Modular Phosphine‐Aminophosphine Ligands Based on Chiral 1,2,3,4‐Tetrahydro‐1‐naphthylamine Backbone: A New Class of Practical Ligands for Enantioselective Hydrogenations

A series of new chiral phosphine‐aminophosphine ligands [(R)‐HW‐Phos] has been prepared from (R)‐1,2,3,4‐tetrahydro‐1‐naphthylamine through a two‐step procedure, and successfully applied in the rhodium‐catalyzed asymmetric hydrogenation of various functionalized olefins such as α‐enol ester phosphonates, α‐enamido phosphonates, (Z)‐β‐(acylamino)acrylates and so on. Excellent enantioselectivities have been achieved in the hydrogenation of most substrates tested, demonstrating the high potential of these newly developed phosphine‐aminophosphine ligands in asymmetric catalysis. The present research also discloses that these newly developed phosphine‐aminophosphine ligands are more efficient than that derived from (S)‐1‐phenylethylamine, suggesting that the increased rigidity conferred by a cyclohexyl fragment in these phosphine‐aminophosphine ligands has a positive effect in the asymmetric induction.     

Enantioselective Synthesis of Chiral β‐Aryloxy Alcohols by Ruthenium‐Catalyzed Ketone Hydrogenation via Dynamic Kinetic Resolution (DKR)

A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl₂[(S)‐SDP][(R,R)‐DPEN]} [(S_a,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved.     

Enantioselective Synthesis of (−)‐CP‐55940 via Ruthenium‐ Catalyzed Asymmetric Hydrogenation of Ketones

A new and efficient catalytic asymmetric synthesis of the potent cannabinoid receptor agonist (−)‐CP‐55940 has been developed by using ruthenium‐catalyzed asymmetric hydrogenation of racemic α‐aryl ketones via dynamic kinetic resolution (DKR) as a key step. With RuCl₂‐SDPs/diamine [SDPs=7,7′‐bis(diarylphophino)‐1,1′‐spirobiindane] catalysts the asymmetric hydrogenation of racemic α‐arylcyclohexanones via DKR provided the corresponding cis‐β‐arylcyclohexanols in high yields with up to 99.3% ee and >99:1 cis‐selectivities. Both ethylene ketal group at the cyclohexane ring and ortho‐methoxy group at the phenyl ring of the substrates 6 have little effect on the selectivity and reactivity of the hydrogenations. Based on this highly efficient asymmetric ketone hydrogenation, (−)‐CP‐55940 was synthesized in 13 steps (the longest linear steps) in 14.6% overall yield starting from commercially available 3‐methoxybenzaldehyde and 1,4‐cyclohexenedione monoethylene acetal.     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

Catalytic Asymmetric Hydrogenation of α‐Arylcyclohexanones and Total Synthesis of (−)‐α‐Lycorane

An efficient catalytic asymmetric hydrogenation of racemic α‐arylcyclohexanones with an ethylene ketal group at the 5‐position of the cyclohexane ring via dynamic kinetic resolution has been developed, giving chiral α‐arylcyclohexanols with two contiguous stereocenters with up to 99% ee and >99:1 cis/trans‐selectivity. Using this highly efficient asymmetric hydrogenation reaction as a key step, (−)‐α‐lycorane was synthesized in 19.6% overall yield over 13 steps from commercially available starting material.     

Synthesis and Characterization of 3,4,5‐Triamino‐1,2,4‐Triazolium 5‐Nitrotetrazolate

3,4,5‐Triamino‐1,2,4‐triazolium 5‐nitrotetrazolate ( 2 ) was synthesized in high yield from 3,4,5‐triamino‐1,2,4‐triazole (guanazine) ( 1 ) and ammonium 5‐nitrotetrazolate. The new compound 2 was characterized by vibrational (IR and Raman) and multinuclear NMR spectroscopy (¹H, ¹³C, ¹⁵N), elemental analysis and single crystal X‐ray diffraction (triclinic, P(‐1), a=0.7194(5), b=0.8215(5), c=0.8668(5) nm, α=75.307(5), β=70.054(5), γ=68.104(5)°, V=0.4421(5) nm³, Z=2, ϱ=1.722 g cm⁻¹, R₁=0.0519 [F>4σ(F)], wR₂(all data)=0.1154). The ¹⁵N NMR spectrum and X‐ray crystal structure (triclinic, P‐1, a=0.5578(5), b=0.6166(5), c=0.7395(5) nm, α=114.485(5)°, β=90.810(5)°, γ=97.846(5)°, V=0.2286(3) nm³, Z=2, ϱ=1.658 g cm⁻¹, R₁=0.0460 [F>4σ(F)], wR₂(all data)=0.1153) of 1 were also determined.     

Enantioselective Phase‐Transfer Catalytic α‐Benzylation and α‐Allylation of α‐tert‐Butoxycarbonyllactones

A new enantioselective α‐benzylation and α‐allylation of α‐tert‐butoxycarbonyllactones was devloped. α‐Benzylation and α‐allylation of α‐tert‐butoxycarbonylbutyrolactone and α‐tert‐butoxycarbonylvalerolactone under phase‐transfer catalytic conditions (50% cesium hydroxide, toluene, −60 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide (1 mol%) afforded the corresponding α‐substituted α‐tert‐butoxycarbonyllactones in very high chemical yields (up to 99%) and optical yields (up to 99% ee). The synthetic potential of this method has been successfully demonstrated by the asymmetric synthesis of unnatural α‐quaternary homoserines, 3‐alkyl‐3‐carboxypyrrolidine and 3‐alkyl‐3‐carboxypiperidine.     

Synthesis of Diastereomeric 1,4‐Diphosphine Ligands Bearing Imidazolidin‐2‐one Backbone and Their Application in Rh(I)‐Catalyzed Asymmetric Hydrogenation of Functionalized Olefins

The diastereomeric 1,4‐diphosphine ligands, (S,S,S,S)‐ 1a , (R,S,S,R)‐ 1b and (R,S,S,S)‐ 1c , with the imidazolidin‐2‐one backbone were synthesized, and utilized for an investigation of the effects of backbone chirality on the enantioselectivity in the Rh(I)‐catalyzed hydrogenation of various functionalized olefinic substrates. It was found that the catalytic efficiencies are largely dependent on the configurations of the α‐carbons to phosphine. Thus, the Rh complex of the pseudo‐C₂‐symmetrical diphosphine, (R,S,S,S)‐ 1c , showed excellent enantioselectivities (93.0–98.6% ees) in the hydrogenations of a broad spectrum of substrates, and especially in the hydrogenations of methyl α‐(N‐acetyamino)‐β‐arylacrylates (95.3–97.0% ees). However, the enantioselectivities obtained with the C₂‐symmetrical (R,S,S,R)‐ 1b were largely dependent on the substrate (19.8–97.3% ees). The Rh complex of ligand 1a having the (S,S,S,S)‐configuration showed the lowest catalytic efficiency for all of the substrates examined (0–84.8% ees).     

γ‐FOX‐7: Structure of a High Energy Density Material Immediately Prior to Decomposition

1,1‐Diamino‐2,2‐dinitroethene, C₂H₄N₄O₄ (FOX‐7), is a novel high energy density material with low friction and impact sensitivity and a high activation barrier to detonation. In this study, the previously unknown crystal structure of the γ‐polymorph of trimorphic FOX‐7 is reported. γ‐FOX‐7 is stable from ∼435 K until the compound decomposes just above 504 K. A single crystal of α‐FOX‐7 (P2₁/n, Z=4, a=694.67(7) pm, b=668.87(9) pm, c=1135.1(1) pm, β=90.14(1)°, T=373 K) was first transformed into a single crystal of β‐FOX‐7 (P2₁2₁2₁, Z=4, a=698.6(1) pm, b=668.6(2) pm, c=1168.7(3) pm, T=423 K) and then into a single crystal of γ‐FOX‐7 at 450 K. The γ‐FOX‐7 crystal was then subsequently quenched to 200 K. The structure of γ‐FOX‐7 (P2₁/n, Z=8, a=1335.4(3) pm, b=689.5(1) pm, c=1205.0(2) pm, β=111.102(8)°, T=200 K) consists of four planar layers, each containing two crystallographically independent FOX‐7 molecules found in the asymmetric unit.     

Enantioselective Synthesis of Optically Active Alkanephos‐ phonates via Rhodium‐Catalyzed Asymmetric Hydrogenation of β‐Substituted α,β‐Unsaturated Phosphonates with Ferrocene‐Based Monophosphoramidite Ligands

A series of chiral β‐substituted alkanephosphonates was synthesized in high enantioselectivities via the first rhodium‐catalyzed asymmetric hydrogenation of the corresponding β‐substituted‐α,β‐unsaturated phosphonates using a ferrocene‐derived monophosphoramidite ligand, with which up to 99.5% ee have been achieved for the hydrogenation of (E)‐substrates and 98.0% ee for (Z)‐substrates.     

Catalytic Hydrogenation of α‐Iminophosphonates as a Method for the Synthesis of Racemic and Optically Active α‐Aminophosphonates

It was shown that the catalytic hydrogenation of α‐iminophosphonates by molecular hydrogen can serve as a convenient method for the synthesis of racemic and optically active α‐aminophosphonates. Up to 94% ee was achieved in the rhodium‐catalyzed enantioselective hydrogenation using chiral ligand (R)‐BINAP.     

Catalytic Asymmetric Alkynylation and Arylation of Aldehydes by an H8‐Binaphthyl‐Based Amino Alcohol Ligand

A novel chiral H₈‐1,1′‐binaphthyl‐based amino alcohol ligand (1R_a,2S,3R)‐ 2 has been synthesized and applied in the direct nucleophilic addition of organozincs (alkynylzinc and arylzinc prepared in situ) to aldehydes, yielding the corresponding optically active propargylic alcohols and diarylmethanols in high yields and good to excellent enantioselectivities. For the asymmetric arylation reaction, one catalyst (1R_a,2S,3R)‐ 2 can afford both enantiomers of many pharmaceutically interesting diarylmethanols by a proper combination of various arylzinc reagents and aldehydes.     

Synthesis and Characterization of 1,4‐Dimethyl‐5‐Aminotetrazolium 5‐Nitrotetrazolate

1,4‐Dimethyl‐5‐aminotetrazolium 5‐nitrotetrazolate ( 2 ) was synthesized in high yield from 1,4‐dimethyl‐5‐aminotetrazolium iodide ( 1 ) and silver 5‐nitrotetrazolate. Both new compounds ( 1, 2 ) were characterized using vibrational (IR and Raman) and multinuclear NMR spectroscopy (¹H, ¹³C, ¹⁴N, ¹⁵N), elemental analysis and single crystal X‐ray diffraction. 1,4‐Dimethyl‐5‐aminotetrazolium 5‐nitrotetrazolate ( 2 ) represents the first example of an energetic material which contains both a tetrazole based cation and anion. Compound 2 is hydrolytically stable with a high melting point of 190 °C (decomposition). The impact sensitivity of compound 2 is very low (30 J), it is not sensitive towards friction (>360 N). The molecular structure of 1,4‐dimethyl‐5‐aminotetrazolium iodide ( 1 ) in the crystalline state was determined by X‐ray crystallography: orthorhombic, F_ddd, a=1.3718(1) nm, b=1.4486(1) nm, c=1.6281(1) nm, V=3.2354(5) nm³, Z=16, ρ=1.979 g cm⁻¹, R₁=0.0169 (F>4σ(F)), wR₂ (all data)=0.0352.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Enantioselective Synthesis of Chiral Tetrahydroisoquinolines by Iridium‐Catalyzed Asymmetric Hydrogenation of Enamines

Chiral iridium complexes based on spiro phosphoramidite ligands are demonstrated to be highly efficient catalysts for the asymmetric hydrogenation of unfunctionalized enamines with an exocyclic double bond. In combination with excess iodine or potassium iodide and under hydrogen pressure, the complex Ir/(S_a,R,R)‐ 3a provides chiral N‐alkyltetrahydroisoquinolines in high yields with up to 98% ee. The L/Ir ratio of 2:1 is crucial for obtaining a high reaction rate and enantioselectivity. A deuterium labeling experiment showed that an inverse isotope effect exists in this reaction. A possible catalytic cycle including an iridium(III) species bearing two monophosphoramidite ligands is also proposed.     

Lipase‐catalyzed dynamic hydrolytic resolution of (R,S)‐2,2,2‐trifluoroethyl α‐chlorophenyl acetate in water‐saturated isooctane

The hydrolytic resolution of (R,S)‐2,2,2‐trifluoroethyl α‐chlorophenylacetate in water‐saturated isooctane containing Lipase MY(I) at 35 °C is selected as the best reaction condition for producing (R)‐α‐chlorophenyl acetic acid. The kinetic constants, and hence an enantiomeric ratio of 33.6, are estimated and employed for the modeling of time‐course conversions of both substrates by considering product inhibition and enzyme deactivation effects. A successful dynamic kinetic resolution is also achieved, giving the desired (R)‐α‐chlorophenylacetic acid of 93.0% yield and ee_P = 89.5% when 80 mmol dm^?3 trioctylamine acting as the racemization catalyst and enzyme activator is initially added. Copyright © 2006 Society of Chemical Industry     

Stereoselective Reduction of 1‐O‐Isopropyloxygenipin Enhances Its Neuroprotective Activity in Neuronal Cells from Apoptosis Induced by Sodium Nitroprusside

Genipin is a Chinese herbal medicine with both neuroprotective and neuritogenic activity. Because of its unstable nature, efforts have been to develop more stable genipin derivatives with improved biological activities. Among the new compounds reported in the literature, (1R)‐isopropyloxygenipin (IPRG001) is a more stable but less active compound compared with the parent, genipin. Here, two new IPRG001 derivatives generated by stereoselective reduction of the C₆=C₇ double bond were synthesized. The 1R and 1S isomers of (4aS,7S,7aS)‐methyl‐7‐(hydroxymethyl)‐1‐isopropoxy‐1,4a,5,6,7,7a‐hexahydrocyclopenta[c]pyran‐4‐carboxylate ( CHR20 and CHR21 ) were shown to be very stable both in high‐glucose cell culture medium and in mice serum at 37 °C. Evaluation using an MTT assay and Hoechst staining showed that CHR20 and CHR21 promote the survival of rat adrenal pheochromocytoma (PC12) and retinal neuronal (RGC‐5) cells from injury induced by sodium nitroprusside (SNP). The neuroprotective effects of CHR20 and CHR21 were greater than both isomers of IPRG001, the parent compounds. These results indicate that reduction of 1‐O‐isopropyloxygenipin enhances its neuroprotective activity without affecting its stability.     

Phase Transformation in Ca3(PO4)2:Eu2+ via the Controlled Quenching and Increased Eu2+ Content: Identification of New Cyan‐Emitting α‐Ca3(PO4)2:Eu2+ Phosphor

A case of phosphor is reported where the cooling rate parameter significantly influences the luminescence property. By quenching the sample after the high‐temperature solid‐state reaction at 1250°C, we successfully prepared the Eu²⁺‐doped α form Ca₃(PO₄)₂ (α‐TCP:Eu²⁺) as a new kind of bright cyan‐emitting phosphor. The unusual emission color variation (from cyan to blue) depends on the cooling rate after sintering and Eu²⁺ doping level as it was observed in the TCP‐based phosphors. By the Rietveld analysis, it is revealed that the cyan‐ and blue‐emitting phosphors are two different TCP forms crystallizing in the monoclinic (space group P2₁/a, α‐TCP) and the rhombohedral structure (space group R3c, β‐TCP), respectively. Upon 365 nm UV light excitation, α‐TCP:Eu²⁺ exhibits an asymmetric broad‐band cyan emission peaking at 480 nm, while β‐TCP:Eu²⁺ displays a relatively narrow‐band blue emission peaking at 416 nm. The Eu²⁺‐doping in Ca₃(PO₄)₂ shifts the upper temperature limit of the stable structural range of β form from 1125°C to ≥1250°C. Moreover, the crystal structures of α/β‐TCP:Eu²⁺ were compared in the aspects of compactness and cation site sets. The emission thermal stability of α/β‐TCP:Eu²⁺ was comparatively characterized and the difference was related to the specific host structural features.     

New Amino‐Acid‐Based β‐Phosphorylated Nitroxides for Probing Acidic pH in Biological Systems by EPR Spectroscopy

There is increasing interest in measuring pH in biological samples by using nitroxides with pH‐dependent electron paramagnetic resonance (EPR) spectra. Aiming to improve the spectral sensitivity (Δa_X) of these probes (i.e., the difference between the EPR hyperfine splitting (hfs) in their protonated and unprotonated forms), we characterized a series of novel linear α‐carboxy, α′‐diethoxyphosphoryl nitroxides constructed on an amino acid core and featuring an (α or α′)‐C?H bond. In buffer, the three main hfs (a_N, a_H, and a_P) of their EPR spectra vary reversibly with pH and, from a_P or a_H titration curves, a two‐ to fourfold increase in sensitivity was achieved compared to reference imidazoline or imidazolidine nitroxides. The crystallized carboxylate 10 b (pK_a ≈3.6), which demonstrated low cytotoxicity and good resistance to bioreduction, was applied to probe stomach acidity in rats. The results pave the way to a novel generation of highly sensitive EPR pH markers.     

Synthesis,Crystal Structure,and Thermal Behaviors of 3‐Nitro‐1,5‐bis(4,4′‐dimethylazide)‐1,2,3‐triazolyl‐3‐azapentane (NDTAP)

The energetic material, 3‐nitro‐1,5‐bis(4,4′‐dimethyl azide)‐1,2,3‐triazolyl‐3‐azapentane (NDTAP), was firstly synthesized by means of Click Chemistry using 1,5‐diazido‐3‐nitrazapentane as main material. The structure of NDTAP was confirmed by IR, ¹H NMR, and ¹³C NMR spectroscopy; mass spectrometry, and elemental analysis. The crystal structure of NDTAP was determined by X‐ray diffraction. It belongs to monoclinic system, space group C2/c with crystal parameters a=1.7285(8) nm, b=0.6061(3) nm, c=1.6712(8) nm, β=104.846(8)°, V=1.6924(13) nm³, Z=8, μ=0.109 mm⁻¹, F(000)=752, and D_c=1.422 g cm⁻³. The thermal behavior and non‐isothermal decomposition kinetics of NDTAP were studied with DSC and TG‐DTG methods. The self‐accelerating decomposition temperature and critical temperature of thermal explosion are 195.5 and 208.2 °C, respectively. NDTAP presents good thermal stability and is insensitive.