Asymmetric electrophilic amination of enolates by a chiral N-alkoxycarbonyloxaziridine

A new chiral 3-aryl-N-alkoxycarbonyloxaziridine, derived from menthol, has been prepared and tested as a reagent for asymmetric electrophilic amination of enolates. The aminated products were obtained in low diastereoselectivities of up to 21% d.e.     

Optically pure N-hydroxy-O-triisopropylsilyl-alpha-L-amino acid methyl esters from AlCl3-assisted ring opening of chiral oxaziridines by nitrogen containing nucleophiles

[reaction: see text] This article reports a straightforward and unprecedented process of AlCl3-assisted oxaziridine ring opening by nitrogen containing nucleophiles, in a totally anhydrous milieu. Under these conditions, nucleophiles exclusively attack the carbon atom of the three-membered heterocycles, obtained from methyl esters of natural alpha-amino acids, generating N-hydroxy-alpha-L-amino acid methyl esters. No nitrones, amides, or other side products, either from unwanted rearrangements or due to the attack of the nucleophile on the N atom of the oxaziridine systems, are formed. The hydroxylamine compounds are recovered in excellent yields, after their site-specific conversion into the corresponding O-triisopropylsilyl derivatives, by exposure to triisopropylsilyl triflate in the presence of 1H-imidazole. Derivatization, performed immediately after the recovery of the N-hydroxylated precursors, allows the chiral integrity of the asymmetric alpha-carbon atoms in the amino acid methyl esters to be retained. It also protects the obtained compounds from frame degradation by disproportionation. N-Hydroxy-O-triisopropylsilyl-alpha-L-amino acid methyl esters are important intermediates in the study of natural alpha-L-amino acid metabolic pathways and are ideal candidates as starting materials in the synthesis of biologically, pharmacologically, and nutritionally important N-hydroxy peptides.     

Asymmetric synthesis with new chiral auxiliaries derived from isosorbide

Chiral aminoethers derived from carbohydrates have been used for asymmetric alkylation of phenylacetic amides giving diastereoisomeric excess up to 83%.     

Reaction of octafluorocyclopentene with various carbon nucleophiles

The treatment of octafluorocyclopentene with organolithium reagents gave the corresponding symmetrical disubstituted perfluorocyclopentenes in good to high yields. The reaction with Grignard reagents led to the monosubstituted perfluorocyclopentenes, which were subjected to the further nucleophilic substitution reaction using another Grignard or aryllithium reagents, unsymmetrical disubstituted perfluorocyclopentenes being obtained in high yields.     

Asymmetric synthesis of alpha,alpha-difluoro-beta-amino acid derivatives from enantiomerically pure N-tert-butylsulfinimines

Addition of the Reformatsky reagent derived from ethyl bromodifluoroacetate to alkyl- and aryl-substituted N-tert-butylsulfinimines furnishes beta-tert-butylsulfinamyl-beta-substituted alpha,alpha-difluoroproponiates in diastereomeric ratios ranging from 80:20 to 95:5. The diastereomers are easily separated and the enantiomerically pure, protected beta-amino esters are readily transformed to the corresponding acid, amide, and amine derivatives as useful synthons for medicinal chemistry targets.     

Novel synthesis of chiral,enantiomerically pure thiodiglycols and diglycols

Natural α-hydroxy acids have been converted in a sequence of O-protection, reduction, O-activation, thioether and ether formation and deprotection to chiral, non-racemic β,β′-dihydroxy thioethers 1a, 1b and ether 1c. Overall yields are excellent (75%). In an attempt to synthesize the respective dihydroxy ether 1d derived from mandelic acid 1,3-dioxolane derivatives 7 were obtained.     

Asymmetric tandem additions to chiral 2-naphthyloxazolines. The synthesis of enantiomerically pure 1,2,2-trisubstituted- 1,2-dihydronaphthalenes

Addition of organolithium reagents to optically active 2-naphthyloxazolines followed by trapping with methyl iodide gives, after oxazoline removal, the titled compounds whose absolute configuration was determined by x-ray diffraction.     

Asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids via methylenedimerization of chiral glycine equivalents with dichloromethane under operationally convenient conditions

We found that simple stirring of a biphasic mixture of the Ni(II) complex of glycine Schiff base 2 solution in dichloromethane with 30% aqueous NaOH in the presence of PT catalyst ⁿBu₄N⁺Br⁻ at room temperature for 24 h results in the formation of diastereo- and enantiomerically pure Ni(II) complex 3, containing (2S,4S) 4-aminoglutamic acid, in high chemical yield. The procedure described in this communication represents a synthetically efficient method for the asymmetric synthesis of 4-aminoglutamic acid on large scale.     

Asymmetric synthesis of (+)-allo-quercitol and (+)-talo-quercitol via free radical cycloisomerization of an enantiomerically pure alkyne-tethered aldehyde derived from a carbohydrate.

We describe for the first time the free radical cyclization of enantiomerically pure alkyne-tethered aldehydes obtained from a carbohydrate (6, 7). The synthesis of compounds 6 and 7 obtained from a derivative of D-ribose is reported. These radical precursors have been submitted to cyclization with tributyltin hydride plus azobisisobutyronitrile to yield, after ring closure, two carbocycles, respectively. These carbocycles have been obtained as mixtures of E and Z vinyltin isomers, but with excellent diastereoselection at the new stereocenter formed during the ring closure. After protodestannylation, only one diastereomer was detected and isolated. The absolute configuration at the new stereocenter formed during the carbocyclization has been established by detailed (1)H NMR analysis. The specific transformation of 7-methoxymethoxy-2,2-dimethyl-4-methylene-5-tert-butyldimethylsilyloxy-(3aR,5S,7S,7aS)-perhydrobenzo[d][1,3]dioxole into optically pure (+)-allo-quercitol and (+)-talo-quercitol is described. From these results, we conclude that under an appropriate choice of radical precursors and conditions, the synthesis of highly functionalized cyclohexane derivatives of biological interest is now available.     

Asymmetric synthesis and molecular docking study of enantiomerically pure pyrrolidine derivatives with potential antithrombin activity

The (2R,4R,5S)- and (2S,4S,5R)-enantiomers of 4-(tert-butyl) 2-methyl 5-(4-bromophenyl)-pyrrolidine-2,4-dicarboxylate 3 were synthesized efficiently with an ee of >90% on a gram scale using a FAM-catalytic methodology. Subsequent modification afforded enantiopure N-((4-chlorophenyl)thio)acetyl pyrrolidine derivatives 4, which are potential thrombin inhibitors according to comprehensive molecular docking studies.     

An efficient synthesis of enantiomerically pure aromatic-fused N-containing heterocycles from common chiral aziridines

An efficient synthesis of enantiomerically pure aromatic-fused N-containing heterocycles was successfully achieved via Pd-catalyzed intramolecular C-N bond formation between the nitrogen originated from the aziridine and the halogen containing aromatic carbon. This reaction has a broad substrate scope to provide various enantiomerically pure (3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanols, 2-hydroxymethyl-1,2,3,4-tetrahydroquinolines and (1,2,3,4-tetrahydroquinoxalin-2-yl)methanols from common chiral aziridines in good yields.     

Synthesis of enantiomerically pure telluronium salts by the reaction of chiral tellurides with alkyl halides

Enantiomerically pure benzyl and ethoxycarbonylmethyl telluronium salts 4, using 2-exo-hydroxy-10-bornyl group as a chiral ligand, have been prepared in good yield and diastereoselectivity by the reaction of chiral tellurides 3 with alkyl halides. A structure with R_Te absolute configuration at the tellurium atom was confirmed by an X-ray analysis of 4a.     

Circular dichroism in the photoelectron angular distributions of camphor and fenchone from multiphoton ionization with femtosecond laser pulses

Shine a light: a circular dichroism effect in the ±10?% regime on randomly oriented chiral molecules in the gas phase is demonstrated. The signal is derived from images of photoelectron angular distributions produced by resonance-enhanced multiphoton ionization and allows the enantiomers to be distinguished. To date, this effect could only be generated with a synchrotron source. The new tabletop laser-based approach will make this approach far more accessible.     

Asymmetric halogenation of camphor-10-sulfonic acid derived esters: an efficient new route to enantiomerically pure halohydrins and epoxides.

Successive treatment of chiral esters 1 with LDA/Me₃SiCl and NBS or NCS gave crystalline α-haloesters 3 which furnished halohydrins 4 and terminal epoxides 5 in high e.e..     

Electrophilic amination of enolates with oxaziridines: effects of oxaziridine structure and reaction conditions

A range of N-alkoxycarbonyl- and N-carboxamido-oxaziridines has been prepared to test the effects of oxaziridine structure on yields of enolate amination product. Side-products arising from reaction of aldehyde-derived oxaziridines with base were identified, while a ketone-derived oxaziridine afforded moderate yields of amination product with stabilised carbanions.     

Asymmetric epoxidation by chiral ketones derived from carbocyclic analogues of fructose.

A number of carbocyclic analogues of the fructose-derived ketone 1 have been prepared and investigated for asymmetric epoxidation. The studies show that the oxygen atom of the pyranose ring of 1 has an impact on the catalyst's activity and selectivity. Conformational, electronic, and steric effects are discussed.     

Asymmetric construction of spirocyclohexanonerhodanines catalyzed by simple diamine derived from chiral tert-leucine

A diamine-catalyzed asymmetric tandem reaction between α,β-unsaturated ketones and rhodanine derivatives has been developed to synthesize various spirocyclic compounds with high stereoselectivities (up to 99% ee and >20?:?1 dr). The products obtained contain two pharmaceutically relevant features: the biologically active rhodanine moiety embedded in a spirocyclic unit.     

Synthesis of novel C2-symmetric and enantiomerically pure bisbenzoxazoles and bisbenzothiazoles derived from l- and d-tartaric acids

Five pairs of novel C₂-symmetric and enantiomerically pure bisbenzoxazoles and a pair of bisbenzothiazoles derived from l- and d-tartaric acids have been synthesized from l- and d-2,3-O-isopropylidenetartaric dichlorides and o-aminophenol derivatives or o-aminothiophenol, respectively, in two- or one-step reactions. The mechanism for the formation of bisbenzoxazoles and bisbenzothiazoles was suggested. The UV and ¹H NMR spectra showed that no coordination between the bisbenzoheterazoles and Cu(I) or Ni(II) cations occurred due to the lack of a sufficiently basic nitrogen donor atom in the benzoheterazole moiety.     

The synthesis of amino acids by reaction of an electrophilic glycine cation equivalent with carbon nucleophiles

Acetate 1, a glycine cation equivalent, is reacted with organocopper reagents to yield products 2, which can readily be converted to the higher amino acids. This method provides access to aryl-substituted amino acids as well as amino acids containing a β-tertiary carbon.