The synthesis of β-lactams via a one-pot Reformatsky reaction of imines promoted by Zn/Cp2TiCl2 (cat.)

In the presence of Zn/Cp₂TiCl₂ (cat.) α-bromoacetates, γ-bromocrotonates or α-bromomethylacrylates react with imines in one-pot to form β-lactams, 3-vinyl-β-lactams or α-methylene-γ-lactams, respectively, at room temperature without the need for pretreatment of the solvent and Zn.     

Alkylative Carboxylation of Ynamides and Allenamides with Functionalized Alkylzinc Halides and Carbon Dioxide by a Copper Catalyst

The alkylative carboxylation of ynamides and allenamides with CO₂ and alkylzinc halides catalyzed by a copper catalyst was developed. A variety of alkylzinc halides bearing functional groups were used for this transformation to afford α,β-unsaturated carboxylic acids, which contain the α,β-dehydroamino acid skeleton, introducing the corresponding alkyl group and CO₂ across the carbon–carbon triple or double bond. This alkylative carboxylation formally consists of Cu-catalyzed carbozincation of ynamides or allenamides with alkylzinc halides and the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO₂. This protocol would be a useful method for the synthesis of α,β-dehydroamino acid derivatives possessing a functionalized alkyl group due to the high regio- and stereoselectivity, simple one-pot procedure as well as the use of CO₂ as a starting material.     

IBX/LiBr-promoted one-pot oxidative anti-Markownikov bromohydroxylation/bromoalkoxylation of Baylis-Hillman olefins

The first example of one-pot oxidative anti-Markownikov bromohydroxylation and bromoalkoxylation of Baylis-Hillman (BH) adducts (olefins) is reported. The reaction is performed at rt using LiBr as the bromine source and 2-iodoxybenzoic acid (IBX) as the oxidant. The process involves oxidation of BH adducts with IBX to give β-ketomethylene compounds in situ, which undergo highly regioselective vicinal functionalization with LiBr/H₂O or LiBr/ROH in the same vessel to afford α-bromo-β-hydroxy or α-bromo-β-alkoxy compounds, respectively, in excellent yields. The α-bromo-β-hydroxy compounds are readily transformed into epoxides in aq NaOH.     

Synthesis of α,β-dibromo ketones by photolysis of α-bromo ketones with N-bromosuccinimide: Photoinduced β-bromination of α-bromo ketones

Irradiation of α-bromopropiophenones in the presence of NBS results in the formation of α,β-dibromopropiophenones, which can be viewed as β-bromination of α-bromopropiophenones. The reaction is believed to go through a series of reactions; photoinduced C–Br bond cleavage, elimination of HBr to give α,β-unsaturated ketone intermediates, and addition of Br₂, which are formed by the reaction between HBr and NBS. From mechanistic studies of the reaction, we have also found a very convenient method for α-debromination of the α,β-dibromopropiophenones which is by simple irradiation of the dibromo ketones in acetone or 2-propanol without the use of any additives. Our results demonstrate that bromine can be added into or eliminated from the alpha, beta, or both positions to the carbonyl group by photochemical methods, which make synthetic options of bromine containing carbonyl compounds versatile.     

Copper-catalyzed enantioselective 1,4-conjugate addition of dialkylzinc reagents to α,β- and α,β,γ,δ-unsaturated ketones

An enantioselective Cu(II)-catalyzed conjugate addition of dialkylzinc reagents to α,β- or α,β,γ,δ-unsaturated ketones with chiral cyclohexane-based amidophosphine ligands was developed. With 2 mol% of Cu(OAc)₂·H₂O/L5, the conjugate addition of diethylzinc to α,β-unsaturated ketones was achieved in good-to-excellent yields (up to 98%) and high enantioselectivities (up to 92% ee). This catalytic system was shown to be efficient for the 1,4-conjugate addition of Et₂Zn to (2E,4E)-1,5-diphenylpenta-2,4-dien-1-one with 85% yield and 90% ee. Moreover, with 1 mol% of Cu(OTf)₂/L11, the conjugate addition of α,β,γ,δ-unsaturated ketones was accomplished with 1,4-regioselectivity, good yields (79–86%) and excellent enantioselectivities (up to 97% ee).     

Nucleic-Acid Analogs with Restricted Conformational Flexibility in the Sugar-Phosphate Backbone (‘Bicyclo-DNA’). Part 5. Synthesis,Characterization, and Pairing Properties of Oligo-α-D-(bicyclodeoxynucleotides) of the Bases Adenine and Thymine (α-Bicyclo-DNA)

A conformational analysis of the (3′S,5′R)-2′-deoxy-3′,5′-ethano-α-D -ribonucleosides (a-D-bicyclodeoxynucleosides) based on the X-ray analysis of N⁴-benzoyl-α-D -(bicyclodeoxycytidine) 6 and on ¹H-NMR analysis of the α-D -bicyclodeoxynucleoside derivatives 1 - 7 reveals a rigid sugar structure with the furanose units in the l′-exo/2′-endo conformation and the secondary OH groups on the carbocyclic ring in the pseudoequatorial orientation. Oligonucleotides consisting of α-D -bicyclothymidine and α-D -bicyclodeoxyadenosine were successfully synthesized from the corresponding nucleosides by phosphoramidite methodology on a DNA synthesizer. An evaluation of their pairing properties with complementary natural RNA and DNA by means of UV/melting curves and CD spectroscopy show the following characteristics: i) α-bcd(A₁₀) and α-bcd(T₁₀) (α = short form of α-D )efficiently form complexes with complementary natural DNA and RNA. The stability of these hybrids is comparable or slightly lower as those with natural β-d(A₁₀) or β-d(T₁₀)( β = short form ofβ-D ). ii) The strand orientation in α-bicyclo-DNA/β-DNA duplexes is parallel as was deduced from UV/melting curves of decamers with nonsymmetric base sequences. iii) CD Spectroscopy shows significant structural differences between α-bicyclo-DNA/β-DNA duplexes compared to α-DNA/β-DNA duplexes. Furthermore, α-bicyclo-DNA is ca. 100-fold more resistant to the enzyme snake-venom phosphodiesterase with respect to β-DNA and about equally resistant as α-DNA.     

Calcium-mediated stereoselective reduction of α,β-epoxy ketones

The development of a calcium-mediated stereoselective reduction of α,β-epoxy ketones is reported. The corresponding α,β-epoxy alcohols are obtained in very good anti diastereoselectivity using Ca(OTf)₂ and NaBH₄. Furthermore, we have shown that our method can diastereoselectively reduce α,β-aziridinyl ketones.     

The reaction of aryl iodides with hindered α,β,γ,δ-dienones in the presence of the [Pd(OAc)2(PPh3)2]-trialkylammonium formate reagent

Hindered α,β,γ,δ-dienones have been shown to react with aryl iodides in the presence of the [Pd(OAc)₂(PPh₃)₂]-trialkylammonium formate reagent to give mainly 1,4-conjugate addition type products. The α,β,γ,δ-dienones were prepared through reaction of the corresponding vinyl triflates with α,β-enones in the presence of Pd(OAc)₂, K₂CO₃, and tetrabutylammonium chloride at room temperature.     

Palladium-catalyzed arylation of α,α-difluoro-allylic-β-hydroxyester

The aryl-substituted α,α-difluoro-allylic-β-hydroxyesters and aryl-substituted α,α-difluoroketones were obtained via the coupling reaction of aryl iodides with α,α-difluoro-allylic-β-hydroxyester in the presence of Pd(OAc)₂ as the catalyst and Et₃N as the base.     

Gold-mediated synthesis of α-ionone

A simple and convenient synthesis of α-ionone, an important component of flowers and fragrances, is reported. The key step in the formation of the α,β-unsaturated ketone moiety involves an NHC-Au^I catalyzed Meyer-Schuster-like rearrangement of readily prepared propargylic esters. The complex [{Au(IPr)}₂(μ-OH)][BF₄] proved to be the most efficient catalyst leading to α-ionone in 70% yield from a propargylic benzoate. This optimized procedure represents a valuable and attractive alternative to classical methods leading to α,β-unsaturated ketones, such as the Wittig or aldol reactions.     

Rh-catalyzed novel α-fluoroalkylation of α,β-unsaturated ketones and its mechanism

Treatment of α,β-unsaturated ketones and fluoroalkyl halides with Et₂Zn in the presence of RhCl(PPh₃)₃ gave novel reductive fluoroalkylation products at the α-position of α,β-unsaturated ketones in moderate to good yields. The rhodium hydride complex derived from Et₂Zn and Rh catalyst seems to have played an important role in this reaction.     

β-Peptides: Synthesis by Arndt-Eistert homologation with concomitant peptide coupling. Structure determination by NMR and CD spectroscopy and by X-ray crystallography. Helical secondary structure of a β-hexapeptide in solution and its stability towards pepsin

The β-hexapeptide (H-β-HVal-β-HAla-β-HLeu)₂-OH ( 2 ) was prepared from the component L -β-amino acids by conventional peptide synthesis, including fragment coupling. A cyclo-β-tri- and a cyclo-β-hexapeptide were also prepared. The β-amino acids were obtained from α-amino acids by Arndt-Eistert homologation. All reactions leading to the β-peptides occur smoothly and in high yields. The β-peptides were characterized by their CD and NMR spectra (COSY, ROESY, TOCSY, and NOE-restricted modelling), and by an X-ray crystal-structure analysis. β-Sheet-type structures (in the solid state) and a compact, left-handed or (M) 3₁ helix of 5-Å pitch (in solution) were discovered. Comparison with the analogous secondary structures of α-peptides shows fundamental differences, the most surprising one at this point being the greater stability of β-peptide helices. There are structural relationships of β-peptides with oligomers of β-hydroxyalkanoic acids, and dissimilarities between the two classes of compounds are a demonstration of the power of H-bonding. The β-hexapeptide 2 is stable to cleavage by pepsin at pH 2 in H₂O for at least 60 h at 37°, while the corresponding α-peptide H-(Val-Ala-Leu)₂-OH is cleaved instantaneously under these conditions. The implication of the described results are discussed.     

Alpha-Acylation and -allylation of β,β,β-trifluoropropionic esters via the ketene silyl acetals

α-Acylation of the ketene silyl acetal of methyl β,β,β-trifluoropropionate and α-allylation via the ester enolate Claisen rearrangement of the 2-alkenyl trifluoropropionates are described which provide the corresponding α-CF₃ β-ketoesters and α-CF₃ γ,δ-unsaturated acids, respectively.     

Development of effective Lewis acids for the catalytic Diels-Alder reaction of α,β-unsaturated lactones with cyclopentadiene

We found that ‘Tf₂CH₂ + Me₃Al’ systems are effective catalytic systems for the DA reaction of less reactive α,β-unsaturated lactone derivatives, compared to α,β-unsaturated ester derivatives, with cyclopentadiene. Mononuclear aluminum methide complex, Tf₂CHAlMe₂, as an active species is formed in these catalytic systems. Effects of lactone ring-size on the reactivity and stereoselectivity were also examined. By expanding ring-size, reactivity of α,β-unsaturated lactones reduced but endo-selectivity notably increased.     

Rhodium-catalyzed 1,4-addition of alkenylzirconocene chlorides to electron deficient alkenes

The 1,4-conjugated addition of alkenylzirconocene chloride complexes to α,β-enones, α,β-enoic acid esters, and α,β-enoic acid amides can be efficiently achieved by the use of [RhCl(cod)]₂ catalyst. A high diastereoselectivity (95% yield, 90% de) was obtained through the reaction of α,β-enoic acid amide derived from Oppolzer's sultam and 2-butenoyl chloride, while the use of Evans' chiral oxazolidinone as a chiral auxiliary in place of Oppolzer's sultam gave a poor diastereoselectivity (98% yield, 26% de).     

Addition of benzene to α,β-unsaturated ketones in a two phase system in the presence of the tba+PdCl−3 catalyst

β-Phenyl derivatives of saturated ketones were obtained from the reaction of α,β-unsaturated ketones and PhHgcl or Ph₄Sn in the presence of catalytic amount of TBA⁺Cl_? and PdCl₂ in a two phase system.     

Free radical-promoted conjugate addition of activated bromo compounds using titanocene(III) chloride as the radical initiator

Free radical-promoted conjugate addition of activated bromo compounds to α,β-unsaturated ketones and reactive α,β-unsaturated esters has been described using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. Cp₂TiCl was prepared in situ from commercially available Cp₂TiCl₂ and activated zinc dust in THF.     

Synthese von tri- und tetrasaccharid-einheiten des O-antigens aus Aeromonas salmonicida

The following oligosaccharide sequences containing the repeating unit of the O-specific chain of lipopolysaccharides from aeromonas salmonicida have been synthesized: α-D-Glcp-(1→3)-α-L-Rhap-(1 →3)-β-D-ManpNAcO(CH₂)₈CO₂Me, α-D-Glcp-(1 →4)-α-D-Glcp-(1→3)-α-L-Rhap-(1→3)-β-D-ManpNAcO(CH₂)₈CO₂Me and α-D-Glcp(1→4)-α-D-Glcp-(1→3)-[β-D-ManpNAc(1→4)]-L-Rha.     

A mild and variable synthesis of α-ketoesters

The ZnCl₂ promoted addition of 1,2-diethoxy-1,2-disilyloxyethylene 1 with electrophiles such as aldehydes, ketones, α,β-unsaturated ketones or tertiary alkyl halides allows for a simple synthesis of α-ketoesters.     

Synthesis of 2-Cycloalkenones (Parts of 1,4-Diacyl-1,3-butadiene Systems) and of a Heterocyclic Analogue by Metal-Catalyzed Decomposition of 2-Diazoacylfurans

Furans with side-chains at C(2) of various lengths terminating in diazomethyl keto groups are shown to undergo Rh₂(OAc)₄-catalyzed furan unravelling with the production of 2-cyclopentenone, 2-cyclohexenone, and 2-cycloheptenone to each of whose olefinic C(β) is attached an acrylaldehyde unit. Interposition of a cyclohexane or a methylaminomethylene moiety between the furan and diazoketo functions leads to the formation of a hydroindenone and pyrrolone, respectively. Replacement of the diazomethylketo terminus by an α-diazoethylketo system or a α-diazo-β-keto-ester function produces 2-substituted 2-cycloalkenones. A furan with a C₄, diazo-methylketo-terminating side-chain at C(3) is described to be transformed into a 4-formylmethylidene-2-cyclohe-xenone.