An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C₆-position affording its corresponding (S)-[6-²H₂]-isotopomer in excellent yield with no loss of stereochemical integrity at its C₃-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-²H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-²H]-phenylalanine methyl esters as hydrochloride salts in good yield.     

Chiral fluoroacetic acid: synthesis of (R)- and (S)-[2H1]-fluoroacetate in high enantiopurity

A two-step synthesis of (R)- and (S)-[²H₁]-fluoroacetate (sodium salts) in high enantioselectivity is reported. The synthesis is the development of a previous one in which the enantioselectivity has been increased from ～38% ee to >95% ee. The improvement in enantioselectivity applied Bio’s methodology, which involved a deoxyfluorination reaction with DAST on either enantiomer of [²H₁]-benzyl alcohol, adding TMS-morpholine to the reaction. The additive promotes an S_N2 inversion process, and suppresses a competing non-stereospecific S_N1 reaction course, and as a result significantly improves the stereointegrity of the C–F bond formation. The intermediate [²H₁]-benzyl alcohols, [²H₁]-benzyl fluorides and the product [²H₁]-fluoroacetates as their hexyl esters were separately assayed for their stereochemical integrity, using the Courtieu method. This method involved measuring their ²H NMR spectra in a chiral matrix of poly-γ-benzyl l-glutamate. The chiral assay demonstrated that there was no significant loss in stereointegrity during the deoxyfluorination reaction and showed that the enantiomers of [²H₁]-fluoroacetate were generated with high enantiomeric purity (95% ee).     

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand: (S)-(+)- and (R)-(-)-[18F]FBFP

Racemic [¹⁸F]FBFP ([¹⁸F]1) proved to be a potent σ₁ receptor radiotracer with superior imaging properties. The pure enantiomers of unlabeled compounds (S)- and (R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized. The two enantiomers (S)-1 and (R)-1 exhibited comparable high affinity for σ₁ receptors and selectivity over σ₂ receptors. The Ca²⁺ fluorescence assay indicated that (R)-1 behaved as an antagonist and (S)-1 as an agonist for σ₁ receptors. The ¹⁸F-labeled enantiomers (S)- and (R)-[¹⁸F]1 were obtained in >99% enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4% ± 2.6% and molar activity of 86–214 GBq/µmol. In ICR mice both (S)- and (R)-[¹⁸F]1 displayed comparable high brain uptake, brain-to-blood ratio, in vivo stability and binding specificity in the brain and peripheral organs. In micro-positron emission tomography (PET) imaging studies in rats, (S)-[¹⁸F]1 exhibited faster clearance from the brain than (R)-[¹⁸F]1, indicating different brain kinetics of the two enantiomers. Both (S)- and (R)-[¹⁸F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging the σ₁ receptors in humans.     

Synthesis of (+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids

(+)-(1S,2R) and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids have been prepared in >97% ee and in 33% and 20% overall yields starting from a single, chiral, bicyclic compound perceived as a chiral uracil equivalent. Construction of the cyclobutane ring is achieved via a [2+2] photocycloaddition reaction of this chiral precursor with ethylene.     

Chiral discrimination in organometallic systems. The reactions of [Fe(CO)3(15-η-2-MeOC6H6)][BF4] with optically active tertiary phosphines

Synthetic and spectroscopic (¹H NMR, CD) studies have been made of the addition of (-)₅₈₉-neomenthyldiphenylphosphine, (S,S)-(-)₅₈₉-chiraphos, and (+)₅₈₉-diop to the dienyl ring of (R,S)-[Fe(CO)₃(15-η-2-MeOC₆H₆)][BF₄] (III). The chiral discrimination observed in these reactions is compared with that previously found in the related addition of (S,S)-(-)₅₈₉-o-phenylenebis-(methylphenylphosphine) to III. In contrast to the earlier study, the diastereo-meric mixtures obtained with the present systems do not undergo subsequent rearrangements.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-H1]-homocitrates and the corresponding dimethyl ester lactones—towards elucidating the stereochemistry of the reaction catalysed by homocitrate synthase and by the Nif-V protein

Trimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitrates, 10b and 10c respectively, and dimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitric lactones, 11b and 11c respectively, have been synthesised from shikimic acid and [2-²H]-shikimic acid by a route which defines the stereochemistry of the two chiral centres in each compound. The NMR spectra of these products will enable the stereochemistry of the biological reaction catalysed by homocitrate synthase and by the protein from the nifV gene to be elucidated.     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Proximal heteroalkylation of monoalkoxycalix[4]arenes in synthesis of inherently chiral molecules

Proximal heteroalkylation of monoalkyl ethers of calix[4]arenes or p-tert-butylcalix[4]arenes in NaH/CH₃CN or NaOH/DMSO, respectively, was applied for synthesis of inherently chiral calixarenes with ABHH substitution pattern. The introduction by the method of (R)- or (S)-N-(α-phenylethyl)acetamide chiral auxiliary group gives mixtures of diastereomeric derivatives of inherently chiral calixarenes, which were separated by column chromatography. The chiral calixarenes were thoroughly characterized by ¹H, ¹³C NMR, and X-ray diffraction methods.     

Synthesis of enantiopure ethyl (1S,9aS)- and (1S,9aR)-1-phenyl-4,9-dioxohexahydropyrrolo[1,2-d][1,4]oxazepine-9a(7H)-carboxylate by carbenoid/ylide/Stevens-[1,2]-shift with ring enlargement

Enantiomerically pure ethyl (1S,9aS)- and (1S,9aR)-1-phenyl-4,9-dioxohexahydropyrrolo[1,2-d][1,4]oxazepine-9a(7H)-carboxylate were obtained by Cu(II)-catalyzed decomposition of an α-diazo carbonyl tethered to a chiral morpholinone. The reaction occurred with moderate diastereoselectivity but with complete enantioselectivity through the carbenoid/spiro-[5,6]-ammonium ylide/Stevens-[1,2]-shift with ring enlargement sequence.     

Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclization of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine

Starting from (1R,2S)- and (1S,2R)-norephedrine, enantiomers of the corresponding 2-(3-butenyl)oxazolines were prepared in a two-step process. The cyclization of the intermediate alkenylamides with phenylselenyl bromide afforded cyclic imidates instead of the expected pyrrolidinones. The electrophile-induced cyclizations of 2-alkenyloxazolines with bromine or iodine produced diastereomeric mixtures of chiral 1,5-disubstituted pyrrolidinones. The ring closure of the all-cis (1R,2S,5R)-diastereomer 7 with NaH resulted in the tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 18, which was alternatively prepared by the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.     

2-Methoxy-2-(1-naphthyl)propionic acid,a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)-2a and (−)-2b, the separation factor α=1.83 being unusually large. The ¹H NMR chemical shift differences, Δδ=δ(R)–δ(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the ¹H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids (S)-(+)-1 and (R)-(−)-1, which are useful for enantioresolution of racemic alcohols.     

Synthesis and characterization of fluorous (S)- and (R)-1-phenylethylamines that effect heat facilitated resolution of (±)-2-(8-carboxy-1-naphthylsulfinyl)benzoic acid via diastereomeric salt formation and study of their circular dichroism

Perfluoroalkyl- or nonafluoro-tert-butoxy-alkyl-substituted enantiopure amines having the structure PhCHCH₃(NR¹R²) [R¹ = H, CH₃; R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃; R¹ = R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃] are obtained in high yields, when (S)-(−)-1-phenylethylamine is reacted with readily accessible alkylating reagents or fluorous 2° amines (R¹ = H; R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃) are methylated in a Leuckart-Wallach reaction. The solubility patterns of these novel chiral amines and their hydrochlorides are qualitatively described for a broad spectrum of solvents and the fluorous partition coefficients of the free bases are determined by GC. A novel method for the resolution of enantiomers is disclosed here, which involves the use a half-equivalent of the selected resolving agent in solvent water that displays low solubility for the crystalline diastereomeric salt(s) formed even at temperatures near to its boiling point. Compound (S)-(−)-PhCHCH₃[NH(CH₂)₃C₈F₁₇] is found to satisfy all the latter conditions and successfully used for the heat facilitated resolution of the title racemic acid. The circular dichroism (CD) spectra of six novel fluorous (S)-(−)-1-phenylethylamine derivatives are measured in ethanol, trifluoroethanol and hexafluoropropan-2-ol and discussed in detail.     

Markierte Vertreter eines möglichen Zwischenprodukts der Biosynthese von Fosfomycin inStreptomyces fradiae: Darstellung von (R,S)-(2-Hydroxypropyl)-, (R,S)-, (R)-, (S)-(2-Hydroxy-[1,1-2H2]propyl)-und (R,S)-(2-[18O]Hydroxypropyl)phosphonsäure

Summary Racemic methyl O-benzyllactate was reduced to the alcohol, transformed into the bromide and reacted with triethylphosphite to give the diethylphosphonate. Removal of protecting groups afforded a phosphonic acid which was purified as its cyclohexylammonium salt. (S)-Ethyl and (R)-isobutyl O-benzyllactate were reduced with LiAlD₄ to the corresponding dideuteriated alcohols, which were transformed in the same way as the racemic compound into the chiral (2-hydroxy-[1,1-²H₂]propyl)phosphonic acids. The optical purity of alcohols (S)- and (R)-6 b was determined by derivatisation with (+)-MTPA-Cl and¹H-NMR-spectroscopy to be 98%. Exchange of the carbonyl-16-oxygen atom of 2-oxopropylphosphonate for oxygen-18 from H₂ ¹⁸O, reduction with NaBH₄, deprotection and addition of cyclohexylamine yielded the salt (±)-18 of (2-[¹⁸O]hydroxypropyl)phosphonic acid.

     

The first preparation of (1S,5R)-(−)- and (1R,5S)-(+)-7-phenyl-3-borabicyclo[3.3.1]non-6-enes and their application for synthesis of chiral cyclohexene derivatives

(1S,5R)-(−)- and (1R,5S)-(+)-7-phenyl-3-borabicyclo[3.3.1]non-6-enes of 97-98% de that differed only by the location of the double bond were prepared by the resolution of diastereomeric intramolecular chelates with l- and d-prolinol. Deboronation of chiral bicyclic boranes obtained was used for synthesis of optically active 3,5-dimethyl- and 3,5-dihydroxymethyl-1-phenylcyclohexenes.     

Synthesis and Stereochemistry of (1S,3S,4S,7R11R)-3-(4-Nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,04,11]undecane

The reaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with glutaraldehyde has been studied. It has been established on the basis of AM1 and PM3 calculations and ¹H NMR spectra recorded in the presence of the shift reagent Eu(fod)₃ that (1S,3S,4S,7R,11R)-3-(4-nitrophenyl)-11-aza-2,6-dioxatricyclo[5,3,1,0^4,11]undecane is formed as the result of the reaction.     

Synthesis and characterization of novel chiral calix[4]arene bearing (R)-(+)-1-phenylethylamine bonded silica particles

Two novel chiral di- and tri-amide derivatives of p-tert-butylcalix[4]arene were synthesized by (R)-(+)-1-Phenylethylamine via convenient reactions and then immobilized on aminopropyl functionalized silica particles. The prepared chiral calix[4]arenes and their silica polymers (Calix-SP1 and Calix-SP2) were characterized using ¹H NMR, ¹³C NMR, FT-IR, and thermal and elemental analysis techniques.     

Stereoselective synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-dione hydrochlorides: bicyclic glutamic acid derivatives

Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones has been achieved. The underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine (1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition-elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data.     

The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (−)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Diastereoselective synthesis of (2S)-2-[(R)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one

Double asymmetric induction in Michael reactions has been studied. Enantioselective alkylation of a cyclic ketone (1-indanone) with α-phenyl-nor-gramine was carried out. The relative configuration of (2S^∗)-2-[(R^∗)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one was established by X-ray diffraction. The relative configuration of (R^∗,R^∗,S^∗)- and (S^∗,R^∗,S^∗)-2-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-ols was established by ¹H NMR studies.