Rational Design and Stereodivergent Construction of Enantioenriched Tetrahydro-β-Carbolines Containing Multistereogenic Centers.

Chiral tetrahydro-β-carbolines, as one of the most intriguing subtypes of indole alkaloids, have emerged as the privileged units in plenty of natural products and biologically active molecules with an impressive range of bioactive properties. However, the stereodivergent construction of these valuable skeletons containing multistereogenic centers from readily available starting materials remains very challenging, especially, in view of the introduction of an axial chirality. Herein, we developed an efficient method toward enantioenriched tetrahydro-β-carbolines with readily available tryptophan-derived aldimine esters and allylic carbonates under mild reaction conditions.

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.

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

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.

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.

β-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 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.

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 -geometrical imine of the allylation intermediate.

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.

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.

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.

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.

Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II-induced cardiac, renal, and vascular injury.

Angiotensin II causes cardiovascular injury in part by aldosterone-induced mineralocorticoid receptor activation, and it can also activate the mineralocorticoid receptor in the absence of aldosterone in vitro. Here we tested whether endogenous aldosterone contributes to angiotensin II/salt-induced cardiac, vascular, and renal injury by the mineralocorticoid receptor. Aldosterone synthase knockout mice and wild-type littermates were treated with angiotensin II or vehicle plus the mineralocorticoid receptor antagonist spironolactone or regular diet while drinking 0.

Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt.

In the setting of high salt intake, aldosterone stimulates fibrosis in the heart, great vessels, and kidney of rats. We used uninephrectomized rats treated with angiotensin II and placed on a high salt diet to exaggerate renal fibrosis. We then tested whether mineralocorticoid receptor blockade by spironolactone or aldosterone synthase inhibition by FAD286 have similar effects on end-organ damage and gene expression.

Endogenous aldosterone contributes to acute angiotensin II-stimulated plasminogen activator inhibitor-1 and preproendothelin-1 expression in heart but not aorta.

To test the hypothesis that angiotensin (Ang) II induces profibrotic gene expression through endogenous aldosterone, we measured the effect of 4 h infusion (600 ng/kg x min) of Ang II on tissue mRNA expression of plasminogen activator inhibitor 1 (PAI-1), preproendothelin-1 (ppET-1), TGF-beta, and osteopontin in wild-type (WT), aldosterone synthase-deficient (AS(-/-)), and AS(-/-) mice treated with aldosterone (either 500 ng/d for 7 d or 250 ng as a concurrent 4 h infusion). Ang II increased aldosterone in WT (P < 0.001) but not in AS(-/-) mice.

E-cadherin promoter polymorphisms are not associated with the aggressiveness of prostate cancer in Caucasian patients.

Background: -160C-->A and -347G-->GA polymorphisms in the promoter region decrease E-cadherin gene transcription. Decreased E-cadherin expression predicts poor outcome among patients with cancer. We sought to investigate whether -160C-->A and/or -347G-->GA polymorphisms were associated with the aggressiveness of prostate cancer.