Photochemische Reaktionen. 78. Mitteilung. Anwendung der π → π*-induzierten Cyclisierung von α,β-ungesättigten γ-Dimethoxymethylketonen auf 19-Methoxy- bzw. 19-Dimethoxy-Steroid-enone und -dienone

Irradiation at 254 nm of 19-dimethoxyandrost-4-en-17 β-ol-3-one acetate ( 8 ) afforded the epimeric cyclization products 9 (yield 20%) and 10 (4%). Similar transformations were also achieved with the analogous dimethoxy-enone 24 (→ 25 , 65%), and-dienone 30 (→ 31 , 72%), and with the methoxy-enone 33 (→ 34 , 30%), and-dienone 35 (→ 36 , 17%).     

Oligosaccharide Analogues of Polysaccharides. Part 4. Synthesis of a monosaccharide-derived octamer

NaSMe in toluene leads to regioselective de-C-silylation of the bis[(trimethylsilyl)ethynyl]saccharide 2 , but to decomposition of butadiynes such as 1 or 12 . We have, therefore, combined the known reagent-controlled, regioselective desilylation of 2 and of 12 (AgNO₂/KCN) with a substrate-controlled regioselective de-C-silylation, based on C-silyl groups of different size. This combination was studied with the fully protected 3 which was mono-desilylated to 4 or to 5 (Scheme 1). Triethylsilylation of 5 (→ 6 ) was followed by removal of the Me₃Si group (→ 7 ), introduction of a (t-Bu)Me₂Si group (→ 8 ) and removal of the Et₃Si group yielded 9 ; these high-yielding transformations proceed with a high degree of selectivity. Iodination of 4 gave 10 . The latter was coupled with 5 to the homodimer 11 and the heterodimer 12 , which was desilylated to 13 . The second building block for the tetramer was obtained by coupling 14 (from 7 ) with 5 , leading to 15 and 16 . Removal of the Me₃Si group (→ 17 ) and iodination led to 18 which was coupled with 13 to the homotetramer 20 and the heterotetramer 19 (Scheme 2). Deprotection of 19 gave 21 , which was, on the one hand, iodinated to 22 , and, on the other hand, protected by the (t-Bu)Me₂Si group (→ 23 ). Removal of the Et₃Si group (→ 24 ) and coupling afforded the homooctamer 26 and the heterooctamer 25 . Yields of iodination, silylation, and desilylation were consistently high, while heterocoupling proceeded in only 50–55%. Cleavage of the (i-Pr)₃SiC and MeOCH₂O groups of 11 (→ 27 ), 15 (→ 28 ), 20 (→ 29 ) and 26 (→ 30 ) proceeded in high yields (Scheme 3). Complete deprotection in two steps of the heterocoupling products 16 (→ 31 → 32 ), 19 (→ 33 → 34 ), and 25 (→ 35 → 36 ) gave the unprotected dimer 32 , tetramer 34 , and octamer 36 in high yields (Scheme 4). Only the dimer 32 is soluble in H₂O; the ¹H-NMR spectra of 32 , 34 , and 36 in (D₆)DMSO (relatively low concentration) show no signs of association.     

Synthesis of Novel 8,14‐Secoursane Derivatives: Key Intermediates for the Preparation of Chiral Decalin Synthons from Ursolic Acid

The novel 8,14‐secoursatriene derivative 6 was synthesized starting from ursolic acid ( 1 ) via methyl esterification of the 17‐carboxylic acid group and benzoylation of the 3‐hydroxy group (→ 2 ; Scheme 1), ozone oxidation of the C(12)?C(13) bond (→ 3 ), dehydrogenation with Br₂/HBr (→ 4 ), enol acetylation of the resulting carbonyl group (→ 5 ; Scheme 2), and ring‐C opening with the aid of UV light (→ 6 ). Ring‐C‐opened dienone derivative 7 of ursolic acid was also obtained via selective hydrolysis of 6 (Scheme 2). Both compounds 6 and 7 are key intermediates for the preparation of chiral decalin synthons from ursolic acid.     

The Active Centres of Agelastatin A,a Strongly Cytotoxic Alkaloid of the Coral Sea Axinellid Sponge Agelas dendromorpha,as Determined by Comparative Bioassays with Semisynthetic Derivatives

Agelastatin A ( 1 ), an unusual alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, can be selectively acetylated (→ 7 ) or methylated at OH? C(8a) (→ 4 ), peracetylated (→ 8 ) or permethylated at OH? C(8a), NH(5), and NH(6) (→ 5 ), or, finally, subjected to C(9)? C(8a) (→ 14 ) or C(5b)? C(8a) β-elimination (→ 11–13 ), in a regiospecific manner or not, depending on the reaction conditions. Under acidic conditions, compound 12 adds H₂O or MeOH, regioselectively though not endo/exo stereoselectively, giving transoid/cisoid mixtures 1/18 or 4/19 , respectively. Similarly 11 or 13 add MeOH to give mixtures (?)- 2/20 or 15/16 , respectively. Compound 13 also adds AcOH giving mixture 8/17 . The intermediate cisoid form obtained on treatment of 21 with H₃O⁺ undergoes N(5)? N(6) bridging affording pentacyclic 22 which constitutes a proof for the cisoid configuration. From conformational studies, rules are devised that allow assigning the configuration of these compounds from NMR data. In vitro comparative cytotoxicity assays of these compounds show that for high cytotoxic activity, such as of 1 in vivo, unsubstituted OH? C(8a), H? N(5), H? N(6) moieties are needed in the natural B/D transoid configuration.     

1,3-Dioxanone Derivatives from β-Hydroxy-carboxylic Acids and Pivalaldehyde. Versatile Building Blocks for Syntheses of Enantiomerically Pure Compounds. A Chiral Acetoacetic Acid Derivative Preliminary Communication

(R)-3-Hydroxybutyric acid (from the biopolymer PHB) and pivalaldehyde give the crystalline cis - or (R,R)-2-(tert-butyl)-6-methyl-1,3-dioxan-4-one ( 1a ), the enolate of which is stable at low temperature in THF solution and can be alkylated diastereoselectively ( →3, 4, 5 , and 7 ). Phenylselenation and subsequent elimination give an enantiomerically pure enol acetal 10 of aceto-acetic acid. Some reactions of 10 have been carried out, such as Michael addition (→ 11 ), alkylation on the CH₃ substituent (→ 13 ), hydrogenation of the C?C bond (→ 1a ) and photochemical cycloaddition (→ 16 ). The overall reactions are substitutions on the one stereogenic center of the starting β-hydroxy acid without racemization and without using a chiral auxiliary.     

Photochemische Reaktionen. 87. Mitteilung. Zur Photolyse von 9-Oxabicyclo[3.3.1]nonan-2-on

Photolysis of Bicyclo[3.3.1]nonan-2-one. Disproportionations, the secondary processes available to the acyl-alkyl biradical b (X(9) = 0) formed from 9-oxabicyclo[3.3.1]-nonan-2-ones a (X(9) = 0) in a primary photochemical process by α-cleavage (Norrish type I cleavage) were studied. Special attention was paid to the selectivity between the two possible H-abstractions: the one at C(3) (→ ketene c , X(9)= 0) and the other one at C(8) (→ alkenal d , X(9) = 0) and to the selectivity of the H-abstraction at a definite methylene group (C(3) or C(8)). In the case of ketene formation (→ c , X(9) = 0) the specificity of the insertion of the migrating H-atom at C(1) was studied. endo-6-Hydroxy-9-oxabicyclo[3.3.1]nonan-2-one ( 6 ) and derivatives of it ( 7, 8, 16, 17, 19, 21, 30 and 38 ) as well as exo-6-hydroxy-9-oxabicyclo[3.3.1]-nonan-2-one ( 41 ) and its derivative 42 were used as substrates. UV.-irradiation of 6 in benzene yielded 1,5-dioxa-2-cis-decalone ( 44 ) by way of a ketene g (R = H) as demonstrated by the photolysis of 7 (→ 45 ), 8 (→ 43 ), and 17 (→ 47 ). Specific labellings with deuterium proved that H-abstraction occurs intramolecularly at C(3) (e.g. 16 → 54 ; 6 + 16 → 44 + 54 ), that one of the H-atoms at C(3) migrates specifically to C(1) ( 21 → 55 ; 19 → 56 ), endo-H–C(3) being favored by a factor of 6. The abstraction showed an unexpected primary isotope effect of about 2. UV-irradiation of 41 in benzene yielded in addition to the expected 1,5-dioxa-2-trans-clecalone ( 63 ) about 3% of an isomeric compound 67 which probably results from H-abstraction at C(8) (→ alkenal 65) followed by cyclisation.     

Ungewöhnlich koordinierte phosphoverbindungen: VII.Neue phosphaalkinen und deren cycloadditionsverhalten gegenüben 1,3-dipolen

The phosphaalkenes are derived from tris(trimethylsilyl)phosphine and acid chlorides, with acylphosphines considered as intermediates of the reaction. Sodium hydroxide-catalysed elimination of hexamethyl disiloxane (120–160°C) at the phosphaalkenes yields the hitherto unknown phosphaalkynes. These are chemically characterised by [3 + 2]-cycloaddition reactions with diazomethane (→1,2,4-diazaphospholes), methyl azide (→ 1,2,3,4-triazapholes) and benzonitriloxide (1,2,4-oxazapholes).     

Synthesis of N-Acetylallosamine-Derived Disaccharides

The protected disaccharide 44 , a precursor for the synthesis of allosamidin, was prepared from the glycosyl acceptor 8 and the donors 26–28 , best yields being obtained with the trichloroacetimidate 28 (Scheme 6). Glycosidation of 8 or of 32 by the triacetylated, less reactive donors 38–40 gave the disaccharides 46 and 45 , respectively, in lower yields (Scheme 7). Regioselective glycosidation of the diol 35 by the donors 38–40 gave 42 , the axial, intramolecularly H-bonded OH? C(3) group reacting exclusively (Scheme 5). The glycosyl acceptor 8 was prepared from 9 by reductive opening of the dioxolane ring (Scheme 3). The donors 26–28 were prepared from the same precursor 9 via the hemiacetal 25 . To obtain 9 , the known 10 was de-N-acetylated (→ 18 ), treated with phthalic anhydride (→ 19 ), and benzylated, leading to 9 and 23 (Schemes 2 and 3). Saponification of 23 , followed by acetylation also gave 9 . Depending upon the conditions, acetylation of 19 yielded a mixture of 20 and 21 or exclusively 20 . Deacetylation of 20 led to the hydroxyphthalamide 22 . De-N-acetylation of the 3-O-benzylated β-D -glycosides 11 and 15 , which were both obtained from 10 , was very sluggish and accompanied by partial reduction of the O-allyl to an O-propyl group (Scheme 2). The β-D -glycoside 30 behaved very similarly to 11 and 15 . Reductive ring opening of 31 , derived from 29 , yielded the 3-O-acetylated acceptor 32 , while the analogous reaction of the β-D -anomer 20 was accompanied by a rapid 3-O→4-O acyl migration (→ 34 ; Scheme 4). Reductive ring opening of 21 gave the diol 35 . The triacetylated donors 38–40 were obtained from 20 by debenzylidenation, acetylation (→ 36 ), and deallylation (→ 37 ), followed by either acetylation (→ 38 ), treatment with Me₃SiSEt (→ 39 ), or Cl₃CCN (→ 40 ).     

Analogues of Sialic Acids as Potential Sialidase Inhibitors. Synthesis of C6 and C7 Analogues of N-Acetyl-6-amino-2,6-dideoxyneuraminic Acid

The piperidines 12 – 18 , piperidmose analogues of Neu5Ac ( 1 ) with a shortened side chain, were synthesized from N-acetyl-D -glucosamine via the azidoalkene 32 and tested as inhibitors of Vibrio cholerae sialidase. Deoxygenation at C(4) of the uronate 22 , obtained from the known D -GlcNAc derivative 20 , was effected by β-elimination (→ 23 ), exchange of the AcO at C(3) with a (t-Bu)Me₂SiO group and hydrogenation (→ 26 ; Scheme 1). Chain extension of 26 by reaction with Me₃SiCH₂MgCl gave the D -ido-dihydroxysilane 28 , which was transformed into the unsaturated L -xylo-mesylate 29 and further into the L -lyxo-alcohol 30 , the mesylate 31 , and the L -xylo-azide 32 . The derivatives 29 – 31 prefer a sickle zig-zag and 32 mainly an extended zig-zag conformation (Fig. 2). The piperidinecarboxylate 15 was obtained from 32 by ozonolysis (→ 33 ), intramolecular reductive animation (→ 34 ), and deprotection, while reductive animation of 34 with glycolaldehyde (→ 35 ) and deprotection gave 16 (Scheme 2). An intramolecular azide-olefin cycloaddition of 32 yielded exclusively the fused dihydrotriazole 36 , while the lactone 39 did not cyclize (Scheme 3). Treatment of 36 with AcOH (→ 37 ) followed by hydrolysis (→ 38 ) and deprotection led to the amino acid 18 . To prepare the (hydroxymethyl)piperidinecarboxylates 12 and 17 , 32 was first dihydroxylated (Scheme 4). The L -gluco-diol 40 was obtained as the major product, in agreement with Kishi's rule. Silylation of 40 (→ 42 ), oxidation with periodinane (→ 44 ), and reductive animation gave the L -gluco-piperidine 45 . It was, on the one hand, deprotected to the amino acid 12 and, on the other hand, N-phenylated (→ 46 ) and deprotected to 17 . While 45 and 12 adopt a ²C₅ conformation, the analogous N-Ph derivatives 46 and 17 adopt a ₅C² and a B_3,6 conformation, respectively, on account of the allylic 1,3-strain. The conformational effects of this 1,3-strain are also evident in the carbamate 47 , obtained from 45 (Scheme 5), and in the C(2)-epimerized bicyclic ether 48 , which was formed upon treatment of 47 with (diethylamino)sulfur trifluoride (DAST). Fluorination of 40 with DAST (→ 49 ) followed by treatment with AcOH led to the D -ido-fluorohydrin 50 . Oxidation of 50 (→ 51 ) followed by a Staudinger reaction and reduction with NaBH₃CN afforded the (fluoromethyl)piperidine 52 , while reductive amination of 51 with H₂/Pd led to the methylpiperidine 55 , which was similarly obtained from the keto tosylate 54 and from the dihydrotriazole 36 . Deprotection of 52 and 55 gave the amino acids 13 and 14 , respectively. The aniline 17 does not inhibit V. cholerae sialidase; the piperidines 12 – 16 and 18 are weak inhibitors, evidencing the importance of an intact 1,2,3-trihydroxypropyl side chain.     

Nucleotides. Part LXXI

A new labelling technique attaching fluorescein via a carbamoyl linker directly to the amino groups of the nucleobases was developed. The amino groups were first converted to the phenoxycarbonyl derivatives (→ 10, 15, 19, 58 ), which reacted under mild conditions with 5‐aminofluorescein to give the corresponding N‐[(fluorescein‐5‐ylamino)carbonyl] derivatives (→ 11 – 14, 16, 17, 20, 59, 60 ). The introduction of the 5‐aminofluorescein residue into properly protected adenylyl‐adenosine dimers (→ 39, 40 ) and trimer (→ 50 ) worked well, and final deprotection of these uniformly blocked precursors led on treatment with DBU (1,8‐diazabicyclo[5.4.0]undec‐7‐ene), in one step to dimer 41 and trimer 51 . Synthesis of an appropriately protected monomeric phosphoramidite building block (→ 75 ) was more difficult, since introduction of the 2‐(4‐nitrophenyl)ethyl residue into the fluorescein moiety in 59 led mainly to trisubstitution to give 61 including the urea function. Formation of the adenylyl dimer 66 and trimer 67 proceeded in the usual manner by phosphoramidite chemistry; however, deprotection of 67 with DBU was incomplete since the O‐alkyl group at the urea moiety was found to be very stable. Finally, the appropriate phosphoramidite building block 75 could be synthesized by the sequence 59 → 72 → 73 → 74 → 75 . The phosphoramidite 75 was used for the synthesis of dimer 77 and trimer 79 by solution chemistry, as well as for that of various oligonucleotides by the machine‐aided approach on solid support carrying the fluorophore at different positions of the chain (→ 84 – 87 ). The attachment of the fluorescein fluorophor via a short carbamoyl linker onto the 6‐amino group of 2′‐deoxyadenosine enables such molecules to function very well in fluorescence‐polarization experiments.     

Dipeptide Derivatives with a Phosphonate Instead of Carboxylate Terminus by C-Alkylation of Protected (Decarboxy-dipeptidyl)phosphonates

Z-Protected diphenyl (decarboxy-dipeptidyl)phosphonates 5a - c with a (decarboxysarcosinyl)phosphonate moiety are prepared from Z-L-alanine ( 1a ). Z-L-valine ( 1b ), and Z-L-phenylalanine ( 1c ) by the following series of steps: coupling with methyl sarcosinate (→ 2a – c ), saponification (→ 3a – c ), Hofer-Moest oxidative decarboxyiation by electrolysis in MeOH (→ 4a – c ), and Arbuzov reaction with P(OPh)₃/TiCl₄ (Scheme 3). Double deprotonation and alkylation lead to non-stereoselective incorporation of side chains next to the phosphonate group (products of type 6 – 8 , nine examples, see Scheme 4). In the cases of 6a – c and 8c , the diastereoisomers could be separated and the configuration of the newly formed stereogenic center deduced. We assign the L,D-configuration to the diastereoisomers for which the ³¹ P-NMR signal appears at higher field.     

Total Synthesis of Crenulatan Diterpenes: Strategy and stereocontrolled construction of a bicyclic keto-lactone building block

The bicyclic keto lactone 26 was synthesized for the purpose of developing a viable route to marine diterpenes of the crenulatan type. Following the efficient conversion of (S)-citronellol ( 5 ) to the allylated alcohol 9a (Scheme 2), the αβ-unsaturated lactone 12 was efficiently accessed in preparation for stereocontrolled conjugate addition. The hydroxymethyl equivalent most suited to this task was (i-PrO)Me₂SiCH₂MgCl, which gave 13 predominantly in the presence of CuI and Me₃SiCl. Once the OH group was deprotected (→ 14 ), it proved an easy matter to implement acid-catalyzed isomerization to lactone 15 , oxidation of which gave the pivotal aldehyde 16 . Condensation of 16 with PhSeCH₂Li led via 21 to 22 (Scheme 3). Once the OH group was protected (→ 22b ), it proved possible to effect aldolization with crotonaldehyde (→ 23 ). Exposure of 23 to acid gave the sub-target compound 25 . Its subsequent oxidation and thermal activation resulted in sequential selenoxide elimination with Claisen rearrangement (→ 26 ). The structural features of 26 require that a chair-like transition state be adopted during the [3.3]sigmatropic event. With the clarification of these issues, a highly serviceable and more advanced assault on the crenulatans should prove capable of being mounted.     

Exploring a New General Pathway to Parent Hydrocarbons Heptafulvene,Heptapentafulvalene, and Heptafulvalene

A new general pathway to the parent cross‐conjugated hydrocarbons heptafulvene ( 1 ) (Scheme 3), sesquifulvalene ( 2 ) (Scheme 4), and heptafulvalene ( 3 ) (Scheme 5) has been explored, starting with easily available 7,7‐dibromobicyclo[4.1.0]hept‐3‐ene ( 13 ). Promising precursors have been synthesized by halo/lithio exchange of 1,1‐dibromocyclopropane 13 → 14 , followed by methylation (→ 1 ), cyclopentadienylation (→ 2 ) and CuCl₂‐induced `carbene dimerization' (→ 3 ) of the carbenoid 14 . So far, the main obstacle of all three sequences (cf. Schemes 3, 4, and 5) is the final base‐induced dehydrobromination of precursors 17 , 24 , and 27 , which should be investigated in more detail.     

Synthesis of the 2‐Alkenyl‐4‐alkylidenebut‐2‐eno‐4‐lactone (=α‐Alkenyl‐γ‐alkylidenebutenolide) Core Structure of the Carotenoid Pyrrhoxanthin via the Regioselective Dihydroxylation of Hepta‐2,4‐diene‐5‐ynoic Acid Esters

A new strategy for the stereoselective synthesis of 4‐alkylidenebut‐2‐eno‐4‐lactones (=γ‐alkylidenebutenolides) with (Z)‐configuration of the exocyclic CC bond at C(4) was developed. It is exemplified by the synthesis of 4‐alkylidenebutenolactone 31 (Scheme 4), which constitutes a substructure of the carotenoids pyrrhoxanthin ( 1 ) and peridinin. The formation of the precursor 4‐(1‐hydroxyalkyl)butenolactone 29 was accomplished either by cyclocarbonylation of the prop‐2‐yn‐1‐ol moiety of 27 (→ 29 ) or by hydrostannylation of the isopropylidene‐protected alkynoic acid ester 26 (→ 28 ) followed by transacetalization/transesterification (→ 30 ). The 4‐alkylidenebutenolactone was formed by the anti‐selective Mitsunobu dehydration 29 → 31 .     

Synthesis and Biological Screening of 2‐Substituted 5,6‐Dihydro‐5‐oxo‐ 4H‐1,3,4‐oxadiazine‐4‐propanenitriles and of Their Intermediates

To evaluate the effect of substituents on biological activities of electron‐rich N‐containing heterocycles, the variably 2‐substituted 5,6‐dihydro‐5‐oxo‐4H‐1,3,4‐oxadiazine‐4‐propanenitriles 26 – 33 were synthesized and evaluated for antibacterial, antifungal, and enzyme‐inhibition activities. The target compounds were obtained from alkyl 4‐ or 3‐hydroxy benzoates 1 and 2 , respectively, and from methyl indoleacetate 3 . The phenolic OH group of benzoates 1 and 2 were substituted with p‐toluenesulfonyl (→ 4 and 5 ), benzoyl (→ 6 and 7 ), and benzyl groups (→ 8 and 9 ) and then converted to 5,6‐dihydro‐5‐oxo‐4H‐1,3,4‐oxadiazine‐4‐propanenitriles. To establish structure‐activity relationships (SAR), a pharmacological screening of the intervening intermediates was also conducted, which revealed that the intermediate hydrazide 11 possesses significant antimicrobial and MAO‐A inhibiting properties and intermediates 12, 24, 28 , and 29 appreciable antifungal activities. Compound 7 inhibits α‐chymotrypsin.     

2′‐Deoxyuridine and 2′‐Deoxyisocytidine as Constituents of DNA with Parallel Chain Orientation: The Stabilization of the iCd⋅Gd Base Pair by the 5‐Methyl Group

Parallel‐stranded oligonucleotides containing 2′‐deoxyuridine ( 2 ) and 2′‐deoxyisocytidine ( 4 ) were synthesized. The phosphoramidite 11 employed in the solid‐phase synthesis carries a (dimethylamino)methylidene residue as amino‐protecting group. This group stabilizes the acid‐labile glycosylic bond of 4 and enables the base‐catalyzed deprotection of oligonucleotides without degrading the nucleoside 4 residues. Oligonucleotide duplexes incorporating the 5‐Me derivatives of 2 (→2′‐deoxythymidine) and 4 (→2′‐deoxy‐5‐methylisocytidine), which are more stable than those containing the unmethylated nucleosides, were also compared. Depending on the nearest‐neighbor environment, Me groups provide an additional stabilization through Me/Me contacts or Me/backbone interactions.     

Synthesis of (2′S)‐2′‐Deoxy‐2′‐C‐methylpurine Nucleosides and Their Phosphoramidites

We describe the stereoselective synthesis of (2′S)‐2′‐deoxy‐2′‐C‐methyladenosine ( 12 ) and (2′S)‐2′‐deoxy‐2′‐C‐methylinosine ( 14 ) as well as their corresponding cyanoethyl phosphoramidites 16 and 19 from 6‐O‐(2,6‐dichlorophenyl)inosine as starting material. The methyl group at the 2′‐position was introduced via a Wittig reaction (→ 3 , Scheme 1) followed by a stereoselective oxidation with OsO₄ (→ 4 , Scheme 2). The primary‐alcohol moiety of 4 was tosylated (→ 5 ) and regioselectively reduced with NaBH₄ (→ 6 ). Subsequent reduction of the 2′‐alcohol moiety with Bu₃SnH yielded stereoselectively the corresponding (2′S)‐2′‐deoxy‐2′‐C‐methylnucleoside (→ 8a ).     

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.     

Oligosaccharide Analogues of Polysaccharides. Part 8. Orthogonally Protected Cellobiose-Derived Dialkynes. A Convenient Method for the Regioselective Bromo- and Protodegermylation of Trimethylgermyl- and Trimethylsilyl-protected Dialkynes

The cellobiose-derived dialkynes 14 and 15 were prepared by glycosidation of the acceptor 9 with the thioglycosides 12 (82%) and 13 (85%), respectively. The acceptor 9 was prepared from the known alcohol 2 via the lactone 7 in five steps (48% overall), and the donors 12 and 13 were prepared from the alkynylated anhydroglucose derivative 10 (60% overall). Acetolytic debenzylation of 14 and 15 (→ 16 and 17 , resp.) followed by deacylation of 16 yielded 60% of the cellobiose-derived dialkyne 18 . Deacylation of 14 (→ 19 ), methoxymethylation (→ 20 ) and trimethylgermylation led to the orthogonally protected dialkyne 21 (69% overall). Protodesilylation of 21 with K₂CO₃/MeOH gave 22 (90%), while the Me₃Ge group was selectively removed with CuBr (19 mol-%) in THF/MeOH to give 20 (95%). Treatment of 21 with aqueous HCl solution led to 19 (80%). Bromodegermylation of 21 (NBS/AgOOCCF₃) led to a mixture of 23 (85%) and 24 (11%). Similar conditions using CuBr instead of AgOOCCF₃ gave exclusively the bromoalkyne 23 (93%). The temperature dependence of the δ values of the OH resonances of 18 in (D₆)DMSO evidence a strong intramolecular H-bond between C(5′)? O…?HO? C(5).     

7-Deazaadenosine: Oligoribonucleotide building block synthesis and autocatalytic hydrolysis of base-modified hammerhead ribozymes

A 7-deazaadenosine ( = tubercidin; c⁷A; 1 ) building block for solid-phase oligoribonucleotide synthesis was prepared. The amino group of 1 was protected with the (dimethylamino)methylidene residue (→ 3 ), and the monomethoxytrityl group was introduced at OH? C(5′) (→ 4 ). Protection of OH? C(2′) was carried out by silylation, showing that use of the (i-Pr)₃Si group resulted in high 2′-O-selectivity (→ 5b , 80%). Reaction of 5b with PCl₃ afforded the phosphonate 7 which was used in solid-phase oligoribonucleotide synthesis. The autocatalytic hydrolysis of hammerhead ribozymes using pG-G-G-A-G-U-C-A-G-U-C-C-C-U-U-C-G-G-G-G-A-C-U-C-U-G-A-A-G-A-G-G-C-G-C as substrate strand (S) and modified G-C-G-C-C-G-A-A-A-C-U-C-C-C as enzyme strand (E) was studied. When c⁷A replaced A¹³ or A¹⁴, a small decrease of catalytic activity was observed, while modification in position A¹⁵ enhanced the autocatalytic hydrolysis. The results demonstrate, that the atom N(7) of adenosine in any of these positions is not crucial for ribozyme action.