Asymmetric synthesis of new chiral long chain alcohols

Sixteen new chiral alcohols with alkyl (C₁₁–C₁₉) and aryl, substituted aryl, hetero aryl and biaryl groups 2a–2t were synthesized by three different asymmetric reduction methods from their corresponding ketones 1a–1t. Chiral NaBH₄ (method A), chiral BH₃ (method B) and chiral AIP (method C) were used as asymmetric reduction catalysts. Chiral NaBH₄ was modified by four different ligands 3a–3d, chiral BH₃ and chiral AIP by four different ligands 4a–4d. Ligand 4c was synthesized for the first time in this work. Chiral NaBH₄ generated chiral alcohols of (R)-configuration and chiral BH₃ and chiral AIP of (S)-configuration with high enantiomeric excesses, were analysed by chiral HPLC. In order to determine the ee values by chiral HPLC, sixteen corresponding racemic alcohols, synthesized by reducing their corresponding ketones via NaBH₄, were used for chiral resolution on a Daicel OD HPLC column. The sixteen starting ketones were synthesized in this study by Friedel–Craft acylation. The new chiral alcohols were characterized by IR, NMR, (¹H and ¹³C), MS, elemental analyses and specific rotation. The reduction methods A, B and C were applied to these ketones for the first time in this study and were compared with each other. The relationship between the structure of the ketone and the yield and the enantiomeric excess was discussed.     

Asymmetric zinc-Reformatsky reaction of Evans chiral imide with acetophenones and its application to the stereoselective synthesis of triazole antifungal agents

The Ni(acac)₂ catalytic ZnEt₂-mediated asymmetric Reformatsky-type reaction of Evans chiral imide with various acetophenones was studied. The chiral imido zinc enolate, which was formed through the metal–halogen exchange reaction of chiral α-bromopropionyl-2-oxazolidinones 2 with diethyl zinc under the catalysis of Ni(acac)₂, performed the asymmetric zinc-Reformatsky reaction with activated α-haloacetophenones 3 to give the chiral β-hydroxyamide 4 in good yields and high ratios of syn-(2R,3R)-isomers (up to >97%). This new asymmetric synthesis technology affords a practical method to synthesize the versatile chiral building block 5 for triazole antifungal agents, such as Voriconazole, Ravuconazole, TAK-187, and RO-0094815.     

Studies on diastereoselective reduction of cyclic β-ketoesters with boron hydrides. Part 4: The reductive profile of functionalized cyclohexanone derivatives

Reduction of 2-allyl-2-carboalkoxycyclohexanones (3d-f), 2-propyl-2-carboethoxycyclohexanone (3g) and 2-benzyl-2-carboethoxycyclohexanone (3h) with boron hydrides in the presence and absence of several chelating agents were studied. Molecular modeling studies using semiempirical PM3 method were performed in order to find a suitable explanation of the diastereoselection of ketone carbonyl faces during the reductive process, which yielded trans-2-allyl-2-carboethoxycyclohexanol (6e) and cis-2-allyl-2-carboethoxycyclohexanol (7e) in good diastereomeric excess by using inexpensive sodium and tetrabutylammonium borohydrides.     

DFT study on mechanism of carbonyl hydrosilylation catalyzed by high-valent molybdenum (IV) hydrides

Density functional theory (DFT) calculations have been employed to investigate hydrosilylation of carbonyl compounds catalyzed by three high-valent molybdenum (VI) hydrides: Mo(NAr)H(Cp)(PMe₃) (1A), Mo(NAr)H(PMe₃)₃ (1B), and Mo(NAr)H (Tp)(PMe₃) (Tp?=?tris(pyrazolyl) borate) (1C). Three independent mechanisms have been explored. The first mechanism is “carbonyl insertion pathway”, in which the carbonyls insert into Mo?H bond to give a metal alkoxide complex. The second mechanism is the “ionic hydrosilylation pathway”, in which the carbonyls nucleophilically attacks η¹-silane molybdenum adduct. The third mechanism is [2 + 2] addition mechanism which was proposed to be favorable for the high-valent di-oxo molybdenum complex MoO₂Cl₂ catalyzing the hydrosilylation. Our studies have identified the “carbonyl insertion pathway” to be the preferable pathway for three molybdenum hydrides catalyzing hydrosilylation of carbonyls. For Mo(NAr)H (Tp)(PMe₃) (Tp?=?tris(pyrazolyl) borate), the proposed nonhydride mechanism experimentally is calculated to be more than 32.6?kcal/mol higher than the “carbonyl insertion pathway”. Our calculation results have derived meaningful mechanistic insights for the high-valent transition metal complexes catalyzing the reduction reaction.     

Fluorometric analysis of borohydrides based on reductive aldehyde-to-alcohol conversion of arylaldehydes

Fluorometric analysis of borohydride (BH₄^–) species by the reduction of arylaldehydes to the corresponding arylmethanols was investigated. 9-Anthracenecarboxaldehyde (9-AA) exhibited pronounced ratiometric fluorescence signaling behavior toward borohydride in alkaline aqueous media. The borohydride-selective signaling of 9-AA was unaffected by the presence of commonly encountered metal ions and anions. 1-Pyrenecarboxaldehyde (1-PA) also showed comparable borohydride signaling behavior. The detection limit was found to be 7.4?μM (0.11?ppm) for 9-AA and 15.7?μM (0.23?ppm) for 1-PA. The utility of the probe with μPAD as a convenient tool for the determination of borohydrides was demonstrated.     

Übergangsmetall-substituierte phosphane,arsane und stibane: XXXVI. Diastereomere dreikernkomplexe mit verbrückenden dimethylarsino-, dimethylstibino- oder dimethylbismutino-einheiten

Interaction of the chiral organometallic Lewis bases Cp(CO)(Me₃P)Fe—EMe₂ (E = As, Sb, Bi) (1a–1c) with the norbornadiene metal complex (C₇H₈)Mo(CO)₄ yields the first examples of trinuclear complexes [Cp(CO)(Me₃P)Fe—EMe₂]₂Mo(CO)₄ (2a–2c), bearing two chiral metal atoms separated by a E—Mo—E-linkage. 2a–2c are generated as a mixture of two diastereomers (RS/SR, RR/SS), which gives rise to a resonance doubling in their ¹H and ³¹P NMR spectra. This phenomenon is not observed for the achiral, in part sterically more crowded derivatives [Cp(CO)₂Fe—SbMe₂]₂Mo(CO)₄ (4) and [Cp(CO)₂(Me₃P)Mo—EMe₂]₂Mo(CO)₄ (E = As, Sb (6a, 6b)), which excludes the existence of conformers resulting from restricted rotation about the FeE or MoE bond in the case of 2a–2c.     

A facile synthesis of chiral polyazamacrocycles and the UV spectroscopic and CD spectra studies on metal complexes

A series of chiral polyazamacrocycles with 12, 18, 24, 27, 36-membered rings were designed and synthesized using (S)-α-phenylethylamine as initial chiral source. Herein 11 new chiral polyazamacrocycles were successfully prepared. The UV spectroscopic titration experiments of polyazamacrocycle 3b with metal ions were carried out and the binding constants and free energy changes were calculated according to the modified Benesi-Hildebrand equation. Circular dichroism spectra were recorded for 3b with metal ions.     

An enantiodivergent synthesis of both (+)- and (−)-disparlure from (R)-2,3-cyclohexylideneglyceraldehyde

Reduction of ketone 3 derived from (R)-2,3-cyclohexylideneglyceraldehyde 1 with some common hydrides took place with syn-selectivity. The resulting major product 4a has been exploited as a common chiral template to prepare both enantiomers Ia,b of disparlure.     

Rhodium dihydride complexes as models for the theoretical analysis of enantioselective hydrogenation reactions

A combination of molecular mechanics methods and extended Hückel calculations has been applied in order to have access to the more stable complexes expected to be involved as catalytic intermediates in the enantioselective hydrogenation of ketopantolactone (KPL) using chiral aminophosphine-phosphinite (AMPP) chlororhodium complexes. The product selectivity has been deduced from correlations between the prevailing configuration of the hydrogenated derivatives and the energetics of competing diastereomeric dihydride complexes of formula [RhCl(H)₂(AMPP)(KPL)] with the assumption that the enantioselectivity is controlled by the relative energies of such intermediates. The calculations have been obtained from the application of sequential and exhaustive search methodologies. The procedure has been applied to complexes bearing the aminophosphine-phosphinites (S)-Cp,Cp-ProNOP (IV) and (S)-Ph,Cp-ProNOP (V) and bis(aminophosphanes) derived from 2-(anilinomethyl)pyrrolidine (VI–IX). The latter induce a reversal of configuration of the major enantiomer of the hydrogenation product when varying specific substituents at the phosphorus atoms. Computations were carried out also for complexes bearing the two enantiomers (S)- and (R)-Ph,Cp-isoAlaNOP. The lowest energy complexes present enantiomeric structures. A novel insight into the local reactivity of the intermediates has been gained from determining the first migrating hydride according to the superdelocalizability parameter calculated for all isomers. Thus, the configurations of pantolactone arising from the alkoxyrhodium species obtained when assuming a nucleophilic attack of one of the hydrides to the carbonyl group of the ketone has been defined and are in total agreement with the experimental data.     

Tailoring Thermodynamics and Kinetics for Hydrogen Storage in Complex Hydrides towards Applications

Solid‐state hydrogen storage using various materials is expected to provide the ultimate solution for safe and efficient on‐board storage. Complex hydrides have attracted increasing attention over the past two decades due to their high gravimetric and volumetric hydrogen densities. In this account, we review studies from our lab on tailoring the thermodynamics and kinetics for hydrogen storage in complex hydrides, including metal alanates, borohydrides and amides. By changing the material composition and structure, developing feasible preparation methods, doping high‐performance catalysts, optimizing multifunctional additives, creating nanostructures and understanding the interaction mechanisms with hydrogen, the operating temperatures for hydrogen storage in metal amides, alanates and borohydrides are remarkably reduced. This temperature reduction is associated with enhanced reaction kinetics and improved reversibility. The examples discussed in this review are expected to provide new inspiration for the development of complex hydrides with high hydrogen capacity and appropriate thermodynamics and kinetics for hydrogen storage.

     

Elaboration of a novel type of planar-chiral methylene bridged biphenols based on [2.2]paracyclophanes

A new class of chiral methylene bridged biphenols with planar chirality has been designed and elaborated. The synthetic approach is based on the use of 4-hydroxy-5-hydroxymethyl[2.2]paracyclophane 9 derived from either racemic or enantiomerically pure (S)-4-formyl-5-hydroxy[2.2.]paracyclophane (FHPC) by reduction with LiAlH₄. The condensation of 9 with chiral racemic 4-hydroxy[2.2]paracyclophane 4 and achiral phenols, such as 2,5-dimethylphenol 10 and 2-isopropyl-5-methylphenol 11, afforded the target bridged biphenols 6, 12 and 13, respectively. The preliminary results on the asymmetric addition of Et₂Zn to benzaldehyde promoted by (S,S)-6 are reported.     

Efficient enantiorecognition of ruthenium(II) complexes by silica-bound teicoplanin

A series of chiral tris-diimine ruthenium(II) complexes have been resolved by HPLC on a chiral stationary phase. The stationary phase (CSP1) was prepared by covalent attachment of the glycopeptide antibiotic teicoplanin to isocyanate activated silica gel. CSP1 selectively retains the enantiomers of [Ru(L)₃]²⁺ (L=2,2′-bypyridine (bpy), 1,10-phenanthroline and 4,7-diphenyl-1,10-phenanthroline), with a preference for the Δ isomer. For the mixed-ligand complexes [Ru(bpy)₂pztr]⁺ and [Ru(bpy)₂pytr]⁺ (Hpztr=3-(pyrazin-2-yl)-1,2,4-triazole, Hpytr=3-(pyridin-2-yl)-1,2,4-triazole), where the triazole unit is bound to the metal centre either through the N² or the N⁴ nitrogen of the ring, CSP1 discriminates both the enantiomers and the regioisomers. Diastereo- and enantioselective association was also observed between CSP1 and the stereoisomers of the dinuclear complex ((Ru(bpy)₂)₂bpt]³⁺ (Hbpt=3,5-bis(pyridin-2-yl)-1,2,4-triazole), with differences in binding affinities of 1.4 kJ/mol between the homochiral enantiomers.     

Unexpected formation of a chiral δ-lactone by reduction of the 1,3-dicarbonylic cyclopentanoid derivatives

We have described the synthesis of highly functionalized chiral cyclopentanoids, which are important building units for synthesis of biological active compounds. The (−)- or (+)-7,7-dimethoxy-1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-endo-yl acetate, obtained from the enzyme catalyzed transesterification of the racemate, was converted to α-diketone chiral. The α-diketone was treated with H₂O₂/NaOH and esterified with CH₂N₂ to furnish a mixture of the compounds (+)- or (−)-10 and (+)- or (−)-11. The reduction of the (+)- or (−)-10 and/or (+)- or (−)-11 with BH₃·THF furnished the lactone (+)- or (−)-13 with excellent yield. The α-diketone was reduced with indium metal in the presence of NH₄Cl furnishing the acyloin (+)-14 in 67% of yield. The treatment of acyloin (+)-14 with Pb(OAc)₄ furnished the aldehyde (+)-15 with 80% of yield. The reduction of the aldehyde (+)-15 with NaBH₄ has again produced the lactone (+)-13.     

Synthesis of chiral oligopeptides by means of catalytic asymmetric hydrogenation of dehydropeptides

Asymmetric hydrogenations of Ac-ΔTyr(Ac)-(S)-Ala-Gly-OMe (6), Ac-ΔTyr(Ac)-(R)-AlaGly-(S)-Phe-OMe (7), Ac-ΔPhe-NH-CH(R) CH₂-OCH₂Ph (10), HCO-ΔPhe-(S)-Leu-OMe (16), X-AA-ΔPhe-AA'-OMe (5: X ^tBOC, CBZ, CF₃CO; AA, AA' = α-amino acid), and ^tBOC-AA-ΔPhe-AA'-NH-Y (21: Y=H, NH-AA'-ΔPhe-AA-^tBOC, NHPh), catalyzed by cationic Rh complexes, [L*Rh(NBD)]⁺ClO₄ (L* = chiral diphosphine), were performed to give the corresponding chiral oligopeptides with high stereoselectivities. It was found that the nature of the N-protecting group of dehydrotripeptides (5) exerted a significant influence on the asymmetric induction as well as catalyst efficiency. The chiral centers in AA' and AA' amino acid residues in 5 were also found to have some influence on the catalytic asymmetric induction. Possible mechanism which can accommodate these effects are discussed. Asymmetric reduction of RCOCO-AA-OMe (13) via hydrosilylation was carried out to give chiral depsipeptide units. The asymmetric hydrogenation of dehydropeptides was successfully applied to the synthesis of enkephalin analogs, Ac-(R)Tyr-(R) -Ala-Gly-(S)-Phe-(S)-Leu-OMe (23) and Ac-(S)Tyr-(R) -Ala-Gly-(S)-Phe-(S)- Leu-OMe (29)     

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.     

Chiral separation of racemic mandelic acids by use of an ionic liquid-mediated imprinted monolith with a metal ion as self-assembly pivot

A new chiral stationary phase based on molecularly imprinted polymers (MIP) was prepared in ionic liquid by use of the metal pivot concept. Imprinted monoliths were synthesized by use of a mixture of R-mandelic acid (template), 4-vinylpyridine, ethylene glycol dimethacrylate, and several metal ions as pivot between the template and functional monomer. A ternary mixture of dimethyl sulfoxide–dimethylformamide–[BMIM]BF₄ containing metal ions was used as the porogenic system. Separation of the enantiomers of rac-mandelic acid was successfully achieved on the MIP thus obtained, with resolution of 1.87, whereas no enantiomer separation was observed on the imprinted monolithic column in the absence of metal ions. The effects of polymerization conditions, including the nature of the metal ion and the ratios of template to metal ions and template to functional monomer, on the chiral separation of mandelic acid were investigated. The results reveal that use of metal ions as a pivot, in combination with ionic liquid, is an effective method for preparation of a highly efficient MIP stationary phase for chiral separation.

Synthesis of novel chiral lipophilic pyridyl-containing β-amino alcohol ligands and enantioselective hydrolysis of α-amino acid esters by chiral metallomicelles

Seven novel chiral lipophilic pyridyl-containing β-amino alcohol ligands have been synthesized by coupling of 6-alkoxymethyl-2-chloromethylpyridine 3 with the corresponding chiral β-amino alcohols or l-cysteine. Their metal ion complexes have been investigated as catalysts for the enantioselective hydrolysis of N-protected α-amino acid esters in aqueous comicellar solution. The results indicate that the hydrophobic interactions between substrate and metallocatalyst, the rigidity of the ligand, the hydroxyl group of the ligand acting as a nucleophile for the transacylation process, and the micellar microenvironment are important factors for the activity and enantioselectivity. Large rate accelerations (up to three orders of magnitude) and moderate enantioselectivities (up to 7.81 (k_R/k_S)) employing 4a–Cu²⁺ have been observed.     

The activation of C-H bonds in C<Subscript>1</Subscript>-C<Subscript>3</Subscript> alkanes by zirconium(III,IV) and titanium(III,IV) hydrides immobilized on the surface of SiO<Subscript>2</Subscript>: a density functional theory study

Model reactions of the (≡Si-O-)₃M^IVH (1), (≡Si-O-)₂M^IVH₂ (2), and (≡Si-O-)₂M^IIIH (3) hydrides, where M = Ti and Zr, immobilized on the surface of silica with methane and propane were studied by the density functional theory with the PBE functional. The reactions involved the breaking of C-H alkane bonds and the formation of the (≡Si-O-)₃MR, (≡Si-O-)₂M(H)R, and (≡Si-O-)₂MR products (R = Me, n-Pr, and i-Pr), respectively. Reactions with the participation of 1 and 2 were found to occur as bimolecular processes without the formation of agostic-type prereaction complexes. With 3, the reaction was accompanied by the formation of stable prereaction and postreaction complexes. The conclusion was drawn that dihydrides 2 and trivalent metal hydrides 3 were much more reactive with respect to alkane C-H bonds than monohydrides 1. All the systems studied were characterized by low reaction regioselectivities.     

Asymmetric addition of phenylboronic acid to cycloalkanones mediated by a Rh/phosphoramidite complex: a comparison between tropos versus nontropos behavior

Herein we report the asymmetric addition of phenylboronic acid to different cycloalkenones, mediated by a Rh(I) complex with the tropos phosphoramidite (S)-L₁ or the nontropos phosphoramidite (S)-L₂ ligand. Different values of enantiomeric purity of the 3-phenylcycloalkanone products have been obtained, mainly depending on the ring size of the substrates, with (S)-L₁ affording higher ee values than (S)-L₂. These results could be explained by reasoning that for the tropos phosphoramidite, a ‘chiral pocket’ is formed when the ligand links to the metal atom. By fitting in this pocket, the substrate can stereoselectively coordinate to the Rh(I) atom, undergoing attack of the phenyl ring from the phenylboronic acid to a preferred enantioface. This causes the high (up to 96%) values of enantioselectivity observed with some of the substrates. A ‘chiral pocket’ cannot be formed with the nontropos ligand (S)-L₂ and, as a consequence, the stereoselectivity is greatly reduced.     

Efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate,a useful intermediate for the synthesis of nociceptin antagonists

An efficient and practical asymmetric synthesis of 1-tert-butyl 3-methyl (3R,4R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1,3-dicarboxylate 1, a useful intermediate for the synthesis of nociceptin antagonists, has been developed. This method includes the following key steps: (1) diastereoselective reduction of a chiral enaminoester 3 having (R)-1-phenylethylamine as a chiral pool constituent with the use of a combined TFA–NaBH₄ reduction system and (2) efficient isomerization from 3,4-cis-substituted piperidine 8 to 3,4-trans-substituted piperidine 1 under basic conditions. The above methods proved to be applicable for large-scale operation and hundred grams of enantiomerically pure compound 1 (>98% ee) was obtained.