Synthesis of iridium complexes with new planar chiral chelating phosphinyl-imidazolylidene ligands and their application in asymmetric hydrogenation

The synthesis of planar chiral phosphinoimidazolium salts such as (R_p)-3-(4-diphenyl-phosphino[2.2]paracyclophan-12-ylmethyl)-1-(2,6-diisopropylphenyl)imidazolium bromide (R_p)-11c starting from enantiopure 4,12-dibromo[2.2]paracyclophane (R_p)-6 is reported. After deprotonation of these salts and a subsequent reaction with [Ir(COD)Cl]₂, chelating iridium imidazolylidene complexes (R_p)-5a–c are obtained. These complexes catalyze the asymmetric hydrogenation of functionalized and simple alkenes with up to 89% ee.     

An improved synthesis of (S)-(+)- and (R)-(−)-[2.2]paracyclophane-4-carboxylic acid

Treatment of 4-bromo[2.2]paracyclophane with n-butyllithium followed by CO₂ produced [2.2]paracyclophane-4-carboxylic acid, 1. Both enantiomeric forms [63% of (+)-(S)-1 and 48% of (−)-(R)-1] were obtained by resolution via the corresponding diastereomeric α-(p-nitrophenylethylammonium salts.     

Planar chiral indoles: synthesis and biological effects of the enantiomers

The paracyclophanyl triflates (R)-4 and (S)-4, which were obtained from racemic precursors through enzymatic-kinetic resolution, could be employed as key intermediates for the synthesis of planar chiral [2.2](4,7)indoloparacyclophanes. Subjecting the double-layered test compounds (R)-8 and (S)-8 to in vitro ligand-binding experiments displayed stereoselective receptor recognition.     

A planar chiral non-metallocenic analogue of the most popular N,N-dimethylbenzylaminate palladacycle

A racemic planar chiral tertiary amine pCp-CH₂NMe₂ (HL¹, pCp = [2.2]paracyclophane-4-yl) was prepared by aminomethylation of the bromide pCp-Br with Eschenmoser’s salt. Direct cyclopalladation of this new ligand with palladium(II) acetate results in the formation of the racemic CN-dimer rac-3 in a moderate yield of 64%. The enantiomerically pure dimer (S_pl, S_pl)-3 was obtained by the standard procedure of racemic palladacycle resolution using (S_C)-prolinate as a chiral derivatising agent. The ortho-palladated structure, absolute configuration of the chiral plane and stereochemical peculiarities of the new CN-palladacycle were established by means of NMR spectroscopy and an X-ray diffraction study of its (S_C)-prolinate derivative.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by monosubstituted [2.2]paracyclophane-based N,O-ligands: remarkable cooperative effects of planar and central chiralities

Diastereomeric monosubstituted [2.2]paracyclophane-based N,O-ligands, which unite the planar and central chiral elements, were optimized for the enantioselective diethylzinc addition to aldehydes. (S)-1-{(S_p)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-α,α-diphenylmethanol (S_p,S)-3 catalyzed the addition to give (R)-1-phenyl-1-propanol in a high yield and with a good enantioselectivity (91% ee).     

Carbocyclic nucleosides from enantiomeric, α-pinane-based aminodiols

Starting from (1R,2S,3S,5R)- and (1S,2R,3R,5S)-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2’-oxiran]-3-ol (?)-8 and (+)-8, two comparative syntheses were developed for pinane-based chiral carbocyclic nucleosides. The regioselective ring opening of the spiro-oxirane ring of (?)-8 and (+)-8 with NaN₃ resulted in azidodiols (?)-9 and (+)-9. Catalytic reduction of (?)-9 and (+)-9 furnished chiral aminodiols (?)-10 and (+)-10, which were transformed by linear synthesis to purine-type nucleosides 16–18 through pyrimidine intermediates. Regioselective ring opening of the oxirane ring of (?)-8 and (+)-8 resulted in adenine-, cytosine- and uracil-based carbocyclic nucleosides 19–21 in a single-step synthesis.     

Structural control in palladium(II)-catalyzed enantioselective allylic alkylation by new chiral phosphine-phosphite and pyridine-phosphite ligands

The ligands 6-[(diphenylphosphanyl)methoxy]-4,8-di-tert-butyl-2,10-dimethoxy-5,7-dioxa-6-phosphadibenzo[a,c]cycloheptene, 1, (S)-4-[(diphenylphosphanyl)methoxy]-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4a′]dinaphthalene, (S)-2, and (S)-4-[(diphenylphosphanyl)methoxy]-2,6-bis-trimethylsilanyl-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalene, (S)-3, (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yloxymethyl)pyridine, (S)-4, and (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yloxy)pyridine, (S)-5, have been easily prepared.The cationic complexes [Pd(η³-C₃H₅)(L-L′)]CF₃SO₃ (L–L′=1–(S)-5) and [Pd(η³-PhCHCHCHPh)(L–L′)]CF₃SO₃ (L–L′=(S)-2–(S)-4) were synthesized by conventional methods starting from the complexes [Pd(η³-C₃H₅)Cl]₂ and [Pd(η³-PhCHCHCHPh)Cl]₂, respectively. The behavior in solution of all the π-allyl- and π-phenylallyl-(L–L′)palladium derivatives 6–14 was studied by ¹H, ³¹P{¹H}, ¹³C{¹H} NMR and 2D-NOESY spectroscopy. As concerns the ligands (S)-4 and (S)-5, a satisfactory analysis of the structures in solution was possible only for palladium–allyl complexes [Pd(η³-C₃H₅)((S)-4)]CF₃SO₃, 11, and [Pd(η³-C₃H₅)((S)-5)]CF₃SO₃, 12, since the corresponding species [Pd(η³-PhCHCHCHPh)((S)-4)]CF₃SO₃, 13, and [Pd(η³-PhCHCHCHPh)((S)-5)]CF₃SO₃, 14, revealed low stability in solution for a long time. The new ligands (S)-2–(S)-5 were tested in the palladium-catalyzed enantioselective substitution of (1,3-diphenyl-1,2-propenyl)acetate by dimethylmalonate. The precatalyst [Pd(η³-C₃H₅)((S)-2)]CF₃SO₃ afforded the allyl substituted product in good yield (95%) and acceptable enantioselectivities (71% e.e. in the S form). A similar result was achieved with the precatalyst [Pd(η³-C₃H₅)((S)-3)]CF₃SO₃. The nucleophilic attack of the malonate occurred preferentially at allylic carbon far from the binaphthalene moiety, namely trans to the phosphite group. When the complexes containing ligands (S)-4 and (S)-5 were used as precatalysts, the product was obtained as a racemic mixture in high yield. The number of the configurational isomers of the Pd-allyl intermediates present in solution in the allylic alkylation and the relative concentrations are considered a determining factor for the enantioselectivity of the process.     

Chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate by a Merrifield resin-bound enantiomerically pure chiral dimethylpyridino-18-crown-6 ligand

Three novel chiral pyridino-18-crown-6 ligands (S,S)-1, (S,S)-2 and (S,S)-3 were prepared and (S,S)-1 was attached to a Merrifield resin. The resulting adsorbent (S,S)-5 was used as a chiral stationary phase in the chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate. Also, a new chiral pyridono-18-crown-6 ligand (S,S)-6, used for the synthesis of (S,S)-1 and (S,S)-2, was prepared in two different ways.     

Planar chiral hydroxy derivatives of [2.2]paracyclophane as auxiliaries for asymmetric allylboration

Allylboronic esters with various structures were synthesized for the first time based on [2.2]paracyclophane derivatives containing one or two hydroxy groups. It was demonstrated that these esters can be used as chiral inductors in the asymmetric allylboration of benzaldehyde. The highest enantiomeric excess of 1-phenylbut-3-en-1-ol (60%) was achieved in the reactions with acyclic bis-O,O′-(paracyclophanyl) allylboronates based on (S)-4-hydroxy-and (S)-12-bromo-4-hydroxy[2.2]paracyclophanes. (S)-4-Hydroxy[2.2]paracyclophane was studied by X-ray diffraction. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2149–2155, November, 2007.     

New chiral β-diketones based on [2.2]paracyclophane

Two chiral β-diketones, 1,3-bis[(S)-(4-[2.2]paracyclophanyl)]propane-1,3-dione (BPPD) and [1-(S)-(4-[2.2]paracyclophanyl)-3-phenyl]propane-1,3-dione (PPPD), were synthesized by acylation of (S)-4-acetyl[2.2]paracyclophane with methyl esters from the corresponding carboxylic acids. 4-Acetyl[2.2]paracyclophane was synthesized in a quantitative yield by the reaction of [2.2]paracyclophane-4-carboxylic acid with methyllithium.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F

Total synthesis of (4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles F 3 was achieved from the chiral bithiazole-type primary alcohols [(S)- and (R)-4-ethoxycarbonyl-2′-(1-hydroxymethylethyl)-2,4′-bithiazoles 8], which were obtained based on the enzymatic resolution of racemic alcohol 8 and its acetate 9. From a direct comparison by means of chiral HPLC between natural cystothiazole F 3 and synthetic compounds [(4R,5S,6E,14S)- and (4R,5S,6E,14R)-cystothiazoles 3], natural cystothiazole F 3 was found to be a 33:67 diastereomeric mixture [(4R,5S,6E,14S)-3:(4R,5S,6E,14R)-3 = 33:67].     

New Types of Planar Chiral [2.2]Paracyclophanes and Construction of One‐Handed Double Helices

New types of planar chiral (R_p)‐ and (S_p)‐4,7,12,15‐tetrasubstituted [2.2]paracyclophanes were synthesized from racemic 4,12‐dihydroxy[2.2]paracyclophane as the starting compound. Regioselective dibromination and transformation afforded a series of planar chiral (R_p)‐ and (S_p)‐4,7,12,15‐tetrasubstituted [2.2]paracyclophanes, which can be used as chiral building blocks. In this study, left‐ and right‐handed double helical structures were constructed via chemoselective Sonogashira–Hagihara coupling. The double helical compounds were excellent circularly polarized luminescence (CPL) emitters with large molar extinction coefficients, good photoluminescence quantum efficiencies, and large CPL dissymmetry factors.     

δ-Lactone formation from δ-hydroxy-trans-α,β-unsaturated carboxylic acids accompanied by trans-cis isomerization: synthesis of (−)-tetra-O-acetylosmundalin

(±)-(4,5-anti)-4-Benzyloxy-5-hydroxy-(2E)-hexenoic acid 6 was subjected to δ-lactonization in the presence of 2,4,6-trichlorobenzoyl chloride and pyridine to give the α,β-unsaturated-δ-lactone congener (±)-7 (87% yield) accompanied by trans-cis isomerization. This δ-lactonization procedure was applied to the chiral synthesis of (+)-(4S,5R)-7 or (−)-(4R,5S)-7 from the chiral starting material (+)-(4S,5R)-6 or (−)-(4R,5S)-6. Deprotection of the benzyl group in (+)-(4S,5R)-7 or (−)-(4R,5S)-7 by the AlCl₃/m-xylene system gave the natural osmundalactone (+)-(4S,5R)-5 or (−)-(4R,5S)-5 in good yield, respectively. Condensation of (−)-(4R,5S)-5 and tetraacetyl-β-d-glucosyltrichloroimidate 22 in the presence of BF₃·Et₂O afforded the condensation product (−)-8 (97% yield), which was identical to tetra-O-acetylosmundalin (−)-8 derived from natural osmundalin 9.     

Enantioselective synthesis of β-amino acids. Part 9: Preparation of enantiopure α,α-disubstituted β-amino acids from 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one,

Double alkylation of enantiopure N,N-acetal pyrimidinone (S)-1, a masked chiral derivative of β-alanine prepared from (S)-asparagine, proceeds with high stereoselectivity to give C(5) disubstituted adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7, and (2S,5S)-7. Acid hydrolysis of these derivatives affords enantiopure α,α-dialkylated β-amino acids (R)-8, (S)-8, (R)-9, and (S)-9 in very good yields.     

Structurally diverse second-generation [2.2]paracyclophane ketimines with planar and central chirality: syntheses, structural determination, and evaluation for asymmetric catalysis

A set of 20 novel [2.2]paracyclophane ketimines with planar and central chirality has been synthesized from enantiomerically pure and racemic 5-acyl-4-hydroxy[2.2]paracyclophane and alpha-branched chiral amines. Their X-ray structures were determined to elucidate the three-dimensional structures and the absolute configuration. The ketimines were used as catalysts in the asymmetric 1,2-addition reactions of diethylzinc with substituted benzaldehydes to furnish chiral alcohols in up to 95 % ee.     

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.     

Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: potential starting compounds for the synthesis of anatoxin-a

9-Azabicyclo[6.2.0]dec-4-en-10-one (±)-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N-hydroxymethylated to (±)-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the (S)-stereogenic centre. High enantioselectivity (E=94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH₄OH/MeOH afforded the corresponding β-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ≥93%), potential starting compounds in anatoxin-a synthesis. The ring opening of lactams (±)-2, (±)-7, 3a and 3b, followed by reduction, resulted in racemic 4–6 and 8 and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic β-amino acid derivatives.     

Asymmetric catalysis. Part 153: Metal-catalysed enantioselective α-ketol rearrangement

Promoted by catalytic amounts of Ni complexes tertiary α-hydroxyketones 1a, 3a–5a undergo rearrangement, forming chiral isomers 1b, 3b–5b. The best enantioselection was obtained with the model system 1-benzoylcyclopentanol 4a/2-hydroxy-2-phenylcyclohexanone 4b. In a ligand screening 2-[4-(S)-tert-butyloxazolin-2-yl]pyridine gave the highest enantiomeric excess of 46% (S)-4b. The analogous isomerisation reactions of α-hydroxyimines 6a, 7a forming chiral α-aminoketones 6b, 7b were established.     

Efficient preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol via lipase-mediated resolution

The practical preparation of enantiomerically pure (E)-4-(tributylstannanyl)but-3-en-2-ol 1 from 3-butyn-2-ol 2 is reported. A modified Guibé's Pd-catalyzed hydrostannation of 2 provided the racemic γ-hydroxy vinylstannane 1 in a good yield. The enzymatic esterification of 1, with an inexpensive lipozyme, afforded (R)-3 and (S)-1 with very high enantiomeric excesses and chemical yields. This procedure is suitable for the multigram scale preparation of the potential chiral building blocks, (R)-1 and (S)-1.