Rhodium(I)/Chiral Diene Complexes Catalyzed Asymmetric Desymmetrization of Alkynyl-Tethered 2,5-Cyclohexadienones Through an Arylative Cyclization Cascade.

Cis-hydrobenzofurans, cis-hydroindoles, and cis-hydrindanes, privileged structural motifs found in numerous biologically active natural and synthetic compounds, are efficiently prepared by a Rh(I)-catalyzed cascade syn-arylation/1,4-addition protocol. This approach starts with the regioselective syn-arylation of the alkyne tethered to 2,5-hexadienone moieties, using a chiral Rh(I) catalyst generated in situ from a chiral bicyclo[2.2.1]hepatadiene ligand L4f. By forging two new carbon-carbon bonds and introducing two chiral centers, the resulting alkenylrhodium species undergoes desymmetrization via an intramolecular 1,4-addition reaction, delivering annulated products with high yields and enantioselectivities.

Asymmetric Synthesis of Trifluoroethyl-Based, Chiral 3-Benzyloxy-1- and -2-Phenyl-quinazolinones of Biomedicinal Interest by Radical Type Cross-Coupling to Olefins.

Several 2-substituted (H, Ph, and S-Me) and 1-substituted (H, Ph, and Bn), 3-hydroxy-1,3-quinazolin(di)ones were utilized for the first time as radical trapping agents in asymmetric 1,2-oxytrifluoromethylation of styrenes catalyzed by chiral vanadyl methoxide complexes bearing 3,5-disubstituted-N-salicylidene-t-leucinate templates. The effects of catalysts and solvents on the asymmetric induction were systematically examined. The best and complementary scenarios involved the use of vanadyl complexes V(O)-1 and V(O)-2, which bear 3-(2,5-dimethyl)phenyl-5-bromophenyl and 3-t-butyl-5-bromophenyl groups in an i-propanol solvent at ambient temperature. The corresponding (R)-cross-coupling products by V(O)-1 were obtained in 45-71% (for 2-substituted series) and 59-93% yields (for 1-substituted series) for p-/m-methylstyrenes and m-halo/CF3/CO2Me-styrenes in 38-63% ees (the best in 2-H case) and 60-84% ees (the best in 1-benzyl cases), respectively. The corresponding (S)-cross-coupling products by V(O)-2 were obtained in 28-55% (for 2-substituted series) and 45-72% yields (for 1-substituted series) for the same substrate class in 50-91% ees (85-91% ees in 2-phenyl cases) and 64-75% ees (up to 74-75% ees for each 1-H, Ph, and Bn cases), respectively. Theoretical calculations were carried out to explain the origin and extent of enantiocontrols. They both may serve as potential inhibitors of acetohydroxyacid synthase and epidermal growth factor receptor (EGFR) kinases.

Application of Rh(I)/Bicyclo[2.2.1]heptadiene Catalysts to the Enantioselective Synthesis of Chiral Amines.

The development of efficient synthetic methods for accessing enantioenriched α-chiral amines is of great importance in the disciplines of medicinal and synthetic organic chemistry. Enantioselective Rh-catalyzed 1,2-addition reactions to activated imine derivatives are regarded as useful protocols for forming α-chiral amines. This personal account outlines our efforts to develop chiral bicyclo[2.2.1]heptadiene ligands for Rh-catalyzed asymmetric additions of various organoboron reagents to a wide range of imine derivatives. Transformations of the thus-obtained adducts into known natural products or molecules of pharmaceutical importance serve to confirm their synthetic usefulness.

Enantioselective Synthesis of 1-Aryl Tetrahydroisoquinolines by the Rhodium-Catalyzed Reaction of 3,4-Dihydroisoquinolinium Tetraarylborates.

The 1-aryl tetrahydroisoquinolines (1-aryl THIQs) are omnipresent in biologically active molecules. Here we report on the direct asymmetric synthesis of these valuable compounds via the reaction of 3,4-dihydroisoquinolinium tetraarylborates. The dual roles of anionic tetraarylborates, which function as both prenucleophiles and stabilizers of 3,4-dihydroisoquinolinium cations, enable this rhodium(I)-catalyzed protocol to convergently provide enantioenriched 1-aryl THIQs in good yields (≤95%) with ≤97% ee, as demonstrated by the formal synthesis of (-)-solifenacin and the facile synthesis of (-)-Cryptostyline I.

Copper-Catalyzed Dual Cyclization for the Synthesis of Quinindolines.

A synthetic approach to quinindoline derivatives by the Cu-catalyzed dual cyclization has been developed. This catalytic reaction is a practical method for the systematic synthesis of quinindoline core structure, which contains a limited-step synthetic strategy and can tolerant a wide variety of substituents. In addition, the mechanistic study reveals that the reaction initiates from a Lewis acid accelerated addition of aniline to nitrile and provides the indole substructure, and then the subsequent Cu-catalyzed C-N coupling reaction furnishes the quinoline subunit and affords the quinindoline structure.

Enantioselective Rhodium-Catalyzed Allylation of Aliphatic Imines: Synthesis of Chiral C-Aliphatic Homoallylic Amines.

Reported herein is a method for the efficient syntheses of optically active 1-alkyl homoallylic amines in yields up to 95%, 13.5:1 dr, and 98% ee under mild, aqueous reaction conditions, via the Rh-catalyzed asymmetric allylation of aliphatic aldimines. This method provides a streamlined synthetic platform for the preparation of indolizidine and piperidine alkaloids, thus demonstrating its usefulness.

Progress in recent development of stereoselective synthesis of ß2-amino acid derivatives from ß-nitroacrylate derivatives.

The synthesis and properties of ß-amino acids have drawn considerable attention owing to their ubiquitous presence in naturally occurring products of biological importance. While ß3-amino acids can be readily prepared from α-amino acids via one-carbon homologation, the synthesis of ß2-amino acids generally requires multistep efforts. This review focuses on the recent advances in the synthesis of ß2-amino acids and their derivatives from substituted ß-nitropropionate analogues obtained from the stereoselective transformation of ß-nitroacrylates.

Stimulation of MMP-9 of oral epithelial cells by areca nut extract is related to TGF-ß/Smad2-dependent and -independent pathways and prevented by betel leaf extract, hydroxychavicol and melatonin.

BACKGROUND: There are 200-600 million betel quid (BQ) chewers in the world. BQ increases oral cancer risk. Matrix metalloproteinase-9 (MMP-9) is responsible for matrix degradation, cancer invasion and metastasis. Whether areca nut extract (ANE), a BQ component, stimulates MMP-9 secretion, and the related signaling pathways awaits investigation. RESULTS: ANE (but not arecoline) stimulated MMP-9 production of gingival keratinocytes and SAS cancer epithelial cells. ANE stimulated TGF-ß1, p-Smad2, and p-TAK1 protein expression. ANE-induced MMP-9 production/expression in SAS cells can be attenuated by SB431542 (ALK5/Smad2 inhibitor), 5Z-7-Oxozeaenol (TAK1 inhibitor), catalase, PD153035 (EGFR tyrosine kinase inhibitor), AG490 (JAK inhibitor), U0126 (MEK/ERK inhibitor), LY294002 (PI3K/Akt inhibitor), betel leaf (PBL) extract, and hydroxychavicol (HC, a PBL component), and melatonin, but not by aspirin. CONCLUSIONS: AN components contribute to oral carcinogenesis by stimulating MMP-9 secretion, thus enhancing tumor invasion/metastasis. These events are related to reactive oxygen species, TGF-ß1, Smad2-dependent and -independent signaling, but not COX. These signaling molecules can be biomarkers of BQ carcinogenesis. PBL, HC and melatonin and other targeting therapy can be used for oral cancer treatment. METHODS: ANE-induced MMP-9 expression/secretion of oral epithelial cells and related TGF-ß1, Smad-dependent and -independent signaling were studied by MTT assay, RT-PCR, western blotting, immunofluorescent staining, and ELISA.

Asymmetric Synthesis of Functionalized Phenylalanine Derivatives via Rh-Catalyzed Conjugate Addition and Enantioselective Protonation Cascade.

The asymmetric conjugate addition of arylboronic acids to N-phthalimidodehydroalanine 1i catalyzed by Rh(I)/L1a enables the facile preparation of chiral functionalized phenylalanines. The reaction proceeds by a conjugate addition and enantioselective protonation cascade, affording a rhodium enolate that undergoes re-face protonation. The reaction tolerates various arylboronic acids and can be used in the gram-scale synthesis of (S)-phenylalanine hydrochloride, demonstrating the reaction scope and the synthetic feasibility of the process.

Asymmetric Synthesis of ß-Aryl ß-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast.

A chiral rhodium(I)-diene catalyst enabled the one-step synthesis of ß-aryl ß-imido sulfones under mild reaction conditions. By selection of the chiral diene ligand L1a or L2, each enantiomer of the chiral ß-aryl ß-imido sulfone target can be accessed with high stereoselectivity. Demonstration of the scope of the reaction, which includes the synthesis of an N-protected chiral ß-amino ß-phenyl sulfone, culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.

Access to ß2-Amino Acids via Enantioselective 1,4-Arylation of ß-Nitroacrylates Catalyzed by Chiral Rhodium Catalysts.

The highly enantioselective conjugate addition of a variety of arylboronic acids to ß-nitroacrylates is reported to provide optically active α-aryl ß-nitropropionates in up to 70% yields and >99.5% ee's, which are useful building blocks for preparing chiral ß2-amino acids. The applicability of this transformation is demonstrated by converting 3aa into the ß2-amino acid 5 and transforming 3ap to ß-amino ester 7 via reduction and reductive N-alkylation. The latter compound is a precursor for preparing ent-ipatasertib.

Rh-Catalyzed Enantioselective Allylation of N-Tosyl- and N-Nosylaldimines: Total Synthesis of (-)-Crispine A.

The unprecedented development of asymmetric Rh-catalyzed 1,2-allylation of N-Ts- and N-Ns-aldimines is achieved. This protocol utilizes potassium allyltrifluoroborates and various aldimines to generate enantioenriched homoallylic amines in the presence of 3.0 mol % of Rh(I)/L1b catalyst with up to 90% yield, 98% ee (R = H), and 10:1 diastereoselectivity (R = Me or Ph), yielding the same major diastereomer when using potassium (E)- and (Z)-crotyltrifluoroborate. Its synthetic utility is also illustrated in the total synthesis of (-)-crispine A.

Design and Synthesis of Chiral Diene Ligands for RhI -Catalyzed Enantioselective Arylation of N-DPP-protected Aldimines: Synthesis of the Antifungal Agent Bifonazole.

Herein we describe the design and synthesis of a novel family of bifunctional, chiral bicyclo[2.2.1]heptadiene ligands bearing aryl and secondary amido groups, and demonstrate their usefulness in the RhI -catalyzed enantioselective addition reaction of arylboronic acids to N-diphenylphosphinyl (N-DPP)-protected aldimines. Unlike the analogous RhI -catalysts comprising diene ligands substituted with aryl and carboxylic ester groups, or only with aryl groups, the addition reaction proceeded with high stereoselectivity. The protocol tolerated a range of N-DPP-aldimines and arylboronic acids, producing the desired optically active N-DPP-protected amines with yields between 31-99 % and with ee values up to 91-99 %. The synthetic utility of the method was demonstrated by the conversion of N-DPP-protected amine 3 ae into the antifungal agent, bifonazole (13).

Synthesis of Quaternary-Carbon-Containing ß2,2 -Amino Acids by the RhI -Catalyzed Enantioselective Arylation of α-Substituted ß-Nitroacrylates.

An enantioselective RhI -catalyzed conjugate addition reaction of α-substituted ß-nitroacrylates with various arylboronic acids by using chiral RhI diene catalysts is described for the first time. The addition reaction proceeds under mild conditions in a range of common organic solvents and additives, and it affords the corresponding quaternary-carbon-containing α,α-disubstituted ß-nitropropionate products in up to 63 % yield and 99 % ee. Reaction of either (E)- or (Z)-ß-nitroacrylates provided the same enantiomer of the product, and a range of esters and aryl groups were tolerated. To demonstrate the utility of the method, ethyl (R)-1,1-methyl-1-phenyl-3-nitropropionate, prepared herein, was converted to the non-proteinogenic ß2,2 -amino acid, (R)-2-(aminomethyl)-2-phenylpropanoic acid, and to the ß2,2 -lactam, (R)-3-methyl-3-phenylazetidin-2-one. In addition, a tripeptide, which comprised l-phenylalanine, l-alanine, and ß2,2 -amino acid 7, was also synthesized.

Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins.

An efficient and trans-diastereoselective Rh(I)-catalyzed 1,4-conjugate addition reaction of alkenylboronic acids and a homochiral (R)-4-silyloxycyclopentenone useful for the synthesis of derivatives of prostaglandins E and F is described for the first time. The reaction functions under mild conditions and is particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol % of [RhCl(COD)]2 is typically required to produce high yields. The method also functions without microwave irradiation at 3 °C in the presence of a stoichiometric amount of KOH. Under these conditions, only 1.5 mol % of [RhCl(COD)]2 is needed, but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-substituted alkenylboronic acids, and its utility has been demonstrated by the synthesis of PGF2α (dinoprost) and tafluprost.

Direct synthesis of chiral 3-arylsuccinimides by rhodium-catalyzed enantioselective conjugate addition of arylboronic acids to maleimides.

Chiral rhodium catalysts comprising 2,5-diaryl- substituted bicyclo[2.2.1]diene ligands L1-L10 were utilized in the enantioselective 1,4-addition reaction of arylboronic acids to N-substituted maleimides. In the presence of 2.5 mol % of Rh(I) /L2, enantioenriched conjugate addition adducts were isolated in 72-99 % yields with 86-98 % ee. This protocol offers a convenient method to access a variety of 3-arylsuccinimides in a highly enantioselective manner. Maleimides with readily cleavable N-protecting groups were tolerated enabling the synthesis of useful synthetic intermediates. Pyrrolidine 4, a biologically active compound, and pyrrolidine 5, an ent-precursor to an HSD-1 inhibitor, were synthesized to demonstrate the utility of this method.

Rhodium/chiral diene complexes in the catalytic asymmetric arylation of ß-pyrazol-1-yl acrylates.

The asymmetric conjugate addition of arylboronic acids to substituted and unsubstituted ß-pyrazol-1-yl (E)-tert-butyl acrylates 4 catalyzed by 5 mol % of the Rh(I)/diene 2a catalyst provided the corresponding addition products in 44-98% yield and 91->99.5% ee. The method was applied to the formal synthesis of (3S)-3-aryl-3-(pyrazol-1-yl)propanoic acid 1b with agonistic activity toward the human GPR40 G-protein coupled receptor.

Enantioselective and rapid Rh-catalyzed arylation of N-tosyl- and N-nosylaldimines in methanol.

Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to N-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt3 as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-d-aspartate (NMDA) receptor.

Highly enantioselective Rh-catalyzed alkenylation of imines: synthesis of chiral allylic amines via asymmetric addition of potassium alkenyltrifluoroborates to N-tosyl imines.

For the first time, simple N-tosyl aryl aldimines, prepared from the condensation of tosyl amide and aromatic aldehydes, can be used as substrates in the rhodium catalyzed 1,2-addition reaction using alkenylboron nucleophiles. In the presence of 1.5 mol % of [RhCl(1e)]2, enantioselective addition of various potassium alkenyltrifluoroborates to aryl aldimines furnished the corresponding chiral allylic amines in 73-96% yield and 72->99.5% ee. Notably, this method efficiently provides the di-, tri-, and tetrasubstituted allylic N-tosyl amines with high asymmetric induction.