Regioselective Transformations of 2′,3′-Seconucleosides into Anhydro Structures and Chiral Crown Ethers

Intramolecular cyclisation of properly protected and activated derivatives of 2′,3′-secouridine ( = 1-{2-hydroxy-1-[2-hydroxy-1-(hydroxymethyl)ethoxy]-ethyl}uracil; 1 ) provided access to the 2,2′-, 2,3′-, 2,5′-, 2′,5′-, 3′,5′-, and 2′,3′-anhydro-2′,3′-secouridines 5, 16, 17, 26, 28 , and 31 , respectively (Schemes 1–3). Reaction of 2′,5′-anhydro-3′-O-(methylsulfonyl)- ( 25 ) and 2′,3′-anhydro-5′-O-(methylsulfonyl)-2′,3′-secouridine ( 32 ) with CH₂CI₂ in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene generated the N(3)-methylene-bridged bis-uridine structure 37 and 36 , respectively (Scheme 3). Novel chiral 18-crown-6 ethers 40 and 44 , containing a hydroxymethyl and a uracil-1-yl or adenin-9-yl as the pendant groups in a 1,3-cis relationship, were synthesized from 5′-O-(triphenylmethyl)-2′,3′-secouridine ( 2 ) and 5′-O,N⁶-bis(triphenylmethyl)-2′,3′-secoadenosine ( 41 ) on reaction with 3,6,9-trioxaundecane-1,11-diyl bis(4-toluenesulfonate) and detritylation of the thus obtained (triphenylmethoxy) methylcompound 39 and 43 , respectively (Scheme 4).     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

Synthesis of [D-alanine, 4'-azido-3',5'-ditritio-L-phenylalanine, norvaline4[alpha-melanotropin as a 'photoaffinity probe' for hormone-receptor interactions (author's transl)]

Synthesis of [D -alanine¹, 4′-azido-3′, 5′-ditritio-L -phenylalanine², norvaline⁴]α-melanotropin as a ‘photoaffinity probe’ for hormone-receptor interactions. The synthesis of an α-MSH derivative containing 4′-azido-3′,5′-ditritio-L -phenylalanine is described: Ac · D -Ala-Pap(³H₂)-Ser-Nva-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val · NH₂. This hormone analogue is being used for specific photoaffinity labelling of receptor molecules. The synthesis was performed in a way to minimize the number of radioactive steps and to introduce the radio-active and the photoaffinity label exclusively into position 2. The dipeptide N(α)-acetyl-D -alanyl- (4′-amino-3′,5′-diiodo)-L -phenylalanine was tritriated and transformed into the azido compound, N(α)-acetyl-D -alanyl-(4′-azido-3′,5′-ditritio)-L -phenylalanine which was then condensed with H · Ser-Nva-Glu(OtBu)-His-Phe-Arg-Trp-Gly-Lys(BOC)-Pro-Val · NH₂ to the tridecapeptide. The α-MSH analog displayed a specific activity of 11 Ci/mmol, and a biological activity of about 4 · 10⁹ U/mmol (10% of α-MSH).     

Nitrostyrene Derivatives of Adenosine 5′-Glutarates Modified with an Alkyl Spacer and their inhibitory activity on epidermal growth factor receptor protein tyrosine kinase

β-Nitrostyrene derivatives of adenosine 5′-glutarates are potent and selective bisubstrate-type inhibitors of the epidermal growth factor receptor protein tyrosine kinase (EGF-R PTK). In an attempt to improve the inhibitory activity, this type of compounds was modified with alkyl spacers of varying length between the nitrostyrene and the glutaryl units. The spacers consisted of 1, 3, 4, and 5 atoms to give compounds of the benzyl, oxyethyl, oxypropyl, and oxybutyl series, respectively (Schemes 1 and 2). Adenosine 5′-esters were prepared in the benzyl and oxypropyl series only. Compared to the compounds in the parent series without spacer (IC₅₀ = 0.7–12 μM ), most of the modified compounds inhibited the EGF-R PTK only marginally or were inactive (IC₅₀ ≥ 100 μM ). The only exceptions were the free acids 19 and 20 with IC₅₀ values of ca. 5 μM . It is noteworthy that esterification of these two hydrogen glutarates with either MeOH or adenosine yielded inactive compounds, which is in contrast to the corresponding substances without spacers.     

Synthesis of 5-Methyluridine and Its 5′-Mercapto-, 2-Amino-, and 4′,5′-Unsaturated Analogues

The stereospecific cis-hydroxylation of 1-(2,3-dideoxy-β-D -glyceropent-2-enofuranosyl)thymine (1) into 1-β-D -ribofuranosylthymine (2) by osmium tetroxide is described. Treatment of 2′,3′-O, O-isopropylidene-5-methyl-2,5′-anhydrouridine (8) with hydrogen sulfide or methanolic ammonia afforded 5′-deoxy-2′,3′-O, O-isopropylidene-5′-mercapto-5-methyluridine (9) and 2′,3′-O, O-isopropylidene-5-methyl-isocytidine (10) , respectively. The action of ethanolic potassium hydroxide on 5′-deoxy-5′-iodo-2′,3′-O, O-isopropylidene-5-methyluridine (7) gave rise to the corresponding 1-(5-deoxy-β-D -erythropent-4-enofuranosyl)5-methyluracil (13) and 2-O-ethyl-5-methyluridine (14) . The hydrogenation of 2 and its 2′,3′-O, O-isopropylidene derivative 4 over 5% Rh/Al₂O₃ as catalyst generated diastereoisomers of the corresponding 5-methyl-5,6-dihydrouridine ( 17 and 18 ).     

Nucleotides. Part XLV. Synthesis of new (2′–5′)adenylate trimers,containing 5′-amino-5′-deoxyadenosine residues at the 5′-end of the oligoadenylate chain,and of its analogues,carrying a 9-[(2-hydroxyethoxy)methyl]adenine residue at the 2′-terminus

The 5′-amino-5′-deoxy-2′,3′-O-isopropylideneadenosine ( 4 ) was obtained in pure form from 2′,3′-O-isopropylideneadenosine ( 1 ), without isolation of intermediates 2 and 3 . The 2-(4-nitrophenyl)ethoxycarbonyl group was used for protection of the NH₂ functions of 4 (→7) . The selective introduction of the palmitoyl (= hexadecanoyl) group into the 5′-N-position of 4 was achieved by its treatment with palmitoyl chloride in MeCN in the presence of Et₃N (→ 5 ). The 3′-O-silyl derivatives 11 and 14 were isolated by column chromatography after treatment of the 2′,3′-O-deprotected compounds 8 and 9 , respectively, with (tert-butyl)dimethylsilyl chloride and 1H-imidazole in pyridine. The corresponding phosphoramidites 16 and 17 were synthesized from nucleosides 11 and 14 , respectively, and (cyanoethoxy)bis(diisopropylamino)phosphane in CH₂Cl₂. The trimeric (2′–5′)-linked adenylates 25 and 26 having the 5′-amino-5′-deoxyadenosine and 5′-deoxy-5′-(palmitoylamino)adenosine residue, respectively, at the 5′-end were prepared by the phosphoramidite method. Similarly, the corresponding 5′-amino derivatives 27 and 28 carrying the 9-[(2-hydroxyethoxy)methyl]adenine residue at the 2′-terminus, were obtained. The newly synthesized compounds were characterized by physical means. The synthesized trimers 25–28 were 3-, 15-, 25-, and 34-fold, respectively, more stable towards phosphodiesterase from Crotalus durissus than the trimer (2′–5′)ApApA.     

Nucleosides. Part LXI. A Simple Procedure for the Monomethylation of Protected and Unprotected Ribonucleosides in the 2′-O- and 3′-O-Position Using Diazomethane and the Catalyst Stannous Chloride

Intensive studies on the diazomethane methylation of the common ribonucleosides uridine, cytidine, adenosine, and guanosine and its derivatives were performed to obtain preferentially the 2′-O-methyl isomers. Methylation of 5′-O-(monomethoxytrityl)-N²-(4-nitrophenyl)ethoxycarbonyl-O⁶-[2-(4-nitrophenyl)ethyl]-guanosine ( 1 ) with diazomethane resulted in an almost quantitative yield of the 2′- and 3′-O-methyl isomers which could be separated by simple silica-gel flash chromatography (Scheme 1). Adenosine, cytidine, and uridine were methylated with diazomethane with and without protection of the 5′ -O-position by a mono- or dimethoxytrityl group and the aglycone moiety of adenosine and cytidine by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group (Schemes 2–4). Attempts to increase the formation of the 2′-O-methyl isomer as much as possible were based upon various solvents, temperatures, catalysts, and concentration of the catalysts during the methylation reaction.     

Umlagerungsreaktionen von (2′-Propinyl)cyclohexadienolen und -semibenzolen

Rearrangements of (2′-Propinyl)cyclohexadienols and -semibenzenes The acid-catalyzed dienol-benzene rearrangement of 3- and 5-methyl-substituted (2′-propinyl)cyclohexadienols has been investigated. Treatment of the dienols with CF₃COOH in CCl₄ yields allenyl- and (2′-propinyl)benzenes via [3,4]- and [1,2]-sigmatropic rearrangements, respectively. The reaction with H₂SO₄ in Et₂O leeds to a mixture of allenyl-, 2′-propinyl-, 3′-butinyl- and (2′,3′-butadienyl)benzenes (Scheme 3). The latter are products of a thermal semibenzene-benzene rearrangement (cf. Scheme 9). The corresponding semibenzenes have been prepared by dehydration of the cyclohexadienols with H₂SO₄ or POCl₃ (Schemes 6 and 7). Under acidic conditions, the p-(2′-propinyl)semibenzenes 33–35 (Scheme 8) undergo [3,4]- and [1,2]-sigmatropic rearrangements to give again allenyl- and (2′-propinyl)benzenes, whereas the thermal rearrangements to the 3′-butinyl- and (2′,3′-butadienyl)benzenes (Scheme 9) involves a radical mechanism. In contrast, the o-(2′-propinyl)semibenzene b (Scheme 7) leads to (2′,3′-butadienyl)benzene 32 via a thermal [3,3]-sigmatropic rearrangement.     

Synthesis and properties of 5-(1,2-dihaloethyl)-2′-deoxyuridines and related analogues

The regiospecific reaction of 5-vinyl-3′,5′-di-O-acetyl-2′-deoxyuridine ( 2 ) with HOX (X = Cl, Br, I) yielded the corresponding 5-(1-hydroxy-2-haloethyl)-3′,5′-di-O-acetyl-2′-deoxyuridines 3a-c . Alternatively, reaction of 2 with iodine monochloride in aqueous acetonitrile also afforded 5-(1-hydroxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3c ). Treatment of 5-(1-hydroxy-2-chloroethyl)- ( 3a ) and 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with DAST (Et₂NSF₃) in methylene chloride at -40° gave the respective 5-(1-fluoro-2-chloroethyl)- ( 6a , 74%) and 5-(1-fluoro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6b , 65%). In contrast, 5-(1-fluoro-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6e ) could not be isolated due to its facile reaction with methanol, ethanol or water to yield the corresponding 5-(1-methoxy-2-iodoethyl)- ( 6c ), 5-(1-ethoxy-2-iodoethyl)- ( 6d ) and 5-(1-hydroxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3c ). Treatment of 5-(1-hydroxy-2-chloroethyl)- ( 3a ) and 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with thionyl chloride yielded the respective 5-(1,2-dichloroethyl)- ( 6f , 85%) and 5-(1-chloro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6g , 50%), whereas a similar reaction employing the 5-(1-hydroxy-2-iodoethyl)- compound 3c afforded 5-(1-methoxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6c ), possibly via the unstable 5-(1-chloro-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine intermediate 6h . The 5-(1-bromo-2-chloroethyl)- ( 6i ) and 5-(1,2-dibromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6j ) could not be isolated due to their facile conversion to the corresponding 5-(1-ethoxy-2-chloroethyl)- ( 6k ) and 5-(1-ethoxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 61 ). Reaction of 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with methanolic ammonia, to remove the 3′,5′-di-O-acetyl groups, gave 2,3-dihydro-3-hydroxy-5-(2′-deoxy-β-D-ribofuranosyl)-furano[2,3-d]pyrimidine-6(5H)-one ( 8 ). In contrast, a similar reaction of 5-(1-fluoro-2-chloroethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6a ) yielded (E)-5-(2-chlorovinyl)-2′-deoxyuridine ( 1b , 23%) and 5-(2′-deoxy-β-D-ribofuranosyl)furano[2,3-d]pyrimidin-6(5H)-one ( 9 , 13%). The mechanisms of the substitution and elimination reactions observed for these 5-(1,2-dihaloethyl)-3′,5′-di-O-acetyl-2′-deoxyuridines are described.     

Synthesis of S-5-pyrrolo[2,3-b]pyridinemethyl and S-5- and S-6-pyrrolo[2,3-d]pyridinemethyl derivatives of 5′-deoxy-5′-thioadenosine

Reaction of 5-dimethylaminomethylpyrrolo[2,3-b]pyridine methiodide or 5-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one methiodide with 5′-deoxy-5′-S-thioacetyl-N⁶-formyl-2′,3′-O-isopropylideneadenosine in ethanolic sodium hydroxide solution, followed by deprotection of the resulting thioether in 80% formic acid, afforded 5′-deoxy-5′-(5-pyrrolo[2,3-b]pyridinemethylthio)adenosine or 5′-deoxy-5′-[5-(pyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine, respectively. Similarly, the metiodide salt of the iso-gramine analog, 2-amino-6-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one afforded 5′-deoxy-5′-[6-(2-aminopyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine.     

Synthese von Alkylphenolen und -pyrocatecholen aus Plectranthus albidus (Labiatae)

Synthesis of Alkylphenols and -catechols from Plectranthus albidus (Labiatae) In the preceding paper, we described the isolation and structure elucidation of a series of even-numbered phenol- or pyrocatechol-derived 1-arylalkane-5-ones. To establish the assigned structures unambiguously and to have larger quantities available for physiological testing, the following compounds were prepared: in the alkylphenol series, 1-(4′-hydroxyphenyl)tetradecan-5-one ( 2a ), 1-(4′-hydroxyphenyl)hexadecan-5-one ( 2b ), and 1-(4′-hydroxyphenyl)octadecan-5-one ( 2c ); in the alkylcatechol series, 1-(3′,4′-dihydroxyphenyl)decan-5-one ( 3a ; not isolated as a natural compound), 1-(3′,4′-dihydroxyphenyl)dodecan-5-one ( 3b ), 1-(3′,4′-dihydroxyphenyl)tetradecan-5-one ( 3c ), 1-(3′,4′-dihydroxyphenyl)hexadecan-5-one ( 3d ), 1-(3′,4′-dihydroxyphenyl)octadecan-5-one ( 3e ), and 1-(3′,4′-dihydroxyphenyl)icosan-5-one ( 3f ); in the alkenylphenol series, (Z)-1-(4′-hydroxyphenyl)octadec-13-en-5-one ( 4a ) and (E)-1-(4′-hydroxyphenyl)octadec-13-en-5-one ( 4b ); in the alkenylcatechol series, (E,E)-1-(3′,4′-dihydroxyphenyl)deca-1,3-dien-5-one ( 1 ) and (Z)-1-(3′,4′-dihydroxyphenyl)octadec-13-en-5-one ( 5 ). All compounds proved to be identical with the previously assigned structures. Compound 1 was synthesized by regioselective aldol condensation of heptan-2-one with (E)-1-(3′,4′-dimethoxyphenyl)prop-2-enal ( 6d ; Scheme 1), the phenols 2a–c and the catechols 3a–f by addition of the corresponding alkyl Grignard reagent to 5-(4′-methoxyphenyl)- or 5-(3′,4′-dimethoxyphenyl)pentanal ( 17c and 18c , resp.; Scheme 4), and the olefins 4a, 4b and 5 from 17c or 18c via the 9-O-silyl-protected 13-(4′-methoxyphenyl)- or 13-(3′,4′-dimethoxyphenyl)tridecanals ( 26 and 27 , resp.) and Wittig olefination as the key steps (Scheme 5).     

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.     

Synthesis of some oxadiazole derivatives of d-mannose

The syntheses of 2-methyl-5-[1′,2′,3′,4′,5′-penta-O-benzoyl-D-manno-pentitol-1′-yl]-1,3,4-oxadiazole and 5-methyl-3-[1′,2′,3′,4′,5′-penta-O-benzoyl-D-manno-pentitol-1-′yl]-1,2,4-oxadiazole, as well as their intermediate products, are described. Their ¹H and ¹³C nmr and ms spectra are presented and their preferential conformation in solution are proposed.     

Synthesis of New Nucleosides by coupling of chloropurines with 2- and 3-deoxy derivatives of N-methyl-D-ribofuranuronamide

The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D -ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D -ribofuranosiduronamide (α-D - 8 ) and the corresponding anomer β-D - 8 were synthesized starting from the commercially available 2-deoxy-D -ribose ( 1 ) (Scheme 1). Reaction of α-D - 8 with the silylated derivative of 2,6-dichloro-9H-purine ( 9 ) afforded regioselectively the N⁹-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D - 8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine ( 17 ) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D -ribofuranuronamide ( 13 ) yielded only the protected β-D -anomers 14 and 18 , respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D - 11 , β-D - 12,15 , and 16 . The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A₁ and A_2A adenosine receptor subtypes.     

Nucleotides. Part LXXVIII

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18 , and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→ 31, 33 , and 35 ; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N²‐[(dimethylamino)methylene]guanosine ( 37 ) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44 , and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine ( 54 ; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline ( 61 ) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64 . The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65 . and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the T_ms in comparison to their parent duplexes were measured (Tables 1–5).     

Untersuchungen über aromatische Amino-Claisen-Umlagerungen

Investigations on Aromatic Amino-Claisen Rearrangements The thermal and acid catalysed rearrangement of p-substituted N-(1′,1′-dimethylallyl)anilines (p-substituent=H (5) , CH₃ (6) , iso-C₃H₇ (7) , Cl (8) , OCH₃ (9) , CN (10) ), of N-(1′,1′-dimethylallyl)-2,6-dimethylaniline (11) , of o-substituted N-(1′-methylallyl)anilines (o-substituent=H (12) , CH₃ (13) , t-C₄H₉ (14) , of (E)- and (Z)-N-(2′-butenyl)aniline ((E)- and (Z)- 16 ), of N-(3′-methyl-2′-butenylaniline (17) and of N-allyl- (1) and N-allyl-N-methylaniline (15) was investigated (cf. Scheme 3). The thermal transformations were normally conducted in 3-methyl-2-butanol (MBO), the acid catalysed rearrangements in 2N -0,1N sulfuric acid. - Thermal rearrangements. The N-(1′,1′-dimethylallyl)anilines rearrange in MBO at 200-260° with the exception of the p-cyano compound 10 in a clean reaction to give the corresponding 2-(3′-methyl-2′-butenyl)anilines 22–26 (Table 2 and 3). The amount of splitting into the anilines is <4% ( 10 gives ? 40% splitting). The secondary kinetic deuterium isotope effect (SKIDI) of the rearrangement of 5 and its 2′,3′,3′-d₃-isomer 5 amounts to 0.89±0.09 at 260° (Table 4). This indicates that the partial formation of the new s?-bond C(2), C(3′) occurs already in the transition state, as is known from other established [3,3]-sigmatropic rearrangements. The rearrangement of the N-(1′-methylallyl)anilines 12–14 in MBO takes place at 290–310° to give (E)/(Z)-mixtures of the corresponding 2-(2′-Butenyl)anilines ((E)- and (Z)- 30,-31 , and -32 ) besides the parent anilines (5–23%). Since a dependence is observed between the (E)/(Z)-ratio and the bulkiness of the o-substituent (H: (E)- 30 /(Z)- 30 =4,9; t-C₄H₉: (E)- 32 /(Z)- 32 =35.5; cf. Table 6), it can be concluded, that the thermal amino-Claisen rearrangement occurs preferentially via a chair-like transition state (Scheme 22). Methyl substitution at C(3′) in the allyl chain hinders the thermal amino-Claisen-rearrangement almost completely, since heating of (E)-and (Z)- 16 , in MBO at 335° leads to the formation of the expected 2-(1′-methyl-allyl) aniline (33) to an extent of only 12 and 5%, respectively (Scheme 9). The main reaction (?60%) represents the splitting into aniline. This is the only observable reaction in the case of 17 . The inversion of the allyl chain in 16 - (E)- and (Z)- 30 cannot be detected - indicated that 33 is also formed in a [3, 3]-sigmatropic process. This is also true for the thermal transformation of N-allyl- (1) and N-allyl-N-methylaniline (15) into 2 and 34 , respectively, since the thermal rearrangement of 2′, 3′, 3′-d₃- 1 yields 1′, 1′, 2′-d₃- 2 exclusively (Table 8). These reaction are accompanied to an appreciable extent by homolysis of the N, C (1′) bond: compound 1 yields up to 40% of aniline and 15 even 60% of N-methylaniline ((Scheme 10 and 11). The activation parameters were determined for the thermal rearrangements of 1, 5, 12 and 15 in MBO (Table 22). All rearrangements show little solvent dependence (Table 5, 7 and 9). The observed ΔH^≠ values are in the range of 34-40 kcal/mol and the ΔS^≠ values very between -13 to -19 e.u. These values are only compatible with a cyclic six-membered transition state of little polarity. - Acid catalysed rearrangements. - The rearrangement of the N-(1′, 1′-dimethylallyl) anilines 5-10 occurs in 2N sulfuric acid already at 50-70° to give te 2-(3′-methyl-2′-butenyl)anilines 22-27 accompanied by their hydrated forms, i.e. the 2-(3′-hydroxy-3′-methylbutyl) anilines 35-40 (Tables 10 and 11). The latter are no more present when the rearrangement is conducted in 0.1 N sulfuric acid, whilst the rate of rearrangement is practically the same as in 2 N sulfuric acid (Table 12). The acid catalysed rearrangements take place with almost no splitting. The SKIDI of the rearrangement of 5 and 2′, 3′, 3′-d₃- 5 is 0.84±0.08 (2 N H₂SO₄, 67, 5°, cf. Table 13) and thus in accordance with a [3,3]-sigmatropic process which occurs in the corresponding anilinium ions. Consequently, the rearrangement of a 1:1 mixture of 2′, 3′, 3′-d₃- 5 and 3, 5-d₂- 5 in 2 N sulfuric acid at 67, 5° occurs without the formation of cross-products (Scheme 13). In the acid catalysed rearrangement of the N-1′-methylallyl) anilines 12-14 at 105-125° in 2 N sulfuric acid the corresponding (E)- and (Z)-anilines are the only products formed (Table 14 and 15). Again no splitting is observed. Furthermore, a dependence of the observed (E)/(Z) ratio and the bulkiness of the o-substituent ( H : (E)/(Z)- 30 = 6.5; t- C ₄ H ₉: (E)- 32 /(Z)- 32 = 90; cf. Table 15) indicates that also in the ammonium-Claisen rearrangement a chair-like transition state is preferentially adopted. In contrast to the thermal rearrangement the acid catalysed transformation in 2 N-O, 1 N sulfuric acid (150-170°) of (E)- and (Z)- 16 as well as of 1 and 15 , occurs very cleanly to yield the corresponding 2-allylated anilines 33, 2 and 34 (Scheme 15 and 18). The amounts of the anilines formed by splitting are <2%. During longer reaction periods hydration of the allyl chain of the products occurs, and in the case of the rearrangement of (E)- and )Z)- 16 the indoline 45 is formed (Scheme 15 and 18). All transformations occur with inversion of the allyl chain. This holds also for the rearrangement of 1 , since 3′, 3′-d₂- 1 gives only 1′, 1′-d₂- 2 (Scheme 17). The activation parameters were determined for the acid catalysed rearrangement of 1, 5, 12 and 15 in 2 N sulfuric acid (Table 22). The ΔH^≠ values of 27-30 kcal-mol and the ΔS^≠ values of +9 to -12 e.u. are in agreement with a [3, 3]-sigmatropic process in the corresponding anilinium ions. The acceleration factors (k_H+/k_Δ) calculated from the activation parameters of the acid catalysed and thermal rearrangements of the anilines are in the order of 10⁵ - 10⁷. They demonstrate that the essential driving force of the ammonium-Claisen rearrangement is the ‘delocalisation of the positive charge’ in the transition state of these rearrangements (cf. Table 23). Solvation effects in the anilinium ions, which can be influenced sterically, also seem to play a role. This is impressively demonstrated by N-(1′, 1′-dimethylallyl)-2, 6-dimethylaniline (11) : its rearrangement into 4-(1′, 1′-dimethylallyl)-2, 6-dimethylaniline (43) cannot be achieved thermally, but occurs readily at 30° in 2 N sulfuric acid. From a preparative standpoint the acid catalysed rearrangement in 2 N-0, 1 N sulfuric acid of N-allylanilines into 2-allylanilines, or if the o-positions are occupied into 4-allylanilines, is without doubt a useful synthetic method (cf. also [17]).     

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.     

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.