New Syntheses of Di-π-Substituted Heptalenes

To study the effect of double-bond shifts (DBS) in different type of heptalenes linked to extended π-systems, several di-π-substituted heptalenes were synthesized. 6-[(E)-Styryl]heptalene-dicarboxylate 4 was smoothly converted to 1-(chloromethyl)heptalene-dicarboxylate 5 by treatment with t-BuOK and C₂Cl₆ in THF at −78°. The one-pot reaction of 5 and P(OEt)₃ in the presence of NaI, followed by Wittig-Horner reaction, afforded the 1,6-di-π-substituted heptalene 6 . The reaction of 6-[(1E,3E)-4-phenylbuta-1,3-dienyl]heptalenes 7 or 15 with t-BuOK and benzaldehyde in THF led to the formation of the 1,6-di-π-substituted heptalenes 13 or 16 , together with transesterification products 14 or 17 . The transformation of the MeOCO group at C(4) of 6-[(E)-styryl]heptalene-dicarboxylate 4 to a phenylbuta-1,3-dienyl substituent afforded the 4,6-di-π-substituted heptalene 21a , which is in thermal equilibrium with its DBS isomer 21b in solution. Oxidation of heptalene 22 with SeO₂ in dioxane gave carbaldehyde 23 , which was then subjected to a Wittig reaction to give the 6,9-di-π-substituted heptalene-dicarboxylate 24 .     

New Results in the Synthesis of Styrylazulene Derivatives: Application of the ‘Anil synthesis’ to the preparation of azulenes substituted with styryl groups at the seven-membered ring

The synthesis of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes 5 (R=H, MeO, Cl) has been performed by Wittig reaction of 4,6,8-trimethylazulene-1-carbaldehyde ( 1 ) and the corresponding 4-(R-benzyl)(triphenyl)phosphonium chlorides 4 in the presence of EtONa/EtOH in boiling toluene (see Table 1). In the same way, guaiazulene-3-carbaldehyde ( 2 ) as well as dihydrolactaroviolin ( 3 ) yielded with 4a the corresponding styrylazulenes 6 and 7 , respectively (see Table 1). It has been found that 1 and 4b yield, in competition to the Wittig reaction, alkylation products, namely 8 and 9 , respectively (cf. Scheme 1). The reaction of 4,6,8-trimethylazulene ( 10 ) with 4b in toluene showed that azulenes can, indeed, be easily alkylated with the phosphonium salt 4b . 4,6,8-Trimethylazulene-2-carbaldehyde ( 12 ) has been synthesized from the corresponding carboxylate 15 by a reduction (LiAlH₄) and dehydrogenation (MnO₂) sequence (see Scheme 2). The Swern oxidation of the intermediate 2-(hydroxymethyl)azulene 16 yielded only 1,3-dichloroazulene derivatives (cf. Scheme 2). The Wittig reaction of 12 with 4a and 4b in the presence of EtONa/EtOH in toluene yielded the expected 2-styryl derivatives 19a and 19b , respectively (see Scheme 3). Again, the yield of 19b was reduced by a competing alkylation reaction of 19b with 4b which led to the formation of the 1-benzylated product 20 (see Scheme 3). The ‘anil synthesis’ of guaiazulene ( 21 ) and the 4-R-benzanils 22 (R=H, MeO, Cl, Me₂N) proceeded smoothyl under standard conditions (powered KOH in DMF) to yield the corresponding 4-[(E)-styryl]azulene derivatives 23 (see Table 4). In minor amounts, bis(azulen-4-yl) compounds of type 24 and 25 were also formed (see Table 4). The ‘anil reaction’ of 21 and 4-NO₂C₆H₄CH=NC₆H₅ ( 22e ) in DMF yielded no corresponding styrylazulene derivative 23e . Instead, (E)-1,2-bis(7-isopropyl-1-methylazulen-4-yl)ethene ( 27 ) was formed (see Scheme 4). The reaction of 4,6,8-trimethylazulene ( 10 ) and benzanil ( 22a ) in the presence of KOH in DMF yielded the benzanil adducts 28 to 31 (cf. Scheme 5). Their direct base-catalyzed transformation into the corresponding styryl-substituted azulenes could not be realized (cf. Scheme 6). However, the transformation succeeded smoothly with KOH in boiling EtOH after N-methylation (cf. Scheme 6).     

Light-Induced,Thermal, and Acid-Catalyzed π-Skeletal Rearrangements of Five-Ring-Annelated Heptalenes

It is shown that, upon irradiation in CDCl₃ solution, 5,6,8,10-tetramethylheptalene-1,2-dicarboxylic anhydride ( 6 ) rearranges to its double-bond-shift (DBS) isomer 7 in an equilibrium reaction (Scheme 2). The isomer 7 is DBS stable at ?50°. At ca. 30°, a thermal equilibrium with 97.8% of 6 and 2.2% of 7 is rapidly established. Similarly, the ‘ortho’-anhydrides 9 and 11 (Schemes 4 and 5) can be rearranged to their corresponding DBS isomers 12 and 13 , respectively. Whereas 12 is DBS stable at 30° (at 100° in tetralin, 94.0% of 9 are in equilibrium with 6.0% of 12 ), the i-Pr-substituted isomer 13 is already at 30° in thermal equilibrium with 11 leading to 98.7% of 11 and 1.3% of 13 . It is shown by rearrangement of diasteroisomeric ‘ortho’-anhydrides of known relative and absolute configuration (Scheme 6) that the DBS in such five-ring-annelated heptalenes occurs with retention of the configuration of the heptalene skeleton as already established for other heptalene compounds. It is found that the DBS process may also take place under acid catalysis (e.g. HCl/CH₃OH), thus yielding 9 from 12 (Scheme 9). The ‘ortho’-anhydrides 21 and 23 (Scheme 10) which are isomeric with 9 and 11 (Scheme 3) undergo rapid DBS' already at room temperature. The thermal equilibrium 21?22 consists of 18% of 21 and 82% of 22 at 30° and that of 23?24 of 17% of 23 and 83% of 24 at ?30°. From these equilibrium mixtures, the pure DBS isomer 22 can be obtained by crystallization. Again, these rapid DBS' occur with retention of configuration of the heptalene skeleton (Fig. 4).     

Formation of Heptaleno[1,2-c]furans and Heptaleno[1,2-c]furanones

The dehydrogenation reaction of the heptalene-4,5-dimethanols 4a and 4d , which do not undergo the double-bond-shift (DBS) process at ambient temperature, with basic MnO₂ in CH₂Cl₂ at room temperature, leads to the formation of the corresponding heptaleno[1,2-c]furans 6a and 6d , respectively, as well as to the corresponding heptaleno[1,2-c]furan-3-ones 7a and 7d , respectively (cf. Scheme 2 and 8). The formation of both product types necessarily involves a DBS process (cf. Scheme 7). The dehydrogenation reaction of the DBS isomer of 4a , i.e., 5a , with MnO₂ in CH₂Cl₂ at room temperature results, in addition to 6a and 7a , in the formation of the heptaleno[1,2-c]-furan-1-one 8a and, in small amounts, of the heptalene-4,5-dicarbaldehyde 9a (cf. Scheme 3). The benzo[a]heptalene-6,7-dimethanol 4c with a fixed position of the C?C bonds of the heptalene skeleton, on dehydrogenation with MnO₂ in CH₂Cl₂, gives only the corresponding furanone 11b (Scheme 4). By [²H₂]-labelling of the methanol function at C(7), it could be shown that the furanone formation takes place at the stage of the corresponding lactol [3-²H₂]- 15b (cf. Scheme 6). Heptalene-1,2-dimethanols 4c and 4e , which are, at room temperature, in thermal equilibrium with their corresponding DBS forms 5c and 5e , respectively, are dehydrogenated by MnO₂ in CH₂Cl₂ to give the corresponding heptaleno[1,2-c]furans 6c and 6e as well as the heptaleno[1,2-c]furan-3-ones 7c and 7e and, again, in small amounts, the heptaleno[1,2-c]furan-1-ones 8c and 8e , respectively (cf. Scheme 8). Therefore, it seems that the heptalene-1,2-dimethanols are responsible for the formation of the furan-1-ones (cf. Scheme 7). The methylenation of the furan-3-ones 7a and 7e with Tebbe's reagent leads to the formation of the 3-methyl-substituted heptaleno[1,2-c]furans 23a and 23e , respectively (cf. Scheme 9). The heptaleno[1,2-c]furans 6a, 6d , and 23a can be resolved into their antipodes on a Chiralcel OD column. The (P)-configuration is assigned to the heptaleno[1,2-c]furans showing a negative Cotton effect at ca. 320 nm in the CD spectrum in hexane (cf. Figs. 3–5 as well as Table 7). The (P)-configuration of (–)- 6a is correlated with the established (P)-configuration of the dimethanol (–)- 5a via dehydrogenation with MnO₂. The degree of twisting of the heptalene skeleton of 6 and 23 is determined by the Me-substitution pattern (cf. Table 9). The larger the heptalene gauche torsion angles are, the more hypsochromically shifted is the heptalene absorption band above 300 nm (cf. Table 7 and 8, as well as Figs. 6–9).     

Synthesis of 1‐Methyl‐6,10‐diphenylheptalene Derivatives

The reduction of heptalene diester 1 with diisobutylaluminium hydride (DIBAH) in THF gave a mixture of heptalene‐1,2‐dimethanol 2a and its double‐bond‐shift (DBS) isomer 2b (Scheme 3). Both products can be isolated by column chromatography on silica gel. The subsequent chlorination of 2a or 2b with PCl₅ in CH₂Cl₂ led to a mixture of 1,2‐bis(chloromethyl)heptalene 3a and its DBS isomer 3b . After a prolonged chromatographic separation, both products 3a and 3b were obtained in pure form. They crystallized smoothly from hexane/Et₂O 7 : 1 at low temperature, and their structures were determined by X‐ray crystal‐structure analysis (Figs. 1 and 2). The nucleophilic exchange of the Cl substituents of 3a or 3b by diphenylphosphino groups was easily achieved with excess of (diphenylphospino)lithium (=lithium diphenylphosphanide) in THF at 0° (Scheme 4). However, the purification of 4a / 4b was very difficult since these bis‐phosphines decomposed on column chromatography on silica gel and were converted mostly by oxidation by air to bis(phosphine oxides) 5a and 5b . Both 5a and 5b were also obtained in pure form by reaction of 3a or 3b with (diphenylphosphinyl)lithium (=lithium oxidodiphenylphospanide) in THF, followed by column chromatography on silica gel with Et₂O. Carboxaldehydes 7a and 7b were synthesized by a disproportionation reaction of the dimethanol mixture 2a / 2b with catalytic amounts of TsOH. The subsequent decarbonylation of both carboxaldehydes with tris(triphenylphosphine)rhodium(1+) chloride yielded heptalene 8 in a quantitative yield. The reaction of a thermal‐equilibrium mixture 3a / 3b with the borane adduct of (diphenylphosphino)lithium in THF at 0° gave 6a and 6b in yields of 5 and 15%, respectively (Scheme 4). However, heating 6a or 6b in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO) in toluene, generated both bis‐phosphine 4a and its DBS isomer 4b which could not be separated. The attempt at a conversion of 3a or 3b into bis‐phosphines 4a or 4b by treatment with t‐BuLi and Ph₂PCl also failed completely. Thus, we returned to investigate the antipodes of the dimethanols 2a, 2b , and of 8 that can be separated on an HPLC Chiralcel‐OD column. The CD spectra of optically pure (M)‐ and (P)‐configurated heptalenes 2a, 2b , and 8 were measured (Figs. 4, 5, and 9).     

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.     

Thermal and Ru-catalyzed Reactions of Styryl-Substituted Azulenes with Dimethyl Acetylenedicarboxylate

The thermal reaction of 1-[(E)-styrl]azulenes with dimethyl acetylenedicarboxylate (ADM) in decalin at 190–200° does not lead to the formation fo the corresponding heptalene-1,2-dicarboxylates (Scheme 2). Main products are the corresponding azulene-1,2-dicarboxylates (see 4 and 9 ), accompanied by the benzanellated azulenes trans- 10a and trans- 11 , respectively. The latter compounds are formed by a Diels-Alder reaction of the starting azulenes and ADM, followed by an ene reaction with ADM (cf. Scheme 3). The [RuH₂(PPh₃)₄]-catalyzed reaction of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes (R=H, MeO, Cl; Scheme 4) with ADM in MeCN at 110° yields again the azulene-1,2-dicarboxylates as main products. However, in this case, the corresponding heptalene-1,2-dicarboxylates are also formed in small amounts (3–5%; Scheme 4). The benzanellated azulenes trans- 10a and trans- 10b are also found in small amounts (2–3%) in the reaction mixture. ADM Addition products at C(3) of the azulene ring as well as at C(2) of the styryl moiety are also observed in minor amounts (1–3%). Similar results are obtained in the [RuH₂(PPh₃)₄]-catalyzed reaction of 3-[(E)-styryl]guaiazulene ((E)- 8 ; Scheme 5) with ADM in MeCN. However, in this case, no heptalene formation is observed, and the amount of the ADM-addition products at C(2) of the styryl group is remarkably increased (29%). That the substitutent pattern at the seven-membered ring of (E)- 8 is not responsible for the failure of heptalene formation is demonstrated by the Ru-catalyzed reaction of 7-isopropyl-4-methyl-1-[(E)-styryl]azulene ((E)- 23 ; Scheme 11) with ADM in MeCN, yielding the corresponding heptalene-1,2-dicarboxylate (E)- 26 (10%). Again, the main product is the corresponding azulene-1,2-dicarboxylate 25 (20%). Reaction of 4,6,8-trimethyl-2-[(E)-styryl]azulene ((E)- 27 ; Scheme 12) and ADM yields the heptalene-dicarboxylates (E)- 30A / B , purely thermally in decalin (28%) as well as Ru-catalyzed in MeCN (40%). Whereas only small amounts of the azulene-1,2-dicarboxylate 8 (1 and 5%, respectively) are formed, the corresponding benzanellated azulene trans- 29 ist found to be the second main product (21 and 10%, respectively) under both reaction conditions. The thermal reaction yields also the benzanellated azulene 28 which is not found in the catalyzed variant of the reaction. Heptalene-1,2-dicarboxylates are also formed from 4-[(E)-styryl]azulenes (e.g. (E)- 33 and (E)- 34 ; Scheme 14) and ADM at 180–190° in decalin and at 110° in MeCN by [RuH₂(PPh₃)₄] catalysis. The yields (30%) are much better in the catalyzed reaction. The formation of by-products (e.g. 39–41 ; Scheme 14) in small amounts (0.5–5%) in the Ru-catalyzed reactions allows to understand better the reactivity of zwitterions (e.g. 42 ) and their triyclic follow-up products (e.g. 43 ) built from azulenes and ADM (cf. Scheme 15).     

Synthesis and Characterization of New Heptalenes with Extended π‐Systems Attached to Them

Methyl heptalenecarboxylates of type A and B with π(1) and π(2) substituents in 1,4‐relation (Scheme 1) were synthetized starting with dimethyl 1‐methylheptalene‐4,5‐dicarboxylates 5b and 6b derived from 7‐isopropyl‐1,4‐dimethylazulene (=guaiazulene) and 1,4,6,8‐tetramethylazulene by thermal reaction with dimethyl acetylenedicarboxylate. The further general way of proceeding for the introduction of the π(1) and π(2) substituents is displayed in Scheme 3, and the thus obtained methyl heptalene‐5‐carboxylates of type A and B are listed in Table 1. The C?C bonds of the 2‐arylethenyl and 4‐arylbuta‐1,3‐dien‐1‐yl groups of π(1) and π(2) were in all cases (E)‐configured and showed s‐trans conformation at the C? C bonds (X‐ray and ¹H‐NOE evidence) in the B ‐type as well as in the A ‐type heptalenes (cf. Figs. 5–12). All B ‐type heptalenes showed a strongly enhanced heptalene band I in the wavelength region 440–490 nm in hexane/CH₂Cl₂ 9 : 1 (cf. Table 4 and Figs. 13–20). The A ‐type heptalenes showed in this region only weak absorption, recognizable as shoulders or simply tailing of the dominating heptalene bands II/III (Table 5). Absorption band I of the B ‐type heptalenes appeared almost at the same wavelength as the longest wavelength absorption band of comparable open‐chain α,ω‐diarylpolyenes (cf. Fig. 21). The cyclic double bond shift (DBS) of the A ‐ and B ‐type heptalenes could be photochemically steered in one or the other direction by selective irradiation (cf. Fig. 22).     

Facile Preparation of (±)-12-Epiprostaglandins from 7-Oxabicyclo[2.2.1]hept-5-en-2-one via an all-cis-formyllactone related to Corey lactone

The bicyclic monoselenoacetal 7 , easily obtained from (±)-7-oxabicyclo[2.2.1]hept-5-en-2-one ( 6 ) via a radical addition-acyl migration sequence, was converted to racemic 12-epiprostaglandins 3 and 4 . The key intermediate was the all-cis-formyllactone 2b related to Corey lactone (see 12 ; Scheme 1). The presence of a (tert-butyl)-dimethylsilyl protective group for the 11-OH substituent (prostaglandin numbering) was found to be crucial in avoidingβ -elimination and epimerization during the Wittig-Horner reaction (Scheme 2). Epimerization at C(12) at the formyllactone stage (see 2b ) was also possible and gave the known precursor 1b of naturally occurring prostaglandins and analogs.     

Double-Bond Shifts in [4n]Annulenes as a New Principle for Molecular Switches: First Results with Dimethyl Heptalene-1,2- and -4,5-dicarboxylates

A new concept for molecular switches, based on thermal or photochemical double-bond shifts (DBS) in [4n]annulenes such as heptalenes or cyclooctatetraenes, is introduced (cf. Scheme 2). Several heptalene-1,2- and -4,5-dicarboxylates (cf. Scheme 4) with (E)-styryl and Ph groups at C(5) and C(1), or C(4) and C(2), respectively, have been investigated. Several X-ray crystal-structure analyses (cf. Figs. 1–5) showed that the (E)-styryl group occupies in the crystals an almost perfect s-trans-conformation with respect to the C?C bond of the (E)-styryl moiety and the adjacent C?C bond of the heptalene core. Supplementary ¹H-NOE measurements showed that the s-trans-conformations are also adopted in solution (cf. Schemes 6 and 9). Therefore, the DBS process in heptalenes (cf. Schemes 5 and 8) is always accompanied by a 180° torsion of the (E)-styryl group with respect to its adjacent C?C bond of the heptalene core. The UV/VIS spectra of the heptalene-1,2- and -4,5-dicarboxylates illustrated that it can indeed be differentiated between an ‘off-state’, which possesses no ‘through-conjugation’ of the π-donor substituent and the corresponding MeOCO group and an ‘on-state’ where this ‘through-conjugation’ is realized. The ‘through-conjugation’, i.e., conjugative interaction via the involved s-cis-butadiene substructure of the heptalene skeleton, is indicated by a strong enhancement of the intensities of the heptalene absorption bands I and II (cf. Tables 3–6). The most impressive examples are the heptalene-dicarboxylates 11a , representing the off-state, and 11b which stands for the on-state (cf. Fig.8).     

Benzo[a]heptalenes from Heptaleno[1,2‐c]furans. Part I

It is shown that heptaleno[1,2‐c]furans 1 , which are available in two steps from heptalene‐4,5‐dicarboxylates by reduction and oxidative dehydrogenation of the corresponding vicinal dimethanols 2 with MnO₂ or IBX (Scheme 4), react thermally in a Diels–Alder‐type [4+2] cycloaddition at the furan ring with a number of electron‐deficient dipolarophiles to yield the corresponding 1,4‐epoxybenzo[d]heptalenes (cf. Schemes 6, 15, 17, and 19). The thermal reaction between dimethyl acetylenedicarboxylate (ADM) and 1 leads, kinetically controlled, via a sterically less‐congested transition state (Fig. 4) to the formation of the (M*)‐configured 1,4‐dihydro‐1,4‐epoxybenzo[a]heptalenes, which undergo a cyclic double‐bond shift to the energetically more‐relaxed benzo[d]heptalenes 4 (Schemes 6 and 7). Most of the latter ones exhibit under thermal conditions epimerization at the axis of chirality, so that the (M*)‐ and (P*)‐stereoisomers are found in reaction mixtures. The (P*)‐configured forms of 4 are favored in thermal equilibration experiments, in agreement with AM1 calculations (Table 1). The relative (P*,1S*,4R*)‐ and (M*,1S*,4R*)‐configuration of the crystalline main stereoisomers of the benzo[d]heptalene‐2,3‐dicarboxylates 4a and 4f , respectively, was unequivocally established by an X‐ray crystal‐structure determination (Figs. 1 and 2). Acid‐induced rearrangement of 4 led to the formation of the corresponding 4‐hydroxybenzo[a]heptalene‐2,3‐dicarboxylates 5 in moderate‐to‐good yields (Schemes 8, 13, and 14). When the aromatization reaction is performed in the presence of trifluoroacetic acid (TFA), trifluoroacetates of type 6 and 13 (Schemes 8, 12, and 13) are also formed via deprotonation of the intermediate tropylium ions of type 7 (Scheme 11). Thermal reaction of 1 with dimethyl maleate gave the 2,3‐exo‐ and 2,3‐endo‐configured dicarboxylates 14 as mixtures of their (P*)‐ and (M*)‐epimers (Scheme 15). Treatment of these forms with lithium di(isopropyl)amide (LDA) at ?70° gave the expected benzo[a]heptalene‐2,3‐dicarboxylates 15 in good yields (Scheme 16). Fumaronitrile reacted thermally also with 1 to the corresponding 2‐exo,3‐endo‐ and 2‐endo,3‐exo‐configured adducts 17 , again as mixtures of their (P*)‐ and (M*)‐epimers (Scheme 17), which smoothly rearranged on heating in dimethoxyethane (DME) in the presence of Cs₂CO₃ to the benzo[a]heptalene‐2,3‐dicarbonitriles 18 (Scheme 18). Some cursory experiments demonstrated that hex‐3‐yne‐2,5‐dione and (E)/(Z)‐hexa‐3‐ene‐2,5‐dione undergo also the Diels–Alder‐type cycloaddition reaction with 1 (Scheme 19). The mixtures of the stereoisomers of the 2,3‐diacetyl‐1,4‐epoxytetrahydrobenzo[d]heptalenes 22 gave, on treatment with Cs₂CO₃ in DME at 80°, only mixtures of the regioisomeric inner aldol products 24 and 25 of the intermediately formed benzo[a]heptalenes 23 (Scheme 20).     

Synthesis of (all-E,2R,2′R)-oscillol

Optically active (all-E,2R,2′R)-oscillol (= (all-E,2R,2′R)-3,4,3′,4′-tetradehydro-1,2,1′,2′-tetrahydro-ψ,ψ-carotene-1,2,1′,2′-tetrol; 1 ) was synthesized according to the C₁₀ + C₂₀ + C₁₀ = C₄₀ strategy, applying the Wittig reaction to couple the synthons 4 and 6 . The chiral centre was introduced by a Sharpless dihydroxylation of 3-methylbut-2-enyl 4-nitrobenzoate ( 8 ).     

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 Unique Ceramides and Cerebrosides Occurring in Human Epidermis

The sphingolipids 1a , b and 2a , b which play important roles in epidermal barrier function, were synthesized by N-acylation of C₁₈-sphingosine 3 and 1-O-glucosylated C₁₈-sphingosine 6 , respectively, with ω-acyloxy-substituted fatty acids 4 and 5 (Scheme 1). These fatty acids were obtained from ω-hydroxy-substituted fatty acids 8 and 9 by esterification with linoleic acid ( 7 ). The C₃₄-fatty acid 8 was prepared as follows: C₂₅-Compound 18 was obtained by means of a Wittig reaction of C₁₃-aldehyde 13 with C₁₂-phosphonium salt 15 or of C₁₂-aldehyde 24 with C₁₃-phosphonium salt 21 , respectively, and subseqent hydrogenation and O-deprotection (Scheme 2). Alternatively, 8 was prepared via 30 by copper-catalyzed coupling of C₁₃-alkyl halide 19 with the Grignard reagent derived from C₁₂-alkyl bromide 14 (Scheme 2). Oxidation of 18 to aldehyde 39 and Wittig reaction with C₉-phosphonium salt 41 furnished the desired ω-hydroxy-substituted fatty acid 8 , after O-deprotection (Scheme 3). Similarly, Wittig reaction of C₁₁-phosphonium salt 22 with C₁₂-aldehyde 24 furnished C₂₃-aldehyde 40 , after hydrogenation, O-deprotection, and oxidation; Wittig reaction with compound 41 and subsequent deprotection afforded the desired C₃₂-fatty and 9 (Scheme 3). an alternative strategy furnished compound 8 by a coupling reaction of alkyne 53 with ω-bromo-substitued fatty acid 52 , obtained from compounds 24 and 47 by Wittig reaction, hydrogenation, and introduction of bromide (Scheme 4). Hydrogenation (Lindlar's catalyst) of the resulting C₃₄-alkyne 54 and deprotection furnished 8 .     

Stereoselektive Synthesen von (Z)-(10-Methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yliden)essigsäure

Stereoselective Syntheses of (Z)-(10-Methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)acetic Acid Two stereoselective syntheses for the antiinflammatory compound 1 ((Z)-isomer) are described. In the first approach (Strategy A, Scheme 1) the stereoselective synthesis of 1 was realized via the bicyclic compound 11 under thermodynamic conditions, followed by a thiophene annelation with retention of the double-bond geometry (Schemes 2–4). Optimized conditions were necessary to avoid (E/Z)-isomerization during annelation. In the second approach (Strategy B, Scheme 1), diastereoisomer 17b was obtained selectively from a mixture of the diastereoisomers 17b and 18b by combining thermodynamic epimerization and solubility differences (Scheme 5). Diastereoisomer 17b was converted into the tricyclic compound 23 using a novel thiophene annelation method which we described recently (Scheme 6). In a final step, a stereospecific ‘syn’-elimination transformed the sulfoxide 24 into the target compound 1 (Scheme 7). To avoid (E/Z)-isomerization, it was necessary to trap the sulfenic acid liberated during the reaction. The key reactions of both approaches are highly stereoselective (> 97:3).     

On the Formation of 2‐Sulfonylbenzo[a]heptalene‐1,3‐diols as Precursors for the Synthesis of Colchicinoids

The benzo[a]heptalene formation from 4‐[(R‐sulfonyl)acetyl]heptalene‐5‐carboxylates 15 and 5‐[(R‐sulfonyl)acetyl]heptalene‐4‐carboxylates 16 (R=Ph or morpholino) in the presence of R′SO₂CH₂Li and BuLi has been investigated (Scheme 6). Only the sulfonyl moiety linked to the C?O group at C(4) of the heptalene skeleton is found at C(3) of the formed benzo[a]heptalene‐2,4‐diols 3 in accordance with the general mechanism of their formation (Scheme 3). Intermediates that might rearrange to corresponding 2‐sulfonylbenzo[a]heptalene‐1,3‐diols lose HO^? under the reaction conditions to yield the corresponding cyclopenta[d]heptalenones of type 11 (Schemes 6 and 7). However, the presence of an additional Me group at C(α) of the lithioalkyl sulfones suppresses the loss of HO^?, and 4‐methyl‐2‐sulfonylbenzo[a]heptalene‐1,3‐diols of type 4c have been isolated and characterized for the first time (Schemes 8 and 10). A number of X‐ray crystal‐structure analyses of starting materials and of the new benzo[a]heptalenes have been performed. Finally, benzo[a]heptalene 4c has been transformed into its 1,2,3‐trimethoxy derivative 23 , a benzo[a]heptalene with the colchicinoid substitution pattern at ring A (Scheme 11).     

Synthese von (6R,all-E)-Neoxanthin und verwandten Allen-Carotinoiden

Synthesis of (6R, all-E)-Neoxanthin and Related Allenic Carotenoids We present the first synthesis of enantiomerically pure neoxanthin ( 1 ) by a Wittig-Horner condensation between the ylide from the novel diethyl 12′-apo-15, 15′-didehydroviolaxanthin-12′-phosphonate ( 35 ) and the allenic C₁₅-aldehyde 31 (Scheme 4) via the crystalline 15, 15′-didehydroneoxanthin ( 36 ; 70% yield). After partial hydrogenation of the triple bond of 36 and isomerisation of the (15Z)-intermediate 37 , neoxanthin ( 1 ) was obtained in good yield. Similar syntheses gave (15Z, 9′Z)-neoxanthin ( 45 ; Scheme 5) and (9Z)-15, 15′-didehydroneoxanthin ( 47 ; Scheme 6). Comparison of the physical data of synthetic 1 with those of a freshly isolated sample of neoxanthin from the flowers of Trollius europaeus confirmed their identity. The unusually low melting point of 1 is caused by a very easy thermal isomerisation into a mixture of the neochromes 4 and 5 (Scheme 1). Such a thermal rearrangement is not observed with 15, 15′-didehydroneoxanthin ( 36 ). To explain this, we assume a zwitterionic excited state of the allenic group that induces the rearrangement of the violaxanthin end group into the furanoid epoxide (Scheme 7).     

Aesculaxanthin,a New Carotenoid Isolated from Pollens of Aesculus hippocastanum

From the pollens of Aesculus hippocastanum, a new apocarotenoid was isolated as the main carotenoid and, based on the spectroscopic data, identified as (all-E,3R)-3-hydroxy-6′-apo-β-caroten-6′-al ( 4 , aesculaxanthin). In addition, (all-E)-lutein ( 3 ) and (all-E)-β-citraurin ( 5 ) were isolated. Furthermore, 6 (aesculaxanthol) was prepared by reduction of 4 with NaBH₄ and tentatively identified as natural carotenoid.     

Benzo[a]heptalenes from Heptaleno[1,2‐c]furans. Part 2

It is shown in this ‘Part 2’ that heptaleno[1,2‐c]furans 1 react thermally in a Diels–Alder‐type [4+2] cycloaddition at the furan ring with vinylene carbonate (VC), phenylsulfonylallene (PSA), α‐(acetyloxy)acrylonitrile (AAN), and (1Z)‐1,2‐bis(phenylsulfonyl)ethene (ZSE) to yield the corresponding 1,4‐epoxybenzo[d]heptalenes (cf. Schemes 1, 5, 6, and 8). The thermal reaction of 1a and 1b with VC at 130° and 150°, respectively, leads mainly to the 2,3‐endo‐cyclocarbonates 2,3‐endo‐ 2a and ‐ 2b and in minor amounts to the 2,3‐exo‐cyclocarbonates 2,3‐exo‐ 2a and ‐ 2b . In some cases, the (P*)‐ and (M*)‐configured epimers were isolated and characterized (Scheme 1). Base‐catalyzed cleavage of 2,3‐endo‐ 2 gave the corresponding 2,3‐diols 3 , which were further transformed via reductive cleavage of their dimesylates 4 into the benzo[a]heptalenes 5a and 5b , respectively (Scheme 2). In another reaction sequence, the 2,3‐diols 3 were converted into their cyclic carbonothioates 6 , which on treatment with (EtO)₃P gave the deoxygenated 1,4‐dihydro‐1,4‐epoxybenzo[d]heptalenes 7 . These were rearranged by acid catalysis into the benzo[a]heptalen‐4‐ols 8a and 8b , respectively (Scheme 2). Cyclocarbonate 2,3‐endo‐ 2b reacted with lithium diisopropylamide (LDA) at ?70° under regioselective ring opening to the 3‐hydroxy‐substituted benzo[d]heptalen‐2‐yl carbamate 2,3‐endo‐ 9b (Scheme 3). The latter was O‐methylated to 2,3‐endo‐(P*)‐ 10b . The further way, to get finally the benzo[a]heptalene 13b with MeO groups in 1,2,3‐position, could not be realized due to the fact that we found no way to cleave the carbamate group of 2,3‐endo‐(P*)‐ 10b without touching its 1,4‐epoxy bridge (Scheme 3). The reaction of 1a with PSA in toluene at 120° was successful, in a way that we found regioisomeric as well as epimeric cycloadducts (Scheme 5). Unfortunately, the attempts to rearrange the products under strong‐base catalysis as it had been shown successfully with other furan–PSA adducts were unsuccessful (Scheme 4). The thermal cycloaddition reaction of 1a and 1b with AAN yielded again regioisomeric and epimeric adducts, which could easily be transformed into the corresponding 2‐ and 3‐oxo products (Scheme 6). Only the latter ones could be rearranged with Ac₂O/H₂SO₄ into the corresponding benzo[a]heptalene‐3,4‐diol diacetates 20a and 20b , respectively, or with trimethylsilyl trifluoromethanesulfonate (TfOSiMe₃/Et₃N), followed by treatment with NH₄Cl/H₂O, into the corresponding benzo[a]heptalen‐3,4‐diols 21a and 21b (Scheme 7). The thermal cycloaddition reaction of 1 with ZSE in toluene gave the cycloadducts 2,3‐exo‐ 22a and ‐ 22b as well as 2‐exo,3‐endo‐ 22c in high yields (Scheme 8). All three adducts eliminated, by treatment with base, benzenesulfinic acid and yielded the corresponding 3‐(phenylsulfonyl)‐1,4‐epoxybenzo[d]heptalenes 25 . The latter turned out to be excellent Michael acceptors for H₂O₂ in basic media (Scheme 9). The Michael adducts lost H₂O on treatment with Ac₂O in pyridine and gave the 3‐(phenylsulfonyl)benzo[d]heptalen‐2‐ones 28a and 3‐exo‐ 28b , respectively. Rearrangement of these compounds in the presence of Ac₂O/AcONa lead to the formation of the corresponding 3‐(phenylsulfonyl)benzo[a]heptalene‐1,2‐diol diacetates 30a and 30b , which on treatment with MeONa/MeI gave the corresponding MeO‐substituted compounds 31a and 31b . The reductive elimination of the PhSO₂ group led finally to the 1,2‐dimethoxybenzo[a]heptalenes 32a and 32b . Deprotonation experiments of 32a with t‐BuLi/N,N,N′,N′‐tetramethylethane‐1,2‐diamine (tmeda) and quenching with D₂O showed that the most acid C? H bond is H? C(3) (Scheme 9). Some of the new structures were established by X‐ray crystal‐diffraction analyses (cf. Figs. 1, 3, 4, and 5). Moreover, nine of the new benzo[a]heptalenes were resolved on an anal. Chiralcel OD‐H column, and their CD spectra were measured (cf. Figs. 8 and 9). As a result, the 1,2‐dimethoxybenzo[a]heptalenes 32a and 32b showed unexpectedly new Cotton‐effect bands just below 300 nm, which were assigned to chiral exciton coupling between the heptalene and benzo part of the structurally highly twisted compounds. The PhSO₂‐substituted benzo[a]heptalenes 30b and 31b showed, in addition, a further pair of Cotton‐effect bands in the range of 275–245 nm, due to chiral exciton coupling of the benzo[a]heptalene chromophore and the phenylsulfonyl chromophore (cf. Fig. 10).     

Studies for a Variable Synthesis of Colchicinoids: Construction of Ring A on a Heptalene Moiety

It is shown that heptalene‐4,5‐dicarboxylates 2 , which react with lithiated methyl sulfones mainly in a Michael fashion at C(3) (cf. Scheme 2), so that the formation of 3‐sulfonylbenzo[a]heptalene‐2,4‐diols 5 is repressed or completely suppressed, can be transformed into corresponding pseudo‐esters 15 (Scheme 4). These pseudo‐esters, on treatment with lithiated methyl sulfones, followed by addition of BuLi, furnish the 3‐sulfonylbenzo[a]heptalene‐2,4‐diols 5 in excellent‐to‐moderate yields without formation of Michael adducts or their follow‐up products (cf. Scheme 5 and 6). The reaction of the pseudo‐ester 15a with Li[¹³C]H₂SO₂Ph, followed by treatment with non‐labeled LiCH₂SO₂Ph and then BuLi, led to the exclusive formation of 3‐(phenylsulfonyl)‐[1‐¹³C]benzo[a]heptalene‐2,4‐diol 5a* (Scheme 9). This experiment demonstrates that the (phenylsulfonyl)acetyl groups at C(4) and C(5) of the heptalene core retain their individual positions in the course of the benzo[a]heptalene‐2,4‐diol formation. These findings are only compatible with an intramolecular rearrangement mechanism as depicted in Scheme 10.