Asymmetric Allylic Substitution Reactions with a Xylophos-Pd Catalyst

 The chiral diphosphine ligand xylophos (1) was tested as an auxiliary in palladium catalyzed allylic substitution reactions. Whereas its activity was found to be generally good only in the case of 1,3-diphenylprop-2-en-1-yl acetate, a fair level of asymmetric induction was achieved with sodium dimethyl malonate (83%ee) and benzylamine (66%ee) as nucleophiles.     

[1,2]-Wittig Rearrangement of Acetals III [1]. New 1,2-Alkoxyalcohols, 1,2-Alkoxyaminesand 1,2-Dialkoxy Compounds as Chiral Ligands for Organomagnesium and Organolithium Compounds and forLithium Aluminum Hydride

Summary.  Eight O-substituted 1,2-diols and one O,N-substituted 1,2-aminoalcohol derived from 2-alkoxyoctahydro-7,8,8-trimethyl-4,7-methanobenzofurans via a [1,2]-Witting rearrangement and subsequent substitution were synthesized and tested as additives for the enantioselective addition of butyllithium and butylmagnesium chloride to benzaldehyde and for the reduction of acetophenone with lithium aluminum hydride. The selectivity of the reactions was determined by GC of the obtained 1-phenyl-1-pentanol and 1-phenylethanol on a chiral phase. Best results with regard to selectivity (52% ee and 94% ee, resp.) were achieved in the formation of 1-phenyl-1-pentanol by addition of the substituted 1,2-aminoalcohol to the organometallic reagent and in the reduction of acetophenone using an α-alkoxyalcohol (62%ee). Received March 10, 2000. Accepted March 23, 2000     

Efficient resolution of (±)-pantolactone by inclusion crystallization with the use of chiral 1,1,2-triphenylethane-1,2-diol

Enantioselective formation of crystalline 1 : 1 host—guest complexes with (R)-or (S)-1,1,2-triphenylethane-1,2-diol as a host compound allows efficient preparative resolution of (±)-pantolactone. Optically active pantolactones (98%ee) were obtained in 65–67% yield. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1489–1490, August, 2000.     

Bacterial Biotransformation of Isoprene and Related Dienes

Summary.  The bacterium Pseudomonas putida ML 2 was used in the oxidative biodegradation of the acyclic dienes isoprene, trans-piperylene, cis-piperylene, and 1,3-butadiene. Regioselective dioxygenase-catalyzed dihydroxylation of alkenes yielded vicinal diols in the preferred sequence monosubstituted > cis-disubstituted > gem-disubstituted > trans-disubstituted. The isolated diol metabolites had an excess of the R configuration (9–97%ee), and further diol oxidation was controlled by addition of propylene glycol as an inhibitor. Stereoselectivity using the ML2 strain resulted from both enzymatic asymmetric alkene dihydroxylation and kinetic resolution of diols. Enantioselective oxidation of the allylic secondary alcohol group of R configuration yielded the corresponding unsaturated ketoalcohol; the residual diol was recovered with a large excess (≥ 93%ee) of the S configuration. In addition to the enzymatic diene oxidation steps yielding unsaturated diols and ketoalcohols, evidence was also found of enzymatic alkene hydrogenation to yield saturated ketoalcohols and diols. Received December 20, 1999. Accepted (revised) February 7, 2000     

Proline-catalysed asymmetric ketol cyclizations: The template mechanism revisited

A modified template mechanism based on modelling studies of energy minimised complexes is presented for the asymmetric proline-catalysed cyclization of triketones1,2 and3 to the 2S,3S-ketols1a,2a and3a respectively. The template model involves a three-point contact as favoured in enzyme-substrate interactions. Our minimisation studies are in agreement with the divergent behaviour of the 6,5-, 6,6-and 6,7-bicyclic systems. They support the high 93.4%ee observed with the 6,5-bicyclic ketol and the lower 73%ee found with the 6,6-bicyclic ketol. The calculations also explain the lack of asymmetric induction with the 6,7-bicyclic system     

Pseudomonas sp. Lipase Immobilized on Magnetic Porous Polymer Microspheres as an Effective and Recyclable Biocatalyst for Resolution of Allylic Alcohols

Magnetic porous polymeric microspheres containing epoxy groups were prepared by suspension polymerization (denoted as magnetic Fe₃O₄@GEM microspheres). Fe₃O₄@GEM with a specific surface area of 30.41 m²/g, average pore diameter of 17.13 nm, and pore volume of 0.13 cm³/g exhibited superparamagnetic behavior with the saturation magnetization of 7.1 emu/g. The content of epoxy groups on Fe₃O₄@GEM was 0.22 mmol/g. Pseudomonas sp. lipase (PSL) was covalently immobilized onto the Fe₃O₄@GEM microspheres through the reaction between the amino groups of the enzyme and the epoxy groups on the microspheres. PSL/Fe₃O₄@GEM exhibited enhanced enantioselectivity for the resolution of allylic alcohol to the corresponding optically active (S)‐allylic alcohol and (R)‐allylic alcohol acetate compared to free PSL. The enantiomeric excess of (S)‐l‐pheny‐2‐propen‐1‐ol for the former (98.1%) was 81.7 times that of the latter (1.2%) when the immobilized PSL was used for transesterification resolution of (R,S)‐l‐pheny‐2‐propen‐1‐ol. Furthermore, the ee_s and ee_p values were still retained at 95.2% and 95.4% after PSL/Fe₃O₄@GEM was recycled 10 times, indicating that PSL/Fe₃O₄@GEM had very good reusability. In addition, the transesterification resolution of (R,S)‐1‐(4‐methylphenyl)‐2‐propen‐1‐ol and (R,S)‐1‐(4‐bromophenyl)‐2‐propen‐1‐ol was catalyzed by PSL/Fe₃O₄@GEM, affording ideal ee_s and ee_p values of 99.3%, 97.4% and 99.6%, 98.2%, respectively. Therefore, PSL/Fe₃O₄@GEM demonstrated its potential as a highly efficient enzymatic reactor and Fe₃O₄@GEM would be very promising carriers for immobilizing enzymes in industrial application.     

Enantioselective Catalysis CXLI [1]. Tridentate Ligands with 1-(Pyridin-2-yl)ethylamine as Chiral Building Block in the Enantioselective Transfer Hydrogenation of Acetophenone

Summary.  A series of novel tridentate ligands with nitrogen and oxygen donor sites was synthesized starting from enantiomerically pure (S)- and (R)-1-(pyridin-2-yl)ethylamine, the preparation and resolution of which was developed. The new optically active ligands were tested as in situ catalysts together with Ru(PPh₃)₃Cl₂ in the enantioselective transfer hydrogenation of acetophenone with isopropanol. The secondary amine ligand (S)-2,4-di-tert-butyl-6-(1-(pyridin-2-yl)ethylamino)methylphenol gave the best results with almost quantitative conversion and 47%ee. Received August 17, 2001. Accepted August 27, 2001     

Regioselective Isomerisation of Highly Substituted 1-Methylenecyclohexenepoxides to the Corresponding Allylic Alcohols. Influence of the Base and of the Protecting Groups

Summary. Highly substituted 1-methylenecyclohexenepoxides 3, useful building blocks for a projected synthesis of wailupemycin A (1), were synthesized from (R)-carvone in eight synthetic steps in 23–40% overall yield. The regioselectivity of the subsequent isomerisation to the corresponding allylic alcohols was shown to depend on the basicity of the reagent and on the bulkiness of the protecting groups existing in 3. With diethylaluminum 2,2,6,6-tetramethylpiperidid (DATMP), secondary allylic alcohols 5 were formed exclusively. With strong bases such as a mixture of lithium di-iso-propylamide and potassium tert-butoxide (LIDAKOR), the tertiary allylic alcohol 6 was obtained as predominant product.To whom inquiries about the X-ray analysis should be addressed     

A chemo-enzymatic approach to optically active 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols

With a view to obtaining both enantiomers of 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols, (R)-1 and (S)-1, from the respective racemate, (±)-1, the hydrolysis of its acetate, (±)-2, in the presence of porcine pancreatic lipase (PPL) has been studied. The optical puriry of (R)-1 and (S)-1 thus obtained was unsatisfactory (ee 22–27%), and could not be increased beyondee 33% by repeated enzymatic hydrolysis of the unconverted fraction of the acetate. In contrast with this, the biohydrogenation of 3-(4-methoxycarbonyl)phenyl-2-methyl-2-propen-1-ol (4) with fermentingSaccharomyces cerevisiae afforded (S)-1 of considerably higher optical purity (ee 41–90 %, depending on the strain). The stereochemical correlation of the products obtained in the two biochemical processes under study shows that the PPL-catalyzed hydrolysis of (±)-2 produces preferably (R)-1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 761–766, April, 1995.The authors express their gratitude to the Russian Foundation for Basic Research for financial support (Grant No. 93-03-5893).     

Enantioselective Homogeneous Hydrogenation of Monosubstituted Pyridines and Furans

Summary.  The first case of an enantioselective hydrogenation of monosubstituted pyridines and furans with homogeneous rhodium diphosphine catalysts with low but significant enantioselectivities and catalyst activities is reported. Best enantioselectivities (ees of 24–27%) were obtained for the hydrogenation of 2- and 3-pyridine carboxylic acid ethyl ester and 2-furan carboxylic acid with catalysts prepared in situ from [Rh(nbd)₂]BF₄ and the chiral ligands diop, binap, or ferrocenyl diphosphines of the josiphos type. Turnover numbers (ton) were in the order of 10–20, turnover frequencies (tof) usually 1–2 h⁻¹. Diphosphines giving 6- or 7-ring chelates led to higher ees than 1,2-diphosphines; otherwise, no clear correlation between ligand properties and catalytic performance was found. In some experiments black precipitates were observed at the end of the reaction, indicating the decomposition of the homogeneous catalysts for certain ligand/metal/substrate combinations. Received April 5, 2000. Accepted (revised) May 2, 2000     

Enantioselective catalysis,C. Decarboxylation of malonic acids in the presence of copper(I) compounds — Not a copper(I) catalysis but a base effect

Summary The catalytic decarboxylation of malonic acids, claimed to be catalyzed by copper(I) compounds, has been investigated. Decarboxylation of different malonic acid derivatives (1–5) in acetonitrile was far more effective with Cu₂O than with CuCl. Thus, the decarboxylation is obviously influenced by the basicity of the anion. In the decarboxylation of phenylmalonic acid (3),bis(tricyclohexylphosphane)copper(I) hydrogenphenylmalonate (6) and potassium hydrogenphenylmalonate (7) show nearly identical rate constants. It is concluded that the monoanions of the malonic acid derivatives are the reactive species undergoing decarboxylation. Further experiments are presented which demonstrate that everything that increases the concentration of the monoanions also increases the rate of decarboxylation. In the enantioselective decarboxylation of the monoethyl ester of methylphenylmalonic acid (2), the enantiomeric excess of (S)-(+)-ethyl 2-phenylpropionate could be raised to 34.5%ee using the alkaloid cinchonine.Dedicated to Prof. Dr.J. Müller on the occasion of his 60^th birthday.     

Enantioselective Sulfoxidations Catalyzedby Horseradish Peroxidase, ManganesePeroxidase, and Myeloperoxidase

Summary.  Horseradish peroxidase (HRP), myeloperoxidase (MPO), and manganese peroxidase (MnP) have been shown to catalyze the asymmetric sulfoxidation of thioanisole. When H₂O₂ was added stepwise to MPO, a maximal yield of 78% was obtained at pH 5 (ee 23%), whereas an optimum in the enantiomeric excess (32%, (R)-sulfoxide) was found at pH 6 (60% yield). For MnP a yield of 18% and a high enantiomeric excess of 91% of the (S)-sulfoxide were obtained at pH 5 and a yield of 36% and an ee of 87% at pH 7.0. Optimization of the conversion catalyzed by horseradish peroxidase at pH 7.0 by controlled continuous addition of hydrogen peroxide during turnover and monitoring the presence of native enzyme as well as of intermediates I, II, and III led to the formation of the sulfoxide in high yield (100%) and moderate enantioselectivity (60%, (S)-sulfoxide). Received November 18, 1999. Accepted January 21, 2000     

Asymmetric aldol condensation in an ionic liquid-water system catalyzed by (<Emphasis Type="Italic">S</Emphasis>)-prolinamide derivatives.

Asymmetric aldol reaction of unmodified aldehydes with ketones catalyzed by 1(R),2(R)-bis((S)-prolinamido)cyclohexane (1) or (Rax)-2,2′-bis((S)-prolinamido)-1,1′-binaphtyl (2) proceeds with high yield (68–99%) and diastereoselectivity (dr ≥ 75/25) in the system (1-butyl-3-methylimida-zolium) tetrafluoroborate ([bmim][BF₄])-water. The dependence of ee of the dominating anti-diastereomer of aldol on the percentage of water has a maximum at 50 vol.%. Catalyst 1 can be recycled 5 times without losses in the aldol yield, dr and ee. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 578–581, March, 2008.     

Synthesis of methyl-α-<Emphasis Type="SmallCaps">d</Emphasis>-glucopyranoside-based azacrown ethers and their application in enantioselective reactions

New chiral monoaza-15-crown-5 compounds anellated to methyl-4,6-O-(1-naphthyl)methylene-α-d-glucopyranoside (2a–2b), to methyl-4,6-O-isopropylidene-α-d-glucopyranoside (3a–3b) and to methyl-α-d-glucopyranoside (4a–4b) have been synthesized. Several representatives of these crown ethers showed significant asymmetric induction as chiral phase transfer catalysts, among them 2a proved to be the most efficient one inducing 90% ee in the Michael addition of 2-nitropropane to chalcone, 48% ee in the Darzens condensation of phenacyl-chloride with benzaldehyde and 89% ee in the epoxidation of chalcone with tert-butyl hydroperoxide. The catalytic results were compared with those obtained earlier with macrocycles 1a–1b incorporating a 4,6-O- benzylidene protecting moiety. It occurred that the enantioselectivity is influenced to a great extent by the substituents on the C(4) and C(6) atoms of the monosaccharide. Lower enantioselectivities were obtained in the reactions of the chalcone analogues in the presence of catalyst 2a than in the case of the proper chalcone. Correspondence: Péter Bakó, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, P.O. Box 91, Hungary.     

Lipase-mediated deracemization of secondary 1-phenyl-substituted propargylic alcohols of different topology

Acetylation of (±)-1-phenylnon-2-yn-1-ol, (±)-1-phenylhept-1-yn-3-ol, and (±)-1-phenylundec-4-yn-3-ol ((±)-5) in the presence of lipase from Candida cylindracea (CCL) proceeds slowly to give products with ee 20%. The acetates of these alcohols are hydrolyzed in the presence of porcine pancreatic lipase (PPL) equally unsatisfactorily. The (⁶-arene)tricarbonylchromium complex of alcohol (±)-5 is acetylated in the presence of CCL up to 22% conversion to give (R)-acetate whose oxidative decomplexation followed by saponification results in alcohol (R)-(–)-5 with ee 95%. The configuration of alcohols (–)-5 and (+)-5 was determined by NMR spectroscopy of their esters with (R)- and (S)-Mosher"s acids.     

Chemoenzymatic Synthesis of Stannylated Metomidate as a Precursor for Electrophilic Radiohalogenations – Regioselective Alkylation of Methyl 1<Emphasis Type="Italic">H</Emphasis>-Imidazole-5-carboxylate [1]

Summary. Metomidate (ee 99%) substituted with iodine in the phenyl ring was prepared from (S)-1-(4-iodophenyl)ethanol (ee >98%) obtained by lipase-catalysed resolution and methyl 1H-imidazole- 5-carboxylate. The two fragments were joined highly regioselectively (alkylation only at N-1 of substituted imidazole) with inversion of configuration using the Mitsunobu reaction. Finally, p-iodometomidate was transformed into the p-trimethylstannyl derivative.     

[1,2]-Wittig Rearrangement of Acetals III [1]. New 1,2-Alkoxyalcohols, 1,2-Alkoxyaminesand 1,2-Dialkoxy Compounds as Chiral Ligands for Organomagnesium and Organolithium Compounds and forLithium Aluminum Hydride

 Eight O-substituted 1,2-diols and one O,N-substituted 1,2-aminoalcohol derived from 2-alkoxyoctahydro-7,8,8-trimethyl-4,7-methanobenzofurans via a [1,2]-Witting rearrangement and subsequent substitution were synthesized and tested as additives for the enantioselective addition of butyllithium and butylmagnesium chloride to benzaldehyde and for the reduction of acetophenone with lithium aluminum hydride. The selectivity of the reactions was determined by GC of the obtained 1-phenyl-1-pentanol and 1-phenylethanol on a chiral phase. Best results with regard to selectivity (52% ee and 94% ee, resp.) were achieved in the formation of 1-phenyl-1-pentanol by addition of the substituted 1,2-aminoalcohol to the organometallic reagent and in the reduction of acetophenone using an α-alkoxyalcohol (62%ee).     

Photochemical Deracemization of Allenes and Subsequent Chirality Transfer

Trisubstituted allenes with a 3‐(1′‐alkenylidene)‐pyrrolidin‐2‐one motif were successfully deracemized (13 examples, 86–98 % ee) employing visible light (λ=420 nm) and a chiral triplet sensitizer as the catalyst (2.5 mol %). The photocatalyst likely operates by selective recognition of one allene enantiomer via hydrogen bonds and by a triplet‐sensitized racemization process. Even a tetrasubstituted allene (45 % ee) and a seven‐membered 3‐(1′‐alkenylidene)‐azepan‐2‐one (62 % ee) could be enantiomerically enriched under the chosen conditions. It was shown that the axial chirality of the allenes can be converted into point chirality by a Diels–Alder (94–97 % ee) or a bromination reaction (91 % ee). Ring opening of the five‐membered pyrrolidin‐2‐one was achieved without significantly compromising the integrity of the chirality axis (92 % ee).     

Bacterial Biotransformation of Isoprene and Related Dienes

 The bacterium Pseudomonas putida ML 2 was used in the oxidative biodegradation of the acyclic dienes isoprene, trans-piperylene, cis-piperylene, and 1,3-butadiene. Regioselective dioxygenase-catalyzed dihydroxylation of alkenes yielded vicinal diols in the preferred sequence monosubstituted > cis-disubstituted > gem-disubstituted > trans-disubstituted. The isolated diol metabolites had an excess of the R configuration (9–97%ee), and further diol oxidation was controlled by addition of propylene glycol as an inhibitor. Stereoselectivity using the ML2 strain resulted from both enzymatic asymmetric alkene dihydroxylation and kinetic resolution of diols. Enantioselective oxidation of the allylic secondary alcohol group of R configuration yielded the corresponding unsaturated ketoalcohol; the residual diol was recovered with a large excess (≥ 93%ee) of the S configuration. In addition to the enzymatic diene oxidation steps yielding unsaturated diols and ketoalcohols, evidence was also found of enzymatic alkene hydrogenation to yield saturated ketoalcohols and diols.     

Ultrafast Iron‐Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines,Oxaheterocycles, and Aminoalcohols

A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h^?1 at ?30 °C highlight the activity of this earth‐abundant metal catalyst which tolerates a large number of functional groups.