disubstituted nitroalkenes is disclosed. A series of biologically important chiral oxindoles, featuring a trifluoromethylated all-carbon quaternary chiral center, were obtained in good yields with excellent enantioselectivities (up to >99% ee).

Copper-catalyzed oxyazidation of unactivated alkenes: a facile synthesis of isoxazolines featuring an azido substituent.

A novel and efficient Cu(OAc)2-catalyzed oxyazidation of unactivated alkenes was developed. The reactions are easy to conduct, occur under mild conditions, and form azido-substituted isoxazolines in good yields.

Bifunctional Organocatalytic Strategy for Inverse‐Electron‐Demand Diels–Alder Reactions: Highly Efficient In Situ Substrate Generation and Activation to Construct Azaspirocyclic Skeletons

The catalytic asymmetric Diels–Alder reaction (DAR) is among the most powerful protocols for the stereoselective construction of six-membered functionalized cyclic frameworks. Its versatility in the synthesis of diverse natural products provides organic chemists with a prodigious starting point to discover new reaction modes for this cycloaddition. In the wake of the emergence of the first metal complexes for the Lewis acid catalyzed asymmetric inverse-electrondemand Diels–Alder reactions (IEDDAR) through the LUMO-lowering strategy reported by the group of Kobayashi, several remarkable studies have been presented involving the activation of dienes through lowering of the LUMO energy by Lewis acidic metal complexes or organic molecules [Eq. (1), Scheme 1]. Recently, amine organocatalysis has been attracting considerable interest since the development of the highly enantioselective organocatalytic DAR by MacMillan and co-workers. Alternatively, Jørgensen and co-workers reported the first organocatalytic asymmetric IEDDAR with dienophiles whose HOMO energy has been raised by an enamine activation [Eq. (2)], and considerable advances in this field have recently been achieved by the Chen group. Bifunctional organocatalysis has emerged as a potentially powerful tool in catalytic asymmetric synthesis. This concept aims to efficiently achieve asymmetric transformations that cannot be approached by using either a Lewis acid or base catalyst alone. To the best of our knowledge, there is no report to date of an asymmetric IEDDAR that is controlled with a single reactive catalyst through a bifunctional activation strategy; that is simultaneous activation of the HOMO of the dienophile and the LUMO of the diene [Eq. (3)]. There is a report on the use of a combination of an enamine with metal Lewis acid activation that proved to have potential for this transformation. Herein, we introduce a bifunctional catalyst for an in situ substrate generation/ activation strategy as a new platform for the design of organocatalytic intermolecular cycoaddition processes. In this context, we document the first highly enantioselective bifunctional catalytic IEDDAR that involves dual control of the HOMOdienophiles and LUMOdienes energies of the substrates. The spirocyclic core is a privileged structural element that is featured in a large number of naturally occurring bioactive alkaloids. Although the significant bioactivity and preparation methods of such motifs attract the interest of chemists, as reported in some elegant works including intramolecular alkylation, metal-based cyclization, intermolecular cycloaddition, rearrangements, and other reactions, the enantioselective catalytic approach to access chiral spiro architectures containing all-carbon quaternary stereocenters still remains challenging. As an important skeleton in the larger spirocycle family, the spirolactam scaffold not only often shows interesting biological activities, but it can also act as an intermediate in the synthesis of more sophisticated spirocyclic frameworks (Figure 1). However, it is worth noting that the enantioselective catalytic synthesis of this kind of skeleton has not yet been established. Given the demand for new catalytic asymmetric methodology for the construction of spirocyclic scaffolds, we present a highly efficient in situ generation/ activation catalytic system that allows rapid construction of highly functionalized chiral spirocyclic skeletons with allcarbon quaternary stereocenters using the above-mentioned bifunctional strategy for catalytic asymmetric IEDDAR of cyclic keto/enolate salts. We postulated that cyclic keto/enolates could serve as the perfect dienophiles because of their high reactivity as well as unique structural characteristics for the construction of spirocycles. However, enolates require harsh conditions and Scheme 1. Different activation strategies for the IEDDAR. LA = Lewis acid, LB = Lewis base.

Asymmetric aza-Mannich addition of oxazolones to N-tosyl aldimines: synthesis of chiral alpha-disubstituted alpha,beta-diamino acids.

An organocatalytic enantioselective addition of oxazolones to N-tosyl aldimines has been developed. The process is promoted by a readily prepared cinchona alkaloid ligand and affords a series of valuable alpha-disubstituted alpha,beta-diamino acid derivatives with excellent enantioselectivities (up to 97% ee) and diastereoselectivities (up to >30:1 dr). The adducts can be transformed into the corresponding protected chiral alpha-disubstituted alpha,beta-diamino acids by a one-pot hydrolyzed reaction smoothly.

Catalytic Asymmetric β,γ Activation of α,β-Unsaturated γ-Butyrolactams: Direct Approach to β,γ-Functionalized Dihydropyranopyrrolidin-2-ones†

Skeleton in the closet: The title reaction enables the development of the first catalytic β,γ-selective Diels-Alder [4+2] annulation of α,β-unsaturated γ-butyrolactams (see scheme; Boc=tert-butoxycarbonyl, Ts=4-toluenesulfonyl). This process provides a direct method for the enantioselective construction of bi- or tricyclic dihydropyranopyrrolidin-2-one skeletons in only one step.

Direct organocatalytic asymmetric aldol reaction of alpha-isothiocyanato imides to alpha-ketoesters under low ligand loading : a doubly stereocontrolled approach to cyclic thiocarbamates bearing chiral quaternary stereocenters

The first doubly stereocontrolled organocatalytic asymmetric aldol reaction of alpha-isothiocyanato imides with alpha-ketoesters by using rosin-derived tertiary amine-thiourea under low ligand loading to form cyclic thiocarbamates bearing quaternary stereogenic centers with high levels of enantio- and diastereoselectivity (up to 99% ee, and 97:3 dr) is presented. This reaction provides a convenient doubly stereocontrolled method to access synthetic useful multiply substituted cyclic thiocarbamates with high optical purity.

Core Scaffold-Inspired Stereoselective Synthesis of Spiropyrazolones via an Organocatalytic Michael/Cyclization Sequence

Herein, the organocatalytic asymmetric Michael/cyclization sequence of α-isothiocyanato imides and esters with a variety of unsaturated pyrazolones is presented, in general, affording functionalized spiropyrazolones containing three contiguous stereogenic centers in high levels of diastereo- and enantioselectivity (up to 20:1 dr and 99% ee). Moreover, the current protocol provides a highly efficient and convenient strategy that allows rapid enantioselective construction of diversely spiropyrazolone skeletons with high optical purity.

Highly Enantioslective Synthesis of Multisubstituted Polyfunctional Dihydropyrrole via an Organocatalytic Tandem Michael/Cyclization Sequence

A unique approach to asymmetric synthesis of various optically pure multisubstituted 2,3-dihydropyrroles catalyzed by a novel rosin-derived tertiary amine-thiourea via a tandem Michael/cyclization sequence with high yield (up to 97%) and good to excellent enantioselectivities (up to 97% ee) is present. This strategy provides an efficient and convenient method to access enantioenrich nitrogen heterocycles.

Asymmetric Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction for the Construction of Bicyclic Skeletons with Multiple Stereocenters by Using a Bifunctional Organocatalytic Strategy: An Efficient Approach to Chiral Macrolides

We have performed the first bifunctional organocatalytic highly enantioselective inverse-electron-demand hetero-Diels-Alder reaction of cyclic ketones with enones to afford densely functionalized bicyclic skeletons that contain three stereocenters (up 82% yield, 10:1 d.r., and 97% ee). Unlike the previous IEDDAR catalytic strategy, this method features a double HOMO(dienophile)/ LUMO(diene)-activated pathway. Moreover, this process provides a promising method for the construction of enantioenriched macrolides.