Synthesis of 2-(2-nitrophenyl)indoline-3-acetic acid derivatives via base-catalyzed cyclization of N-(2-nitrobenzyl)-2-aminocinnamic acid derivatives.

A protocol for the synthesis of 2-(2-nitrophenyl)indoline-3-acetic acid derivatives was developed via base-catalyzed cyclization of N-(2-nitrobenzyl)-2-aminocinnamic acid derivatives. The synthetic utility of this methodology was illustrated by the concise synthesis of dihydropaullone, a partially saturated analog of paullone. Furthermore, the indoline scaffold could be further converted to the corresponding indoles and other indole-fused heterocycles.

Precisely Localized Bone Regeneration Mediated by Marine-Derived Microdroplets with Superior BMP-2 Binding Affinity.

Prompt and robust bone regeneration has been clinically achieved using supraphysiological doses of bone morphogenetic protein-2 (BMP-2) to overcome the short half-life and rapid clearance. However, uncontrolled burst release of exogenous BMP-2 causes severe complications such as heterotopic ossification and soft tissue inflammation. Therefore, numerous researches have focused on developing a new BMP-2 delivery system for a sustained release profile by immobilizing BMP-2 in various polymeric vehicles. Herein, to avoid denaturation of BMP-2 and enhance therapeutic action via localized delivery, a complex coacervate consisting of fucoidan, a marine-derived glycosaminoglycan, and poly-l-lysine (PLL) is fabricated. Superior BMP-2 binding ability and electrostatic interaction-driven engulfment enable facile and highly efficient microencapsulation of BMP-2. The microencapsulation ability of the coacervate significantly improves BMP-2 bioactivity and provides protection against antagonist and proteolysis, while allowing prolonged release. Moreover, BMP-2 containing coacervate is coated on conventional collagen sponges. The bioactivity and localized bone regenerating ability are confirmed through in vitro (human-derived stem cells), and in vivo (calvarial bone defect model) evaluations.

Total Synthesis of Rucaparib.

A concise total synthesis of rucaparib, an FDA-approved drug for ovarian and prostate cancers, is reported. The Heck reaction of the commercially available aryl iodide with acrylonitrile provided the desired (E)-2-aminocinnamonitrile derivative. A subsequent imino-Stetter reaction of the aldimine derived from 2-aminocinnamonitrile and aldehyde furnished indole-3-acetonitrile bearing the desired substituents at appropriate positions. The construction of the final azepinone scaffold via reduction of the nitrile group followed by seven-membered lactamization afforded rucaparib. Notably, the synthesis of rucaparib is achieved using commercially available starting materials in only three separation operations with 54% overall yield.

Real-Time Reaction Monitoring with In Operando Flow NMR and FTIR Spectroscopy: Reaction Mechanism of Benzoxazole Synthesis.

In operando observation of reaction intermediates is crucial for unraveling reaction mechanisms. To address the sensitivity limitations of commercial ReactIR, a flow cell was integrated with a Fourier transform infrared (FTIR) spectrometer yielding a "flow FTIR" device coupled with an NMR spectrometer for the elucidation of reaction mechanisms. The former device detects the low-intensity IR peaks of reaction intermediates by adjusting the path length of the FTIR sample cell, whereas the flow NMR allows the quantitative analysis of reaction species, thus offsetting the limitations of IR spectroscopy resulting from different absorption coefficients of the normal modes. Using the flow NMR and FTIR device, the controversial mechanism of benzoxazole synthesis was conclusively determined by spectroscopic evaluation of the reaction intermediates. This system enabled the accurate acquisition of previously elusive kinetic data, such as the reaction time and rate-determining step. The implementation of reaction flow cells into NMR and FTIR systems could be widely applied to study various reaction mechanisms, including dangerous and harsh reactions, thus avoiding contact with potentially harmful reaction intermediates.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids.

Total syntheses of the antirhine alkaloids are described. The cyanide-catalyzed imino-Stetter reaction of the aldimine derived from ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde provided a 2-pyridinyl substituted indole-3-acetate, which was further converted into the corresponding indoloquinolizidinium intermediate through C-ring formation. Subsequent trans-selective installation of the homoallylic alcohol side-chain at C-15 in the resulting indoloquinolizidinium allowed the total syntheses of antirhine and its known epimer.

Atroposelective Total Syntheses of Naphthylisoquinoline Alkaloids with (P)-Configuration.

Asymmetric total syntheses of naphthylisoquinoline alkaloids with a (P)-configuration are described. An atroposelective Suzuki-Miyaura reaction between naphthyl pinacol boronate and an aryl iodide bearing an (S)-2-(N-acetylamino)propyl group at the ortho-position using Pd(OAc)2 in the presence of SPhos and Ba(OH)2 provided the (P)-selective biaryl product as the major product without any external chiral sources. This biaryl product was converted into naphthylisoquinoline alkaloids with a (P)-configuration via stereoselective construction of the isoquinoline framework with the appropriate oxidation state and stereochemistry.

Total Synthesis of Iheyamine A via the Cyanide-Catalyzed Imino-Stetter Reaction.

The total synthesis of iheyamine A from readily available ethyl 2-aminocinnamate and 5-methoxyindole-2-carboxaldehyde is described. The cyanide-catalyzed imino-Stetter reaction of an aldimine derived from ethyl 2-aminocinnamate and 5-methoxyindole-2-carboxaldehyde provided the desired unsymmetrical 2,2'-bisindole-3-acetic acid derivative. The subsequent introduction of an amino group at the C-3' position, followed by the formation of the azepine ring, completed the total synthesis of iheyamine A.

Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building Block Strategy.

A concise and general strategy for the total synthesis of the phenanthroquinolizidine alkaloids has been developed. An iterative Suzuki-Miyaura coupling reaction between the requisite aryl boronic acid, 2-bromo-4,5-dimethoxyphenyl N-methyliminodiacetate (MIDA) boronate derived from boronic acid, and a suitable bromopyridine substrate bearing a homopropargyl alcohol at the 2-position generated the desired ortho-aza-terphenyl compounds. Hydrogenation of the triple bond followed by treatment with methanesulfonyl chloride afforded their corresponding tetrahydroquinolizinium ion intermediates, which were subsequently reacted with NaBH4 to provide the desired hexahydroquinolizine products. A final oxidative electrocyclization reaction gave the target phenanthroquinolizidine natural products. This synthetic approach only requires the use of three chromatographic separations throughout the entire synthesis.

Chemistry of Cyanide Adducts of Aldimines from Aniline Derivatives.

The chemistry of hydrogen cyanide adducts of imines is well-developed, but that of cyanide adducts remains unexplored. This is presumably because these cyanide adducts are not stable and thus not readily available in their isolated forms. In this personal account, we present the progress made in our research program towards the development of novel organic transformations utilizing cyanide adducts of imines as key intermediates. We also report the application of these methodologies to the total synthesis of natural products including indole alkaloids.

On-Water Synthesis of 2-Substituted Quinolines from 2-Aminochalcones Using Benzylamine as the Nucleophilic Catalyst.

On-water synthesis of 2-substituted quinolines from 2-aminochalcone derivatives was developed using benzylamine as the nucleophilic catalyst. Various 2-aminochalcones could be applied to this protocol, and the desired 2-substituted quinoline products were isolated in excellent yields by simple filtration. Furthermore, we elucidated the role of benzylamine in this transformation and provided the detailed reaction mechanism. This protocol has several additional advantages, such as simple operation, broad substrate scope, good functional group tolerance, easy product isolation, recycling of the catalyst, and gram-scale synthesis.

Synthesis of 2-Substituted Quinolines from 2-Aminostyryl Ketones Using Iodide as a Catalyst.

A new protocol for the synthesis of 2-substituted quinolines from 2-aminostyryl ketones has been developed using iodide as a nucleophilic catalyst. Conjugate addition of iodide to 2-aminostyryl ketones yielded the corresponding ß-iodoketones, which could have a conformation where the amino and carbonyl groups are proximal through free rotation about the Cα-Cß single bond. Subsequent condensation between the amino and carbonyl groups followed by elimination of hydrogen iodide provided the corresponding quinolines, with regeneration of the iodide catalyst.

Enantioselective Synthesis of Tetrahydroquinolines from 2-Aminochalcones via a Consecutive One-Pot Reaction Catalyzed by Chiral Phosphoric Acid.

A new asymmetric protocol for the synthesis of chiral tetrahydroquinolines from 2-aminochalcones via a two-step one-pot consecutive process (cyclization/asymmetric reduction) has been developed using chiral phosphoric acid as the sole catalyst. 2-Aminochalcones were converted into the corresponding quinolines through chiral phosphoric acid-catalyzed dehydrative cyclization, and the resultant quinolines were subsequently reduced to the chiral tetrahydroquinolines via chiral phosphoric acid-catalyzed asymmetric reduction with Hantzsch ester. Various 2-aminochalcones could be applicable to this protocol, and the desired tetrahydroquinolines were obtained in excellent yields and with excellent enantioselectivities. Furthermore, the utility of this protocol has been successfully demonstrated in the highly efficient synthesis of estrogen receptor modulator.

A general strategy for the synthesis of indoloquinolizine alkaloids via a cyanide-catalyzed imino-Stetter reaction.

A new strategy applicable to the synthesis of indoloquinolizine natural products has been developed. A cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines, derived from 2-aminocinnamic acid derivatives and 2-pyridinecarboxaldehydes, provided indole-3-acetic acid derivatives bearing a pyridyl ring at the 2-position. Reduction of the carboxylic acid moiety to an alcohol followed by activation of the resulting alcohol with Tf2O or TsCl generated indoloquinolizinium salts, which were utilized as precursors for indoloquinolizine natural products. The advantage of this protocol was successfully demonstrated in the total syntheses of arborescidine A and nauclefidine.

Synthesis of 2-Vinylindole-3-Acetic Acid Derivatives via Cyanide-Catalyzed Imino-Stetter Reaction.

A new method for the synthesis of 2-vinylindole-3-acetic acid derivatives from aldimines, which are derived from 2-aminocinnamic acid derivatives and α,ß-unsaturated aldehydes, via a cyanide-catalyzed imino-Stetter reaction is described. Various types of 2-aminocinnamic acid derivatives and α,ß-unsaturated aldehydes could be used in this protocol, and the desired 2-vinyl substituted indole-3-acetic acid derivatives were obtained in high yields. This cyanide-catalyzed imino-Stetter reaction was further extended to the preparation of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives.

Synthesis of Optically Pure 3,3'-Disubstituted-1,1'-Bi-6-Methoxy-2-Phenol (BIPhOL) Derivatives via Diastereomeric Resolution.

A new protocol for the enantioselective synthesis of 3,3'-disubstituted-1,1'-bi-6-methoxy-2-phenol (BIPhOL) derivatives is described. Diastereomeric resolution of racemic BIPhOL boronic acid using a boronic acid moiety as a resolving group generated two diastereomers and subsequent Suzuki-Miyaura coupling reaction of the resulting diastereomers with aryl halides provided BIPhOL derivatives without any loss of enantioselectivity. In addition, the absolute stereochemistry of chiral BIPhOL was determined by comparison of the optical rotation with the reported value.

Enantioselective Synthesis of ß-Arylamines via Chiral Phosphoric Acid-Catalyzed Asymmetric Reductive Amination.

A new method for the synthesis of chiral ß-aryl amines via chiral phosphoric acid-catalyzed enantioselective reductive amination of benzyl methyl ketone derivatives with Hantzsch ester was developed. Various chiral ß-aryl amines were obtained in high yields and with good to high enantioselectivities. This transformation is applicable to gram-scale reactions, and the catalyst loading can be reduced to 1 mol % without sacrificing any catalytic efficacy. Furthermore, the resulting ß-aryl amine was successfully converted into a tetrahydroisoquinoline compound without any loss of enantioselectivity.

Formation of Amides from Imines via Cyanide-Mediated Metal-Free Aerobic Oxidation.

A new protocol for the direct formation of amides from imines derived from aromatic aldehydes via metal-free aerobic oxidation in the presence of cyanide is described. This protocol was applicable to various aldimines, and the desired amides were obtained in moderate to good yields. Mechanistic studies suggested that this aerobic oxidative amidation might proceed via the addition of cyanide to imines followed by proton transfer from carbon to nitrogen in the original imines, leading to carbanions of α-amino nitriles, which undergo subsequent oxidation with molecular oxygen in air to provide the desired amide compounds.

Synthesis of 2-aminoquinoxalines via one-pot cyanide-based sequential reaction under aerobic oxidation conditions.

A highly efficient synthesis of 2-aminoquinoxalines has been developed via the one-pot two-step cyanide-mediated sequential reactions of ortho-phenylenediamines with aldehydes under aerobic oxidation conditions. A variety of substrates, including aliphatic aldehydes bearing acidic α-protons, are applicable to this protocol and afford the desired 2-aminoquinoxalines in high yields.

Metal-free protodeboronation of electron-rich arene boronic acids and its application to ortho-functionalization of electron-rich arenes using a boronic acid as a blocking group.

The metal-free thermal protodeboronation of various electron-rich arene boronic acids was studied. Several reaction parameters controlling this protodeboronation, such as solvent, temperature, and a proton source, have been investigated. On the basis of these studies, suitable reaction conditions for protodeboronation of several types of electron-rich arene boronic acids were provided. On the basis of this protodeboronation, a new protocol for the synthesis of ortho-functionalized electron-rich arenes from these boronic acids was developed using the boronic acid moiety as a blocking group in the electrophilic aromatic substitution reaction, followed by the removal of the boronic acid moiety via thermal protodeboronation. Mechanistic studies suggested that this protodeboronation might proceed via the complex formation of a boronic acid with a proton source, followed by the carbon-boron bond fission through σ-bond metathesis, to afford the corresponding arene compound and boric acid.

Diastereomeric resolution of rac-1,1'-bi-2-naphthol boronic acid with a chiral boron ligand and its application to simultaneous synthesis of (R)- and (S)-3,3'-disubstituted 1,1'-bi-2-naphthol derivatives.

A new concept of diastereomeric resolution has been developed where a boronic acid functionality was employed as (1) a diastereomeric resolving group with a chiral boron ligand and (2) a masked functional group for further transformation thereafter. This new diastereomeric resolution method was successfully applied to the preparation of both (R)- and (S)-3,3'-disubstituted 1,1'-bi-2-naphthol (BINOL) derivatives in a step-ecomonical manner. Racemic BINOL boronic acid reacted with a commercially available pinene-derived iminodiacetic acid as a chiral boron ligand to generate the two diastereomers in quantitative yields over a gram-scale quantity. After the removal of the chiral boron ligand from the diastereomers under mild conditions, the subsequent Suzuki coupling reaction of the resulting chiral BINOL boronic acids with aryl halides provided a series of both (R)- and (S)-BINOL derivatives in good yields. Further, both resulting diastereomers could be directly applied to the Suzuki coupling reaction without the removal of the chiral ligand.