Synthetische Verwendung von Epoxynitronen. I. N-(2,3-Epoxypropyliden)-cyclohexylamin-oxid,ein neues Reagens zur Synthese von α-Methyliden-γ-lactonen aus Olefinen

Synthetic Application of Epoxynitrones I. Nitrone, a New α-Methylidene-γ-lactone Annelating Reagent The N-(2, 3-epoxypropyliden)-cyclohexylamine-N-oxide/CF₃SO₃SiR₃ reagent descried in this communication opens a new and interesting entry to the versatile N-substituted N-propenylnitrosonium ions of type b (Scheme 6). One of the uses of this reagent is shown to be the synthesis of α-methylidene-γ-lactones from olefins. This new method shows similar features as the method based on 2, 3-dichloropropylidenamine-oxide/AgBF₄ originally developed for the same purpose by Petrzilka, Felix and Eschenmoser. Epoxynitrone 18 can be transformed to the positively charged heterodiene of type b (Scheme 5) using the highly electrophilic reagents CF₃SO₃SiMe₃ ( 23 ) and CF₃SO₃Si (t-Bu)Me₂ ( 24 ), respectively. Low temperature ¹H- and ¹³C-NMR. spectroscopy at ?78° showed the sole formation of the nitrone-O-silyl-ethers a (Scheme 5). Epoxid opening leading to the diene b and subsequent reactions are observed only at about ?30°. The diene b prepared in situ, adds to isolated double bonds by way of an inverse Diels-Alder reaction to afford cycloadducts of type 27 (Scheme 7). Their stable cyanoderivatives, e.g. 28 (Scheme 7), can be isolated and transformed via 31 , 44 and 54 into cis annelated α-methylidene-γ-lactones of type 55 (Scheme 11). Using trisubstituted olefins, substitution at the lower substituted olefinic C-atom competes efficiently with the cycloaddition (e.g. 34 , Scheme 8).     

Antiplatelet α-Methylidene-γ-butyrolactones: Synthesis and evaluation of quinoline,flavone, and xanthone derivatives

As a continuation of our previous studies on the synthesis and antiplatelet activity of coumarin derivatives of α-methylidene-γ-butyrolactones, certain quinoline, flavone, and xanthone derivatives were synthesized and evaluated for 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 quinolin-8-ol, flavon-7-ol, and xanthon-3-ol, respectively, via alkylation and Reformatsky-type condensation (Schemes 1–3). By the comparison with comparison with coumarin α-methylidene-γ-butyrolactone 3a , flavone and xanthone derivatives, 3b and 3c , respectively, are more selective in which only AA- and collagen-induced aggregation are strongly inhibited. Most of the quinoline derivatives ( 9a–e ) exhibited broad-spectrum antiplatelet activities.     

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.     

Totalsynthese von natürlichem α-Tocopherol. 2. Mitteilung. Aufbau der Seitenkette aus (−)-(S)-3-Methyl-γ-butyrolacton

Total Synthesis of Natural α-Tocopherol A short and efficient route to optically pure (+)-(3 R, 7 R)-trimethyldodecanol ( 14 ) is demonstrated, 14 serving as side chain unit in the preparation of natural vitamin E. The synthesis of 14 is based on the concept of using a single optically active C₅-synthon of suitable configuration and functionalization to introduce both asymmetric centres in 14 . (?)-(S)-3-Methyl-γ-butyrolacton ( 1 ) and ethyl (?)-(S)-4-bromo-3-methylbutyrate ( 2 ), respectively, is used in a sequence of either two Grignard C,C-coupling reactions 5 → 8 and 12 → 13 or two Wittig reactions 17a → 18 and 20 → 21 to achieve this goal. 14 is converted to (2 R, 4′R, 8′R)-α-tocopherol (= vitamin E) by coupling with a chroman unit in known manner. Optical purity of products and intermediates is established.     

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.     

Geiparvarin Analogues: Synthesis and Anticancer Evaluation of α-Methylidene-γ-butyrolactone-Bearing Coumarins

To determine some of the structural features of geiparvarin that account for its cytostatic activity in vitro, certain geiparvarin analogues modified in the furan-3(2H)-one moiety and the alkenyloxy substituent were synthesized and tested against the growth of 60 human cancer cell lines derived from nine cancer-cell types. These compounds demonstrated a strong growth-inhibitory activity against leukemia cell lines but were relatively inactive against non-small-cell lung cancers and CNS cancers. Comparison of the mean log GI₅₀ values of γ-[(E)-1-methylprop-1-enyl]-α-methylidene-γ-butyrolactones 7 – 9 revealed that 7-[(E)-3-(2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl)but-2-enyloxy]-2H- 1-benzopyran-2-one ( 8 ; −5.47) was more active than its 6-substituted counterpart 7 (−5.21) and its 3-chloro-4-methyl derivative 9 (−5.31) and had a potency similar to that of geiparvarin (log GI₅₀=−5.41). These results indicated that the furan-3(2H)-one moiety of geiparvarin could be replaced by an α-methylidene-γ-butyrolactone unit without losing the anticancer potency, and that the best substitution site at the coumarin moiety was C(7). The alkenyloxy substituent of 8 was also replaced by a methoxy substituent. Among these α-methylidene-γ-butyrolactones, 7-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]-2H-1-benzopyran-2-one ( 11 ) was the most potent with a mean log GI₅₀ value of −5.83 and a range value of 132 (10^2.12).     

γ-Lactones from malonic acid derivatives

The acid catalyzed cyclization of isopropylidene malonate derivatives of ketones to form α-earboxy-γ-lactones has been shown to occur with boron trifluoride etherate or p-toluenesulfonic acid, as well as with concentrated sulfuric or polyphosphoric acids. A similar cyclization of a diethyl ylidenemalonate to a lactone ester, in relatively poor yield, has also been accomplished. Acid catalyzed cyclization of the ylidenemalononitrile derived from pinacolone to form an α-carbamoyl-γ-lactone has been shown to occur with rearrangement. However, that derived from 2,2-dimethyleyclohexanone cyclized to the secondary carbon of the ring without rearrangement. The isopropylidene malonate derivatives of several ring-substituted and bridged ketones have been converted to α-earboxy-γ-laetones without rearrangement.     

Anwendung der α-Alkinon-Cyclisierung: Synthese von rac-Modhephen

Application of the α-Alkynone Cyclization: Synthesis of rac-Modhephene rac-Modhephene 1 , the first sesquiterpene with a propellane C-skeleton and its epimer rac-epi-modhephene 27 , were synthesized starting from bicyclo[3.3.0]oct-1(5)-en-2-one ( 2 ). The key step in the construction of the [3.3.3]-propellane system is an application of the α-alkynone cyclization, namely 3 → 4 and 11 → 14 . The preferred formation of the propellanes 4 and 14 in this step shows that the insertion of the postulated alkylidene carbene intermediate into tertiary C,H-bonds outweighs the one into the secondary ring-C,H-bonds leading to 12/13 and 15/16 , respectively. The two starting materials for the α-alkynone cyclization, 3 and 11 , were prepared from 2 by the reactions shown in Scheme 3. The further elaboration and separation of the cyclization products 4 and 14 to rac-modhephene 1 and its epimer 27 are outlined in Scheme 5.     

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.     

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.     

Stereoelectronic and steric effect in the Baeyer–Villiger rearrangement of steroidal α-chlorocyclobutanones

The regioselectivity of the Baeyer–Villiger oxidation of α-chlorocyclobutanone derivatives is markedly affected by substituents in position γ to the carbonyl group. The reaction of steroidal α-chlorocyclobutanones with m-chloroperoxybenzoic acid results in the formation of γ-chloro-γ-lactones and/or α-chloro-γ-lactones depending on the substitution pattern of the four-membered ring. In the reactions of γ-unsubstituted α-chlorocyclobutanones, the exclusive formation of γ-chloro-γ-lactone results from the migration of the chlorinated substituent (CHCl) versus the alkyl group (CH₂), contrary to the expected migratory aptitude. In explaining the unusual regioselectivity observed in these reactions, steric effects and dipole interactions in the formation of the reactive Criegee intermediates are considered and the stereoelectronic effect is postulated to be more important than the intrinsic migratory aptitude.     

Photochemische und nicht-photochemische A/D-Secocorrin→Corrin-Cyclisierungen bei 19-Carboxy- und 19-Formyl-1-methyliden-1,19-secocorrinaten. Decarboxylierbarkeit und Deformylierbarkeit von Nickel (II)-19-carboxy- bzw. 19-formyl-corrinaten. Vorläufige Mitteilung

Photochemical and non-photochemical A/D-secocorrin→corrin-cyclizations of 19-carboxy- and 19-formyl-1-methylidene-1,19-secocorrinates. Decarboxylation (and deformylation) of nickel(II)-19-carboxy-(resp. 19-formyl)-corrinates Nickel (II) 1-methylidene-2,2,7,7,12,12-hexamethyl-15-cyano-19-carboxy-1,19-secocorrinate can be induced to cyclize with concomitant decarboxylation to the corresponding corrinate (Scheme 9). Experiments with deuterated derivatives (Scheme 10) indicate that in this decarboxylative A/D-secocorrin→corrin-cyclization the ring closure step precedes decarboxylation. In accord therewith is the finding that the corresponding intermediate nickel(II) 19-carboxy-corrinate (synthesized via photochemical cyclization of the corresponding cadmium complex, Schemes 6 and 9) decarboxylates under very mild conditions. Nickel(II) 1-methylidene-2,2,7,7,12,12-hexamethyl-15-cyano-19-formyl-1,19-secocorrinate cyclizes smoothly to the corresponding 19-formyl-corrinate in the presence of acetic acid/triethylamine. The formyl group of the cyclization product can be eliminated hydrolytically in essentially quantitative yield by treatment with 2N KOH in ethanolic solution (Scheme 11). The non-photochemical (A→D)-cyclization of 19-formyl-1,19-secocorrinoids represents formation of the corrin chromophore at the oxidation level of porphyrinogens and exemplifies how a C₁-fragment that eventually leaves the ligand can fulfill a specific function in the (A→D)-ring closure to a corrin.     

Regio and stereospecific ring expansion of optically active cyclopropylvinylcarbinols. Diastereoselective synthesis of cis Quercus- lactone b.

(-)-(S) dimethyl α-methylsuccinate, from enzymatic resolution, underwent acyloin cyclization followed by stereospecific C4→ C3 ring contraction to provide chiral cyclopropylvinylcarbinols. Then, BF₃-Et₂O induced regio- and stereospecific C3 → C4 ring expansion led to optically active cyclobutanones precursors of cis γ-lactones, with high enantiomeric excesses.     

A 13C and 1H NMR study of diastereomeric α-methylidene-β-hydroxy-γ-alkoxy esters

The ¹³C and ¹H NMR spectra of α-methylidene-β-hydroxy-γ-alkoxy-pentanoates and -decanoates are presented. These data are consistent with a preferred conformation in which an intramolecular hydrogen bond is present. Very characteristic steric shifts in the ¹³C and ¹H NMR spectra provide an efficient tool for the configurational assignment for this class of compounds.     

Investigation of the Cyclopentenone Formation via the α-Alkynone Cyclisation: Synthesis of the Acorone Intermediate 8-Methylspiro[4.5]deca-3,7-dien-2-one

As a further application of the cyclopentenone formation A→C via the thermal α-alkynone cyclisation B→C and in order to test the fate of an isolated C,C-double bond within a molecule under these conditions, we investigated the synthesis of the acorone intermediate 3 starting from the known carboxylic acid 1 . The α-alkynone 2 was obtained from 1 via the acyl chloride 6 and a Pd(II)-catalysed route (22%). The thermolysis of 2 at 550° provided the target molecule 3 (48%) together with the product 9 (20%) of a competing intramolecular ene reaction and its dimer 10 (4%). At a higher thermolysis temperature (650°), the spiro ketone 3 was found to be unstable, affording the retro-Diels-Alder fragments 4-methylidene-2-cyclopentenone ( 12 ) (33%) and isoprene (32%). A further example of the influence of an isolated double bond on the yield of the cyclopentenone-formation sequence A→C was provided by the comparison of the annelation 14→20 (5% overall with Pd(II)-catalysed acylation) with that of its non-olefinic analogue 17→21 (53% overall with Friedel-Crafts acylation).     

Totalsynthese von natürlichem α-Tocopherol. 1. Mitteilung. Herstellung bifunktioneller,optisch aktiver Synthesebausteine für die Seitenkette mit Hilfe mikrobiologischer Umwandlungen

Total Synthesis of Natural α-Tocopherol. I. Preparation of Bifunctional Optically Active Precursors for the Synthesis of the Side Chain by Means of Microbiological Transformations Our concept for a new total synthesis of natural α-tocopherol includes the synthesis of a corresponding (3 R, 7 R)-configurated C₁₅ side chain to be built up by using twice an optically active C₅ unit together with an achiral C₅ end part. (S)-3-methyl-γ-butyrolactone ( 11 ) and (S)-2-methyl-γ-butyrolactone ( 9 ) represent suitable bifunctional C₅-precursors for this purpose. These two key compounds have been prepared by fermentative transformation including the enantioselective hydrogenation of the double bond of ethyl-4, 4-dimethoxy-3-methylcrotonate ( 5 ) by bakers yeast (yielding 11 after ester hydrolysis and cyclization of the fermentation product) and (E)-3-(1′, 3′-dioxolan-2′-yl)-2-buten-1-ol ( 8 ) by the fungus Geotrichum candidum (yielding directly 9 ).     

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.     

Formale Totalsynthese von (±)-Isocomen durch Anwendung der α-Alkinon-Cyclisierung

Formal Total Synthesis of (±)-Isocomen by Application of the α-Alkinon Cyclization A total synthesis of the racemic form of the sesquiterpene isocomene ( A ) was accomplished by application of the cyclopentenone anellation B→D (Scheme 1) which includes the α-alkynone cyclization C→D , a gas-phase flow thermolytic process. Starting with the known product 2 (Scheme 3) of the anellation B→D , the elaboration of ring C of A proceeded in 9 steps to the α-alkynone 16 (Scheme 5) which was cyclized at 540° selectively to give the angularly fused triquinane 4 (77%). A two-step procedure then led to 5 (Scheme 6), a last but one intermediate in a known total synthesis of (±)- A . The conversion of 16 to 4 also demonstrated the compatibility of an acetoxy function with the anellation sequence B→D .     

1, 3-Cycloadditions to Highly Substituted,Strained Double Bonds: Spiro β-lactams from α-methylidene-β-lactams by reactions with diphenylnitrilimine,acetonitrile oxide,nitrones, and diazomethane

Substituted dihydropyrazole-spiro-β-lactams and isoxazolidine-spiro-β-lactam derivatives are regio- and stereoselectively prepared by 1, 3-cydoadditions between substituted α-methylidene-β-lactams and diazomethane, nitrones, or the in-situ-prepared dipoles ‘diphenylnitrilimine’ and acetonitrile oxide. These reactions represent examples for 1, 3-cycloadditions to the highly substituted, strained double bonds of α-methylidene-β-lactams, and they need special experimental conditions as all reaction products are relatively unstable. Especially in solution, the reverse reaction is highly favoured. Regioselectivity and stereoselectivity of the reactions are elucidated mainly by NMR techniques such as 2D-INEPT, ATP, and NOE experiments.     

Totalsynthese von natürlichem α-Tocopherol 3. Mitteilung. Aufbau der Seitenkette mit (−)-(S)-2-Methyl-γ-butyrolacton als zentralem Baustein

Total Synthesis of Natural α-Tocopherol (?)-(S)-2-Methyl-γ-butyrolactone ( 2 ) represents a versatile chiral C₅-synthon. It serves as key intermediate in one of the syntheses of certain isoprenoid derivatives such as (R)-dihydrocitronellol, (3R, 7R)-hexahydrofarnesol and vitamin E of natural configurations. Their syntheses are described in detail.