Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

ß-Substituted Alkenyl Heteroarenes as Dipolarophiles in the Cu(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides Empowered by a Dual Activation Strategy: Stereoselectivity and Mechanistic Insight.

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 ß-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.

Synergistic Cu/Pd-Catalyzed Asymmetric Allenylic Alkylation of Azomethine Ylides for the Construction of α-Allene-Substituted Nonproteinogenic α-Amino Acids.

An unprecedented asymmetric allenylic alkylation of readily available imine esters, which was enabled by a synergistic Cu/Pd catalysis, has been developed. This dual catalytic system possesses good substrate compatibility, delivering a diverse array of nonproteinogenic α-allenylic α-mono- or α,α-disubstituted α-amino acids (α-AAs) with high yields and generally excellent enantioselectivities. Furthermore, the scalability and practicability of the current synthetic protocol were proven by performing gram-scale reactions and by the first catalytic asymmetric synthesis of naturally occurring (S)-γ-allenic α-amino acid, respectively.

Dysprosium(III)-Catalyzed Ring-Opening of meso-Epoxides: Desymmetrization by Remote Stereocontrol in a Thiolysis/Elimination Sequence.

An unprecedented asymmetric desymmetrization of meso-epoxides, derived from cyclopentene-1,3-diones, with 2-mercaptobenzothiazoles has been realized. It was efficiently catalyzed by a chiral Dy(III) /N,N'-dioxide complex through a thiolysis/elimination sequence. This remote stereocontrol strategy provides facile access to synthetically versatile cyclopentene derivatives bearing an all-carbon quaternary stereogenic center in high yield and excellent enantioselectivity. Intriguingly, optically active thiophene could be readily generated from the obtained product through an efficient one-pot protocol.

Copper/ruthenium relay catalysis enables 1,6-double chiral inductions with stereodivergence.

The dual catalysis strategy is an efficient and powerful tool to fulfill the stereodivergent synthesis of stereoisomeric products from the same set of starting materials. Great attention has been given to the construction of chiral compounds with two contiguous stereocenters. However, the synthesis of two remote noncontiguous stereocenters is more challenging and is less developed, despite the high demand for synthetic tactics. We herein developed an unprecedented example of the stereodivergent preparation of synthetically useful and biologically important chiral ζ-hydroxy amino ester derivatives containing remote 1,6-noncontiguous stereocenters and a unique ß,γ-unsaturation moiety. This cascade dehydrogenation/1,6-Michael addition/hydrogenation protocol between readily-available ketoimine esters and racemic branched dienyl carbinols was rationally realized with bimetallic copper/ruthenium relay catalysis. The key features of the process were atom economy, step economy, and redox-neutrality. All four stereoisomers of chiral ζ-hydroxy amino ester derivatives were easily achieved by the orthogonal permutations of a chiral copper catalyst and chiral ruthenium catalyst. Importantly, a much more challenging stereodivergent synthesis of all eight stereoisomers of chiral peptide products containing three remote stereocenters was accomplished with excellent results through the cooperation of two chiral catalyst pairs and substrate enantiomers.

Iridium-catalyzed asymmetric cascade dearomative allylation/acyl transfer rearrangement: access to chiral N-substituted 2-pyridones.

Iridium-catalyzed dearomative allylation/acyl transfer rearrangement has been developed using easily available 2-pyridinyl benzoates and vinyl ethylene carbonate. This protocol enabled the expedient synthesis of a variety of chiral N-substituted 2-pyridones in good to high yields with excellent enantioselectivity. It has the advantages of high atom economy, wide substrate scope, gram-scale synthesis, and versatile synthetic transformations.

Palladium catalyzed cascade umpolung allylation/acetalation for the construction of quaternary 3-amino oxindoles.

Herein we reported a highly diastereoselective synthesis of quaternary 3-amino oxindoles bearing an acetal unit via a palladium catalyzed three-component cascade umpolung allylation/acetalation process. An array of 3-amino 3-allyl oxindoles incorporating diversified functional groups were prepared in good yields with exclusive diastereoselectivities. Further investigation demonstrated that the current method could also be extended to cascade umpolung allenylation/acetalation.

Catalytic Asymmetric Umpolung Allylation/2-Aza-Cope Rearrangement for the Construction of α-Tetrasubstituted α-Trifluoromethyl Homoallylic Amines.

A general protocol for the preparation of enantioenriched α-tetrasubstituted α-trifluoromethyl homoallylic amines is disclosed. Despite the significant challenge in stereoselectivity control, Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoromethylated fluorenone imines with allylic carbonates was realized with excellent efficiency and remarkable stereoselectivity. These were enabled by the suitable protective imino moiety and an unexpectedly exclusive E-geometrical imine of the allylation intermediate. This methodology is also applicable to facile access to chiral α-trisubstituted α-trifluoromethyl homoallylic amines in similarly high yield and stereoselectivity.

Catalytic Asymmetric Synthesis of α-Trifluoromethyl Homoallylic Amines via Umpolung Allylation/2-Aza-Cope Rearrangement: Stereoselectivity and Mechanistic Insight.

An unprecedented Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoroethylisatin ketimines has been realized. The current method provides a facile access to biologically important α-trifluoromethyl-containing homoallylic amines in high yields with excellent enantioselectivity. Notably, umpolung reactivity of trifluoroethylisatin ketimine was discovered for the first time. Mechanism studies revealed the key intermediates in the initial umpolung allylation and the stereospecific chirality transfer in the subsequent 2-aza-Cope rearrangement.

Ligand-controlled stereodivergent 1,3-dipolar cycloaddition of azomethine ylides with 3-methyl-4-nitro-5-styrylisoxazoles.

An unprecedented Ag(i)-catalyzed ligand-controlled stereodivergent 1,3-dipolar cycloaddition of azomethine ylides with 3-methyl-4-nitro-5-styrylisoxazoles has been developed to afford heterocycles bearing both methylisoxazole and pyrrolidine moieties. The endo- and exo-cycloadducts were obtained in good yields with excellent stereoselectivities, assisted by (t)Bu-Phosferrox and phosphoramidite as chiral ligands, respectively.

Endostatin polymorphism 4349G/A(D104N) is not associated with aggressiveness of disease in prostate [corrected] cancer.

Endostatin is an important inhibitory molecule which mediates the sequential steps involved in angiogenesis. Lower level or impaired function of endostatin is associated with a higher risk of developing malignant solid tumors and with a worse prognosis of the disease. The endostatin N104 polymorphism might be associated with an impaired ability to inhibit angiogenesis. We analyzed the tissues from 98 Caucasian prostate cancer patients for the presence of D104N polymorphism. The frequencies of homozygous 4349G/G(104D/D), and heterozygous 4349G/A(104D/N) were 83.67%(82/98) and 16.33%(16/98), respectively; no individuals were homozygous 4349A/A(104N/N). With the Fisher's exact test we found the genotype of D104N was not significantly related to age, tumor grade, PSA and clinical stage (P > 0.05). There was no difference in relapse free survival(RFS) or overall survival(OS) between patients with 104D/N and those with 104D/D (P = 0.8283, 0.3713 respectively). We concluded that endostatin polymorphism was not associated with the aggressiveness of prostate cancer in Caucasian patients.