2,4-Disubstituted Pyrrolo[2,3-d]pyrimidine α-D- and β-D-Ribofuranosides Related to 7-Deazaguanosine

Nucleobase-anion glycosylation (KOH, tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), MeCN) of the pyrrolo[2,3-d]pyrimidines 4a – d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribo-furanosyl chloride ( 5 ) gave the protected β-D -nucleosides 6a – d stereoselectively (Scheme 1). Contrary, the β-D -halogenose 8 yielded the corresponding α-D -nucleosides ( 9a and 9b ) apart from minor amounts of the β-D -anomers. The deprotected nucleosides 10a and 11a were converted into 4-substituted 2-aminopyrrolo[2,3-d]-pyrimidine β-D -ribofuranosides 1 . 10c , 12 , 14 , and 16 and into their α-D -anomers, respectively (Scheme 2). From the reaction of 4b with 5 , the glycosylation product 7 was isolated, containing two nucleobase moieties.     

Mono- and Dialkylation of Derivatives of (1R, 2S)-2-Hydroxycyclopentanecarboxylic Acid and -cyclohexanecarboxylic acid via bicyclic dioxanones: Selective generation of three contiguous stereogenic centers on a cyclohexane ring

Ethyl (1R, 2S)-2-hydroxycyclopentanecarboxylate and -cyclohexanecarboxylate ( 1a and 2a , respectively) obtained in 40 and 70% yield by reduction of 3-oxocyclopentanecarboxylate and cyclohexanecarboxylate, respectively (Scheme 2), with non-fermenting yeast, are converted to bicyclic dioxanone derivatives 3 and 4 with formaldehyde, isobutyraldehyde, and pivalaldehyde (Scheme 3). The Li-enolates of these dioxanones are alkylated (→ 5a – 5i , 5j , 6a – 6g ), hydroxyalkylated (→ 51, m, 6d, e ), acylated (→ 5k, 6c ) and phenylselenenylated (→ 7 – 9 ) with usually high yields and excellent diastereoselectivities (Scheme 3, Tables and 2). All the major isomers formed under kinetic control are shown to have cis-fused bicyclic structures. Oxidation of the seleno compounds 7–9 leads to α, β-unsaturated carbonyl derivatives 10 – 13 (Scheme 3) of which the products 12a – c with the C?C bond in the carbocyclic ring (exocyclic on the dioxanone ring) are most readily isolated (70–80% from the saturated precursors). Michael addition of Cu(I)-containing reagents to 12a – c and subsequent alkylations afford dioxanones 14a – i and 16a – d with trans-fused cyclohoxane ring (Scheme 4). All enolate alkylations are carried out in the presence of the cyclic urea DMPU as a cosolvent. The configuration of the products is established by NMR measurements and chemical correlation. Some of the products are converted to single isomers of monocyclic hydroxycyclopentane ( 17 – 19 ) and cyclohexane derivatives ( 20 – 23 ; Scheme 5). Possible uses of the described reactions for EPC synthesis are outlined. The observed steric course of the reactions is discussed and compared with that of analogous transformations of monocyclic and acyclic derivatives.     

Amino acids in the synthesis of heterocyclic systems. Synthesis of γ-(5-(1,2,4-Triazinylidene))-α,β-dehydro-α-amino acid derivatives and 6H-pyrido[1,2-d][1,2,4]triazin-6-ones

5-(1,2,4-Triazinyl) substituted enamines 3 react with 5(4H)-oxazolones 4 in acetic anhydride to give acetylated products 5 , while in toluene-acetic acid mixture nonacetylated products 9 are formed. Both types of products were isolated as (E,Z) mixtures. Compounds 5 and 9 rearrange into 6H-pyrido[1,2-d]-[1,2,4]triazin-6-ones 12 by heating in formic acid or in xylene, respectively. Compounds 5 are transformed in the presence of nucleophiles, such as sodium alkoxides or sodium amides via anionic form 10 into corresponding esters 13 and amides 14 of γ-(5-(1,2,4-triazinylidene)) substituted derivatives of α-amino-2-butenoic acid, which exist in 2-(Z),4-(Z) form.     

Synthese von diastereo- und enantio-selektiv deuterierten β,ε-, β,β-, β,γ- und γ,γ-Carotinen

Synthesis of Diastereo- and Enantioselectively Deuterated β,ε-, β,β-, β,γ- and γ,γ-Carotenes We describe the synthesis of (1′R, 6′S)-[16′, 16′, 16′-²H₃]-β, εcarotene, (1R, 1′R)-[16, 16, 16, 16′, 16′, 16′-²H₆]-β, β-carotene, (1′R, 6′S)-[16′, 16′, 16′-²H₃]-γ, γ-carotene and (1R, 1′R, 6S, 6′S)-[16, 16, 16, 16′, 16′, 16′-²H₆]-γ, γ-carotene by a multistep degradation of (4R, 5S, 10S)-[18, 18, 18-²H₃]-didehydroabietane to optically active deuterated β-, ε- and γ-C₁₁-endgroups and subsequent building up according to schemes \documentclass{article}\pagestyle{empty}\begin{document}${\rm C}_{11} \to {\rm C}_{14}^{C_{\mathop {26}\limits_ \to }} \to {\rm C}_{40} $\end{document} and C₁₁ → C₁₄; C₁₄+C₁₂+C₁₄→C₄₀. NMR.- and chiroptical data allow the identification of the geminal methyl groups in all these compounds. The optical activity of all-(E)-[²H₆]-β,β-carotene, which is solely due to the isotopically different substituent not directly attached to the chiral centres, is demonstrated by a significant CD.-effect at low temperature. Therefore, if an enzymatic cyclization of [17, 17, 17, 17′, 17′, 17′-²H₆]lycopine can be achieved, the steric course of the cyclization step would be derivable from NMR.- and CD.-spectra with very small samples of the isolated cyclic carotenes. A general scheme for the possible course of the cyclization steps is presented.     

Asymmetric Synthesis of α-Aminophosphonic Acids by Cycloaddition of N-Glycosyl-C-dialkoxyphosphonoylnitrones

Addition of dialkyl phosphites to the nitrone 6 , formed in situ from the oxime 5 and formaldehyde gave the hydroxylamines 7 (86%) and 8 (88%), which reacted with p-benzoquinone in the presence of ethylene via the C-dialkoxyphosphonoylnitrones 9 and 10 to yield the cycloaddition products 11 – 14 (80–85%) with a diastereoselectivity of about 50%. The cycloaddition products were transformed into the monoisopropylidene derivatives 15 – 18 and the diacetates 19 – 22 . Comparison of the NMR spectra and the specific rotations of the compounds 19 – 22 with those of the corresponding α-ammo-acid derivatives 23 – 26 of known configuration indicated preferential formation of the L -isomers. The cycloaddition products were transformed in good yield into the L -α-aminophosphonic acids 29 , 30 , 36 , and 39 .     

The reaction of 2-ethoxycarbonyl-3-isothiocyanatopyridine with α-amino acids. The synthesis of 3-substituted 2-thiooxo-2,3-dihydropyrido[3,2-d]pyrimidin-4(3H)-ones

2-Ethoxycarbonyl-3-isothiocyanatopyridine ( 1 ) reacts with α-amino acids 2–11 and β-alanine ( 12 ) to give pyrido[3,2-d]pyrimidine derivatives 13–23 with the nitrogen of the amino acid component being incorporated into the fused pyrimidine ring at position 3 . Methylation of 14 and 15 with DMFDMA produces S-methylated products 24 and 25 , while in the reaction of 14 with hydrazine the corresponding hydrazide 26 is formed. The reactions proceed under mild conditions, so that no racemization of chiral substituents was observed.     

A case of highly diastereoselective addition to unsymmetrical ketones: lk-addition of (2-alkenyl)triphenoxytitanium derivatives

(2-Butenyl)-, (4-methyl-2-pentenyl)-, and (2-heptenyl)triphenoxytitanium ( 2a – c ) add to dialkyl, alkyl aryl-, and alkinyl aryl ketones to give high yields of tertiary homoallylic alcohols ( 5 – 12 ), which are diastereomerically enriched up to 98%. Configurational assignment by degradation of two of the products to olefins 15 and 18 - through β-hydroxy acids 13 and 16 and β-lactones 14 and 17 - leads to the proposal of a general mechanism and of a specification of the relative topicity lk of the process (Scheme 5). The allylic Ti-compounds 2 can serve as d²-reagents (see the d²-synthon II and the aldol-type structures 1 ).     

Synthesis and Evaluation of α-Methylidene-γ-butyrolactone bearing flavone and xanthone moieties

In a search for inhibitors of platelet aggregation, a number of α-methylidene-γ-butyrolactones 5 and 6 bearing flavone or xanthone moieties, respectively, were synthesized and evaluated for their antiplatelet activity against thrombin(Thr)-, arachidonic-acid(AA)-, collagen(Col)?, and platelet-activating-factor(PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 7-hydroxyflavone ( 1 ) or 3-hydroxyxanthone ( 2 ) via O-alkylation (→ 3 and 4 , resp.) and Reformatsky-type condensation (Scheme). Most of the flavone-containing α-methylidene-γ-butyrolactones 5a – d showed potent antiplatelet effects on AA- and Col-induced aggregation, while xanthone derivatives 6c – e were found to have the same pharmacological profile than aspirin in which only AA-induced aggregation was inhibited (Table 1). However, 6c – e were approximately three to ten times more potent than aspirin (Table 2). For the vasorelaxing effects, 5a was the only compound which exhibited significant inhibitory activity on the high-K⁺ medium, Ca²⁺-induced vasoconstriction (Table3). Both 5a and 6a , with an aliphatic Me substituent at C(γ) of the lactone, were active against norepinephrine-induced phasic and tonic constrictions while their γ-aryl-substituted counterparts 5b – f and 6b – f were inactive.     

α-Alkylation of Amino Acids without Racemization. Preparation of Either (S)- or (R)-α-Methyldopa from (S)-Alanine

Enantiomerically pure cis- and trans-5-alkyl-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-ones ( 1, 2, 11, 15, 16 ) and trans-2-(tert-butyl)-3-methyl-5-phenylimidazolidin-4-one ( 20 ), readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21 ). Diastereoselective alkylation of these enolates to 5,5-dialkyl- or 5-alkyl-5-arylimidazolidinones ( 5, 6, 9, 10, 13a-d, 17, 18, 22 ) and hydrolysis give α-alkyl-α-amino acids such as (R)- and (S)-α-methyldopa ( 7 and 8a , resp.), (S)-α-methylvaline ( 14 ), and (R)-α-methyl-methionine ( 19 ). The configuration of the products is proved by chemical correlation and by NOE ¹H-NMR measurements (see 23, 24 ). In the overall process, a simple, enantiomerically pure α-amino acid can be α-alkylated with retention or with inversion of configuration through pivaladehyde acetal derivatives. Since no chiral auxiliary is required, the process is coined ‘self-reproduction of a center of chirality’. The method is compared with other α-alkylations of amino acids occurring without racemization. The importance of enantiomerically pure, α-branched α-amino acids as synthetic intermediates and for the preparation of biologically active compounds is discussed.     

Michael Reactions of α-Unsubstituted Trisubstituted 1H-Pyrroles

To obtain stable derivatives of α-unsubstituted pyrroles, the reaction of the test pyrrole 9 with a series of chalcones 14a – h were studied. Michael adducts 16b – h could be isolated. In order to synthesize coloured derivatives, the reaction of different pyrroles 9, 21, 23 , and 25 with diphenylpropynone 19 was investigated. In these cases, too, Michael-addition products were formed. The intense absorption band around 400 nm makes the identification of these derivatives easy.     

Synthesis and Anticancer Evaluation of Some Novel Thiophene,Thieno[3,2‐d]pyrimidine,Thieno[3,2‐b]pyridine,and Thieno[3,2‐e][1,4]oxazepine Derivatives Containing Benzothiazole Moiety

In an attempt to establish novel candidate with promising anticancer activity, two derivatives of (benzo[d]thiazol‐2‐yl)thiophene backbone 1 and 14 were synthesized, and they further reacted with various chemical reagents to afford the corresponding substituted thiophene derivatives 6 , 8 , 10 , 15 , 17 , and 20 , thieno[3,2‐d]pyrimidine derivatives 2 – 5 , 7 , 9 , 16 , 21 , 23 , and 24 , thieno[3,2‐b]pyridine derivatives 11 – 13 , and thieno[3,2‐e][1,4]oxazepine derivative 18 . Structures of prepared compounds were affirmed via spectral and elemental data. Among the obtained compounds, seven derivatives 2 , 3 , 4 , 5 , 11 , 12 , and 13 were chosen by National Cancer Institute, USA. Such compounds were screened for their antitumor activity versus 60 cancer cell lines in one‐dose (10 μmol) screening assay. The outcomes showed that all selected compounds exhibited moderate to high anticancer activity towards many cancer cell lines among which compounds 5 and 11 exerted potent antitumor activity against numerous malignant growth cell lines particularly Ovarian Cancer IGROV1.     

The Photodecarbonylation of α-Aryl Aldehydes: 1-Formyl-1-methyl-indan and heterocyclic analogues

The singlet photodecarbonylation of the indanyl aldehyde 7 – a benzohomologue of laurolenal ( 1 ) and also a conformationally rigid ‘out-of-plane’ analogue of the α-aryl aldehyde 4 previously studied [5] [6], – and of the heterocyclic derivatives 8 – 10 in degassed solutions, has been investigated. While 7 decarbonylates uniformly to the niethylindan 30 in close analogy to the examples studied previously, 8 and 9 decompose to the corresponding Δ²-unsaturated compounds 33 , 35 in addition to decarbonylation to 32 , 34 . The results provide an independent indication for intermediate photolytically formed radical pairs (a) in which heteroatoms facilitate radical removal of hydrogen from C(2), and thus introduce disproportionation to give unsaturated products + CH₂O, competing with the otherwise exclusive alternative affording saturated products +CO.     

Acid-Catalysed Rearrangements of α-Vinylcyclobutanones

The BF₃ · Et₂O- and the CH₃SO₃H-catalysed rearrangements of 10 α-vinylcyclobutanones have been examined. With little acid, the β,β-dialkyl derivatives 1 were transformed into linear dienones 2 and 3 ; with more acid, they were converted into cyclopentenones 4 by Nazarov cyclisation of initially formed 2/3 . The β-monoalkyl (including the β,γ-dialkyl) derivatives 7 rearranged only with a high acid concentration to afford the cyclopentenones 8 by 1,2-acyl migration. In the case of 7a , the cyclopentenone 8a was accompanied by the unexpected constitutional isomer 9a , which is explained by a reversible interconversion of the cyclobutanone 7a with its isomer 19 via a cyclopropane intermediate like 18 . In the case of the β,β-dialkyl derivative 5 , which contains an α-isobutenyl (instead of an α-vinyl) group, the acid-catalysed rearrangement product was the bicyclo[3. 1. 0]hexanone derivative 6 .     

Photochemische Reaktionen. 103. Mitteilung [1]. Zur Photochemie konjugierter Epoxy-en-carbonylverbindungen der Jonon-Reihe: UV.-Bestrahlung α,β-ungesättigter ε-Oxo-γ, δ-epoxy-carbonylverbindungen und Untersuchung des Mechanismus der Epoxy-enon/Furan-Isomerisierung

The Photochemistry of Conjugated γ,δ-Epoxy-ene-carbonyl Compounds of the Ionone Series: UV.-Irradiation of α,β-Unsaturated ε-Oxo-γ,δ-epoxy Compounds and Investigation of the Mechanism of the Isomerization of Epoxy-enones to Furanes On ¹n, π*-excitation (λ ≥ 347 nm; pentane) of the enonechromophore of 3 , three different reactions are induced: (E/Z)-isomerization to give 13 (7%), isomerization by cleavage of the C(γ)–C(δ) bond to yield the bicyclic ether 14 (36%) and isomerization by cleavage of the C(γ)? O bond to give the cyclopentanones 15 (13%) and 16 (11%; s. Scheme 2). On ¹π, π*-excitation (λ = 254 nm; acetonitrile) 13 (14%), 15 (6%), and 16 (6%) are formed, but no 14 is detected. In contrast, isomerization by cleavage of the C(δ)? O bond to give the cyclopentanone 17 (23%) is observed. The reaction 3 → 17 appears to be the consequence of an energy transfer from the excited enone chromophore to the cyclohexanone chromophore, which then undergoes β-cleavage. Irradiation of 4 with light of λ = 254 nm (pentane) yields the analogous products 20 (18%), 21 (9%), 22 (7%), and 24 (7%; s. Scheme 2). Selective ¹n, π*-excitation (λ ≥ 280 nm) of the cyclohexanone chromophore of 4 induces isomerization by cleavage of the C(δ)? O bond to give the cyclopentanones 23 (9%) and 24 (44%). Triplet-sensitization of 4 by excited acetophenone induces (E/Z)-isomerization to provide 20 (12%) and isomerization by cleavage of the C(δ)? O bond to yield 21 (26%) and 22 (20%), but no isomerization via cleavage of the C(δ)? O bond. It has been shown, that the presence of the ε;-keto group facilitates C(γ)? C(δ) bond cleavage to give a bicyclic ether 14 , but hinders the epoxy-en-carbonyl compounds 3 and 4 from undergoing cycloeliminations. The activation parameters of the valence isomerization 13 → 18 , a thermal process, have been determined in polar and non-polar solvents by analysing the ¹H-NMR. signal intensities. The rearrangement proceeds faster in polar solvents, where the entropy of activation is about ?20 e.u. Opening of the epoxide ring and formation fo the furan ring are probably concerted.     

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).     

Diazoaldehyde Chemistry. Part 1. Transdiazotization of Acylacetaldehydes in Neutral-to-Acidic Medium. A Direct Approach to the Synthesis of α-Diazo-β-oxoaldehydes

First ever non-deformylating transdiazotization of acylacetaldehydes was achieved: the reactions of 2-azido-l-ethylpyridinium tetrafluoroborate ( 4 ) with acylacetaldehydes 3 proceeded partially without deformylation to yield 16 new α-diazo-β-oxoaldehydes 1 along with diazomethyl ketones 2 , especially in the presence of NaOAc (Scheme 1, Tables 1 and 2). The product distribution was substituent-dependent and could be correlated quantitatively. This new diazotization reaction appears as an alternative, direct, and more general method for the synthesis of these diazooxoaldehydes. α-Oxocycloalkanecarbaldehydes 5 gave only traces (if any) of α-diazocycloalkanones 7 , and rearrangement products 6 were isolated (Scheme 2). Mechanisms of the reactions are discussed (Schemes 4 and 5).     

Asymmetric α-Acetoxylation of Carboxylic Esters. Preliminary Communication

Using the readily accessible chiral auxiliaries 1 – 3 the sulfonamide-shielded O-silylated esters 5 underwent π-face-selective α-acetoxylation on successive treatment with Pb(OAc)₄ and NEt₃ HF to give after recrystallization α-acetoxy ester 6 in 55–67% yields and in 95–100% d.e. Starting from conjugated enoates addition of RCu and subsequent acetoxylation 10 → 11 → 12 yielded α,β-bifunctionalized esters 12 with >95% configurational control at both C_α and C_β. Nondestructive removal of the auxiliary ( 6 → 7 , 6 → 8 and 12 → 13 ) gave either α-hydroxycarboxylic acids or terminal α-glycols in high enantiomeric purity. The prepared glycols 8c and 13a are key intermediates for previously reported syntheses of the natural products 16 and 17 , respectively.     

Versatile Stereoselective Synthesis of Completely Protected Trifunctional α-Methylated α-Amino Acids Starting from Alanine

A new route to completely protected α-methylated α-amino acids starting from alanine is described (see Scheme). These derivatives, which are obtained via base-catalyzed opening of the oxazolidinones (2S,4R)- and (2R,4S)- 2 , can be directly employed in peptide synthesis. The synthesis of both enantiomers of Z-protected α-methylaspartic acid β-(tert-butyl)ester (O⁴-(tert-butyl) hydrogen 2-methylaspartates (R) or (S)- 4a ), α-methyl-glutamic acid γ-(tert-butyl) ester (O⁵-(tert-butyl) hydrogen 2-methylglutamate (R)- or (S)- 4b ), and of N^ε-bis-Boc-protected α-methyllysine (N⁶,N⁶-bis[(tert-butyloxy)carbonyl]-2-methyllysine (R)- or (S)- 4c ) is described in full detail.     

Reaction of Cα,O-dilithiooximes with functionalized carbonyl compounds. Part 2 . Reaction with α-chloroketones and α,β-unsaturated aldehydes and ketones

The reaction of Cα,O-Dilithiooximes 2 and α-chloroketones afforded 5-(hydroxymethyl)-Δ²-soxazolines 4 . α,β-Unsaturated aldehydes and ketones reacted with 2 to give the corresponding acyclic 1,2-addition products 5 . The latter were cyclized with phosphorus pentoxide to 5-vinyl-Δ²-isoxazolines 6 .     

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.