Stereoselective synthesis,solution structure and metal complexes of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids

The highly stereoselective synthesis of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids was achieved by addition of dimethyl phosphite to N-protected aminoaldehydes. Relative configuration and solution conformations of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids (in D₂O) and their dimethyl esters (in CDCl₃ and CD₃OD) were established by means of NMR basing on the dependence between observed values of coupling constants (³J_HH, ³J_PC, ³J_HP) and corresponding dihedral angles. Potentiometric and spectroscopic methods were used for the evaluation of the structure of the complexes of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids with Zn(II) and Cu(II) ions in aqueous solutions.     

Synthesis and reactions of N-acetyl- and N-(2-chloroacetyl)-N-[(2E)-1-methylbut-2-en-1-yl]-2-iodoanilines

The reaction of N-(1-methylbut-2-en-1-yl)-2-iodaniline with Ac₂O or ClCH₂C(O)Cl results in a mixture of syn- and anti-atropisomers of N-acetyl- and N-chloroacetyl-N-(1-methylbut-2-en-1-yl)-2-iodaniline in a ratio of 1:1. Ozonolysis of the latter followed by reduction with dimethyl sulfide in CH₂Cl₂ gives rise to the atropisomers mixture of 2-[N-(chloroacetyl)-N-(2-iodophenyl)]aminopropanal in a ratio of 1:3. When heated in boiling benzene, the mixture of atropoisomeric aldehydes reacts with triphenylphosphine to afford a mixture of 2-[(N-acetyl)-N-(2-iodophenyl)]aminopropanal atropisomers in 1:3 ratio.     

Enantioselective hydrogenation of functionalized olefins catalyzed by Rh-chiral bidentatephosphite complexes

A novel catalytic system for the hydrogenation of dimethyl itaconate has been developed by using rhodium–diphosphite complexes. These chiral diphosphite ligands were derived from glucopyranoside, d-mannitol derivatives, and binaphthyl or H₈-binaphthyl phosphochloridites. The ligands based on the methyl 3,6-anhydro-α-d-glucopyranoside backbone and (R)- and (S)-binaphthol and/or (R)- and (S)-2,2′-dihydroxy-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthol gave almost complete conversion of the dimethyl itaconate and both enantiomers of dimethyl 2-methylsuccinate with excellent enantioselectivities. The stereochemically matched combination of methyl 3,6-anhydro-α-d-glucopyranoside and H₈-(S)-binaphthyl in ligand 2,4-bis{[(S)-1,1′-H₈-binaphthyl-2,2′-diyl]-phosphite} methyl 3,6-anhydro-α-d-glucopyranoside was essential to afford dimethyl 2-methylsuccinate with up to 98% ee. The sense of the enantioselectivity of products was predominantly determined by the configuration of the biaryl moieties of the ligands. An initial screening of [Rh(cod)₂]BF₄ with these ligands in the hydrogenation of (E)-2-(3-butoxy-4-methoxybenzylidene)-3-methylbutanoic acid was carried out. Good enantioselectivity (75% ee) and low yield for (R)-2-(3-butoxy-4-methoxybenzyl)-3-methylbutanoic acid were obtained.     

Solvent effect on radical homo- and copolymerization of di-2-[2-(2-methoxyethoxy)ethoxy]ethyl itaconate

Solvent effect on homo- and copolymerization of di-2-[2-(methoxyethoxy)ethoxy]ethyl itaconate (DMEI) was studied at 50 °C using dimethyl 2,2^′-azobisisobutyrate as radical initiator. The polymerization rate (R_p) highly depended on the kind of solvent; 19 solvents were used. The highest R_p (in 1-tetradecanol) is 13 times the smallest (in chloroform). On the other hand, the solvents did not exert as great an effect on the molecular weight of the resulting polymers. The propagation rate constant (k_p) was determined in 15 different solvents by means of ESR spectroscopy. The highest k_p (4.5 l/mol s in toluene) is 5.6 times the lowest (0.8 l/mol s in chloroform). A noticeable solvent effect was also observed in the copolymerization of DMEI (M₁) and styrene (M₂), where nine solvents were used. The highest r₁ (0.46 in 1-butanol) is about 6 times the lowest (0.08 in methanol). The r₂ value falls in the range of 0.2 (dimethyl sulfoxide) and 0.52 (benzene). The solvent effects thus observed were analyzed according to the linear solvation energy relationship proposed by Taft and co workers.     

Synthesis and structural characterization of a dichloro zinc complex of N,N′-bis-(2,6-dichloro-benzyl)-(R,R)-1,2-diaminocyclohexane: Application to ring opening polymerization of rac-lactide

A novel dichloro zinc complex (L¹)ZnCl₂, where L¹ is N,N′-bis-(2,6-dichloro-benzyl)-(R,R)-1,2-diaminocyclohexane, has been synthesized and characterized. The dimethyl derivatives, generated in situ from the well characterized dichloro zinc complexes (L¹)ZnCl₂ and (L²)ZnCl₂, where L² is N,N′-bis-(benzyl)-(R,R)-1,2-diaminocyclohexane, were employed as initiators for the ring opening polymerization (ROP) of rac-lactide (rac-LA). The complexes were found to be highly efficient initiators yielding the polylactide (PLA) with a narrow molecular weight distribution. The catalytic activity and heterotactic selectivity of the Zn(II) complexes were affected by the substituents on the phenyl groups of benzyl moieties in (R,R)-1,2-diaminocyclohexane. The dimethyl derivative of (L²)ZnCl₂ produced highly stereocontrolled PLA with P_r = 0.75 at −25 °C.     

New non-C2-symmetric phosphine-phosphonites as ligands in asymmetric metal catalysis

Starting from 1,2-dibromobenzene, the synthesis of N,N,N′,N′-tetraethyl-[2-(diphenylphosphino)phenyl]phosphonous acid tetraamide is possible in two simple steps. This key compound reacts with a variety of chiral diols such as (R)- and (S)-binaphthol, 1,2:5,6-diisopropylidene-d-mannitol or (1R,2R)-1,2-diphenyl-1,2-ethane diol to form the corresponding non-C₂-symmetric phosphine-phosphonite compounds. These ligands react with Rh(COD)₂BF₄ to form bidentate Rh-complexes which serve as catalysts in the asymmetric hydrogenation of dimethyl itaconate with ee values of up to 88%.     

Quantum-chemical investigation of reactions of (dialkylamino)ethynylphosphonates with amines

Structural parameters and molecular energies of diethyl piperidylethynylphosphonate, dimethyl (diethylamino)ethynylphosphonate, dimethyl[2-(t-butylamino)-2-(diethylamino)vinyl]phosphonate, N,N-diethyl-N′-t-butyl(dimethoxyphosphinoyl)acetamidine, dimethyl [2-(diethylamino)-2-(phenylamino)vinyl]phosphonate, N,N-diethyl-N′-phenyl(dimethoxyphosphinoyl)acetamidine, and the cations formed by protonation of the phosphinoyl group, nucleophilic carbon atom, or nitrogen were determined by means of B3LYP/6-311G(d₅,p)&;6-31G(d₅,p) quantum-chemical calculations. Acid-base properties of the related amines and their adducts with boron trifluoride in CCl₄ are estimated. The mechanism of the reactions of (dialkylamino)ethynylphosphonates with amines is discussed.     

Synthesis and X-ray crystal structure of dichloro[S-1-phenyl-N-(S-pyrrolidin-2-ylmethyl)ethanamine]zinc(II) and its catalytic application to rac-lactide polymerization

New dichloro zinc(II) complex ligated by the homochiral bidentate ligand S-1-phenyl-N-(S-pyrrolidin-2-ylmethyl)ethanamine (PPMA) was synthesized and characterized by X-ray crystallography. The geometry of the (PPMA)ZnCl₂ is a distorted tetrahedron comprising of zinc metal as a center linked with two N atoms of the PPMA in a bidentate coordination mode along with two chloro ligands. The catalytic capacity of the complex was evaluated in ring opening polymerization (ROP) of rac-lactide. The active catalyst species was generated in situ by treating MeLi to complex (PPMA)ZnCl₂. The dimethyl derivative of the (PPMA)ZnCl₂ showed highly activity in ROP of rac-lactide and gave preference to heterotactic polylactide.     

Preparation of dimethyl (R)- and (S)-2-(2-aminophenyl)-2-hydroxyethylphosphonate from anthranilic acid

An efficient synthesis of both enantiomers of dimethyl δ-amino-β-hydroxyethylphosphonate 6 has been achieved starting from anthranilic acid, through the resolution of dimethyl (±)-2-(2-N,N-dibenzylaminophenyl)-2-hydroxyethylphosphonate 9 with (S)-O-methylmandelic acid. The absolute configuration of the enantiomers 9 was assigned by the Dale and Mosher approach using the extended Newman projections and molecular mechanics.     

Tandem radical addition reactions to substituted indoles under atom-transfer and oxidative conditions

The dimethyl methylmalonyl radical was generated upon photolysis of dimethyl bromomethylmalonate or treatment of dimethyl methylmalonate with Mn(OAc)₃·2 H₂O. This radical was added to an exocyclic olefin appended to 1-acyl or 3-acyl indoles, with subsequent cyclization to generate 1,2- or 2,3- fused indole derivatives, respectively.     

Asymmetric cycloaddition reactions between 2-benzopyrylium-4-olates and 3-(2-alkenoyl)-2-oxazolidinones in the presence of 2,6-bis(oxazolinyl)pyridine-lanthanoid complexes

Highly enantioselective (96% ee) and endo-selective (>99:1) cycloaddition reactions were observed between carbonyl ylides, generated from o-(p-bromobenzyloxy)carbonyl-α-diazoacetophenone, and 3-crotonoyl-2-oxazolidinone using (4S,5S)-Pybox-4,5-Ph₂-Yb(OTf)₃ (20 mol %) as the chiral Lewis acid catalyst. In contrast, high exo-selectivity (exo/endo=82:18; 96% ee, exo) was observed for the reaction of o-methoxycarbonyl-α-diazoacetophenone with 3-acryloyl-2-oxazolidinone under similar conditions as reported previously. In the case of cycloaddition reactions between 2-benzopyrylium-4-olate, generated from o-methoxycarbonyl-α-diazoacetophenone, and 3-cinnamoyl- or 3-[(E)-3-(ethoxycarbonyl)propenoyl]-2-oxazolidinones, using the same chiral Lewis acid, the reaction favored the endo-adduct with relatively good enantioselectivity (72 and 78% ee, respectively).     

Three-component coupling reactions of isoquinolines, dimethyl acetylenedicarboxylate and indoles: a facile synthesis of 3-indolyl-1,2-dihydro-2-isoquinolinyl-2-butenedioate

A three-component coupling of isoquinolines, dimethyl acetylenedicarboxylate (DMAD) and indoles is achieved for the first time to produce dimethyl (E)-2-[1-(1H-3-indolyl)-1,2-dihydro-2-isoquinolinyl]-2-butenedioates in excellent yields and with high selectivity. The reaction proceeds smoothly at room temperature without a catalyst. Quinoline, DMAD and indole also undergo smooth coupling to furnish dimethyl (E)-2-[2-(1H-3-indolyl)-1,2-dihydro-1-quinolinyl]-2-butenedioate under similar conditions. This method is very useful to functionalize both indoles and aza-aromatic compounds in a one-pot operation.     

Preparation of dimethyl (R)- and (S)-2-(2-hydroxyphenyl)-2-hydroxyethylphosphonate derived from salicylaldehyde via resolution using (S)-methoxyphenylacetic acid (MPA)

The efficient preparation of both enantiomers of dimethyl δ,β-dihydroxyethylphosphonate 2 has been achieved from salicylaldehyde as a starting material, through the resolution of dimethyl (±)-2-(2-O-benzylphenyl)-2-hydroxyethylphosphonate 4 using (S)-methoxyphenylacetic acid (MPA). The absolute configuration was assigned by the Dale and Mosher approach using extended Newman projections and ab initio calculations.     

Asymmetric nitrogen

The possibility of tranferring chirality from nitrogen to carbon by a three-step transformation of racemic dimethyl 1-methoxyaziridine-2,2-dicarboxylate into 3-amino-2-chloromethyl-2-methoxyaminopropan-1-ol was demonstrated. The first representative of 1-silyloxyaziridines,viz., dimethyl 1-(tert-butyldimethylsilyloxy)aziridine-2,2-dicarboxylate, was synthesized by acidolysis or thermolysis of triazoline, obtained by the reaction oftert-butyldimethylsilyloxime of dimethy mesoxalate with CH₂N₂     

Synthesis of electron-poor 4-halo-2-azabuta-1,3-dienes by Rh(II)-catalyzed diazo ester-azirine coupling. 2-Azabuta-1,3-diene-2,3-dihydroazete valence isomerism

The Rh₂(OAc)₄-catalyzed reaction of alkyl 2-acyl-2-diazoacetates and dimethyl diazomalonate with methyl 2-bromo- and 2-chloro-3-phenyl-2H-azirine-2-carboxylates gives rise to electron-poor 4-halo-substituted (3E)-2-azabuta-1,3-dienes. Their formation proceeds with complete stereoselectivity via ring-opening of the intermediate azirinium ylide. 2-Azabuta-1,3-dienes with electron-withdrawing substituents at the 1,1,4-positions are stable compounds at room temperature, but are in equilibrium with cyclic valence isomers, 2,3-dihydroazetes, at elevated temperatures.     

Synthesis of electron-rich platinum centers: Platinum0(carbene)(alkene)2 complexes

The synthesis and molecular structure of the zero-valent platinum-mono-carbene-bis-alkene complexes [Pt⁰(NHC)(dimethyl fumarate)₂] (NHC = 1,3-dimesityl-imidazol-2-ylidene (1a); 1,3-dimesityl-dihydroimidazol-2-ylidene (2a); diphenyl-dihydroimidazol-2-ylidene (2b) are described. Two routes have been evaluated for the synthesis of 1a and 2a, involving reaction of a zero-valent platinum compound either with an isolated carbene ligand, or with an in situ generated carbene ligand. The in situ method proved to be easier and gave similar yields of about 50% after crystallization. Attempts have been made to synthesize similar compounds with N-phenyl and N-alkyl groups, of which the latter met with little success. However, (1,3-diphenyl-dihydroimidazol-2-ylidene)-bis(η²-dimethyl fumarate) platinum(0) (2b) could be obtained in 49% yield, after crystallization, from the appropriate Wanzlick dimer.Compound 1a reacts with H₂ and D₂ in sequences of oxidative addition, migration–insertion involving dimethyl fumarate, and reductive elimination to form neutral hydrido platinum (II) carbene complexes, probably containing a metallacyclic (R)–CO … Pt unit.     

Synthesis of 2-amino-1,3-dihydroxypropylphosphonates from Garner aldehyde

In the presence of triethylamine or ionic fluoride catalysts, the addition of dimethyl or diethylphosphite to Garner aldehyde proceeded with good (1:9) diastereoselectivity leading to a separable mixture of (1S,2S)- and (1R,2S)-hydroxyphosphonates. Almost equal amounts (43:57) of the respective phosphonates were formed when titanium(IV) isopropoxide was applied as a catalyst. The e.e.s of the hydroxyphosphonates reached 93–97% in the reactions catalysed by Ti(OiPr)₄ and dropped to 80–91% when triethylamine was used to catalyse the reaction.     

New developments in the Pd-catalysed cyclisation-coupling reaction of alkene-containing carbonucleophiles with organic halides (and triflates). The first examples of asymmetric catalysis.

The results of our preliminary investigations directed toward asymmetric catalysis of the cyclocarbopalladation of alkenes bearing a proximate nucleophile with organic halides (or triflates) are disclosed. A series of bidentate phosphine ligands were evaluated in intramolecular versions of this reaction using (E)-2-[7-(2-bromophenyl)-hept-4-enyl]-malonic acid dimethyl ester (1) and (Z)-2-[7-(2-trifluoromethanesulfonyloxy-phenyl)-hept-4-enyl]-malonic acid dimethyl ester (9) as model substrates. The highest enantioselective induction was obtained with aryl triflate 9 which produced the corresponding cyclopentylindane as a single diastereomer in 54% chemical yield and 43% ee by using PdCl₂[S-(−)-TolBINAP] as chiral catalyst and K₂CO₃ as base.     

Preparation of the Key Dolutegravir Intermediate via MgBr2-Promoted Cyclization

A novel approach for synthesizing the key dolutegravir intermediate is described via MgBr₂-promoted intramolecular cyclization. Condensation of commercially available methyl oxalyl chloride and ethyl 3-(N,N-dimethylamino)acrylate afforded the vinylogous amide in an excellent yield. Subsequent substitution by aminoacetaldehyde dimethyl acetal and methyl bromoacetate gave rise to the expected precursor for cyclization, which was promoted by MgBr₂ to highly selectively convert into pyridinone diester. The key dolutegravir intermediate was finally prepared by the selective hydrolysis of the corresponding diester via LiOH.     

Diastereoselective addition of dimethyl phosphite to 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde

Addition of dimethyl phosphite to racemic 3,3′,4,4′-tetramethyl-1,1′-diphosphaferrocene-2-carboxaldehyde gives almost exclusively one diastereomer of the corresponding α-hydroxyphosphonate (d.r. ?96:4). Its absolute configuration (S, R_p)-(R, S_p) was established by X-ray diffraction.