Neue Zugänge zu einigen aromatischen Retinoiden

New Approaches to Some Aromatic Retinoids Starting from 2,3,5-trimethylphenol ( 2 ), two pathways to ethyl (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate ( 1 ) and to some of its (Z)-isomers have been developed. The first one is based on a Pd(O)-catalyzed arylation of (Z)-3-methylpent-2-en-4-yn-l-ol ( 6 ) with 4-bromo-2,3,5-trimethylanisol ( 5 ). The acetylenic C₁₅?alcohol 9 was transformed into the corresponding acetylenic phosphonium salt 10 , which was catalytically hydrogenated to the olefinic Wittig salt. Wittig olefination led, then, to the (6Z, 8Z)- and (4Z, 6Z, 8Z)-isomers, 7 and 8 , respectively. In a second approach, Friedel-Crafts reaction of 3-methylpent-l-en-4-yn-3-ol with the 2,3,5-trimethylanisol gave a C₁₅-intermediate with a terminal C?C bond in the side chain. After deprotonation and reaction with a C₅ aldehyd, the corresponding C₂₀-intermediate could be isolated in high yield. Finally, further conversion led predominantly to the (all-E)-retinoid, accompanied by its (9Z)- and (13Z)-isomers.     

Synthesis of Bixin and Three Minor Carotenoids from Annatto (Bixa orellana)

The three apocarotenoids methyl (9Z)-8′-oxo-6,8′-diapocaroten-6-oate ( 2 ), methyl (9Z)-10′-oxo-6,10′-diapocaroten-6-oate ( 4 ), and methyl (9Z)-14′-oxo-6,14′-diapocaroten-6-oate ( 5 ), recently isolated from annatto, were synthesized. The key step of all three syntheses was the Wittig reaction of the (Z)-terminus 6 with the phosphonium salts 15 , 18 , and 24 , carrying the polyene chain. Bixin ( 1 ) was synthesized from 2 in a Horner-Emmons reaction.     

Technical Procedures for the Syntheses of Carotenoids and Related Compounds from 6-Oxo-isophorone: Syntheses of (3R,3′R)-Zeaxanthin. Part II

Starting from the readily available, optically active (4R)-hydroxy-2,2,6-trimethylcyclohexanone ( 2 ), a new technical synthesis of (3R,3′R)-zeaxanthin is described. According to a completely new C₉+C₂+C₄ = C₁₅ scheme, the ketone 2 was protected, ethynylated with Li-acetylide, and the C₁₁-intermediate 6 was acetylated, followed by dehydration. The product 10 was protected, deprotonated, and subsequently reacted with methyl vinyl ketone to provide the C₁₅-propargylate 13 . Reduction in situ of 13 with Vitride yielded the olefinic C₁₅-alcohol 11 which was transformed into the known C₁₅-Wittig salt 3 . A double Wittig reaction of this salt with the C₁₀-dialdehyde 4 afforded nature-identical zeaxanthin ( 1 ).     

An Expeditious Synthesis of Methyl Jasmonate

We present an efficient three‐step, two‐pot synthesis of methyl jasmonate (trans‐ 1 ) based on Diels–Alder cycloaddition of cyclopent‐2‐enone ( 2 ) and chloroprene (= 2‐chlorobuta‐1,3‐diene; 3d ) in either CHCl₃ or CH₂Cl₂, catalyzed by SnCl₄ (0.2 mol‐equiv.) at 20° (75% yield). Subsequent ozonolysis of a cis/trans 55 : 45 mixture of the cycloadduct 4d in either CH₂Cl₂ or AcOEt at ? 78°, followed by addition of Me₂S and MeOH in the presence of NaHCO₃, afforded, in 64% yield, a cis/trans 40 : 60 mixture of the known aldehyde 5c . The latter was reacted at ? 50° under salt‐free conditions with the propyl Wittig reactant to furnish 1 as a cis/trans 20 : 80 mixture ((E/Z) 3 : 97). Alternatively, a cis/trans 7 : 93 mixture ((E/Z) 4 : 96) was obtained in 88% yield from epimerized 5c (AcOH, H₂O, 40°; 99%) under usual Wittig conditions at ? 20°.     

Catalytic Cyclopropanation of Ricinolic Acid Derivatives with Diazomethane

The reaction of ricinolic acid methyl ester with diazomethane in the presence of Co(BF₄)₂·6H₂Oresults in selective methylation of the hydroxy group. Methyl (2Z'12R)-12-acetoxy-9-octadecenoate reactswith diazomethane in the presence of Pd(acac)₂, leading to formation of a mixture of cis-cyclopropanated(9S'10S'12R)-, (9R'10R'12R)-diastereoisomers at a ratio of 3:2 (overall yield 73%). Under similarconditions methyl (9Z)-12-oxo-9-octadecenoate gives rise to optically inactive methyl cis-8-[2-(2-oxooctyl)-cyclopropyl]octanoate.     

Asymmetric Total Synthesis of (11R, 12S, 13S, 9Z, 15Z)-9, 12, 13-Trihydroxyoctadeca-9, 15-dienoic Acid,a self-defensive agent against rice-blast disease

The Diels-Alder adduct of furan and 1-cyanovinyl (1′R)-camphanate was converted into methyl [(tert-butyl)-dimethylsilyl 5-deoxy-2, 3-O-isopropylidene-β-L -ribo-hexofuranosid] uronate ((+)- 4 ). Reduction with diisobutyl-aluminium hydride gave the corresponding aldehyde which was condensed with the ylide derived from triphenyl-(propyl)phosphonium bromide to give (1R, 2S, 3S, 4S)-1-[(tert-butyl)dimethylsilyloxy]tetrahedro-2, 3-(isopropyl-idenedioxy)-4-[(Z)-pent-2′ -enyl]furan ((+)- 7 ). Removal of the silyl protective group gave a mixture of the corresponding furanose that underwent Wittig reaction with the ylide derived from [8-(methoxycarbonyl)-octyl]triphenylphosphonium bromide to yield methyl (11R, 12S, 13S, 9Z, 15Z)-13-hydroxy-11, 12-(isopropylidene-dioxy)octadeca-9, 15-dienoate ((?)- 9 ). Acidic hydrolysis, then saponification afforded (11R, 12S, 13S, 9Z, 15Z)-11, 12, 13-trihydroxyoctadeca-9, 15-dienoic acid ( 1 ).     

Sterospecific Syntheses and Spectroscopic Properties of Isomeric 2,4,6,8-Undecatetraenes. New Hydrocarbons from the Marine Brown Alga Giffordia mitchellae. Part IV.

Giffordene (=(2Z,4Z,6E,8Z)-2,4,6,8-undecatetraene; 9f ) and five steroisomers are new C₁₁H₁₆ hydrocarbons from the marine brown alga Giffordia mitchellae. Their synthesis is based on non-stereoselective Wittig reactions of (E)-2-alkenals with appropriate acetylenic phosphoranes and subsequent chromatographic separation of the resulting (E/Z)-pairs. The uniform enynes (>98% purity) are then stereospecifically reduced to (Z)-alkenes with Zn(Cu/Ag) in aq. MeOH at r.t. ¹³C- and ¹ H-NMR data of the new tetraenes are presented. Biosynthetically, giffordene ( 9f ) originates from dodeca-3,6,9-trienoic acid via an unstable (3Z,5Z,8Z)-1,3,5,8,-undecatetraene followed by a thermally allowed antarafacial 1,7-sigmatropic hydrogen shift to the (2Z,4Z,6E,8Z)-isomer 9f .     

Synthesen der stereoisomeren (±)-γ-Damascone

Under the conditions of the Wharton reaction, the (±)-epoxy-γ-dihydroionones 2 and 3 are transformed into the allylic alcohols 4–10 . γ-Damascols 4, 5 and 8 were oxidised to cis- and trans-γ-damascone 12 and 13 . Alternatively, dehydro-γ-damascol 18 was obtained by Wittig rearrangement of butinyl ether 17 , and converted into damascones 12 and 13 .     

Epoxidation of Polyunsaturated Fatty Acid Double Bonds by Dioxirane Reagent: Regioselectivity and Lipid Supramolecular Organization

The use of dimethyldioxirane (DMD) as the epoxidizing agent for polyunsaturated fatty acids was investigated. With fatty acid methyl esters, this is a convenient method for avoiding acidic conditions, using different solvents, and simplifying the isolation procedures, with less contamination due to by‐products. The reagent was also tested with free fatty acids in water. In this case, the supramolecular organization of fatty acids influenced the reaction outcome, and the epoxidation showed interesting regioselective features. The C?C bonds closest to the aqueous‐micelle interface is the most favored for the interaction with dimethyldioxirane. The preferential epoxidation of linoleic acid (= (9Z,12Z)‐octadeca‐9,12‐dienoic acid) to the 9,10‐monoepoxy derivative was achieved, with a high yield and 65% regioselectivity. In case of arachidonic acid (= (5Z,8Z,11Z,14Z)‐eicosa‐5,8,11,14‐tetraenoic acid) micelles, the regioselective outcome with formation of the four possible monoepoxy isomers was studied under different conditions. It resulted to be a convenient synthesis of ‘cis‐5,6‐epoxyeicosatrienoic acid’ (= 3‐[(2Z,5Z,8Z)‐tetradeca‐2,5,8‐trienyl]oxiran‐2‐butanoic acid), whereas in reverse micelles, epoxidation mostly gave ‘cis‐14,15‐epoxyeicosatrienoic acid (= (5Z,8Z,11Z)‐13‐(3‐pentyloxiran‐2‐yl)trideca‐5,8,11‐trienoic acid).     

Enantioselectivity and cis/trans-Selectivity in Dirhodium(II)-Catalyzed addition of diazoacetates to olefins

The Rh¹¹-catalyzed carbenoid addition of diazoacetates to olefins was investigated with [Rh₂{(4S)-phox}₄] ( 1 ;phox = tetrakis[(4S)-tetrahydro-4-phenyloxazol-2-one]), [Rh₂{(2S)-mepy}₄] ( 2 ; mepy = tetrakis[methyl (2S)-tetrahydro-5-oxopyrrole-2-carboxylate]), and [Rh₂(OAc)₄] ( 3 ). While catalysis with 2 and 3 afford preferentially trans-cyclopropanecarboxylates, the cis-isomers are the major products with 1 . In general, the enantioselectivities achieved with 1 and 2 are comparable. Additions catalyzed by 1 are strongly sensitive to steric effects. Highly substituted olefins afford cyclopropanes in only poor yield. The preferential cis-selectivity observed in reactions catalyzed by 1 is attributed to dominant interactions between the ligand of the catalyst and the substituents of both olefin and diazoacetate, which overrule the steric interactions between olefin and diazoacetate in the transition state for carbene transfer.     

2, 3-Alkadiensäureester als Dienophile; Anwendung bei der Synthese von (+)-(R)-Lasiodiplodin

2,3-Alkadienoates as Dienophiles, Application in the Synthesis of (+)-(R)-Lasiodiplodin Methyl 2, 3-alkadienoates 2 are shown to react at 80° with l, 1-dimethoxy-3trimethylsilyloxy-l, 3-butadiene (1) to give the adducts 3 in good yields. Rearrangement of 3 , catalyzed by p-toluenesulfonic acid or by sodium methoxide, affords the 6-substituted methyl 4-hydroxy-2-methoxybenzoates 4 (R ? H, CH₃, C₆H₅). An analogous reaction sequence starting with (-)-(11 R)-dodeca-2, 3-dien-11-olide ((-) -6 ) and 1 leads, via the adduct (R)-7 , to (+)-( R )-lasiodiplodin ((+) ?8 ) with properties identical to those of the natural product. The allene lactone (-) -6 was prepared by an intramolecular Wittig condensation of (R) ?5 , produced from (–)-(R)-9-hydroxydecanoic acid.     

Analogues of α‐Campholenal (= (1R)‐2,2,3‐Trimethylcyclopent‐3‐ene‐1‐acetaldehyde) as Building Blocks for (+)‐β‐Necrodol (= (1S,3S)‐2,2,3‐Trimethyl‐4‐methylenecyclopentanemethanol) and Sandalwood‐like Alcohols

To complete our panorama in structure–activity relationships (SARs) of sandalwood‐like alcohols derived from analogues of α‐campholenal (= (1R)‐2,2,3‐trimethylcyclopent‐3‐ene‐1‐acetaldehyde), we isomerized the epoxy‐isopropyl‐apopinene (?)‐ 2d to the corresponding unreported α‐campholenal analogue (+)‐ 4d (Scheme 1). Derived from the known 3‐demethyl‐α‐campholenal (+)‐ 4a , we prepared the saturated analogue (+)‐ 5a by hydrogenation, while the heterocyclic aldehyde (+)‐ 5b was obtained via a Bayer‐Villiger reaction from the known methyl ketone (+)‐ 6 . Oxidative hydroboration of the known α‐campholenal acetal (?)‐ 8b allowed, after subsequent oxidation of alcohol (+)‐ 9b to ketone (+)‐ 10 , and appropriate alkyl Grignard reaction, access to the 3,4‐disubstituted analogues (+)‐ 4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)‐ 4b or its methyl ketone (+)‐ 4h , afforded stereoselectively the trans‐epoxy derivatives 11a,b , while the minor cis‐stereoisomer (+)‐ 12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C₂ or C₃ side chain). Alternatively, the corresponding trans‐epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans‐epoxy aldehyde (+)‐ 11a or by stereoselective epoxidation of the α‐campholenol (+)‐ 15a or of its acetate (?)‐ 15b , respectively. Their cis‐analogues were prepared starting from (+)‐ 12a . Either (+)‐ 4h or (?)‐ 11b , was submitted to a Bayer‐Villiger oxidation to afford acetate (?)‐ 16a . Since isomerizations of (?)‐ 16 lead preferentially to β‐campholene isomers, we followed a known procedure for the isomerization of (?)‐epoxyverbenone (?)‐ 2e to the norcampholenal analogue (+)‐ 19a . Reduction and subsequent protection afforded the silyl ether (?)‐ 19c , which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)‐ 20c . Further oxidation and epimerization furnished the trans‐ketone (?)‐ 17a , a known intermediate of either (+)‐β‐necrodol (= (+)‐(1S,3S)‐2,2,3‐trimethyl‐4‐methylenecyclopentanemethanol; 17c ) or (+)‐(Z)‐lancifolol (= (1S,3R,4Z)‐2,2,3‐trimethyl‐4‐(4‐methylpent‐3‐enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)‐ 4b gave the saturated cis‐aldehyde (+)‐ 21 , readily reduced to its corresponding alcohol (+)‐ 22a . Similarly, hydrogenation of β‐campholenol (= 2,3,3‐trimethylcyclopent‐1‐ene‐1‐ethanol) gave access via the cis‐alcohol rac‐ 23a , to the cis‐aldehyde rac‐ 24 .     

α-Methylidene- and α-Alkylidene-β-lactams from Nonproteinogenic Amino Acids

Treatment of methyl 2-(1-hydroxyalkyl)prop-2-enoates 1 with conc. HBr solution afforded methyl (Z)-2-(bromomethyl)alk-2-enoates 2 , which were transformed regioselectively into N-substituted methyl (E)-2- (aminomethyl)alk-2-enoates 3 (S_N2 reaction) and into N-substituted methyl 2-(1-aminoalkyl)prop-2-enoates 4 (S_N2′ reaction). Regiocontrol of nucleophilic attack by amine was accomplished simply by choice of solvent, the S_N2 reaction occurring in MeCN and the S_N2′ reaction in petroleum ether. Hydrolysis and lactamization afforded β-lactams 7 and 8 , containing an exocyciic alkylidene and methylidene group at C(3), respectively.     

Technical Procedures for the Syntheses of Carotenoids and Related Compounds from 6-Oxo-isophorone: Syntheses of (3R,3′R)-Zeaxanthin. Part I

Starting from the readily available, optically active (4R)-4-hydroxy-2,2,6-trimethylcyclohexanone ( 1 ), a new technical synthesis of (3R,3′R)-zeaxanthin is described. According to a 2(C₉ + C₆) + C₁₀ = C₄₀ construction scheme, the ketone 1 was first transformed with (E)-3-methylpent-2-en-4-yn-1-ol ( 5 ) into a C₁₅-intermediate which, by a three-step sequence, could be converted into the known olefinic C₁₅-Wittig salt 4 . Optimized conditions for the final Wittig reaction of 4 with the C₁₀-dialdehyde 3 are discussed. Based on 1 , the overall yield of the entire technical process is ca. 40%.     

Stereocontrolled synthesis of (3Z,5E)-6-aryl-3-methylhexa-3,5-dien-1-ols,intermediates in the synthesis of strobilurin antibiotics

(2E,4E)-5-Aryl-2-(2-benzyloxyethyl)penta-2,4-dien-1-als (aryl is phenyl and 4-methox-yphenyl) were reduced with NaBH₄ quantitatively and stereospecifically to the corresponding penta-2(E),4(E)-dien-1-ols. The hydroxymethyl group in the latter was transformed into a methyl one with a stereoselectivity of 92–97%. Debenzylation of the resulting (1E,3Z)-1-aryl-6-benzyloxy-4-methylhexa-1,3-dienes with AlCl₃ in the presence of PhNMe₂ afforded the target (3Z,5E)-6-aryl-3-methylhexa-3,5-dien-1-ols; the configuration of the C=C bonds in the conjugated aryl diene systems was retained at 95%.     

Synthesis of cannabinoid model compounds. Part 2: (3R, 4R)-Δ1(6)-Tetrahydrocannabinol-5″-oic acid and 4″(R,S)-Methyl-(3R, 4R)-Δ1(6)-tetrahydrocannabinol-5″-oic Acid

Two novel cannabinoid model compounds, (3R, 4R)-Δ¹⁽⁶⁾-tetrahydrocannabinol-5″-oic acid (22) and 4″(R, S)-methyl-(3R, 4R)-Δ¹⁽⁶⁾-tetrahydrocannabinol-5″-oic acid (23) were synthesized by acid-catalyzed condensation of (+)-trans-p-mentha-2, 8-dien-l-ol (1) with the substituted resorcinols 18 and 19 obtained by a Wittig reaction between 3, 5-bis(benzyloxy)benzaldehyde (7) and methyl 4-bromobutanoate (10) or methyl 4-bromo-2(R, S)-methylbutanoate (11) resp. with subsequent hydrogenation. The resulting methyl esters 20 and 21 were hydrolyzed to give acids 22 and 23 .     

Stereoselective Iodolactonization of 4‐Allenoic Acids with Efficient Chirality Transfer: Development of a New Electrophilic Iodination Reagent

A highly stereoselective iodolactonization of 4‐allenoic acids with a new sterically demanding electrophilic iodination reagent to afford optically active γ‐butyrolactones has been developed. The reaction shows high efficiency of axial chirality transfer and excellent Z/E selectivity and has been applied to the synthesis of chiral cis‐β,γ‐disubstituted γ‐butyrolactones to give very high diastereomeric and enantiomeric excess values. The reaction has been successfully utilized in the synthesis of naturally occurring compounds (+)‐cis‐whisky lactone and (+)‐cis‐3‐methyl‐4‐decanolide.     

Synthese des (R)-trans-11-Hydroxy-8-dodecensäure-lactons (Recieifeiolid)

Synthesis of Recifeiolide The synthesis of the mould metabolite recifeiolide (VIII), a 12-membered ring lactone, is described. 1,3-Butandiol was resolved with (?)-camphanic acid via (R)-1-iodo-3-butanol (II) into (R)-3-hydroxybutyl triphenyl phosphonium iodide (III). Wittig condensation of the phosphorane derived from III with methyl 8-oxo-octanoate (V) led to the methyl trans-11-hydroxy-8-dodecenoate (VI). The corresponding hydroxy acid VII was transformed into the S-(2-pyridyl) carbothioate which cyclizes under the influence of silver ion to the lactone VIII. With (?)-(R)-1,3-butandiol (I) as starting material the naturally occurring (+)-(R)-recifeiolide (VIII) is produced in 70% yield from VII.     

Stereoselective Synthesis of Isomers of the Naturally Occurring 13-Hydroxy-2,4,9-tetradecatrienoic Acid. Part II [1]

The stereoselective syntheses of four unsaturated hydroxy fatty acids 13S,2E,4E,9E)- 13-hydroxy-2,4,9-tetradecatrienoic acid, (13S,9Z,11E)-13-hydroxy-9,11-tetradecadienoic acid, (13S,9E, 11E)-13-hydroxy-9,11-tetradecadienoic acid, and (13S,2E,4E,9E)-13-hydroxy-2,4,9,11-tetradecatrienoic acid, are described. Wittig reactions, regioselective oxidation of dialcohol 3, and diastereomerization were used.     

(Z)-4,7-Octadiensäure-äthylester und (Z)-Buttersäure-3,5-hexadienylester,zwei neue Aromastoffe der roten Passionsfrucht

Ethyl (Z)-4,7-Octadienoate and (Z)-3,5-Hexadienyl Butyrate, two New Aroma Components of the Purple Passionfruit The isolation of ethyl (Z)-4,7-octadienoate ( 1 ) and (Z)-3,5-hexadienyl butyrate ( 2 ), two new and important aroma constituents of the purple passionfruit (Passiflora edulis SIMS ) is reported. Ester 1 was synthesized by two different routes: (1) via a Wittig reaction between the known 4-oxobutyrate 4 and 3-butenylidenephosphorane, and (2) by thermolysis of (Z)-8-acetoxy-4-octenoate 7 which was readily accessible from (Z,Z)-1,5-cyclooctadiene. Ester 2 was prepared from the known hex-3-yn-5-en-1-ol ( 8 ) by a stereoselective (Z)-reduction of the triple bond to 9 , using Rieke's active metallic zinc, followed by esterification. The organoleptic properties and the taste threshold values of 1 and 2 are given.