An approach to an asymmetric synthesis of stemofoline

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxododecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give (1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.     

Coordination behaviour in transition metal complexes of asymmetric NPN ligands

Two bicyclic, chiral aminophosphine ligands, namely 4R, 9R-1,3-bis(pyridin-2-ylmethyl)-2-(2-propyl)octahydro-1H-1,3,2-benzodiazaphosphole (1) and 4R, 9R-1,3-bis(pyridin-2-ylmethyl)-2-(2-ethoxy)octahydro-1H-1,3,2-benzodiazaphosphole (2) have been prepared from 1R, 2R-diaminocyclohexane and the appropriate dichlorophosphine and the nature of their coordination to a number of transition metals explored. Ligand 1 coordinates to Pd(II) and Pt(II) as a terdentate donor to give complexes of the type [M(κ³-N,P,N-1)Cl]⁺ whereas ligand 2 favours bidentate κ²-P,N coordination to give the complexes M(κ²-P,N-2)Cl₂. The study of the coordination chemistry of the NPN ligand 1 is frustrated by its ready decomposition to an unknown species which appears to be promoted by transition metals. The ligand 2 does not undergo such a transformation and its metal chemistry is more readily examined. Aside from the Pt(II) and Pd(II) complexes above, 2 has been coordinated to Cr(0) and Mo(0) in the octahedral complexes M(κ²-P,N-2)(CO)₄ and Au(I) in linear Au(κ¹-P-2)Cl. All the complexes have been fully characterised by spectroscopic and analytical techniques including a single-crystal X-ray structure analysis of [Pt(κ³-N,P,N-1)Cl]Cl, 3.     

Chirality changes in reactions of asymmetric molybdenum complexes

Optical rotatory dispersion and circular dichroism studies have allowed the determination of the changes in configuration at the molybdenum center upon displacement of carbonyl and iodide in neomenthylcyclopentadienyl—Mo(allyl)(NO)X systems. Displacement of carbonyl by iodide occurs with retention of configuration. Replacement of iodide with benzenesulfonate followed by replacement of the sulfonate with iodide occurs stereospecifically with net retention of configuration. In the case of cyclopentadienylMo(cyclooctenyl)(NO)I, the enantiomers were separated via a spontaneous resolution through crystallization of the complex in the space group P2₁2₁2₁. These studies have allowed the correlation not only of the absolute configuration at the metal center with CD studies, but also have established that a long wavelength optically active transition at approximately 400 nm can be correlated with endo-exo isomerism. Comparison of the rates of interconversion suggest that endo to exo isomerization occurs via a clockwise rotation of the allyl in the (R)-isomer. Crystallographic details: (—)-(S)-(NMCp)Mo(allyl)(NO)I crystallizes in the space group P2₁2₁2₁ with a 7.221(1), b 12.686(7), c 21.603(7) Å, Z = 4, V = 1979(2) ų; R₁ = 0.039, R₂ = 0.046; (—)-(S)-(Cp)Mo(cyclooctenyl)(NO)I crystallizes in the space group P2₁2₁2₁ with a 8.466(1), b 10.449(2), c 16.372(2) Å, Z = 4, V = 1448.3(6), R₁ = 0.038, and R₂ = 0.046.     

Titanium mediated asymmetric aldol reaction with α-fluoropropionimide enolates

Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl₄ have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivities. When (αR)- and (αS)-N-(α-fluoropropyl)-2-(4S)-oxazolidinones were explored as substrates they gave rise to identical aldol diastereoisomer products. Examination of the enolates formed in each case by ¹⁹F NMR, after treatment with TiCl₄, indicated that both preparations gave the same predominant enolate. This was assumed to be the E-enolate. The α-fluoro-β-hydroxy-aldol products were removed from the auxiliary either by alcoholysis or reduction and converted to the corresponding α,β-difluoro products by treatment with Deoxofluor™.     

2-Chlorotetrafluoroethanesulfinamide induced asymmetric vinylogous Mannich reaction

The generality of (S)-2-chlorotetrafluoroethanesulfinamide (CTFSA) induced asymmetric vinylogous Mannich (AVM) addition reaction has been investigated. The reaction of aldimines derived from (S)-CTFSA with 2-(tert-butyldimethylsilyloxy) furan (TBSOF) took place regioselectively at the γ-site at room temperature in DMSO under air atmosphere to give the desired addition products in syn-configuration with high diastereoselectivities (up to 98:2 dr). However, anti-configuration product as major isomer was obtained in the presence of tetra-butyl ammonium fluoride (TBAF) at −78 °C. Facile removal of the auxiliary group without epimerization demonstrated their synthetic potential for piperidone derivatives.     

Catalytic asymmetric transfer hydrogenation of ketones using terpene-based chiral β-amino alcohols

Catalytic asymmetric transfer hydrogenations of aromatic alkyl ketones have been studied using [RuCl₂(p-cymeme)]₂ and terpene-based β-amino alcohols. The limonene derived amino alcohol, (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(methylamino)cyclohexanol gave the most promising results. Chiral secondary alcohols were obtained in good to excellent yields and moderate enantioselectivities (up to 71%).     

First asymmetric synthesis of an acyclic β,β-dialkylated-γ-aminobutyric acid

Enantiomerically pure (R)-γ-amino-β-benzyl-β-methylbutyric acid, an acyclic β,β-dialkyl GABA derivative, is efficiently synthesised from (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate by a sequence based on benzylation, Arndt-Eistert homologation and nitrile reduction. Benzylation of (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl 2-cyanopropanoate using potassium carbonate under not strictly anhydrous conditions occurs diastereoselectively to afford (1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl (S)-2-cyano-2-methyl-3-phenylpropanoate, the key chiral intermediate from which the desired γ-amino acid is obtained in five steps in 65% overall yield.     

Optically active phenanthrolines in asymmetric catalysis. Rhodium-catalyzed asymmetric transfer hydrogenation of acetophenone

The catalyst formed in situ from [Rh(1,5-cyclooctadiene)Cl]₂ and (+)-(S)-3-s-butyl-1,10-phenanthroline promotes the asymmetric transfer hydrogenation of acetophenone in isopropanol solution; optical yields of up to 31% are obtained.     

Chiral N-heterocyclic carbenes as asymmetric acylation catalysts

Chiral N-heterocyclic carbenes are generated from C₂-symmetric 1,3-bis(1-arylethyl)imidazolium salts and potassium tert-butoxide. These C₂-symmetric imidazolidenyl carbenes catalyze enantioselective acylation of racemic secondary alcohols. The asymmetric acylation of 1-(1-naphthyl)ethanol was achieved in up to 68% ee of the acylated product, using (R,R)-1,3-bis[(1-naphthyl)ethyl]imidazolium tetrafluoroborate as a precursor of the chiral N-heterocyclic carbene and vinyl propionate as the acyl donor.     

Fine tuning of the structure of phosphine–phosphoramidites: application for rhodium-catalyzed asymmetric hydrogenations

Diastereomers of (4-(diphenylphosphino)pentan-2-yl)-N-isopropyl-{dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxa-phosphepin-2-yl}-4-amine, (S)-(2S,4S)-1, and (S)-(2R,4R)-3; the octahydro derivative 4 of (S)-(2S,4S)-1, and derivative 2 of (S)-(2S,4S)-1 containing a 1,3-propanediyl backbone, have been synthesized and used for rhodium-catalyzed asymmetric hydrogenations of prochiral olefins in order to study the role of the stereogenic elements in the backbone and in the terminal moiety. The central chirality in the bridge has been found to determine the configuration of the product with a cooperative effect from the terminal groups. Excellent ee’s (up to 99.9%) were obtained in the hydrogenation of methyl (Z)-α-acetamidocinnamate using a rhodium complex with the matched arrangement (S)-(2S,4S)-1. The hydrogenation is accomplished in a highly enantioselective manner by using green solvents such as propylene carbonate.     

Microwave-mediated ruthenium-catalyzed asymmetric hydrogen transfer

Ru-catalyzed hydrogen transfer from propan-2-ol to acetophenone under microwave conditions using monotosylated (R,R)-diphenylethylenediamine as the chiral source afforded (R)-1-phenylethanol in >90% yield and 82% e.e. within 9 min, while use of ephedrine or norephedrine gave the same compound in high yield with 70 and 46% e.e., respectively. t-Butylphenylketone was reduced to (R)-2,2-dimethyl-1-phenyl-1-propanol under the same conditions in close to quantitative yield, although with low enantioselectivity.     

First asymmetric synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine

The enantioselective synthesis of a C₂-symmetric 2-endo,6-endo-disubstituted bispidine (3,7-diazabicyclo[3.3.1]nonane) has been accomplished for the first time. The key step was a Michael addition of the protected β-amino ester methyl (R)-3-{N-benzyl-N-[(S)-1-phenylethyl]amino}-3-phenylpropionate to its α-methylene derivative delivering an anti,anti-configured α,α′-methylene-bridged bis(β-amino ester) as the major diastereomer. Deprotection, reduction and cyclisation furnished (1R,2R,5R,6R)-2,6-diphenyl-3,7-bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane in six steps and 15% overall yield.     

Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing (R)-β-amino butyric acid, (R)-β-amino pentanoic acid, (S)-β-leucine, (R)-β-amino octanoic acid, (S)-β-phenylalanine, (S)-β-tyrosine methyl ether, (S)-β-tyrosine hydrochloride and (S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products (R)-β-DOPA and (R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.     

High asymmetric induction using a diastereomeric mixture of axially dissymmetric ligands

We have reported that our new axially dissymmetric ligand with two chiral centers, (R_a)-2,2′-bis[(R)-1H-1-hydroxyperfluorooctyl]biphenyl ((R_a)-(R)₂-1c, or tentatively called as (R_a)-(R)₂-PFCAB-7), worked as a good asymmetric inducer for the reaction of benzaldehyde with diethylzinc. Now, a mixture of (R_a)-(R)₂- and (S_a)-(R)₂-PFCAB-7 even in 1:4 ratio (−60% de) was found to give nearly the same asymmetric induction as pure (R_a)-(R)₂-PFCAB-7 of the corresponding molar percents. This result suggests that both isomers do not form complex and that (R_a)-(R)₂-PFCAB-7 accelerates the reaction and induces high asymmetry, while (S_a)-(R)₂-1c does not accelerate the reaction significantly and does not induce asymmetry at all. This ligand of low ee, (R_a)-(R)₂-PFCAB-7 of 20% ee, did not show appreciable asymmetric amplification, suggesting no formation of heterochiral complex.     

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%.     

Rapid asymmetric synthesis of amino acids via NiII complexes based on new fluorine containing chiral auxiliaries

New fluorine-containing chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2-fluorobenzyl)-, (S)-N-(2-benzoylphenyl)-1-(3-fluorobenzyl)-, and (S)-N-(2-benzoylphenyl)-1-(4-fluorobenzyl)-pyrrolidine-2-carboxamide and their Ni^II complexes of Schiff bases with glycine and alanine have been synthesized. The greater efficiency of the complexes in terms of faster reaction rates and stereoselectivities in the asymmetric synthesis of (S)-α-amino acids has also been demonstrated.     

Lipase-catalyzed asymmetric acylation in the chemoenzymatic synthesis of furan-based alcohols

Eight racemic 1-(furan-2-yl)ethanols were prepared from the corresponding carbonyl compounds for enantioselective acylation studies, and seven of them were used in preparative-scale kinetic resolutions with Candida antarctica lipase B (Novozym 435) and vinyl acetate in dried diisopropyl ether. Mechanism-based competition between the (R)-acetate (enzymatic acylation product), vinyl acetate (added acylating reagent), and acetic acid (enzymatic hydrolysis product) toward CAL-B, together with the residual water of the lipase were shown to be potential reasons for side reactions, which affected the course of the kinetic resolution of 1-[5-(2-chlorophenyl) and (4-bromophenyl)furan-2-yl]ethanols. Clear effects were not observed with the other alcoholic substrates. Alcoholysis of the enantiomerically enriched (R)-acetates with methanol and CAL-B in diisopropyl ether was shown to be a potential method for the deprotection of the (R)-acetates and the formation of (R)-alcohols.     

Total,asymmetric synthesis of ethyl d-ido-4-heptulosuronate derivatives starting from diethyl 4-oxopimelate

Bromination of diethyl 4-oxopimelate, followed by double elimination of HBr and ketalization provided diethyl (E,E)-4,4-(ethylidenedioxy)hepta-2,5-dienedioate 4. Sharpless asymmetric dihydroxylation of 4 produced diethyl (2S,3S)-4,4-(ethylidenedioxy)-2,3-dihydroxyhept-5-enedioate (+)-5, with 78% e.e. The corresponding tetrol could not be obtained in one step. Silylation of (+)-5 and a second asymmetric dihydroxylation, followed by silylation led to 20% of meso-diester 9 and 60% of diethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)heptanedioate (−)-10. Reductive desymmetrization of (−)-10 with DIBAL-H furnished, after selective oxidation, ethyl (2S,3S,5S,6S)-2,3,5,6-tetrakis-[(t-butyl)dimethylsilyloxy]-4,4-(ethylidenedioxy)-7-oxoheptanoate (+)-13 which was then converted into ethyl 1,2,3,6-O-tetraacetyl-4,4-ethylidenedioxy-α- and β-d-ido-heptapyranuronate (−)-15α,β and into the corresponding 3-(α-d-pyranosyl)propene (−)-16.     

Chelation-controlled asymmetric aminohalogenation reaction

The chelation-controlled asymmetric aminohalogenation of α,β-unsaturated 3-aryl-N-acyl-N-4-phenyl-2-oxazolidinones have been established by using palladium(II) acetate as the catalyst and as the chelation metal. The reaction is very convenient to perform by simply mixing the three reactants, cinnamates, N,N-dichloro-p-toluenesulfonamide and catalyst together with 4 Å molecular sieves at rt in any convenient vial of appropriate size without special protection from inert gases. Unlike the previous asymmetric aminohalogenation, the ionic liquid, [BMIM][NTf₂], was found to be superior to [BMIM][BF₄] as the reaction media. It was also found that palladium(II) acetate has to be used together with 1 equiv of MeCN to achieve the opposite chelation control. The resulting absolute stereochemistry of the product was unambiguously determined by X-ray structural analysis.     

First asymmetric total synthesis of (+)-curcutetraol

The first asymmetric total synthesis of (+)-curcutetraol, a marine phenolic bisabolane-type sesquiterpene, was achieved in eight steps in ca. 50% overall yield. The chiral tertiary benzylic alcohol moiety in the o-position of a phenol was constructed in high optical yield (99% ee) by an asymmetric synthesis using a chiral aminal, (2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane.