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An enantiomerically enriched 3-hydroxymethyl pentenal unit is one of the key structural cores in plenty of natural products and drug candidates with significant biological activities. However, very few synthetic methodologies for the facile construction of the related skeletons have been reported to date. Herein, an elegant iridium-catalyzed asymmetric cascade allylation/retro-Claisen reaction of readily available β-diketones with VEC was successfully developed, and a wide range of functionalized chiral 3-hydroxymethyl pentenal derivatives could be prepared in good yields with excellent enantioselectivities. Various 1,3-diketones and functionalized ketones containing different electron-withdrawing groups on the β-position were well tolerated as outstanding partners with high reactivity and excellent regio-/chemo-/enantioselectivity. The synthetic utility of product chiral 3-hydroxymethyl pentenal derivatives was well shown through gram-scale transformation, hydrogenation, cyclopropanation, hydroboration, and olefin metathesis. Moreover, this elegant protocol demonstrated synthetic applications in the concise synthesis of synthetically useful chiral building block (

The catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides with various electron-deficient alkenes provide the most straightforward protocol for the preparation of enantioenriched pyrrolidines in organic synthesis. However, the employment of conjugated alkenyl heteroarenes as dipolarophiles in such protocols to afford a class of particularly important molecules in medicinal chemistry is still a great challenge. Herein, we report that various β-substituted alkenyl heteroarenes, challenging internal alkene substrates without a strong electron-withdrawing substituent, were successfully employed as dipolarophiles for the first time in the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This reaction furnishes a large array of multistereogenic heterocycles incorporating both the biologically important pyrrolidine and heteroarene skeletons in good yields with exclusive diastereoselectivity and excellent enantioselectivity. Our extensive density functional theory (DFT) calculations proposed a working model to explain the origin of the stereochemical outcome and elucidated uncommon dual activation/coordination of both the dipole and dipolarophile substrates by the metal, in which a sterically bulky, rigid, and monodentate phosphoramidite ligand with triple-homoaxial chirality plays a pivotal role in providing an effective chiral pocket around the metal center, resulting in high enantioselectivity. The additional coordination of the heteroatom in the dipolarophile substrate to Cu is also critical for the exclusive diastereoselectivity and enhanced reactivity. Our calculations also predicted the reverse and high enantioinduction for the corresponding substrates with monocyclic heteroarenes as well as regiospecific cycloaddition to the less reactive internal C═C bond of one related dipolarophile diene substrate. Such unique steric effect-directed enantioswitching and coordination-directed regioselectivity were verified experimentally.

Cu/Ir dual catalysis has been developed for the stereodivergent α-allylation of aldimine esters. The method enables the preparation of a series of nonproteinogenic α-amino acids (α-AAs) bearing two contiguous stereogenic centers in high yield with excellent stereoselectivity. All four product stereoisomers could be obtained from the same set of starting materials via pairwise combination of two chiral catalysts. Notably, one-pot protocol could be successfully applied for the preparation of the bimetallic Cu/Ir complexes to simplify the manipulation of Cu/Ir dual catalysis. This method could be further utilized for the construction of the key intermediate of a bioactive pyrrolidine derivative and the concise synthesis of a plant growth regulator (2S,3S)-2-amino-3-cyclopropylbutanoic acid.

An unprecedented cascade vinylogous Mukaiyama 1,6-MA/MA of 2-silyloxyfurans and azoalkenes was realized with a Cu(II)/(t)Bu-Box complex. An array of fused butyrolactones containing multiple stereocenters was generally obtained in good yield (up to 90% yield) with exclusive diastereoselectivity (20:1 dr) and excellent enantioselectivity (up to 99% ee). Carbon isotope effects measured by (13)C NMR revealed a stepwise mechanism for this annulation process.

An unprecedented Cu(I)-catalyzed asymmetric [6 + 3] cycloaddition of tropone with azomethine ylides was reported, which performs well over a broad scope of substrates and offers a unique and facile access to the synthetically useful bridged azabicyclo[4.3.1]decadiene derivatives in good yields with high levels of diastereoselectivities and enantioselectivities under mild conditions.

An unprecedented multicomponent cascade asymmetric inverse-electron-demand Diels-Alder/nucleophilic addition/ring-opening reaction involving 2-methoxyfurans as efficient dienophiles was successfully developed with Cu(I)/(t)Bu-Box complex as the catalyst. A diverse array of tetrahydropyridazines containing unexpectedly stable γ-hydroxyl ester moiety was obtained in generally good yield with exclusive regioselectivity and excellent stereoselectivity.

A novel catalytic asymmetric Michael addition of azomethine ylide with β-substituted alkylidene bisphosphates was realized in the presence of a chiral copper(I)/TF-BiphamPhos complex. The present system provides a unique and facile access to enantioenriched unnatural α-amino acid derivatives containing gem-bisphosphonates (gem-BPs) in high yields with excellent diastereoselectivities and enantioselectivities. Subsequent transformations lead to the expedient preparation of biologically active unnatural α-amino acid derivatives containing BPs and bisphosphonic acids without loss of diastereo- and enantiomeric excess.

Conjugated cyclic trienes without nonbenzenoid aromatic characteristic were successfully employed as fine-tunable dipolarophiles in the Cu(I)-catalyzed asymmetric azomethine ylide-involved 1,3-dipolar [3 + 6] cycloaddition for the first time, affording a variety of bridged heterocycles bearing piperidine moiety in good yield with exclusive regioselectivity and excellent stereoselectivity. 2-Acyl group is the key factor that determines the annulation preferentially through [3 + 6]-pathway, while 2-ester group modulates the annulation through [3 + 2]-pathway.

A new and highly efficient Cu(I)/TF-BiphamPhos catalytic system exhibited excellent reactivity, enantio-/diastereoselectivity, and structural scope in asymmetric 1,3-dipolar cycloaddition of azomethine ylides with 0.1-3 mol % of catalyst loading. The present methodology is the best result for asymmetric cycloaddition of azomethine ylides, especially derived from amino esters other than glycinate in terms of reactivity and enantioselectivity.