Photochemie von tricyclischen β, γ-γ′, δ′-ungesättigten Ketonen. 50. Mitteilung über Photoreaktionen

Photochemistry of tricyclic β, γ-γ′, δ′-unsaturated ketones The easily available tricyclic ketone 1 (cf. Scheme 1) with a homotwistane skeleton yielded upon direct irradiation the cyclobutanone derivative 3 by a 1,3-acyl shift. Further irradiation converted 3 into the tricyclic hydrocarbon 4 . However, acetone sensitized irradiation of 1 gave the tetracyclic ketone 5 by an oxa-di-π-methane rearrangement. Again with acetone as a sensitizer the ketone 5 was quantitatively converted to the pentacyclic ketone 6 . The conversion 5 → 6 represents a novel photochemical 1,4-acyl shift. The possible mechanisms are discussed (see Scheme 7). The tricyclic ketone 2 underwent similar types of photoreactions as 1 (Scheme 2). Unlike 5 the tetracyclic ketone 9 did not undergo a photochemical 1,4-acyl shift. The epoxides 10 and 14 derived from the ketones 1 and 2 , respectively, underwent a 1,3-acyl shift upon irradiation followed by decarbonylation, and the oxa-di-π-methane rearrangement (Schemes 3 and 4). The diketone 18 derived from 1 behaved in the same way (Scheme 5). The tetracyclic diketone 21 cyclized very easily to the internal aldol product 22 under the influence of traces of base (Scheme 5). Upon irradiation the γ, δ-unsaturated ketone 24 underwent only the Norrish type I cleavage to yield the aldehyde 25 (Scheme 6).     

Preparation and Transmetallation of a Triphenylstannyl β-D-Glucopyranoside: A highly stereoselective route to β-D-C-glycosides via glycosyl dianions

The triphenylstannyl β-D -glucopyranoside 4 was synthesized in one step from the 1,2-anhydro-α-D -glucopyranose 3 with (triphenylstannyl)lithium (Scheme 1). Transmetallation of 4 with excess BuLi, followed by quenching the dianion 7 with CD₃OD gave (1S)-1,5-anhydro-3,4,6-tri-O-benzyl-[1-²H]-D - glucitol ( 8 ) in 81% yield (Scheme 2). Trapping of 7 with benzaldehyde, isobutyraldehyde, or acroleine gave the expected β-D -configurated products 11, 12 , and 13 in good yields. Preparation of C-acyl glycosides from acid chlorides, such as acetyl or benzoyl chloride was not practicable, but addition of benzonitrile to 7 yielded 84% of the benzoylated product 14 . Treatment of 7 with MeI led to 15 (30%) along with 40% of 18 , C-alkylation being accompanied by halogen-metal exchange. Prior addition of lithium 2-thienylcyanocuprate increased the yield of 15 to 50% and using dimethyl sulfate instead of MeI led to 77% of 15 . No α-D -anomers could be detected, except with allyl bromide as the electrophile, which yielded in a 1:1 mixture of the anomers 16 and 17 .     

Glycosylidene Carbenes. Part 19. Regioselective glycosidation of allyl 2-deoxy-2-phthalimido-D-allopyranosides

The regio- and stereoselectivity of the glycosidation of the partially protected mono-alcohols 3 and 7 , the diols 2 and 8 , and the triol 4 by the diazirine 1 have been investigated. Glycosidation of the α-D -diol 2 (Scheme 2) gave regioselectively the 1,3-linked disaccharides 11 and 12 (80%, α-D /β-D 9:1), whereas the analogous reaction with the βD -anomer 8 led to a mixture of the anomeric 1,3- and 1,4-linked disaccharides 13 (12.5%), 14 (16%), 15 (13%), and 16 (20.5%; Table 2). Protonation of the carbene by OH–C(4) of 2 is evidenced by the observation that the α-D -mono-alcohol 3 did not react with 1 under otherwise identical conditions, and that the β-D -alcohol 7 yielded predominantly the β-D -glucoside 18 (52%) besides 14% of 17 . Similarly as for the glycosidation of the diol 2 , the influence of the H-bond of HO? C(4) on the direction of approach of the carbene, the role of HO? C(4) in protonating the carbene, and the stereoelectronic control in the interception of the ensuring oxycarbenium cation are evidenced by the reaction of the triol 4 with 1 (Scheme 3), leading mostly to the α-D -configurated 1,3-linked disaccharide 19 (41%), besides its anomer 20 (16%), and some 4-substituted β-D -glucoside 21 (9%). No 1,6-linked disaccharides could be detected. In agreement with the observed reactivity, the ¹H-NMR and IR spectra reveal a strong H-bond between HO? C(3) and the phthalimido group in the α-D -, but not in the β-D -allosides. The different H-bonds in the anomeric phthalimides are in keeping with the results of molecular-mechanics calculations.     

Glycosylidene Carbenes. Part 7. Neighbouring-group participation by the 2-benzyloxy group in the glycosidation of strongly acidic hydroxy compounds

To demonstrate the neighbouring-group participation of the 2-benzyloxy group in the glycosidation of phenols and of strongly acidic alcohols by the diazirine 1 , we examined the glycosidation of 4-nitrophenol, 4-methoxyphenol, (CF₃)₂CHOH, MeOH, and i-PrOH by the diazirine 11 , derived from the 2-deoxypyranose 6 . Oxidation of the oximes 7 yielded (E)- and (Z)- 8 . In solution, (E)- 8 isomerised to (Z)- 8 . Similarly, the (E)-configurated mesylate 9 , prepared from 8 , underwent acid-catalysed isomerisation to (Z)- 9 . Treatment of (Z)- 9 with NH₃, followed by oxidation of the resulting diaziridine 10 with I₂, yielded the desired diazirine 11 . Glycosidation by 11 of the above mentioned hydroxy compounds yielded the glycosides 12–21 . In agreement with the postulated neighbouring-group participation, these glycosidation proceeded without, or with a very low diastereoselectivity, favouring the axial anomers.     

Glycosylidene Carbenes. Part 14. Glycosidation of partially protected galactopyranose-, glucopyranose-, and mannopyranose-derived vicinal diols

The relation between H-bonding in diequatorial trans-1,2 and axial, equatorial cis-1,2-diols and the regioselectivity of glycosidation by the diazirine 1 was examined. H-Bonds were assigned on the basis of FT-IR and ¹H-NMR spectra (Fig. 1). Glycosidation by 1 of the gluco-configurated diequatorial trans-2,3-diols 4–7 yielded the mono-glucosylated products 16/17/20/21 (69–89%); 1,2-/1,3-linked products (37–46:63–54), 24/25/28/29 (60–63%; 1,2-/1,3-linked products 46–51:54–49), 32–35 (69–94%; 1,2-/1,3-linked products 45–52:55–48), and 36/37/40/41 (59–63%; 1,2-/1,3-linked products 52–59:48–41), respectively (Scheme 1, Table 3). The disaccharides derived from 4, 5 , and 7 were characterized as their acetates 18/19/22/23, 26/27/30/31 , and 38/39/42/43 , respectively. Glycosidation of the galacto-configurated diequatorial 2,3-diols 8 and 9 and the manno-configurated diequatorial 3,4-diol 10 by 1 (Scheme 2, Table 3) also proceeded in fair yields to give the disaccharides 44–47 (69–80%;1,2-/1,3-linked products ca. 1:1), 48–51 (51–61%;1,2/-1,3-linked products 54–56:56–54), and 56/57/60/61 (71–80%; 1,3-/1,4-linked products 49–54:51–46), respectively. The 1,3-linked disaccharides 56/57 derived from the diol 10 were characterized as the acetates 58/59 . The regio- and stereoselectivities of the glycosidation by 1 were much better for the α-D -manno-configurated axial, equatorial cis-2,3-diol 11 and the galacto-configurated axial, equatorial cis-3,4-diol 13 (1,2-/1,3-linked disaccharides ca. 3:7 for 11 and 1,3-/1,4-linked disaccharides ca. 4:1 for 13 ; Scheme 3, Table 4). The regio- and stereoselectivity for the β-D -manno-configurated cis-2,3-diol 12 were, however, rather poor (1,2-/1,3-linked products 48:52). The 1,2-linked disaccharides 66/67 derived from 12 were characterized as the acetates 70/71 . Koenigs-Knorr-type glycosidation of the cis-diols 11–13 by 2 or 3 proceeded with a similar regio- and a higher stereoselectivity (α-D > β-D with the donor 2 and α-D < β-D with the donor 3 ) than with 1 , with the exception of 12 which did not react with 2 . The regioselectivity of the glycosidations by 1 agrees fully with the H-bonding scheme of the diols and with the hypothesis that the intermediate carbene is preferentially protonated by the most weakly H-bonded OH group. The regioselectivity of the glycosidation by 2 and by 3 is determined by a higher reactivity of the equatorial OH groups and by H-bonding. Several H-bonded and equilibrating isomers of a given diol may intervene in the glycosidation by 1 , or by 2 and 3 , resulting in the same regioselectivity. The low nucleophilicity of 12 and the low degree of regioselectivity in its reaction with 3 show that stereoelectronic effects may also profoundly influence the nucleophilicity of OH groups.     

Synthesis of Galactose- and N-Acetylglucosamine-Derived Tetrazoles and their evaluation as β-glycosidase inhibitors

The title compounds 6 and 7 have been prepared from the known 2,3-di-O-benzyl-4,6-O-benzylidene-D -galactose ( 18 ) and N²-acetyl-tri-O-benzyl-D -glucosamine oxime ( 29 ) in eight and six steps, respectively. The azidonitrile leading to the benzylated galacto-tetrazole 16 was prepared from 14 and cyclized under the conditions of its formation (Scheme 1). The alcohol 13 was obtained by oxidation of 10 followed by reduction. Better yields and diastereoselectivities were realized, when the benzylidene-protected D -galacto-alcohol 20 was subjected to oxido-reduction, yielding the L -altro-alcohol 22 via the ketone 21 (Scheme 2). Treatment of the corresponding tosylate 24 with NaN₃ yielded the tetrazole 25 , which was deprotected to 6 . The tetrabenzyl ether 16 (from 14 , or from 25 via 27 ) was reduced to 28 and deprotected to give the known deoxygalactostain 8 (Scheme 2). Oxidation of the hydroxynitrile 30 , derived from 29 , followed by reduction of 32 yielded mostly the L -ido-hydroxynitrile (Scheme 3), which was tosylated and treated with NaN₃ to give the tetrazole 35a and its manno-isomer 36a , while Al(N₃)₃ yielded (E)- and (Z)- 38 (Scheme 4). The intermediate azide 39 was isolated besides 40 when NH₄N₃/DMF was used; thermolysis of 39 gave mostly 35a , which was deprotected to 7 , besides some elimination product 41 . Both 6 and 7 are stable in the pH range 1–10; at pH 12, 6 is unaffected but, 7 shows some epimerization to the manno-configurated isomer 43 . The tetrazole 6 is a competitive inhibitor of the β-galactosidases from E. coli (K₁ = 1 μM , pH 6.8) and bovine liver (K₁ = 0.8 μM , pH 7.0); the N-acetyl-β-D -glucosaminidase from bovine kidney is competitively inhibited by 7 (K₁ ? 0.2 μM , pH 4.1).     

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.     

A New Synthesis of Benzylidene Acetals

Aryl-halo-diazirines react under basic conditions with 1,3-cis-, 1,2-cisand 1,2-trans-diols to give acetals. Yields are high. Diastereoselectivities depend upon the diol and upon the reaction conditions. Thus, reaction of the 1,3-cis-diol 1 (Scheme 1) with 2 gave 3 as a single diastereoisomer. The 1,2-cis-diols 4 and 7 led to the endo- and exo-acetals 5 / 6 (93:7) and 8 / 9 (ca.10:1), respectively, The 1,2-trans-diols 10 , 16 , and 19 reacted with 2 to afford 11 / 12 (90:10), 17 / 18 (1:1), and 20 / 21 (6:1), respectively. Reaction of the (4-nitrophenyl)diazirine 13 with 10 at higher temperatures yielded 14 / 15 (6:4). The uracil moiety, the acetamido group, and the enol-ether moiety are compatible with the reaction conditions. The diastereoselectivity is rationalized on the basis of a reaction sequence involving alkoxy-halogen exchange, which is regioselective or not, thermolysis of the ensuing alkoxydiazirine(s), protonation of the alkoxycarbene to form an (E)-configurated oxycarbenium ion, and attack of the neighboring oxy or hydroxy group, which is only possible for a limited range of conformers.     

Glycosylidene Carbenes. Part 15. Synthesis of disaccharides from allopyranose-derived vicinal 1,2-diols. Evidence for the protonation by a H-bonded hydroxy group in the σ-plane of the intermediate carbene,followed by attack on the oxycarbenium ion in the π-plane

The α-D -allo-diol 9 possesses an intramolecular H-bond (HO? C(3) to O? C(1)) in solution and in the solid state (Fig. 2). In solution, it exists as a mixture of the tautomers 9a and 9b (Fig. 3), which possess a bifurcated H-bond, connecting HO? C(2) with both O? C(1) and O? C(3). In addition, 9a possesses the same intramolecular H-bond as in the solid state, while 9b is characterized by an intramolecular H-bond between HO? C(3) and O? C(4). In solution, the β-D -anomer 12 is also a mixture of tautomers, 12a and presumably a dimer. The H-bonding in 9 and 12 is evidenced by their IR and ¹H-NMR spectra and by a comparison with those of 3–8, 10 , and 11 . The expected regioselectivity of glycosidation of 9 and 12 by the diazirine 1 or the trichloroacetimidate 2 is discussed on the basis of the relative degree of acidity/nucleophilicity of individual OH groups, as governed by H-bonding. Additional factors determining the regioselectivity of glycosidation by 1 are the direction of carbene approach/proton transfer by H-bonded OH groups, and the stereoelectronic control of both the proton transfer to the alkoxy-alkyl carbene (in the σ-plane) and the combination of the thereby formed ions (π-plane of the oxycarbenium ion). Glycosidation of 9 by the diazirine 1 or the trichloroacetimidate 2 proceeded in good yields (75–94%) and with high regioselectivity. Glycosidation of 9 and 12 by 1 or 2 gave mixtures of the disaccharides 14–17 and 18–21 , respectively (Scheme 2). As expected, glycosidation of 12 by 1 or by 2 gave a nearly 1:1 mixture of regioisomers and a slight preference for the β-D -anomers (Table 4). Glycosidation of the α-D -anomer 9 gave mostly the 1,3-linked disaccharides 16 and 17 (α-D β-D ) along with the 1,2-linked disaccharides 14 and 15 (α-D < β-D , 1,2-/1,3-linked glycosides ca. 1:4), except in THF and at low temperature, where the β-D -configurated 1,2-linked disaccharide 15 is predominantly formed. Similarly, glycosidation of 9 with 2 yielded mainly the 1,3-linked disaccharides (1,2-/1,3-linked products ca. 1:3 and α-D /β-D ca. 1:4). Yields and selectivity depend upon the solvent and the temperature. The regioselectivity and the unexpected stereoselectivity of the glycosidation of 9 by 1 evidences the combined effect of the above mentioned factors, which also explain the lack of regio-complementarity in the glycosidation of 9 by 1 and by 2 (Scheme 3). THF solvates the intermediate oxycarbenium ion, as evidenced by the strong influence of this solvent on the regio- and stereoselectivity, particularly at low temperatures, where kinetic control leads to a stereoelectronically preferred axial attack of THF on the oxycarbenium ion.     

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.     

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%).     

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 .     

Cob(I)alamin als Katalysator, 5. Mitteilung [1]. Enantioselektive Reduktion α,β-ungesättigter Carbonylderivate

Cob(I)alamin as Catalyst. 5. Communication [1]. Enantioselective Reduction of α,β-Unsaturated Carbonyl Derivatives The cob(I)alamin-catalyzed reduction of an α,β-unsaturated ethyl ester in aqueous acetic acid produced the (S)-configurated saturated derivative 2 with an enantiomeric excess of 21%. The starting material 1 is not reduced at pH = 7.0 in the presence of catalytic amounts of cob(I)alamin (see Scheme 2). It is shown that the attack of cob(I)alamin and not of cob(II)alamin, also present in Zn/CH₃COOH/H₂O, accounts for the enantioselective reduction observed. All the (Z)-configurated starting materials 1 , 3 , 5 , 7 , 9 and 11 have been transformed to the corresponding (S)-configurated saturated derivatives 2 , 4 , 6 , 8 , 10 and 12 , respectively. The highest enantiomeric excess revealed to be present in the saturated product 12 (32,7%, S) derived from the (Z)-configurated methyl ketone 11 (see Scheme 3 and Table 1). The reduction of the (E)-configurated starting materials led mainly to racemic products. A saturated product having the (R)-configuration with a rather weak enantiomeric excess (5.9%) has been obtained starting from the (E)-configurated methyl ketone 23 (see Scheme 5 and Table 2). The allylic alcohols 16 and 24 have been reduced to the saturated racemic derivative 17 .     

The separation of acyl protection groups in alkali-sensitive glucosides. Synthesis of podophyllotoxin-beta-D-glucoside

The synthesis of podophyllotoxin-β-D -glucoside (III), an antimitotic lignan compound isolated from Podophyllum species, is reported. Reaction of podophyllotoxin (I) with tetra-O-acetyl-α-D -glucopyranosyl bromide in acetonitrile in the presence of Hg(CN)₂ yields tetra-O-acetyl-podophyllotoxin-α-D -glucoside (II), which is converted into podophyllotoxin-β-D -glucoside (III) by ZnCl₂-catalysed methanolysis. This transesterification is an advantageous method for the preparation of glycosides, sensitive to base and acid, from their corresponding acetyl derivatives. Scope and conditions of the reaction are discussed.     

Glycosylidene Carbenes. Part 2. Synthesis of O-Aryl Glycosides

Phenol, 4-methoxyphenol, 4-nitrophenol, methyl orsellinate ( 1 ), and 2,6-di(tert-butyl)-4-methylphenol (BHT; 2 ) have been glycosylated by thermal reaction (20–60°) with various glycosylidene-derived diazirines. 4-Methoxyphenol reacted with the D-glucosylidene-derived diazirine 3 to give O-glucosides ( 4 and 5 , 69%, 3:1) and C-glucosides ( 6 and 7 , 16%, 1:1). Similarly, phenol yielded O-glucosides ( 10 and 11 , 70%, 4:1) and C-glucosides ( 12 and 13 , 13%, 1:1). 4-Nitrophenol gave only O-glycosides, 3 leading to 14 and 15 (75%, 3:2; Scheme 1), and the D-galactosylidene-derived diazirine 17 to 22 and 23 (52% (from 16 ), 65:35; Scheme 2). The reaction of phenol with 17 yielded 58% (from 16 ) of the O-galactosides 18 and 19 (4:1) and 14% of the C-galactosides 20 and 21 (1:1). From the D-mannosylidene-derived diazirine 25 , we predominantly obtained the α-D-configurated 26 (38 % from 24 ). These results are interpreted by assuming that an intermediate (presumably a glycosylidene carbene) first deprotonates the phenol to generate an ion pair which combines to give O- and - with electron-rich phenolates - also C-glycosides. A competition experiment of 3 with 4-nitro- and 4-methoxyphenol gave the products from the former ( 14 and 15 ) and the latter phenol ( 4-7 ) in almost equal amounts. Differences in the kinetic acidity of OH groups, however, may form the basis of a regioselective glycosidation, as evidenced by the reaction of 3 with methyl orsellinate ( 1 ) yielding exclusively the 4-O-monoglycosylated products 27 and 28 (78%, 85:15), although diglycosidation is possible ( 27 → 31 and 32 ; 67%, 4:3; Scheme 3). Steric hindrance does not affect this type of glycosidation; 3 reacted with the hindered BHT ( 2 ) to afford 33 and 34 (81 %, 4:1). The predominant formation of 1,2-trans -configurated O-aryl glycosides is rationalized by a neighbouring-group participation of the 2-benzyloxy group.     

Reaction mechanism of the ammoximation of ketones catalyzed by TS-1

Summary The liquid-phase adsorption of acetone, butanone, cyclohexanone, 3-methylcyclohexanone and 4-butylcyclohexanone on TS-1 were measured, and the direct ammoximation reactions of these ketones with H₂O₂and NH₃catalyzed by TS-1 were studied. The catalysts after reaction were characterized by TGA. The adsorption results showed that acetone, butanone, cyclohexanone and 3-methylcyclohexanone could enter into the cavity of TS-1, while 4-butylcyclohexanone could not. In the ammoximation reactions, all the ketones were converted into the corresponding oximes in highconversions and selectivities. In combination with the TGA results, it is inferred thatthe ammoximation reactions of acetone and butanone may occur to some extent inside the pores of TS-1. For cyclohexanone and 3-methylcyclohexanone, the ketone-involving step may occur inside the pores of TS-1 to a limited extent but for 4-butylcyclohexanone, may only occur outside the catalyst.</o:p>     

Cross-aldol reactions of levoglucosenone and its derivatives with cyclohex-1-en-1-ol ethers

The reaction of levoglucosenone with cyclohex-1-en-1-yl trimethylsilyl ether under Mukaiyama reaction conditions gave [1 + 2]-Michael–aldol condensation product with participation of the acetal center. The reaction was accompanied by opening of the 1,6-anhydro bridge and intramolecular hemiketalization by the hydroxy group of the 2-oxocyclohex-1-enyl fragment. Under analogous conditions, dihydrolevoglucosenone gave rise to four diastereoisomeric 1,2-addition products. Internal cyclohex-1-en-1-ol ether obtained by treatment of the Michael adduct of levoglucosenone and cyclohexanone with Ac₂O–ZnCl₂ underwent intramolecular Mukaiyama reaction involving substituted α-carbon atom of the cyclohexanone fragment and acetal moiety to afford spiro derivative and product of subsequent AdE1 acetylation of intermediate α′-cyclohexenyl ether fragment.     

Synthesis of New Nucleosides by coupling of chloropurines with 2- and 3-deoxy derivatives of N-methyl-D-ribofuranuronamide

The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D -ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D -ribofuranosiduronamide (α-D - 8 ) and the corresponding anomer β-D - 8 were synthesized starting from the commercially available 2-deoxy-D -ribose ( 1 ) (Scheme 1). Reaction of α-D - 8 with the silylated derivative of 2,6-dichloro-9H-purine ( 9 ) afforded regioselectively the N⁹-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D - 8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine ( 17 ) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D -ribofuranuronamide ( 13 ) yielded only the protected β-D -anomers 14 and 18 , respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D - 11 , β-D - 12,15 , and 16 . The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A₁ and A_2A adenosine receptor subtypes.     

Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

Glycosylidene Carbenes. Part 4. Synthesis of Spirocyclopropanes from Acetamidoglycosylidene-Derived Diazirines

The synthesis of the first glycosylidene-derived 2-acetamido-2-deoxydiazirine 4 from N-acetylglucosamine 6 is described. Thus, 6 was transformed into the 3-O-mesylglucopyranoside 9 by glycosidation with allyl alcohol, benzylidenation, and mesylation (Scheme 2). Solvolysis of 9 gave the allopyranoside 10 which, upon benzylation and glycoside cleavage, yielded the hemiacetals 12 . Using our established method (via the lactone oxime 14 and the diaziridines 16 ), 12 gave the diazirine 4 . Thermolysis of this diazirine in the presence of i-PrOH gave the dihydro-1,3-oxazole 5 (Scheme 1); in the presence of acrylonitrile, the four diastereoisomeric spirocyclopropanes 17–20 and the acetamidoallal 21 were obtained and separated by prep. HPLC (Scheme 3). Assignment of the configuration of 17–20 is based on NOE measurements and on the effect of diamagnetic anisotropy of the CN group. The ratio of the four cyclopropanes, which is in keeping with earlier results, is rationalized.