Chiral N-phosphonyl imine chemistry: new reagents and their applications for asymmetric reactions

Novel chiral N-phosphonyl imines 2 have been designed and synthesized using chiral N-phosphoramide 1. These N-phosphonyl imines have been successfully utilized for asymmetric aza-Darzens reaction and asymmetric aza-Henry reaction. The C₂-symmetric chiral auxiliary tolerates oxidation, is not sensitive to racemization and can be recycled for large scale synthesis.     

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.     

Retention of stereochemistry in the microwave assisted synthesis of 1H-tetrazole bioisosteric moiety from chiral phenyl-acetic acid derivatives

Chiral substituted phenylethyl-1H-tetrazoles were built-up from the corresponding carboxylic acid derivatives by a useful three-step synthesis. The procedure, that preserves the chiral center from racemization, was successfully applied to a selection of several hit compounds by conversion of the carboxylic acid moiety to the nitrile derivatives and subsequent reaction with trimethylstannyl azide, under microwave conditions. A useful application to the corresponding tetrazole analogue has been found also in the conversion of the aminoacidic moiety like (R)-N-Cbz-phenylglycine showing a wide potential synthetic application.     

A mild and efficient synthesis of a chiral pyridazinone derivative

We found a mild and efficient reaction condition for construction of a chiral 5-methyl-4,5-dihydropyridazin-3(2H)-one from a chiral β-methyl γ-ketocarboxylic acid via the corresponding acid hydrazide without racemization. Furthermore, we demonstrated that this two-step reaction can be attained by one-pot reaction. This method could be applied to various kinds of substrates because of the mild reaction conditions.     

Kinetics and mechanism of racemization of Tic-hydantoins, potent sigma-1 agonists

The configurational stability of seven Tic-hydantoin sigma-1 agonists 1-7 was studied in organic and aqueous media to mimic conditions encountered during either their synthesis or their evaluation as a drug candidate (physico chemical property determination and pharmacological study). This study was performed from the enantiomers directly obtained by asymmetric synthesis (hydantoins 1, 3-7) or after semi-preparative separation of the racemic obtained according to the same asymmetric procedure (thiohydantoin 2), by chiral HPLC. The racemization phenomenon was followed using recently validated chiral HPLC and capillary electrophoresis separation methods using derivatized cellulose and amylose chiral stationary phases (Chiralcel OD-H and Chiralpak AD) and highly sulphated cyclodextrins [highly S-β-CD in the background electrolyte (BGE)], respectively. The kinetic parameters (rate constant, half-life and apparent free energy barriers) of racemization were calculated using a first-order reaction model. The influence of the acid-base content, pH in aqueous medium, concentration of the buffer, and temperature were investigated. The fastest racemization rates were observed under basic conditions. All hydantoins were shown to present the same magnitude of configurational stability, whereas thiohydantoin 2 was characterized by a high chiral instability, especially in ethanolic and aqueous media: its high instability in ethanol explains that a racemic mixture was obtained after asymmetric synthesis; its instantaneous racemization observed from the neutral pH makes the preparation of the enantiomers of 2 not relevant. Finally, the mechanism of racemization was elucidated using nuclear magnetic resonance (NMR): the comparison of the kinetics of the deuteration to the kinetics of the racemization suggests the involvement of a common reaction mechanism of S_E1 type for hydantoin 1, while an S_E2 type reaction seems to be involved for thiohydantoin 2.     

Synthesis of enantiomeric pure lithium and potassium benzamidinate complexes

A new synthesis leading to the chiral amidines (S,S)- and (R,R)-N,N-bis-(1-phenylethyl)benzamidine ((S)- and (R)-HPEBA) in good yields is presented. Further reaction of (S)-HPEBA with n-BuLi gave the chiral lithium salt (S)-LiPEBA. Treatment of KH with (S)-HPEBA in boiling THF afforded the corresponding potassium salt (S)-KPEBA. In contrast by performing the reaction in boiling toluene a fast racemization was observed. In the solid state racemic KPEBA formed a dimer, in which all four nitrogen atoms are in a plane. To each potassium atom a toluene molecule is η⁶-coordinated.     

Copper nanoparticles catalyzed N-H functionalization: An efficient solvent-free N-tert-butyloxycarbonylation strategy

A chemoselective transformation of amines to their tert-butyloxycarbonyl (Boc) protected derivatives (NBoc) is described using Cu-NPs under solvent-free conditions. Simple method, rapid reaction rate, mild conditions, tolerance of a wide range of functional groups, excellent yield, ease recovery and high catalytic turnover are the salient features of this approach. tert-Butyloxycarbonylation of chiral amino acid esters and amino alcohols were performed without racemization.     

Synthesis of chiral α-amino anilides via a DMEDA-promoted selective C─N coupling reaction of aryl halides and α-aminoamides

A DMEDA-promoted and copper-catalyzed approach has been designed for the coupling of aryl halides and chiral α-aminoamides to afford a range of functionalized chiral α-amino anilides. This method has a higher yield and better reproducibility than those under ligand-free conditions. Of the two amino groups in the same molecule, only the amide NH₂ is observed to react, showing high regioselectivity. In addition, no racemization occurs, and the ee can reach 99%. For certain hydroxyl-containing substrates, such as l-tyrosine amide and l-threonine amide, addition of a phase transfer catalyst (15-Crown-5) is necessary for such a transformation.     

An Optimized Ni-catalyzed Chan-Lam Type Coupling: Enantioretentive Access to Chiral N-Aryl Sulfinamides

C−N bond formation takes on a critical significance in reactions of organic synthesis, material production and pharmaceutical manufactory. Chan-Lam has proposed a useful methodology to furnish secondary arylamides under mild conditions. However, when chiral sulfinamides serve as the coupling precursors, the Cu-catalyzed coupling reaction is found with low efficacy. Complex side-products are generated under classic conditions. Moreover, it led to the racemization of the coupling product. In this study, an optimized Ni-catalyzed Chan-Lam type coupling conditions were proposed, which resulted in clean conversion from chiral sulfinamides and arylboronic acids to offer N-aryl sulfinamides efficiently and enantioretentively. The trans-N¹,N²-dimethylcyclohexane-1,2-diamine was proven as the most efficient ligand. Under the optimized conditions, a series of chiral N-aryl sulfinamides was prepared with high chemical yield without racemization. Furthermore, a plausible and novel mechanism was proposed. Interestingly, the method could efficiently furnish a wide variety of C−X bonds by coupling arylboronic acids with different nucleophiles.     

Characterization of racemization of chiral pesticides in organic solvents and water

Eight chiral pesticides, which were selected to cover different pesticide species and origins of chirality, were investigated to explore their chiral stability in organic solvents and water. Profenophos, fenamiphos, quizalofop-ethyl, dichlorprop-methyl (DCPP-methyl) and acetochlor were showed stable under all test conditions. However, significant racemization was observed for malathion, phenthoate and fenpropathrin in methanol, ethanol and water, but not in n-hexane, isopropanol, acetone or methylene chloride. The kinetic parameters (rate constant k and half-life T_1/2) of the abiotic racemization were calculated through a mathematical model of the first-order reaction. Furthermore, the extent of racemization varied among the solvents and was also affected by temperature dependence. The racemization of malathion, phenthoate and fenpropathrin in water was documented to be pH-dependent and took place more rapidly at pH 7.0 than at pH 5.8. The observed racemization was deduced to occur via a proton exchange process at the chiral center, and the relationship between the abiotic racemization and pesticide structure was further explored. Findings from this study are useful for better understanding enantioselectivity of chiral pesticides in environment and also for proper analysis, formulating or handling of enantiopure products.     

Solid-phase synthesis of 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-ones

The solid-phase synthesis of 1,5-substituted 2-(N-alkylamino)-imidazolidin-4-one from resin-bound amino acid is described. Using a guanidinylating reagent in solution to form the guanidine moiety instead of resin-bound carbodiimide, an N-alkyl substitution is introduced specifically onto the 2-amino position. Combined with an alkylation step of the resin-bound amino acid prior to guanidinylation, all desired substitutions of the final products are achieved without racemization at chiral centers. This reaction sequence is also compatible with a variety of protected amino acid side chains.     

Ligand-free CuI-catalyzed selective C–N coupling of aliphatic amino group of α-amino acid amides with ortho-dihaloarenes

Many synthetic methods of racemic N-aryl (including N-(2-haloaryl)) α-amino acid amides have been reported, but there are only a few for eutomers and none for inactivated halo(hetero)arenes. Selective C–N coupling of aliphatic amino group of α-amino acid amides is a direct and valuable method, but still unresolved. Here we disclose a simple and cheap ligand-free CuI-catalyzed selective synthesis of chiral N-(2-halo(hetero)aryl) amino acid amides without obvious racemization. A rational mechanism is proposed.     

Novel axially chiral bis-arylthiourea-based organocatalysts for asymmetric Friedel-Crafts type reactions

It has been shown that catalytic amounts (10-20 mol %) of novel axially chiral bis-arylthioureas promote the asymmetric organocatalytic Friedel-Crafts type addition of indole and N-methylindole to nitroolefins. The optimum catalyst is capable of promoting the reaction between challenging substrates such as N-methylindole and nitroolefins bearing aliphatic β-substituents with enantioselectivity unprecedented for an organocatalytic system.     

Mild non-transition metal catalyzed deprotection of N-allyloxycarbonyl amines

A synthesis of methyl (2S)-2-amino-4-oxo-2,4-diphenylbutanoate has been achieved via a novel one-pot non-transition metal mediated deprotection of the N-allyloxycarbonyl amine using iodine in wet acetonitrile. The applicability of this transformation has been demonstrated by deprotecting a variety of N-allyloxycarbonyl amines, α-aminomethyl esters and simple N-allyloxycarbonyl alkyl amines. Deprotection occurs in high yield (82-93%) without erosion of the optical purity of the chiral substrates.     

Chiral N,N′‐Dioxide‐Organocatalyzed Regio‐, Diastereo‐ and Enantioselective Michael Addition–Alkylation Reaction

A highly regio‐, diastereo‐ and enantioselective Michael addition–alkylation reaction between α‐substituted cyano ketones and (Z)‐bromonitrostyrenes has been realized by using a chiral N,N′‐dioxide as organocatalyst. A variety of substrates performed well in this reaction, and the corresponding multifunctionalized chiral 2,3‐dihydrofurans were obtained in up to 95 % yield with 95:5 dr and 93 % ee.     

Preparation of chiral bipyridine bis-N-oxides by oxidative dimerization of chiral pyridine N-oxides

The direct preparation of chiral 2,2′-bipyridine bis-N-oxides has been developed. The method involves two stages, first, the deprotonation of substituted chiral pyridine N-oxides and second, the oxidative dimerization of the resulting 2-lithiopyridine N-oxides. Optimization of the reaction conditions led to the selection of LiTMP in THF for the deprotonation and molecular iodine as the oxidant. The corresponding 2-iodopyridine N-oxide is invariably formed as a by-product. A series of 11 chiral pyridine N-oxides was prepared that bear substituents at the C(2) and C(5) positions. Oxidative dimerization of these mono-N-oxides proceeded in 33–77% yield. In all cases, the dimerization was highly diastereoselective for the formation of the P-configuration of the chiral axis.     

Acid catalyzed monodehydro-2,5-diketopiperazine formation from N-α-ketoacyl amino acid amides

We have developed a new synthetic method for monodehydro-2,5-diketopiperazines (monodehydroDKPs), which is based on an acid catalyzed cyclization of N-α-ketoacyl amino acid amides. Using this cyclization reaction, monodehydroDKP was formed with no or slight racemization in case that N-α-ketoacyl amino acid amides with β-aliphatic-α-ketoacyl groups and sterically unhindered N-substituting groups at the C-terminal amide nitrogen were used in the presence of catalytic amount of p-TsOH (3-5 mol %) or 10% TFA. In the case of β-aryl-α-ketoacyl amino acid derivatives, in which an enol form predominantly exists by conjugation with the aromatic ring, racemization could be minimized by optimizing the reaction conditions (5 mol % p-TsOH, reflux for 6 h), although the chemical yield could not be dramatically improved. However, this reaction condition was successfully applied to the synthesis of a tubulin depolymerization agent, (−)-tert-butyl-oxa-phenylahistin, with no racemization.     

Kinetics of racemization of enantiopure N-imidazole derivatives,aromatase inhibitors: studies in organic,aqueous, and biomimetic media

The configurational stability of N-imidazole derivatives, aromatase inhibitors, was investigated under organic, aqueous, and biomimetic media, by studying the effect of organic solvent, pH, and temperature. Validated chiral HPLC or CD-EKC methods allowed us to quantify the presence of both enantiomers. The rate constants, half-lives, and apparent free energy barriers of the racemization phenomenon were determined using a mathematical model of this first-order reaction.The presence of triethylamine (2000 equiv) at high temperature (70 °C) induces the fastest racemization with a t_1/2 rac less than 7 h. This result can be related to the lability of benzylic proton in these strongly basic conditions. Biomimetic media (the presence of bovine serum albumin in a pH 7.4 buffer at 37.4 °C) do not seem to preserve the initial configuration of each enantiomer.     

First enantiospecific Baker–Venkataraman-rearrangements aiming at the total synthesis of chiral anthrapyran antibiotics

The base-catalyzed acyl transfer (Baker–Venkataraman reaction) of chiral 2-acetyl-1-hydroxyanthraquionone esters 6 of 2-methylbutanoic acid or 11 of O-allyl lactic acid proceeds with virtually no racemization to ketides 7 and 12. The subsequent acid-catalyzed cyclization to the chiral anthra[1,2-b]pyran antibiotics such as (S)-1″-11-dideoxyespicufolin 8 or 13 also occurs with a very low racemization.     

Synthesis of enantiopure (S)-(E)-1-haloalk-1-ene-3-amines with total or very high diastereoselectivity by halomethylenation of α-amino aldehydes promoted by CrCl2

Highly diastereoselective synthesis of enantiopure (S)-(E)-1-haloalk-1-ene-3-amines was achieved by reaction of α-amino aldehydes with trihalomethane promoted by chromium dichloride. The absence of racemization in the halomethylenation reaction was checked by chiral HPLC. A mechanism to explain this transformation is proposed.