Synthesis of 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] and derivatives: precursors of long-chain polyketides

Racemic 1,1′-methylene[(1RS,1′RS,3RS,3′RS,5RS,5′RS)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] ((±)-6) derived from 2,2′-methylenedifuran has been resolved kinetically with Candida cyclindracea lipase-catalysed transesterification giving 1,1′-methylenedi[(1R,1′R,3R,3′R,5R,5′R)-8-oxabicyclo[3.2.1]oct-6-en-3-ol] (−)-6 (30% yield, 98% ee) and 1,1′-methylenedi[(1S,1′S,3S,3′S,5S,5′S)-8-oxabicyclo[3.2.1]oct-6-en-3-yl] diacetate (+)-8, (40% yield, 98% ee). These compounds have been converted into 1,1′-methylenedi[(4S,4′S,6S,6′S)- and (4R,4′R,6R,6′R)-cyclohept-1-en-4,6-diyl] derivatives.     

Total, asymmetric synthesis of (1r-1-c-(6′-amino-7′h-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy-d-erythro-pentitol.

The “naked sugar” (+)-(1R,2R,4R)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((+)-3) was converted in ten synthetic steps into the new C-nucleoside (1R)-1-C-(6′-amino-7′H-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy- D-erythro-pentitol ((+)-2) in 19% overall yield.     

Synthesis and X-ray crystal structures of rac- and meso-2,2′-propylidene-bis(1-indenyl) zirconium dichlorides

An improved synthesis of 2,2′-bis(1-indenyl)propane and the corresponding ansa-complexes of zirconium are reported. Synthesis of a mixture of rac- and meso-2,2′-propylidene-bis(1-indenyl)zirconium dichlorides involves a treatment of ZrCl₄ with bis[3-(trialkyltin)inden-1-yl]propane, where alkyl = ethyl, butyl, in toluene. This reaction gives the products in 92% yield and might be a convenient synthetic pathway to a number of straightforward ansa-metallocenes. Both rac- and meso-2,2′-propylidene-bis(1-indenyl)zirconium dichlorides were separated and isolated using simple work-up processes, and characterized by X-ray crystal structure analysis (rac:C2/c; a = 15.903(3) Å, b = 11.105(2) Å and c = 11.520(2) Å; β = 121.61(3)°; Z = 4; V = 1732.6(5) ų; R = 0.0350; meso-: P1¯; a = 9.739(2) Å, b = 12.798(4) Å and c = 15.322(4) Å; = 101.18(2)°; β = 121.61(2)°; γ = 90.54(2)°, Z = 4; V = 1795.4(8) ų; R = 0.0417).     

Studies on the synthesis of biphenylneolignans. Part 1: Enantioselective synthesis of (S,S)- and (R,R)-2,2′-dimethoxy-4-(3-hydroxy-1-propenyl)-4′-(1,2,3-trihydroxypropyl)diphenyl ether

Two erythro-isomers of 2,2′-dimethoxy-4-(3-hydroxy-1-propenyl)-4′-(1,2,3-trihydroxypropyl)diphenyl ether, (7′S, 8′S)-9 and (7′R, 8′R)-9, were synthesized in seven steps, in which an improved method for the synthesis of the key intermediate 3 was developed. The absolute configuration of the target molecules was also confirmed.     

Synthesis, characterization and catalytic activity in Heck-type reactions of orthometallated Pd and Pt complexes derived from (1R,2R)-1,2-diaminocyclohexane

The chiral bis-imine (1R,2R)-C₆H₁₀-[E---N=CH---C₆H₃---3,4-(OMe)₂]₂ 1 (LH) reacts with [Pd(OAc)₂] (1:1 molar ratio; OAc=acetate) giving the orthometallated [Pd(OAc)(C₆H₂---4,5-(OMe)₂---2-CH=N-(1R,2R)-C₆H₁₀---N=CH---C₆H₃-3′,4′-(OMe)₂-κ-C,N,N)] 2 (abbreviated as [Pd(OAc)(L-κ-C,N,N)]), through C---H bond activation on only one of the aryl rings and N,N-coordination of the two iminic N atoms. 2 reacts with an excess of LiCl to give [Pd(Cl)(L-κ-C,N,N)] 3. The reaction of 3 with AgClO₄ and neutral or anionic ligands L′ (1:1:1 molar ratio) affords [Pd(L-κ-C,N,N)(L′)](ClO₄) (L′=PPh₃ 4a, NCMe 5, pyridine 6, p-nitroaniline 7) or [Pd(I)(L-κ-C,N,N)] 8. Complex 4a reacts with wet CDCl₃ giving [Pd(C₆H₂---4,5-(OMe)₂---2-CH=N-(1R,2R)---C₆H₁₀---NH₂-κ-C,N,N)(PPh₃)](ClO₄) 4b as a result of the hydrolysis of the C=N bond not involved in the orthometallated ring. The molecular structure of 4b·CH₂Cl₂ has been determined by X-ray diffraction methods. Cleavage of the Pd---N bond trans to the C_aryl atom can be accomplished by coordination of strongly chelating ligands, such as acetylacetonate (acac) or bis(diphenylphosphino)ethane (dppe), forming [Pd(acac-O,O′)(L-κ-C,N)] 9 and [Pd(L-κ-C,N)(dppe-P,P′)](ClO₄) 12, while classical N,N′-chelating ligands such as 1,10-phenantroline (phen) or 2,2′-bipyridyl (bipy) behave as monodentate N-donor ligands yielding [Pd(L-κ-C,N,N)(κ¹-N-phen)](ClO₄) 10 and [Pd(L-κ-C,N,N)(κ¹-N-bipy)](ClO₄) 11. Treatment of 1 with PtCl₂(DMSO)₂ (1:1 molar ratio) in refluxing 2-methoxyethanol gives Cl₂Pt[(NH₂)₂C₆H₁₀---N,N′] 13a and [Pt(Cl)(C₆H₂---4,5-(OMe)₂---2-CH=N-(1R,2R)---C₆H₁₀---NH₂-κ-C,N,N)] 13b, while [Pt(Cl)(L-κ-C,N,N)] 14 can be obtained by reaction of [Pt(μ-Cl)(η³-2-Me---C₃H₄)]₂ with 1 in refluxing CHCl₃. Complexes 2 and 3 catalyzed the arylation of methyl acrylate giving good yields of the corresponding methyl cinnamates and TON up to 847 000. Complex 3 also catalyzes the hydroarylation of 2-norbornene, but with lower yields and without enantioselectivity.     

3-exo,3′-exo-(1R,1′R)-Bithiocamphor — a versatile source for functionally different 3,3′-bibornane derivatives — I. Ring-closure reactions and prototropic rearrangements

The title compound 3, derived from (+)-camphor, allows preparatively useful conversions to be carried out at the 3,3′-bibornane skeleton. The reactions are characterized by steric factors. Despite the increasing steric strain in the bicyclic units, ring-closure reactions of 3 to born-2-ene anellated sulfur-heterocycles are possible, including the formation of the 1,2-dithiine (6), thiophene (11), and 1,2,3-trithiepine system (13), respectively. Compound 6 is distinguished by several unusual properties. In contrast to the normal behaviour of aliphatic thioketones, 3 cannot exist as enthiol. The latter and related intermediates are immediately stabilized by 1,5-prototropic rearrangements leading to bornylidene units e.g. in 16 and consecutive products.     

Mild synthesis of enantiomerically pure imidazo-[1,2-a]azepines mediated by Yb(OTf)3

The reaction of various chiral 2,2′-diaryldialdehydes with achiral and chiral 1,2-diamines in the presence of Lewis acids to give imidazo[1,2-a]azepines was investigated. Best results were achieved with Yb(OTf)₃; the reaction outcome is strongly dependent upon the geometric features of both reactants. Kinetic resolution of rac-2,2′-dinaphthyldialdehyde with (R,R)-1,2-diphenyl-1,2-diamminoethane (up to 92% e.e.) was achieved.     

Syntheses and absolute configurations of the cytokinins 1′-methylzeatin and its 9-riboside

On the basis of the chiral syntheses of (1′R)-I and (1′S)-I and of their 9-ribosides (1″R)-III and (1″S)-III from D- and L-alanines, the structures of the cytokinins 1′-methylzeatin and its 9-riboside have been established to be (1′R)-I and (1″R)-III.     

Enantioselektive Katalyse VII. Komplexe von (P(R,S),3R,4R,P′(R,S))-3,4-Bis(phenylphosphino)pyrrolidinen. Die Darstellung optisch reiner 1,2-Bisphosphanliganden mit vier Stereozentren, die zusätzliche funktionnelle Gruppen enthalten

Diastereomeric mixtures of the palladium, the platinum, and the rhodium complexes were prepared from [P(R,S),3R,4R,P′(R,S)]-3,4-bis(phenylphosphino)pyrrolidine (1a). The phosphorus atoms in bis[(P(R,S),3R,4R,P′(R,S))-1-(t-butoxycarbonyl)-3,4-bis(phenylphosphino)pyrrolidine-P,P′]dihalogenopalladium (2) can be alkylated stereoselectively with iodomethane. The P---H bonds in 2 open epoxides, and add to Michael systems, to give new ligands, which can be split off from the palladium with cyanide. The three isomerically pure [(PR,3R,4R,P′R)(PS,3R,4R,P′S)(PR,3R,4R,P′S)]-1-(t-butoxycarbonyl)-3,4- bis[(2-cyanoethyl)phenylphosphino]pyrrolidines were prepared via the neutral diiodopalladium complexes. [(PS,3R,4R,P′S)1-(t-butoxycarbonyl)-3,4-bis[(2-cyanoethyl)phenylphosphino]pyrrolidine-P,P′]diiodopalladium(II) (14-1) was characterised by X-ray crystallography.     

Stereoselective synthesis of (1R,2S)-2-amino-1,3-diols from (R)-cyanohydrins

Vinyl substituted (1R,2S)-amino alcohols 5 were obtained by addition of vinyl magnesium bromide to the corresponding cyanohydrin O-trimethylsilyl ethers (R)-2. The O- and N-protected vinyl amino alcohols 6 were ozonized at −78°C in methanol yielding (1R,2S)-2-amino-1,3-diols7 in high enantiomeric and diastereomeric excesses. For purification, compounds 7 in some cases were acetylated to give the derivatives (1R,2S)-8. Racemic 6a was converted by oxidative ozonolysis at −78°C in methanolic NaOH solution to the corresponding methyl N-acetyl-β-hydroxy propanoate 9a. The configuration of (1R,2S)-8a was confirmed by x-ray crystallographic analysis.     

Structures of 3,3′-dicarbometoxy-2,2′-bipyridine complexes with silver(I) and copper(II) cations

The structures of 3,3′-dicarbometoxy-2,2′-bipyridine (dcmbpy) complexes with copper(II) and silver(I) cations have been determined using single crystal X-ray-diffraction. The crystals of Cu(dcmbpy)Cl₂ are monoclinic, C2/c, a = 16.966(3), b = 18.373(3), c = 13.154(2) Å, β = 126.543(3)°. The crystals of Ag(dcmbpy)NO₃ · H₂O are also monoclinic, C2/c, a = 16.7547(13), b = 11.0922(9), c = 18.7789(18) Å, β = 100.228(7)°. The results have been compared with the literature data on the complexes of dcmbpy and its precursors: 2,2′-bipyridine (bpy) and 3,3′-dicarboxy-2,2′-bipyridine (dcbpy). Two types of complexes of 3,3′-carboxy derivatives of bpy are distinguished: (1) with metal atom bonded to two N atoms of the same molecule and (2) with metal atom bonded to two N atoms of two different molecules. The Cu(dcmbpy)Cl₂ complex belongs to the first type, whereas Ag(dcmbpy)NO₃ · H₂O belongs to the second type.     

Structural, spectral and thermal studies of N-2-(4-picolyl)- and N-2-(6-picolyl)-N′-(2-chlorophenyl)thioureas and N-2-(6-picolyl)-N′-(2-bromophenyl)thiourea

N-2-(4-picolyl)-N′-2-chlorophenylthiourea, 4PicTu2Cl, monoclinic, P2₁/c, a=10.068(5), b=11.715(2), β=96.88(4)°, and Z=4; N-2-(6-picolyl)-N′-2-chlorophenylthiourea, 6PicTu2Cl, triclinic, P-1, a=7.4250(8), b=7.5690(16), c=12.664(3) Å, =105.706(17), β=103.181(13), γ=90.063(13)°, V=665.6(2) ų and Z=2 and N-2-(6-picolyl)-N′-2-bromophenylthiourea, 6PicTu2Br, triclinic, P-1, a=7.512(4), b=7.535(6), c=12.575(4) Å, a=103.14(3), β=105.67(3), γ=90.28(4)°, V=665.7(2) ų and Z=2. The intramolecular hydrogen bonding between N′H and the pyridine nitrogen and intermolecular hydrogen bonding involving the thione sulfur and the NH hydrogen, as well as the planarity of the molecules, are affected by the position of the methyl substituent on the pyridine ring. The enthalpies of fusion and melting points of these thioureas are also affected. ¹H NMR studies in CDCl₃ show the NH′ hydrogen resonance considerably downfield from other resonances in their spectra.     

Structural and spectral studies of N-2-(pyridyl)-, N-2-(3-, 4-, 5-, and 6-picolyl)- and N-2-(4,6-lutidyl)-N′-2-thiomethoxyphenylthioureas

Structures of the following compounds have been obtained: N-(2-pyridyl)-N′-2-thiomethoxyphenylthiourea, PyTu2SMe, monoclinic, P2₁/c, a=11.905(3), b=4.7660(8), c=23,532(6) Å, β=95.993(8)°, V=1327.9(5) ų and Z=4; N-2-(3-picolyl)-N′-2-thiomethoxyphenyl-thiourea, 3PicTu2SeMe, monoclinic, C2/c, a=22.870(5), b=7.564(1), c=16.941(4) Å, β=98.300(6)°, V=2899.9(9) ų and Z=8; N-2-(4-picolyl)-N′-2-thiomethoxyphenylthiourea, 4PicTu2SMe, monoclinic P2₁/a, a=9.44(5), b=18.18(7), c=8.376(12) Å, β=91.62(5)°, V=1437(1) ų and Z=4; N-2-(5-picolyl)-N′-2-thiomethoxyphenylthiourea, 5PicTu2SMe, monoclinic, C2/c, a=21.807(2), b=7.5940(9), c=17.500(2) Å, β=93.267(6)°, V=2893.3(5) ų and Z=8; N-2-(6-picolyl)-N′-2-thiomethoxyphenylthiourea, 6PicTu2SMe, monoclinic, P2₁/c, a=8.499(4), b=7.819(2), c=22.291(8) Å, β=90.73(3)°, V=1481.2(9) ų and Z=4 and N-2-(4,6-lutidyl)-N′-2-thiomethoxyphenyl-thiourea, 4,6LutTu2SMe, monoclinic, P2₁/c, a=11.621(1), b=9.324(1), c=14.604(1) Å, β=96.378(4)°, V=1572.4(2) ų and Z=4. Comparisons with other N-2-pyridyl-N′-arylthioureas having substituents in the 2-position of the aryl ring are included.     

(R)-bis-Binaphthoxy iodo lanthanides as catalysts for Diels–Alder reactions

[(R)-1,1′bi-2,2′-Naphthoxy]LnI(THF)₂ (Ln: Yb, Sm, La) 5 have been prepared by reaction of the bispotassium salt of (R)-binaphthol with lanthanide triiodides, and characterized. They are active catalysts for Diels–Alder reactions although with low asymmetric inductions. The lanthanum iodo bisbinaphthoxide gives a slightly higher enantiomeric excess than the two other complexes.     

(R)-Binaphthoxy diiodide lanthanides

The synthesis and characterization of novel enantiopure binaphthoxy-diiodo lanthanides [(R)-2-(1-naphthol)-1′-naphthoxide)LnI₂(THF)₃] (Ln=Sm (4a), Yb (4b), La (4c)) are described. These complexes have been prepared by reacting the mono potassium salt of (R)-binaphthol with the corresponding lanthanide triiodides and were characterized by elemental analysis, IR and NMR spectroscopies. Recrystallization of 4c from THF–hexane led to monocrystals of [(R)-2-(1-naphthol)-1′-naphthoxide)]-diiodolanthane-tetrakistetrahydrofurane] (4c*). Complex 4c* crystallizes in the orthorhombic space group, P2₁2₁2₁ with cell parameters a=13.086(1) Å, b=15.496(1) Å, c=18.854(1) Å, V=3823.2(6) ų, and Z=4.     

Enantioselective inclusion of (R)-phenylglycyl-(R)-phenylglycine with benzyl methyl sulfoxides

A crystalline dipeptide, (R)-phenylglycyl-(R)-phenylglycine (RR-1), recognized p-halobenzyl methyl sulfoxides with high R-enantioselectivity (86–99% ee) to form inclusion compounds. The single-crystal X-ray analyses showed that RR-1 molecules are arranged in parallel and zigzags via hydrogen bonding to construct a pleated sheet. The guest molecules that form hydrogen bond with ⁺NH₃ of RR-1 are accommodated in the channel cavity between the layers. In contrast to the inclusion crystals of parent benzyl methyl sulfoxide, in which a rectangular cavity is formed, the cavity including p-halobenzyl methyl sulfoxides becomes rhomboidal. We also examine the guest exchange in these inclusion compounds and it was found that the guest exchanges occur when the host structure changes.     

Enzymatic production of (3S,4R)-(−)-4-(4′-fluorophenyl)-6-oxo-piperidin-3-carboxylic acid using a commercial preparation from Candida antarctica A: the role of a contaminant esterase

The enantioselective hydrolysis of (3RS,4RS)-trans-4-(4′-fluorophenyl)-6-oxo-piperidin-3-ethyl carboxylate (±)-2 was effected using a commercial preparation of lipase from C. antarctica A (CAL-A). We found that the hydrolytic activity of the lipase (immobilized on a number of very different supports) with this substrate was negligible. However, a contaminant esterase with Mw of 52 KDa from this commercial preparation exhibited much higher activity with (±)-2. This enzyme was purified and immobilized on PEI-coated support and the resulting enzyme preparation was highly enantioselective in the hydrolysis of (±)-2 (E >100), hydrolyzing only the (3S,4R)-(−)-3, which is a useful intermediate for the synthesis of pharmaceutically important (−)-paroxetine. Optimization of the reaction system was performed using a racemic mixture with a substrate concentration of 50 mM. This enzyme preparation was used in three reaction cycles and maintained its catalytic properties.     

Facile synthesis of enantiopure 1,1′-binaphthyl-2,2′-dicarboxylic acid via lipase-catalyzed kinetic resolution

Enantiopure 1,1′-binaphthyl-2,2′-dicarboxylic acids (R)-1 and (S)-1 have been synthesized through the lipase-catalyzed kinetic resolution of the racemic 2,2-bis(hydroxymethyl)-1,1′-binaphthyl (±)-2 and subsequent oxidation of the hydroxymethyl groups.     

Rhenium(I) methoxo carbonyl complexes containing tetraphosphine or triphosphine ligands; facile separation and X-ray crystallographic studies of d/l- and meso-[{Re2(μ-OMe)2(CO)6}2(μ,μ′-1,1,4,7,10,10-hexaphenyl-1,4,7,10-tetra-phosphadecane)]

Reaction of the activated mixture of Re₂(CO)_10, Me₃NO and MeOH with a 1:1 mixture of rac (d/l)- and meso-1,1,4,7,10,10-hexaphenyl-1,4,7,10-tetraphosphadecane (hptpd) yields a mixture of (d/l)- and meso-[{Re₂(μ-OMe)₂(CO)₆}₂(μ,μ′-hptpd)] 1. The diastereomers can be easily separated by selective dissolution of d/l-1 in benzene, and give clearly distinguishable ¹H- and ³¹P-NMR spectra. The fluxional behavior of d/l-1 in solution has been studied by variable-temperature ¹H- and ³¹P-{¹H}-NMR spectroscopy. The crystal structures of both d/l- and meso-1 have been determined. Both molecules consist of two {Re₂(μ-OMe)₂(CO)₆} moieties which are bridged by the two P---CH₂---CH₂---P moieties of the hptpd ligand. Whilst the molecules of meso-1 possess crystallographic i-symmetry, those of d/l-1 do not have any crystallographic symmetry. These diastereomers therefore give clearly distinguishable Raman spectra in the solid state. Reaction of tris[2-(diphenylphosphino)ethyl]phosphine (tdppep) with the activated mixture affords the complex [{Re₂(μ-OMe)₂(CO)₆}(μ,η²-tdppep)] 2, and the analogous reaction involving bis[2-diphenylphospinoethyl)phenylphosphine (triphos) gives [{Re₂(μ-OMe)₂(CO)₆}(μ,μ′,η³-triphos){Re₂(CO)₉}] 3 and [{Re₂(μ-OMe)₂(CO)₆}(μ,η²-triphos)] 4.     

Synthesis of new chiral amino ether derivatives: synthetic application of meso aziridinium ions prepared from β-amino alcohols

Methods of synthesis of new chiral amino ether derivatives through the opening of aziridinium ions, prepared in situ using trans-(±)-2-(1-N,N-dialkylamino)cyclohexyl mesylate with (R)-(+)-1,1′-bi-2-naphthol, are described. The (R,R,R)-diastereomer was obtained as the major product and isolated as an enantiopure salt, and characterized by single crystal X-ray analysis. The C₂-chiral (R,R,R,R,R)-diamino ether was obtained as the major product by opening of the aziridinium ion, prepared using trans-(±)-2-(1-pyrrolidino)cyclohexyl mesylate and (R)-(+)-1,1′-bi-2-naphthol in the presence of aq NaOH. This was also characterized by single crystal X-ray analysis.