Ruthenium catalyzed synthesis of enaminones

The Grubbs first-generation catalyst has been found to be an effective catalyst for the synthesis of enaminones by coupling thioamides with α-diazodicarbonyl compounds. The reaction is successful in converting primary, secondary, and tertiary thioamides into their corresponding enaminones. The reaction is also suitable for the synthesis of chiral enaminones.     

C−N Axial Chiral Hypervalent Iodine Reagents: Catalytic Stereoselective α-Oxytosylation of Ketones

A simple synthesis of a library of novel C−N axially chiral iodoarenes is achieved in a three-step synthesis from commercially available aniline derivatives. C−N axial chiral iodine reagents are rarely investigated in the hypervalent iodine arena. The potential of the novel chiral iodoarenes as organocatalysts for stereoselective oxidative transformations is assessed using the well explored, but challenging stereoselective α-oxytosylation of ketones. All investigated reagents catalyse the stereoselective oxidation of propiophenone to the corresponding chiral α-oxytosylated products with good stereochemical control. Using the optimised reaction conditions a wide range of products was obtained in generally good to excellent yields and with good enantioselectivities.     

Truly catalytic and enantioselective pinacol coupling of aryl aldehydes mediated by chiral Ti(III) complexes

A variety of chiral Ti(IV) complexes were reduced in situ with zinc in acetonitrile. The resulting chiral Ti(III) complexes were found to catalyze the pinacol coupling reaction stereoselectively. The best results were obtained from the Ti-SALEN complex, which was found to be an efficient catalyst at 10 mol % concentration. Various aromatic aldehydes were coupled to obtain chiral hydrobenzoin derivatives with high diastereoselectivity and enantioselectivity. A plausible mechanism is proposed that rationalizes the stereochemical outcome of the reaction.     

CN-assisted oxidative cyclization of cyano cinnamates and styrene derivatives: a facile entry to 3-substituted chiral phthalides

The asymmetric dihydroxylation (AD) of o-cyano cinnamates and styrene derivatives leads to efficient construction of chiral phthalide frameworks in high optical purities. This unique reaction is characterized by unusual synergism between CN and osmate groups resulting in rate enhancement of the AD process. The method is amply demonstrated by the synthesis and the structural/stereochemical assignment of the natural products.     

Regio‐ and Stereoselective Modification of Chiral α‐Amino Ketones by Pd‐Catalyzed Allylic Alkylation

Chiral α‐amino ketones are excellent nucleophiles for stereoselective palladium‐catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives.     

Triple asymmetric synthesis for fragment assembly: Validity of approximate multiplicativity of the three diastereofacial selectivities

A strategy of triple asymmetric synthesis is illustrated to be effective for stereochemical control in fragment assembly, a task often encountered in convergent natural product synthesis. The stereochemical outcome of aldol reactions involving three chiral components supports a rule of approximate multiplicativity of facial selectivities intrinsic to the chiral reactants involved in each reaction.     

Stereoselective synthesis of spiro-β-lactams using d-(+)-glucose derived chiral pool: remarkable influence of the torquoelectronic effect

Diastereoselective synthesis of spiro-β-lactams via [2+2] cycloaddition reaction of imines and chiral ketenes is described. The chiral ketene was prepared from commercially available, inexpensive d-glucose. Although, theoretically four diastereomers are possible, the reaction yielded only two diastereomers stereoselectively in good to moderate yields. The stereochemical outcome of the reaction was in accordance with the torquoelectronic model.     

Regio- and enantiospecific rhodium-catalyzed arylation of unsymmetrical fluorinated acyclic allylic carbonates: inversion of absolute configuration

The transition metal-catalyzed allylic substitution with unstabilized carbon nucleophiles represents an important cross-coupling reaction for the construction of ternary carbon stereogenic centers. We have developed a new regio- and enantiospecific rhodium-catalyzed allylic alkylation of acyclic unsymmetrical chiral nonracemic allylic alcohol derivatives with aryl zinc bromides. This study demonstrates that the hydrotris(pyrazolyl)borate rhodium catalyst and zinc(II) halide salt are crucial for efficiency, while the addition of lithium bromide to the catalyst is necessary for obtaining optimal regiospecificity. The stereochemical course of this reaction was established through the synthesis of (S)-ibuprofen, which demonstrated that the alkylation proceeds with net inversion of absolute configuration consistent with direct addition of the nucleophile to the metal center followed by reductive elimination.     

Configurational stability and transfer of stereochemical information in the reactions of enantioenriched organolithium reagents

The conversion of a prochiral methylene group into a stereogenic center by means of a lithiation/substitution sequence has emerged as a powerful synthetic transformation over the past 15 years. This reaction proceeds via a chiral organolithium intermediate, and the stereochemical fidelity of the overall reaction sequence is intimately dependent on the stereochemical behavior of the chiral organolithium as well as on the rate and stereochemical sense of the electrophilic substitution step. Chiral organolithium reagents were first reported by Letsinger, Curtin, and Applequist half a century ago. The lithiated intermediates in these early studies were not highly configurationally stable, and applications in stereoselective synthesis were not immediately forthcoming. The two decades that followed the 1980 report by Still and Sreekumar of a configurationally stable alpha-oxyorganolithium were marked by an increased interest in these reagents. As the synthetic applications of chiral organolithium reagents have grown, so have accompanying mechanistic studies of these intermediates which serve as the basis for this review.     

Which Stereoinductor Is Better for Asymmetric Functionalization of α-Amino Acids in a Nickel(II) Coordination Environment? Experimental and DFT Considerations

The results of extended comparative investigation of nickel(II) Schiff base complexes (containing various auxiliary chiral moieties) commonly used as a methodological platform for the asymmetric synthesis of tailor-made α-amino acids are provided. The following issues are addressed: 1) redox activity (determining the possibility for electrochemically induced reactions); 2) quantitative estimation of the reactivity of deprotonated complexes towards electrophiles; and 3) quantum-chemical estimation of noncovalent interactions in the metal coordination environment (which shed light on the origin of the stereochemical outcome observed for different stereoinductors). Possible mechanisms that determine the relationship between the stereochemical configuration of a molecule and its electronic structure are discussed. The DFT-calculated HOMO–LUMO energies and localization, as well as relative energies for the (S)- and (R)-alanine derivatives, that determine the stereoinduction efficiency in thermodynamically controlled reactions in nickel(II) coordination are provided. The computational data are supported by experimental results on the monobenzylation of glycine derivatives.     

Stereoselective Mannich Reactions in the Synthesis of Enantiopure Piperidine Alkaloids and Derivatives

Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.     

Asymmetric 1,2-Carbamoyl Rearrangement of Lithiated Chiral Oxazolidine Carbamates and Diastereoselective Synthesis of α-Hydroxy Amides

Asymmetric 1,2-carbamoyl rearrangement of lithiated 2-alkenyl carbamates has been investigated. Deprotonation of chiral 2-alkenyl oxazolidine carbamates with sec-butyllithium in ether at −78 °C followed by warming of the resulting 1-lithio-2-alkenyl derivatives to room temperature resulted in 1,2-carbamoyl rearrangement to provide α-hydroxy amides. The rearrangement proceeded with excellent diastereoselectivity and in good to excellent isolated yield of the α-hydroxy amide derivatives. The substrate scope of the reaction was investigated with a variety of 2-alkenyl and benzyl oxazolidine carbamates. A stereochemical model is provided to explain the stereochemical outcome associated with the rearrangement. Acid-catalyzed removal of the chiral oxazolidine afforded α-hydroxy acid in high optical purity.     

Role of the countercation in diastereoselective alkylations of pyramidalized bicyclic serine enolates. An easy approach to alpha-benzylserine

The use of a chiral serine equivalent as an excellent chiral building block has been demonstrated in the synthesis of alpha-benzylserine through a diastereoselective lithium enolate alkylation reaction and subsequent acid hydrolysis. The role of a coordinating countercation (lithium) in the alkylation reaction has been investigated. Theoretical studies have been performed in order to elucidate the stereochemical outcome of the alkylation process, which occurs with total retention of configuration.     

Highly enantioselective synthesis of cyclopropylphosphonates catalyzed by chiral ruthenium porphyrins

[reaction: see text] The asymmetric addition of diisopropyl diazomethylphosphonate to styrene derivatives was carried out by using chiral ruthenium porphyrins as catalysts. The reaction proceeded under mild conditions and gave trans-cyclopropylphosphonates with good yields and high ee's (up to 92%). A progressive increase for stereochemical effectiveness exists between enantiomeric excess and the number of chiral goups linked to ruthenium porphyrins.     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

Synthesis of new homochiral 2,3-dialkylpiperazines derived from (R)-(−)-phenylglycinol

The synthesis of four new 2,3-dialkylpiperazines in yields of 70–99% using (R)-(−)-phenylglycinol as a chiral inductor is described. The synthesis involved reduction of the oxazino–oxazine type derivatives obtained by condensation of glyoxal and phenylglycinol to give hydroxyethylenediamine precursors which were further condensed with glyoxal, butanedione and 1-phenyl-1,2-propanedione and then reduced to provide the corresponding piperazines. The stereochemical outcome is determined by the configuration of the bisoxazolidine precursors, which is in turn dictated by steric effects exerted by the substituents on the five membered ring. The structures of five derivatives were established by X-ray analysis.     

Base-promoted reaction of C60Cl6 with thioamides: an access to [60]fullereno[1,9-d] thiazoles

Regioselective reaction of C₆₀Cl₆ with thioamides via a radical annulation to form fullereno thiazole derivatives is reported. The reaction is promoted by K₂CO₃, which might deprotonate thioamide to initiate a single electron transfer from thioamide anion to C₆₀Cl₆. The experiments with various thioamides establish the proposed base-promoted reaction as a facile route for synthesis of fullereno fused thiazole derivatives starting from C₆₀Cl₆, a prevalent synthon in fullerene chemistry. In addition, the tunable electrochemical properties of the fullereno thiazole products have been investigated for their potential photovoltaic application.     

Asymmetric Dearomatization of Indole Derivatives with N‐Hydroxycarbamates Enabled by Photoredox Catalysis

Dearomatization of indoles provides efficient synthetic routes for substituted indolines. In most cases, indoles serve as nucleophiles. Reported here is an asymmetric dearomatization reaction of indole derivatives that function as electrophiles. The combination of a photocatalyst and chiral phosphoric acid open to air unlocks the umpolung reactivity of indoles, enabling their dearomatization with N‐hydroxycarbamates as nucleophiles. A variety of fused indolines bearing intriguing oxy‐amines were constructed in excellent yields with moderate to high enantioselectivities. Mechanistic studies show that the realization of two sequential single‐electron transfer oxidations of the indole derivatives is key, generating the configurationally biased carbocation species while providing the source of stereochemical induction. These results not only provide an efficient synthesis of enantioenriched indoline derivatives, but also offer a novel strategy for further designing asymmetric dearomatization reactions.     

Double diastereoselection in aldol reactions mediated by dicyclohexylchloroborane between chiral aldehydes and a chiral ethyl ketone derived from L-erythrulose. synthesis of a C1-C9 fragment of the structure of the antifungal metabolite soraphen A1alpha

[Chemical reaction: See text] Both matched and mismatched diastereoselections have been observed in the aldol reactions of a range of chiral aldehydes with the dicyclohexylboron enolate of a chiral ethyl ketone related to L-erythrulose. As was previously observed in the corresponding aldol reactions with L-erythrulose derivatives, the Felkin-Anh model provides an adequate explanation for the stereochemical outcome of reactions with chiral alpha-methyl aldehydes. However, a satisfactory account of the results observed with alpha-oxygenated aldehydes was only possible with the Cornforth model. As a practical application of the methodology described herein, a C1-C9 fragment of the structure of the antifungal macrolide soraphen A1alpha has been prepared in a convergent and stereoselective way.     

Room-temperature highly diastereoselective Zn-mediated allylation of chiral N-tert-butanesulfinyl imines: remarkable reaction condition controlled stereoselectivity reversal

[reaction: see text] An efficient method for the highly diastereoselective synthesis of chiral homoallylic amines by Zn-mediated allylation of chiral N-tert-butanesulfinyl imines at room temperature was developed. By simply tuning the reaction conditions, the method allows the achievement of a highly remarkable opposite stereocontrol, affording the desired stereochemical outcome in good yield and with excellent diastereoselectivity (up to 98% dr). With N-sulfinyl ketimines, the corresponding quaternary carbon-containing chiral homoallylic amines could also be produced.