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.     

A Total Synthesis of (±)-Trichodiene

Trichodiene (1), a sesquiterpene hydrocarbon, was isolated from the extract of mycelium of Trichothecium roseum. The structure of trichodiene (1) was elucidated by Nozoe and Machida in 1970 via degradation and spectroscopy.¹ Trichodiene (1) has been shown to be the biogenetic precursor of the trichothecane family of sesquiterpenoids as characterized by the cytotoxic fungal metabolite (-)-trichodermin (2).^2,3 The structure and absolute stereochemistry of (-)-trichodermin (2) were determined by X-ray diffraction and, therefore, the structure and absolute stereochemistry of trichodiene (1) are now firmly established.⁴ We wish to report a total synthesis of (±)-trichodiene (1) via previously reported lactone 3.^5,6     

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).     

Synthesis of Some Non-Conjugated Dienones in the Retro-α-Ionone Series1

In the course of a study on the photochemical and thermal behaviour of β,γ-δ,ε-dienones^1-4, (E)-retro-α-ionone (2a) and a series of methylated (3, 4) and desmethyl analogues (2b-2e) have been synthesized by a simple deconjugative isomerization of the corresponding conjugated dienones in strong alkaline solution. 3-Methyl- (3) and 3,3-dimethyl-retro-α-ionone (4) have been prepared by addition of methyl chloride to a strongly alkaline solution of β-ionone (1a).⁵     

A Convenient Synthesis of (Z)-7-Nonadecen-Ll-One and (Z)-7-Eicosen-Ll-Cne -the Pheromones of Peach Fruit Moth

In 1977 Tamaki¹ et al have isolated and synthesized² (Z)-7-nonadecen-ll-one (la) and (Z)-7-eicosen-l1-one (1b) which are active components of the female sex pheromones of the peach fruit moth Carposina niponensis Walsingham, a major economic pest of apple, peach and other fruits of Japan. We report in this communication a practical, convenient and stereospecific route to 1a and 1b.     

Synthesis of γ-Lactone of 1R-CIS 2,2-Dimethyl-3-(2,2,2-tribromo-1-hydroxyethyl)cyclopropane Carboxylic Acid,A Key Intermediate for Deltamethrin,From (+)-3-Carene

1R-cis-2,2-Dimethyl-3-(2,2-dibromovinyl)cyclopropane carboxylic acid¹ (1), the acid moiety of the highly potent photostable pyrethroid deltamethrin (2) has been obtained either by a Wittig reaction on 1R-cis-caronaldehyde ester (3) employing 1, 1-dibromomethylenetriphenylphosphorane or from the bicyclic tribromo-lactone^2,3 (4) by reaction with zinc and acetic acid. Lactone (4) is thus an important intermediate in the deltamethrin synthesis.     

The structure of cis and trans lsomers of 1-(p-Bromobenzylidene)-2-indanone

Abstract

In this communication we wish to report an interesting case of the isolation and characterization of the cis and trans isomers of 1-(p-bromobenzylidene)-2-indanone and their ketals. Prior to this work, Hoogstreen and Trenner² had reported on the cis and trans isomers of 1-(p-chlorobenzylidene)-2-methyl-5-methoxyindenylacetic acid. The condensation of 2-(N-morpholinyl)-indene (1, prepared by the reaction of 2-indanone³ and morpholine) with P-bromobenzaldehyde was conducted by refluxing them in the presence of acetic acid for 4 hours. Acid hydrolysis of the reaction mixture followed by dry column chrcmatography over sillica gel using a fraction collector afforded two iscmeric monobenzylidenes, compounds 2(36.6%, mp 110–111°)and 3(1.3%, mp 115–116°) and a dibenylidene, compound 4 (8.7%, mp 205°). The relative rations of the mono- and dibenzylidenes seemed to depend on the reaction conditions. Higher yields of the monobenzylidenes 2 and 3 were obtained by conducting the reaction in the presence of UV light. The structures of these monobenzylidenes were established as cis and trans isomers of 1-(p-bromobenzylidenes)-2-indanone on the Basis of elemental analyses and ir and nmr spectroscopy. The ir spectra⁴ (CHCl₃)

of compounds 2 [1725 (c=0), 1620 (c=c)cm^?1] and 3[1710 (c=o), 1570, 1600 (c=c) cm^?1] were consistent with the structures. The molecular ion peaks as well as the fragmentation patterns in the mass spectra of both these compounds were consistent with the assigned structures. Before going into the omr discussion it should be pointed out that treatment of compound 2 with athylene glycol in the presence of p-toluene sulfonic acid produced two ketals, 5 (38.3% mp, 118–120°) and 6 (30.6% mp, 125–126°). As depicted; the ketals 5and 6 were also found (by omr) to be related to each other as cis and trans isomers. Furthermore, each of them could be hydrolyzed with acid to the corresponding monobenzylidenes 2 and 3 without any isomerization. However, UV irradiation of compounds 2 and 3 gave equilibrium mixtures containing both the isomers, indicating isomerization had occurred under photolytic conditions.     

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.     

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.     

The Reaction of Diethanolamine with 2-Chloronitrobenzene-A Reinvestigation

In a report on the reaction of 2-chloronitrobenzene (1) with diethanolamine (2), Meltsner et al ¹ claim that the expected S_NAr product, N-(2-nitrophenyl)diethanolamine (3), is not formed; rather that the products are 2,2′-dichloroazobenzene (4), 2-nitrophenol (5), 2-chloroaniline (6) and 4-(2-aminophenyl)morpholine (7). Similar products in which the nitro function is reduced are also reported² for the corresponding reaction with ethanolamine. In this laboratory, in an attempted preparation of 2,2′-dichloroazobenzene (4) for reference purposes in photochemical studies on the antineoplastic agent 5-(3-azido-4-chlorophenyl)-6-ethyl-pyrimidin-2,4-diamine³, the expected S_NAr product (3) was obtained along with other products.     

Synthesis of Retro-γ-Ionols and the Corresponding-Ionones1

Both the direct² and the sensitized^3,4 photolyses of (E)-β-ionol (2) have been studied in some detail. In a preliminary publication⁵ we have indicated that direct photolyses of (E)-β-ionol (2) with λ = 254 nm yields (Z)-retro-γ-ionol (3) as the primary product; upon further irradiation 3 is converted into the corresponding (E)-isomer (4) which rapidly yields the bicyclic alcohol 5. A quantitative study revealed that the photoconversion of (E)-β-ionol with λ = 254 nm to 3 is about 10 times faster than the conversion of 3 into (E)-retro-γ-ionol.⁶ This rate difference thus allows the photosynthesis of 3.     

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.     

Directional Specificity in the Boronate Cleavage of Unsaturated 1,3-Diol Derivatives

Recently Miyashita, Yanami, and Yoshikoshi reported an apparent case of peripheral bond cleavage in the fragmentation of the boronate 2 derived from octalin 1 to give aldehyde 4 (Scheme I, Path a).¹ Since previous examples of related fragmentations had been shown to proceed with exclusive cleavage of the more highly substituted carbon-carbon bond² (i.e. 2 → 3) it was of interest to examine the above system in greater detail to determine if the neighboring hydroxyl substituent caused the unexpected bond cleavage or if an alternative pathway (Scheme I, Path b) might be operative in this case.³ To that end, we first examined the behavior of the methyl ether derivative (5) of alcohol 1 which was prepared along the lines described below for ether 15 (Scheme II). However hydroboration of unsaturated ether 5 followed by base treatment led to no identifiable product. Evidently steric factors retard the hydroboration and / or basic cleavage of the intermediate boronate.     

A Simple Preparation of 3-Formyl-Cycloalkenones

Recently, we required a convenient method for preparing the 3-formyl-cyclohexenone, 1, starting from dihydroresorcinol. The conversion of dihydroresorcinol into the cyclohexenone derivative 2, could be readily accomplished using the elegant method of Stork and Danheiser,¹ however, existing methods for the transformation of the ketone group of 2 into the formyl group of 1 did not prove satisfactory.² We describe here, a simple and general method for the transformation of 2 into 1 (Scheme I).     

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.     

Stereoselective Synthesis of 3-C-Branched-Chain Sugars by Aldol Reaction of Furanos-3-Uloses with Acetone

Abstract

Aldol reaction of 1,2-O-isopropylidene-5-O-tertbutyl-dimethylsilyl-α-D-erythro-pentofuranos-3-ulose (1) with acetone in the presence of aqueous K₂CO₃ afforded 3-C-acetonyl-1,2-O-isopropylidene-5-O-tertbutyl-dimethylsilyl-α-D-ribofuranose(2). Similar reaction of 1,2:5, 6-di-o-isopropylidene- α-D-ribo-hexofuranos-3-ulose (3) afforded 3-C-acetonyl-1,2:5, 6-di-o-isopropylidene- α-D-allofuranose (4) and (1R, 3R, 7R, 8S, 10R)-perhydro-8-hydroxy-5,5,10-trimethyl-2,4,6,11,14-pentaoxatetracyclo[8,3,1,0^1,8,0^3,7] tetradecane. The stereochemistry of the new chiral centers were determined by ¹H NOE experiments.     

Synthesis of Bioactive Pyrethroid, 3-Phenoxybenzyl 1R-trans-2, 2-Dimethyl-3-(2-chloro-1-propenyl) Cyclopropanecarboxylate

The title compound 1 has been prepared from (+)-3-carene (2) and found to have the same order of activity as its IR-cis isomer 3 reported by us earlier¹ The key intermediate methyl IR-trans-2, 2-dimethyl-3-(2-oxopropyl)cyclopropanecarboxylate (4) has been characterised.     

Selective α-D-Galactosylation of Benzyl 4,6-O-Benzyhdene-β-D-Galacto-Pyranoside with 2,3,4,6-Tetra-O-Benzyl-α-D-Galactopyranosyl Bromide Under Catalysis by Halide Ion

Abstract

Selective glycosylation of benzyl 4,6-O-benzylidene-β-D-galacto-pyranoside (1) with 1.5 mole equivalent of 2,3,4,6-tetra-O-binzyl-α-D-galactopyranosyl bromide (2) catalyzed by halide ion gave the (1→2)-α-(5) and (l→3)-α-D-linked disaccharide (7) derivatives in 22 and 40% yields, respectively. The D-galactose unit at the reducing end of 2-O-α-D-galactopyranosyl-D-galactose [11) at equilibrium in D₂O was shown By ¹³C NMR spectroscopy to exist in the pyranose and furanose forms in the ratio of ～2:1.     

Syntisis of 4-Demethoxy-7, 11-dideoxydaunomycinone

Our continued interest in the total synthesis of natural and unnatural antitumor anthracyclines¹ especially the aglycones such as daunomycinone (1)² and 4-demethoxydaunomycinone (2)³, 11-deoxydaunomycinone (3)⁴ and 4-demethoxy-11-deoxydaunomycinone (4)⁵ led us to probe methods of obtaining these products of absolute enantitomeric purity. Earlier it was demonstrated that the AB ring synthon 5 having a chiral centre on fusion with phthalic anhydride gave 4-demethoxy-7-deoxy-daunomycinone (6) with no loss of optical purity⁶ and the same was further transformed to 2 [7-(S)-9(S)].