Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

Synthesis of (2S,3R)- and (2S,3S)-[3-H1]-proline via highly stereoselective hydrolysis of a silyl enol ether

A straightforward synthesis of (2S)-[3,3-²H₂]-proline 1c and (2S,3R)- and (2S,3S)-[3-²H₁]-proline, 1b and 1a, respectively, has been devised. The key step of the route to the latter compounds involves highly stereoselective hydrolysis of the silyl enol ethers 3 and 3a, respectively, with protonation (deuteriation) from the re-face of the silyl enol ether.     

Half-sandwich η-benzene Ru(II) complexes of phenolate-based pyridylalkylamine/alkylamine ligands: Synthesis, structure, and stabilization of one-electron oxidized species

Four half-sandwich ruthenium(II) complexes [(η⁶-C₆H₆)Ru(L¹-O)][PF₆] (1), [(η⁶-C₆H₆)Ru(L²-O)][PF₆] (2), [(η⁶-C₆H₆)Ru(L³-O)][PF₆] (3), [(η⁶-C₆H₆)Ru(L⁴-O)][PF₆] (4a), and [(η⁶-C₆H₆)Ru(L⁴-O)][BPh₄] (4b) [L¹-OH, 4-nitro-6-{[(2′-(pyridin-2-yl)ethyl)methylamino]methyl}-phenol; L²-OH, 2,4-di-tert-butyl-6-{[(2′-(pyridin-2-yl)ethyl)methylamino]methyl}-phenol; L³-OH, 2,4-di-tert-butyl-6-{[2′-((pyridin-2-yl)benzylamino)methyl}-phenol; L⁴-OH, 2,4-di-tert-butyl-6-{[(2′-imethylaminoethyl)methylamino]methyl}-phenol (L⁴-OH)], supported by a systematically varied series of tridentate phenolate-based pyridylalkylamine and alkylamine ligands are reported. The molecular structures of 1-3, 4a, and 4b have been elucidated in solution using ¹H NMR spectroscopy and of 1, 3, and 4b in the solid state by X-ray crystallography. Notably, due to coordination by the ligands the Ru center assumes a chiral center and in turn the central amine nitrogen also becomes chiral. The ¹H NMR spectra exhibit only one set of signals, suggesting that the reaction is completely diastereoselective [1: S_Ru,S_N/R_Ru,R_N; 2: R_Ru,R_N/S_Ru,S_N; 3: S_Ru,R_N/R_Ru,S_N; 4b: S_Ru,R_N/R_Ru,S_N]. The crystal packing in 1 and 3 is stabilized by C-H^…O interactions, in 4b no meaningful secondary interactions are observed. From the standpoint of generating phenoxyl radical, as investigated by cyclic voltammetry (CV), complex 1 is redox-inactive in MeCN solution. However, 2, 3, and 4a generate a one-electron oxidized phenoxyl radical coordinated species [2]²⁺, [3]²⁺, and [4a]²⁺, respectively. The radical species are characterized by CV, UV-Vis, and EPR spectroscopy. The stability of the radical species has been determined by measuring the decay constant (UV-Vis spectroscopy).     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Polyhydroxylated pyrrolizidines. Part 8. Enantiospecific synthesis of looking-glass analogues of hyacinthacine A5 from DADP

(1R,2S,3S,5R,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine[(−)-3-epihyacinthacine A₅, 1a] and (1S,2R,3R,5S 7aS)-1,2-dihydroxy-3-hydroxymethylpyrrolizidine[(+)-3-epihyacinthacine A₅, 1b] have been synthesized either by Wittig's or Horner-Wadsworth-Emmond's (HWE's) methodology using aldehydes 4 and 9, both prepared from (2S,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (2, partially protected DADP), and the appropriate ylides, followed by cyclization through an internal reductive amination process of the resulting α,β-unsaturated ketones 5 and 10, respectively, and total deprotection.     

Complementary kinetic and thermodynamic resolution of a chiral biaryl axis

The condensation of 2′-formylbiphenyl-2-carboxylic acid 4 with (S)-valinol proceeds under kinetic control to give a major product, (4bR,7S,aS)-6,7-dihydro-7-isopropyldibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-one 6a (84%), in which the biaryl axis has the (S)-configuration. Heating 6a at 140°C with a catalytic amount of acid gives rise to an equilibrium dominated by the diastereoisomeric (4bS,7S)-lactam 6b (6a:6b ratio 27:73), in which the biaryl unit has the (R)-configuration. The structures of both lactams were established by X-ray crystallography; no other diastereoisomers were obtained.     

Probes for narcotic receptor mediated phenomena. Part 31: Synthesis of rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-10-ol, and azocine-8-ol, the ortho-c and the para-c oxide-bridged phenylmorphan isomers

Two of the 12 possible oxide-bridged phenylmorphans, were synthesized, rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-10-ol (7) (the ortho-c compound), and rac-(3R,6aS,11aS)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocine-8-ol (8) (the para-c compound). Single-crystal X-ray diffraction studies indicated that the dihedral angle between the least squares planes through the phenyl ring and the atoms C₁, C_11a, C₁₂, and C₃ in the piperidine ring in both 7·CHCl₃ and 8·HBr was 6.9°. The C₁₂-C_6a-C_6b-C_10a torsion angle was found to be 139.3° for both compounds. The angular relationship between the phenolic ring and the piperidine ring in phenylmorphans that interact with specific opioid receptors as agonists or antagonists is of considerable theoretical interest.     

Stabilization of the labile metal configuration in halfsandwich complexes [CpRh(PN)Hal]X

PN ligands 3 and 4, derived from 2-diphenylphosphanylmethylpyridine 2a, were synthesized, to which in the backbone a tether to a cyclopentadiene system and for comparison an ⁱPr substituent were attached. The chiral compounds were resolved by introduction of a menthoxy substituent into the 2-position of the pyridine system and/or palladium complexes with enantiomerically pure co-ligands. The tripod ligand 3b contains three different binding sites (Cp, P, N) connected by a resolved chiral carbon atom. (S_C)-configuration of this tripod ligand enforces (R_Rh)-configuration at the metal atom in the halfsandwich rhodium complex (L_Ment,S_C,R_Rh)-7b. The opposite metal configuration is inaccessible. Substitution of the chloro ligand in (L_Ment,S_C,R_Rh)-7b by halide (Br, I) or pseudohalide (N₃, CN, SCN) ligands occurs with retention of configuration to give complexes 8b-11b. However, in the reaction of (L_Ment,S_C,R_Rh)-7b with PPh₃ the pyridine arm of the tripod ligand in compound 13b becomes detached from the metal atom. In the Cp*Rh and CpRh compounds of the bidentate PN ligands 4a and 4b both metal configurations are accessible and in complexes 14a-17a and 14b-17b they equilibrate fast. The stereochemical assignments are corroborated by 9 X-ray analyses.     

Salen-ligands based on a planar-chiral hydroxyferrocene moiety: Synthesis, coordination chemistry and use in asymmetric silylcyanation

Condensation of the O-protected hydroxyferrocene carbaldehyde (S_p)-1 with suitable diamines, followed by liberation of the hydroxyferrocene moiety leads to a new type of ferrocene-based salen ligands (3). While the use of ethylenediamine in the condensation reaction yields the planar-chiral ethylene-bridged ligand [(S_p,S_p)-3a], reaction with the enantiomers of trans-1,2-cyclohexylendiamine gives rise to the corresponding diastereomeric cyclohexylene-bridged systems [(S,S,S_p,S_p)-3b and (R,R,S_p,S_p)-3c], which feature a combination of a planar-chiral ferrocene unit with a centrochiral diamine backbone. Starting with the ferrocene-aldehyde derivative (R_p)-1, the enantiomeric ligand series (3d/e/f) is accessible via the same synthetic route.The (S_p)-series of these newly developed N₂O₂-type ligands was used for the construction of the corresponding mononuclear bis(isopropoxy)titanium (4a/b/c), methylaluminum (5a/b/c) and chloroaluminum-complexes (6a/b/c), which were isolated in good yields and identified by X-ray diffraction in several cases. The aluminum complexes (5/6) were successfully used in the Lewis-acid catalyzed addition of trimethylsilylcyanide to benzaldehyde, yielding the corresponding cyanohydrins in 45-62% enantiomeric excess.     

Synthesis, crystal structure analysis, and pharmacological characterization of desmethoxy-sila-venlafaxine, a derivative of the serotonin/noradrenaline reuptake inhibitor sila-venlafaxine

rac-Desmethoxy-sila-venlafaxine (rac-3) is a derivative of the noradrenaline-selective serotonin/noradrenaline reuptake inhibitor rac-sila-venlafaxine (rac-1b), a silicon analogue of the serotonin-selective serotonin/noradrenaline reuptake inhibitor rac-venlafaxine (rac-1a) (rac-1a, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol; rac-1b, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol). The synthesis and crystal structure analyses of rac-3 and rac-3 · HCl are reported, and the pharmacological properties of rac-1a, rac-1b, rac-2 (a sila-venlafaxine derivative with a silacyclopentanol skeleton instead of a silacyclohexanol framework), and rac-3 are compared (comparison of the pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition).     

Synthesis and characterization of heterometallic Rh/Ru complexes supported by 1,2-dichalcogenolato-o-carborane ligands

The 16-electron half-sandwich complexes Cp^∗Rh[E₂C₂(B₁₀H₁₀)] (E = S, 1a; Se, 1b) react with [Ru(COD)Cl₂]_x under different conditions to give different types of heterometallic complexes. When the reactions were carried out in THF for 24 h, the binuclear Rh/Ru complexes [Cp^∗Rh(μ-Cl)₂(COD)Ru][E₂C₂(B₁₀H₁₀)] (E = S, 2a; Se, 2b) bridged by two Cl atoms and the binuclear Rh/Rh complexes (Cp^∗Rh)₂[E₂C₂(B₁₀H₁₀)] (E = S, 3a; Se, 3b) with direct Rh-Rh bond can be isolated in moderate yields. [Ru(COD)Cl₂] fragments in 2a and 2b have inserted into the Rh-E bond. If the [Ru(COD)Cl₂]_x was reacted with 1a in the presence of K₂CO₃ in methanol solution, the product [Cp^∗Rh(COD)]Ru[S₂C₂(B₁₀H₁₀]] (4a), K[(μ-Cl)(μ-OCH₃)Ru(COD)]₄ (5a) and 3a were obtained. The B(3)-H activation in complex 4a was found. However, when the reaction between 1b and [Ru(COD)Cl₂]_x was carried out in excessive NaHCO₃, the carborane cage opened products {Cp^∗Rh[S₂C₂(B₉H₁₀)]}Ru(COD) (6b), {Cp^∗Rh[S₂C₂(B₉H₉)]}Ru(COD)(OCH₃) (7b) and 3b were obtained. All complexes were fully characterized by their IR, ¹H NMR and elemental analyses. The molecular structures of 2a, 2b, 3b, 4a, 5a, and 7b have been determined by X-ray crystallography.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-H1]-homocitrates and the corresponding dimethyl ester lactones—towards elucidating the stereochemistry of the reaction catalysed by homocitrate synthase and by the Nif-V protein

Trimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitrates, 10b and 10c respectively, and dimethyl (2S,3R)- and (2R,3R)-[2-²H₁]-homocitric lactones, 11b and 11c respectively, have been synthesised from shikimic acid and [2-²H]-shikimic acid by a route which defines the stereochemistry of the two chiral centres in each compound. The NMR spectra of these products will enable the stereochemistry of the biological reaction catalysed by homocitrate synthase and by the protein from the nifV gene to be elucidated.     

New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3

Conceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2-a]-A-ring phosphine oxides (+)-4 and (−)-4 were successfully prepared from methyl 2-pyrone-3-carboxylate and (S)- or (R)-2-(tert-butyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectively. In addition, (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D₃3a and 3b as new A-ring-modified analogs of the natural hormone 1α,25-dihydroxyvitamin D₃ were readily synthesized by using Lythgoe-type coupling of the A-ring phosphine oxides (+)-4 and (−)-4 with C,D-ring ketone (+)-5.     

The role of intermolecular interactions in the assemblies of Fe and Co tetrakis-isothiocyanatometalates with tris(1,10-phenanthroline)-Ru: Crystal structures of two dual-metal assemblies featuring octahedral cationic and tetrahedral anionic modules

Two new dual-metal assemblies: 2[Ru(phen)₃]²⁺·[Fe(SCN)₄]²⁻·2SCN⁻·4H₂O 1 and [Ru(phen)₃]²⁺·[Co(SCN)₄]²⁻2, (phen:1,10-phenanthroline), have been prepared and their structures were characterized by X-ray diffraction. In 1, the cationic octahedral enantiomers are arranged with a ΛΔΛΔΛ sequence supported by π-π stacking and the anionic inorganic tetrahedral units are oriented between these stacks by interacting with the nearby water molecules through strong O-H?O and O-H?S hydrogen bonds. In 2, homochiral double helices in the b-direction are revealed, with tetrakis-isothiocyanate Co^II anions arranged in the crystal to furnish one-dimensional (1D)-helical chains with S?S intermolecular interactions at 3.512(2) and 3.966(2) Å supporting [Ru(phen)₃]²⁺Λ- and Δ-helices with Ru?Ru shortest distance of 8.676(7) Å. In both 1 and 2, the supramolecular assembly is maintained by C-H?S hydrogen bonds extending between the phenanthroline aromatic carbons in the cationic nodes and the sulphur atoms of the isothiocyanates anions. Analysis of S?S interactions in isothiocyanate containing compounds using Cambridge structural database (CSD) showed an angle dependence categorizing these interactions into “type-I” and “type-II”.     

Different recognitions of (E)- and (Z)-1,1′-binaphthyl ketoximes using lipase-catalyzed reactions

Lipase-catalyzed hydrolysis of (E)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1a] and (Z)-2-[α-(acetoxyimino)benzyl]-1,1′-binaphthyl [(±)-1b] yielded optically active (E)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(S)-2a] and (Z)-2-[α-(hydroxyimino)benzyl]-1,1′-binaphthyl [(R)-2b], respectively, with high enantiomeric excess. Selectivity for the opposite enantiomer of the axial binaphthyl skeleton was shown by (Z)-isomer 1b against (E)-isomer 1a.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-protected derivatives (R)-2b-d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a-d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was favored.     

Aluminum and zinc complexes supported by functionalized phenolate ligands: Synthesis, characterization and catalysis in the ring-opening polymerization of ε-caprolactone and rac-lactide

A series of aluminum and zinc complexes supported by functionalized phenolate ligands were synthesized and characterized. Reaction of 2-(3,5-R₂C₃N₂)C₆H₄NH₂ (R = Me, Ph) with salicylaldehyde or 3,5-di-tert-butylsalicylaldehyde afforded 2-((2-(1H-pyrazol-1-yl)phenylimino)methyl)phenol derivatives 2a-2d. Treatment of 2a-2d with an equiv. of AlR²₃ (R² = Me, Et) gave corresponding aluminum aryloxides 3a-3e, while reaction with an equiv. of ZnEt₂ afforded zinc aryloxides 4a-4d. Treatment of 2c with 0.5 equiv. of ZnEt₂ formed diphenolato zinc complex 5. All new compounds were characterized by ¹H and ¹³C NMR spectroscopy and elemental analyses. The structures of complexes 3a, 4a and 5 were further characterized by single crystal X-ray diffraction techniques. The catalytic activity of complexes 3-5 toward the ring-opening polymerization of ε-caprolactone was studied. The zinc complexes (4a-4d) exhibited higher catalytic activity than the aluminum complexes (3a-3e). The diphenolato zinc complex 5 showed lower catalytic activity than the ethylzinc complexes 4a-4d. The aluminum complex (3b) is inactive to initiate the ROP of rac-lactide, while the zinc complex (4d) is active initiator for the ROP of rac-lactide, giving atactic polylactide.     

Novel (η-arene)-ruthenium(II) complexes containing bis(iminophosphorano)methanide and methandiide ligands

The novel bis(iminophosphorano)methanes CH₂[P{NP(S)(OR)₂}Ph₂]₂ (R = Ph (1a), Et (1b)) have been obtained by oxydation of dppm with the corresponding thiophosphorylated azides (RO)₂P(S)N₃. Deprotonation of 1a,b with KH generates the methanide species KCH[P{NP(S)(OR)₂}Ph₂]₂ (R = Ph (2a), Et (2b)). The ruthenium(II) dimer [{Ru(η⁶-p-cymene)(μ-Cl)Cl}₂] reacts with 2a,b to afford the cationic complexes [Ru(η⁶-p-cymene)(κ³-C,N,S-CH[P{NP(S)(OR)₂}Ph₂]₂)]⁺ (R = Ph (3a), Et (3b)), via selective κ³-C,N,S-coordination of the bis(iminophosphorano)methanide anions to ruthenium. The structure of [Ru(η⁶-p-cymene)(κ³-C,N,S-CH[P{NP(S)(OEt)₂}Ph₂]₂)][PF₆] (3b) has been confirmed by single-crystal X-ray crystallography. Deprotonation of complexes 3a,b with NaH leads to the neutral carbene derivatives [Ru(η⁶-p-cymene)(κ²-C,N-C[P{NP(S)(OR)₂}Ph₂]₂)] (R = Ph (4a), Et (4b)).     

Synthesis, characterization and anticancer activity of new chiral Pd(II)-complexes derived from unsymmetrical α-diimine ligands

A set of new diastereopure unsymmetrical α-diimine ligands 2a-d derived from methylglyoxal and optically pure primary amines 1a-d afforded the new chiral Pd(II)-complexes (S,S)-3a, (S,S)-3b, (S,S)-3c, and (1S, 2S, 3S, 5R)-3d. All compounds have been characterized by IR, ¹H, and ¹³C NMR spectroscopies along with MS-FAB⁺ spectrometry. The crystal and molecular structure for the complexes 3a, 3b and 3d have been fully confirmed by single-crystal X-ray studies. Likewise, complexes 3a-d have also been screened for their in vitro cytotoxicity against different classes of cancer: leukemia (K-562 CML), colon cancer (HCT-15), human breast adenocarcinoma (MCF-7), central nervous system (U-251 Glio) and prostate cancer (PC-3) cell lines.