Synthesen von enantiomerenreinen Apoviolaxanthin-säuren, -olen und -alen (Persicaxanthin,Sinensiaxanthin und β-Citraurin-epoxid) und ihrer furanoiden Umlagerungsprodukte

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.     

Investigations Concerning an Unexpected Reaction between the Dimsyl Anion ( = (Methylsulfinyl)methanide) and a γ,δ-Epoxy-ketone

The reaction of 2,2-dimethyl-5-(1,2-epoxypropyl)cyclohexanone ( 7 ) with t-BuOK in DMSO furnished a small amount of 5-(1-hydroxyprop-2-enyl)-2,2-dimethylcyclohexanone ( 12 ) and the 4 unexpected products 13–16 which contain one to three additional C-atoms (Scheme 2). The relative configuration of the major product 1-(4′,4′-dimethyl-2′,3′-dimethylidenecyclohexyl)propane-1,2-diol ( 15 ) was shown to be 1RS, 2RS,1′SR via NOE measurements performed on a derivative thereof. A crossover experiment in DMSO/[¹³C₂]DMSO 1:1 as solvent showed that the two additional C-atoms of this product originate from a single molecule of DMSO (Scheme 5). A tentative mechanistic scheme, consistent with all experimental observations, is proposed which involves a [2,3]-sigmatropic rearrangement of an (allylsulfinyl)methanide to a sulfenic acid as one of the key steps ( V → 24 , Scheme 8). We corroborated part of this hypothetic scheme by taking recourse to a model compound (7-(methylsulfinyl)-p-mentha-1,8-diene ( 32/33 ), readily prepared in two steps from perilla alcohol ( 30 )), which reacted as predicted by the proposed mechanism (Schemes 9 and 10).     

2′, 3′-Dideoxy-3′-fluorotubercidin and Related Dideoxyribonucleosides:. Synthesis via a 2′-deoxy-3′-oxoribofuranoside intermediate and conformation studies

An efficient synthesis of the unknown 2′-deoxy-D-threo-tubercidin ( 1b ) and 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine ( 5 ) with (tert-butyl)diphenylsilyl chloride yielded 6 which gave the 3′-keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH₄ reduction (→ 8 ) followed by deprotection with Bu₄NF(→ 9a )and nucleophilic displacement at C(6) afforded 1b as well as 7-deaza-2′-deoxy-D-threo-inosine ( 9b ). Mesylation of 4-chloro-7-{2-deoxy-5-O-[(tert-butyl)diphenylsilyl]-β-D-threo-pentofuranosyl}-7H-pyrrolo[2,3-d]-pyrimidine ( 8 ), treatment with Bu₄NF (→ 12a ) and 4-halogene displacement gave 2′, 3′-didehydro-2′, 3′-dideoxy-tubercidin ( 3 ) as well as 2′, 3′-didehydro-2′, 3′-dideoxy-7-deazainosne ( 12c ). On the other hand, 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→ 10a ), subsequent 5′-de-protection with Bu₄NF (→ 10b ), and Cl/NH₂ displacement. ¹H-NOE difference spectroscopy in combination with force-field calculations on the sugar-modified tubercidin derivatives 1b , 2 , and 3 revealed a transition of the sugar puckering from the ^3′T_2′ conformation for 1b via a planar furanose ring for 3 to the usual ^2′T_3′ conformation for 2.     

Acid-Catalyzed [3,3]-Sigmatropic Rearrangements of N-Propargylanilines

The acid-catalyzed rearrangement of N-(1′,1′-dimethylprop-2′-ynyl)-, N-(1′-methylprop-2′-ynyl)-, and N-(1′-arylprop-2′-ynyl)-2,6-, 2,4,6-, 2,3,5,6-, and 2,3,4,5,6-substituted anilines in mixtures of 1N aqueous H₂SO₄ and ROH such as EtOH, PrOH, BuOH etc., or in CDCl₃ or CCl₄ in the presence of 4 to 9 mol-equiv. trifluoroacetic acid (TFA)has been investigated (cf. Scheme 12-25 and Tables 6 and 7). The rearrangement of N-(3′-X-1′,1′-dimethyl-prop-2′-ynyl)-2,6- and 2,4,6-trimethylanilines (X = Cl, Br, I) in CDCl₃/TFA occurs already at 20° with τ_1/2 of ca. 1 to 5 h to yield the corresponding 6-(1-X-3′-methylbuta-1,2′-dienyl)-2,6-dimethyl- or 2,4,6-trimethylcyclohexa-2,4-dien-1-iminium ions (cf. Scheme 13 and Footnotes 26 and 34) When the 4 position is not substituted, a consecutive [3,3]-sigmatropic rearrangement takes place to yield 2,6-dimethyl-4-(3′-X-1′,1′-dimethylprop-2′-ynyl)anilines (cf. Footnotes 26 and 34). A comparable behavior is exhibited by N-(3′-chloro-1′-phenylprop-2′-ynyl)-2,6-dimethylaniline ( 45 ., cf. Table 7). The acid-catalyzed rearrangement of the anilines with a Cl substituent at C(3′) in 1N aqueous H₂SO₄/ROH at 85-95°, in addition, leads to the formation of 7-chlorotricyclo[3.2.1.0^2,7]oct-3-en-8-ones as the result of an intramolecular Diels-Alder reaction of the primarily formed iminium ions followed by hydrolysis of the iminium function (or vice versa; cf. Schemes 13,23, and 25 as well as Table 7). When there is no X substituent at C(1′) of the iminium-ion intermediate, a [1,2]-sigmatropic shift of the allenyl moiety at C(6) occurs in competition to the [3,3]-sigmatropic rearrangement to yield the corresponding 3-allenyl-substituted anilines (cf. Schemes 12,14–18, and 20 as well as Tables 6 and 7). The rearrangement of (?)?(S)-N-(1′-phenylprop-2′-ynyl)-2,6-dimethylaniline ((?)- 38 ; cf. Table 7) in a mixture of 1N H₂SO₄/PrOH at 86° leads to the formation of (?)-(R)-3-(3′-phenylpropa-1′,2′-dienyl)-2,6-dimethylaniline ((?)- 91 ), (+)-(E)- and (?)-(Z)-6-benzylidene-1,5-dimethyltricyclo[3.2.1.0^2′7]oct-3-en-8-one ((+)-(E)- and (?)-(Z)- 92 , respectively), and (?)-(S)-2,6-dimethyl-4-( 1′-phenylprop-2′-ynyl)aniline((?)- 93 ). Recovered starting material (10%) showed a loss of 18% of its original optical purity. On the other hand, (+)-(E)- and (?)-(Z)- 92 showed the same optical purity as (minus;)- 38 , as expected for intramolecular concerted processes. The CD of (+)-(E)- and (?)-(Z)- 92 clearly showed that their tricyclic skeletons possess enantiomorphic structures (cf. Fig. 1). Similar results were obtained from the acid-catalyzed rearrangement of (?)-(S)-N-(3′-chloro-1′phenylprop-2′-ynyl)-2,6-dimethylaniline ((?)- 45 ; cf. Table 7). The recovered starting material exhibited in this case a loss of 48% of its original optical purity, showing that the Cl substituent favors the heterolytic cleavage of the N–C(1′) bond in (?)- 45. A still higher degree (78%) of loss of optical activity of the starting aniline was observed in the acid-catalyzed rearrangement of (?)-(S)-2,6-dimethyl-N-[1′-(p-tolyl)prop-2′-ynyl]aniline ((?)- 42 ; cf. Scheme 25). N-[1′-(p-anisyl)prop-2-ynyl]-2,4,6-trimethylaniline( 43 ; cf. Scheme 25) underwent no acid-catalyzed [3,3]-sigmatropic rearrangement at all. The acid-catalyzed rearrangement of N-(1′,1′-dimethylprop-2′-ynyl)aniline ( 25 ; cf. Scheme 10) in 1N H₂SO₄/BuOH at 100° led to no product formation due to the sensitivity of the expected product 53 against the reaction conditions. On the other hand, the acid-catalyzed rearrangement of the corresponding 3′-Cl derivative at 130° in aqueous H₂SO₄ in ethylene glycol led to the formation of 1,2,3,4-tetrahydro-2,2-dimethylquinolin-4-on ( 54 ; cf. Scheme 10), the hydrolysis product of the expected 4-chloro-1,2-dihydro-2,2-dimethylquinoline ( 56 ). Similarly, the acid-catalyzed rearrangement of N-(3′-bromo-1′-methylprop-2′-ynyl)-2,6-diisopropylaniline ( 37 ; cf. Scheme 21) yielded, by loss of one i-Pr group, 1,2,3,4-tetrahydro-8-isopropyl-2-methylquinolin-4-one ( 59 ).     

Stereochemische Korrelationen zwischen (2R,4′R,8′R)-α-Tocopherol, (25S,26)-Dihydroxycholecalciferol, (–)-(1S,5R)-Frontalin und (–)-(R)-Linalol

Stereochemical Correlations between (2R,4′R,8′R)-α-Tocopherol, (25S,26)-Dihydroxycholecalciferol, (–)-(1S,5R)-Frontalin and (–)-(R)-Linalol The optically active C₅- and C₄-building units 1 and 2 with their hydroxy group at a asymmetric C-atom were transformed to (–)-(1S,5R)-Frontalin ( 7 ) and (–)-(3R)-Linalol ( 8 ) respectively; 1 and 2 had been used earlier in the preparation of the chroman part of (2R,4′R,8′R)-α-Tocopherol ( 6a , vitamin E), and for introduction of the side chain in (25S,26)-Dihydroxycholecalciferol ((25S)- 4 ), a natural metabolite of Vitamin D₃. The stereochemical correlations resulting from these converions fit into a coherent picture with those correlations already known from literature and they confirm our earlier stereochemical assignments. A stereochemical assignment concerning the C(25)-epimers of 25,26-Dihydroxycholecalciferol that was in contrast to our findings and that initiated the conversion of 1 and 2 to 7 resp. 8 for additional stereochemical correlations has been corrected in the meantime by the authors [26].     

Nucleoside und Nucleotide. Teil 15. Synthese von Desoxyribonucleosid-monophosphaten und -triphosphaten mit 2(1H)-Pyrimidinon, 2(1H)-Pyridinon und 4-Amino-2(1H)-pyridinon als Basen

Nucleosides and Nucleotide. Part 15. Synthesis of Deoxyribonucleoside Monophosphates and Triphosphates with 2(1H)-Pyrimidinone, 2(1H)-Pyridinone and 4-Amino-2(1H)-pyridinone as the Bases The phosphorylation of the modified nucleosides 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone (M_d, 4 ), 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone (Z_d, 6 ) and the synthesis of 1–2′-deoxy-β-D -ribofuranosyl-2(1 H)-pyrimidinone-5′-O-triphosphate (pppM_d, 1 ), 1-(2′-deoxy-β-D ribofuranosyl)-2(1 H)-pyridinone-5′-O-triphosphate (pppII_d, 2 ), and 4-amino-1-(2′-deoxy-βD -ribofuranosyl)-2(1 H)-pyridinone-5′-O-triphosphate (pppZ_d, 3 ) are described. The nucleoside-5′-monophosphates pM_d (5) and pZ_d (7) were obtained by selective phosphorylation of M_d (4) and Z_d (6) , respectively, using phosphorylchloride in triethyl phosphate or in acetonitril. The reaction of pM_d (5) pII _d (8) or pZ_d (7) with morpholine in the presence of DCC led to the phosphoric amides 9, 10 and 11 , respectively, which were converted with tributylammonium pyrophosphate in dried dimethylsulfoxide to the nucleoside-5′triphosphates 1, 2 and 3 , respectively.     

Synthesis of certain 1,2,4-triazole nucleoside derivatives

The syntheses of 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and its 2′-deoxy analog 8b as well as 5-amino-2-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-3-one ( 12 ) have been accomplished. Compounds 8a and 8b were synthesized via glycosylation of 3-bromo-5-nitro-1,2,4-triazole which was followed by replacement in three steps of the 3-bromo function to yield 3-nitro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 4a ) and its 2′-deoxy analog 4b . Compounds 4a and 4b were methylated at N², hydrogenated and deblocked to give 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and the 2′-deoxy analog 8b . Compound 12 was synthesized by glycosylation of 3-amino-1-methyl-1,2,4-triazolin-5(2H)-one ( 10 ). The structures of 8b and 12 were confirmed by single crystal X-ray diffraction analysis.     

A New Approach to the Synthesis of Long-Chain Polypropionates Based on the Diels-Alder Monoadditions of 2,2′-Ethylidenebis[3,5-dimethylfuran]

Acidic condensation of 2,4-dimethylfuran with acetaldehyde provided 2,2′-ethylidenebis[3,5-dimethylfuran] ( 7 ) which added 1 equiv. of methyl bromopropynoate to give a major adduct 8 . Regio- and stereoselective hydroboration of the latter 7-oxanorbornadiene derivative followed by alcohol protection and methanolysis of its β-bromoacrylate moiety gave (1RS,2RS,4RS,5SR,6SR,1′RS)-methyl 4-[1′-(3″,5″-dimethylfuran-2″-yl)ethyl]-3,3-dimethoxy-6-exo-[(2-methoxy)ethoxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptane-2-endo-carboxylate ( 24 ) (Schemes 2 and 3). Reduction of 24 with LiAlH₄, followed by H₂O and MeOH elimination gave the 3-methyl-idene-7-oxanorbornan-2-one derivative 26 which underwent 7-oxa ring opening through a S_N2′ type of reaction with Me₂CuLi (Scheme 4). Stereoselective hydrogenation and ketone reduction provided (1RS, 2SR,3RS,4RS,5RS,6RS,1′SR)-1- [1″-(3 ″,5″-dimethylfuran-2″-yl)]-c-3-ethyl-c-5-[(2-methoxyethoxy)m e-c-ethyl-c-c-5-(2-methoxyethoxy)methoxy]-t-4,t-6-dimethyl-cyclohexane-r-1,c-2-diol ( 32 ), the oxidative cleavage of which with Pb(OAc)₄ generated a 6-oxo-aldehyde 33 (Schemes 4 and 5). Chemoselective protection of 33 and chemo- and stereoselective reductions generated (2RS,3RS,4SR,5SR,6SR,7RS)-7-(3′,5″-dimethylfuran-2′-yl)-2-ethyl-6-hydroxy-4-[(2-methoxyethoxy)methoxy]-3,5-dimethyloct-1-yl pivaloate ( 36 ) and its 4-hydroxy 6-epimer 40 (12 and 13 steps, resp., from adduct 8 ; Scheme 5). Oxidation of the furan ring of 36 led to a (2RS,3SR,4RS,5SR,6RS,7RS)-7-ethyl-3,5,8-trihydroxy-2,4,6-trimethyl-octanoic acid derivative 44 , a polypropionate fragment with six contiguous stereogenic centres (Scheme 6).     

Synthesis of racemic and enantiomerically pure 2′-thia-2′,3′-dideoxycytidine as potential anti-hepatitis B virus agents

A novel class of nucleosides with the C₁, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine ( 6 ) and (±)-α-2′-thia-2′,3′-dideoxycytidine ( 7 ) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate ( 8 ) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine ( 26 ) was the most active against human hepatitis B virus with an ED₅₀ of 3 μM.     

Synthesis and Conformational Studies of Unnatural Pyrimidine Nucleosides

ABSTRACT

Starting from 3,4-di-O-acetyl-L-rhamnal (6) and thymine (7) the unsaturated nucleosides 1-(2′,3′,6′-trideoxy-4′-O-acetyl-α- and β-L-erythro-hex-2′-enopyranosyl)-thymine (8a and 8b) were prepared in anomerically pure form. In solution 8a was shown to be present in the ⁵ H _o and ⁰ H ₅ conformations, whereas the predominant conformation of 8b was ⁵ H _o. Chemical transformation of 8a and 8b led to the saturated nucleosides 1-(2′,3′,6′-trideoxy-α- and β-L-erythro-hexopyranosyl)thymine (10a and 10b, respectively), which were converted into 1-(4′-azido-2′,3′,4′,6′-tetradeoxy-α- and β-L-threo-hexopyranosyl)thymine (12a and 12b). Preliminary biological studies showed that 9b was inactive against the HIV-1 and HIV-2 viruses.     

Nucleoside und Nucleotide. Teil 16. Verhalten von 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyrimidinon-5′-triphosphat, 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)pyridinon-5′-triphosphat und 4-Amino-1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyridinon-5′-triphosphat gegenüber DNA-Polymerase

Nucleosides and Nucleotides. Part 16. The Behaviour of 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidinone-5′-triphosphate, 1-(2′-Deoxy-β-D -ribofuranosyl-2(1H))-pyridinone-5′-triphosphate and 4-Amino-1-(2′-desoxy-β-D -ribofuranosyl)-2(1H)-pyridinone-5′-triphosphate towards DNA Polymerase The behaviour of nucleotide base analogs in the DNA synthesis in vitro was studied. The investigated nucleoside-5′-triphosphates 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone-5′-triphosphate (pppM_d), 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppII_d) and 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppZ_d) can be considered to be analogs of 2′-deoxy-cytidine-5′-triphosphate. However, their ability to undergo base pairing to the complementary guanine is decreased. When pppM_d, pppII_d or pppZ_d are substituted for pppC_d in the enzymatic synthesis of DNA by DNA polymerase no incorporation of these analogs is observed. They exhibit only a weak inhibition of the DNA synthesis. The mode of the inhibition is uncompetitive which shows that these nucleotide analogs cannot serve as substrates for the DNA polymerase.     

Synthesis of spiro[indoline‐3,3′‐pyrrolizines] by 1,3‐dipolar reactions between isatins,l‐proline and electron‐deficient alkenes

Two spiro[indoline‐3,3′‐pyrrolizine] derivatives have been synthesized in good yield with high regio‐ and stereospecificity using one‐pot reactions between readily available starting materials, namely l ‐proline, substituted 1H‐indole‐2,3‐diones and electron‐deficient alkenes. The products have been fully characterized by elemental analysis, IR and NMR spectroscopy, mass spectrometry and crystal structure analysis. In (1′RS ,2′RS ,3SR ,7a′SR )‐2′‐benzoyl‐1‐hexyl‐2‐oxo‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizine]‐1′‐carboxylic acid, C₂₈H₃₂N₂O₄, (I), the unsubstituted pyrrole ring and the reduced spiro‐fused pyrrole ring adopt half‐chair and envelope conformations, respectively, while in (1′RS ,2′RS ,3SR ,7a′SR )‐1′,2′‐bis(4‐chlorobenzoyl)‐5,7‐dichloro‐2‐oxo‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizine], which crystallizes as a partial dichloromethane solvate, C₂₈H₂₀Cl₄N₂O₃·0.981CH₂Cl₂, (II), where the solvent component is disordered over three sets of atomic sites, these two rings adopt envelope and half‐chair conformations, respectively. Molecules of (I) are linked by an O—H…·O hydrogen bond to form cyclic R ₆⁶(48) hexamers of (S ₆) symmetry, which are further linked by two C—H…O hydrogen bonds to form a three‐dimensional framework structure. In compound (II), inversion‐related pairs of N—H…O hydrogen bonds link the spiro[indoline‐3,3′‐pyrrolizine] molecules into simple R ₂²(8) dimers.     

Organic Diodes Based on Redox-Polymer Bilayer-Film-Modified Electrodes

The synthesis of four electropolymerizable 2,2′-bipyridinium salts with tuned reduction potential (E₁^°) is described (N,N′-ethylene-4-methyl-4′-vinyl-2,2′-bipyridinium dibromide ( 4 ; E₁^° ?–0.48 V), 4-methyl-N, N′-(trimethylene)-4′-vinyl-2,2′-bipyridinium dibromide ( 5 ; E₁^°? ?0.66 V), N,N′-ethylene-4-methyl-4′-[2-(1H-pyrrol-1-yl)ethyl]-2, 2′-bipyridinium bis(hexafluorophosphate) ( 6b ; E₁^°? ?0.46 V), and 4-methyl-4′-[2-(1H-pyrrol-1-yl)ethyl]-N, N′-(trimethylene)-2,2′-bipyridinium bis(hexafluorophosphate) ( 7b ; E₁^°? ?0.66 V)). E₁^°-Tuning is based on the torsional angle C(3)–C(2)–C(2′)–C(3′), imposed by the N,N′-ethylene and N,N′-(trimethylene) bridge. The vinylic compounds 4 and 5 undergo cathodic, the pyrrole derivatives 6b and 7b anodic electropolymerization on glassy carbon electrodes from MeCN solutions, yielding thin, surface-confined films with surface concentrations of redox-active material in the range 5 · 10^?9 < Γ < 2.10^?8 mol/cm², depending on experimental conditions. The modified electrodes exhibit reversible ‘diquat’ electrochemistry in pure solvent/electrolyte. Copolymerization of 6b or 7b with pyrrole yields most stable electrodes. Bi ayer-film-modified electrodes were prepared by sequential electropolymerization of the monomers. The assembly electrode/poly- 6b /poly- 7b behaves as a switch, it transforms – as a Schmitt trigger – an analog input signal (the electrode potential) into a digital output signal (redox state of the outer polymer film). Forward-(electrode/poly- 7b /poly- 6b ) and reverse-biased assemblies (electrode/poly- 6b /poly- 7b ) were coupled to the electrochemical reduction of redox-active solution species, e.g. N- (cyanomethyl)-N′-methyl-4,4′-bipyridinium bis(hexafluorophosphate) ( 8 ). Zener-diode-like behavior was observed. Aspects of redox-polymer multilayer-film assemblies, sandwiched between two electronic conductors, are discussed in terms of molecular electronic devices.     

1-Amino-2-phthalimido-diazen-1-oxide: Bildung,Eigenschaften und Fragmentierungen in Imido- und Amino-nitrene

1-Amino-2-phthalimido-diazene-1-oxides: Formation, Properties and Fragmentation Reactions into Imido- and Amino-nitrenes¹) Oxidatively generated phthalimido-nitrene ( 1 ) reacts with the nitrosoamines 2a-d (see Scheme 1) to give the corresponding (Z)-1-amino-2-phthalimido-diazene-1-oxides 3a-d in good yields. With the O-nitroso compound 2e , no addition of the nitrene 1 took place. The constitution the adducts 3 (R = NR′₂) is deduced from their spectroscopic properties (UV., IR., ¹H-NMR. and MS.) as compared to those of (Z)-1-aryl- and (Z)-1-alkyl-2-phthalimido-diazene-1-oxides 3 (R = aryl and alkyl, resp.). The (Z)-configuration of 3 (R = NR′₂) follows from an X-ray analysis which is reported separately. Compounds 3 (R = NR′₂) are cleaved photolytically as well as by acid to the corresponding nitrosoamines 2 (R = NR′₂) and the nitrene 1 , which could be trapped by cyclohexene to give 40% of 7-phthalimido-7-azabicyclo [4.1.0]heptane ( 8 ) and by dimethylsulfoxide to yield 96% of S, S-dimethyl-N-phthalimido-sulfoximide ( 13 ). Nucleophilic attack leads to fragmentation of 3 (R = NR′₂) into derivatives of phthalic acid and degradation products of intermediate aminonitrenes 24 corresponding to the respective nitrosoamines 2 (R = NR′₂) with loss of oxygen. A general rationalization for the formation of 24 includes as a key step of N- to C-migration of the O-atom (see Scheme 6). The final fate of 24 is depending on the type of the nucleophile used. Thus, hydrazinolysis of 3b and of 3c generates besides N, N′-phthaloylhydrazine ( 15 ), morpholine ( 14 ) from 3b and 1, 3-dihydroisoindole ( 16 ) together with 6′-methylidene-1, 2, 3, 4-tetrahydronaphthalene-2-spiro-1′-cyclohexa-2′, 4′-diene ( 17 ) from 3c (see Scheme 5). Treatment of 3b and of 3c with sodium methylate leads in both reactions to monomethyl phthalate ( 33 ) and, with 3b , to 1, 2-dimorpholinodiazene ( 31 ) and, with 3c , to 17 (see Scheme 7). Finally, the reaction of 3b with diethylamine generates N, N-diethylphthalamic acid ( 36 ), morpholine ( 14 ), 1,1,4,4-tetraethyl-2-tetrazene( 34 ) and l,l-diethyl-4,4-(3-oxapentamethylene)-2-tetrazene ( 35 ) (see Scheme 8).     

Stereoselective synthesis of pyrrolo[2,3-d]pyrimidine α- and β-D-ribonucleosides from anomerically pure D-ribofuranosyl chlorides: Solid-Liquid Phase-Transfer Glycosylation and 15N-NMR Spectra

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethye]amine ( = TDA-1), MeCN) of pyrrolo[2,3-d]pyrimidines such as 3a and 3b with an equimolar amount of 5-O-[(1,1 -dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribofuranosyl chloride (1) [6] gave the protected β-D -nucleosides 4a and 4b , respectively, stereoselectively (Scheme). The β-D -anomer 2 [6] yielded the corresponding α-D -nucleosides 5a and 5b with traces of the β-D -compounds. The 6-substituted 7-deazapurine nucleosides 6a , 7a , and 8 were converted into tubercidin (10) or its α-D -anomer (11) . Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T₁ values of H? C(8) in the α-D -series are significantly increased compared to H? C(8) in the β-D -series while the opposite is true for T₁ of H? C(1′). ¹⁵N-NMR data of 6-substituted 7-deazapurine D -ribofuranosides were assigned and compared with those of 2′-deoxy compounds. Furthermore, it was shown that 7-deaza-2′deoxyadenosine ( = 2′-deoxytubercidin; 12 ) is protonated at N(1), whereas the protonation site of 7-deaza-2′-deoxyguanosine ( 20 ) is N(3).     

Die diasteromeren Aurochrome: Synthese,Analytik und Chiroptische Eigenschaften

The Diastereomeric Aurochromes: Their Synthesis, Analysis and Chiroptical Properties (all-E)-Aurochrome (5,8:5′,8′-diepoxy-5,8,5′,8′-tetrahydro-β,β-carotene; 1 ) has two pairs of constitutionally identical chiral centres and, therefore, is expected to exist in four pairs of enantiomers and two meso-forms. Using starting materials with well-defined configuration, we performed the syntheses of the following pure aurochromes: (5R,8R,5′R,8′R)-aurochrome ( 2 ) and its racemate, Meso-(5R,8R,5′S,8′S)-aurochrome ( 3 ), (5 R,8 S,5′ R,8′ S)-aurochrome ( 4 ) and its racemate, meso-(5R,8S,5′S,8′R)-aurochrome ( 5 ), (5R,8R,5′R,8′S)-aurochrome ( 6 ) and its racemate. The (5RS,8RS,5′SR,8′RS)-aurochrome ( 7 ) was detected chromatographically, using a HPLC system that allows clean separation of the four racemic- (or optically active) and the two meso-aurochromes. The optically active autochromes 2 and 4 exhibit non-conservative CD spectra with strong Cotton effects of opposite but not mirror-like tracings. Solutions of aurochromes in CHCl₃, in the presence of HCl, undergo epimerization at C(8). Those epimers with CH₃ trans to C(9) slightly predominate under equilibrium conditions. Deprotonation of the phosphonate (±)- 14 with strong base causes isomerization at the terminal oxirane into a dihydrofuran. This reaction allowed convenient syntheses of the diastereoisomeric aurochromes (±)- 2, 3 , (±)- 4, 5 , (±)- 6 , and (±)- 7 and of (5RS, 8RS)- and (5RS, 8SR)-12′-apo-aurochrome-12′-als ( 21 and 22 , respectively).     

Purine nucleosides XXVIII. The synthesis of 7-(2′-deoxy-α- and β-d-ribofuranosyl)purines from 2′-deoxyribofuranosylimidazoles. Preparation of the 2′-deoxy derivative of the nucleoside from pseudovitamin B12 factor G

The synthesis of 1-(2′-deoxyribofuranosyl)imidazoles have been achieved for the first time via the fusion method of glycosidation. 4-Amino-5-carboxamido-1-(2′-deoxy-α-D-ribofuranosyl)-imidazole ( 8 ) and 4-amino-5-carboxamido-1-(2′-deoxy-β-D-ribofuranosyl)imidazole ( 10 ) have been obtained and their structures established by spectroscopic methods. The first examples of 7-(2′-deoxyglycosyl)purines [7-(2′-deoxy-α-D-ribofuranosyl)hypoxanthine ( 6 ) and 7-(2′-deoxy-β-D-ribofuranosyl)hypoxanthine ( 11 )] have been obtained from the requisite 2′-deoxyribofuranosylimidazoles. The preparation of 6 has furnished the 2′-deoxy derivative (α-configuration) of the nucleoside from pseudovitamin B₁₂ Factor G, which constitutes the first 2′-deoxy derivative of any nucleoside isolated from the various naturally occurring pseudovitamin B₁₂ factors.     

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH₂, CH₂CH₂, or CH₂NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.     

Mechanistic and Synthetic Studies on the Formation of 1,2,4-Trioxanes Related to Arteannuin. Photooxygenation of a bicyclic dihydropyran

The photooxygenation of (4R,4aS,7R)-4,4a,5,6,7,8-hexahydro-4,7-dimethyl-3H-2-benzopyran ( 16 ) was performed in (i) MeOH, (ii) acetaldehyde, and (iii) acetone at ?78°. The products obtained respectively were (i) (2R)-2-[(1S,4R)-4-methyl-2-oxocyclohexyl]propyl formate ( 17 ; 72% yield), (ii) 17 (54.5%), (1R,4R,4aS,7R)-3,4,4a,5,6,7-hexahydro-4,7-dimethyl-1H-2-benzopyran-2-yl hydroperoxide ( 19 ; 16.7%), a 12:1 ratio of (3R,4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,7,10-trimethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4-trioxane ( 20 ) and its C(3)-epimer 21 (17%), together with evidence for the 1,2-dioxetane ( 22 ) originating from the addition of dioxygen to the re-re face of the double bond of 16 , and iii) unidentified products and traces of 22 . Addition of trimethylsilyl trifluoromethanesulfonate (Me₃SiOTf) to the acetone solution of 16 after photooxygenation afforded (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4,-trioxane ( 23 , 40%). The photooxygenation of 16 in CH₂Cl₂ at ?78° followed by addition of acetone and Me₃SiOTf afforded 17 (11%), 23 (59%), and (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[8a,1-e]-1,2,4-trioxane ( 24 ; 5%. Repetition of the last experiment, but replacing acetone by cyclopentanone, gave 17 (16%), (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[1,8a-e]-1,2,4-trixane] ( 25 ; 61%), and (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[8a,1-e]-1,2,4-trixane] ( 26 , 4%). The X-ray analysis of 23 was performed, which together with the NMR data, established the structure of the trioxanes 20, 21, 24, 25 , and 26 . Mechanistic and synthesis aspects of these reactions were discussed in relation to the construction of the 1,2,4-trioxane ring in arteannuin and similar molecules.