Enantioselective synthesis of (2R,4'R,8'R)-alpha-tocopherol (vitamin E) based on enzymatic function

Syntheses of (S)-chroman-2-carboxaldehyde congener 1 and (S)-chiral isoprene unit 3 were achieved based on the enzymatic acetylation of (+/-)-chroman-2-methanol 6 and (+/-)-(2,3)-anti-2-methyl-3-(p-methoxyphenyl)-1,3-propane diol 12, respectively. Synthesis of the side-chain part corresponding to (3R,7R)-3,7,11-trimethyldodecan-1-ol 27 was achieved by the coupling reaction of (S)-3 and (R)-3,7-dimethyloctyl iodide 4. The Wittig reaction of (3R,7R)-phosphonium salt 2 derived from (3R,7R)-27 and (S)-1 gave the olefin 28 which was subjected to catalytic hydrogenation to afford (2R,4'R,8'R)-alpha-tocopherol.     

Azines and Azoles: CXXI. Alkylation of 5,7-Dihydro-4H-pyrano[2,3-d:6,5-d']- dipyrimidine-4,6(3H)-dione and Its 5-Phenyl Derivative

Methylation of 5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(3H)-dione and its 5-phenyl analog with dimethyl sulfate in the presence of LiOH in aqueous solution gives rise to the corresponding 3,7-dimethyl derivatives. The same isomers are formed by methylation of 5-phenyl-5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(3H)-dione with methyl iodide in the presence of K2CO3 in N,N-dimethylacetamide. However, with ethyl bromide, propyl iodide, or butyl bromide instead of methyl iodide, mixtures of 3,7- and 1,7-dialkyl-5-phenyl-5,7-dihydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6-diones were obtained.     

Synthesis of 2-butyl-4,9-decadienoic and 2-butyl-4,9-dimethyl-4,9-decadienoic acids,structural analogues of cygerol

2-Butyl-4,9-decadienoic and 2-butyl-4,9-dimethyl-4,9-decadienoic acids, structural isomers of 2-cyclohexylgeranylacetic acid, which is an active component of the wound healing ointment cygerol, have been synthesized. Hydrocarbon chains C₁₀ have been obtained by the one-pot method of formation of long-chain hydrocarbons, namely, by the telomerization reaction of 1,3-dienes with nucleophiles catalyzed by palladium complexes. A heterogeneous palladium-zeolite catalyst has been used for the first time in telomerization of isoprene with piperidine.     

Nickel(II) Complexes of 1‐Alkyl‐1‐azonia‐3,5‐diaza‐7‐phosphatricyclo[3.3.1.13,7]decane – Synthesis and Solid‐State Structures

Complexes [NiI₃(mpta)₂]I ( 1 ) and [NiI₃(ppta)₂]I ( 2 ) have been synthesized by reaction of nickel(II) halide salts with ‐1‐methyl‐1‐azonia‐3,5‐diaza‐7‐phosphatricyclo[3.3.1.1^3,7]decane iodide (mpta⁺I^?) and 1‐(n‐propyl)‐1‐azonia‐3,5‐diaza‐7‐phosphatricyclo[3.3.1.1^3,7]decane bromide (ppta⁺Br^?) respectively. The crystal structures of compounds 1 and 2 are described and are similar, with both compounds crystallizing in monoclinic space groups. The geometry about both nickel atoms is that of a trigonal bipyramid with the cationic phosphine ligands found in the axial positions and the iodide ligands arranged in the equatorial plane.     

Telomerization and dimerization of isoprene by in situ generated palladium-carbene catalysts

The palladium-catalyzed telomerization of isoprene with methanol and dimerization of isoprene have been studied in presence of in situ generated palladium-carbene catalysts. Unprecedented catalyst productivity has been observed for these two reactions. A selectivity switch from the telomer to the dimer product occurred by using different substituted carbene ligands. Among the imidazolium salts tested 1,3-dimesitylimidazolium mesylate (1), 1,3-dimesityl-4,5-dihydroimidazolium chloride (3) gave the best yields for telomerization reaction whereas 1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazolium tetrafluoroborate (5) and 1,3-bis-(2,6-diisopropylphenyl)-4,5-dimethyl-4,5-dihydroimidazolium chloride (9) form dimers in high yield and good selectivity.     

Cyclization of ylidenemalononitriles. X. Synthesis of benzazapropellane derivatives from α-Cyano-β-chloroalkylcinnamonitriles

The reaction of nucleophilic and non-nucleophilic bases wtih 2-carbamoyl-3-(γ-chloropropyl)-1-indenone ( 5 ) have been investigated. Condensation of γ-chlorobutyrophenone with malono-nitrile afforded α-cyano-β-(3-ehloropropyl)cinnamonitrile which was cyclized in concentrated sulfurie acid to produce 5 . Two other products obtained from the cyclization reaction were 2-carbamoyl-3-(γ-ehloropropylidene)-1-indanone ( 4 ) and α-carbamoyl-β-(3-chloropropyl)cinnam-amide. Treatment of a solution of 4 in ethyl acetate with piperidine resulted in cyclization of the γ-chloropropyl side chain to give 2-carbamoyl-3-cycIopropyl-1-indanone. The same compound was obtained in improved yield by the treatment of 4 or 5 with sodium hydroxide solution. The reaction of dirnethylamine with 5 in benzene gave initial Michael addition of the amine followed by internal alkylation of the carbanion so formed to yield 3a-dimethylamino-2,3,3a,8-tetrahydro-8-oxoeyclopent[a]indene-8a(lH)earboxamide ( 7a ). Similarly addition of ammonia, pyrrolidine, piperidine, benzenethiol, p-toluenethiol, 2-naphthalenethiol and nitromethane to the indenone I gave respective analogs of type 7 . Treatment of 5 with sodium cyanide in aqueous t-butyl alcohol resulted in a similar Michael addition followed by internal alkylation. In addition, cyclization between the nitrile and the carbamoyl functions occurred in the same step to give 2-oxo-4-imino-7,8-benzo-3-aza[3.3.3]-propellan-6-one ( 13a ). Hydrolysis of the iminopyrrolido ring in 13a to the corresponding suecin-irnide gave 2,4-dioxo-7,8-benzo-3-aza[3.3.3]propellan-6-one ( 13b ). Reactión of 13b with methyl iodide, allyl bromide, benzyl bromide, and diethyluminoethyl chloride afforded the corresponding N-alkylated products. A similar sequence starling with δ-ehlorovalerophenone led to 5,6-fused ring systems, including a [4.3.3]propellane. 2,9-Dioxo-4-methyl-7,8-benzo-3-aza[4.3.3]propell-4-ene was obtained by the reaction of 5 with acetone in dilute alkali.     

7-Substituted 8-vinyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diones and their broncholytic activity

Summary Alkylation of 8-vinyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (1) with alkyl halides inDMF in the presence of potassium carbonate, or alternatively, alkylation of its sodium salt (2) with alkyl iodide or hydroxyalkyl iodide afforded the 7-alkyl- or 7-(-hydroxyalkyl)-8-vinyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diones3. 2-Substituted oxiranes reacted with1 catalyzed by2 or Triton B to yield 7-(2-hydroxyalkyl)-8-vinyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-diones4. Compounds3 and4 were tested for broncholytic activity. The most effective derivatives were3c and4b.

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7-Substituierte 8-Vinyl-1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dione und ihre broncholytische Wirkung

Zusammenfassung Alkylierung von 8-Vinyl-1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dion (1) mit Halogenalkanen in Gegenwart von Kaliumkarbonat inDMF oder Alkylierung seines Natrium-Salzes (2) mit Iodalkanen beziehungsweise Iodalkanolen führte zu den 7-Alkyl- bzw. 7-(-Hydroxyalkyl)-8-vinyl-1,3-dimethyl-3,7-dihydro-1H-purin-2,6-dionen3. 2-Substituierte Oxirane reagierten mit Verbindung1 unter Katalyse durch2 oder Triton B zu den entsprechenden 7-(2-Hydroxyalkyl)-derivaten4. Die Substanzen3 und4 wurden auf ihre broncholytische Wirkung geprüft. Die höchste Aktivität wurde bei den Derivaten3c und4b festgestellt.

     

Acyl iodides in organic synthesis. Reactions with morpholine,piperidine, and <Emphasis Type="Italic">N</Emphasis>-hydrocarbylpiperidines

Acyl iodides RCOI (R = Me, Ph) reacted with morpholine and piperidine to give the corresponding N-acyl derivatives and morpholine or piperidine hydroiodides. Reactions of acyl iodides with N-methyl- and N-ethylpiperidines involved cleavage of the exocyclic R-N bond with formation of N-acylpiperidine and alkyl iodide and were accompanied (to insignificant extent) by cleavage of the endocyclic N-C bond, leading to N-alkyl-N-(5-iodopentyl)acylamides. In the reaction of acetyl iodide with N-phenylpiperidine, the main process was cleavage of just endocyclic N-C bond to produce N-(5-iodopentyl)-N-phenylacetamide and its dehydroiodination product, N-(pent-4-en-1-yl)-N-phenylacetamide. Analogous reaction with benzoyl iodide afforded N-(5-iodopentyl)-N-phenylbenzamide in a poor yield.     

Low-Spin and High-Spin Perferryl Intermediates in Non-Heme Iron Catalyzed Oxidations of Aliphatic C−H Groups

The selectivity patterns of iron catalysts of the Fe(PDP) family in aliphatic C−H oxidation with H₂O₂ have been studied (PDP=N,N′-bis(pyridine-2-ylmethyl)-2,2′-bipyrrolidine). Cyclohexane, adamantane, 1-bromo-3,7-dimethyloctane, 3,7-dimethyloctyl acetate, (−)-acetoxy-p-menthane, and cis-1,2-dimethylcyclohexane were used as substrates. The studied catalyst systems generate low-spin (S=1/2) oxoiron(V) intermediates or high-spin (S=3/2) oxoiron(V) intermediates, depending on the electron-donating ability of remote substituents at the pyridine rings. The low-spin perferryl intermediates demonstrate lower stability and higher reactivity toward aliphatic C−H groups of cyclohexane than their high-spin congeners, according to the measured self-decay and second-order rate constants k₁ and k₂. Unexpectedly, there appears to be no uniform correlation between the spin state of the oxoiron(V) intermediates, and the chemo- and regioselectivity of the corresponding catalyst systems in the oxidation of the considered substrates. This contrasts with the asymmetric epoxidations by the same catalyst systems, in which case the epoxidation enantioselectivity increases when passing from the systems featuring the more reactive low-spin perferryl intermediates to those with their less reactive high-spin congeners.     

Synthesis and reactions of 1-[1-oxido-2-(3,4)-pyridinyl]-2-methyloxiranes with nitrogen nucleophiles

Reaction of 2(3,4)-pyridinecarboxaldehydes (5) with ethylidenetriphenylphosphorane afford a mixture of stereoisomers Z-( 6 ) and E-1-[2(3,4)-pyridinyl]-1-propenes ( 7 ). m-Chloroperbenzoic acid oxidation of 6 and 7 yields a 60:40 mixture of Z-( 8 ) and E-1-[1-oxido-2(3,4)-pyridinyl]-2-methyloxiranes ( 9 ). The regiospecific reaction of Z-isomers 8a-c with cyclic amines as piperidine give rise to threo-1-hydroxy-1-[1-oxido-2(3,4)-pyridinyl]-2-(1-piperidino)propanes ( 10 ) while the E-isomer 9a yields erythro- 11 . On tho other hand, the E-isomers 9b and 9c having 1-oxido-3(4)-pyridinyl substituents afford erythro- 12 resulting from attack by piperidine at C-1 of the oxirane. Reductive deoxygenation using 10% palladium on charcoal and hydrogen gas effectively removed the N-oxide substituent from the threo- 10 and erythro- 11 β-aminoalcohols. Dilute solution ir spectroscopy indicated the existance of strong intramolecular hydrogen bonding in the β-aminoalcohols 10 and 11 . The assignment of relative configuration of diastereoisomers 10 and 11 was based on the magnitude of the vicinal coupling constant J where J threo is greater than J erythro.     

Synthesis of α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetic acid derivatives

α-(Aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate, 3 and 8 , have been synthesized by catalytic hydrogenation of 6-cyanomethylene-9-methoxymethylpurine derivatives 2 and 7 which were obtained by the substitution of 6-chloro-9-(methoxymethyl)purine ( 1 ) with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of 3 and 8 with amines gave the corresponding N-substituted α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate 4 and 10 . Reaction of 3 with piperidine gave 9-(methoxymethyl)-9H-purine-6-acetamide ( 5 ).     

Synthesis of a Glucose-Derived Tetrazole as a New β-Glucosidase Inhibitor. A New Synthesis of 1-Deoxynojirimycin

The tetrazole 1 is a new β-glucosidase inhibitor (IC₅₀=8·10^?5 M , Emulsin), obtained (92%) by deprotection of 22 , the product of an intramolecular cycloaddition of the azidonitrile 20 . This azidonitrile was formed as an intermediate by treating the L -ido-bromide 14 or the L -ido-tosylate 19 with NaN₃ at 110–120°. It was isolated in a separate experiment. The yield of 22 from 19 reached 70%; 21 was formed as by-product (10%). The bromide 14 (42%) and the iodide 15 (30–35%) were obtained from the nitrile 13 , together with the 2,5-anhydro-L -idononitrile 16, which was formed in ca. 35–45%. The tosylate 19 was obtained from 18 (97%). To obtain 18 , the nitrile 13 was oxidized according to Swern (→17, 92%) and then reduced (NaBH₄, CeCl₃), leading to 18 and 13 (92%, 18/13 93:7). Reduction of the tetrahydropyridotetrazole 22 with LiAlH₄ afforded 83 % of the piperidine 23 , which was deprotected to (+)-1-deoxynojirimycin hydroacetate (2·AcOH, 86%) and further converted into the corresponding hydrochloride and into the free base 2 .     

An asymmetric synthesis of α-tocopherol side chain

A stereospecific synthesis of (3R,7R)?3,7,11-trimethyldodecanal (2) with highly optical purity was achieved by utilizing the coupling reaction of the amino sulfone (9) with(R)?3,7-dimethyloctyl magnesium bromide (7), and the asymmetric isomerization of the resulting(E)-allylic amine (10).     

Favorskii Rearrangement in the Reaction of 3-(1-Adamantyl)-1-chloro-2-propanone with Amines

The reaction of 3-(1-adamantyl)-1-chloro-2-propanone with amines [diethylamine, (1-adamantyl)methylamine, p-toluidine, and piperidine] in diethyl ether at room temperature involves the Favorskii rearrangement and yields N,N-disubstituted amides of 3-(1-adamantyl)propanoic acid.     

Investigating the mechanism of 1,3,5-cycloheptatriene formation: Condensation of 1-methylethyl 3-oxo-4-(triphenylarsoranylidene)butanoate with 7-methoxy-3,7-dimethyloctanal

Condensation of [3-(1-methylethoxycarbonyl)-2-oxopropyl]triphenylarsonium bromide 8 with 7-methoxy-3,7-dimethyloctanal 10 in the presence of a base gave bis(1-methylethyl) 4,7-dihydroxy-2-(6-methoxy-2,6-dimethylheptyl)-3,5,7-cycloheptatriene-1,3-dicarboxylate 7b. The formation of 7b can be explained by a number of consecutive steps. The mechanism, strongly supported by liquid secondary ion mass spectrometry, suggests that an aldol condensation of the γ-arsonium ylide 2b and the aldehyde 10 takes place as the initiating step and is followed by a Michael addition of the aldol product and the γ-arsonium ylide 2b. Then an intramolecular nucleophilic substitution and elimination of triphenylarsine, followed by base-catalyzed elimination of a second molecule triphenylarsine takes place to produce 7b. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:411–418, 1998     

Synthesis of macrolides containing an azine or hydrazide fragment via successive tishchenko disproportionation and [1 + 1]-condensation

Eight potentially useful 15-, 17-, 20-, and 22–25-membered macrolides having an azine or hydrazide fragment were synthesized starting from L-menthol, tetrahydropyran, and 4-methyltetrahydropyran via [1 + 1]-condensation of hydrazine hydrate and some dicarboxylic dihydrazides with 7-oxooctyl 7-oxooctanoate, 3-methyl-7-oxooctyl 3-methyl-7-oxooctanoate, and (3R)-3,7-dimethyl-6-oxooctyl (3R)-3,7-dimethyl-6-oxooctanoate obtained by the Tishchenko reaction from 7-oxo-, 3-methyl-7-oxo, and (3R)-3,7-dimethyl-6-oxooctanals, respectively.     

C(1)-Phenethyl Derivatives of [closo-1-CB11H12]− and [closo-1-CB9H10]− Anions: Difunctional Building Blocks for Molecular Materials

C(1)-vinylation of [closo-1-CB₉H₁₀]⁻ ( A ) and [closo-1-CB₁₁H₁₂]⁻ ( B ) with 4-benzyloxystyryl iodide followed by hydrogenation of the double bond and reductive deprotection of the phenol functionality led to C(1)-(4-hydroxyphenethyl) derivatives. The phenol functionality was protected as the acetate. The esters were then treated with PhI(OAc)₂ and the resulting isomers were separated kinetically (for derivatives of anion A ) or by chromatography (for derivatives of anion B ) giving the difunctionalized building blocks in overall yields of 9 % and 50 %, respectively. A similar series of reactions was performed starting with anions A and B and 4-methoxystyryl bromide and iodide. Significant differences in the reactivity of derivatives of the two carborane anions were rationalized with DFT computational results. Application of the difunctionalized carboranes as building blocks was demonstrated through preparation of two ionic liquid crystals. The extensive synthetic work is accompanied by single crystal XRD analysis of six derivatives.     

Photochemistry synthesis. Part 1: Syntheses of xanthine derivatives by photolysis of 1-(5′-oxohexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (pentoxifylline): an ambident chromophore

We investigated the use of photochemistry to make novel derivatives of pentoxifylline. Under conditions that favour singlet excited states, we obtained 1-allyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione, (R^∗,R^∗)-(±)-1-{[2-hydroxy-2-methylcyclobutyl]methyl}-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione and 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione. Naphthalene or molecular oxygen increases the yields and triplet sensitisers (acetophenone, benzophenone and acetone) decrease the yields. Efficient intramolecular triplet energy transfer from the carbonyl to the xanthine moiety allows the carbonyl moiety to react from a singlet excited state only. In solvents with an α-hydroxyalkyl hydrogen under conditions that favour triplet excited states, we obtained 8-substituted pentoxifylline derivatives: 8-(1-hydroxy-1-methylethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione in isopropanol, 8-(1-hydroxymethyl)-3,7-dimethyl-1-(5-oxo-hexyl)-3,7-dihydro-1H-purine-2,6-dione in methanol and 8-(1-hydroxyethyl)-3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione in ethanol. The xanthine moiety reacts from a triplet state via a radical mechanism and yields are considerably improved by the addition of catalytic amounts of di-tert-butyl peroxide.     

Transformations of 1-amino-2-(3-hydroxyalk-1-ynyl)-9,10-anthraquinones in the presence of amines

When heated in piperidine, 1-amino-2-(3-hydroxyalk-1-ynyl)-9,10-anthraquinones undergo cyclization into 2-(1-hydroxyalkyl)naphtho[2,3-g]indole-6,11-diones. In contrast, 1-amino-2-(3-hydroxy-3-phenylpropynyl)-9,10-anthraquinone reacts with primary and secondary amines to give the corresponding 1-amino-2-(1-amino-2-benzoylvinyl)-9,10-anthraquinones, which undergo cyclization into 4-dialkylamino- or 4-alkylamino-2-phenylnaphtho[2,3-h]quinoline-7,12-diones. Heating of the starting phenylpropynol with Et₃N causes its dehydrogenation and isomerization.     

Plant coumarins. 4.* Synthesis of <Emphasis Type="Italic">N</Emphasis>-containing derivatives of oreoselone

Bromination of peucedanin by various reagents was studied. Conditions for forming 2-(1,3-dibromopropan-2-ylidene)-2H-furo[3,2-g][1]benzopyran-3,7-dione were found. Several 2-aminofuranocoumarins were synthesized by reaction of 2-bromoreoselone with derivatives of pyrrolidine, piperidine, and piperazine. The new compounds were interesting as potential biologically active compounds. *For Part 2, see [1]. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 289–294, May–June, 2009.