Enantiomeric forms of 9-(5,6-dideoxy-α-d-arabino-hex-5-enofuranosyl)adenine and preparation of 9-(6-deoxy-β-d-galactofuranosyl)adenine: Further results with the acetolysis of hexofuranosides

Acetolysis of methyl 5,6-dideoxy-2,3-0-isopropylidene-β-d-ribo-hex-5-enofuranoside (1) and condensation of the product with 6-benzamidochloromercuripurine by the TiCl₄ method, gave 9-(5,6-dideoxy-α-d-arabino-hex-5-enofuranosyl) adenine (3) in low yield after removal of blocking groups. The main product was the D ribo nucleoside which was selectively destroyed by periodate oxidation to facilitate chromatographic purification of 3. The enantiomer 6 was prepared from methyl 5,6-dideoxy-2,3-0-isopropylidene-β-l-ribo-hex-5-enofuranoside (5) by the exact same route. The acetolysis reaction, in contrast to most previous experience, failed to epimerize C-2 of the sugar completely. An improved preparation of 6 is described which started from D-galactose. In addition, the latter pathway was used to prepare 9-(6-deoxy-β-d-galactofuranosyl)adenine (17).     

Synthesis of 6-amino-6-deoxy-d-gulono-1,6-lactam and l-gulono-1,6-lactam derived from corresponding 5,6-O-sulfinyl hexono-1,4-lactones

Syntheses of 6-amino-6-deoxy-2,3-O-isopropylidene-d-gulono- and l-gulono-1,6-lactams 3 and 4 from corresponding glycono-1,4-lactones are described. Activation of the primary hydroxyl group requires 5,6-cyclic sulfite intermediate to obtain 6-azido-6-deoxy derivatives, which are cyclized after reduction.     

The intramolecular conjugate addition of benzylamine to a d-glucose derived α,β-unsaturated ester: an efficient synthesis of trihydroxylated pyrrolidine alkaloids as potential glycosidase inhibitors

A short and efficient synthesis of 1,4,5-trideoxy-1,4-imino-l-xylo-hexitol 2a and 1,4,5-trideoxy-1,4-imino-d-arabino-hexitol 2b is reported using the intramolecular conjugate addition of in situ generated benzylamine to the α,β-unsaturated ester 4, derived from d-glucose, as the key step.     

Self-sacrificing acetylation observed during attempted desilylation of 1-[4-benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine

Desilylation of 1-[4-benzenesulfonyl-3-O-(tert-butyldimethylsilyl)-2-deoxy-5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine (4) with Bu₄NF/THF, when carried out at room temperature, gave four products. Among these, there were 1-[3-O-acetyl-4-benzenesulfonyl-2-deoxy-5-O-methanesulfonyl-α-l-threo-pentofuranosyl]thymine (7) and thymine. A possible reaction mechanism is proposed, which suggests the origin of 3′-O-acetyl group of 7 and thymine as well as structures of the other two products (9a and 9b).     

Biphenylenes-xxxi: Condensation of benzocyclobutene-1,2-dione with aliphatic and heterocyclic 1,2-diamines and the synthesis of cis-2-cyano-3-(2'-cyanovinyl)-1,4-diaz

As possible routes to 1,4-diazabiphenylene and its 2,3-disubstituted derivatives we have studied the condensation of benzocyclobutene-1,2-dione (BBD) with various 1,2-diamines. Instead of giving the 1,4-diazabiphenylene ring system, BBD reacted with ethylenediamine, diaminomaleonitrile, 4,5-diaminopyrimidine, 2-aminopyridine, also 2,3- and 3,4-diaminopyridine to give, respectively, 2-o-carboxyphenylimidazolidinium acetate 4, 3,4-dicyano-2,5-dihydro[2,5]benzodiazocine-1,6-dione 10, 4-amino-5a,9b-dihydro-5-,9b-dihydroxybenzo [3',4']cyclobuta[1',2'-4,5]imidazo[1,2-c]pyrimidine 14, 5a,9b-dihydro-5a,9b-dihydroxybenzo[3',4']cyclobuta[1',2'-4,5] imidazo[1,2-a]pyridine 17, the 4-amino derivative 16 of the latter, and the zwitter ion 18 of 4-amino-3(2-carboxy-benzylideneamino) However, BBD reacted with 4,5-diaminobenzotriazole to give the expected 1,2,3,6,11-penta-aza-1-H-indeno [4,5-b]biphenylene 20, which, on amination followed by oxidation, gave a very low yield of cis-2-cyano-3-(2'-cyanovinyl)-1,4-diazabiphenylene 3. In model experiments, 7,8-diphenylfurazano [3,4-f]quinox-aline 28 was reduced to 2,3-diamino-5,6-diphenyl quinoxaline 29, which on oxidation, gave a mixture of cis- and trans-2-cyano-3-(2'-cyanovinyl)5,6-diphenylpyrazine, 30 and 31. The pentacyclic compounds, 1,3,6,II-tetra-aza-2-oxa-2H-indeno [4,5-b]biphenylene 23 and 1,3,5,10-tetra-aza-1-H-indeno[5,6-b] biphenylene 25, were formed from BBD and the appropriate 1,2-diamines but the 5-membered heterocyclic rings could not be cleaved by reduction and hydrolysis respectively) to give tetracyclic diamines which might have undergone oxidation to give derivatives of 1,4-diazabiphenylene. Compounds 14, 16, 20, 23, 25 and 28 are derivatives of new heterocyclic systems.     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N-O bond reductive cleavage followed by deprotection of -OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N-O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

Silicon-carbon unsaturated compounds. 73. Photolysis of cis- and trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane in the presence of tert-butyl alcohol and acetone

Irradiation of cis-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1a) in the presence of tert-butyl alcohol in hexane with a low-pressure mercury lamp bearing a Vycor filter proceeded with high stereospecificity to give cis-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2a), in 33% isolated yield, together with a 15% yield of 1-[(tert-butoxy)methylphenylsilyl]-4-(methylphenylsilyl)butane (3). The photolysis of trans-1,2-dimethyl-1,2-diphenyl-1,2-disilacyclohexane (1b) with tert-butyl alcohol under the same conditions gave stereospecifically trans-2,3-benzo-1-tert-butoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (2b) in 41% isolated yield, along with a 12% yield of 3. Similar photolysis of 1a and 1b with tert-butyl alcohol-d₁ produced 2a and 2b, respectively, in addition to 1-[(tert-butoxy)(monodeuteriomethyl)(phenyl)silyl]-4-(methylphenylsilyl)butane. When 1a and 1b were photolyzed with acetone in a hexane solution, cis- and trans-2,3-benzo-1-isopropoxy-1,4-dimethyl-4-phenyl-1,4-disilacyclooct-2-ene (4a and 4b) were obtained in 25% and 23% isolated yield. In both photolyses, 1-(hydroxymethylphenylsilyl)-4-(methylphenylsilyl)butane (5) was also isolated in 4% and 5% yield, respectively. The photolysis of 1a with acetone-d₆ under the same conditions gave 4a-d₆ and 5-d₁ in 18% and 4% yields.     

One-pot carbanionic access to methylenebis(phosphonate) analogues of natural P,P-glycosyl-disubstituted pyrophosphates

Two novel lithiated carbanions derived from ethyl (1,2:3,4-diisopropylidene-α-d-galactopyranosyl) methyl phosphonate 3a and ethyl (1-O-methyl-2,3-O-isopropylidene-β-d-ribofuranosyl) methylphosphonate 3b were used in the one-pot alkylidene diphosphorylation of 2,3-O-isopropylidene uridine or 2,3:5,6-di-O-isopropylidene-d-mannofuranose to synthesise the methylenebis(phosphonate) analogues of natural P¹,P²-glycosyl-disubstituted pyrophosphates.     

First synthesis of 4,5-O-isopropylidene-6-thio-d-galactono-1,6-lactone as a precursor of d-galactothioseptanose

Displacement of the bromide group in methyl 6-bromo-6-deoxy-2,3:4,5-di-O-isopropylidene-d-galactonate 7, with potassium thioacetate gave methyl 6-(S)-acetyl-2,3:4,5-di-O-isopropylidene-6-thio-d-galactonate 8 in quantitative yield. Regioselective removal of the 2,3-ketal protecting group afforded methyl 6-(S)-acetyl-4,5-O-isopropylidene-6-thio-d-galactonate 11 in 70% yield. Saponification of compound 11 gave the 6-(S)-4,5-O-isopropylidene-6-thio-d-galactonic acid 12 in quantitative yield. Treatment of 12 with DIC/HOBt as coupling reagents gave, after cyclisation; the target compound: 4,5-O-isopropylidene 6-thio-d-galactono-1,6-lactone 13 in 49% yield.     

Synthesis of 4-octuloses. Part 7: Highly stereoselective synthesis of 2,3-anhydrosugar derivatives as key intermediates in the preparation of sugar β-lactams

Reaction of either 1 or 4 with (N,N-dibenzylcarbamoylmethylene)dimethylsulfurane 2 in DMSO afforded 2,3-anhydro-4,5-O-isopropylidene-d-arabino-pentonamide 3 or N,N-dibenzyl 2,3-anhydro-4,5:6,7-di-O-isopropylidene-β-d-glycero-d-galacto-oct-4-ulo-4,8-pyranosonamide 5, respectively. The configurations of 3 and 5 were determined on the basis of their spectroscopic data, in the first case, and by chemical transformation into the known 2,3-anhydro-4,5:6,7-di-O-isopropylidene-β-d-glycero-d-galacto-oct-4-ulo-4,8-pyranose 11. Treatment of 3 and 5 with lithium hexamethyldisilazide in THF provided the corresponding sugar β-lactams 12, 13 and 14, respectively.     

Unexpected reaction of 2-amino-1,4-naphthoquinone with aldehydes: new synthesis of naphtho[2,1-d]oxazole compounds

Treatment of 3-substituted 2-amino-1,4-naphthoquinones 3 with an aldehyde in a solution of hydrobromic acid in acetic acid led to 2,4-disubstituted naphtho[2,1-d]oxazol-5-ols. The outcome of this simple conversion is even more remarkable in view of the very similar reactions reported in literature, which all give rise to completely different products. Furthermore, the acquired naphthoxazoles 5-11 could be oxidatively ring opened by means of PIFA or CAN into a series of N-acylated 2-amino-1,4-naphthoquinones. A synthetic pathway towards 2-substituted naphtho[2,3-d]oxazole-4,9-diones was also disclosed as the outcome of CAN mediated oxidation of a 4-chloronaphtho[2,1-d]oxazol-5-ol.     

Conjugate addition of lithiated Schöllkopf's bislactim ether to 1E,3E-butadienylphosphonates: Stereocontrolled access to 2,3-anti-4E 2-amino-6-phosphono-4-hexenoic acid derivatives

Face-selective 1,6-addition of lithiated Schöllkopf's bislactime ether 5 to 4-substituted, 1,4- or 3,4-disubstituted 1E,3E-butadienylphosphonates6a-d allows a direct and stereocontrolled access to semi-rigid AP6 analogues, the 2,3-anti-4E 2-amino-6-phosphono-4-hexenoic acid derivatives 4a-c. The relative stereochemistry was assigned from a NMR study of the cyclic derivative 12c. Ten-membered trans-fused chair-boat-like transition states are invoked to rationalize the stereochemical outcome of the addition.     

Stereoselective synthesis of both enantiomers of 1,4-anhydro-alditols, 1,4-anhydro-2-amino-alditols and d- and l-isonucleosides from 2,3-O-isopropylidene-d-glyceraldehyde using iodine-induced cyclization as the key step

We have stereoselectively prepared the enantiomeric 1,4-anhydro-alditols (−)-15 and (+)-15, 1,4-anhydro-2-amino-alditols (−)-19 and (+)-19, and isonucleosides (−)-22, (+)-22 and 25, from 2,3-O-isopropylidene-d-glyceraldehyde. The key step was the iodine-induced cyclization of 4-pentene-1,2,3-triols 2 and 3 to give, respectively, the tetrahydrofuran derivatives 4 and 5. In these compounds we have optimized the substitution of iodine for oxygen-bearing groups. Results were best when we used potassium superoxide as a nucleophile.     

N-Nosyl as a stereoselectivity-improving and easily removable group in the O-glycosylation of d-allal and d-galactal-derived allyl aziridines. Stereospecific synthesis of 4-amino-2,3-unsaturated-O-glycosides

The glycosylation of alcohols, phenol, and partially protected monosaccharides with the diastereoisomeric d-allal and d-galactal-derived N-nosyl aziridines 2α and 2β leads to the corresponding 4-N-(nosylamino)-2,3-unsaturated-α-O- (6α) and β-O-glycosides and disaccharides (6β), respectively, in a stereospecific substrate-dependent O-glycosylation process. The N-(nosylamino) group of 6α and 6β can easily be deprotected to give the corresponding 4-amino-2,3-unsaturated-O-glycosides 7α and 7β, with an increased value to our glycosylation protocol.     

Stereoselective preparation of O-alkoxy d-tetrose,d-pentose, 2-deoxy-d-glycero tetrose and 2,3-dideoxy-d-erythro pentose derivatives by an iterative elongation of 2,3-O-isopropylidene-d-glyceraldehyde

All d-pentoses are synthesized by one-carbon chain elongation commencing with the addition of the lithium salt of ethyl ethylthiomethyl sulfoxide to 2-O-(t-butyldimethylsilyl)-3,4-O-isopropylidene-d-erythrose and d-threose, 16 and 17. The addition of the above-mentioned nucleophile to 2-deoxy-3,4-O-isopropylidene-d-glycero tetrose, 19, gave rise to 2,3-dideoxy-d-glycero pentose. The starting aldehydes, 16, 17 and 19, are easily available from 2,3-O-isopropylidene-d-glyceraldehyde, 1, and ethyl ethylthiomethyl sulfoxide.     

Synthesis of 3-deoxy-d-manno-2-octulosonic acid (Kdo) and d-glycero-d-talo-2-octulosonic acid (Ko) and their α-glycosides

Reaction of 2,3:5,6-di-O-isopropylidene-d-mannofuranose 1 with C-2 lithio derivatives of glyoxylate mercaptal in the presence of MgBr₂ afforded d-glycero-d-galacto-2-octulosonates 2 and 3, respectively. Their 3-O-deoxygenation led to Kdo. N-Iodosuccinimide treatment of 3 gave thioglycoside 11 directly, which was transformed into Ko derivative 12 via epimerisation of the 3-hydroxy group. 3-O-Benzoylation of 12 and then transformation into phosphite furnished 15, an efficient glycosyl donor. Reaction of 15 with 6-O-unprotected glucosamine derivative 22 as acceptor gave α-glycoside 23, which was successfully transformed either into Kdo-disaccharide 27 or into Ko-disaccharide 29.     

Stereocontrolled palladium(0)-catalyzed preparation of unsaturated azidosugars: an easy access to 2- and 4-aminoglycosides

The palladium-catalyzed substitution of alkyl 4,6-di-O-acetyl-α-d-erythro-hex-2-eno-pyranosides using NaN₃ as the nucleophile gave predominantly the corresponding alkyl 2-azido-2,3,4-trideoxy-α-d-threo-hex-2-enopyranosides in the presence of Pd(PPh₃)₄. However, alkyl 6-O-acetyl-4-azido-2,3,4-trideoxy-α-d-erythro-hex-2-enopyranosides were obtained as the major products using Pd(PPh₃)₄ as the catalyst in the presence of dppb as the added ligand. Conversely, alkyl 6-O-(tert-butyldimethylsilyl)-4-O-methoxycarbonyl-2,3-dideoxy-α-d-hex-2-enopyranosides gave exclusively alkyl 4-azido-6-O-(tert-butyldimethylsilyl)-2,3,4-trideoxy-α-d-erythro-hex-2-enopyranosides in the presence of Pd₂(dba)₃/PPh₃ as the catalyst and Me₃SiN₃ as the nucleophile. The bis-hydroxylation followed by hydrogenation of ethyl 4-azido-2,3,4-trideoxy-α-d-erythro-hex-2-enopyranoside afforded the corresponding 4-amino-α-d-mannopyranoside, when propyl 2-azido-2,3,4-trideoxy-α-d-threo-hex-3-enopyranoside gave the 2-amino-α-d-altropyranoside under the same conditions.     

Stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes—a novel preparation of N-acetyl-l-daunosamine

A general route for the stereoselective synthesis of 3-amino-4,5-dihydroxyaldehydes, with almost any desired configuration at the three stereogenic centers, is described by applying a combination of enzymatic and chemical steps. l-Daunosamine 1, for example, the glycosidic fragment of many important anthracycline antibiotics has been prepared by this route starting from O-allyl-l-lactaldehyde (S)-6a. (R)-Hydroxynitrile lyase (HNL) catalyzed addition of HCN to (S)-6a yields the 2,3-dihydroxynitrile (2S,3S)-7a with high stereoselectivity (91% de) in 75% yield. The addition of allyl Grignard to the O-protected 2,3-dihydroxynitrile (2S,3S)-9a and subsequent hydrogenation of the imino intermediate leads to 4-amino-2,3-dihydroxy-1-heptene (4S,5S,6S)-12a, which after ozonization and deprotection gives N-acetylated l-daunosamine 14a in a total yield of 15% referring to (S)-6a. The general applicability of this chemoenzymatic multistep procedure is demonstrated in the stereoselective synthesis of the unnatural aminodeoxy sugar (2S,3S,4S)-14b, starting from isovaleraldehyde 3.     

Selective synthesis of Neu5Ac2en and its oxazoline derivative using BF3·Et2O

Application of the Lewis acid BF₃·Et₂O to the selective synthesis of 5-acetamido-2,6-anhydro-3,5-dideoxy-d-glycero-d-galacto-non-2-enonic acid (Neu5Ac2en) and the related oxazoline, methyl 7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-2,3-didehydro-2,3-trideoxy-4′,5′-dihydro-2′-methyloxazolo[5,4-d]- d-glycero-d-talo-non-2-enonate is described.     

Determination of the configurations of tertiary alcoholic centers in branched-chain carbohydrate derivatives : PMR spectroscopy with a lanthanide shift-reagent

Examination of the PMR spectral changes (expressed as shift gradients of individual protons) wrought by graduated addition of the paramagnetic lanthanide complex tris [1,1,1,2,2,3,3-heptafluoro- 7,7-dimethyloctane-4,6-dionato]europium(III) [Eu(fod)₃] permitted assignment of the configuration at tertiary alcoholic centers of certain sugar derivatives. The configurations of the tertiary position of 3- C-(1,3-dithian-2-yl)-1,2:5,6-di-O-isopropylidene-α-d-allofuranose (1), lethyl of 4,6-O-benzylidene-2- deoxy-3-C-(dithian-2-yl)-α-d-ribo-hexopyranoside (2) and the corresponding 3-C-butyl compound (2a), and methyl 2-C-(1,3-dithian-2-yl)-3,4-O-isopropylidene-δ-d-ribopyranoside (3) were assigned by comparison with reference spectra. The proton shift-gradients for 5-C-benzoyloxymethyl-2,3-O- cyclohexylidene-1-O-p-tolylsulfonyl-1(R),2(S),3(S),5(R)-cyclohexanetetrol (4), taken in conjunction with the spin-spin coupling values, permit direct assignment of relative stereochemistry in the latter compound.