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.     

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 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.     

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.     

Oligosaccharide Analogues of Polysaccharides. Part 3. A new protecting group for alkynes: Orthogonally protected dialkynes

Dialkynes of the type 3 (Scheme 1) are regioselectively deprotected by treating them either with base in a protic solvent (→ 4 ), or– after exposing the OH group– by catalytic amounts of base in an aprotic solvent (→ 5 and 8 ). The Me₃Si-protected 12 (Scheme 2) is inert to catalytic BuLi/THF which transformed 11 into 9 , while K₂CO₃/MeOH transformed both 10 into 9 , and 12 into 13 , evidencing the requirement for a more hindered (hydroxypropyl)silyl substituent. C-Silylation of the carbanions derived from 17–19 (Scheme 3) with 15 led to 20–22 , but only 22 was obtained in reasonable yields. The key intermediate 27 was, therefore, prepared by a retro-Brook rearrangement of 23 , made by silylating the hydroxysulfide 16 with 15 . The OH group of 27 was protected to yield the {[dimethyl(oxy)propyl]dimethylsilyl}acetylenes (DOPSA's) 21, 28 , and 29 . The orthogonally protected acetylenes 20–22, 28 , and 29 were de-trimethylsilylated to the new monoprotected acetylene synthons 30–34 . The scope of the orthogonal protection was checked by regioselective deprotection of the dialkynes 39–42 (Scheme 4), prepared by alkylation of 35 (→ 39 ), or by Pd⁰/CuI-catalyzed cross-coupling with 36–38 (→40–42 ). The cross-coupling depended upon the solvent and proceeded best in N,N,N′,N′ -teramethylethylenediamine (TMEDA). Main by-product was the dimer 43 . On the one hand, K₂CO₃/MeOH removed the Me₃Si group and transformed 39–42 into the monoprotected 44–47 ; catalytic BuLi/THF, on the other hand, transformed the alcohols 48–51 , obtained by hydrolysis of 39–42 , into the monoprotected dialkynes 52–55 , all steps proceeding in high yields. Addition of the protected DOPSA groups to the lactones 56 (→57–59 ) and 62 (→63 ) (Schemes 5 and 6) gave the corresponding hemiketals. Reductive dehydroxylation of 57 and 58 failed; but similar treatment of 59 yielded the alcohol 61 . Similarly, 63 was transformed into 64 which was protected as the tetrahydropyranyl (Thp) ether 65 . In an optimized procedure, 62 was treated sequentially with lithiated 31 , BuLi, and Me₃SiCl (→ 66 ), followed by desilyloxylation to yield 60% of 67 , which was protected as the Thp ether 68 . Under basic, protic conditions, 68 yielded the monoprotected bisacetylene 69 ; under basic, aprotic conditions, 67 led to the monoprotected bisacetylene 70 . These procedures are compatible with the butadiynediyl function. The butadiyne 73 was prepared by cross-coupling the alkyne 69 and the iodoalkyne 71 (obtained from 70 , together with the triiodide 72 ) and either transformed to the monosilylated 76 or, via 77 , to the monosilylated 78 . Formation of the homodimers 74 and 75 was greatly reduced by optimizing the conditions of cross–coupling of alkynes.     

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.     

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.     

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%).     

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.     

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.     

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.     

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).     

Glyconothio-O-lactones Part II. Cycloaddition to Dienes,Diazomethane, and Carbenoids

The addition of dienes, diazomethane, and carbenoids to the manno- and ribo-configurated thio-γ-O-lactones 1 and 2 was investigated. Thus, 1 (Scheme 1) reacted with 2,3-dimethylbutadiene (→ 4 , 73%), cyclopentadiene (→ 5a/b 1:1, 70%), cyclohexa- 1,3-diene (→ 9a/b 2:3, 92%), and the electron-rich butadiene 6 (→ 7a/b 3:1, 82%). Wheras 5a/b was separated by flash chromatography, 7a/b was desilylated leading to the thiapyranone 8 . Selective hydrolysis of one isopropylidene group of 9a/b and flash chromatography gave 10a and 10b . The structures of the adducts were elucidated by X-ray analysis ( 4 ), by NOE experiments ( 4 , 5a , 5b , 7a/b , 10a , and 10b ), and on the basis of a homoallylic coupling ( 7a/b ). The additions occurred selectively from the ‘exo’ -side of 1 . Only a weak preference for the ‘endo’-adducts was observed. Hydrogenation of 9a/b with Raney-Ni (EtOH, room temperature) gave the thiabicyclo [2.2.2]octane 11 . Under harsher conditions (dioxane, 110°), 9a/b was reduced to the cyclohexyl ß-D C-glycoside 12 which was deprotected to 13 . X-Ray analysis of 13 proved that the desulfuration occurred with inversion of the anomeric configuration. The regioselective addition of the dihydropyridine 14 to 1 (Scheme 2) and the methanolysis of the crude adduct 15 gave the lactams 16a (32%) and 16b (38%). Desilylation of 15 with Bu₄NF · 3H₂O, however, gave the unsaturated piperidinedione 17 (92%) which was deprotected to the tetrol 18 (65%). Similarly, 2 was transformed via 19 (62%) into the triol 20 (74%). The cycloaddition of 1 with CH₂N₂ (Scheme 3) gave a 35:65 mixture of the 2,5-dihydro- 1,3,4-triazole 21 and the crystalline 4,5-dihydro 1,2,3-triazole 22 . Treatment of 21 and 22 with base gave the hydroxytriazoles 23 and 24 , respectively. The structure of 24 was established by X-ray analysis. The triazole mixture 21/22 was separated by prep. HPLC at 5°. At room temperature, 21 already decomposed (half-life 21.6 h) leading in CDCI₃ solution to a complex mixture (containing ca. 20–25% of the spirothiirane 27 and ca. 7–10% of its anomer) and in MeOH solution exclusively to the O,O,S-ortholactone 26 . Crystals of 22 proved be stable at 105°. Upon heating in petroleum ether at 100°, 22 was transformed into a ca. 1:1 mixture of 27 and the enol ether 28 . The reaction of 1 with ethyl diazoacetate (Scheme 4) in the presence of Rh₂(OAc)₄. 2H₂O gave the unsaturated esters 29 (33%) and 30 (26%), whereas the analogous reaction with diethyl diazomalonate afforded the spirothiirane 31 (68%) and the enol ether 32 (29%). Complete transformation of 31 into 32 was achieved by the treatment with P(NEt₂)₃. Similary, 33 (69%) was prepared from 2 .     

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.     

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 ).     

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.     

7-Deazaguanosine: Synthesis of an oligorbonucleotide building block and disaggregation of the U-G-G-G-G-U G4 structure by the modified base

Building blocks derived from 7-deazaguanosine (c⁷G, 1 ) were prepared for solid-phase oligoribonucleotide synthesis. Compound 1 was converted into the isobutyurl derivative 2b and the (dimethylamino)methylidene compound 3 (Scheme 1). After tritylation (→ 4a , b ), silylation was studied with regard to regioselectivity. It was found that the triisopropylsilyl group in combination with the (dimethylamino)methylidene residue gave the highest 2′ -selectivity (→ 5e ). The 2′ -O -silyl derivative 5e was reacted with PCl₃ affording the 3′ -phosphonate 7 which was used in solid-phase oligoribonucleotide synthesis. Oligonucleotides derived from U-G-G-G-G-U with an increasing number of c⁷G residues instead of G were synthesized. Aggregation was studied by polyacrylamidegel electrophoresis and CD Spectroscopy. Disaggregation of the G₄-structure of U-G-G-G-G-U was observed when c⁷G replaced G, demonstrating that guanine N(7) participates in the aggregation process.     

Synthesis of a Phosphonic Acid Analogue of N-Acetyl-2,3-didehydro-2-deoxyneuraminic Acid,an Inhibitor of Vibrio cholerae Sialidase

The synthesis of the phospha analogue 10 of DANA ( 2 ) is described. Bromo-hydroxylation of the known 11 (→ 12 and 13 ) followed by treatment of the major bromohydrin 13 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the oxirane 14 (Scheme 1). Depending on the solvent, TiBr₄ transformed 14 into 16 or into a 15 / 16 mixture. Reductive debromination of 16 (→ 17 ), followed by benzylation provided 18 . Oxidattve decarboxylation (Pb(OAc)₄) of the acid, obtained by saponification of 18 , yielded the anomeric acetates 19 and 20 . While 19 was inert under the conditions of phosphonoylation, the more reactive imidate 22 , obtained together with 23 from 19 / 20 via 21 (Scheme 2), gave a mixture of the phosphonates 24 / 25 and the bicyclic acetal 26 . Debenzylation of 24 / 25 and acetylation led to the acetoxyphosphonates 27 / 28 . Since β-elimination of AcOH from 27 / 28 proved difficult, the bromide 34 was prepared from 27 / 28 by photobromination and subjected to reductive elimination with Zn/Cu (→ 35 ; Scheme 3). This two-step sequence was first investigated using the model compounds 30 and 31 . Transesterification of 35 , followed by deacetylation gave 10 , which is a strong inhibitor of the Vibrio Cholerae sialidase.