Optically active seleninamides: isolation, absolute configuration, and racemization mechanism

Optically active seleninamides were obtained for the first time by chromatographic resolution on an optically active column. The absolute configurations of the optically active seleninamides were determined by comparing their chiroptical properties with those of analogous sulfinamides, the stereochemistry of which was determined by transformation into chiral sulfoxides of known configurations. The optically active seleninamides were found to racemize in solution. Kinetic studies of the racemization and theoretical studies clarified that the racemization of the optically active seleninamides in solution proceeds via hypervalent hydrates formed by the reaction with water.     

Isolation of stable enantiomerically pure telluroxides and their stereochemistry

Optical resolution of kinetically and thermodynamically stabilized diaryl telluroxides possessing bulky substituents (rac-1a-d) and amino group (rac-2a-c), respectively, by liquid chromatography using optically active columns yielded stable enantiomerically pure telluroxides. The absolute configurations of the optically active telluroxides were determined by comparing their specific rotations and CD spectra with those of sulfur or selenium analogues. The kinetics for the racemization of optically active telluroxides in solution was studied, and it was found that kinetic and thermodynamic stabilization were very effective preventing the racemization of telluroxides. The stabilization energy of telluroxides by intramolecular coordination of the amino group to the tellurium atom was estimated to be ca. 5 kcal mol-1 by variable temperature 1H NMR measurement. The mechanism for the racemization of optically active telluroxides was studied by an isotope experiment using H2(18)O, and the results indicated that optically active telluroxides underwent racemization via an achiral tetracoordinated hydrate.     

Amino acids and peptides—IV: Novel peptide bond formation catalysed by metal ions—II Formation of optically active peptide esters

The novel peptide bond formation previously reported in the reaction of glycine ester with Cu(II) ion in an anhydrous solvent, was examined using several kinds of optically active amino acid esters. Various reaction conditions were studied in detail for Phe-OEt. From Phe-OEt, Ala-OMe, Leu-OMe, Trp-OMe, Ser-OMe, and Met-OMe, the expected dipeptide esters with the same amino acid components were obtained without racemization. Asp(OEt)-OEt, and Glu(OMe)-OMe gave only optically active α-dipeptide esters. No formation of dipeptide esters was observed with Ile-OMe, Cys-OMe, His-OMe, and Pro-OEt. However, Lys-OMe, and Orn-OMe afforded optically active lactam derivatives. Some explanations of these abnormal observations have been given.Attempts to prepare di- and tri-peptide esters carrying different kinds of amino acid units were also studied.     

Synthesis of polynucleotide analogs by grafting optically active adenine,cytosine, and hypoxanthine derivatives onto polytrimethylenimine

A new family of polynucleotide analogs were prepared by grafting nucleic acid base derivatives onto polytrimethylenimine. Several new optically pure α-nucleic acid base substituted propanoic acids were prepared as pendant groups. The (R)-ethyl adeninylpropanoate was obtained from adenine and (S)-ethyl lactate by utilizing a diethyl azodicarboxylate-triphenyl phosphine method. Subsequent hydrolysis of the ester in aqueous acid gave the (R)-adeninylpropanoic acid without racemization. The reaction of cytosine sodium salt with (S)-ethyl 2-[(methylsulfonyl)oxy] propanoate produced the 20% racemized (R)-ethyl 2-(cytosin-1-yl)propanoate. The optically pure ester was obtained by recrystallization from ethyl alcohol, which was hydrolyzed in aqueous acid to give the (R)-acid with 66% enantiomeric excess. The (R)-2-(hypoxanthin-9-yl)propanoic acid was prepared by reaction of (R)-2-(adenin-9-yl)propanoic acid with sodium nitrite. The pendant groups were allowed to react with N-hydroxy compounds in the presence of dicyclohexylcarbodiimide to give the active esters. These active esters underwent reaction with N,N-dipropylamine to provide monomer model compounds. The pendant groups were grafted onto polytrimethylenimine by using the active ester method. The racemization reactions were observed in the grafting reactions. The resulting polymers showed a range of percent grafting from 60 to 80%.     

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.     

High-pressure transesterification of sterically hindered esters

A mild, rapid, and efficient method for the solvolysis of sterically hindered esters under high pressure is described. Transesterification is carried out in the presence of DBU at room temperature and at a pressure of 10 kbar to give quantitative conversions within short reaction times. The substrates examined included aromatic and aliphatic esters of sterically hindered alcohols and phenols. An optically pure benzyl ester of phenylalanine was chosen to study racemization of the amino acid esters under high-pressure reaction conditions.     

Stabilizing effect of intramolecular lewis base toward racemization of optically active selenoxides

2‐(Methylchalcogenomethyl)diphenyl selenoxides 1 and 2‐{2′‐(N,N‐dimethylamino)ethyl}phenyl alkyl (or aryl) selenoxides 2 , which were expected to be stabilized toward racemization by intramolecular coordination, were synthesized and optically resolved into their enantiomers on an optically active column using high‐performance liquid chromatography. Relationship between the absolute configurations and the chiroptical properties of the enantiomers was clarified by comparing with those of sulfur analogues. Stabilities toward racemization of optically active selenoxides 1a and 1b were nearly equal to that of 2‐{(N,N‐dimethylamino)methyl}diphenyl selenoxide and mesityl phenyl selenoxide. The rates of racemization for optically active selenoxides 2 were found to be faster than that of 2‐{(N,N‐dimethylamino)methyl}phenyl alkyl (or aryl) selenoxides. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:301–311, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20299     

N-BROMOSUCCINIMIDE-CATALYSED TRANSESTERIFICATION AND RACEMIZATION OF SULPHINATES

Abstract

Both aliphatic and aromatic sulphinates undergo transesterification reaction in the presence of N-bromosuccinimide. Isopropanolysis of optically active alkyl arenesulphinates was found to give racemic isopropyl arenesulphinates. The rate of racemization of optically active isopropyl p-toluenesulphinate was found to be first order with respect to both N-bromosuccinimide and isopropyl alcohol, suggesting that the reaction is a bimolecular nucleophilic substitution at the sulphur atom. The para electrodonating substituents in the aromatic ring accelerate slightly the rate of racemization. At the same time the rate of racemization was found to be retarded by the increase of steric requirements of the substituent at the sulphinyl sulphur atom suggesting that the initial formation of bromoxonium salt is the rate-determining step. Completely nonstereospecific isopropanolysis of optically active alkyl p-toluenesulphinates suggests that a sulphurane is formed as an intermediate in the exchange step of the reaction.     

Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active alpha,beta-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized alpha,beta-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into alpha,beta-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.     

Optisch aktive phosphine durch asymmetrische substitution prochiraler,homochiral substituierter phosphonite

Phenylphosphonous acid dimenthylester and its dibornylester react with bulky nucleophiles to give diastereomeric phosphinous acid esters. The asymmetric induction is as high as 95% d.e. If reaction conditions favouring inversion at phosphorus are used then the (R)-menthoxy group of the prochiral starting material is substituted. The phosphinous acid esters can be converted, with partial racemization, into optically active Horner-phosphines.     

Optical resolution and racemization mechanism of a tellurinic acid

[reaction: see text] Optically active tellurinic acid was obtained for the first time by chromatographic resolution of racemic 2,4,6-triisopropylbenzenetellurinic acid (1) using a chiral column. Optically active tellurinic acid (+)-1 was stable toward racemization in hexane, although racemization occurred in hexane/2-propanol. The kinetic studies for the racemization, oxygen exchange reaction using H(2)(18)O, and theoretical studies clarified that the racemization of the optically active tellurinic acid in solution proceeds via a hypervalent tellurane formed by addition of water remaining in solvent.     

Total synthesis of optically active chanoclavine-I

The total synthesis of optically active chanoclavine-I, an ergot alkaloid, was accomplished using palladium-catalyzed intramolecular cyclization (Heck reaction) as a key step. The conjugate ester (6) was obtained in 2 steps from optically active 4-bromotryptophan (10), and the cyclization of 6 proceeded smoothly without racemization to give the key intermediate, tricyclic tetrahydrobenz[c,d]indole derivative (7), in high yield.     

Catalytic enantioselective sulfinyl transfer using cinchona alkaloid catalysts

[reaction: see text] Practical reaction conditions for the catalytic enantioselective synthesis of sulfinate esters are reported. Commercially available cinchona alkaloids were found to be superior catalysts for the sulfinyl transfer reaction of tert-butanesulfinyl chloride and a variety of benzyl alcohols. Sulfinyl transfer with 2,4,6-trichlorobenzyl alcohol and 10 mol % of the commercially available, inexpensive catalyst quinidine provided the pure sulfinate ester product in 92% isolated yield and with 90% ee.     

Preparation and characterization of new chiral nitronyl nitroxides bearing a stereogenic center in the imidazolyl framework

A synthetic procedure for optically active and racemic alpha-nitronyl nitroxides (alpha-NNs) having a stereogenic center at the 4-position of the imidazolyl ring is described. This procedure consists of (1) the synthesis of a dissymmetric vic-dinitro compound by Kornblum reaction, (2) the enantiomeric resolution of the racemate by a diastereomer method for obtaining the optically active sample, (3) the quick reduction of the optically active or racemic vic-dinitro compound to the bis(hydroxyamino) derivative with Al/Hg, (4) the solvent-free condensation of the bis(hydroxyamino) compound with an aldehyde to give the 1,3-dihydroxyimidazolidine, and (5) the final oxidation of the alpha-NN precursor with aqueous NaIO(4). The absolute configuration of the optically active alpha-NNs was assigned by correlating with the X-ray crystal structure of the (-)-(1S,4R)-camphanic acid ester derivative of the optically active vic-dinitro compound. The molecular conformation of the optically active alpha-NNs was found to be folded both in solution and in the solid state by CD spectroscopy and energy minimization with the Monte Carlo method. The magnetic properties of both optically active and racemic alpha-NNs in solution and in the solid state were characterized by EPR spectroscopy and magnetic susceptibility measurement, respectively.     

Condensation of 1-alkoxy-1,3-butadienes with optically active glyoxylic acid esters

The condensation of 1-alkoxy-1,3-butadienes with optically active esters of glyoxylic acid leading to esters of 2-alkoxy-5,6-dihydro-2H-pyran-6-carboxylic acids was studied and the dependence of asymmetric induction on the following parameters examined: alkoxy group in dienes, dissymetric group in glyoxylates, solvent and the temperature of condensation. The optical yield and absolute configuration of the adducts were determined by optical rotation measurements of methyl malate obtained by degradation. The data are rationalized by postulating parallel formation of four active complexes corresponding to a transoid and cisoid conformation of the glyoxylate ester in the transition state.     

An asymmetric synthesis of carboxylic acid derivatives,including lactic acid and α-amino acid derivatives,from optically active 1-chlorovinyl p-tolyl sulfoxides and ester lithium enolates with creation of chirality at the α-position

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from symmetrical ketones or methyl formate and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with lithium enolate of carboxylic acid tert-butyl esters gave optically active adducts having a substituent (alkyl, alkoxy, or dibenzylamino group) at the α-position with high 1,4-chiral induction from the sulfur chiral center. The adducts were converted to optically active esters, lactic acid, and α-amino acid derivatives having a chiral center at the α-position. When this addition reaction was carried out with an ester enolate generated from excess carboxylic acid tert-butyl ester with LDA in the presence of HMPA, the diastereomer of the adduct was obtained. By using the two reaction conditions for the generation of the ester enolate, a new method for asymmetric synthesis of both enantiomers of carboxylic acid derivatives having a substituent at the α-position from the one chiral source, (R)-(−)-chloromethyl p-tolyl sulfoxide, was achieved.     

Synthesis and polymerization of optically active L-[α-(N-p-acryloxybenzoyl)alanine ethyl esters]

New optically active monomers L -[α-(N-p-acryloxybenzoyl)alanine ethyl esters] (I) and their polymers were synthesized. The title monomers (I) were prepared by the reaction of 1-p-acryloxybenzoyloxy-4-chlorobenzotriazoles (II) with L -alanine ethyl ester hydrochloride, by aminolysis of the active monoester. The new typical active ester (II) was synthesized by the N-hydroxy compound active-ester methods in excellent yield. Before the synthesis of the optically active monomers was carried out, a model study of the aminolysis of the two active esters was performed.     

Thioamides and selenoamides with chirality solely due to hindered rotation about the C–N bond: enantioselective complexation with optically active hosts

Several thioformamides and selenoformamides, with chirality solely due to restricted rotation about the C–N bond, were resolved to enantiomers by inclusion crystallization with optically active diols (TADDOLs). The absolute configuration of the guest molecules was deduced from the X-ray crystal structures of the inclusion complexes. The optical activity of the resolved compounds is manifested by their CD spectra showing relatively strong Cotton effects in the region of thioamide or selenoamide n–π* transition. The optically active thioformamides and selenoformamides are configurationally labile compounds and gradually racemize in solution but are stable in the form of the inclusion complexes. The first-order kinetics of the racemization in solution allowed us to assign the C–N rotation barriers of thioformamides by spectropolarimetric measurements.     

Synthesis of polyamides from rigid and sterically hindered dicarboxylic acids and diamines under mild conditions

The rate of polycondensation of piperazine with the 2,4-dinitrophenyl, succinimido, phthalimido, and 4-nitrophenyl esters of bicyclo[2.2.2]octane-trans-2,3-dicarboxylic acid was measured and found to decrease in this sequence. In the reaction of two moles of piperazine with one mole of diester, the reactivity of both ester groups was equal. In equimolar mixtures, the second ester group reacts with the second group about ten times slower because of steric hindrance. In the reaction of the esters with N,N′-dimethylethylenediamine no such effects were observed. The aminolysis of the N-hydroxyphthalimido ester stops at low conversions unless a very large excess of triethylamine is added. The catalytic effect of 1,2,4-triazole on the aminolysis was proportional to the triazole concentration. From the rate of ester consumption in the presence of pure triethylamine, the extent of possible racemization of the optically active dicarboxylic acid was estimated. In view of the rate data, the extent of polycondensation, and side reactions, only 2,4-dinitrophenyl and N-hydroxysuccinimido diesters are suitable for the synthesis of polyamides derived from rigid and sterically hindered dicarboxylic acids.     

Asymmetric transformation of N-nitrosamines by inclusion crystallization with optically active hosts.

Several N-nitrosopiperidines with chirality solely due to a hindered rotation about the N-N bond were resolved to enantiomers by inclusion crystallization with optically active diols (TADDOLs). The absolute configuration of the guest nitrosamines was deduced from the X-ray crystal structures of the inclusion complexes. The enclathrated nitrosamines were liberated by a competitive complexation of the host diols with piperazine. The optical activity of the resolved nitrosamines is manifested by their CD spectra. A simple chirality rule was proposed for a rationalization of the observed Cotton effect sign corresponding to the n-pi* electronic transition. The optically active nitrosamines are configurationally labile compounds and gradually racemize in solution but they are indefinitely stable in the solid state. The first-order kinetics of the racemization in solution allowed us to assign the N-N rotation barriers by simple polarimetric measurements.