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Bicontinuous lipidic cubic phases (LCPs) exhibit a combination of material properties that make them highly interesting for various biomaterial applications: they are nontoxic, biodegradable, optically transparent, thermodynamically stable in excess water, and can incorporate active molecules of virtually any polarity. Here we present a molecular system comprising host lipid, water, and designed lipidic additive, which form a structured, pH-sensitive lipidic matrix for hydrophilic as well as hydrophobic drug incorporation and release. The model drug doxorubicin (Dox) was loaded into the LCP. Tunable interactions with the lipidic matrix led to the observed pH-dependent drug release from the phase. The rate of Dox release from the cubic phase at pH 7.4 was low but increased significantly at more acidic pH. A small amount of a tailored diacidic lipid (lipid 1) added to the monoolein LCP modified the release rate of the drug. Phase identity and structural parameters of pure and doped mesophases were characterized by small-angle X-ray scattering (SAXS), and release profiles from the matrix were monitored electrochemically. Analysis of the release kinetics revealed that the total amount of drug released from the LCP matrix is linearly dependent on the square root of time, implying that the release mechanism proceeds according to the Higuchi model.

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 CC 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 CC 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).

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 CH bond is HC(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).

Azulenes and acetylenedicarboxylates react under acid catalysis (Bronsted or Lewis) and form (2aRS,8aSR)-2a,8a-dihydrocyclopenta[cd]azulene-1,2-dicarboxylates as intermediate products, which then dimerize by central bond-formation between C(2a1) and C(2′a1) and various peripheral C,C′-atoms of the dihydroazulene fragments, depending on the substituents present. The reactions are often accompanied by the formation of side-products, such as 2-(azulen-1-yl)fumarates and -maleates and others caused by H-shifts of the primary intermediates. H-Shifts between the two tetrahydrocyclopenta[cd]azulene parts of the heptacyclic structures were also found.

Incubation of deuteriated precursors in cultures of Flavobacterium produced specifically deuteriated carotenoids. Analysis of these led to several conclusions: i) Lycopene is a direct precursor of β,β-carotene. ii) Its terminal Me groups retain their integrity during cyclization: there is a stereospecific folding of the 1,5-diene. The Me(16,16′) groups of lycopene become the Me(16,16′) of β,β-carotene. Consequently, the folding must follow the C2(E,E) mode. iii) Incorporation of deuterium was sufficiently extensive to permit CD measurements on the isolated β,β-carotene, allowing its centers of chirality to be assigned as (1S,1′S). iv) The same chirality resulted from incorporation of [2H3]mevalonate into zeaxanthin. The syntheses of specifically deuteriated [2H3]GPP, [2H3]FPP, and [2H3]GG are described.

The reaction of guaiazulene (4) and dimethyl acetylenedicarboxylate (ADM) in tetralin or toluene, catalyzed by 5 mol-% of trifluoroacetic acid (TFA) at ambient temperature, leads to the formation of the corresponding heptalene-4,5-dicarboxylate 6 and a guaiazulenyl-substituted 2,2a,4a,8b-tetrahydrocyclopent[cd]azulene derivative 7 beside the expected guaiazulenyl-substituted ethenedicarboxylates (E)-5 and (Z)-5 as main products (Scheme 2). The structure of 7 was unequivocally established by an X-ray crystal-structure analysis (Fig. 1). Precursor of 7 must be the 2a,4a-dihydrocyclopent[cd]azulene-3,4-dicarboxylate 9 which reacts, under TFA catalysis, with a second molecule of 4 (Scheme 3). No formation of products of type 7 has been observed in the TFA-catalyzed reaction of 4,6,8-trimethyl- and 1,4,6,8-tetramethylazulene (13 and 16, respectively) and ADM (Scheme 4). On the other hand, the TFA-catalyzed reaction of azulene (18) itself and ADM at ambient temperature gives rise to a whole variety of new products (Scheme 5), the major part of which is derived from dimethyl 2a,4a-dihydrocyclopent[cd]azulene-3,4-dicarboxylate (25) as the main intermediate (Scheme 6). Nevertheless, for the formation of the 2a,4a,6,8b-tetrahydrocyclobut[a]azulene derivatives (E)-24a and (E)-24b, a corresponding 2a,8b-dihydro precursor 29 has to be postulated as crucial intermediate (Scheme 8).

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 CC bond of the (E)-styryl moiety and the adjacent CC 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 CC 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).

A series of novel lipids with designed functionalities were synthesized. These lipids are based on conjugation of α-amino acids and their esters, cationic, anionic, neutral, and photochromic moieties to the lipophilic 9-cis octadecenyl chains by amide, ester, thioester, or amine bonds. Because of the plasticity of lipidic cubic phases, it is envisaged that when mixed with monooleoyl-rac-glycerol (monoolein, MO) and water at appropriate proportions, they would assemble to form bicontinuous lipidic cubic phases (LCPs) that exhibit the well-known material properties of LCPs such as phase stability, optical transparency, and chemical permeability. Moreover, due to the nature and position of the functionality at the headgroup region, we envision them to perform as functional materials by design.

Azulene-1-carbaldehydes which have Me substituents at C(3) and C(8) and no substituent at C(6) react with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° to yield exclusively the Diels-Alder adduct at the seven-membered ring (cf. Scheme 3). The corresponding 1-carboxylates behave similarly (Scheme 4). Azulene-1-carbaldehydes which possess no Me substituent at C(8) (e.g.11, 12 in Scheme 2) gave no defined products when heated with ADM in decalin. On the other hand, Me substitutents at C(2) may also assist the thermal addition of ADM at the seven-membered ring of azulene-1-carbaldehydes (Scheme 6). However, in these cases the primary tricyclic adducts react with a second molecule of ADM to yield corresponding tetracyclic compounds. The new tricyclic aldehydes 16 and 17 which were obtained in up to 50% yield (Scheme 3) could quantitatively be decarbonylated with [RhCl(PPh3)3] in toluene at 140° to yield a thermally equilibrated mixture of four tricycles (Scheme 8). It was found that the thermal isomerization of these tricycles occur at temperatures as low as 0° and that at temperatures > 40° the thermal equilibrium between the four tricycles is rapidly established via [1,5]-C shifts. The establishment of the equilibrium makes the existence of two further tricycles necessary (cf. Scheme 8). However, in the temperature range of up to 85° these two further tricycles could not be detected by 1H-NMR. When heated in the presence of excess ADM in decalin at 180°, the ‘missing’ tricyclic forms could be evidenced by their tetracyclic trapping products ‘anti’-45 and ‘anti’-48, respectively (Scheme 9).

The reaction of highly alkylated azulenes with dimethyl acetylenedicarboxylate (ADM) in decalin or tetralin at 180–200° yields, beside the expected heptalene- and azulene-1,2-dicarboxylates, tetracyclic compounds of type ‘anti’-V and tricyclic compounds of type E (cf. Schemes 2–4 and 8–11). The compounds of type ‘anti’-V represent Diels-Alder adducts of the primary tricyclic intermediates A with ADM. In some cases, the tricyclic compounds of type E also underwent a consecutive Diels-Alder reaction with ADM to yield the tetracyclic compounds of type ‘anti’- or ‘syn’-VI (cf. Schemes 2 and 8–11). The tricyclic compounds of type E, namely 4 and 8, reversibly rearrange via [1,5]-C shifts to isomeric tricyclic structures (cf. 18 and 19, respectively, in Scheme 6) already at temperatures > 50°. Photochemically 4 rearranges to a corresponding tetracyclic compound 20via a di-π-methane reaction. The observed heptalene- and azulene-1,2-dicarboxylates as well as the tetracyclic compounds of type ‘anti’'-V are formed from the primary tricyclic intermediates Avia rearrangement (heptalenedicarboxylates), retro-Diels-Alder reaction ( azulenedicarboxylates), and Diels-Alder reaction with ADM. The different reaction channels of A are dependent on the substituents. However, the main reaction channel of A is its retro-Diels-Alder reaction to the starting materials (azulene and ADM). The highly reversible Diels-Alder reaction of ADM to the five-membered ring of the azulenes is HOMO(azulene)/LUMO(ADM)-controlled, in contrast to the at 200° irreversible ADM addition to the seven-membered ring of the azulenes to yield the Diels-Alder products of type E. This competing reaction must occur on grounds of orbital-symmetry conservation under SHOMO(azulene)/LUMO(ADM) control (cf. Schemes 20–22). Several X-ray diffraction analyses of the products were performed (cf. Chapt. 4.1).

The thermal reaction of 7-isopropyl-1,3,4-trimethylazulene (3-methylguaiazulene; 2) with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° leads to the formation of the corresponding heptalene- (5a/5b and 6a/6b; cf. Scheme 3) and azulene-1,2-dicarboxylates (7 and 8, respectively). Together with small amounts of a corresponding tetracyclic compound (‘anti’-13) these compounds are obtained via rearrangement ( 5a/5b and 6a/6b), retro-Diels-Alder reaction ( 7 and 8), and Diels-Alder reaction with ADM ( ‘anti’-13) from the two primary tricyclic intermediates (14 and 15; cf. Scheme 5) which are formed by site-selective addition of ADM to the five-membered ring of 2. In a competing Diels-Alder reaction, ADM is also added to the seven-membered ring of 2, leading to the formation of the tricyclic compounds 9 and 10 and of the Diels-Alder adducts ‘anti’-11 and ‘anti’-12, respectively of 9 and of a third tricyclic intermediate 16 which is at 200° in thermal equilibrium with 9 and 10 (cf. Scheme 6). The heptalenedicarboxylates 5a and 5b as well as 6a and 6b are interconverting slowly already at ambient temperature (Scheme 4). The thermal reaction of guaiazulene (1) with excess ADM in decalin at 190° leads alongside with the known heptalene- (3a) and azulene-1,2-dicarboxylates (4; cf. Schemes 2 and 7) to the formation of six tetracyclic compounds ‘anti’-17 to ‘anti’-21 as well as ‘syn’-19 and small amounts of a 4:1 mixture of the tricyclic tetracarboxylates 22 and 23. The structure of the tetracyclic compounds can be traced back by a retro-Diels-Alder reaction to the corresponding structures of tricyclic compounds (24--29; cf. Scheme 8) which are thermally interconverting by [1,5]-C shifts at 190°. The tricyclic tetracarboxylates 22 and 23, which are slowly equilibrating already at ambient temperature, are formed by thermal addition of ADM to the seven-membered ring of dimethyl 5-isopropyl-3,8-dimethylazulene-1,2-dicarboxylate (7; cf. Scheme 10). Azulene 7 which is electronically deactivated by the two MeOCO groups at C(1) and C(2) shows no more thermal reactivity in the presence of ADM at the five-membered ring (cf. Scheme 11). The tricyclic tetracarboxylates 22 and 23 react with excess ADM at 200° in a slow Diels-Alder reaction to form the tetracyclic hexacarboxylates 32, ‘anti’-33, and ‘anti’-34 (cf. Schemes 10–12 as well as Scheme 13). A structural correlation of the tri- and tetracyclic compounds is only feasible if thermal equilibration via [1,5]-C shifts between all six possible tricyclic tetracarboxylates (22, 23, and 35–38; cf. Scheme 13) is assumed. The tetracyclic hexacarboxylates 32, ‘anti’-33, and ‘anti’-34 seem to arise from the most strained tricyclic intermediates (36–38) by the Diels-Alder reaction with ADM.

Azulene-1-carbaldehydes which have Me substituents at C(3) and C(8) and no substituent at C(6) react with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° to yield exclusively the Diels-Alder adduct at the seven-membered ring (cf. Scheme 3). The corresponding 1-carboxylates behave similarly (Scheme 4). Azulene-1-carbaldehydes which possess no Me substituent at C(8) (e.g.11, 12 in Scheme 2) gave no defined products when heated with ADM in decalin. On the other hand, Me substitutents at C(2) may also assist the thermal addition of ADM at the seven-membered ring of azulene-1-carbaldehydes (Scheme 6). However, in these cases the primary tricyclic adducts react with a second molecule of ADM to yield corresponding tetracyclic compounds. The new tricyclic aldehydes 16 and 17 which were obtained in up to 50% yield (Scheme 3) could quantitatively be decarbonylated with [RhCl(PPh3)3] in toluene at 140° to yield a thermally equilibrated mixture of four tricycles (Scheme 8). It was found that the thermal isomerization of these tricycles occur at temperatures as low as 0° and that at temperatures > 40° the thermal equilibrium between the four tricycles is rapidly established via [1,5]-C shifts. The establishment of the equilibrium makes the existence of two further tricycles necessary (cf. Scheme 8). However, in the temperature range of up to 85° these two further tricycles could not be detected by 1H-NMR. When heated in the presence of excess ADM in decalin at 180°, the ‘missing’ tricyclic forms could be evidenced by their tetracyclic trapping products ‘anti’-45 and ‘anti’-48, respectively (Scheme 9).

Azulene (1) and its alkyl derivatives 2–15 were oxidized in a UV-irradiated stationary system by mercury(II) trifluoroacetate in dichloromethane. These derivatives are: 4,6,8-trimethyl-(2), 1,4,6,8-tetramethyl-(3), 6-tert-butyl-1,4,8-trimethyl-(4), 2,4,6,8-tetramethyl-(5), 1,3-dimethyl-(6), 1,3-ditert-butyl-(7), 1,3,5-tri-tert-butyl-(8), 1,3,6-trimethyl-(9), 6-tert-butyl-1,3-dimethyl-(10), 1,3,5,7-tetramethyl-(11), 1,3,4,6,8-pentamethyl-(12), 1,3,4,8-tetramethyl-6-propyl-(13), 6-tert-butyl - 1,3,4,8-tetramethyl-(14) and 1,2,3,4,6,8-hexamethyl-azulene (15). Only radical cations substituted in both reactive positions C-1 and -3 (6˙+-15˙+) were sufficiently persistent to be characterized by their hyperfine data with the use of EPR spectroscopy. Those bearing tert-butyl substituents at C-1 and -3 (7˙+ and 8˙+) or having three alkyl groups at the seven-membered ring in addition to the 1,3-dimethyl substituents (12˙+-15˙+) were also amenable to ENDOR and TRIPLE resonance studies. In contrast, the radical cations with none (1˙+, 2˙+ and 5˙+) or only one methyl group in the positions C-1 and -3 (3˙+ and 4˙+) rapidly reacted to yield follow-up products. For 1˙+-4˙+these products were identified by EPR and EN DOR spectroscopy as the radical cations of correspondingly substituted 1, 1′-biazulenyls (1a–4a). A mechanism is proposed for the formation of the primary (6˙+-15˙+) and the secondary radical cations (1a˙+-4a˙+). The failure to detect the radical cation of biazulenyl 5a˙+, starting from 5, must be due to instability of 5a˙+ in which two pairs of methyl substituents sterically interact. The high reactivity of the azulene radical cations in the positions C-1 and -3 is consistent with the unusually high π-spin populations ρ1.3 at these centres, as manifested by the largest by far coupling constants |aH1,3| of the α and methyl β-protons.

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 CC 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 (–)-5avia 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).

The reaction of highly alkylated azulenes with dimethyl acetylenedicarboxylate (ADM) in decalin or tetralin at 180–200° yields, beside the expected heptalene- and azulene-1,2-dicarboxylates, tetracyclic compounds of type ‘anti’-V and tricyclic compounds of type E (cf. Schemes 2–4 and 8–11). The compounds of type ‘anti’-V represent Diels-Alder adducts of the primary tricyclic intermediates A with ADM. In some cases, the tricyclic compounds of type E also underwent a consecutive Diels-Alder reaction with ADM to yield the tetracyclic compounds of type ‘anti’- or ‘syn’-VI (cf. Schemes 2 and 8–11). The tricyclic compounds of type E, namely 4 and 8, reversibly rearrange via [1,5]-C shifts to isomeric tricyclic structures (cf. 18 and 19, respectively, in Scheme 6) already at temperatures > 50°. Photochemically 4 rearranges to a corresponding tetracyclic compound 20via a di-π-methane reaction. The observed heptalene- and azulene-1,2-dicarboxylates as well as the tetracyclic compounds of type ‘anti’'-V are formed from the primary tricyclic intermediates Avia rearrangement (heptalenedicarboxylates), retro-Diels-Alder reaction ( azulenedicarboxylates), and Diels-Alder reaction with ADM. The different reaction channels of A are dependent on the substituents. However, the main reaction channel of A is its retro-Diels-Alder reaction to the starting materials (azulene and ADM). The highly reversible Diels-Alder reaction of ADM to the five-membered ring of the azulenes is HOMO(azulene)/LUMO(ADM)-controlled, in contrast to the at 200° irreversible ADM addition to the seven-membered ring of the azulenes to yield the Diels-Alder products of type E. This competing reaction must occur on grounds of orbital-symmetry conservation under SHOMO(azulene)/LUMO(ADM) control (cf. Schemes 20–22). Several X-ray diffraction analyses of the products were performed (cf. Chapt. 4.1).

The thermal reaction of 7-isopropyl-1,3,4-trimethylazulene (3-methylguaiazulene; 2) with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° leads to the formation of the corresponding heptalene- (5a/5b and 6a/6b; cf. Scheme 3) and azulene-1,2-dicarboxylates (7 and 8, respectively). Together with small amounts of a corresponding tetracyclic compound (‘anti’-13) these compounds are obtained via rearrangement ( 5a/5b and 6a/6b), retro-Diels-Alder reaction ( 7 and 8), and Diels-Alder reaction with ADM ( ‘anti’-13) from the two primary tricyclic intermediates (14 and 15; cf. Scheme 5) which are formed by site-selective addition of ADM to the five-membered ring of 2. In a competing Diels-Alder reaction, ADM is also added to the seven-membered ring of 2, leading to the formation of the tricyclic compounds 9 and 10 and of the Diels-Alder adducts ‘anti’-11 and ‘anti’-12, respectively of 9 and of a third tricyclic intermediate 16 which is at 200° in thermal equilibrium with 9 and 10 (cf. Scheme 6). The heptalenedicarboxylates 5a and 5b as well as 6a and 6b are interconverting slowly already at ambient temperature (Scheme 4). The thermal reaction of guaiazulene (1) with excess ADM in decalin at 190° leads alongside with the known heptalene- (3a) and azulene-1,2-dicarboxylates (4; cf. Schemes 2 and 7) to the formation of six tetracyclic compounds ‘anti’-17 to ‘anti’-21 as well as ‘syn’-19 and small amounts of a 4:1 mixture of the tricyclic tetracarboxylates 22 and 23. The structure of the tetracyclic compounds can be traced back by a retro-Diels-Alder reaction to the corresponding structures of tricyclic compounds (24--29; cf. Scheme 8) which are thermally interconverting by [1,5]-C shifts at 190°. The tricyclic tetracarboxylates 22 and 23, which are slowly equilibrating already at ambient temperature, are formed by thermal addition of ADM to the seven-membered ring of dimethyl 5-isopropyl-3,8-dimethylazulene-1,2-dicarboxylate (7; cf. Scheme 10). Azulene 7 which is electronically deactivated by the two MeOCO groups at C(1) and C(2) shows no more thermal reactivity in the presence of ADM at the five-membered ring (cf. Scheme 11). The tricyclic tetracarboxylates 22 and 23 react with excess ADM at 200° in a slow Diels-Alder reaction to form the tetracyclic hexacarboxylates 32, ‘anti’-33, and ‘anti’-34 (cf. Schemes 10–12 as well as Scheme 13). A structural correlation of the tri- and tetracyclic compounds is only feasible if thermal equilibration via [1,5]-C shifts between all six possible tricyclic tetracarboxylates (22, 23, and 35–38; cf. Scheme 13) is assumed. The tetracyclic hexacarboxylates 32, ‘anti’-33, and ‘anti’-34 seem to arise from the most strained tricyclic intermediates (36–38) by the Diels-Alder reaction with ADM.

Azulene (1) and its alkyl derivatives 2–15 were oxidized in a UV-irradiated stationary system by mercury(II) trifluoroacetate in dichloromethane. These derivatives are: 4,6,8-trimethyl-(2), 1,4,6,8-tetramethyl-(3), 6-tert-butyl-1,4,8-trimethyl-(4), 2,4,6,8-tetramethyl-(5), 1,3-dimethyl-(6), 1,3-ditert-butyl-(7), 1,3,5-tri-tert-butyl-(8), 1,3,6-trimethyl-(9), 6-tert-butyl-1,3-dimethyl-(10), 1,3,5,7-tetramethyl-(11), 1,3,4,6,8-pentamethyl-(12), 1,3,4,8-tetramethyl-6-propyl-(13), 6-tert-butyl - 1,3,4,8-tetramethyl-(14) and 1,2,3,4,6,8-hexamethyl-azulene (15). Only radical cations substituted in both reactive positions C-1 and -3 (6˙+-15˙+) were sufficiently persistent to be characterized by their hyperfine data with the use of EPR spectroscopy. Those bearing tert-butyl substituents at C-1 and -3 (7˙+ and 8˙+) or having three alkyl groups at the seven-membered ring in addition to the 1,3-dimethyl substituents (12˙+-15˙+) were also amenable to ENDOR and TRIPLE resonance studies. In contrast, the radical cations with none (1˙+, 2˙+ and 5˙+) or only one methyl group in the positions C-1 and -3 (3˙+ and 4˙+) rapidly reacted to yield follow-up products. For 1˙+-4˙+these products were identified by EPR and EN DOR spectroscopy as the radical cations of correspondingly substituted 1, 1′-biazulenyls (1a–4a). A mechanism is proposed for the formation of the primary (6˙+-15˙+) and the secondary radical cations (1a˙+-4a˙+). The failure to detect the radical cation of biazulenyl 5a˙+, starting from 5, must be due to instability of 5a˙+ in which two pairs of methyl substituents sterically interact. The high reactivity of the azulene radical cations in the positions C-1 and -3 is consistent with the unusually high π-spin populations ρ1.3 at these centres, as manifested by the largest by far coupling constants |aH1,3| of the α and methyl β-protons.

Syntheses of the Enantiomeric Aleuriaxanthins. Detection of a Predominant (Z)-Aleuriaxanthin in Aleuria The enantiomeric C10-building blocks 9 ((+)-(2 E, 6 R)-6, 7-dihydroxy-3, 7-di methyl-2-octen-l-yl acetate) and ent-9, and 11 ((+)-(2 E, 6 R)-3, 7-dimethyl-2, 7-octadien-l, 6-diyl diacetate) and ent-11, prepared from the optically active epoxy-geraniols 7 and ent-7, respectively, have been used for the syntheses of (2′ R)-aleuriaxanthin (1) and (2′ S)-aleuriaxanthin (ent-1). At room temperature aleuriaxanthin exhibits no significant CD. nor ORD. However, at −180° a very distinct CD. was observed, which in the UV. range showed a surprising resemblance to that of (3 R, 3′ R)-zeaxanthin. By direct comparison of 1 with aleuriaxanthin isolated from Aleuria aurantia [2], the (2′ R)-chirality assigned to the latter by Liaaen-Jensen et al. [5] is confirmed. HPLC. separation of the mixture of carotenoids from Aleuria shows the presence of a predominant (Z)-aleuriaxanthin of yet undetermined structure.

Synthesis of Enantiomerically Pure Apoviolaxanthinoic Acids, Apoviolaxanthinols, and Apoviolaxanthinals (Including Persicaxanthin, Sinensiaxanthin, and β-Citraurin Epoxide) and of their Furanoid Rearrangement Products Starting from (1′S,2′R,4′S,2E,4E)-5-(1′,2′-epoxy-4′-hydroxy-2′,6′,6′-trimethylcyclohexy1)-3-methy1-2,4-pentadienal (3), a recently described synthon [6], a full range of C20-, C25-, C27-, and C30-polyenic acids, alcohols, and aldehydes and their (8R)- and (8S)-diastereoisomeric furanoid rearrangement products was prepared. The synthetic C25-alcohols proved to be identical with persicaxanthin (= 12′-apoviolaxanthin-12′-ol) and perisicachromes (= 12′-apoauroxanthin-12′-ols) and the C27-alcohols analogously with sinensiaxanthin and sinensiachromes. A correlation between the sign of the Cotton effects in the CD spectra of 5,6-and 5,8-epoxides and their configuration at C(6) and C(8), respectively, was established.

Optically Active 4,5-Epoxy-4,5-dihydro-α-ionones; Synthesis of the Stereoisomeric 4,5:4′,5′-Diepoxy-4,5,4′,5′-tetrahydro-ϵ,ϵ-carotenes and the Steric Course of their Hydrolysis We prove that epoxidation with peracid of α-ionone, contrary to a recently published statement, predominantly leads to the cis-epoxide. Acid hydrolysis affords a single 4,5-glycol whose structure, established by an X-ray analysis, shows that oxirane opening occurred with inversion at the least substituted position (C(4)). Stable cis-and trans-epoxides are prepared by epoxidation of the C15-phosphonates derived from α-ionone. Both the racemic and optically active form are used for the synthesis of the 4,5:4′,5′-diepoxy-4,5,4′,5′-tetrahydro-ϵ,ϵ-carotenes having the following configuration in the end groups: meso-cis/cis, meso-trans/trans, rac-cis/trans, rac- and (6R, 6′ R)-cis/cis, rac- and (6R, 6′R)-trans/trans, rac- and (6R, 6′R)-cis/trans, and (6R, 6′ R)-cis/ϵ. Acid hydrolysis of the cis/cis-epoxycarotenoids under relatively strong conditions occurs again with inversion at C(4)/C(4′) in case of the cis/cis-epoxycarotenoids, but at C(5)/C(5′) in case of the trans/trans-epoxycarotenoids. An independent synthesis of this 4,5,4′,5′-tetrahydro-ϵ,ϵ-carotene-4,5,4′,5′-tetrol is presented. The irregular results of the oxirane hydrolysis are explained by assumption of neighbouring effects of the lateral chain. 400-Mz-1H-NMR data are given for each of the stereoisomeric sets. In the visible range of the CD spectra, the (6R, 6R′)-epoxycarotenoids compared with (6R, 6R′)-ϵ,ϵ-carotene exhibit an inversion of the Cotton effects.

Syntheses of Carotenes with ψ-End Groups and (Z)-Configuration at Terminal Conjugated Double Bonds Five carotenes bearing (5Z)-ψ-end groups were synthesized and carefully characterized: (5Z)-lycopene (6), (5Z5′Z)-lycopene (7), (5′Z)-neurosporene (8), (5′Z)-β,ψ-carotene (12), and (5′Z)-e,ψ-carotene (14).

Irradiation (280–350 nm light) of a benzene solution of 3-phenyl-2H-azirines 1a–e in the presence of carboxylate esters, whose carbonyl groups are activated by electron withdrawing groups situated in the acyl or alkyl moiety, produces 5-alkoxy-3-oxazolines (Tab. 1 and 4, Scheme 2) isolated in 18–82% yield. These heterocycles undoubtedly originate by regiospecific addition of the ester carbonyl group to the azirine-derived benzonitrile-methylide ‘dipole’ (Scheme 1). The 5-(2,′ 2′, 2′-trifluoroethoxy)-3-oxazolines, derived from 2′, 2′, 2′-trifluoroethyl carboxylic esters, on treatment with methanolic hydrogen chloride at low concentration, are smoothly transformed into the corresponding 5-methoxy-3-oxazolines (e.g. 16 17, Tab. 5). Utilizing this process, various hitherto relatively unknown 9. 5-alkoxy-3-oxazolines become accessible. The constitution of the adducts is based essentially on spectral data. The structure of trans-5-methoxy-2,4-diphenyl-5-trifluoromethyl-3-oxazoline (trans-14), the addition product of methyl trifluoroacetate and the benzonitrile-benzylide from 2,3-diphenyl-2H-azirine (1d), was determined by X-ray crystallography (Section 5). Benzonitrile-isopropylide (22), resulting from the photochemical transformation of 2,2-dimethyl-3-phenyl-2H-azirine (1a), also reacts with S-methyl thiobenzoate to give 2,2-dimethyl-5-methylthio-4,5-diphenyl-3-oxazoline (26). Ethyl cyanoacetate protonates predominantly the dipolar species derived from 1a at the nitrile C-atom and yields after work-up ethyl α-cyano-cinnamate (29) and ethyl isopropylidene-cyanoacetate (30) (Scheme 4). The relative rate of addition (krel) of benzonitrile-isopropylide (22) to methyl α-haloacetates and dimethyl oxalate was determined by competition experiments (Section 6). Log krel correlated satisfactorily (r = 0.97) with the pKa of the acide derived from the ester reactant: log krel = − 1.72 pKa + 2.58 or with Taft's substituent constants σ*: log krel = 2.06 σ* − 4.11 [krel(methyl dichloroacetate) = 1; Section 7.1]. On the basis of the results obtained, the mode of reaction of the so-called benzonitrile-methylide ‘dipole’ is discussed and a model for the transition state of addition of ester-carbonyl groups is proposed that accounts for the observed regiospecifity and steroselectivity.

Synthesis and Chirality of (5R, 6R)-5,6-Dihydro-β, ψ-carotene-5,6-diol, (5R, 6R, 6′R)-5,6-Dihydro-β, e-carotene-5,6-diol, (5S, 6R)-5,6-Epoxy-5,6-dihydro-β,ψ-carotene and (5S, 6R, 6′R)-5,6-Epoxy-5,6-dihydro-β,e-carotene Wittig-condensation of optically active azafrinal (1) with the phosphoranes 3 and 6 derived from all-(E)-ψ-ionol (2) and (+)-(R)-α-ionol (5) leads to the crystalline and optically active carotenoid diols 4 and 7, respectively. The latter behave much more like carotene hydrocarbons despite the presence of two hydroxylfunctions. Conversion to the optically active epoxides 8 and 9, respectively, is smoothly achieved by reaction with the sulfurane reagent of Martin [3]. These syntheses establish the absolute configurations of the title compounds since that of azafrin is known [2].

10′-Apolycopen-10′-ol and 10′-Apolycopen-10′-oic Acid from the Petals of the Rose Hybrid ‘Marechal Niel’ The novel 10′-apolycopen-10′-ol (1) and 10′-apolycopen-10′-oic acid (4) were isolated from the yellow petals of the once world-renowned rose hybrid ‘Marechal Niel’. The relative amount of either 1 or 4 produced by the plant depends upon the climatic conditions. Both 1 and 4 together with related compounds were synthetisized and characterized by spectral data.

Synthesis and Chirality of the Enantiomeric 6-Hydroxy-α-ionones and of cis- and trans-5,6-Dihydroxy-5,6-dihydro-β-ionones We describe the synthesis of (−)-(5R,6S)-5,6-dihydroxy-5,6-dihydro-β-ionone (10) and (+)-(5S,6S)-5,6-dihydroxy-5,6-dihydro-β-ionone (12). The absolute configuration of these compounds has been established by correlation with (R)-4-hydroxy-β-ionone (1). Therefore, by comparison, the 5,6-dihydroxy-5,6-dihydro-β-ionone recently isolated from Rehmannia glutinosa var. purpurea by Endo et al.[4] has the (5R,6R)-configuration ((−)−12). The same holds for the 5-β-D-glucopyranoside (15) isolated from Aeginetia indica var. gracilis.

Spiro 3-Oxazolines from the 1,3-Dipolar Cycloaddition of Benzonitrilio-2-propanide and 1,4-Quinones On irradiation with light of wavelength 290–350 nm, 2,2-dimethyl-3-phenyl-2H-azirine (1b) reacts with 1,4-naphthoquinone to give the 1H-benzo [f]isoindol-4,9-dione (11)(Scheme 3) via cycloaddition of the benzonitrilio-2-propanide (2b) onto the quinone C, C-double bond. With 2-methyl- and 2,3-dimethyl-1,4-naphthoquinone, the nitrile ylide 2b undergoes cycloaddition preferentially onto the C, O-double bond of the quinone, leading to spiro-oxazolines 12 and 14(Scheme 4). Steric as well as electronic effects can be discussed to explain the observed site selectivity of the cycloaddition. With the 1,4-benzoquinones 15a, 15b, 15d and 15f, nitrile ylide 2b undergoes the 1,3-dipolar cycloaddition exclusively onto the C, O-double bond. The corresponding spiro-oxazolines have been isolated in 17–32% yield. This contrasts with the previously reported results with benzonitrilipo-phenylmethanide (2a), which undergoes cycloaddition to the C, C-double bond of 1,4-benzoquinones (cf. [1]). This difference in the site selectivity of the 1,3-dipolar cycloaddition can be explained with Houk's concept of LUMO-polarization, that is, the stronger nucleophilic dipol 2b polarizes the LUMO of a α,β-unsaturated carbonyl compound more efficient than the less nucleophilic 2a. This leads to a preference of the cycloaddition to the C, O-double bond in the case of 2b. With 2,3-dimethyl- (15c) and 2,3,5,6-tetramethyl-1,4-benzoquinone (15e), nitrile ylide 2b undergoes C, O- as well as C, C-cycloaddition (Schemes 7 and 8).

Optically Active Lycopene Epoxides and Lycopene Glycols: Synthesis and Chiroptical Properties We present extensive spectral and chiroptical data on the pure and crystalline lycopene diepoxides 1–3 and glycols 4–9. A first synthetic approach to 1–9 with (+)-malic acid as starting material afforded 30 as a complex mixture of isomers (Scheme 1). Pure stereoisomers 1–9 were obtained using the enantiomerically pure epoxygeraniol 31 as starting material (Scheme 2). Differentiation of the (5Z)-from the (all-E)-isomers by 1H-NMR and UV/VIS alone is very difficult.

Synthesis of (+)-(5S, 6S)-Azafrin Methyl Ester; Absolute Configuration of Aeginetic Acid and of Further Vicinal Apocarotenediols We describe the synthesis of a series of optically active vicinal apo-β-carotenediols. Thus, starting from (+)-(5S, 6S)-5,6-dihydroxy-5,6-dihydro-β-ionone (2) we have prepared the (Z/E)-isomeric (+)-C15-esters 7 and 8, the (+)-retinoic derivatives 14, 15, 18, 19 and (+)-methyl azafrinate (22), the enantiomer of the naturally occur-ring compound (s. Scheme 1). Our synthesis also establishes the absolute configura-tion of aeginetic acid (24), aeginetoside (25) and aeginetin (26), compounds isolated from the root parasite Aeginetia indica by Indian and Japanese workers (s. Scheme 2). The presented synthesis of optically active methyl azafrinate confirms our previous assignment [14] of the absolute configuration of azafrin (1a), which was based on degradative evidence.

Syntheses of Enantiomerically Pure Violaxanthins and Related Compounds The epoxides 16 and ent-16, prepared by Sharpless-Katsuki oxidation of 15 in excellent yield and very high enantiomeric purity, were used as synthons for the preparation of (+)-(S)-didehydrovomifoliol (45), (+)-(6S, 7E, 9E)-abscisic ester 46, (+)-(6S, 7E, 9Z)-abscsic ester 47, (−)-(3S, 7E, 9E)-xanthoxin (49), (−)-(3R, 7E, 9E)-xanthoxin (50), (3S, 5R, 6S, 3′S,5′R, 6′S, all-E)-violaxanthin (1) (3R, 5R,6S,3′R,5′R,6′S, all-E)-violaxanthin (55) and their (9Z) (see 53, 57), (13Z) (see 54, 58), and (15Z) (see 60) isomers. The novel violadione (61) was prepared from 1 by oxidation with DMSO/Ac2O. By base treatment, 61 was converted into violadienedione (62), a potential precursor of carotenoids with phenolic end groups.

HPLC of Carotenes with ψ-End Groups and (Z)-Configuration at Terminal Conjugated Double Bonds; Isolation of (5Z)-Lycopene from Tomatoes Five carotenes bearing (5Z)-ψ-end groups were synthesized and carefully characterized: (5Z)-lycopene (6), (5Z5′Z)-lycopene (7), (5′Z)-neurosporene (8), (5′Z)-β,ψ-carotene (12), and (5′Z)-e,ψ-carotene (14). Lycopene 6 was isolated from tomatoes and its structure proven by 1H-NMR spectroscopy.