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Notes: Abstract The 20S proteasome (prosome) is a highly organized multiprotein complex with approximate molecular weight of about 700 kDa. Whilst the role of the proteasome in the processing and turnover of cellular proteins is becoming clearer, its relationship with RNA remains still obscure. Here we focus on the nature and function of proteasome associated endonuclease activity. Thus the involvement of a proteasome α-type subunit in RNA-degradation, the catalytic requirements, the interaction of proteasomes with their RNA-substrate and the identification of a well defined cleavage site in the 3-UTR of short-lived cellular mRNAs will be described in detail. All data indicate that proteasomes associated endonuclease activity could be involved in post-transcriptional gene control at the level of translation. Abbreviations: Hu – human; Mu – murine; β IFN – fibroblast interferon; γ IFN – lymphoblast interferon; c FOS – fos proto-oncogene; G-CSF – granulocyte colony stimulating factor.

Notes: Transcyclopropanation during the Tetrabromination of a Tricyclic Ketone to 3 exo, 4 endo, 6exo-Tribromo-7-bromomethyl-1,5-dimethyl-tricyclo[3.2.1.02,7]octan-8-oneBromination of the tricyclic ketone 1 with an excess of bromine at low temperature gives in approximately 30% yield the highly crystalline tricyclic tetrabromide 2 (Scheme 1). The structure of 2 was established by NMR.- and especially X-ray-analysis (Fig.1).Treatment of 1 with 1 mol-equ. of bromine gives an unstable dibromide, to which the structure 3 was assigned on the basis of its NMR.-spectrum and its further bromination to 2 (Scheme 1). In the course of the tetrabromination of 1 the original cyclopropane ring is opened in the first step (1 → 3) and another cyclopropane ring is formed in the second step (3 → 2) (cf. Scheme 3).

Notes: Photochemical Generation and Reactions of Benzonitrile-benzylideThe low temperature irradiation of 2,3-diphenyl-2H-azirine (1) in DMBP-glass at -196° has been reinvestigated. It was possible to convert 1 nearly quantitatively into the dipolar species benzonitrile-benzylide (3, Φ3 = 0,78), which exhibits UV.-absorptions at 344 (∊ = 48000) and 244 nm (∊ = 28500) (Fig. 1, Tab. 1). Irradiation of 3 with 345 nm light at -196° resulted in almost complete reconversion to the azirine 1 (Φ = 0,15; Fig. 2). When the solution of 3 in the DMBP-glass was warmed up to about -160° a quantitative dimerization to 1,3,4, 6-tetraphenyl-2,5-diaza-1,3,5-hexatriene (8) occurred. This proves that 8 is not only formed by the indirect route 3 + 1 → 7 \documentclass{article}\pagestyle{empty}\begin{document}$ \mathop {\longrightarrow }\limits^{hv} $\end{document} 11 → 8 known before (Scheme 1), but also by dimerization of 3 either by direct head to head coupling or via the intermediate e (p. 2675), followed by a fast thermal hydrogen transfer reaction.The occurrence of the dipolar intermediate 11 in the photochemical conversion of the bicyclic compound 7 to 8 could also be demonstrated by low temperature experiments: On irradiation at -196° 7 gave the cherry red dipolar intermediate 11 (λmax = 520 nm), which at -120° isomerizes to 8. It should be noted, that neither 7 nor 11 are formed by dimerization reactions of 3.Experiments carried out at room temperature demonstrate, that both processes for the formation of 8 may compete: Irradiation of a solution of 1 (DMBP, c = 8 × 10-4 to 5 × 10-3M) with 350 nm light of high intensity (which does not excite the bicyclic compound 7) leads to a relative high photostationary concentration of the dipolar species 3. Under these conditions the formation of 8 is due to dimerization of 3 (Φ8 = 0,19). With low light intensity only a very low stationary concentration of 3 can be obtained. Therefore the reaction of 3 with 1, leading to the bicyclic intermediate 7, becomes now predominant (Φ-1 = 1,55, which corresponds with the expected value of 2 × 0,8). Irradiation of 1 at -130° with 350 nm light of high intensity gives 8 with a quantum yield of 0,44. This is in agreement with the theoretical value Φ8 = 0,4 for an exclusive formation of 8 by dimerization of 3. The lower quantum yield for the formation of 8 at room temperature makes probable that under these conditions 3 not only dimerizes to 8, but also to another, so far unidentified dimer, e.g. 2,3,5,6-Tetraphenyl-2,5-dihydropyrazine.By flash photolysis of a solution of 1 (cyclohexane, c = 10-4M, 25°) the disappearance of 3 could directly be measured by UV.-spectroscopy: At relative high concentrations (c ≥ 10-7M) 3 disappeared according to a second order reaction with the rate constant k = 5 × 107M-1S-1. At lower concentrations (c ≤ 10-7M) the rate of disappearance of 3 follows first order kinetics. The rate constant of this pseudo first order reaction (3 + 1 → 7) has been determined to be 1 → 104M-1S-1.Using Padwa's table of relative rates for the cycloaddition of the dipolar species 3 to various dipolarophiles, including the azirine 1, an absolute rate constant of k ≈ 8 × 108M-1S-1 for the addition of 3 to the most active dipolarophile fumaronitrile could be estimated. In cyclohexane at room temperature, the diffusion controlled rate constant equals 6,6 × 109M-1S-1.In Table 1 the UV.-maxima of several nitrile-ylides, among them a purely aliphatic one, are given.

Notes: 3-Alkyl-1-benzoxepin-5-one derivatives and 2-alkyl-1,4-naphtoquinones from 2-acylaryl propargyl ethers.It was found that 3-alkyl-1-benzoxepin-5(2H)-ones of type B can be synthesized by treating 2-acylaryl propargyl ethers of type A with sodium methylsulfinyl methide (NaMSM, dimesyl sodium) (Scheme 13). Oxepinone derivatives of type B undergo ring contraction with base (also NaMSM) to yield the quinol derivatives C which, oxidize (during work-up), if R2 = H, to the 1,4-naphthoquinones D (Scheme 13).The propargyl ethers used are listed in Scheme 1. The naphthalene derivatives 1 and 3 give oxepinones (E-9 and a mixture of 14/15 respectively), whereas the expected oxepinone from 2 is transformed directly into the quinone 11 (Scheme 2, 3 and 5). Isomerizations of 2-acetylphenyl propargyl ethers (4, 5 and 6) (Schemes 6, 7 and 8) are less successful because of side reactions. If however the acetyl group is replaced by a propionyl or substituted propionyl group (as in ethers 7 and 8) oxepinones are obtained again in good yield (Scheme 9).The mechanistic pathway for the transformation of naphthyl propargyl ethers (and phenyl derivatives) under influence of NaMSM is shown in Scheme 10. The base-catalysed conversion of 4-phenyl-l-benzoxepin-5(2H)-one,benzo[f]furo[2,3-c](10 H)-oxepin-4-oncsand 3-methoxy-G,11- dihydro-dibenzo[b, e]loxepin-11-oneinto thc corresponding quinones has been reported [13] [20] [21].The conversion of 2-acylaryl propargyl others via the isolable benzoxepin-5-one derivativcs or directly into the specifically substituted 1,4-naphthoquinone derivatives is of synthetic interest.

Notes: Synthesis and reactions of the valence polaromeric compound (4,4-dimethyl-2-thiazoline-5-dimethyliminium)-2-thiolate ⇌ 1-dimethylthiocarbamoyl-1-methyl-ethyl isothiocyanate from 3-dimethylamino-2,2-dimethyl-2H-azirine and carbon disulfide.3-Dimethylamino-2,2-dimethyl-2H-azirine (1) reacts with carbon disulfide to give crystals which have the dipolar structure 3a [(4,4-dimethyl-2-thiazoline-5-dimethyliminium)-2-thiolate, Scheme 1]. In solution, the non-dipolar (charge-free) isomeric form 3b (1-Dimethyl-thiocarbamoyl-1-methyl-ethyl isothiocyanate) is almost exclusively populated. Reaction products are derived from both forms: Derivatives of 3a are the hydrolysis product 6, the sodium borohydride reduction product 7 and the methylation products 9 and 10, respectively (Scheme 2). The isothiocyanate form 3b is responsible for the various reaction products with amines (Scheme 3). One of the reaction products with ammonia, namely 20, is also obtained by the reaction of 1 with thiocyanic acid.Thermolysis of the azirine/carbon disulfide adduct 3 leads to 2-dimethylamino-4,4-dimethyl-2-thiazoline-5-thione (17) in high yield. A possible mechanism is outlined in Scheme 4. The same compound is also formed by rearrangement of 3 under the catalytic influence of dimethylamine. Its structure has been established by X-ray crystallography (section 4). Again a rearrangement is involved in the reductive (NaBH4) conversion of 17 to 7, the direct reduction product of the dipolar species 3a (Scheme 5).The isothiocyanate form 3b is able to react with a second molecule of 3-dimethylamino-2,2-dimethyl-2H-azirine (1) to yield compound 25, which in the crystalline or dissolved state appears to be almost entirely populated by the carbodiimide form with structure 25b (Scheme 7), though all reaction products of 25 (reduction with sodium borohydride, addition of water or hydrogen sulfide, Schemes 7 and 8) are derived from the dipolar form 25a, not detectable as such; here again therefore there is a dynamic equilibrium 25a ⇌ 25b.The two forms of adduct 3, namely 3a and 3b, are obviously very easily interconverted at room temperature and therefore can be considered as valence polaromeric forms (section 5). A classification of the dipolar (zwitterionic) form is given, which allows a comparison of various dipolar species and gives as indication of charge stabilization by delocalization.The versatile reactivity of the 3-dimethylamino-2,2-dimethyl-2H-azirine/carbon disulfide adduct is demonstrated by the fact that with simple reagents approximately 25 derivatives have been obtained, most of them being new heterocyclic compounds.

Notes: Photocyclization of 1, 1′-Polymethylene-di-2-pyridones.Benzophenone sensitized irradiation of the four dipyridones 1-4 gave the internal photocyclization products 6 (64%, Scheme 4), 7 (60%, Scheme 5), 8 (Scheme 6), and 11 (26%, Scheme 7), respectively. The decamethylene compound 5 yielded only polymeric material.The primary [2+2] photoproduct 8 from dipyridone 3 (Scheme 6) is relatively unstable. Further irradiation or heating to 65° induced a Cope rearrangement to give compound 9 which, on heating to 137°, was converted into the isomeric compound 10. This product, as well as the other photoproducts mentioned, are rearranged back to their respective starting materials upon direct irradiation with 254 nm light or by heating to higher temperatures. The various possibilities for cycloadditions of pyridones are discussed as well as the possible factors which are responsible for the highly regioselective photoreactions of the dipyridones 1-4.

Notes: Synthesis of the Macrocyclic Spermidine Alkaloids Oncinotine, Neooncinotine, Isooncinotine and Pseudooncinotine in Racemic Forms.The four isomeric spermidine alkaloids (Scheme 1) mentioned in the title were synthesized as follows: Reaction of the piperidine derivative 5 and the bromide 6 led to the intermediate 13 which was converted to (±)-oncinotine (±-1) and (±)-pseudooncinotine (±-4) (Scheme 3). The analogous reaction of 5 and the isomeric bromid 7 gave the intermediate 22 from which (±)-neooncinotine (±-2) and (±)-isooncinotine (±-3) were synthesized (Scheme 4). The overall yields were found to be between 22 (±-1) and 54% (±-3).

Notes: Synthesis of new polycyclic compounds by means of intramolecular Diels-Alder reactions of cyclohexa-2,4-dien-1-one derivativesThermal rearrangement of mesityl penta-2,4-dienyl ether (1), consisting of the isomers E (93%) and Z (7%), furnished, besides mesitol, the two mesityl penta-1,3-dienyl ethers 2 (24%) and 3 (3%), and the two tricyclic ketones 4 (4,5%) and 5 (12,5%) (Scheme 1). A probable mechanism for this formation of 2 involves a [1,5]-hydrogen shift in (Z)-1. Isomerisation of (E)-1 to (Z)-1 at 145° occurs via reversible sigmatropic [3,3]- and [5,5]-rearrangements of (E)-1 to the cyclohexadienones 38 and 39 respectively (see Chapter A p. 1710, and Scheme 15). Formation of 3 from either (Z)-1 or 2 is rationalized by a series of pericyclic reactions as outlined in Chapter A and Scheme 16.The tricyclic ketones 4 and 5 are undoubtedly formed by internal Diels-Alder reactions of the 6-pentadienyl-cyclohexa-2,4-dien-1-one 6 (Scheme 2). In fact, at 80° 6 is converted into 4 (5%) and 5 (35%). At 80° the cyclohexadienone derivative 7 furnished the corresponding tricyclic ketones 8 (15%) and 9 (44%) (Scheme 2). 5 and 9 contain a homotwistane skeleton. 8 and 9 are easily prepared by reaction of sodium 2,6-dimethylphenolate with 3-methyl-penta-2,4-dienyl bromide at ambient temperature, followed by heating, and finally separation by cristallization and chromatography.The cyclohexadienones 6 and 7 have mainly (E)-configuration. Here too (E) → (Z) isomerization is a prerequisite for the internal Diels-Alder reaction, and this partly takes place intramolecularly through reversible Claisen and Cope rearrangements (Scheme 17). On the other hand, experiments in the presence of 3,5-d2-mesitol have shown (Table 1) that intermolecular reactions, involving radicals and/or ions, are also operating (see Chapter B, p. 1712).Two different modi (I and II) exist for intramolecular Diels-Alder reactions (Scheme 18). Whereas only modus I is observed in the cyclization of 5-alkenyl-cyclohexa-l,3-dienes, in that of (2)-cyclohexadienones 6 and 7 (Scheme 2) both modi are operating. Only in modus 11-type transitions is the butadienyl conjugation of the side chain retained, so that modus 11-type addition is preferred (Chapter C p. 1716).Analogously to the synthesis of the tricyclic ketones 4, 5, 8 and 9, the tricyclic ketone 15 (Scheme 4) and the tetracyclic ketone 11 (Scheme 3) are prepared from mesitol, pentenyl bromide and cycloheptadienyl bromide, respectively.From the polycyclic ketones derivatives such as the alcohols 16, 17, 18, 19, 23, 24 and 25 (Schemes 9 and 11), policyclic ethers 20, 21, 22 and 26 (Scheme 10), epoxides 30, 32 (Scheme 13), diketones 31, 33 (Scheme 13) and ether-alcohols 35 and 36 (Scheme 14) have been prepared. Most of these conversions show high stereoselectivity.

Notes: Localization of the keto group in Inandenin-ones.By Schmidt degradation of the spermidine alkaloids inandenine-12-on (1) and inandenine-13-on (2) from Oncinotis inandensis followed by hydrolysis, acetylation and esterification four different types of products were obtained: the dicarboxylic diesters 9 and 10, the ω-amino-carboxylic esters 11 and 12, the acetylated polyamines 14 and 15, and the acetylated triaminecarboxylic esters 16 and 17. By GLC. and mass spectral analysis of these degradation products, and by comparison with synthetic compounds it was possible to confirm the structures 1 and 2. The same alkaloid mixture (1+2) was obtained from the leaves of Oncinotis nitida BENTH.

Notes: The constitution and absolute configuration of the rhoeadine alkaloids (+)-alpinigenine and (+)-cis-alpinigenine.The fundamental structure of the hemi-acetal phenylbenzazepine alkaloid (+)-alpinigenine (1), isolated from Papaver bracteatum LINDL., was derived essentially from 1H-NMR.- and mass-spectra of 1 and its derivatives 7, 10 and 14 (cf. Scheme 2). The positioning of the four methoxy groups in the two aromatic rings could be deduced from the 1H-NMR.-spectra of the N-oxides 14 and 15 in which, as a result of favourable sterical and conformational behaviour, an interaction exists between the N-oxide oxygen atom and one of the two ortho protons in ring C.The B/D-trans-fused 1 undergoes isomerization in 1N HCl to cis-alpinigenine (16). A stereochemical correlation between bases in the trans-and cis-series was enabled via an Emde degradation of the corresponding methylacetal-methyliodides 21 resp. 19 leading to the enantiomeric isochroman derivatives 22 resp. 23 which are achiral at C (2) (Scheme 4).The configuration at C (14) in the hemi-acetals (eg. 1 and 16) and the methyl ethers (eg. 7 and 8) is discussed in detail (cf. Scheme 7). (+)-Alpinigenine (1) has the (1S, 2R, 14R) configuration and (+)-cis-alpinigenine (16), in chloroform or acetone solution, the (1R, 2R, 14R) configuration.