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.     

Synthesis of Enantiomerically Pure Ferrocenes from Glycofuranosyl-cyclopentadienes,synthetic equivalents of (alkoxyalkyl)fulvenes

Cyclopentadienyl C-glycosides (= glycosyl-cyclopentadienes) have been prepared as latent fulvenes. Their reaction with nucleophiles leads to cyclopentadienes substituted with (protected) alditol moieties and, hence, to enantiomerically pure metallocenes. Treatment of 1 with cyclopentadienyl anion gave the epimeric glycosyl-cyclopentadienes 6 / 7 (Scheme 1). Each epimer consisted of a ca. 1:1 mixture of the 1, 3-and 1, 4-cyclopentadienes a and b , respectively, which were separated by prep. HPLC. Slow regioisomerisation occurred at room temperature. Diels-Alder addition of N-phenylmaleimide to 6a / b ca. 3:7 at room temperature yielded three ‘endo’-adducts, i.e., a disubstituted alkene ( 8 or 9 , 25%) and the trisubstituted alkenes 10 (45%) and 11 (13%). The structure of 10 was established by X-ray analysis. Reduction of 6 / 7 (after isolation or in situ) with LiAlH₄ gave the cyclopentadienylmannitols 12a / b (80%) which were converted to the silyl ethers 13a / b (Scheme 2). Lithiation of 13a / b and reaction with FeCl₂ or TiCl₄ led to the symmetric ferrocene 14 (76%) and the titanocene 15 (34%), respectively. The mixed ferrocene 16 (63%) was prepared from 13a / b and pentamethylcyclopentadiene. Treatment of 6 / 7 with PhLi at ?78° gave a 5:3 mixture of the 1-C-phenylated alcohols 17a / b and 18a / b (71%) which were silylated to 19a / b and 20a / b , respectively. Lithiation of 19 / 20 and reaction with FeCl₂ afforded the symmetric ferrocenes 21 and 22 and the mixed ferrocene 23 (54:15:31, 79%) which were partially separated by MPLC. The configuration at C(1) of 17–22 was assigned on the basis of a conformational analysis. The reaction of the ribofuranose 24 with cyclopentadienylsodium led to the epimeric C-glycosides 27a / b and 28a (57%, ca. 1:1, Scheme 3). The in-situ reduction of 27 / 28 with LiAlH₄ followed by isopropylidenation gave 25a / b (65%) which were transformed into the ferrocene 26 (79%) using the standard method. Phenylation of 27 / 28 , desilylation, and isopropylidenation gave a 20:1 mixture of 33a / b and 34a / b (86%) which was separated by prep. HPLC. The same mixture was obtained upon phenylation of the fulvene 32 which was obtained in 36% yield from the reaction of the aldehydo-ribose 30 with cyclopentadienylsodium at ?100°. Lithiation of 33 / 34 and reaction with FeCl₂ gave the symmetric ferrocene 35 (88%). Similarly, the aldehydo-arabinose 36 was transformed via the fulvene 37 (32%) into a 18:1 mixture of 38a / b and 39a / b (78%) and, hence, into the ferrocene 40 (83%). Conformational analysis allowed to assign the configuration of 33–35 , whereas an X-ray analysis of 40 established the (1S)-configuration of 38a / b and 40 . The opposite configuration at C(1) of 38a / b and 33a / b was established by chemical degradation (Scheme 4). Hydrogenation (→ 41 and 44 , resp.), deprotection (→ 42 and 45 , resp.), NaIO₄ oxidation, and NaBH₄ reduction yielded (+)-(S)- 43 and (?)-(R)- 43 , respectively.     

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 .     

Simultaneous inversion of configurations of C22, C23 in 24S-ethyl-3,5-cyclo-cholestane-22S,23S-diol-6-one

In this paper, obtainment of 3 by simultaneous inversion of configurations of C₂₂, C₂₃, in 2 via its ditosylate or dimesylate was unsuccessful, leading to elimination products instead. However, monotosylate of 2 can be readily obtained with exclusive regioselectivity, which in turn gave a single epoxide 7b Hydrolysis of 7b gave 3 and 2 is a ratio of 2:1, with a combined yield of 80%. The-recovered 2 can of course be recycled again.     

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.     

N‐ and C‐acyclic thionuleoside analogues of 1,2,3‐triazole

Cycloaddition of the azide derivative 5 with 1,4‐dihydroxybutyne afforded the N‐thio‐acyclic nucleoside 6 , which prepared alternatively from coupling of the bromo derivative 8 with 2‐acetoxy‐ethylmercaptan. Deblocking of 6 gave the free nucleoside 7 . Mesylation of 6 furnished the dimesylate 9 , which gave three rearranged products 14–16 on treatment with chloride anion. These compounds might be obtained via the episulfonium ion 10 , which is subjected to nucleophilic displacement and further sulfur participation. Deblocking of 14–16 afforded the free nucleoside analogues 17–19 , and their structures were confirmed by COSY, ROESY, HMQC, and HMBC NMR techniques. Compound 16 was prepared alternatively from chlorination of alcohol 6 with Ph₃P‐CCl₄. Carbomoylation of 6 led to the carbamate 20 , which gave the free nucleoside analogue 21 on deblocking. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:380–387, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20030     

Glyconothio-O-lactones. Part III. Thermolysis of a 4,5-Dihydro-1,2,3- and a 2,5-Dihydro-1,3,4-thiadiazole

Addition of CH₂N₂ to 2,3:5,6-di-O-isopropylidene-1-thio-mannono-1,4-lactone ( 1 ) gave the 2,5-dihydro-1,3,4-thiadiazole 2 and the 4,5-dihydro-1,2,3-thiadiazole 3 . First-order kinetics were observed for the thermolysis of 3 (Scheme 3) at 80–110° in C₆D₅Cl solution and of 2 (Scheme 3) at 20–35° in CDC1₃, respectively. The 1,2,3-thiadiazole 3 led to mixtures of the thiirane 9 , the starting thionolactone 1 , the thiono-1,5-lactone 8 , and the enol ether 7 , while the isomeric 1,3,4-thiadiazole 2 led to mixtures of the anomeric thiiranes 9 and 12 , the O-hydrogen S,O,O-ortholactone α-D - 14 , the S-methyl thioester 15 , the S,S,O-ortholactone 13 , and the 2,3:5,6-di-Oisopropylidene-mannono-1,4-iactone ( 16 ). Pure products of the thermolysis were isolated by semipreparative supercritical fluid chromatography (SFC), whereas preparative HPLC led to partial or complete decomposition. Thus, the β-D -mannofuranosyl β-D -mannofuranoside 10 , contaminated by an unknown S species, was isolated by preparative HPLC of the crude product of thermolysis of 3 at 115–120° and partially transformed in CD₃OD solution into the symmetric di(α-D -mannofuranosyl) tetrasulfide 11 . Its structure was evidenced by X-ray analysis. Similarly, HPLC of the thermolysis product of 2 gave the enethiol 17 , the sulfide 19 , and the mercapto alcohol 18 as secondary products. Thermolysis of the thiirane 9 at 110–120° (Scheme 4) led to the anomeric thiirane 12 which was transformed into mixtures of the enethiol 17 and the enol ether 7. Addition of H₂O to 17 and 7 gave the corresponding hemiacetals 18 and 20. The mechanism of the thermolysis of the dihydrothiadiazoles 2 and 3 , and the thiiranes 9 and 12 is discussed.     

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).     

Approaches to the Synthesis of Cytochalasans Part9. A versatile concept leading to all structural types of cytochalasans

Starting from D-glutamic acid ( 5 ), the bicyclic compounds 4a and 4b were synthesized via 17 (Schemes 1 and 2). The reaction leading to 4g and 4h with LiCuPh₂ was not successful. But treatment of the N-protected model lactams 19 , 21 , and 22 with Li₂Cu(CN)Ph₂ gave the amino ketones 24 , 26 , and 27 , respectively (Scheme 3). The desired compound 23 was obtained from 20. Conversion of the unprotected lactams 28 , 31 , and 32 gave the phenyl derivative 34 in excellent yields. Ester 35 was transformed to the α -amino-γ- oxo-acid derivative 36. This conversion opens a novel access to this type of compounds.     

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).     

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 .     

7‐Oxanorbornane and Norbornane Mimics of a Distorted β‐D‐Mannopyranoside: Synthesis and Evaluation as β‐Mannosidase Inhibitors

The racemic 7‐oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45 , and 46 were synthesized and tested as snail β‐mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate 9 and furan 10 . Esterification provided 11 that underwent an intramolecular Diels–Alder reaction to the 7‐oxanorbornene 12 . Reduction of 12 to 13 , desulfonylation, isopropylidenation, and cis‐dihydroxylation gave 16 . A second isopropylidenation to 17 , followed by debenzylation and a Mitsunobu–Gabriel reaction provided 19 that was deprotected via 20 to 3 . Diels–Alder cycloaddition of furfuryl acetate and maleic anhydride to 21 , followed by alcoholysis of the anhydride, cis‐dihydroxylation, isopropylidenation, and Barton decarboxylation gave the ester 25 . Deacetylation to 26 and a Mitsunobu–Gabriel reaction led to 27 that was transformed into the N‐Boc analogue 29 , reduced to the alcohol 30 , and deprotected to 4 . The 1‐aminonorbornane 5 was obtained from Thiele's Acid 31 . Diels–Alder cycloaddition of the cyclopentadiene obtained by thermolysis of the diester 32 , methanolysis of the resulting anhydride 33 , dihydroxylation, isopropylidenation, Barton decarboxylation, and Curtius degradation led to the benzyl carbamate 39 that was reduced to the alcohol 40 , transformed into the N‐Boc carbamate 41 , and deprotected to 5 . The alcohol 40 was also transformed into the benzylamine 42 , aniline 45 , and hydroxylamine 46 . Snail β‐mannosidase was hardly inhibited by 3, 4, 42, 45 , and 46 . Only the amino triol 5 proved a stronger inhibitor. The inhibition by 5 depends on the pH value (at pH 3.5: K_i = 1900 μM ; at pH 4.5: K_i = 340 μm; at pH 5.5: K_i = 110 μm). The results illustrate the strong dependence of the inhibition by bicyclic mimics upon the precise geometry and orientation of the amino group as determined by the scaffold. It is in keeping with the hypothesis that the reactive conformation imposed by snail β‐mannosidase is close to a ^1,4B/¹S₃.     

Thermal Reactions of Epoxyenones and Epoxydienes in the Ionone Series

On flash vaccum thermolysis at temperatures between 390 and 585°, the epoxyenones 1 – 9 and the epoxydienes 10 – 12 undergo various types of reactions involving C? C and/or C? O bond cleavage in the oxirane ring. Thus, the compounds 1 , 4 – 9 , 11 , and 12 were transformed to the divinyl ethers 13 , 20 , 21 , 24 , 25 , 29 , and 38 by a reversible [1,5] homosigmatropic H-shift. On thermolysis of the epoxides 1 – 12 , several products formed via carbonyl-ylide intermediates were also isolated. The extent of the formation of ylide products is clearly related to the conjugating ability of the functional groups neighboring the oxirane. Thus, the epoxides 3 , 5 , and 7 – 10 , bearing a C(3)?C(4) bond, a 5-oxo function, a 3,4-epoxy or a 3,4-methano group, preferentially underwent reactions via a carbonyl-ylide intermediate. As a further reaction pathway, the epoxides 1 – 12 undergo cleavage of the C–O bonds of the oxirane, which, however, is presumably an acid-catalyzed rather than a thermal reaction.     

Totalsynthese von Nojirimycin

Total synthesis of Nojirimycin Addition of the nitrone 3 (from 8 and 9 ) to furane, followed by oxidation with OsO₄ and then isopropylidenation gave the fully functionalized glycoside 12 (40% from 8 ) via the glycal 10 and the hemiacetal 11 . Since the glycoside cleavage of 12 , leading to 13 after benzyloxycarbonylation proceeded in a mediocre yield, and since the acetolysis of 12 giving 14 (69%) was not practical, compound 12 was transformed into the hydroxy ester 17 by sequential hydrogenolysis, hydrolysis and benzyloxycarbonylation (69% overall). The hydroxy ester 17 was lactonized to give 18 (87%). Reduction of 18 first with LiBH₄ (97%) and then with H₂/Pd gave the key compound 20 which was transformed into nojirimycin ( 1 ) and into 1-deoxy-nojirimycin ( 2 ) using prior art. The overall yield of 1 was 19.5%.     

Preparation of optically active flowery and woody-like odorant ketones via Corey-Chaykovsky oxiranylation: Irones and analogues

α-, β-, and γ-Irones and analogues have been prepared from optically active ketones (+)- 1 , (+)- 6a,b , and (+)- 17 , via a Corey-Chaykovsky oxiranylation (Me₂S, Me₂SO₄, Me₂SO, NaOH) followed by isomerisation (SnCl₄ or MgBr₂). (+)-Dihydrocyclocitral ( 19a ), obtained from (?)-citronellal, and analogue (+)- 19b , were condensed with various ketones to afford (+)- 21a–f , and after hydrogenation (+)- 22a–f. A mild oxidative degradation of aldehydes (+)-trans-and (?)-cis- 8a,b , to ketones (?)- 16a,b , as well as olfactive evaluations, ¹³C-NMR assignments, and absolute configurations of the intermediate epoxides, aldehydes, and alcohols are presented.     

Glycosylidene Carbenes. Part 23. Regioselective glycosidation of deoxy- and fluorodeoxy-myo-inositol derivatives

To demonstrate the relevance of the kinetic acidity of individual OH groups for the regioselectivity of glycosylation by glycosylidene carbenes, we compared the glycosylation by 1 of the known triol 2 with the glycosylation of the diol D - 3 and the fluorodiol L - 4 . Deoxygenation with Bu₃SnH of the phenoxythiocarbonyl derivative of 5 (Scheme 1) or the carbonothioate 6 gave the racemic alcohol (±)- 7 . The enantiomers were separated via the allophanates 9a and 9b , and desilylated to the deoxydiols D - and L - 3 , respectively. The assignment of their absolute configuration is based upon the CD spectra of the bis(4-bromobenzoates) D - and L - 10 . The (+)-(R)-1-phenylethylcarbamates 13a and 13b (Scheme 2) were prepared from the fluoroinositol (±)- 11 via (±)- 4 and the silyl ether (±)- 12 and separated by chromatography. The absolute configuration of 13a was established by X-ray analysis. Decarbamoylation of 13a ( → L - 12 ) and desilylation afforded the fluorodiol L - 4 . The H-bonds of D - 3 and L - 4 in chlorinated solvents and in dioxane were studied by IR and ¹H-NMR spectroscopy (Fig. 2). In both diols, HO? C(2) forms an intramolecular, bifurcated H-bond. There is an intramolecular H-bond between HO? C(6) and F in solutions of L - 4 in CH₂Cl₂, but not in 1,4-dioxane; the solubility of L - 4 in CH₂Cl₂ is too low to permit a meaningful glycosidation in this solvent. Glycosidation of D - 3 in dioxane by the carbene derived from 1 (Scheme 3) followed by acetylation gave predominantly the pseudodisaccharides 18/19 (38%), derived from glycosidation of the axial OH group besides the pseudodisaccharides 16 / 17 (13%) and the epoxides 20 / 21 (7%), derived from protonation of the carbene by the equatorial OH group. Similarly, the reaction of L - 4 with 1 (Scheme 4) led to the pseudodisaccharides 28 / 29 (46%) and 26 / 27 (14%), derived from deprotonation of the axial and equatorial OH groups, respectively. Formation of the epoxides involved deprotonation of the intramolecularly H-bonded tautomer, followed by intramolecular alkylation, elimination, and substitution (Scheme 4). The regio- and diastereoselectivities of the glycosidation correlate with the H-bonds in the starting diols.     

Heterocyclic Spiro-naphthalenones. Part I: Synthesis and reactions of some spiro [(1 H-naphthalenone)-1,3′-piperidines]

The title compounds 14–16 were obtained via an intramolecular Mannich condensation by treating 11–13 with CH₂O at RT. The unsaturated ketones 14 and 15 were reduced to the allylic alcohols 18 and 19 respectively. Ring cleavage of compound 18 on treatment with 2N HCl gave the substituted aminopropanol 20 . The allylic alcohols 18 and 19 were hydrogenated to 22 and 23 respectively. With CH₂O, the amino-alcohol 23 gave the methano-naphthoxazocine 24 , whereas 22 and 23 , on heating in polyphosphoric acid (PPA), afforded the naphthazepines 25 and 26 respectively. With organolithium compounds, the unsaturated ketones 14 and 16 gave the teriary allylic alcohols 27–29 , which were hydrogenated and dehydrated to the olefins 36–40 ; these were cyclized via an intramolecular alkylation to the methanodibenzo-octahydrocyclooctapyridines 41–43 . On heating in PPA, the allylic alcohol 29 was converted into the naphthazepine 44 . With CH₂O, the naphthol 49 gave the naphthoxazocine 50 , in equilibrium with the spiro-naphthalene-pyrrolidinone 51 in solution. Finally, in the presence of CH₂O, the naphthazepine 57 afforded the methano-naphthazepinone 58 , which, by a 4-stage degradation, was transformed to the benzisoquinoline 62 .     

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 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.