A novel access to tetrahydro-beta-carbolines via one-pot hydroformylation/fischer indole synthesis: rearrangement of 3,3-spiroindoleninium cations

The two component one-pot hydroformylation/Fischer indole synthesis sequence of 2,5 dihydropyrroles and phenyl hydrazines allows a facile and convenient access to tetrahydro-beta-carbolines in moderate to good yields.     

Synthesis of pharmacologically relevant indoles with amine side chains via tandem hydroformylation/Fischer indole synthesis

[reaction: see text] The sequence of hydroformylation and Fischer indole synthesis starting from amino olefins and aryl hydrazines is described. In a convergent manner, the two units bearing pharmacologically relevant substituents are assembled in the final indolization step. This modular and diversity-oriented approach to tryptamines and homotryptamines can be conducted in water and allows synthesis of branched and nonbranched tryptamines as well as tryptamine-based pharmaceuticals such as the 5-HT1D agonist L 775 606.     

Toward the enantioselective total synthesis of lyngbyatoxin A: on the stereocontrolled introduction of the quaternary stereogenic centre

This paper deals with an approach to the enantioselective total synthesis of Lyngbyatoxin A, with focus on the stereocontrolled introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediated rearrangement of chiral vinyl epoxides carrying a 7-substituted indole moiety.     

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold‐catalyzed synthesis of methylidene 2,3‐cyclobutane‐indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two‐step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative C?C bond‐forming event turned out to be the rate‐determining step.     

Organocatalytic domino reactions: synthesis of densely functionalized cyclohexene derivatives

A highly enantioselective domino reaction of α,β-unsaturated aldehydes and 4-acetyl-5-oxohexanal catalyzed by a chiral secondary amine catalyst has been developed, providing an efficient synthetic approach for the synthesis of densely functionalized chiral cyclohexene derivatives with high yields (up to 96%) and enantioselectivities (up to 97% ee) under mild conditions.     

Protease-catalyzed peptide synthesis on solid support

The direct enzymatic synthesis of peptides from amino acids is widely used as a useful alternative to chemical synthesis. However, good yields of such enzyme-catalyzed reactions require altered reaction conditions to overcome the bias for hydrolysis in aqueous medium. We argue that the synthesis/hydrolysis equilibrium can be shifted toward synthesis in aqueous medium by immobilizing the amine on solid support. In this report, we show the first examples of solid-phase peptide synthesis catalyzed by a protease in bulk aqueous buffer.     

Microwave assisted synthesis of enantiomerically pure allylboronates

Stable allylboronates with a stereogenic centre α to the boronic ester moiety represent versatile reagents for stereoselective synthesis of homoallylic alcohols. Use of microwave irradiation in desilylation and sigmatropic rearrangement reactions allows rapid synthesis of α-chiral allylboronates utilized in the highly diastereo- and enantioselective synthesis of (Z)-configured homoallylic α-hydroxy esters by allyl additions to ethyl glyoxylate.     

Enantioselective Morita-Baylis-Hillman reaction of isatins with acrylates: facile creation of 3-hydroxy-2-oxindoles

The first tertiary amine catalyzed enantioselective Morita-Baylis-Hillman (MBH) reaction of isatins with acrylates has been demonstrated, allowing asymmetric synthesis of biologically significant 3-substituted-3-hydroxy-2-oxindoles in good yields and with excellent enantioselectivities. The C6'-OH group of β-isocupreidine (β-ICD) is believed to facilitate the key proton transfer step in the MBH reaction, via an intramolecular proton relay process.     

Highly enantioselective synthesis of polysubstituted tetrahydroquinolines via organocatalytic Michael/Aza-Henry tandem reactions

Highly enantioselective chiral bifunctional thiourea catalyzed asymmetric tandem reactions for synthesis of substituted tetrahydroquinolines are described. Substituted tetrahydroquinolines were given in good yields (up to 98%), high enantioselectivities (up to >99% ee), and diastereoselectivities (up to 20:1 dr).     

Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts

Catalytic enantioselective indole oxidation is a process of particular relevance to the chemistry of complex alkaloids, as it has been implicated in their biosynthesis. In the context of synthetic methodology, catalytic enantioselective indole oxidation allows a rapid and biomimetic entry into several classes of alkaloid natural products. Despite this potentially high utility in the total synthesis, reports of catalytic enantioselective indole oxidation remain sparse. Here we report a highly chemoselective catalytic system for the indole oxidation that delivers 3-hydroxy-indolenines with good chemical yields and moderate to high levels of enantio- and diastereoselectivity (up to 95:5 er and up to 92:8 dr). These results represent, to our knowledge, the most selective values yet reported in the literature for catalytic asymmetric indole oxidation. Furthermore, the utility of enantioenriched hydroxy-indolenines in stereospecific rearrangements is demonstrated.     

Enantioselective total synthesis of aspidophytine

[structure: see text] An enantioselective total synthesis of aspidophytine is described. The indole fragment bearing a cis-alkene substituent was efficiently prepared through radical cyclization of a 2-alkenylphenylisocyanide followed by Sonogashira coupling of the generated 2-iodoindole derivative with a functionalized acetylene unit. After formation of the 11-membered cyclic amine, the aspidosperma skeleton and lactone ring were constructed to complete the total synthesis.     

Michael Addition of Thiols to á,(a)-Unsaturated Carbonyl Compounds Catalyzed by Bifunctional Organocatalysts:Asymmetric Michael Addition and Asymmetric Protonation

Recently the hydrogen-bond activated reactions have attracted much attention.1 Takemoto2 reported a highly enantioselective Michael addition of manolate to nitroolefins catalyzed by a bifunctional organocatalyst with tertiary amine and thiourea moiety. As we known,stereoselective conjugate additions of thiols are interesting due to the standpoint of biological and synthetic importance, however, only very limited good results have been obtained except for the works of Shibasaki3, Kanemasa4 and Deng5 et al.In this letter, we report an efficient catalytic asymmetric Michael reactions of thiols to a,a-unsaturated carbonyl compounds promoted by bifunctional organocatalysts. A series of organocatalysts with chiral amine and thiourea structures were designed and synthesized and have been successfully applied in the conjugated additions of thiols to a,a-unsaturated imides and enones.The reactions got quantitative yields and the ee values were up to 84%. It is noteworthy that the a-asymmetric protonation (up to 43% ee) also could be achieved.The Michael addition between aromatic thiols and a,a-unsaturated carbonyl compounds isdescribed as follows:Works to further increase the enantioselectivity is under investigation in our laboratory.     

Sequential reactions from catalytic hydroformylation toward the synthesis of amino compounds

Different families of new amino compounds were efficiently synthesized, through optimized sequential processes, involving rhodium catalyzed hydroformylation as the key step. The selection of appropriate hydroformylation catalytic systems and reaction conditions allowed obtaining aldehydes derived from several n-alkyl olefins, cholest-4-ene and 3-vinyl-1H-indole, which were subsequently transformed, in one-pot, in to α-amino acids via hydroformylation/Strecker reaction, and in to tertiary amines via hydroaminomethylation, with excellent yields.     

An efficient ultrasound-promoted method for the synthesis of bis(indole) derivatives

In this paper, the reaction of indole with electron-deficient alkenes in aqueous media is reported. This procedure allows the synthesis of bis(indole) derivatives in good to high yields at 90 °C under silent and ultrasound irradiation conditions. Short reaction times and high yields of desired products are the main advantages of the presented procedure. This reaction catalyzed by 12-tungstophosphoric acid is operationally simple and considers environmental aspects by avoiding toxic catalysts and solvents.     

Enantioselective Phosphine‐Catalyzed Formal [4+4] Annulation of α,β‐Unsaturated Imines and Allene Ketones: Construction of Eight‐Membered Rings

The first highly enantioselective phosphine‐catalyzed formal [4+4] annulation has been developed. In the presence of amino‐acid‐derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole‐derived α,β‐unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (≥98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight‐membered rings by phosphine catalysis.     

Mimicking enzymatic transaminations: attempts to understand and develop a catalytic asymmetric approach to chiral alpha-amino acids

Attempts are made to build a bridge between asymmetric catalysis and enzymatic reactions by mechanistic investigations and the development of a catalytic and enantioselective approach to amination of alpha-keto esters by primary amines catalyzed by chiral Lewis acids as a model for transamination enzymes. Different Lewis acids can catalyze the half-transamination of alpha-keto esters using primary amine nitrogen sources such as pyridoxamine and 4-picolylamine. The mechanistic studies of the Lewis-acid catalyzed half-transamination using deuterium-labelled compounds show the incorporation of deuterium atoms in several positions of the alpha-amino acid derivative, indicating that the enol of the alpha-keto ester plays an important role along the reaction path. The catalytic enantioselective reactions are dependent on the pKa-value of the solvent since enantioselectivities were only obtained in solvents with high pKa-values relative to methanol. However, stronger acidic conditions generally gave better yields, but poor enantioselectivities. A series of chiral Lewis acids were screened as catalysts for the enantioselective half-transamination reactions and moderate yields and enantioselectivities of up to 46% ee were obtained.     

Asymmetric synthesis of (+)-stagonolide C and (−)-aspinolide A via organocatalysis

A new enantioselective synthesis of two important fungal metabolites, (+)-stagonolide C and (?)-aspinolide A, has been described from readily available raw materials. Proline catalyzed asymmetric α-aminooxylation and Jorgensen’s epoxidation of aldehydes are the key reactions employed in the introduction of chirality. The formation of the 10-membered lactone core structure was finally accomplished via Steglich esterification and ring closing metathesis reactions.     

Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

A new method for one‐step construction of the tetracyclic core structure of the indole alkaloid (+)‐minfiensine was developed utilizing a palladium‐catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)‐minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.     

Direct catalytic asymmetric method for the synthesis of tetrahydropyranopyrazoles through allene zwitterion chemistry

The enantioselective synthesis of the tetrahydropyranopyrazole scaffold has been achieved. The quinidine catalyzed reaction of allenoates with arylidenepyrazolones proceeded with high enantio- and diastereoselectivity while the reactions of alkylidenepyrazolones were less efficient. Allene ketones also afforded tetrahydropyranopyrazole derivatives in high yields, however, with only moderate enantioselectivity. The primary adduct undergoes further functional group transformations without effecting the initially formed chiral centre.     

Bronsted acid catalysis of achiral enamine for regio- and enantioselective nitroso aldol synthesis

Two types of chiral Br?nsted acid catalysts have been shown to catalyze regio- and enantioselective nitroso aldol synthesis between nitrosobenzene and achiral enamine. The combination of Br?nsted acidity and amine moiety of enamine realizes complete regioselectivity with high enantioselectivity. After a survey of Br?nsted acid catalysts, 1-naphthyl glycolic acid is found to be optimal in the O-nitroso aldol pathway, while 1-naphthyl TADDOL is the best catalyst for the N-nitroso aldol pathway. This is based on our finding on the control of regioselectivity by changing the amine moiety of enamine and the choice of Br?nsted acidity.