Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles using squaramide as the catalyst

The organocatalyzed enantioselective synthesis of a series of chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles was achieved using bifunctional squaramides as the catalysts. The tandem Michael addition–cyclization reaction of cyclohexane-1,3-diones and benzylidenemalononitriles gave the corresponding products in excellent yields (up to 99%) and moderate to good enantioselectivities (up to 83% ee). This investigation provides an efficient and useful process for the synthesis of chiral 2-amino-4H-chromenes.     

Synthesis of chiral β2-amino acids by asymmetric hydrogenation

The synthesis of chiral β²-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepared by a Baylis–Hillman reaction, followed by acylation and amination. For the asymmetric hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing commercially available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H₂-pressure, temperature, solvent), full conversions and products with up to 99% ee were achieved.     

Preparation of pyrrolidine-oxazoline containing ligands and their application in asymmetric transfer hydrogenation

Nine members of a new ligand class incorporating both an oxazoline ring and a pyrrolidine unit were prepared in an efficient four-step synthesis starting from readily available chiral amino alcohols and proline. A study of these ligands in the asymmetric transfer hydrogenation of acetophenone showed that the catalysts formed from [Ir(cod)Cl]₂ were the most active while those derived from [Ru(p-cymene)Cl₂]₂ gave the highest enantioselectivities (up to 61% ee).     

Synthesis of novel P-stereogenic phenylphosphonamides and their application to Lewis base-catalyzed asymmetric allylation of benzaldehyde

The synthesis of novel P-stereogenic phenylphosphonamides 3 and 11 via an intramolecular nucleophilic substitution of P-stereogenic phosphoramide 8 is described. These compounds were used as chiral Lewis basic catalysts for the asymmetric allylation of benzaldehyde, providing the corresponding homoallylic alcohol derivatives in up to 54% ee.     

Catalytic stereoselective alkene aziridination with sulfonimidamides

Diastereoselective copper-catalyzed alkene aziridination has been investigated using chiral nitrenes generated from sulfonimidamides in the presence of an iodine(III) oxidant. Starting from a stoichiometric amount of the substrates, the corresponding aziridines were isolated with excellent yields of up to 96%. Good levels of asymmetric induction were obtained in the case of electron-poor olefins, with an optimal de of 94% being reached starting from tert-butyl acrylate. Matching and mismatching effects were also observed upon the use of chiral copper catalysts for the aziridination of styrene.     

Isosteric expansion of the structural diversity of chiral ligands: Design and application of proline-based N,N′-dioxide ligands for copper-catalyzed enantioselective Henry reactions

Chiral N,N′-dioxide catalysts were designed based on isosteric approach. Using l-Proline as the starting material, a variety of chiral N,N′-dioxide ligands were obtained via conventional functional group transformations and were utilized in asymmetric Henry reactions between nitromethane and aromatic aldehydes. Using the N,N′-dioxide-copper(II) complexes as the catalysts, asymmetric Henry reaction produced the corresponding β-nitroalcohols in up to 66% yields and up to 83% ee's under mild conditions. The reactions were easy to carry out, and special care such as air or moisture-free conditions was not required.     

Asymmetric synthesis of novel 1,4-aminoalcohol ligands with norbornene and norbornane backbone: use in the asymmetric diethylzinc addition to benzaldehyde

The asymmetric synthesis of cis-1,4-aminoalcohols with norbornene and norbornane backbone was performed starting with (2S,3R)-(−)-cis-hemiester 1 (98% ee). Chemoselective amination with HMPTA followed by Grignard reactions and subsequent LAH reductions afforded compounds 5a–d. cis-Hemiester 1 was also transformed into chiral ligands 7a–f and 9a–d with the DCC coupling method followed by LAH reduction using acyclic, heterocyclic amines and various aniline derivatives and p-toluenesulfonamide, respectively. The chiral ligands were subjected to asymmetric diethylzinc addition to examine their effectiveness as chiral catalysts. Among these, arylamine and tosyl substituted chiral ligands 9a–d exhibited the highest selectivities (up to 97% ee).     

N-Salicyl-β-aminoalcohols as a new class of ligand for catalytic asymmetric Strecker reactions

An enantioselective Strecker synthesis employing novel chiral titanium complex catalysts derived from structurally simple chiral N-salicyl-β-amino alcohols is described. Reactions of N-benzylidenebenzylamine with trimethylsilyl cyanide in the presence of the catalyst (10 mol%) gave the corresponding α-aminonitrile in good to excellent yields, along with relatively high enantioselectivity (up to 86% ee). Similar reactions with various imines derived from aromatic aldehydes resulted in moderate to good enantioselectivity (44-81% ee).     

Synthesis of new chiral cyclic 1,2-diamines and their evaluation as catalysts for enantioselective Diels-Alder reactions

The synthesis of new, enantiomerically pure cyclic 1,2-diamine structures was realized through a zinc promoted coupling of chiral bis-imines easily prepared starting from a chiral biphenyl dicarboxylic acid. The catalytic properties of such novel compounds were preliminarily studied; the trifluoroacetate salts of these chiral 1,2-diamines were shown to be able to catalyze the Diels-Alder reaction between cyclopentadiene and α,β-unsaturated aldehydes with good exo stereoselectivity and enantioselectivities up to 71%.     

Synthesis and evaluation of the catalytic properties of semicarbazides derived from N-triphenylmethyl-aziridine-2-carbohydrazides

A straightforward synthesis of a series of new catalysts derived from N-triphenylmethyl-aziridine-2-carbohydrazides is described. The new compounds have been tested for the enantioselective addition of diethyl- and phenylethynylzinc to aryl and alkyl aldehydes, which afforded the corresponding chiral alcohols in high chemical yields (up to 92%) and with excellent ee’s of approximately 90%.     

A general and enantiodivergent method for the asymmetric synthesis of piperidine alkaloids: concise synthesis of (R)-pipecoline, (S)-coniine and other 2-alkylpiperidines

A simple and very efficient protocol for the preparation of highly enantioenriched 2-alkylpiperidines has been set up, which allows the preparation of the final heterocycles with any wanted configuration at the stereogenic center starting from the same starting material. The key step of the synthesis relies on a diastereodivergent aza-Michael reaction protocol using the readily available and cheap reagent (+)-(S,S)-pseudoephedrine as chiral auxiliary.     

Synthesis of chiral norbornane derivatives as γ-amino alcohol catalysts: the effect of the functional group positions on the chirality transfer

Starting from (1S,4R) chiral ketone (+)-6, we developed a synthetic route to the synthesis of new chiral γ-amino alcohols (+)- and (−)-syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2) and C(7) positions, play an important role in the catalytic activity.     

Mandelic acid derived α-aziridinyl alcohols as highly efficient ligands for asymmetric additions of zinc organyls to aldehydes

A straightforward synthesis of a series of new catalysts containing secondary hydroxyl and aziridine moieties as nucleophilic centers built on the chiral scaffold of (S)-(+)-mandelic acid is described. The new compounds have been tested for the enantioselective addition of diethylzinc and phenylethynylzinc to aryl and alkyl aldehydes, which yielded the corresponding chiral alcohols in high chemical yields (up to 95%) and with excellent ee’s of ca. 90%. The strong influence of the stereogenic center located at the aziridine subunit on the stereochemical outcome is also reported on.     

A novel layered organic polymer-inorganic hybrid zinc poly (styrene-phenylvinylphosphonate)-phosphate immobilized chiral salen Mn(III) catalyst large-scale asymmetric epoxidation of unfunctionalized olefins

A novel layered organic polymer-inorganic hybrid zinc poly (styrene-phenylvinylphosphonate)-phosphate (ZnPS-PVPA) has been synthesized under mild conditions and diphenol-modified ZnPS-PVPA was used to successfully immobilize the chiral salen Mn(III) by axial coordination. The obtained heterogeneous chiral catalysts exhibited excellent activities and enantioselectivities using sodium periodate as an oxidant for asymmetric epoxidation of unfunctionalized olefins, especially for the epoxidation of α-methylstyrene (conversion: up to 97%; ee: exceed 99%). Moreover, these synthesized catalysts were relatively stable and could be expediently separated from the reaction system, and could be recycled at least ten times without obvious loss of activity and enantioselectivity. These novel catalysts could be efficiently used in large-scale reactions with the enantioselectivity being maintained at the same level, which offer a great possibility for application in industry.     

Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.     

First total synthesis of the E- and Z-isomers of cytospolide-D

A simple, convergent, and efficient approach for the total synthesis of the bioactive E- and Z-isomers of cytospolide-D is described. The key features of the synthetic strategy include stereoselective methylation, regioselective epoxide opening, olefin cross-metathesis, and a Yamaguchi protocol reaction for the formation of the E-olefinic geometry of the 10 membered ring; Steglich esterification and ring-closing metathesis reaction for the formation of the 10 membered ring with a Z-olefinic geometry in the skeleton. l-Malic acid was used as a chiral pool starting material for the construction of the olefinic acid fragment while d-mannitol was used as a chiral pool starting material for the building of the olefinic alcohol fragment.     

d-Mannitol-derived novel chiral thioureas: Synthesis and application in asymmetric Henry reactions

Five novel thioureas have been obtained through multi-step reactions from d-Mannitol as starting material and applied as catalysts in the asymmetric Henry reaction. Using catalyst 7a, (1S,2R)-2-nitro-1-phenylpropan-1-ol containing two chiral centers was obtained in high yield and with high selectivity (up to 95% yield, 87% ee, 91:9 dr). This catalyst also retained activity in the presence of water, affording a up to 93% yield, 88% ee, and 94:6 dr.     

Enantioselective organocatalytic synthesis of the chiral chromenes by domino oxa-Michael-aldol reaction

The proline based chiral organocatalyst has been found to be an efficient catalyst for enantioselective domino oxa-Michael-aldol reaction. This catalytic system provided the synthesis of substituted 2-aryl-2H-chromenes-3-carbaldehyde in good to high yields (73%–97%) with excellent enantioselectivity (up to 97%) and reasonable reaction times. The atom economy, high yield and mild reaction conditions are some of the important features of this protocol.     

A family of novel bifunctional organocatalysts:Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X7 receptor antagonists

A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides.The hemiesters were obtained in high yield with up to 93%ee.The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X₇ receptor antagonists.     

First total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA

The first total synthesis of the anti-inflammatory and pro-resolving lipid mediator 16(R),17(S)-diHDHA, derived from docosahexaenoic acid (DHA), and its 16-epimer have been achieved. Two synthetic approaches are described for the synthesis of 16(R),17(S)-diHDHA. The first strategy started from DHA and used an enzymatic reaction, a vanadium catalyzed allylic epoxidation and a base-promoted epoxide isomerization. The second approach utilized a chiral pool strategy starting from 2-deoxy-d-ribose to establish the chiral centers; Wittig reactions, mild acetonide cleavage and ester hydrolysis were the key steps in the synthesis.