Thermische Lactonisierung von Estern γ-Brom-α, β-ungesättigter Carbonsäuren zu Δα-Butenoliden. Direkte γ-Bromierung von α, β-ungesättigten Säuren

By heating with iron powder at 120–150° some γ-bromo-α, β-unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ^7alpha;-butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ-bromocrotonate ( 1c ) and the corresponding acid ( 1d ) to Δ^α-butenolide ( 8a ), methyl γ-bromotiglate ( 3c ) and the corresponding acid ( 3d ) to α-methyl-Δ^α-butenolide ( 8b ), a mixture of methyl trans- and cis-γ-bromosenecioate ( 7c and 7e ) and a mixture of the corresponding acids ( 7d and 7f ) to β-methyl-Δ^α-butenolide ( 8c ). The procedure did not work with methyl trans-γ-bromo-Δ^α-pentenoate ( 5c ) nor with its acid ( 5d ). Most of the γ-bromo-α, β-unsaturated carboxylic esters ( 1c, 7c, 7e and 5c ) are available by direct N-bromosuccinimide bromination of the α, β-unsaturated esters 1a, 7a and 5a ; methyl γ-bromotiglate ( 3c ) is obtained from both methyl tiglate ( 3a ) and methyl angelate ( 4a ), but has to be separated from a structural isomer. The γ-bromo-α, β-unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β-unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine-carrying carbon anti to the carboxylic ester group; an exception is methyl γ-bromo-senecioate, for which the two isomers (cis, 7e , and trans, 7d ) have about the same stability. The N-bromosuccinimide bromination of the α,β-unsaturated carboxylic acids 1b , 3b , 4b , 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ-bromocrotonic acid ( 1 d ), γ-bromotiglic acid ( 3 d ), trans- and cis-γ-bromosenecioic acid ( 7d and 7f ) as well as trans-γ-bromo-Δ^α-pentenoic acid ( 5d ) have been prepared. Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond. α-Methyl-Δ^α-butenolide ( 8b ) was converted to 1-benzyl-( 9a ), 1-cyclohexyl-( 9b ), and 1-(4′-picoly1)-3-methyl-Δ^α-pyrrolin-2-one ( 9 c ) by heating at 180° with benzylamine, cyclohexylamine, and 4-picolylamine. The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.     

Catalyst-Controlled Regiodivergent Synthesis of α/β-Dipeptide Derivatives via N-Allylic Alkylation of O-Alkyl Hydroxamates with MBH Carbonates

A controllable and regiodivergent N-allylation reaction involving readily available O-alkyl hydroxamates derived from natural α-amino acids has been developed, allowing regiospecific access to α/β-dipeptides containing α-unsaturated β-amino acids moieties in moderate to good yields. The regioselectivity could be conveniently switched by alternation of the catalysts and solvents.     

Conjugate addition of grignard reagents to N-(α,β-unsaturated)acylpyrazoles. Diastereoselective β-alkylation using 3-phenyl-l-menthopyrazole

The conjugate additions of N-(α,β-unsaturated)acylpyrazoles were carried out by the treatment with Grignard reagents in the presence of cuprous halides. The reaction of 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3a-h occurred in higher chemical yields and with asymmetric inductions on β-position, where the addition of magnesium bromide as a Lewis acid influenced to the yields and the diastereoselectivities. In the case of α-methylated 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3i-n , the excellent asymmetric induction on the α-position was also observed through the diastereofacial protonation.     

1,3-Dipolar cycloaddition of nitrones with α,β-unsaturated sulfones

C,N-Diphenyl nitrones react with substituted α,β-unsaturated phenylsulfones yielding isoxazolidinic cycloadducts whose structure and stereochemistry were assigned on the basis of ¹H and ¹³C nmr data. The ycloaddition regioselectivity is discussed in accordance with frontier orbital considerations.     

Stereochemical effects in the nitrosation of some α,β-unsaturated ketoximes. Formation of 1-hydroxypyrazole 2-oxides and 4-oximino-4,5-dihydroisoxazoles

Several α,β-unsaturated ketoximes R¹CH=CHC(=NOH)R² were nitrosated using butyl nitrite in aqueous ethanol in the presence of copper(II) sulfate and pyridine. The product distribution varied depending on whether the oxime hydroxyl group was syn or anti with respect to the carbon?carbon double bond. The anti-oximes gave the copper complexes of 1-hydroxypyrazole 2-oxides in high yields. The isomeric syn-oximes gave lower yields of the pyrazole complexes along with 4-oximino-4,5-dihydroisoxazole derivatives. For the syn-oximes where R¹ is phenyl and R² is either methyl or ethyl, conversion of the oximes to the parent ketones was also observed. The results may be explained by processes involving N-nitrosonitrone intermediates.     

AM1 calculations of parts of the enthalpy surfaces for additions of active methylene nitriles to α β-unsaturated nitriles

The nucleophilic additions of active methylene nitriles (MNs), R₁R₂CH⁻, where R₁=CN and R₂=CN, and CSNH₂, to acetaldehyde and to the resultant α, β-unsaturated nitriles have been studied theoretically by the AM1 semiempirical MO method. The additions of MNs anions to acetaldehyde are found to be endothermic with late productlike transition states (TSs) on the reaction coordinate. Their additions to α,β-unsaturated nitriles may conceivably proceed via two pathways: addition to the C=C double bond and addition to the C≡N triple bond. It has been found that the nucleophilic attack at the &alpha,β-unsaturated linkage is exothermic, while that at the nitrile group is endothermic and has a relatively high enthalpy barrier. Both additions have late productlike transition states. The reactivity of the nucleophilic attack has been discussed in the light of the frontier molecular orbital theory and in terms of the HOMO–LUMO two-electron interaction. The calculations have been compared with experimental results. © 1997 John Wiley & Sons, Inc.     

Ionization Shifts in 1H-NMR Spectra of α,β-Unsaturated Carboxylic Acids

Changes in chemical shifts of olefinic protons in a number of α,β- and α,β,γ,δ-unsaturated carboxylic acids caused by ionization of the COOH group were investigated. The ionization shifts of α-H-atoms are ?0.09 to 0.07 ppm, those of β-H-atoms are 0.32?0.47 ppm. The ionization shifts of δ-H-atoms are substantially larger than those of γ-H-atoms. The ionization shifts can be used for immediate determination of the esterification site in monoesters of (2E,4Z)-2,4-hexadienedioic (muconic) acid, which are of interest in connection with synthetic studies on verrucarins. Thus, isomerization by heating in aqueous solution of monoesters of (2Z,4Z)-2,4-hexadienedioic acid yields 1-monoesters rather than 6-monoesters of (2E,4Z)-2,4-hexadienedioic acid, in accordance with the isomerization mechanism involving anchimeric assistance of the free COOH group. Solutions of the ABXY spectra of olefinic protons of monomethyl (2E,4E)- and (2Z,4Z)-2,4-hexadienedioate are reported.     

Stereoregularity of poly(alkyl α-chloroacrylates) and mechanism of isotactic polymerization

The catalytic activity of the complexes prepared by the reaction of Grignard reagents with ketones, esters, and an epoxide as polymerization catalysts of methyl and ethyl α-chloroacrylates was investigated. The modifiers which gave isotactic polymers were α,β-unsaturated ketones such as benzalacetophenone, benzalacetone, dibenzalacetone, mesityl oxide, and methyl vinyl ketone, and α,β-unsaturated esters such as ethyl cinnamate, ethyl crotonate, and methyl acrylate. Catalysts with butyl ethyl ketone, propiophenone, and propylene oxide as modifiers produced atactic polymers but no isotactic polymers. It was revealed that the complex catalysts having a structure ? C?C? O? MgX (X is halogen) gave isotactic polymers. The mechanism of isotactic polymerization was discussed. In addition, for radical polymerization of ethyl α-chloroacrylate, enthalpy and entropy differences between isotactic and syndiotactic additions were calculated to give ΔH_i^* ? ΔH_s^* = 910 cal/mole and ΔS_i^* ? ΔS_s^* = 0.82 eu.     

Highly Substituted Spiro[4.4]nonatrienes from a β-Amino-Substituted α,β-Unsaturated Fischer Carbene Complex and Three Molecules of an Arylalkyne

A novel mode of reaction towards arylethynes is shown by the β-trimethylsilyl-substituted α,β-unsaturated Fischer carbene complexes 1 . A mixture of the isomeric, highly substituted spiro[4.4]nonatrienes 2 and 3 is formed by the formal insertion of three alkyne molecules and subsequent cyclization (see scheme). Such selective triple insertions of alkynes into ethenylcarbene complexes have not been previously observed.     

Photochemische Reaktionen 111. Mitteilung [1] Zur Photochemie α, β-ungesättigter γ, δ-Epoxyester I: Singulett- versus Triplettreaktivität

On triplet excitation (E)- 2 isomerizes to (Z)- 2 and reacts by cleavage of the C(γ), O-bond to isomeric δ-ketoester compounds ( 3 and 4 ) and 2,5-dihydrofuran compounds ( 5 and 19 , s. Scheme 1). - On singulet excitation (E)- 2 gives mainly isomers formed by cleavage of the C(γ), C(δ)-bond ( 6–14 , s. Scheme 1). However, the products 3–5 of the triplet induced cleavage of the C(γ), O-bond are obtained in small amounts, too. The conversion of (E)- 2 to an intermediate ketonium-ylide b (s. Scheme 5) is proven by the isolation of its cyclization product 13 and of the acetals 16 and 17 , the products of solvent addition to b . - Excitation (λ = 254 nm) of the enol ether (E/Z)- 6 yields the isomeric α, β-unsaturated ε-ketoesters (E/Z)- 8 and 9 , which undergo photodeconjugation to give the isomeric γ, δ-unsaturated ε-ketoesters (E/Z)- 10 . - On treatment with BF₃O(C₂H₅)₂ (E)- 2 isomerizes by cleavage of the C(δ), O-bond to the γ-ketoester (E)- 20 (s. Scheme 2). Conversion of (Z)- 2 with FeCl₃ gives the isomeric furan compound 21 exclusively.     

Massenspektrometrische Untersuchung von Amiden. VIII—Vinyloge α-Spaltung und Nachbargruppenbeteiligung bei der Fragmentierung von Piperididen α,β-ungesättigter Carbonsäuren

The electron-impact-induced fragmentation of piperidides from β-substituted α, β-unsaturated carboxylic acids proceeds preferentially via 4-membered cyclic transition states. The development of a 6-membered ring, which is typical for α,β-unsaturated esters, occurs only to a minor extent. The mechanism of the reaction is best rationalised by the assumption of a vinylogous α-cleavage and a simultaneous neighbouring group participation of the amide function     

Synthese makrocyclischer, α,β-ungesättigter γ-Oxolactone durch Ringerweiterungsreaktionen; ein neuer Weg zum makrocyclischen Lacton-Antibiotikum A 26771 B

Synthesis of Macrocyclic α,β-Unsaturated γ-Oxolactones by Ring-Enlargement Reactions; a New Path to the Macrocyclic Lactone Antibiotic A 26771 B A new synthetic route to the α,β-unsaturated γ-oxolactones 2a and 2b , involving two ring-enlarement reactions, is described. Ring opening of bicyclic α-nitroketones of the type 3 gave ring-enlarged compounds of the type 4 which were converted to monoprotected diketones of the type 10 by using a variation of the Nef reaction as a key step. Macrocyclic lactones of the type 11 were obtained by Baeyer-Villiger oxidation and converted into compounds of the type 2 . The conversion of 2b to the macrocyclic lactone antibiotic A 26771 B ( 1 ) is already described in the literature.     

Über einen neuartigen synthetischen Zugang zu β,γ-ungesättigten α-Aminocarbonsäuren

A New Synthetic Route to β,α-Unsaturated α-Amino Acids A versatile new synthetic pathway for the preparation of βγ-unsaturated α-amino acids ( 1 ) is presented. Cu(I)-catalyzed addition of ethyl isocyanoacetate ( 2 ) to α-chloro carbonyl compounds ( 3 ) gives 5-chloroalkyl-2-oxazolin-4-carboxylates ( 4 ) in high yields. A reductive elimination on 4 by means of zinc yields the N-formyl derivatives of βγ-unsaturated α-amino carboxylates ( 5 ), which on acid hydrolysis lead to the free amino acids 1 . The five different βγ-dehydro-α-amono acids 1b-1f have been prepared by this method.     

Isoxazolium enolates derived from α,β-unsaturated and 1,3-dicarbonyl compounds. The through-space effect of the enolate moiety on the chemical shift of α-protons

The reaction of 4-phenyl-3,5-dihydroxyisoxazole with α,β-unsaturated cyclic ketones and 1,3-cyclic diketones was studied. β-Substituted α,β-unsaturated ketones give pairs of isomeric isoxazolium enolates. The remarkable influence of the heterocyclic betaine on the proton chemical shifts is discussed. 1,3-Cyclic diketones reacted spontaneously with 4-phenyl-3,5-dihydroxyisoxazole yielding isoxazolium enolate enols and enol ethers.     

Photochemische Reaktionen. 68. Mitteilung. Die Photoisomerisierung von α,β-ungesättigten γ,δ-Epoxyketonen: 9α, 10α- und 9β, 10β-Oxido-3-oxo-17β-acetoxy-Δ4-östren

Irradiation in the n→π* absorption band of the α,β-unsaturated γ,δ-epoxyketone 5 in ethanol at ?65° exclusively afforded the rearranged ene-dione 13 , whereas at + 24° under otherwise unchanged reaction conditions or upon triplet sensitization with Michler's ketone and with acetophenone at + 24° essentially identical mixtures of 13 (major product), 14 , and 15 were obtained. Selective π→π* excitation of 5 at ?78° and + 24° led to similar product patterns. The 9β,10β-epimeric epoxyketone 7 selectively isomerized to 14 and 15 at + 24° and n → π* or π → π* excitation. Neither the epoxyketones 5 and 7 nor the photoproducts 13–15 were photochemically interconverted. In separate photolyses each of the latter gave the double bond isomers 16 , 18 , and 19 , respectively. Cleavage of 13 to the dienone aldehyde 17 competed with the double bond shift ( → 16 ) when photolyzed in alcoholic solvents instead of benzene. The selective transformations 5 → 13 (at ?65° and n → π* excitation) and 7 → 14 + 15 are attributed to stereoelectronic factors facilitating the skeletal rearrangements of the diradicals 53 and 55 , the likely primary photoproducts resulting from epoxide cleavage in the triplet-excited compounds 5 and 7 , via the transition states 54 , 56 , and 57 . The loss of selectivity in product formation from 5 at higher temperature and n → π* excitation or triplet sensitization is explicable in terms of radical dissociation into 58 and 59 increasingly participating at the secondary thermal transformations of 53 . The similar effect of π → π* excitation even at ?78° indicates that some of the π,π* singlet energy may become available as thermal activation energy. It is further suggested that the considerably lesser ring strain in 14 and 15 , as compared with 13 , is responsible that selectivity in product formation from 7 is maintained also at +24° and at π → π* excitation.     

HBTU Mediated Synthesis of α,β-Unsaturated γ-Lactams from E-α,β-Unsaturated γ-Amino Acids

The α,β-unsaturated γ-lactams have been found in many biologically active peptide natural products. Due to their biological activities, extensive efforts have been made in the literature to synthesize the α,β-unsaturated γ-lactams. Here, we are reporting the spontaneous transformation of E-α,β-unsaturated γ-amino acids into α,β-unsaturated γ-lactam through in-situ activation of free carboxylic acid using peptide coupling reagent HBTU and base DIPEA at room temperature. The transformation also involves the E→Z isomerization of α,β-unsaturated γ-amino acids. The reaction is also compatible with the peptides consisting of E-α,β-unsaturated amino acids at the C-terminus. The α,β-unsaturated γ-lactams were isolated in very good yields. Even though the reaction required very mild conditions, the products were isolated in the form of a racemic mixture. However, the products can be separated under a chiral environment. No α,β-unsaturated γ-lactams were observed if the reaction was performed in the presence of free amines. In addition, no racemization was observed during the peptide synthesis. The analysis of the reactions of various substrates revealed that amide NH and γ-CH are important for lactamization. No α,β-unsaturated γ-lactams or E→Z isomerization products were observed in the case of N-Me-(E)-α,β-unsaturated γ-amino acids, whereas in the case of E-α,β-unsaturated γ,γ-dimethyl amino acid α,β-unsaturated γ-lactam was isolated, however, with low yield.     

The Synthesis of β,γ- and α,β-Unsaturated Aldehydes via Polyene Epoxides

A substitute for the Darzens glycidic ester synthesis for converting unsaturated ketones or aldehydes into the homologated β,γ- or α,β-unsaturated aldehydes employing sulfur ylides is described. The carbonyl group is converted into the unsaturated oxirane which is then rearranged to the new aldehyde. High yields of isomerically pure aldehydes are available by this method and the process is of practical importance in the conversion of β-ionone into the β-C₁₄-aldehyde, a key intermediate in the Isler synthesis of vitamin A. The efficient preparation of α- and β-cyclocitral by the novel process is also described.     

Ultrasound Promoted 1, 3-Dipolar Cycloaddition Reactions of Nitrile Oxides with α, β-Unsaturated Acetals

The 1,3-dipolar cycloaddition reactions of nitrile oxides and α,β-unsaturated 1,3-dioxolanes were effectively accelerated by ultrasound irradiation to give the A²-isoxazolines with yields and regioselectivities surpassing those of the corresponding thermal reactions.     

β-lithiations of carboxamides. Synthesis of β-substituted-α,β-unsaturated amides

N-Methyl-2-methyl-3-(benzotriazol-l-yl)propanamide, on treatment with butyllithium forms a dianion which on treatment with alkyl and benzyl halides, aldehydes and ketones affords monosubstituted products; with ethyl p-toluate, a lactam is formed. The alkylated derivatives eliminate benzotriazole in the presence of base to afford trisubstituted α,β-unsaturated amides.     

Preparation and Structure of β-Peptides Consisting of Geminally Disubstituted β2,2- and β3,3-Amino Acids: A Turn Motif for β-Peptides

We report on the synthesis of new and previously described β-peptides ( 1 – 6 ), consisting of up to twelve β^2,2- or β^3,3-geminally disubstituted β-amino acids which do not fit into any of the secondary structural patterns of β-peptides, hitherto disclosed. The required 2,2- and 3,3-dimethyl derivatives of 3-aminopropanoic acid are readily obtained from 3-methylbut-2-enoic acid and ammonia (Scheme 1) and from Boc-protected methyl 3-aminopropanoate by enolate methylation (Scheme 2). Protected (Boc for solution-, Fmoc for solid-phase syntheses) 1-(aminomethyl)cycloalkanecarboxylic-acid derivatives (with cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings) are obtained from 1-cyanocycloalkanecarboxylates and the corresponding dihaloalkanes (Scheme 3). Fully ¹³C- and ¹⁵N-labeled 3-amino-2,2-dimethylpropanoic-acid derivatives were prepared from the corresponding labeled precursors (see asterixed formula numbers and Scheme 4). Coupling of these amino acids was achieved by methods which we had previously employed for other β-peptide syntheses (intermediates 18 – 23 ). Crystal structures of Boc-protected geminally disubstituted amino acids ( 16a – d ) and of the corresponding tripeptide ( 23a ), as well as NMR and IR spectra of an isotopically labeled β-hexapeptide ( 2a* ) are presented (Figs. 1 – 4) and discussed. The tripeptide structure contains a ten-membered H-bonded ring which is proposed to be a turn-forming motif for β-peptides (Fig. 2).