Oligosaccharide Analogues of Polysaccharides. Part 1. Concept and synthesis of monosaccharide-derived monomers

It is proposed to study the influence of interresidue H-bonds on the structure and properties of polysaccharides by comparing them to a series of systematically modified oligosaccharide analogues where some or all of the glycosidic O-atoms are replaced by buta-1,3-diyne-1,4-diyl groups. This group is long enough to interrupt the interresidue H-bonds, is chemically versatile, and allows a binomial synthesis. Several approaches to the simplest monomeric unit required to make analogues of cellulose are described. In the first approach, allyl α-D -galactopyranoside ( 1 ) was transformed via 2 and the tribenzyl ether 3 into the triflate 4 (Scheme 2). Substitution by cyanide (→ 5–7 ) followed by reduction with DIBAH led in high yield to the aldehyde 9 , which was transformed into the dibromoalkene 10 and the alkyne 11 following the Corey-Fuchs procedure (Scheme 3). The alkyne was deprotected via 12 or directly to the hemiacetal 13 . Oxidation to the lactone 14 , followed by addition of lithium (trimethylsilyl)acetylide Me₃SiC?CLi/CeCl₃ (→ 15 ) and reductive dehydroxylation afforded the disilylated dialkyne 16 . The large excess of Pd catalyst required for the transformation 11 → 13 was avoided by deallylating the dibromoalkene 10 (→ 17 → 18 ), followed by oxidation to the lactone 19 , addition of Me₃SiC?CLi to the anomeric hemiketals 20 (α-D /β-D 7:2), dehydroxylation to 21 , and elimination to the monosilylated dialkyne 22 (Scheme 3). In an alternative approach, treatment of the epoxide 24 (from 23 ) with Me₃SiC?CLi/Et₂AlCl according to a known procedure gave not only the alkyne 27 but also 25 , resulting from participation of the MeOCH₂O group (Scheme 4). Using Me₃Al instead of Et₂AlCl increased the yield and selectivity. Deprotection of 27 (→ 28 ), dibenzylation (→ 29 ), and acetolysis led to the diacetate 30 which was partially deacetylated (→ 31 ) and oxidized to the lactone 32 . Addition of Me₃SiC?CLi/TiCl₄ afforded the anomeric hemiketals 33 (α-D /β-D 3:2) which were deoxygenated to the dialkyne 34 . This synthesis of target monomers was shortened by treating the hydroxy acetal 36 (from 27 ) with (Me₃SiC?C)₃Al (Scheme 5): formation of the alkyne 37 (70%) by fully retentive alkynylating acetal cleavage is rationalised by postulating a participation of HOC(3). The sequence was further improved by substituting the MeOCH₂O by the (i-Pr)₃SiO group (Scheme 6); the epoxide 38 (from 23 ); yielded 85% of the alkyne 39 which was transformed, on the one hand, via 40 into the dibenzyl ether 29 , and, on the other hand, after C-desilylation (→ 41 ) into the dialkyne 42 . Finally, combined alkynylating opening of the oxirane and the 1,3-dioxolane rings of 38 with excess Et₂Al C?CSiMe₃ led directly to the monomer 43 which is thus available in two steps and 77% yield from 23 (Scheme 6).     

Oligosaccharide Analogues of Polysaccharides. Part 2. Regioselective deprotection of monosaccharide-derived monomers and dimers

The Me₃Si? C(1) bond of the bis-(trimethylsilyl)ethynylated anhydroalditol 2 is selectively cleaved with BuLi to yield 3 / 4 , while AgNO₂/KCN in MeOH cleaves the Me₃Si? C(2′) bond, leading to 5 (Scheme 1). Both Me₃Si groups are removed with NaOH in MeOH (→ 7 ), the (i-Pr)₃Si group is selectively cleaved with HCl in aq. MeOH ( → 6 ); all silyl substituents are removed with Bu₄NF ( → 8 ). Acetolysis transformed 9 into 13 , which was desilylated to 14 , while thiolysis of 9 led to a mixture 11 / 12 . The tetraacetate 14 has also been obtained from 9 via 10 . Oxidative dimerisation of either 3 or 5 , or of a mixture 3 / 5 yields only the homodimers 15 and 16 (Scheme 2); treatment of 16 with AgNO₂/KCN yielded 17 , deprotection proceeding much more slowly than the cleavage of the Me₃Si? C(2′) group of 2 . The iodoalkyne 20 , required for the cross-coupling with 5 according to Cadiot-Chodkiewicz, was prepared by deprotection of 3 / 4 to 18 , methoxymethylation (→ 19 ), and iodination. Cross-coupling yielded mostly 21 , besides the homodimer 22 . Similarly, cross-coupling of 20 and 23 (obtained from 5 ) led to 24 and 22 . The structure of 24 was established by X-ray analysis (Fig.), showing a C(6)–C(5′) distance of 5.2 Å. The conditions for deprotecting 2 were applied to 21 , and led to 25 (AgNO₂/KCN), 26 (aq. NaOH), 27 (Bu₄NF), and 29 (HCl/MeOH; Scheme 3). Attempted deprotection of the propargylic-ether moiety with BuLi, however, failed. The dimer 27 was further deprotected to 28 . Acetolytic (Ac₂O/Me₃SiOTf) debenzylation of the dimer 30 , obtained from 10 , gave 31 (83%) which was deacetylated to 32 (Scheme 4). Cross-coupling of 5 and the bromoalkyne 33 , obtained from 10 , yielded 34 ; again, acetolysis proceeded well, leading to 35 . The cellobiose derivative 38 was prepared from the lactone 36 via 37 . The glycosidic linkage of 38 proved resistant to the conditions of acetolysis, leading to 39 . Acetolysis of the benzylated thiophene 40 (from 30 with Na₂S) yielded the octaacetate 41 , but proceeded in substantially lower yields (50%).     

Oligosaccharide Analogues of Polysaccharides. Part 6. Orthogonal protecting/activating groups in an improved binomial synthesis of ‘acetyleno-oligosaccharides’

Bromination of the monosilylated dialkynylated monomer 1a (Scheme 1), dimer 3 and tetramer 5 by N-bromosuccinimide (NBS) in the presence of CF₃COOAg gave 2, 4 , and 6 , respectively, in over 93%. Similar conditions led to bromodesilylation. Either silyl group of the diprotected monomer 1c was selectively removed by bromolysis. On the one hand, bromodesilylation of 1c gave 2 in yields varying between 80 and 99%. On the other hand, bromodesilylation of 7 , obtained from 1c by hydrolytic removal of the tetrahydro-2H-pyran-2-yl (Thp) group, yielded 91% of 8 . Mechanistic considerations suggested that the deprotective bromination should be improved by replacing the Me₃Si by a Me₃Ge group. Indeed, bromodegermylation of 1b was quantitative and ca. 60 times faster than bromodesilylation of 1c . The Me₃Si and Me₃Ge groups can be used for an orthogonal protection/activation of dialkynes. This was shown by desilylating 12 to 11 (Scheme 2), while bromination yielded 13 . Both reactions proceeded in high yields; 9 was isolated as a minor by-product of 13 . The reactivity towards bromolysis decreases in the series H-DOPS > Me₃Ge ≈ H > Me₃Si > Thp-DOPS (DOPS = [dimethyl(oxy)-p ropyl]dimethylsilyl). Orthogonal bromolysis of DOPS- and Me₃Ge-substituted dialkynes is slightly more selective than the one of Me₃Si- and Me₃Ge-substituted analogues. Coupling of 7 with the bromoalkyne 2 gave the dimer 15 (76%), 14 (2%), and 16 (4%) (Scheme 3). The binomial synthesis was optimized so that each cycle, doubling the size of the precursor, requires the minimal number of transformations (Scheme 4). The orthogonally protected monomer 1b , dimer 19 , and tetramer 22 were, on the one hand, hydrolyzed to the alcohols 18 (95%), 21 (91%), and 24 (91%), respectively, and, on the other hand, bromodegermylated to 2 (99%), 4 (97%), and 6 (93%). Cross-coupling of 18 with 2, 21 with 4 , and 24 with 6 gave the orthogonally protected dimer 19 (73%), tetramer 22 (87%), and octamer 25 (83%), respectively.     

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 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 ).     

Synthesis of Allosamidin

The previously prepared disaccharide 2 was deprotected (→ 3 ) and transformed into the trichloroacetimidate 4 . In the presence of Me₃SiOTf, 4 reacted regioselectively with the racemic allosamizoline benzyl ether 5 , to yield (61%) the pseudotrisaccharides 7–10 (44:40:9:7) and the elimination product 6 (Scheme 1). Selective dephthaloylation (MeNH₂, MeOH) of 7 and 8 , followed by acetylation, gave 12 (73%) and 13 (74%), respectively (Scheme 2); harsher conditions (NH₂NH₂.H₂O, EtOH, reflux), followed by acetylation, transformed 7 into 11 . Deacetylation of 11–13 yielded 14–16 , respectively. Allosamidin ( 1 ) was obtained in high yield by hydrogenation of 15 under acidic conditions (Scheme 3). Similarly, 16 and 14 were transformed into 17 and 18 , respectively. Preliminary data on the inhibition of endochitinases by 1 and 17 are reported.     

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.     

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.     

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).     

Chiral Acylsilanes in Organic Synthesis. Part 3. Silicon-directed stereoselective preparation and Ireland ester-enolate rearrangement of O-acyl-substituted α-silylated allyl alcohols

Stereocontrolled addition of alk-1-enylmetal reagents to the chiral (alkoxymethyl)-substituted acylsilanes (±)- 6 gave rise to α-silylated allyl alcohols, which were converted to the corresponding acetates or propionates 11–16 (Scheme 2). Deprotonation and silylation with Me₃SiCl afforded – in an Ireland ester-enolate-accelerated Claisen rearrangement – stereoselectively αδ-silylated γδ-unsaturated carboxylic acids 18–24 (Scheme 4). The Me₃Si groups in α-position to the COOH group of these compounds were removed chemoselectively in presence of the chiral silyl group in δ-position by treatment with Bu₄NF · 3 H₂O or Et₃N · 3 HF (→ 27–32 ; Scheme 5). The reaction sequence allows a novel stereocontrolled access to chiral C-frameworks possessing a vinylsilane moiety with its full reaction potential.     

Potential antipsychotic agents. Part 8. Antidopaminergic properties of a potent series of 5-substituted (−)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-dimethoxybcnzaimides. Synthesis via common lithio intermediates

A series of 5-substituted (?)-(S)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-diniethoxybenzanndes were made by reaction of the corresponding benzoyl chlorides with (S)-1-ethylpyrrolidine-2-methylaruine (→ 14–16 , 18–21 ). The acids required were prepared in a regiospecific manner from 5-bromo-2,3-dimethoxybenzoic acid which was protected as dihydrooxazole (→ 4–8 ), metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC1³CCl³ or MeSSMe), and hydrolyzed (→ 9–13 ). Alternatively, (-)-(S)-5-bromo-N-[(1-ethylpyrrolidin-2-yl)methyl]-2,3-di-methoxybenzamide was treated with KH followed by BuLi and an electrophile (I₂ or Me³SiCl) to give the 5-iodo and 5-(trimethylsilyl) derivatives 17 and 22 , respectively. All 5-substituted amides were highly potent inhibitors of [³H]spiperone binding in rat striatal membranes with IC⁵⁰ values of 0.5 to 5 nM (Table 3). Thus, a relatively large steric bulk can be accomodated in the position para to the 2-MeO group. This work also supports the notion that a positive as well as negative electrostatic potential can be located in this position. A selected number of derivatives were also investigated in vivo and found to inhibit apomorphine-induced behavioural responses in the same dose range as haloperidol and raclopride (Table 4). This new group of benzamides is suitable for investigations of dopamine D-2 receptors in labelled or unlabelled form.     

Synthese eines 1,2-trans-konfigurierten, äquatorialen Glycosyl-phosphonat-Analogen von D-myo-Inositol-1,4,5-trisphosphat

Synthesis of a 1,2-trans-Configurated, Equatorial Glycosylphosphonate Analogue of D -myo-Inositol 1,4,5-Trisphosphate The diphosphonate analogue 3 of D -myo-inositol 1,4,5-trisphosphate ( 1 ), a 1,2-trans-configurated, equatorial glycosylphosphonate, was synthesized and characterized as its hexasodium salt 3a . In a first approach, the silylated galactal 4 (Scheme 1) was transformed into the oxirane 5 and hence, by treatment with Me₃SiP(OMe)₂, into a mixture of the glycosylphosphonate 6 and its silyl ether 7 . This mixture was desilylated and then treated with acetone and FeCl₃ to yield 8 and 9 (64 and 22%, resp., from 4 ). In a second approach, the acetates 11/12 (Scheme 2) were treated with P(OMe)₃/Me₃SiOTf in MeCN to afford the anomeric glycosylphosphonates 16/17 (1:1, 60%), while the trichloroacetimidate 10 gave mostly the αD -anomer 16 . The αD -anomer 20 was obtained from 12 and P(OPh)₃. The highest yield of a β-D phosphonate was realized by treating 12 with the cyclic phosphite 15 (→ 18/19 , 40% each). The β-D -phosphonate 17 was debenzylated (→ 21 ) and protected to give 8 . Transformation of 8 into the bromide 22 (43%) proved difficult due to the facile demethylation of thephosphonate, and was best followed by treatment of the crude product with CH₂N₂ and 2,2-dimethoxyporpane. Phosphorylation of 22 yielded 41% of the (dimethoxyphosphoryl)phosphate 23 . The conditions of the Arbuzov reaction slowly converted the bromide 23 into the bis(phosphoryl)phosphate 24 (69%), which was then deprotected. The resulting 3 was purified via the ammonium salt and transformed into 3a (72%).     

Synthesis of Pyrrolidine Analogues of N-Acetylneuraminic Acid as Potential Sialidase Inhibitors

The pyrrolidine derivatives 3 , 4 , and 5 were prepared from the methyl ester 7 of Neu2en5Ac via lie pyrrolidine-borane adduct 33 . They inhibit Vibrio cholerae sialidase competitively with K_i = 4. 4 10^?3 M, 5. 3 10^?3 M, and 4. 0 10^?2 M, respectively. Benzylation of 7 gave the fully O-benzylated 8 besides 9, 10 , and 11. Ozonolysis and reduction with NaBH₄ of 8 and 9 gave the 1, 4-diols 12 and 15 , the hydroxy acetates 13 and 16 , and the furanoses 14 and 17 (Scheme 1), respectively. The diol 12 was selectively protected (→ 19 → 20 → 23 ) and transformed into the azide 27 by a Mitsunobu reaction. Selective base-catalysed deprotection of the diacetate 22 , obtained from 12 , was hampered by an easy acetyl-group migration. The mesylate 28 proved unstable. The azide 27 was transformed via 29 into the ketone 30 (Scheme 2). Hydrogenation of 30 gave the dihydropyrrole 31 and, hence, the pyrrole 32. The adduct 33 was obtained from 30 by a Staudinger reaction (→31) and reduction with LiBH₄/HBF⁴. It was transformed into the pyrroudine 34 . The structure of 34 was established by X-ray analysis. Reductamination of the pyrrolidine-borane adduct with glyoxylic acid gave 40 and, hence, 3. N-Alkylation afforded 44 and, hence, the phosphonate 4. The acid 5 was obtained from 33 by acylation (→ 47 ) and deprotection (Scheme 4).     

Synthesis of the 6-C-Methyl and 6-C-(Hydroxymethyl) Analogues of N-Acetylneuraminic Acid and of N-Acetyl-2,3-didehydro-2-deoxyneuraminic Acid

The synthesis of 6-C-methyl-Neu2en5Ac ( 4 ), 6-C-(hydroxymethyl)-Neu2en5Ac ( 5 ), and 6-C-methyl-Neu5Ac ( 6 ) is described. The 4-methylumbellyferyl glycosides 8 and 9 were also prepared but proved unstable. Protection of the previously reported nitro ether 10 (→ 11 ) followed by a Kornblum reaction gave the branched-chain derivative 13 which was transformed into aldehyde 14 and hence via 16 into the-protected 6-C-hydroxymethylated 20 and into the 6-C-methyl-substituted 18 (Scheme 1). Debenzylidenation of 20 and 18 afforded the diols 21 and 19 , respectively. Selective oxydation of 19 followed by esterification (→ 22 ), acetylation (→ 23 ), and elimination led to the protected 6-C-methyl-Neu2en5Ac derivative 24 (Scheme 2). Bromomethoxylation yielded mainly 25 and some 26 , which were reductively debrominated to 27 and 28 , respectively. Attempted deprotection of 27 did not lead to the corresponding acid, but to the 2,7- and 2,8-anhydro compounds 29 and 30 which were characterised as their peracetylated esters 31 and 32 (Scheme 3). The structure of 32 was established by X-ray analysis. Oxydation of 19 and 21 , followed by deprotection, esterification, and acetylation gave 37 and 38 , respectively (Scheme 4). The branched-chain Neu2en5Ac derivatives 4 and 5 were obtained by β-elimination (→ 39 and 40 ) and deprotection. Omission of the esterification after oxydation of 33 and 34 gave the lactones 35 and 36 which were transformed into 37 and 38 , respectively. Bromoacetoxylation of 39 gave 41-43 which were reductively debrominated to 44 (from 41 and 42 ) and 45 (Scheme 5). Bromoacetoxylation of 40 yielded 46 which was debrominated to 47. Glycosidation of the glycosyl chlorides obtained from 44 and 47 led to the α -D-glycosides 48 and 49 and to the elimination products 39 and 40 , respectively (Scheme 6). Transesterification of 48 , followed by saponification gave the unstable glycoside 8 and hence 6-C-methyl-Neu5Ac ( 6 ). The unstable glycoside 9 was obtained by similar treatment of 49 but yielded 50 under acidic conditions. The branched-chain 4 and 5 were weak inhibitors of Vibrio cholera sialidase, and 8 and 9 were very poor substrates.     

Glycosylsulfenyl- und (Glycosylthio)sulfenyl-halogenide (Halogeno- bzw. Halogenothio-(1-thioglycoside)): Herstellung und Umsetzung mit Alkenen

Glycosylsulfenyl snf (Glycosylthio) sulfenyl Halides (Halogeno and Halogenothio 1-Thioglycosides, Resp.): Preparation and Reaction with Alkenes The disulfides 11–17 and 20 were prepared from 7, 9 , and 18 via the dithiocarbonates 8, 10 , and 19 , respectively (Scheme 2). The structure of 11 and of 13 was established by X-ray analysis. Chlorolysis (SO₂Cl₂) of 11 gave mostly the sulfenyl chloride 24 , characterized as the sulfenamide 26 , a small amount of 21 , characterized as the (glycosylthio)sulfenamide 23 , and the glycosyl chloride 27 (Scheme 3). Bromolysis of 11 followed by treatment of the crude with PhNH₂ yielded only 28 . Chlorolysis of the diglycosyl disulfide 13 , however, gave mostly the (glycosylthio)sulfenyl chloride 21 and 27 , besides 24 . Bromolysis of 13 (→ 22 and traces of 25 ) followed by treatment with PhNH₂ gave an even higher proportion of 23 . Similarly, 20 led to 29 and hence to 30 . In solution (CH₂Cl₂), the sulfenyl chloride 24 decomposes faster than the (thio)sulfenyl chloride 21 , and both interconvert. Addition of crude 24 to styrene (?78°) yielded the chloro-sulfide 31 and some 37 , both in low yields. The product of the addition of 24 to l-methylcyclohexene was transformed into the triol 32 . Silyl ethers of allylic alcohols reacted with 24 only at room temperature, yielding, after desilylation, isomer mixtures 33 and 34 , and pure 35 . Much higher yields were achieved for the addition of (thio)sulfenyl halides yielding halogeno-disulfides. Good diastereoselctivites were only obtained with 21 , its cyclohexylidene-protected analogue, and 22 , and this only in the addition to styrene (→ 36, 37, 38 ), to (E)-disubstituted alkenes (→ 46, 48, 49a/b, 50a/b, 53 ), and to trisubstituted alkenes (→ 47, 51, 52, 54, 55 ). Other monosubstituted alkenes (→ 41–45 ) and (Z)-hex-2-ene (→ 49c/d,50c/d ) reacted with low diastereoselectivities. Where structurally possible, a stereospecific trans-addition was observed; regioselectivity was observed in the addition to mono- and trisubstituted alkenes and to derivatives of allyl alcohols. The absolute configuration of the 2-chloro-disulfides was either established by X-ray analysis ( 47a ) or determined by transforming (LiAlH₄) the chloro-disulfides into known thiiranes (Scheme 5). Thus, 37, 48 , and the mixture of 49a/b and 50a/b gave the thiiranes 56, 61 , and 64 , respectively, in good-to-acceptable yields (Scheme 5). Harsher conditions transformed 56 into the thiols 57 and 58 . Similarly, 61 gave 62 . The enantiomeric excesses of these thiols were determined by GC analysis of their esters obtained with (?)-camphanoyl chloride. Addition of 21 to {[(E)-hex-2-enyl]oxy}trimethylsilane, followed by LiAlH₄ reduction and desilylation, gave the known 66 (63%, e.e. 74%). The diastereoselectivity of the addition of 21 to trans-disubstituted and trisubstituted alkenes is rationalized by assuming a preferred conformation of the (thio)sulfenyl chloride and destabilizing steric interactions with one of the alkene substituents, while the diastereoselectivity of the addition to styrene is explained by postulating a stabilizing interaction between the phenyl ring and the C(1)–S substituent (Fig.4).     

Oligonucleosides with a Nucleobase‐Including Backbone,Part 2, Synthesis and Structure Determination of Adenosine‐Derived Monomers

The synthesis and structure determination of adenosine‐derived monomeric building blocks for new oligonucleosides are described. Addition of Me₃Si‐acetylide to the aldehyde derived from the known partially protected adenosine 1 led to the epimeric propargylic alcohols 2 and 3 , which were oxidised to the same ketone 4 , while silylation and deprotection led to 7 and 9 (Scheme 1). Introduction of an I substituent at C(8) of the propargylic silyl ethers 10 and 11 was not satisfactory. The protected adenosine 12 was, therefore, transformed in high yield into the 8‐chloro derivative 13 by deprotonation and treatment with PhSO₂Cl; the iodide 15 was obtained in a similar way (Scheme 2). The 8‐Cl and the 8‐I derivatives 13 and 15 were transformed into the propargylic alcohols 17 , 18 , 25 , and 26 , respectively (Scheme 3). The propargylic derivatives 2 , 10 , 17 , 19 , 23 , 25 , and 27 were correlated, and their (5′R) configuration was determined on the basis of NOEs of the anhydro nucleoside 19 ; similarly, correlation of 3 , 11 , 18 , 20 , 24 , 26 , and 28 , and NOE's of 20 evidenced their (5′S)‐configuration.     

Deoxy-nitrosugars. 17th communication. Synthesis of ketose-derived nucleosides from 1-deoxy-1-nitroribose

A new approach to ketose-derived nucteosides is described. It is based upon a chain elongation of 1-deoxy-1-nitroaldoses, followed by activation of the nitro group as a leaving group, and introduction of a pyrimidine or purine base. Thus, the nitroaldose 7 was prepared from 3 by pivaloylation (→ 4 ), synthesis of the anomeric nitrones 5/6 , and ozonolysis of 6 (Scheme 1). Partial hydrolysis of 4 yielded 8/9 , which were characterized as the acetates 10/11 and transformed into the nitrones 12/13 . Ozonolysis of 12/13 gave 14/15 , which were acetylated to 16/17 . Henry reaction of 7 lead to 19 and 20 , which were acetylated to 21 and 22 (Scheme 2). Michael addition of 7 to acrylonitrile and to methyl propynoate yielded the anomers 23/24 and 25/26 , respectively. Similar reactions of 16/17 were prevented by a facile β-elimination. Therefore, the nitrodiol 15 was transformed into the orthoesters 27 and then, by Henry reaction, partial hydrolysis, and acetylation, into 28 and 29 (Scheme 2). The structure of 19 was established by X-ray analysis. It was the major product of the kinetically controlled Henry reaction of 7 . Similarly, the β-D-configurated nitroaldoses 23 and 25 were the major products of the Michael addition. This indicates a preferred ‘endo’-attack on the nitronate anion derived from 7 . AMI calculations for this anion indicate a strong pyramidalization at C(1), in agreement with an ‘endo’-attack. Nucleosidation of 21 by 31 afforded 32 and 33 . Yields depended strongly upon the nature and the amount of the promoter and reached 77% for 33 , which was transformed into 34 , 35 , and the known ‘psicouridine’ ( 36 ; Scheme 3). To probe the mechanism, the trityl-protected 30 was nucleosidated yielding 37 , or 37 and 38 , depending upon the amount of FeCl₃. Nucleosidation of the nitroacetate 28 was more difficult, required SnCl₂ as a promoter, and yielded 39 and 40 . The β-D-anomer 40 was transformed into 36 . Nucleosidation of 23 (SnCl₄) yielded the anomers 41 and 42 , which were transformed into 43 and 44 , and hence into 45 and 46 (Scheme 4). Similarly, nucleosidation of 25 yielded 47 and 48 , which were deprotected to 49 and 50 , respectively. The nucleoside 49 was saponified to 51 . Nucleosidation of 21 by 52 (SnCl₂) afforded the adenine nucleosides 53 and 54 (Scheme 5). The adenine nucleoside 53 was deprotected (→ 55 → 56 ) to ‘psicofuranine’ (1), which was also obtained from 58 , formed along with 57 by nucleosidation of 28 . The structure and particularly the conformation of the nitroaldoses, nitroketoses, and nucleosides are examined.     

Glycosylidene Carbenes. Part 22. α-D-Selectivity in the Glycosidation by Carbenes Derived from 2-Acetamido-hexoses

Glycosylidene carbenes derived from the GlcNAc and AllNAc diazirines 1 and 3 were generated by the thermolysis or photolysis of the diazirines. The reaction of 1 with i-PrOH gave exclusively the isopropyl α-D -glycoside of 5 besides some dihydrooxazole 9 (Scheme 2). A similar reaction with (CF₃)₂CHOH yielded predominantly the α-D -anomer of 6 , while glycosidation of 4-nitrophenol (→ 7 ) proceeded with markedly lower diastereoselectivity. Similarly, the Allo-diazirine 3 gave the corresponding glycosides 12–14 , but with a lower preference for the α-D -anomers (Scheme 3). The reactions of the carbene derived from 1 with Ph₃COH (→ 8 ) and diisopropylideneglucose 10 (→ 11 ) gave selectively the α-D -anomers (Scheme 2). The αD -selectivity increases with increasing basicity (decreasing acidity) of the alcohols. It is rationalized by an intermolecular H-bond between the acetamido group and the glycosyl acceptor. This H-bond increases the probability for the formation of a 1,2-cis-glycosidic C–O bond. The gluco-intermediates are more prone to forming a N–H…?(H)OR bond than the allo-isomers, since the acetamido group in the N-acetylallosamine derivatives forms an intramolecular H-bond to the cis-oriented benzyloxy group at C(3), as evidenced by δ/T and δ/c experiments.     

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 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.