Jun-Cheng Zheng

Asymmetric Nazarov Reaction Catalyzed by Chiral Tris(oxazoline)/Copper(II)†

The frequent occurrence of five-membered carbocycles in natural products and other biologically active compounds has provided a major impetus for the development of efficient methods for their construction. Towards this end, the Nazarov cyclization, a stereospecific 4p electrocyclization that converts divinyl ketones into cyclopentenones through a conrotatory cyclization, has distinguished itself as a powerful tool for the synthesis of such compounds. Over several decades, great efforts have been devoted to the exploitation of the Nazarov reaction, further highlighting its synthetic utility, as demonstrated by its increasing use in total syntheses. However, the asymmetric Nazarov reaction with a catalytic amount of chiral source was not reported until the end of 2003, probably because of the complex mechanism of the reaction. Of those catalytic asymmetric reactions developed, few examples have been reported that give good to excellent enantiocontrol in good yields, except for divinyl ketones that belong to type A or B (Scheme 1).

Highly diastereoselective and enantioselective formal [4 + 1] ylide annulation for the synthesis of optically active dihydrofurans.

On the basis of the reactions of camphor-derived sulfur ylide with alpha-ylidene-beta-diketones, highly efficient and selective synthesis of optically active dihydrofurans has been achieved.

Highly enantioselective synthesis of isoxazoline N-oxides

The reaction of cinchonidine (cinchonine)-derived ammonium salts with nitroolefins in the presence of Cs2CO3 to afford optically active isoxazoline N-oxides with excellent ee and high de values has been developed.

Tunable carbonyl ylide reactions: selective synthesis of dihydrofurans and dihydrobenzoxepines.

The stereoselective preparation of highly substituted oxygen heterocycles has attracted considerable attention. Over the past decades, it has been well established that the transitionmetal-catalyzed decomposition of diazo compounds can generate transient carbonyl ylides, which can either be trapped by suitable dipolarophiles or cyclize intramolecularly for the synthesis of oxygenated heterocycles. Asymmetric versions of some of these reactions have also been developed. However, for these reactions, the five-membered furan derivatives are usually obtained as the major products and very few reactions gave the seven-membered oxepine derivatives. For example, AnaÅ et al. recently reported that a-benzylidene-b-dicarbonyl compounds reacted with dimethyl diazomalonate to afford dihydrofurans or mixtures of dihydrofurans and dihydrobenzoxepines (about 1:1). During our investigations into the asymmetric reaction of a-benzylidene-b-dicarbonyl compound 1a and ethyl diazoacetate, the seven-membered heterocyclic product was observed together with the desired dihydrofuran (Scheme 1). Noticeably, both products were obtained with moderate ee values, thus suggesting that the ligand has a strong influence on the chemoselectivity and stereochemistry of the reaction. Considering the importance of both products in organic synthesis and pharmaceutical science, we wondered whether the product distribution could be controlled by using different ligands. Herein we report the first successful realization of this aim and density functional theory (DFT) studies that give an understanding of how these tunable processes occur. On the basis of our initial optimization of the copper catalysts (see Scheme S1 in the Supporting Information) we decided to study the influence of the ligands (Figure 1) on the reaction when using CuSbF6 as the catalyst in CH2Cl2 at room temperature with molecular sieves (4 ) as an additive, which can ensure a clean reaction system. As shown in Table 1, the structure of the ligand had a significant influence on both the reactivity and the chemoselectivity of the reaction. When using 2,2’-bipyridine as the ligand, the dihydrofuran 3 was mainly obtained but with low diastereoselectivity (Table 1, entry 1). However, when the 1,2-diimine L1, which contains two bulky 2,6-diisopropylphenyl groups, was used as the ligand the reaction gave dihydrobenzoxepine 4a as the major product but also dihydrofurans 3a and 3a’ as by-products (Table 1, entry 2). We were gratified to find that the bulky and structurally rigid Brookhart-type ligand L4 gave 4a predominately in 71% yield (Table 1, entry 5). Interestingly, we observed that the substituents on the 1,2-diimine

Highly selective ylide-initiated Michael addition/cyclization reaction for synthesis of cyclohexadiene epoxide and vinylcyclopropane derivatives.

On the basis of the reactions of camphor-derived sulfur ylide with alpha,beta-unsaturated ketone, highly efficient and selective synthesis of optically active cyclohexadiene epoxides and vinylcyclopropanes with excellent diastereoselectivities, moderate to high enantioselectivities, and yields has been achieved.

One-pot highly diastereoselective synthesis of cis-vinylaziridines via the sulfur ylide-mediated aziridination and palladium(0)-catalyzed isomerization.

Highly diastereoselective synthesis of cis-trisubstituted vinylaziridines containing a quaternary carbon center is realized by a one-pot protocol in which the combination of sulfur ylide-mediated aziridination of cyclic ketimines and Pd(0)-catalyzed isomerization is employed successfully.

Iron carbenoid-mediated ylide reactions

Electrophilic metal carbenoids, readily available from diazo compounds, prove to be good reagents for the preparation of ylides under neutral conditions. We have extended the strategy to synthesize allenes from diazoacetates with both stable and unstable ketenes in the presence of PPh3 and Fe(TCP)Cl (0.5 mol %), which provided an easy access to optically active 4,4-disubstituted allenic esters by employing enantiopure phosphines. The mechanism involving the generation of ylide through catalytic transfer of an iron(II) carbene to phosphine was confirmed. A tandem Wittig–Nazarov cyclization reaction was further developed based on these results, culminating in a straightforward method for the construction of β-methylenecyclopentenones in a multistep one-pot manner without isolation of inter-mediates. By combining AsPh3 and iron carbenoids, a catalytic Wittig reaction in toluene/water biphasic system was accomplished, affording α,β-unsaturated esters in high yields with E/Z above 50/1. Surprisingly, crotonate-derived phosphorus ylide reacted with electrophilic iron carbenoid, affording 1,1,4-trisubstituted 1,3-butadienes with high regio- and stereo-selectivities, where a new ylide generated via formal intermolecular carbenoid insertion into olefinic C–H bonds of the crotonate-derived phosphorus ylide was proposed.