Chiral Methyl Research Articles

ChemInform Abstract: Concerning the Diastereofacial Selectivity of Aldol Reactions of Chiral Methyl Ketone Enolates: Evidence for Remote Chelation in the Bafilomycin Aldol Reaction.

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Biocatalytic reduction system for the production of chiral methyl (R)/(S)-4-bromo-3-hydroxybutyrate

An effective method for producing methyl 4-bromo-3-hydroxybutyrate enantiomers was developed using an engineered protein. Escherichia coli transformant cells containing a mutant β-keto ester reductase (KER-L54Q) from Penicillium citrinum and a cofactor-regeneration enzyme such as glucose dehydrogenase (GDH) or Leifsonia sp. alcohol dehydrogenase (LSADH) were used to produce methyl (S)-4-bromo-3-hydroxybutyrate from methyl 4-bromo-3-oxobutyrate. On the other hand, the production of methyl (R)-4-bromo-3-hydroxybutyrate was achieved by asymmetric reduction of methyl 4-bromo-3-oxobutyrate with a mutant phenylacetaldehyde reductase (PAR-HAR1) from Rhodococcus sp. ST-10.

Conjugate addition of amines to chiral 3-aziridin-2-yl-acrylates

Conjugate addition of benzylamine to chiral methyl cis-3-aziridin-2-yl-acrylates was successfully proceeded to yield 3-aziridin-2-yl-3-benzylaminopropionates in high yield with high stereoselectivity. The addition products were used for the asymmetric synthesis of vicinal diamine derivatives including 4-amino-5-methylpyrrolidin-2-one, 3,4-diaminopentanoate, and 5-chloromethyl-4-alkoxycarbonylmethylimidazolidin-2-one.

Asymmetric Conjugate Addition of Crotylstannane: Synthesis of (-)-Lasiol

Lasiol, the major component of the mandibular gland secretion, serves as the primary sex attractant of the male ant, Lasius meridionalis. Our interest in lasiol stems from the stereochemistry of the chiral methyl substituents and the synthetic challenges posed by this common structural motif. As such, an asymmetric 1,4-conjugate addition of an allylic stannane to produce the 1,2-anti-dimethyl arrangement with high stereocontrol has resulted in the synthesis of (-)-lasiol.

Crystal structures of crown ethers containing an alkyl diarylphosphinate or a diarylphosphinic acid unit

This paper describes the structures of pseudo-18-crown-6 compounds (2, R,R-4 and 5) in the crystals together with theoretical calculations of the electronic circular dichroism (ECD) spectra. The achiral macrocyclic phosphinic acid 5 forms hydrogen-bonded dimers in the crystal. The O1–O2 distance (2.489 Ǻ) indicates strong H-bondings. The conformations of the macrorings of the achiral phosphinate 2 and the monomers of the achiral phosphinic acid 5 are chiral. A comparison of the torsion angles of the achiral methyl phosphinate 2 and the monomeric units of achiral 5 indicates a similar geometry. The torsion angles of the chiral methyl phosphinate (R,R)-4 differ more significantly from those in achiral methyl phosphinate 2. A negative 1Bb exciton couplet was observed in the ECD spectrum of monomeric (R,R)-6 in MeOH and H2O as in the spectra of (R,R)-4 in all solvents. To support the idea that (R,R)-4 has basically the same conformation in the crystal and in solution, the ECD spectrum of (R,R)-4 was calculated using the geometry of the molecule in the crystal. The calculated ECD spectrum shows a reasonable agreement with the ECD spectra obtained in solution. This shows that the steric structure observed in the crystal is predominant in solution as well.

Chiral sulfoxides as activators of allyl trichlorosilanes in the stereoselective allylation of aldehydes

Chiral aryl methyl sulfoxides proved to be efficient activators in the asymmetric allylation of aldehydes with allyl trichlorosilanes. High enantioselectivity was found in the case of electron-poor aldehydes. The high levels of diastereoselectivity and the detection of nonlinear effects have allowed the elucidation of some mechanistic aspects of the reaction.

Core chirality based tailoring of the liquid crystalline properties of supermolecular tetrapedes

A series of novel supermolecular star-shaped tetrapede chiral liquid crystals (LCs), incorporating carbohydrates, methyl α-D-glucopyranoside or methyl α-D-mannopyranoside, as chiral cores surrounded by four cyanobiphenyl mesogenic groups linked by either C6 or C11 alkyl chain spacers, have been synthesised. These non-conventional thermotropic carbohydrate-based chiral liquid crystals exhibit chiral nematic and smectic A mesophases over broad temperature ranges. The mesomorphic properties were characterized by polarized optical microscopy (POM) and differential scanning calorimetry (DSC). The effect of the flexible spacer length in addition to the stereogenic and conformational properties of the chiral cores is discussed.

1,4- syn-Asymmetric induction in the titanium-mediated aldol reactions of chiral methyl α-silyloxy ketones

Good levels of 1,4- syn asymmetric induction are obtained in the TiCl 4-mediated aldol reaction of methyl α-silyloxy ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient syntheses of natural products.

The Chiral Auxiliary N-1-(1′-Naphthyl)ethyl-O-tert-butylhydroxylamine: A Chiral Weinreb Amide Equivalent

The chiral auxiliary N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine is readily prepared from N-hydroxyphthalimide in four steps, with resolution giving access to both enantiomers in > 98% ee, on a multigram (> 25 g) scale. Conversion to a range of N-acyl derivatives, followed by highly diastereoselective alkylation (> or = 94% de) gives the corresponding chiral, 2-substituted derivatives as single diastereoisomers (> 98% de) after chromatography. Reductive cleavage with LiAlH(4) allows direct access to chiral aldehydes, and treatment with MeLi gives chiral methyl ketones in excellent enantiopurity (> or = 94% ee). The auxiliary can be recovered in > 98% ee and recycled.

Stereochemistry of Intermolecular Oxypalladation: PdII-Catalyzed 1,3-Chirality Transfer Reaction of Chiral Allylic Alcohol with Methanol

The intermolecular oxypalladation of chiral nonracemic allylic alcohols (S)-1, (R)-1, and (R)-3 in methanol gave chiral nonracemic methyl allyl ethers (S)-2 and/or (R)-2 with excellent selectivity. The reaction induced the 1,3-chirality transfer to give syn-S(N)2' product exclusively through syn oxypalladation. On the other hand, the anti-S(N)2' product was produced in 20-33% in THF, toluene, and CH2Cl2 and predominantly in CH3CN. The pi-olefin-Pd complexes I and II are proposed as important intermediates to explain the syn- and anti-oxypalladation pathways. The byproduct 9 was formed through the second syn-oxypalladation from the methyl allyl ether 2, though the rate of this second reaction was far slower than that of allylic alcohol.

Diastereoselective Synthesis of Chiral Tertiary Methyl Ethers

An auxiliary-based synthesis of chiral tertiary methyl ethers 3 through addition of titanium enolates to dialkyl ketals is reported. The products, obtained in good yields and moderate selectivities, are densely functionalized and constitute an important class of chiral synthons. The motif is difficult to obtain through aldol condensation owing to the low reactivity of ketones; however, examples can be found utilizing chiral auxiliaries (P. C. Bulman Page and co-workers J. Org. Chem. 2000, 65, 6027) or chiral catalysts (M. Shibasaki and co-workers J. Am. Chem. Soc. 2006, 128, 7164). Reductive aldol reactions have also been applied (O. Riant and co-workers Angew. Chem. Int. Ed. 2006, 45, 1292).

Investigation of lipase-catalyzed Michael-type carbon–carbon bond formations

Conjugate additions of carbon nucleophiles to appropriate acceptor molecules were investigated with respect to the synthetic potential and stereochemistry of the products. Reactions of short-chain α,β-unsaturated ketones and mono-substituted nitroalkenes with CH-acidic carboxylic ester derivatives were catalyzed by various immobilized lipases. Using methyl nitroacetate complete conversion with methyl vinyl ketone and trans-β-nitrostyrene was obtained. The reactions proceeded without enantioselectivity. Evidence for enzyme catalysis is provided by the observation that after denaturation of Candida antarctica lipase B or inhibition no reaction took place. Docking studies with the chiral addition product methyl 2-methyl-2-nitro-5-oxohexanoate did not reveal any specific binding mode for this reaction product, which would have been the requirement for stereoselective additions. These results support the experimental findings that the conjugate addition takes place without enantiopreference.

Syntheses and structural analyses of chiral rhenium containing amines of the formula (η 5-C 5H 5)Re(NO)(PPh 3)((CH 2) nNRR′) ( n = 0, 1)

The reaction of the racemic chiral methyl complex (η 5-C 5H 5)Re(NO)(PPh 3)(CH 3) ( 1) with CF 3SO 3H and then NH 2CH 2C 6H 5 gives [(η 5-C 5H 5)Re(NO)(PPh 3)(NH 2CH 2C 6H 5)] + CF 3 SO 3 - ([ 4a-H] + CF 3 SO 3 - ; 73%), and deprotonation with t-BuOK affords the amido complex (η 5-C 5H 5)Re(NO)(PPh 3)(NHCH 2C 6H 5) (76%). Reactions of 1 with Ph 3C + X − and then primary or secondary amines give [(η 5-C 5H 5)Re(NO)(PPh 3)(CH 2NHRR′)] + X − ([ 6-H] + X −; R/R′/X = a, H/NH 2CH 2C 6H 5/BF 4; a′, H/NH 2CH 2C 6H 5/PF 6; b, H/NH 2CH 2(CH 2) 2CH 3/PF 6; c, H/( S)-NH 2CH(CH 3)C 6H 5/BF 4); d, CH 2CH 3/CH 2CH 3/PF 6; e, CH 2(CH 2) 2CH 3/CH 2(CH 2) 2CH 3/PF 6; f, CH 2C 6H 5/CH 2C 6H 5/PF 6; g, -CH 2(CH 2) 2CH 2-/PF 6; h, –CH 2(CH 2) 3CH 2–/PF 6; i, CH 3/CH 2CH 2OH/PF 6 (62–99%). Deprotonations with t-BuOK afford the amines (η 5-C 5H 5)Re(NO)(PPh 3)(CH 2NRR′) ( 6a– i; 99–40%), which are more stable and isolated in analytically pure form when R ≠ H. Enantiopure 1 is used to prepare ( R Re S C)-[ 6c-H] + BF 4 - , ( R Re S C)- 6c, ( S)-[ 6g-H] + PF 6 - , and ( S)- 6g. The crystal structures of [ 4a-H] + CF 3 SO 3 - , a previously prepared NH 2CH 2Si(CH 3) 3 analog, [ 6a′, d, f, h-H] + PF 6 - , ( R Re S C)- 6c, and 6f are determined and analyzed in detail, particularly with respect to cation/anion hydrogen bonding and conformation. In contrast to analogous rhenium containing phosphines, 6a– i show poor activities in reactions that are catalyzed by organic amines.

Asymmetrically Substituted Benzene‐1,3,5‐tricarboxamides: Self‐Assembly and Odd–Even Effects in the Solid State and in Dilute Solution

Molecular organization: Chiral benzene tricarboxamides with methyl substituents at defined positions self-assemble into supramolecular polymers of preferred helicity by three-fold alpha-helical-type hydrogen bonding. The odd-even effect is operative and all derivatives are liquid crystalline showing a Col(ho) phase (see figure).Asymmetric benzene-1,3,5-tricarboxamides (aBTAs) comprising two n-octyl and one chiral methyl-alkyl side chain were synthesised and characterised. The influence of the position and the configuration of the chiral methyl group (methyl at the alpha, beta or gamma position) in the aliphatic side chains on the liquid-crystalline properties and the aggregation behaviour of the aBTAs was systematically studied and compared to symmetrical benzene-1,3,5-tricarboxamides (sBTAs). Solid-state characterisation (polarised optical microscopy, IR spectroscopy, X-ray diffraction and differential scanning calorimetry) revealed that all aBTAs show threefold, alpha-helical-type intermolecular hydrogen bonding between neighbouring molecules and exhibit a columnar hexagonal organisation from room temperature to well above 200 degrees C. Moving the chiral methyl group closer to the amide group stabilises the liquid-crystalline state, as evidenced by a higher clearing temperature and corresponding enthalpy. The self-assembly of dilute solutions of the aBTAs in methylcyclohexane ( approximately 10(-5) mol L(-1)) was investigated with circular dichroism (CD) spectroscopy. The sign of the Cotton effect demonstrated a pronounced odd-even effect, whereas the value of the molar ellipticity, Deltaepsilon, in the aBTAs was independent of the position of the methyl group. Subsequent temperature-dependent CD measurements showed that the aggregation of all aBTAs can quantitatively be described by the nucleation-growth model and that the stability of the aggregates increases when the chiral methyl group is closer to the amide moiety. The results presented herein illustrate that even small changes in the molecular structure of substituted benzene-1,3,5-tri-carboxamides affect their solid-state properties and their self-assembly behaviour in dilute solutions.

Neutral and cationic aluminium complexes containing a chiral (OSSO)-type bis(phenolato) ligand: synthesis, structures and polymerization activity

Reaction of trimethylaluminium with the linked bis(phenol) trans-1,4-dithiocyclohexanediyl-2,2-bis(4,6-di-tert-butylphenol) (cydtbpH2, 1a) led to the chiral methyl aluminium complex [Al(cydtbp)Me] (2a) as both racemate and resolved enantiomers, which were characterized by multinuclear NMR spectroscopy and elemental analysis. Rac-{trans-1,2-dithiocyclohexanediyl-2,2-bis(6-tert-butyl-4-methylphenol)} (cytbmpH2, rac-1b) similarly gave rac-2b. Single-crystal X-ray diffraction of (S,S)-2a and rac-2b showed a strongly distorted trigonal bipyramidal geometry with significantly differing Al-S distances. Reaction of rac-2b with (-)-borneol gave the alkoxy complex 5 as a mixture of two diastereomers. Methyl abstraction from the neutral metal complex rac-2a using B(C6F5)3 gave the cationic complex [rac-Al(cydtbp)(THF)2]+[MeB(C6F5)3]- (rac-6 x (THF)2) that according to X-ray crystallography adopts an octahedral coordination geometry. Upon reacting trimethylaluminium with a bis(phenol) with a longer link, 3,4-trans-butanediyl-1,6-dithiahexanediyl)-2,2-bis(6-tert-butyl-4-methylphenol), (cmtbmpH2, 3, a dinuclear compound 4 was obtained that contains two square pyramidal aluminium centers with two "fly-over" bis(phenolate) ligands. The neutral methyl aluminium complexes are active in the polymerization of methyl methacrylate (MMA) and in the ring-polymerization of rac-lactide (LA), producing PMMAs and PLAs in a controlled fashion. The cationic aluminium complexes were active in the cationic polymerization of isoprene and benzofuran.

Biosynthesis of chiral methyl ketone cyanohydrins catalyzed by oxynitrilase in Chaenomeles speciosa seed meal

The oxynitrilase in Chaenomeles Speciosa seed meal was used as the biocatalyst to synthesize a series of chiral methyl ketone cyanohydrins with satisfactory conversion and conspicuous enantiomeric excess. The optimized reaction conditions including the organic solvent, the ratio of biphasic solvents as well as the pH of the reaction system were investigated.

Chemo- and Enantioselective Routes to Chiral Fluorinated Hydroxyketones Using Ketoreductases

Chiral fluorinated hydroxyketones were synthesized with excellent ee (>98%) and yield by a chemo- and stereoselective reduction of prochiral methyl/trifluoromethyl diketones using commercially available ketoreductase enzymes. By using p- and m-trifluoroacetyl substituted acetophenones, we demonstrate that ketoreductases can selectively differentiate between methyl and trifluoromethyl ketones within the same molecule. As a result, useful catalysts were identified that eliminated the need for costly and time-consuming protection/deprotection of the ketone moiety, enabling a more convergent synthesis of hydroxyketones. Further, a route to chiral methyl hydroxyketones is provided where an enzyme selectively reduces the unactivated ketone.

Diastereoselective Synthesis of Chiral Methyl 2-Piperidin-2-ylpropanoates.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

A New Method for Efficient Coupling of Indole and Epoxide Catalyzed with Yb(OTf)3, and Application to the Total Synthesis of Kurasoin B

The Yb(OTf) 3 catalyzed reaction between indole and epoxide in simple and mild condition was developed. This method is suitable for gram-scale synthesis of 3-indolelactic acid derivatives. The asymmetric synthesis of kurasoin B was achieved using chiral 3-indolelactic acid methyl ester as the starting material.

Diastereoselective Synthesis of Chiral Methyl 2-Piperidin-2-ylpropanoates

We report the synthesis of methyl (25,2'R)-2-piperidin-2-ylpropanoate by the diastereoselect ion of the tetrasubtituted double bond of piperidine β-enamino ester (1)ive reduct.