New developments in the synthesis of pyrrolizidinone-based dipeptide isosteres

1,3-Dipolar cycloaddition of acrylamide with the cyclic nitrone derived from proline tert-butyl ester has been employed in the synthesis of bicyclic Gly-(s-cis)Pro isosteres suitably protected for the Fmoc-based solid phase peptide synthesis. (R)-1-Phenylethylamine was introduced as chiral auxiliary to resolve racemic intermediates and obtain enantiopure compounds. Using methacrylamide as dipolarophile, the analogous Ala-Pro mimetics have been prepared in racemic form, whereas the same strategy applied to methyl itaconate failed to give the corresponding Asp-Pro mimetic.     

From oxides of internal perfluoroolefins to fluorocontaining camphor thiazolinylhydrazones

The reaction of oxides of internal trans- and cis-perfluoroolefins with (1S, 4S)- or racemic camphor thiosemicarbazone leads to the formation of trans- and cis-isomers of (1S, 4S)- or racemic camphor 5′-fluoro-4′-hydroxy-4′,5′-di(perfluoroalkyl)-1′,3′-thiazolinyl-2′-hydrazones, respectively. Unsymmetrical dodecafluoro-2,3-epoxyhexane yields a mixture of regioisomeric hydrazones. The molecular structure of the trans-isomer of (1S, 4S)-camphor 5′-fluoro-4′-hydroxy-4′,5′-bis(trifluoromethyl)-1′,3′-thiazolinyl-2′-hydrazone has been established by X-ray crystallography. The quite rare example of cocrystallization of two diastereomers of the latter in homochiral crystal (sp. group P2₁) has been revealed.     

Application of a chiral copper-1,1-bis{2-[(4S)-tert-butyloxazolinyl]}cyclopropane catalyst for asymmetric cyclopropanation of styrene

The structural effects of the bridge moiety and 5-position on bisoxazoline ligands were studied for the copper-catalyzed asymmetric cyclopropanation of styrene with ethyl diazoacetate. The 1,1-bis{2-[(4S)-tert-butyloxazolinyl]}cyclopropane ligand showed a remarkable enhancement in the stereoselectivities (trans/cis = 84/16, >99.9% ee for the trans product) compared with the previously reported best ligand, 2,2-bis{2-[(4S)-tert-butyloxazolinyl]}propane (trans/cis = 75/25, 99.0% ee for the trans product).     

Enantio- and diastereoselective cyclopropanation with tert-butyl α-diazopropionate catalyzed by dirhodium(II) tetrakis[N-tetrabromophthaloyl-(S)-tert-leucinate]

The first successful example of a catalytic asymmetric cyclopropanation with α-diazopropionates is described. The cyclopropanation reaction of 1-aryl-substituted and related conjugated alkenes with tert-butyl α-diazopropionate has been achieved by catalysis with dirhodium(II) tetrakis[N-tetrabromophthaloyl-(S)-tert-leucinate], Rh₂(S-TBPTTL)₄, providing the corresponding cyclopropane products containing a quarternary stereogenic center in good to high yields and with high diastereo- and enantioselectivities (trans:cis = 90:10 to >99:1, 81-93% ee).     

Synthesis,characterization and crystal structure of a dioxomolybdenum(VI) complex with a N,O type bidentate Schiff base ligand as a catalyst for homogeneous oxidation of olefins

The synthesis of a Mo(VI) Schiff base complex, cis-[MoO₂{(4,6-bis(tert-butyl)-2-{(benzyl)iminomethyl}phenolate)₂}], cis-[MoO₂(L)₂] where L = 4,6-bis(tert-butyl)-2-{(benzyl)iminomethyl}phenol, derived from benzylamine and 3,5-di-tert-butylsalycilaldehyde is reported. Full characterization of this complex was accomplished with elemental analyses, spectroscopic studies (NMR, IR and electronic) and X-ray structure analysis. This complex was tested as a catalyst for the homogeneous oxidation of olefins. The Mo(VI) complex is catalytically active for the epoxidation of aliphatic substrates at 80 °C, yielding the epoxide as the sole product in yields up to 100% and turnover numbers up to 5000. Under the optimized conditions styrene was oxidized in an 81% conversion to produce styrene oxide, benzaldehyde, and acetophenone.     

Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully prepared by optical resolution of (±)-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to provide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl 4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaborolidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with 30 equiv of Ba(OH)₂·8H₂O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamine 4.     

Synthesis of fluorinated glutamic acid derivatives via vinylalumination

A variety of structural types of fluorinated allylic acetates, prepared by vinylalumination of fluorinated aldehydes, were reacted with the benzophenone imine of glycine tert-butyl ester to provide 4-(fluorobenzylidenyl)- and 4-(fluoroalkylidenyl) glutamic acid derivatives in 61-96% yield. The 4-(4-fluorobenzylidenyl) glutamic acid derivative was hydrolyzed to give the 4-(4-fluorobenzylidenyl)pyroglutamate and then hydrogenated to the 4-(4-fluorobenzyl)pyroglutamate. The catalytic enantioselective conjugate addition-elimination of the benzophenone imine of glycine tert-butyl ester with the fluorinated allylic acetates prepared from fluoral, pentafluorobenzaldehyde, and 2,6-difluorobenzaldehyde provided the corresponding 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic acid derivatives in 42, 45 and 80% ee, respectively.     

Synthesis and evaluation of new fluorescent derivatization reagents for resolution of chiral amines by RP-HPLC

New fluorescent chiral derivatization reagents (i.e., DBD-trans-4-hydroxy-l-proline, DBD-cis-4-hydroxy-l-proline, DBD-cis-4-hydroxy-d-proline, and DBD-trans-3-hydroxy-l-proline) were synthesized from the reaction of 4-(N,N-dimethylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole with corresponding hydroxy-prolines. These reagents reacted with chiral amine to produce a couple of diastereomers. The labeling efficiently proceeded in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and pyridine as the activation reagents. The reaction conditions are mild and no racemization occurred during both the reagent synthesis and the diastereomer formation (<0.4%). The resulting diastereomers fluoresce at around 560 nm (excitation at around 450 nm). Good linearity of the calibration curves was obtained in the range of 1-75 pmol and the detection limits on chromatogram were less than 1 pmol. The separability of the diastereomers was evaluated in terms of separation factor (α) and resolution value (Rs). DBD-trans-4-hydroxy-l-proline was efficient for the resolution of dl-phenylalanine methylester; while DBD-cis-4-hydroxy-d(or l)-proline was excellent for the separation of 1-(1-naphtyl)ethylamines, as comparing with trans-4-hydroxy isomer. The reagents of cis-isomer seemed to be predominant for the resolution of hydrophobic enantiomers. On the other hand, trans-isomers were suitable for the separation of the racemic amines containing ester in the structure. With respect to the position of OH group, the effect seems to be less, judging from the results of DBD-trans-4-hydroxy-l-proline and DBD-trans-3-hydroxy-l-proline toward phenylalanine methylester. The results suggest that the separation is dependent upon both structures of the amines and the reagent used. Thus, the stereostructure, hydrophobicity and hydrogen bonding of the diastereomer, etc. seem to be affecting the separation.     

Enzymatic transesterification of pharmacologically interesting β-aminocycloalkanol precursors

Chemoenzymatic syntheses of both enantiomers of cis- and trans-2-aminocyclopentanol as well as cis- and trans-2-aminocyclohexanol, which are valuable building blocks for a plethora of ligands and pharmaceuticals have been efficiently carried out. The strategy involves the stereospecific syntheses of racemic aminocycloalkanol precursors via tagging of a phthalimide as a masking group and subsequent lipase-catalyzed kinetic resolution. Most of the lipases exhibited excellent enantioselectivity (E ? 200) in the transesterification reactions of trans-derivatives, with both N-protected (R,R)-amino acetates and (S,S)-amino alcohols being isolated in enantiopure form. With regard to cis-derivatives, lipases were also very selective, even though the biotransformations were significantly slower.     

Lipase-catalyzed kinetic resolution of 2-aminocyclopentane- and 2-aminocyclohexanecarboxamides

Candida antarctica lipase B (CAL-B)-catalyzed N-acylation with 2,2,2-trifluoroethyl butanoate in solvent mixtures of tert-butyl methyl ether and tert-amyl alcohol was used to prepare all the enantiomers of cis- and trans-2-aminocyclopentane- and -cyclohexanecarboxamides. An unexpected change in enantiopreference, accompanied by low enantioselectivity, was observed when Pseudomonas cepacia lipase (cis-cyclohexane substrate) or C. antarctica lipase A (cis-cyclopentane and -cyclohexane substrates) replaced CAL-B.     

Insertion of Pt into CH and CS bonds of thiophene derivatives. The X-ray crystal structure of a thiaplatinacycle of 3,6-dimethylthieno[3,2-b]thiophene

Treatment of the zerovalent platinum complex [Pt(PEt₃)₄] with 3,6-dimethylthieno[3,2-b]thiophene leads to a six-membered, approximately planar thiaplatinacycle, which has been characterised spectroscopically and by a single crystal X-ray determination. The reaction of [Pt(PEt₃)₄] with 2,2′-bithiophene and 1-methyl-2-(2-thienyl)pyrrole produced two types of products, thiaplatinacycles resulting from CS insertion and platinum(II) hydrides arising from CH insertion. These complexes were characterised spectroscopically.     

Platinum complexes of 2-diphenylphosphinobenzaldehyde-derived P-alkene ligands and their application in the hydroformylation of styrene

Neutral complexes of the formula PtCl₂L₂ (where L = diethyl 2-diphenylphosphino-benzylidene-malonate (1), diisopropyl 2-diphenylphosphino-benzylidene-malonate (2), di-tert-butyl 2-diphenylphosphino-benzylidene-malonate (3), methyl E-2-(2′-diphenylphosphinophenyl)-acrylate (4), tert-butyl E-2-(2′-diphenylphosphinophenyl)acrylate (5)) were prepared. These complexes proved to be excellent precursors to active catalysts for the hydroformylation of styrene. The platinum-containing catalytic systems prepared from malonate-based ligands 1 and 2 provided the highest activity. Chemoselectivities of up to 87% were obtained, while the two aldehyde regioisomers were formed in almost equimolar ratio. The in situ studies by using lower ligand to Pt ratios resulted in slight decrease in both regio- and chemoselectivities.³¹P NMR studies on the PtCl₂L₂ complexes revealed that the formation of trans isomers is highly preferred in the case of benzylidene malonate-type ligands with two ester functionalities (1-3) probably due to steric hindrance. A mixture of cis/trans geometrical isomers (on the Pt) with a predominance of the trans isomer was formed when acrylate-type ligands with one ester functionality (4 and 5) were used.     

Synthesis of chiral nonracemic 4-trans-substituted pipecolic acid derivatives

The syntheses and resolutions of enantiomerically enriched 4-phenyl, 4-tert-butyl, and 4-isopropyl pipecolic acids are described. Optically active diastereomers were prepared by diastereomeric salt formation with the chiral base, l-tyrosine hydrazide, to provide Cbz or Boc protected 4-cis-d-pipecolic acid derivatives in >98% ee. Subsequent esterification followed by sodium methoxide catalyzed epimerization provided the isomeric 4-trans-l-pipecolic esters. In addition, an efficient synthesis of 4-phenyl-cis-pipecolic acid is described.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

Addition of lithium ethyl fluoroacetate to cis and trans α,β-epoxyaldehydes. Access to C2 fluorinated butyrolactones

The aldolisation reaction of lithium ethyl fluoroacetate with cis and trans α,β-epoxyaldehydes in their racemic forms proceeds with good C₃-OH diastereoselectivity and much less at the C₂-F carbon atom. A two-step reaction on the major aldol compounds (iodination, lactonisation) led to racemic functionalised C₂ fluorinated lactones, possessing a C₂/C₃cis relationship between the fluorine and hydroxyl groups.     

In situ variable temperature X-ray diffraction studies on the transformations of nano-precursors to La-Ni-O phases

In situ variable temperature XRD (VT-XRD) measurements on the transformation of nano-precursors to LaNiO phases are presented. Experimental results showed that LaNiO₃ and La₂NiO₄ phases were formed at ca. 700 °C via the reaction of La₂O₃ and NiO (from the initial nano-precursors), where a relatively low temperature of 700 °C was found for the synthesis of La₂NiO₄. The formation of La₃Ni₂O₇ at higher temperature (up to 1150 °C) appeared to proceed through a further reaction of La₂NiO₄ with unreacted NiO, whilst the formation of La₄Ni₃O₁₀ (at 1075 °C) proceeded via a further decomposition of LaNiO₃. Although phase pure La₃Ni₂O₇ and La₄Ni₃O₁₀ were not directly obtained under the processing conditions herein, the results of this study allow for a better understanding of formation pathways, particularly for the higher order La-Ni-O phases.     

Ionic liquid-mediated Darzens condensation: An environmentally-friendly procedure for the room-temperature synthesis of α,β-epoxy ketones

This room-temperature Darzens condensation of α-chloroacetophenone with various aromatic aldehydes mediated by [bmim][BF₄] ionic liquid in the presence of sodium tert-butoxide resulted in the sole formation of good to excellent yields of trans-α,β-epoxy ketones in short time periods. In contrast, tert-butyl 2-chloroacetate underwent Darzens reactions with aldehydes giving mixtures of both cis and trans products with low selectivity. In all reactions, the ionic liquid was recovered and reused in the subsequent reactions without significant loss of activity.     

Interactions intramoléculaires. XXVI—Constantes de couplage et hétérogénéités conformationnelles dans une série de R-3 et R-5 cyano-4 cyclohexènes deutériés (R=méthyl ou t-butyl)

For trans-3-R- and 5-R-1-acetoxy-4-cyanocyclohexene-6,6-d₂ the molar fractions of diequatorial conformers are 0.83 (3-methyl), 0.68 (5-methyl), 0.57 (3-tert-butyl) and 0.55–0.69 (5-tert-butyl). For the last two compounds the values of the coupling constants are in agreement with the hypothesis of an ee?aa equilibrium. For the cis isomers, the molar fractions of equatorial alkyl conformers are 0.76 (3-methyl and 5-methyl) and 1.0 (3-tert-butyl and 5-tert-butyl). The cis-1-acetoxy-3-tert-butyl-4-methoxycarbonyl-cyclohexene presents a conformational heterogeneity. The conformational free energy of the methyl group in position 4 has been evaluated as ?0.6 kcal mol^?1 (2.5 kJ mol^?1).     

Oxidative kinetic resolution of racemic alkyl aryl carbinols by an electronically tuned chiral nitroxyl radical

A method for oxidative kinetic resolution of racemic alcohols catalyzed by chiral nitroxyl radical (R,R)-1 has been developed. This method is especially effective for the kinetic resolution of tert-butyl aryl carbinols (s = up to 23).     

Kinetic resolution of 5-substituted cycloalkenones by peptidic amidophosphane-copper-catalyzed asymmetric conjugate addition of dialkylzinc

Asymmetric conjugate alkylation reaction of racemic 5-substituted cyclohexenones with dialkylzinc reagents was catalyzed by 2-5 mol % of dipeptidic amidophosphane-Cu(MeCN)₄BF₄ in toluene at 0 °C for 20 min to recover enantioenriched starting 5-substituted cyclohexenones with 88-98% ee in 28-41% yield along with trans major 3-alkylated 5-substituted cyclohexanones with 81-90% ee in 53-60% yield. Complete consumption of starting racemic 5-TMS-cyclohexenone by treating with diethylzinc under the catalytic asymmetric reaction conditions gave trans major 85:15 mixture of trans- and cis-3-ethyl-5-TMS-cyclohexanones with 15% ee (for trans) in 83% combined yield, indicating that the conformation-controlled trans-alkylation of cyclohexenone prevails over chiral catalyst-controlled enantiofacial differentiation.