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).     

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 ).     

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.     

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

The cellobiose-derived dimer 18 , tetramer 48 , and octamer 49 have been prepared. Acetolytic debenzylation transformed the dimer 15 , obtained from the partially benzylated, dialkynylated cellobiose 2 (Scheme 1), into 16 that was deacetylated to 18 (Scheme 2), but the analogous debenzylation of the tetramer 14 proved unsatisfactory. We, therefore, avoided benzyl groups and prepared the cellobiose-derived monomer 32 by glycosidation of 27 with the crystalline trichloroacetimidates 30 or 31 (Scheme 3). The acceptor 27 was synthesised from 1,6-anhydroglucose in 7 steps (48% overall yield), and the trichloroacetimidates 30 and 31 were obtained in good overall yields from the alkynylated glucopyranoses 29 (Scheme 3). The structure of the anomeric trichloroacetimidates 30 and 31 was determined by single crystal X-ray analysis. The alkyne 34 , orthogonally C-protected by SiMe₃ and GeMe₃ groups, was transformed by a binomial strategy into the dimer 37 , the tetramer 41 , and the octamer 47 (Scheme 4). The unprotected mono- and oligomers 1 , 18 , 48 , and 49 are soluble in H₂O, MeOH, and DMSO. Their ¹H-NMR specta ((D₆)DMSO ( 1 , 18 , 48 , 49 ), CD₃OD ( 1 , 18 , 48 ), D₂O ( 49 )) show no signs of association.     

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.     

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.     

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 .     

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.     

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.     

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.     

Synthesis of Enantiomerically Pure Carbohydrate-Derived Annulated Cyclopentadienes and Ferrocenes

The cyclopentadienes 3a/b/c, 8b/c, 12a/b/d , and 16a/b/d were prepared as mixtures of regioisomers from the D -mannitol-derivatives 1,6,10 , and 14 and transformed into the ferrocenes 17, 18 , and 19 (73%; 38:17:45), 23, 24 , and 25 (70%; 6:42 :52), 26 (31%), and 27 (27%), respectively. Deprotection of 17–19 with HCl/MeOH gave the H₂O-soluble ferrocenes 20–22 ; chloromercuration and iodination of 17 via 29 led to the C₂-symmetric diiodo-ferrocene 30 . The mono(chloromercurio) derivative 28 , obtained as a by-product, was also transformed into 29 . The structure of the ferrocenes 18 and 19 , and of the bis(chloromercurio)ferrocene 29 has been established by X-ray analysis. The starting cyclopentadienes 3 were obtained in 50% yield from 1 by dialkylation of CpNa, followed by thermolysis of the spiro-annulated 2 . Similarly, dimesylate 6 (from 4 ) gave the spiro-annulated diene 7 and the annulated dienes 8 in about equal amounts; thermolysis transformed 7 into 8 (62%). The dienes 12 were prepared in 15% yield from the ditriflate 10 via 11 , the dimesylate 9 proving insufficiently reactive, and the dienes 16 (49%) from 14 via 15 .     

Glyconothio-O-lactones. Part I. Preparation and reactions with nucleophiles

Furanoid and pyranoid glyconothio-O-lactones were prepared by photolysis of S-phenacyl thioglycosides or by thermolysis of S-glycosyl thiosulfinates, which gave better results than the thionation of glyconolactones with Lawesson's reagent. Thermolysis of the thiosulfinates obtained from the dimannofuranosyl disulfide 7 or the manofuranosyl methly disulfide 8 (Scheme 2) gave low yields of the thio-O-lactone 2 . However, photolysis of the S-phenacyl thioglycoside 6 obtained by in situ alkylation of the thiolato anion derived from 5 led in 78–89% to 2 . Similarly, the dithiocarbonate 10 was transformed, via 11a , into the ribo-thio-O-lactone 12 (79%). Thermolysis of the peracetylated thiosulfinates 14 (Scheme 3) led to the intermediate thio-O-lactone 15 , which underwent facile β-elimination of AcOH (→ 16 , 75%) during chromatography. The perbenzylated S-glucopyranosyl dithiocarbonate 18 (Scheme 4) was transformed either into the S-phenacyl thioglucoside 19 or into a mixture of the anomeric methyl disulfides 21a/b . Whereas the photolysis of 19 led in moderate yield to 2-deoxy-thio-O-lactone 20 , oxidation of 21b and thermolysis of resulting thiosulfinates gave the thio-O-lactone 4 (79%), which was transformed into 20 (36%) upon photolysis. The pyranoid manno-thio-O-lactone 26 was prepared in the same way and in good yields from 22 via the dithiocarbonate 24b and the disulfide 25 . The ring conformations of the δ-thio-O-lactones, flattened ⁴C₁ for 15 and 4 and B_2,5 for 26 , are similar to the ones of the O-analogous oxo-glyconolactones. The reaction of 2 (Scheme 5) with MeLi and then with MeI gave the thioglycoside 27 (29%) and the dimeric thio-O-lactone 29 (47%). The analogous treatment of 2 with lithium dimethylcuprate (LiCuMe₂) and MeI led to a 4:1 mixture (47%) of 31 and 27 . The structure of 2 was proven by an X-ray analysis, and the configuration at C(6) and C(5) of 29 was deduced from NOE experiments. Substitution of MeI by CD₃I led to the CD₃S analogues of 27 , 29 , and 31 , i.e. 28 , 30 , and 32 , respectively, evidencing carbophilic addition and ‘exo’-attack on 2 by MeLi and the enethiolato anion derived from 2 . The preferred ‘endo’-attack of LiCuMe₂ is rationalized by postulating a single-electron transfer and a diastereoselective pyramidalization of the intermediate radical anion.     

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.     

Singlet-Oxygen Ene Reactions of (E)-4-Propyl[1,1,-2H3]oct-4-ene. Short Communication

Rose bengal-sensitized photooxygenation of 4-propyl-4-octene ( 1 ) in MeOH/Me₂CHOH 1:1 (v/v) and MeOH/H₂O 95:5 followed by reduction gave (E)-4-propyl-5-octen-4-ol ( 4 ), its (Z)-isomer 5 , (E)-5-propyl-5-octen-4-ol ( 6 ), and its (Z)-isomer 7 . Analogously, (E)-4-propyl[1,1,1-²H₃]oct-4-ene ( 2 ) gave (E)-4-propyl[1,1,1-²H₃]oct-5-en-4-ol ( 14 ), its (Z)-isomer 15 , (E)-5-[3′,3′,3′-²H₃]propyl-5-octen-4-ol ( 16 ), its (Z)-isomer 17 , and the corresponding [8,8,8-²H₃]-isomers 18 and 19 (see Scheme 1). The proportions of 4–7 were carefully determined by GC between 10% and 85% conversion of 1 and were constant within this range. The labeled substrate 2 was photooxygenated in two high-conversion experiments, and after reduction, the ratios 16/18 and 17/19 were determined by NMR. Isotope effects in 2 were neglected and the proportions of corresponding products from 1 and 2 assumed to be similar (% 4 ≈? % 14 ; % 5 ≈? % 15 ; % 6 ≈? % ( 16 + 18 ): % 7 ≈? % ( 17 + 19 )). Combination of these proportions with the ratios 16/18 and 17/19 led to an estimate of the proportions of hydroperoxides formed from 2 . Accordingly, singlet oxygen ene additions at the disubstituted side of 2 are preferred (ca. 90%). The previously studied trisubstituted olefins 20–25 exhibited the same preference, but had both CH₃ and higher alkyl substituents on the double bond. In these substrates, CH₃ groups syn to the lone alkyl or CH₃ group appear to be more reactive than CH₂ groups at that site beyond a statistical bias.     

A New Approach to 5-Thiosugars: 5-Thio-D-Gluconhydroximo-1,5-lactone,Synthesis and Evaluation as β-Glucosidase Inhibitor

The thiolactone oxime 10 was synthesized in ten steps from the known tri-O-benzylglucose 13 , which was transformed into the oxime 14 , silylated (→ 15 ), and mesylated (→ 16 ). Treatment of 16 with Bu₄NF yielded the L -ido-epoxide 17 and the hydroxylamine 18 ; the isomeric D -gluco-configurated hydroxylamine 20 was prepared from 17 . Reaction of 17 with thiourea yielded the thiirane 19 . Ring opening was best effected with HBr (→ 22 ·HBr). The N-glycosylhydroxylamine 22 was immediately oxidized to 24 , as it reverted to 19 . Similarly, 19 was transformed into the chlorides 21 and 23 . The iodide 25 reacted with TEMPO to afford 29 besides 26 and 30 ; nucleophilic substitution of 23 , 24 , or 25 gave unsatisfactory yields of 26 or 27 , and 28 . Birch reduction transformed 29 into 10 which was isolated via the pentaacetate 32 , which was also transformed into the tetraacetate 33 . The weak activity of 10 as an inhibitor of sweet-almond and Agrobacter β-glucosidase is in keeping with categorization of the lactone and lactam oximes 1–5 and the 5-thiosugars 6–9 as transition-state and substrate analogs, respectively.     

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.     

Synthesis of a Glucose-Derived Tetrazole as a New β-Glucosidase Inhibitor. A New Synthesis of 1-Deoxynojirimycin

The tetrazole 1 is a new β-glucosidase inhibitor (IC₅₀=8·10^?5 M , Emulsin), obtained (92%) by deprotection of 22 , the product of an intramolecular cycloaddition of the azidonitrile 20 . This azidonitrile was formed as an intermediate by treating the L -ido-bromide 14 or the L -ido-tosylate 19 with NaN₃ at 110–120°. It was isolated in a separate experiment. The yield of 22 from 19 reached 70%; 21 was formed as by-product (10%). The bromide 14 (42%) and the iodide 15 (30–35%) were obtained from the nitrile 13 , together with the 2,5-anhydro-L -idononitrile 16, which was formed in ca. 35–45%. The tosylate 19 was obtained from 18 (97%). To obtain 18 , the nitrile 13 was oxidized according to Swern (→17, 92%) and then reduced (NaBH₄, CeCl₃), leading to 18 and 13 (92%, 18/13 93:7). Reduction of the tetrahydropyridotetrazole 22 with LiAlH₄ afforded 83 % of the piperidine 23 , which was deprotected to (+)-1-deoxynojirimycin hydroacetate (2·AcOH, 86%) and further converted into the corresponding hydrochloride and into the free base 2 .     

Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

Glycosylidene Carbenes. Part 13. Synthesis and thermolysis of representative 1-azi-glycoses

In the context of the hypothesis postlating a heterolytic cleavage of a C? N bond during thermolysis of alkoxydiazirines (Scheme 1), we report the preparation of the diazirines 4 , 5 , 7 , and 8 , the kinetic parameters for the thermolysis in MeOH of the diazirines 1 and 4–9 , and the products of their thermolysis in an aprotic environment. The diazirines 4 , 57 , and 8 (Scheme 2–5) were prepared from the known hemiacetals 10 , 19 , 34 (prepared from 31 in an improved way), and 42 according to an established method. The oximes 11 , 20 , 35 , and 43 were obtained from the corresponding hemiacetals as (E/Z)-mixtures; 43 was formed together with the cyclic hydroxylamine 44 . Oxidation of 11 , 35 , and 43 (N-chlorosuccinimide/1,8-diazabicyclo[5.4.0]undec-7-ene (NCS/DBU) or NaIO₄) gave good yields of the (Z)-hydroximolactones 12 , 36 , and 45 , while the oxime 20 led to a mixture of the (E)- and (Z)-hydroximolactones 21 and 22 , which adopt different conformations. Their configuration was assigned, inter alia, by a comparison with the enol ethers 28 and 29 , which were obtained, together with 30 , from the reaction of the diazirine 5 with benzaldehyde and PBu₃. Treatment of the hydroximolactone O-sulfonates 13 , 23 , 37 , and 46 with NH₃/MeOH afforded the diaziridines 15 , 25 , 38 , and 47 in good yields, while the (E)-sulfonate 24 decomposed readily. Oxidation of the diaziridines gave 4 , 5 , 7 , and 8 , respectively. Thermolysis of the diazirines 1 and 4–9 in MeOH yielded the anomeric methyl glycosides 50/51 , 16/17 , 26/27 , 52/53 , 39/40 , 48/49 , and 54/55 , respectively. A comparison of the kinetic data of the thermolysis at four different temperatures shows the importance of conformational and electronic factors and is compatible with the hypothesis of a heterolytic cleavage of a C? N bond. An early transition state is evidenced by the absence of torsional strain by an annulated 1,3-dioxane ring. Thermolysis of 1 in MeCN at 23° led mostly to the diasteroisomeric (Z,Z)-, (E,E)-, and (E,Z)-lactone azines 56 , 57 , and 58 (Scheme 6), which convert to 56 under mild conditions, and to 59 (3%). The benzyloxyglucal 59 was obtained in higher yields (18%), together with 44% of 56–58 , by thermolysis of solid 1 . Similarly, thermolysis at higher temperatures of 4 in toluene, THF, or dioxane and of 9 in CH₂Cl₂ or THF yielded the (Z,Z)-lactone azines 60 and 61 , respectively, the latter being accompanied by the dihydro-oxazole 62 .