Preparative High-Performance Liquid Chromatographic Separation of Natural Farnesol Isomers (1)

Abstract

Farnesol, 3,7,11-trimethyl-2,6,10-dodecatrien-1-ol, is a naturally occurring sesquiterpenoid that is used in perfumery and synthesis. In synthesis, it is used as a starting material for other terpenoids and insect juvenile hormone derivatives. A preparative high-performance liquid chromatographic separation procedure was developed whereby 2.1 g of 2E,6E-farnesol could be readily isolated from 4.8 g of a 1:1 mixture of the 2E,6E- and 2Z,6E-isomers of farnesol. This rapid one-step procedure simplifies the separation of the mixed isomers on a preparative scale.     

The β-Methoxyethoxymethyl Protecting Group in Alkaloid Synthesis. Synthesis of Abresoline

The isolation of abresoline (1), the only seco-Lythraceae alkaloid, is one of the few pieces of evidence for the proposed oxidative coupling pathway for the biosynthesis of the Type I Lythraceae alkaloids.¹ We required compound 2 for our study of oxidative ary1 coupling as a synthetic route to these alkaloids. The similarity between 1 and 2 prompted the investigation of the synthesis of abresoline as a model for the preparation of 2 and related compounds.     

Reaktionen Mit Trimethylsilylhalogeniden an Derivaten Der Digitoxose

Abstract

Treatment of methyl 3,4-di-O-acyl-2,6-dideoxy-α-D-ribo-hexo-pyranoside 1 or 2 with trimethylsilyl halide leads to the formation of a complex mixture of α-D-ribo-hexopyranosyl halides 3 or 5 together with the educts 1 or 2 as well as their β-anomers 8 or 9. The bromides 3 and 5, suitable for glycosidations, are preferably obtained by reaction of the digitoxose acetate derivatives 6 and 7, respectively, which in turn are prepared from 1 and 2 by mild acetolysis. Further reaction of the halides 3 to 5 with trimethylsilyl halides gives rise to a quantitative formation of the 2,3,6-trideoxy-4-0-acyl-3-halo-α-D -arabino-hexopyranosyl halides 10 to 12. In another reaction sequence starting with the olivose triacetate 20 the formation of 10 via the halide 13 is demonstrated. Structural evidence for the halides 10 to 12 is given by ¹H NMR data as well as by analyses of their glycosides 14 to 19. The results support a mechanistic interpretation for the formation of 10 to 12 via a 3,4-acetoxonium ion as the key intermediate obtained from 3 by an S_Nfi and from 13 and S_N2i step. Final conversion into the terminal halodeoxy compounds 10 to 12 proceeds by and S_N2 reaction with the halide ion.     

Synthetic Application of Partially Protected Fructopyranoses

Partial deacetonation of 1-O-benzoyl-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose (2) yielded the related 2,3-O-isopropylidene derivative (3) that was subsequently transformed into the corresponding 1-O-benzoyl-4,5-O-dibutylstannylene-2,3-O-isopropylidene-β-D-fructopyranose (4). Reaction of 4 with benzyl bromide proceeded with high regioselectivity to afford 1-O-benzoyl-5-O-benzyl-2/3-O-isopropylidene-β-D-fruc-topyranose (5) together with a small quantity of the 4-O-benzyl derivative (6). Oxidation of 5 gave the 4-oxo derivative (10) which was reduced to yield a mixture of 5 and its 4-epimer (11). Debenzylation of 11, followed by a debenzoylation reaction produced 2,3-O-isopropylidene-β-O-tagatopyranose (13). Aceto-nation of 13 yielded 1,2:3,4-di-O-isopropylidene-α-D-tagatofuranose (14). Structures and configurations of the above compounds were established on the basis of their analytical and spectroscopic data.     

Synthetic Mucin Fragments: Methyl-3-O-(2-Acetamido-2-Deoxy-4-O- and 6-O-β-D-Galactopyranosyl-β-D-Glucopyranosyl)-β-D-Galactopyranoside and Methyl 3-O-(2-Acetamido-2-Deoxy-4-O- and 3-O-Methyl-β-D-Glucopyranosyl-3-D-Galactopyranoside

Abstract

Glycosylation of methyl 3-O-(2-acetamido-3, 6-di-O-benzyl-2-deoxy-β-D-glucopyranosyl)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (2) with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (1), catalyzed by mercuric cyanide, afforded a trisaccharide derivative, which was not separated, but directly O-deacetylated to give methyl 3-O-(2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-β-D-galactopyranosyl-β-D-giucopyranosyl)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (8). Hydrogenolysls of the benzyl groups of 8 then furnished the title trisaccharide (9). A similar pflyccsylation of methyl 3-O-(2-acetamido-3-O-acetyl-2-deoxy-β-D-glucopyranosyl)-2,4,6-tri-O-benzyl- β-D-galactopyranoside (obtained by acetylation of 4, followed by hydrolysis of the benzylidene acetal group) with bromide 1 gave a tribenzyl trisaccharide, which, on catalytic hydrogenolysls, furnished the isomeric trisaccharide (12). Methylation of 4 and 2 with methyl iodide-silver oxide in 1:1 dichloro-methane-N, N-dimethylformamide gave the 3-O- and 4-O-monomethyl ethers (13) and (15), respectively. Hydrogenolysis of the benzyl groups of 13 and 15 then provided the title monomethylated disaechartdes (15) and (16), respectively. The structures of trisacchacides 9 and 12, and disaccharides 14 and 16 were all established by ¹³C MMR spectroscopy.     

Synthesis of the Oligosaccharide Moieties of Musettamycin,Marcellomycin and Aclacinomycin A,Antitumor Antibiotics

Abstract

Condensation of benzyl 2,3,6-trideoxy-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (5) with 4-O-acetyl-3-O-benzyl-2,6-dideoxy-α-L-lyxo-hexopyranosyl bromide (10) carried out under Koenigs-Knorr conditions gave 12. Total deprotection of 12 and N-dimethylation at C-3 led to 17 while selective removal of the 4-O-acetyl group led to 13, a synthetic intermediate for preparing 24 and 33. Condensation of 13 with di-O-acetyl-L-fucal (18) or 4-O-acetyl-L-amicetal (25) in the presence of N-iodosuccinimide followed by hydrogenolysis of the C-2-I bond gave 20 and 27 respectively. The trisaccharide 24 then was obtained from 20 by the same sequence of reactions used to convert 12 into 17. After deacetylation and oxidation, this set of reactions also transformed 27 into 33.     

Photochemical Reactions in Carbohydrate Synthesis. Conversion of L-Arabinose Into L-Streptose

Abstract

A synthesis for L-streptose (1) is described. This synthesis differs from those previously reported in several ways, one of which is the use of photochemical reactions in two important steps. These reactions are part of a sequence leading from L-arabinose (2) to 5-deoxy-1,2-O-isopropylidene-β-L-threo-pentofuranos-3-ulose (3). Two other photochemical reactions are considered as a part of the conversion of 3 into L-streptose (1) but neither proved useful. L-Streptose (1) is synthesized from 3 by a sequence of reactions which involves formation of 5-deoxy-l,2-O-isopropylidene-3-C-nitromethyl-β-L-lyxo-furanose (10) and subsequent reaction of 10 with titanium(III) chloride.     

Preparation and Pyrolysis of Cyclooctyl Phenyl Sulfoxide

We recently reported a facile synthesis for bicyclo-[n.2.0]alkanediols of the general structure 1. ¹ The recent demonstration² that cis-bicyclo[3.2.0]heptane-1,7-diol(3) can be converted to the novel, highly-strained trans-bicyclo[4.1.0]heptane system increases the interest in this class of compounds. Comparison of our diols with materials used by Paukstelis and Kao in the rearrangement studies² and further work in our laboratory has shown that the diols reported in our initial communication are trans-diols and should be assigned structures 4 and 5.     

Synthesis of O-α-L-Fucopyranosyl-(1→2)-O-β-D-galactopyranosyl-(1→4)-2-acetamido-2-deoxy-D-glucopyranose. The H-Blood Group Specific Trisaccharide

Abstract

Different reaction conditions were investigated for the preparation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside (5). Compound 5 on reaction with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide afforded the 4-O-substituted 2-acetamido-2-deoxy-β-D-glucopyranosyl derivative which, on O-deacetylation, gave benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-β-D-galactopyranosyl-β-D-glucopyranoside (8). The trimethylsilyl (Me₃Si) derivative of 8, on treatment with pyridineacetic anhydride-acetic acid for 2 days, gave the disaccharide derivative having an O-acetyl group selectively introduced at the primary position and Me₃Si groups at the secondary positions. The latter groups were readily cleaved by treatment with aqueous acetic acid in methanol to afford benzyl 2-acetamido-4-O-(6-O-acetyl-β-D-galactopyranosyl)-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside, which on isopropylidenation gave the desired, key intermediate benzyl 2-acetamido-4-O-(6-O-acetyl-3,4-O-isopropylidene-β-D-galactopyranosyl)-3,6-di-O-benzyl-2-deoxy-β-D-glucopyranoside (12). Reaction of 12 with 2,3,4-tri-O-benzyl-α-L-fucopyranosyl bromide under catalysis by bromide ion afforded the trisaccharlde derivative from which the title trisaccharide was obtained by systematic removal of the protective groups. The structures of the final trisaccharide and of various intermediates were established by ¹H and ¹³C NMR spectroscopy.     

Reactions of Cyclic Anhydrides XIV. Facile Syntheses of Fused Heterocycles via Anilic Acids Pyridobenzoxazinones,Isoquinolinobenzoxazinones and Isocoumarinoquinolines

o-Carboxyhomomaleanilic acids (5) and o-carboxyhomophthalanilic acids (6) on treatment with sodium acetate-acetic anhydride furnished pyridobenzoxazinones (8) and isoquinolinobenzoxazinones (9) respectively in quantitative yields. Conversion of o-formylhomophthalanilic acid (7) to isocoumarinoquinoline (11) via 2-axo-3(o-carboxyphenyl)quinoline (10) is also described.     

Reactions of a New Type of Intermediate Formed by Triflate Rearrangement

Treatment of methyl 4-O-benzoyl-2, 6-dideoxy-β-D-arabino-hexopyranoside (6) with triflic anhydride in The presence of 2, 6-di-t-butyl-4-methylpyridine (7) produces methyl 4-O-benzoyl-2, 6-dideoxy-3-O-(tri-fluoromethylsulfonyl) -β-D-arabino-hexopyranoside (8), a compound which rearranges to a new and highly unstable triflate (10) upon standing at room temperature. Bromide ion reacts with 10 to give methyl 4-O-benzoyl-3-bromo-2,3,6-trideoxy-β-D-arabino-hexopyranoside (11), a product of displacement at C-3. A similar reaction takes place with nitrate ion to give methyl 4-O-benzoyl-2, 6-dideoxy-3-O-nitro-β-D)-arabino-hexopyranoside (15). Reaction of 10 with water and with tributyltin hydride results in capture of the cation 12, formed by ionization of 10, to give methyl 3-O-benzoyl-2,6-dideoxy-β-D-ribo-hexopyranoside (14) and methyl 3, 4-O-benzylidene-2, 6-dideoxy-β-D-ribo-hexopyranosi de (16), respectively. The cation 12 also reacts with methanol to afford the orthobenzoates 17 and 18.     

Nonreducing-Sugar Subunit Analogs of Bacterial Lipid a Carrying the Ester-Bound (3R)-3-(Acyloxy)Tetradecanoyl Group

Abstract

In order to elucidate further the relationship between the composition of the fatty acyl groups in the nonreducing-sugar subunit of bacterial lipid A and its biological activity, 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-2-[(3R)-3-hydroxytetradecanamido]-4-O-phosphono-D-glucose [GLA-63(R, R) and GLA-64(R, R)], and 3-O-[(3R)-3-(acyloxy)tetradecanoyl]-2-deoxy-4-O-phosphono-2-tetradecanamido-D-glucose [GLA-67(R), GLA-68(R) and GLA-69(R)] have been synthesized. Benzyl 2-[(3R)-3-(benzyloxymethoxy)tetradecanamido]-2-deoxy-4,6-O-isopropylidene-β-D-glucopyranoside (5) and benzyl 2-deoxy-4,6-O-isopropylidene-2-tetradecanamido-β-D-glucopyranoside (6) were each esterified with (3R)-3-dodecanoyloxytetradecanoic acid (1), (3R)-3-tetradecanoyloxytetradecanoic acid (2) or (3R)-3-hexadecanoyloxy-tetradecanoic acid (3), to give 7-11, which were then transformed, by the sequence of deisopropylidenation, 6-O-tritylation and 4-O-phosphorylation, into a series of desired compounds.     

A General Method for Stepwise Elongation of the (1→5)-α-D-Arabinofuranan Chain

Condensation reaction of 3,5-di-O-benzoyl-1,2-O-(1-cyanoben-zylidene)-β-D-arabinofuranose (2) with benzyl and allyl 2,3-di-O-benzoyl-5-O-triphenylmethyl-α-L-arabinofuranosides (5a and 5b) in methylene chloride in the presence of triphenylcarbenium tetrafluoroborate as catalyst under high vacuum gave α-(1→5)-linked dimeric D-arabinofuranoside derivatives (6a and 6b). One of the dimeric compounds (6a) was debenzoylated, triphenylmethylated, and rebenzoylated to give a dimeric homolog of 5a (8). Similarly for the preparation of 6a, 8 was condensed with 2 to provide an α-(1→5)-linked trimeric D-arabinofuranoside derivative (9). Further elongation of the glycoside chain might be possible in the same way.     

First Stereqselective Synthesis of Nitrophenyl 2-Deoxy- β-D-glycosides

α-Dithiophosphates of peracetylated 2-deoxyhexc-pyranoses, 1a, 1b and 2, uhich are easily prepared by addition of organic phosphorodithioic acids to glycais react smoothly with resin-bound 2- and 4-nitrophenoxides to give stereoselectively the respective nitrophenyl 2-deoxy-β-D-hexopyranosides (3, 4, 5 and 6) in high yields. Glycosylation of the 2, 4-dinitro'phenoxide, however, leads with comparable stereoselectivity to 2,4-dinitrophenyl 2-deoxy- α-D-hexopyranosides (7 and 8).

Glycosides 3 - 6 are quantitatively deacetylatec by Amberlyst A-26 (OH^-), whereas glycosides 7 and 8, under the same reaction conditions undergo splitting of the O-glycosidic bond.     

Diborane Reduction of O-(Tert-Butyldimethylsilyi.)galactaramides. A Model Study for Aminoalditol Synthesis

Tert-butyldimethylsilylation of dimethyl galactarate (1) with tert-butylchlorodimethylsilane/imidazole/N,N-dimethylformamide at 25 [ddot]C dimethyl 2,5-bis-O-(tert-butyldimethylsilyl)galactarate (2) as the principal product, with methyl 2,3,5-tris-O-(tert-butyldimethylsilyl)-D,L-galactarate-l,4-lactone (3) and methyl 2,3-bis-O-(tert-butyldimethyl)-D,L-galactarate-l,5-lactone (4) as minor products. When the reaction was carried out at 65 [ddot]C, the only product was the 1,4-lactone, 3 Ammonolysis of 2 in methanol gave 2,5-bis-O-(tert-butyldimethyl)-galactaramide (5, 94%), which was conveniently reduced with borane- THF to 1,6-diamino-1,6-dideoxygalactitol, isolated as its dihydrochloride 9. Ammonolysis of 3 in methanol gave a mixture of 5; 2,3,4-tris-O-(tert-butyldimethylsilyl)-D,L-galactaramide (6), 2,3,5-tris-O-(tert-butyldimethylsilyl)-D,L-galactaramide (7), and 2,3,5-tris-Q-(tert-butyldimethylsilyl)-D,L-1,4-lactonogalactaramide (8). Borane-THF reduction of a mixture of 6 and 7 also yielded 9. This study served as a model for the use of O-silylated carbohydrate amides in the preparation of aminodeoxyalditols.     

Synthesis of Potential Antimicrobial Agents from Maltose. III. Introduction of an Amino Group Into the 3′-Position of 1,6-Anhydro-Disaccharides

Abstract

Regioselective cleavage of 1,6-anhydro-maltose (1) with periodate and the subsequent recyclization with nitromethane gave 1,6-anhydro-3′-deoxy-3′-nitro-disaccharides (3). Three diastereomers, prepared by benzylidenation of 3, were separated by column chromatography. Each of 4′,6′-O-benzylidene derivatives successively underwent debenzylidenation, reduction of the nitro group, and peracetylation to give 3′-acetamido-3′-deoxy-disaccharide derivatives (7, 8, and 9). The configurations of the 3-amino sugar moietres in 7 (D-gluco), 8 (D-manno) and 9 (D-galacto) were determined on the basis of the ¹H NMR data. The main product (7) was further modified to the 6-deoxy-6-nitro derivative.     

Darstellung Von β-D-Olivosyl(1→3)-D-olivosiden Aus Mithramycin

Abstract

The benzyl glycoside 4 obtained from 2-bromo-2-deoxy-α-0-quinovosyl bromide 1, readily accessible by the dibromomethyl methyl ether reaction of 2, is deformylated to give the monohydroxy compound 5 which is used in glycosidation reactions. Treatment of 3 with dibromomethyl methyl ether results in the formation of the labile β-furanosyl bromide 7 and the cyrstalline pyranosyl bromide 8 in a ratio of 1:2, both of which are further characterized by their methyl glycosides 10 and 11, respectively. Action of dibromomethyl methyl ether at room temperature on the benzyl ether 6, conventionally prepared from 3, is shown to proceed initially to the glycosyl bromide 9. Compound 9 is cleaved to the 4-formyl-blocked pyranosyl bromide 12, and only after prolonged reaction time gives the pyranosyl halide 8. The glycosidation of the glycosyl bromide 1 with benzyl-4–0-benzyl-α-D-olivoside 13 in the presence of silver carbonate and silicate is a sluggish reaction and gives rather low yields of the β-and the α, l-3-linked disaccharides 15 and 16 in the ratio 3–4:1. With silver triflate the yield is improved to the 61% and the ratio 6:1 in favour of 15.

Further transformations lead to both the syrupy olivosyl olivosides 17. and 18. In a more favourable reaction sequence 1 is condensed with the alcohol component 5 and silver triflate as promoter and yields the crystalline β-(19) and the α, 1→3-linked disaccharides (20) in 92% and a ratio of 6.5: 1. By subsequent transformations the protected title tetradeoxy disaccharide 21 is obtained.     

Synthesis of C-Glycosyl α-Glycines

Abstract

A scheme of asymmetric synthesis of C-glycosyl α-glycines is described. Reductive hydrolysis of 2-deoxy-3,5-di-O-p-toluoyl-β D-erythropentofuranose 1-cyanide (4) in the presence of N,N-diphenylethylenediamine gave the imidazolidine 5, which was converted to 2,5-anhydro-3-deoxy-4,6-di-O-p-toluoyl-β-D-allose (3)by acid hydrolysis. The aldehyde (3), chiralamine, benzoic acid and t-butyl isocyanide four component condensation afforded in good yield two diastereomeric adducts (6a and 6b), which were separated by column chromatography and deblocked to furnish 2-deoxy-β-D-erythropentofuranosyl R and S-glycines (1a) and (1b).     

Reactions of Per-O-Acetylated Carbohydrate Triflates With Halide Ions

Abstract

The reactions of bromide, chloride, and iodide ions with 1,3,4, 6-tetra-O-acetyl-2-O-(trifluoromethylsulfonyl) -α-D-glucopyranose (2) and with 1, 3, 4, 6-tetra-O-acetyl-2-O-(trifluoromethylsulfonyl)-β-D-mannopyranose (3) gave good to excellent yields of the corresponding deoxyhalogeno sugars. In contrast, when the gluco triflate 2 and tetra-butylammonium fluoride were heated under reflux in benzene, only 5-(acetoxymethyl)-2-formylfuran (13) was formed. Reaction of the manno triflate 3 under similar conditions produced 1, 3,4, 6-tetra-O-acetyl-2-deoxy-2-fluoro-β-D-gluco-pyranose (17), 1. 3, 4. 6-tetra-O-acetyl-2-deoxy-β-D-erythro-hex-2-eno-pyranose (18), 4,6-di-O-acetyl-1, 5-anhydro-2-deoxy-D-erythro-hex-l-enitol-3-ulose (19), and 1, 2, 3, 4, 6-penta-O-acetyl-β-D-glucopyranose (20). The mechanisms of the reactions of The triflates 2 and 3 with fluoride ion are discussed.     

Synthesis of N-Alkyl-N'-cyano-N″-4-pyridylguanidines from 4-Pyridyldithiocarbamic Acid via N-Alkyl-N′-4-Pyridylthioureas,or via 4-Pyridylcyaniminothiocarbamic Acid

Several years ago a number of antihypertensive N-alkyl-N′-cyano-N″-pyridylguanidines was prepared by addition of cyanamide to N-alkyl-N′-pyridylcarbodiimides which were obtained from the respective thioureas and phosgene or triphenylphosphine/carbon tetrachloride¹. Recently we have described some attractive synthetic methods for N-alkyl-N′-4-pyridylthioureas², based on 4-pyridyldithiocarbamic acid (1) (Scheme 1). We now report on the synthesis of N-alkyl-N′-cyano-N″-4-pyridylguanidines (4) from (1) by two different routes which ultimately may pass through a common intermediate (3) (Scheme 1).