Synthesis of N-[2-S -(2-Acetamido-2,3-dideoxy-D-glucopyranose-3-y1)-2-Thio-D-Lactoyl]-L-alanyl-D-isoglutamine

Abstract

N-[2-S-(2-Acetamido-2,3-dideoxy-D-glucopyranose-3-y1)-2-thio-D-lactoyl]-L-alanyl-D-isoglutamine, in which the oxygen atom at C-3 of N-acetylmuramoic acid moiety in N-acetylmuramoyl-L-alanyl-D-isoglutamine (MDP) has been replaced by sulfur, was synthesized from allyl 2-acetamido-2-deoxy-β-D-glucopyranoside (1).

Treatment with sodium acetate of the 3-O-mesylate, derived from 1 by 4,6-O-isopropylidenation and subsequent mesylation, gave allyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-β-D-allopyranoside (4). When treated with potassium thioacetate, the 3-O-mesylate, derived from 4, afforded allyl 2-acetamido-3-S-acetyl-2-deoxy-4,6-0-isopropylidence-β-D-glucopyranoside (6). S-Deacetylation of 6, condensation with 2-L-chloropropanoic acid, and subsequent esterification, gave the 3-s[D-1(methoxycarbonyl)ethyl]-3-thio-glucopyranoside derivative (7). Coupling of the acid, derived from 7, with the methyl ester of L-alanyl-D-isoglutamine, and subsequent hydrolysis, yielded the title compound.     

Synthesis of 2, 3-dideoxy-4-O-p-methoxybenzyl-L-erythro-hex-2-enono-1, 5-lactone

The synthesis of 2, 3-dideoxy-4-O-p-methoxy-benzyl-L-erythro-hex-2-enono-1, 5-lactone 9 from L-serine, using (1RS, 3S)-3, 4-isopropylidene-1-methoxy-1-phenylthio-butan-2-one 2 as key chiral intermediate, is described. Compound 9 is an interesting chiral precursor for the synthesis of L-sugars.     

Synthesis of 2-Aryl-1H-s-Triazolo[1, 5-a] Benzimidazoles

2-Aroylaminobenzimidazoles (2) have been converted into 1(2-benzimidazolyl)-5-aryl-1H-tetrazoles (4) by treatment with PCl₅ followed by azidation with NaN₃ in aqueous acetone solution. Pyrolysis of 4 in diphenylether yielded 2-aryl-1H-s-triazolo [1,5-a] benzimidazoles (6). The product of benzylation of 6a has been characterised. A reasonable pathway for the formation of 6 from 4 has been suggested.     

Synthesis of (3-Ethoxycarbonyl But-3-en-2-yl)phenyl Sulfone and (2-Ethoxycarbonyl But-2-en-1-yl)phenyl Sulfone from Ethyl 2-Bromomethyl But-2-enoate

The synthetic usefullness of “acrylic” tin compounds has been largely demonstrated by BALDWIN and coworkers¹. We wanted to apply this methodology to prepare the peroxide precursors. Thus, we needed to synthesize (2-ethoxycarbonyl prop-2-enyl) phenyl sulfone 1, (2-ethoxycarbonyl but-2-en-1-yl) phenyl sulfone 2 and (3-ethoxycarbonyl but-3-en-2-yl) phenyl sulfone 3. We wish to report the synthesis of such compounds using the advantage of the complexing effect of Polyethyleneoxide 400 (PEO 400) on alkali cations. We also must to report the isomerisation of 2 to 3 in presence of traces of sodium sulfinate which make access to 2 difficult.     

A new Method for the Synthesis of 5-Benzyl-1-(2-Hydroxyethoxy Methyl)Uracil (Bau), A Potent Uridine Phosphorylase Inhibitor,And Its N3-And N1, N3, -Substituted Analogs

A new methodology for the synthesis of 5-benzyl-l-(2-hydroxyethoxymethyl)uracil (BAU)² (1), a potent uridine phosphorylase inhibitor, has been developed. The coupling of bis(trimethylsilyl) derivative of 5-benzyl uracil with 2-acetoxyethoxymethyl bromide, followed by removal of the protecting 0-acetyl group, afforded compound 1. However, treatment of the silyl derivatives of 5-benzyluracil with 2-acetoxyethyl acetoxymethyl ether in the presence of stannic chloride as catalyst, followed by deblocking, gave three products,1, 2 and 3, respectively.     

Synthesis of the Pheromones, (E)-3, 7-Dimethyl-2, 7-Octadienyl Propionate, (E)-3, 7-Dimethyl-2-Octene-1, 8-Diol and Frontalin from a Common Intermediate1

Ketal ester 9 has been prepared in five steps from methyl levulinate 4 (scheme 1). The propionate 1, diol 2 and (±) frontalin 3 were prepared from ester 9 employing the routes shown in scheme 2,3 and 4 respectively. The branched chain alkenes 13 and 20 were prepared conveniently from the primary alcohols 11 and 10 following the procedure of S.Wolff. Triethyl phosphonopropionate 7 has been prepared by methylating triethylphosphonoacetate with methyl iodide in the presence of sodium hydride.     

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.     

Oxygenation of Trimethylsilylallenes Readily Obtainable from Organoboranes. Syntheses of 1-Trimethylsilyl-1-alkyn-3-ones and 1-Trimethylsilyl-1-alkyn-3-ols

Abstract

Recently we have reported that the reaction of sodium methoxide with ate-complexes (1) readily prepared from trimethyl-silylpropargyl phenyl ether and organoboranes gives trimethyl-silylallenes (2) selectively (eq. 1).¹ In an attempt to find a new synthetic application of such silylallenes (2), the oxidation of 2 was examined. Although the usual oxidants such as m-chloro-perbenzoic acid were found to be unsuitable for the oxidation of the silylallenes, it was discovered that 2 was autoxidized at room temperature to propargylic hydroperoxide (3) (eq. 2). For example, the acidified starch-iodine test² strongly suggested the presence of the organic hydroperoxide in the reaction mixture obtained from 1,2-heptadienyltrimethylsilane (2, R=Bu) and oxygen. The hydroperoxide (3, R=Bu) was isolated in a 40% yield by distillation, 45–48 [ddot]C/0.1 mmHg. In the infrared spectrum, the OH stretching frequency appears at 3430 cm^?1 and the C°C at 2180 cm,^?1     

Oxidation of 4-Oxo-4H-1-Benzopyran-3-Carboxaldehydes with N-Bromosuccinimide

4-Oxo-4-H-1-benzopyran-3-carboxylic acids and their derivatives (esters and amides), 2, are known to possess interesting pharmacological activities.¹ As part of our synthetic studies of biologically active compounds, we needed to prepare a variety of 2 (carboxylic acids, esters, amides, etc.). An elegant method for the preparation of 4-oxo-4H-1-benzopyran-3-carboxaldehydes, 1, was reported independently by Nohara et al. ² and Harnish.³ However, despite a rather extensive effort by Nohara et al., the oxidation of 1 to 2 (Y=OH) has not been realized in good yield; thus the yields by Jones oxidation, the best reported method, ranged only from 9.5 to 39%.⁴     

Reaction of Aziridinones with 2-Lithio-1, 3-Dithiane: Selective Cleavage of the Aziridinone Ring

The reaction of aziridinones (1a-1d) with tert-butyllithium at room temperature affords α-hydroxy imines (5ax-5dx).¹ One possible pathway leading to these products involves the formation of 2 as an intermediate, followed by rearrangement to 3. In fact, under carefully controlled conditions that prevent the rearrange-of 2 to 3, α-amino ketones (4ax-4dx), which arise from the protonation of 2, can be isolated. Other α-amino ketones were synthesized in a like manner from aziridinones by treatment with a variety of alkyllithium reagents.² Baumgarten and co-workers³ subsequently reported similar products from the reaction of phenyllithium and methyllithium with an aziridinone. In an attempt to extend this study to other organolithium reagents, especially those bearing functional groups, we have investigated the reaction of     

An Efficient and Unambiguous Synthesis of 2-Hydroxymethyl-1, 3-Propanediol

In 1949, Fujui³ reported the synthesis of what was presumed to be 2-hydroxymethyl-1, 3-propanediol (4) in 70% yield by the condensation of acetaldehyde with formaldehyde (1:2.5 molar ratio) in the presence of calcium hydroxide, and subsequent catalytic hydrogenation over a nickel catalyst. The product was reported to have a melting point of 182°. In 1955, the triester tris-(carbethoxy) methane (5) was reduced with lithium aluminum hydride to give a product with a reported melting point of 58–62°; the yield was only 5%.⁴ Owing to the conflicting data in the literature and the vast potential of 4; we have developed an efficient and unambiguous route to 4; this scheme is also adaptable to clean conversions to mono-, di- and tri-O-substituted derivatives of 4:     

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.     

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.     

N-(Chlorosulfinyl)-Imidazole as a New Imidazole Transfer Reagent1

The usefulness of diimidazoles² such as N, N′-carbonyldi-imidazole (1), and N, N′-thionyldiimidazole (2) in organic synthesis has been accumulated recently. In connection with the continuing our studies on the reaction using 1 or 2 ³ (carbonyl, thionyl, and imidazole transfer reactions), our particular interest was focused on the synthesis of N-(chlorosulfinyl)-imidazole (3) in which one imidazole group in 2 was replaced by the other leaving group (Cl). Also, 3 was interesting for preparative purposes as a chlorine atom could be introduced via the addition reaction of 3 to carbonyl compounds as known in the reaction of 1 or 2 with ketones.     

Condensation Op 3-Acetyl-and 3-Acetyl-4-Methyl-2H-1-Benzopyran-2-One with Aromatic Adehydes

The reactivities of 3-acetyl-2H-1-benzo-pyran-2-one (2) and 3-acetyl-4-methyl-2H-1-benzopy-ran-2-one (3)are compared in the condensation with aromatic aldehydes. It is established that the benzopyrones 2 and 4 condense with various aromatic aldehydes in chloroform containing some drops of piperidine by boiling for 7 hours and azeotropic distillation of water, yielding 3-cinnamoyl-2H-1-benzopyran-2-ones (3a-g) and 4-(2-arylvinyl)-3-acetyl-2H-1-benzopyran-2-ones (6a-f), respectively. Evidence is provided that benzopyrone 4 participates in the condensation with the methyl group in position 4. A probable mechanism of the process is proposed.     

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     

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 2-Methyl-3-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine

For our synthetic work we needed the title compound. Literature survey revealed that 2-amino-4-oxo-4H-[1] benzopyran-3-carboxaldehyde (2-amino-3-formylchro-mone) can undergo condensation with diethyl malonate (or ethyl cyanoacetate) forming ethyl 2-hydroxy(or amino)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate¹.     

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.     

An Allylic Rearrangement Arising from Reaction of Fluoride Ion and A 3-Chloro, 4,5-Unsaturated Uronate Derivative

Reaction of methyl [benzyl 2-[(benzyloxycarbonyl)-amino]-3-chloro-2,3,4-trideoxy-β-L-threo-hex-4-enopyrano-sid]uronate,3,4-trideoxy-β-L-threo-hex-4-enopyranosidjuronate (7) with silver fluoride gave the 5-fluoro, 3,4-unsaturated uronate derivative 8, which, on treatment with methanolic ammonia, afforded the corresponding 5-meth-oxy, uronamide 9. The structures of 8 and 9 were confirmed by spectral data and by x-ray crystallographic analysis of 8. ¹H NMR spectroscopy parameters for 9 and its diastercomen 11 have been used to probe the conformational preferences in solution.