Diastereoselective atom transfer radical cyclization reactions of unsaturated α-bromo oxazolidinone imides catalyzed by Lewis acids

A new Lewis acid-catalyzed atom transfer radical cyclization reaction of unsaturated α-bromo oxazolidinone imides is reported. In the presence of Lewis acids such as Mg(ClO₄)₂ and Yb(OTf)₃, a series of trans cyclic products was obtained in high yield (up to 87%) between 0°C and room temperature. The loading of strong Lewis acids, such as Yb(OTf)₃, can be reduced to 0.1 equiv. without significantly compromising the yield. Excellent diastereoselectivity could be achieved by using 1,2-stereocontrol or a chiral oxazolidinone auxiliary. For substrates 1e and 1f bearing a β-methyl substituent and the chiral auxiliary, (S)-(−)-4-benzyl-5,5-dimethyl-2-oxazolidinone, respectively, the diastereomeric ratio of the products was greater than 50:1.     

Ring opening of chiral 2-(1-aminoalkyl)epoxides by aliphatic thiols with total selectivity: synthesis of enantiopure 3-amino-1-(alkylthio)alkan-2-ols

We have studied the thiolysis of (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)epoxides 1 or 2 in the presence of BF₃·OEt₂. The ring opening took place at C-3 with complete regioselectivity, affording the corresponding enantiopure (2R,3S)- or (2S,3S)-3-amino-1-(alkylthio)alkan-2-ols 3 or 4 in good or high yield. The structures of compounds 3 and 4 have been proposed based on HMBC NMR experiments.     

Stereoselective synthesis and characterization of novel trans-4-(thiophenyl)pyrazolyl-β-lactams and their C–3 functionalization

A stereoselective synthesis and C–3 functionalization of a long series of novel hybrid 4-(thiophenyl)pyrazolyl-β-lactams have been carried out. The divergent substrate scope and mechanistic insights were examined to delineate the generality of reaction that favored trans-β-lactams 4a-q almost exclusively in all cases. The C–3 functionalization was achieved by Lewis acid assisted nucleophilic substitution reaction of cis-3-chloro-β-lactams 6a-e to afford cis-3-monosubstituted-β-lactams 7a-e. The cis stereochemistry of β-lactams 7a-e was further established by stereospecific desulfurization with Raney-nickel, in representative cases (7a,b), leading to the formation of cis-β-lactams 8a,b. The structures and stereochemical assignments for synthesized β-lactams have been unambiguously confirmed using FT-IR, 1D NMR (¹H and ¹³C), 2D NMR (¹H–¹H COSY, ¹H–¹³C HSQC and ¹³C DEPT–135), elemental analysis (CHN), mass spectrometry (ESI-MS) and single crystal X-ray crystallography, in representative cases (4b,e). The cis and trans configuration of the hydrogen/chloro/nucleophile substituent at C–3 was assigned with respect C4–H of the β-lactam ring.     

A facile synthetic route to 2-trifluoromethyl-substituted polyfunctionalized chromenes and chromones

A method for the preparation of methyl 4-hydroxy-2-(trifluoromethyl)-4H-chromenes-3-carboxylate derivatives 3a–j from readily available trifluoromethylated building block methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate 1 was described. Treatment of 3a–j with Sarrett reagent in CH₂Cl₂ generated methyl 4-oxo-2-(trifluoromethyl)-chromene-3-carboxylate derivatives 4a–h with moderate to good yields, which can be converted to 2-trifluoromethyl-substituted multifunctional benzoxepins through cyclopropanation and Lewis acid-catalyzed ring opening.     

Stereochemical studies—XIII: Cyclic aminoalcohols and related compounds—VI synthesis of the four 2-amino-4-t-butylcyclopentanol isomers

From diethyl 3-t-butyladipate (5), via cis- and trans-4-t-butylcyclopentene-1,2-oxide (31, 32) as key compounds, the syntheses of cis-2-amino-cis-4-t-butylcyclopentanol (1), cis-2-amino-trans-4-t-butylcyclopentanol (2), trans-2-amino-cis-4-t-butylcyclopentanol (3) and trans-2-amino-trans-4-t-butylcyclopentanol (4) have been achieved. 1, 3 and 4 were also synthesized from the corresponding 2-hydroxy-4-t-butylcarboxylic acids by Curtius degradation of the hydrazides (11, 18, 19). The steric course of process leading to the above compounds is discussed.     

Asymmetric azo-ene reactions using the chiral azo-enophile di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate

The preparation of di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate 4 is described. Reaction of (1R,2S)-2-phenyl-1-cyclohexanol 1 with excess phosgene in the presence of quinoline afforded chloroformate 2 which was treated directly with hydrazine monohydrate (0.5 equiv.) to afford di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazanedicarboxylate 3. Oxidization of 3 to the azo-enophile 4 was then readily effected in high yield using N-bromosuccinimide and pyridine. The azo-ene reactions of 4 with the alkenes cyclohexene 5, cyclopentene 6, trans-3-hexene 7 and trans-4-octene 8 were carried out using the Lewis acid tin(IV) chloride. Use of cyclohexene 5 afforded the ene adduct 9 in 80% yield with a diastereomeric excess of >97:3 whilst the use of cyclopentene 6, trans-3-hexene 7 and trans-4-octene 8 afforded the ene adducts 10 (77%), 11 (71%) and 12 (92%) with a diastereomeric excess of 86:14 in each case. Use of the conjugated aromatic acyclic alkene 13 afforded the product of an ionic addition, namely, chloride 14 in 57% yield. Cleavage of the N–N bond of the ene adduct 9 was effected using lithium in liquid ammonia affording the carbamate 16 in moderate yield.     

Synthesis of a 2-deoxy-ribose type 1-N-iminosugar

A 2-deoxy-ribose-type 1-N-iminosugar 5 was synthesized, in multi-gram scale, from fumaric acid monoethyl ester employing Sharpless asymmetric epoxidation followed by a Lewis acid-catalyzed (Yamammoto's aluminum reagent) cyanide epoxy ring-opening reactions.     

Chiral aziridine-2-carboxylates: versatile precursors for functionalized tetrahydroisoquinoline (THIQ) containing heterocycles

Preparation of functionalized 3,4-dihydroisoquinolines 17a–j from (S)-N-methoxy-N-methyl-1-[(R)-1-phenylethyl]aziridine-2-carboxamide 4 is an effective route for the synthesis of 3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-4-ols. Stereoselective reduction of the cyclic imines 17a–j resulted in (1S,3S,4R)-4-(tert-butyldimethylsilyl-oxy)-3-[(tert-butyldimethylsilyloxy)methyl]-6,7-dimethoxy-1,2-disubstituted-1,2,3,4-tetrahydroisoquinolines and the desilylation of the TBS groups afforded (1S,3S,4R)-3-(hydroxymethyl)-6,7-dimethoxy-1,2-disubstituted-1,2,3,4-tetrahydroisoquinolin-4-ols 19a–i in good yields. Also, an asymmetric synthesis of novel tetracyclic 3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-4-ols 23 and 25 was successfully achieved via Pd-catalyzed N-arylation and C–C coupling reaction.     

Conjugate addition of lithiated Schöllkopf's bislactim ether to 1E,3E-butadienylphosphonates: Stereocontrolled access to 2,3-anti-4E 2-amino-6-phosphono-4-hexenoic acid derivatives

Face-selective 1,6-addition of lithiated Schöllkopf's bislactime ether 5 to 4-substituted, 1,4- or 3,4-disubstituted 1E,3E-butadienylphosphonates6a-d allows a direct and stereocontrolled access to semi-rigid AP6 analogues, the 2,3-anti-4E 2-amino-6-phosphono-4-hexenoic acid derivatives 4a-c. The relative stereochemistry was assigned from a NMR study of the cyclic derivative 12c. Ten-membered trans-fused chair-boat-like transition states are invoked to rationalize the stereochemical outcome of the addition.     

The synthesis of potential Neramexane metabolites: cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids

A seven step synthetic route toward potential Neramexane metabolites cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids, cis-1 and trans-1, has been developed from isophorone. The synthetic procedure represents a useful method for the preparation of γ-amino acids with both amino and carboxyl groups situated at tertiary carbon atoms.     

Chemoenzymatic synthesis of glycosylated enantiomerically pure 4-pentene 1,2- and 1,3-diol derivatives

1-Dimethylthexylsiloxy-2-chloroacetoxy-4-pentene 2 and 1-dimethylthexylsiloxy-3-chloroacetoxy-4-pentene 3 were saponified with Pseudomonas lipase to give (R)-1-dimethylthexylsiloxy-4-pentene-2-ol (ee=99%) and (S)-2 (ee=99%) and (S)-1-dimethylthexylsiloxy-4-pentene-3-ol (ee=99%) and (R)-3 (ee=98%), respectively. All enantiomers were chemically transformed into the corresponding enatiomerically pure 2-benzoyloxy-4-pentene-1-ols 8 and 3-benzoyloxy-4-pentene-1-ols 14, respectively. Mannosylation of (R)-8 and (S)-14 with 2,3,4,6-tetra-O-benzoyl-a-d-mannopyranosyl trichloroacetimidate afforded the corresponding mannopyranosides.     

Coordination behaviour of acetylacetone-derived Schiff bases towards rhenium(I) and (V)

The oxo-bridged dinuclear rhenium(V) complex [(μ-O){ReOCl(amp)}₂] (1) was prepared by the reaction of trans-[ReOCl₃(PPh₃)₂] and 6-amino-3-methyl-1-phenyl-4-azahept-2-ene-1-one (Hamp) in acetone. The characterization of 1 by elemental analysis, infrared and ¹H NMR spectroscopy and X-ray crystallography shows that amp is coordinated as a monoanionic NNO-donor chelate as an amino-amido ketone. However, the reaction of the similar ligand 7-amino-4,7-dimethyl-5-aza-3-octen-2-one (Hada) with [Re(CO)₅Br] produced fac-[Re(CO)₃Br(Hada)], with Hada coordinated as a neutral bidentate N,N-donor amino-imino-ketone.     

Reactions of internal perfluoroolefin oxides with urea

Internal perfluoroolefin oxides reacted with urea to give, depending on the solvent nature, two types of new fluorine-substituted nitrogen-containing heterocycles. 1,5-Bis(perfluoroalkyl)tetraazabicyclo[3.3.0]octane-3,7-diones were formed in dimethyl sulfoxide, N,N-dimethylacetamide, and acetonitrile, while the reaction in dioxane resulted in the formation of unexpected products, 2-amino-5-fluoro-4,5-bis(perfluoroalkyl)-4,5-dihydrooxazol-4-ols, existing mainly as trans isomers. trans Orientation of perfluoroalkyl substituents in these compounds was determined by analysis of ¹⁹F-¹⁹F spin-spin coupling constants in the ¹⁹F NMR spectra. The molecular structure of trans-2-amino-5-fluoro-4,5-bis(trifluoromethyl)-4,5-dihydrooxazol-4-ol was studied by X-ray analysis.     

Synthesis and thermal behavior of cis- and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene

The cothermolysis of benzoyl(tert-butyl)bis(trimethylsilyl)silane with 2,3-dimethylbutadiene in a sealed tube at 140 °C for 24 h afforded cis- and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene (2 and 3) in a ratio of approximately 1:1 in 66% combined yield. When cis-silacyclohex-4-ene 2 was heated in a sealed tube at 250 °C for 24 h, dyotropic ring contraction took place to give 1-[(tert-butyl)(trimethylsiloxy)(trimethylsilyl)silyl]-3,4-dimethyl-1-phenylcyclopent-3-ene (4), but not trans-2-tert-butyl-4,5-dimethyl-2-phenyl-1-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene (6). The thermolysis of trans-silacyclohex-4-ene 3 under the same conditions, however, afforded two products, 1-silyl-1-phenylcyclopent-3-ene 4 and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-1-(trimethylsiloxy)-2-(trimethylsilyl)-1-silacyclohex-4-ene (5). The theoretical calculations were carried out to characterize the transition states and other local minima, and to evaluate the activation energies for the dyotropic rearrangement of 2 to 4 and 6, and 3 to 4 and 5. The energy barriers between 2 and 4, between 3 and 4, and between 3 and 5 were evaluated to be 188, 191, 192 kJ mol⁻¹, respectively. The energy barrier between 2 and 6, however, was calculated to be 201 kJ mol⁻¹ or higher. These results are consistent with the experimental finding that the thermal isomerization of 2 affords only 4, but 3 produces both 4 and 5.     

Straightforward synthesis of [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl](diphenyl)methanol: novel chiral ligands for the catalytic addition of diethylzinc to benzaldehyde to give rise to an extensive turn in the sense of asymmetric induction

Enantiopure [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol 5a and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]-(diphenyl)methanol 5b, new β-amino alcohols based on l-pipecolinic acid (homoproline), have been prepared straightforwardly from rac-alaninol and rac-2-amino-1,1-diphenylpropan-1-ol, respectively. The described route constitutes as a model procedure for the preparation of other related C(4) or/and C(3)-substituted 2-piperidinylmethanols.The new chiral ligands have shown a singular behaviour on the stereocontrol of the benchmark reaction of benzaldehyde and diethylzinc compared with other C(4)-unsubstituted analogues prepared by ourselves from l-pipecolinic acid (compounds 5c, 5d, 5e and 5f). The catalytic activity, the sense of asymmetric induction and the degree of the enantioselectivity depend on the appropriate combination of the substituents on the structural scaffold, but also on the metal-alkoxide involved in the catalysis (zinc or lithium alkoxides). The enantioselective addition of diethylzinc to benzaldehyde mediated by ligands 5a and 5c has been studied with DFT methods. The theoretical evaluation was performed in connection with a working hypothesis based on the different loadings of cis- and trans-catalysts in the reaction medium.     

Resolution of racemic 3-aryloxy-1-nitrooxypropan-2-ols by lipase-catalyzed enantioselective acetylation

Both (R)- and (S)-enantiomers of 3-aryloxy-1-nitrooxypropan-2-ols (R)-(−)-1, (S)-(+)-2 were prepared in high enantiomeric excess by lipase from Pseudomonas cepacia (Amano PS) or Pseudomonas fluorescens (Amano AK)-catalyzed acetylation of racemic alcohols 1a–g with vinyl acetate in n-hexane at 4 or 22°C. The enantioselectivity of this transformation was dependent on the substitution pattern of the aryl ring with E-values ranging from 31 to 111.     

Cyclization reaction of cyclopentadienone with prop-2-yn-1-ol in priority to Diels-Alder reaction

2,5-Bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone (1a) reacts with prop-2-yn-1-ols (2) to give 3-methylene-2,3,3a,6a-tetrahydrocyclopenta[b]furan-4-one derivatives in the presence of trialkylamines.     

Synthesis,characterization and biological activity of Hg(II), Fe(III) complexes with 1,3,4-oxadiazole, 1,2,4-triazole derivatives from L-methionine

Four novel heterocyclic1,3,4-oxadiazole, 1,2,4-triazole derivatives, namely: 5-[1-amino-3-(methylsulfanyl)propyl]-1,3,4-oxadiazole-2(3H)-thione (4), 4-amino-5-[1-amino-3-(methylsulfanyl)propyl]-4H-1,2,4-triazole-3-thiol (5), 1-amino-3-[1-amino-3-(methylsulfanyl)propyl]-1H-1,2,4-triazole-5-thiol (7), and 5-[1-amino-3-(methylsulfanyl)propyl]-1H-1,2,4-triazole-3-thiol (9) have been synthesized from l-methionine and characterized by different spectroscopic techniques (FT-IR, UV–Vis, ¹H NMR, ¹³C NMR and MS). Complex formation with Hg⁺⁺ and Fe⁺⁺⁺ ions were formed from the four heterocyclic 4, 5, 7 and 9. The antimicrobial activities for synthetic intermediates and final four products were assisted using paper disk diffusion method against Gram-negative bacteria: Escherichia coli, Pseudomonas aeroginosae and Gram-positive bacteria: Staphylococus aureus 25923, Staphylococus aureus 43300 and showed variant activity against some of the microorganisms tested.     

Synthesis of conformationally constrained analogues of RGD tripeptide

Convergent syntheses of N-functionalized (3S,4S)-3-amino-4-vinyl-piperidin-2-one 10, trans-3-substituted proline 18 and (3S)-3-amino-piperidin-2-one 28 are developed. By incorporating these building blocks to an appropriate position, conformationally constrained analogues of RGD tripeptide (Arg-Gly-Asp) 2, 3 and 4 are designed and synthesized.     

Novel synthesis of 3-(3,3,3-trifluoroprop-1-en-2-yl)furans via stereoselective processing and palladium-catalyzed cycloisomerization

The 3,3,3-trifluoroprop-1-en-2-yl-substituted furans (4) were synthesized via palladium-catalyzed cyclization-isomerization of 1,1,1-trifluoro-2-[(tert-butyldimethylsilyloxy)methyl]-3-alkynylbut-2-en-1-ols (3), which were readily obtained from 1,1,1-trifluoro-2-[(tert-butyldimethylsilyloxy)methyl]-3,3-dibromoprop-2-ene (1) in three steps.