Efficient synthesis and biological activity of enantiomeric pairs of thiolactomycin and its 3-demethyl derivative

The title total synthesis was achieved by employing deconjugative asymmetric α-sulfenylation of the chiral 3-(α,β,γ,δ-unsaturated acyl)oxazolidin-2-one with a 3,3-dimethoxypropyl methanethiosulfonate as a key step. From the biological activity assay carried out using the title compounds, it appeared evident that in vitro antibacterial and mammalian type I FAS inhibitory activity can be cleanly separated by changing not only the substituent at the C₃-position but also the absolute configuration at the C₅-position, and that unnatural (S)-(−)-3-demethylthiolactomycin and its congeners might be usable as selective mammalian type I FAS inhibitors.     

Long branching in poly(vinyl acetate) and poly(vinyl alcohol). III. Kinetic study of the branching reaction in the radical polymerization of vinyl acetate

The branching reaction in the radical polymerization of vinyl acetate was studied kinetically. Branching occurs by polymer transfer as well as terminal double-bond copolymerization. The chain-transfer constants to the main chain (C_p,2) and to the acetoxy methyl group (C_p,1) on the polymer were calculated on the basis of the experimental data described in the preceding paper giving C_p,2 = 3.03 × 10^?4, C_p,1 = 1.27 × 10^?4 at 60°C, and C_p,2 = 2.48 × 10^?4, C_p,1 = 0.52 × 10^?4 at 0°C. Chain transfer to monomer is important with respect to the formation of the terminal double bond. The total values of transfer constants to the α- or β-position in the vinyl group and the acetoxymethyl group in vinyl acetate was determined to be 2.15 × 10^?4 at 60°C. The transfer constant to the acetyl group in the monomer (C_m,1) was also evaluated to be 2.26 × 10^?4 at 60°C from the quantitative determination of the carboxyl terminals in PVA. These facts suggest that the chain-transfer constant to the α- or β-position in the monomer (C_m,2) is nearly equal to zero within experimental error. Copolymerization reactivity parameters of the terminal double bond were also estimated. In conclusion, it has become clear that the formation of nonhydrolyzable branching by the terminal double-bond reaction can be almost neglected, and hence that the long branching in PVA is formed only by the polymer transfer mechanism. On the other hand, a large number of hydrolyzable branches in PVAc are prepared by the terminal double-bond reaction rather than by polymer transfer.     

Über die Dicyanierung der 1,4-Diaminoanthrachinone und die Reaktivität der 1,4-Diamino-9,10-dihydroanthracen-2,3-dicarbonitrile gegenüber nucleophilen Reagenzien 3. Mitteilung über Arylierungen und Heterocyclisierungen von Anthrachinonsystemen

The Dicyanation of 1,4-Diaminoanthraquinones and the Reactivity of 1,4-Diamino-9,10-dioxo-9,10-dihydroanthracene-2,3-dicarbonitriles towards Nucleophilic Reagents The reaction of 1-amino-9, 10-dioxo-4-phenylamino-9,10-dihydroanthracene-2-sulfonic acid ( 1 , R?C₆H₅) with cyanide in water yields a mixture of 1-amino-9,10-dioxo-4-phenylamino-9,10-dihydroanthracene-2-carbonitrile ( 3 , R ? C₆H₅) and 1-amino-4-(phenylamino)anthraquinone ( 4 , R ? C₆H₅) under the usual reaction conditions (Scheme 1). In dimethylsulfoxide, however, a second cyano group is introduced, and 1-amino-9,10-dioxo-4-phenylamino-9,10-dihydroanthracene-2,3-dicarbonitrile (7) is formed (Scheme 2). The cyano groups are very reactive towards nucleophiles. The cyano group in 2-position can be substituted by hydroxide and aliphatic amines (Schemes 5 and 6). The cyano group in 3-position can be eliminated by aliphatic amines and hydrazine (Scheme 7). Nucleophilic attack at the cyano C-atom of the 2-cyano group by suitable reagents leads to ring formation, yielding e.g. 2-(Δ²-1, 3-oxazolin-2-yl)-, 2-(benz[d]imidazol-2-yl)- and 2-(1H-tetrazol-5-yl)anthraquinones (Schemes 8 and 10).     

An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of (R)-[α-2H]-phenylalanine methyl esters

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C₆-position affording its corresponding (S)-[6-²H₂]-isotopomer in excellent yield with no loss of stereochemical integrity at its C₃-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-²H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-²H]-phenylalanine methyl esters as hydrochloride salts in good yield.     

Intramolekularer ligandenaustausch in einkernigen heterodien-eisentricarbonylkomplexen

The intramolecular CO-exchange in several dieneiron tricarbonyls with heteroatoms in 1- and/or 4-position is studied by temperature dependent ¹³C NMR spectroscopy. π, π-Bonded polar dienes show the highest barriers (10–14 kcal mol^?1, while the investigated σ,π- and σ,σ-diazadiene chelates have barriers of activation <9 kcal mol^?1. This is in agreement with the local C_3v-symmetry of the Fe(CO)₃ moiety in these complexes.     

Directive effect of a methyl substituent in the exchange reaction of ring hydrogen with molecular deuterium in dicyclopentadienyltitanium complexes

Hydrogenated (1-methylallyl)dicyclopentadienyltitanium(III) exchanges its ring hydrogen atoms with deuterium gas. The deuterated complex can be oxidized with hydrogen chloride and air to (C₅D₅)₂TiCl₂. In the related methyl-substituted complex, obtained by hydrogenation of allylbis(methylcyclopentadienyl)titanium(III), only the ring hydrogen atoms in β-position to the methyl substituent exchanged with deuterium, the hydrogen in α-position to the substituent proved to be relatively unreactive. In the exchange reaction, an intermediate is proposed having a structure with a bridged π- as well as σ-bonded C₅H₄ or C₅H₃CH₃ group.     

Mass spectrometric decomposition processes of 2-methyl-1-hexene

Unimolecular decompositions of 2-methyl-1-hexene and several labelled analogues were studied following 70 eV electron impact (normal and metastable spectra) and field ionization (field ionization kinetic measurements). Molecules labelled with ¹³C in the 1-position and the methyl position were found to behave essentially identically. This is attributed to rapid transfer of a hydrogen atom mainly from C-5 to C-1 (γ-hydrogen shift). Loss of ethene, propene or propenyl do not involve loss of the methyl carbon or C-1. All three reactions are better than 90% specific in this respect under all conditions studied. At shorter times, C₃H₆ loss is the dominant reaction, while at longer times C₂H₆ loss accounts for >90% of the ion current. It is proposed that at least two distinct pathways for C₂H₄ loss operate in linear 1-alkenes, one of which (loss of carbons 1 and 2) is blocked by a 2-methyl substituent. The [C₆H₁₁]^+˙ and [C₅H₁₀]^+˙ ions formed from ¹³C labelled 2-methyl-1-hexenes fragment in an essentially statistical fashion.     

On the reactivity of μ2-acetylenes coordinated to cobalt : II. Regiospecifity of the carbonylation of internal acetylenes

The μ₂-carbonyl- μ₂-spiro(2,3-substituted-2-butene-4-olide-4-ylidene)bis(tricarbonylcobalt)(CoCo), Co₂(CO)₇(C₄O₂R¹R²), “lactone” complexes were prepared from internal acetylenes. It was found that the reaction is regiospecific; in the products from an asymmetric internal alkyne the sp carbon atom which had the higher value of the ¹³C NMR chemical shift (δ) occupied the 2-, while that with the lower δ value the 3-position of the lactone ring. fa]For Part I, see ref. 1. Some results or this work were presented at the Annual Meeting of the Hungarian Chemical Society (MKE Vegyészkonferencia), Aug. 23–26, 1977. Debrecen. Abstracts (Elöadások összefoglalói) p. 156     

Synthesis of potential antimalarials

A series of quinoline derivatives containing a 2-thienyl ring in the 2-position and CO₂H, CH₂OH, CHO, CH(OH)CN, CH(OH)CO₂H, CO₂C₂H₅, COCH[N(C₂H₅)₂]CO₂C₂H₅, COCH₂N(C₂H₅)₂, COCH₃, substituents in the 4-position was synthesized. Both intermediate and target compounds were tested for antimalarial activity. A second series with a 5-bromo-2-thienyl group in the 2-position and CHOHCH₂N(C₂H₅)₂, CHOHCH₂N(CH₂)₆, and CHOHCH₂N(CH₂C₆H₅)₂ substituents in the 4-position was also prepared, it was found that, although these quinoline methanols were moderately active antimalarials, they exhibited a high degree of phototoxicity. A third series of compounds with 2-alkyl substituents (methyl, t-butyl) was also synthesized, and these were found to combine a modest degree of antimalarial activity with low phototoxicity. Several novel synthetic routes to the above compounds were developed and are detailed.     

Shedding Light on the Diverse Reactivity of NacNacAl with N-Heterocycles

The aluminum(I) compound NacNacAl (NacNac=[ArNC(Me)CHC(Me)NAr]⁻, Ar=2,6-iPr₂C₆H₃, 1 ) shows diverse and substrate-controlled reactivity in reactions with N-heterocycles. 4-Dimethylaminopyridine (DMAP), a basic substrate in which the 4-position is blocked, induces rearrangement of NacNacAl by shifting a hydrogen atom from the methyl group of the NacNac backbone to the aluminum center. In contrast, C−H activation of the methyl group of 4-picoline takes place to produce a species with a reactive terminal methylene. Reaction of 1 with 3,5-lutidine results in the first example of an uncatalyzed, room-temperature cleavage of an sp² C−H bond (in the 4-position) by an Al^I species. Another reactivity mode was observed for quinoline, which undergoes 2,2′-coupling. Finally, the reaction of 1 with phthalazine produces the product of N−N bond cleavage.     

13C-NMR studies of polyfluorinated hydrocarbons,carboxylic acid derivatives,alcohols and ethers

δ¹³C values and coupling constants (¹J(¹³C¹H), ¹J(¹³C¹³C), ⁿJ(¹⁹F¹³C) are reported for 19 polyfluorinated organic compounds. It is shown that the shielding of carbon depends upon the number of fluorine atoms in α -position. If the R_F-group is linked to a π -system hyperconjugative $\text{and}$ η-π interaction accounts for the δ¹³C data. The values ¹J(¹³C¹H) and ¹J(¹³C¹³C) are in qualitative agreement with changes of the s-character of the respective bonds.     

Synthesis of optically active 2-fluoroalk-1-en-3-yl esters and chirality transfer in their Claisen-type rearrangements

A series of enantioenriched long chain 2-fluoroalk-1-en-3-ols 1 has been prepared by lipase-catalyzed resolution of the racemic compounds synthesized from terminal alkenes. The lipase of Candida antarctica was shown to be the most efficient one in terms of enantioselectivity. Transesterification of the fluorinated allylic alcohols 1 was superior over the hydrolysis in a phosphate buffer of the corresponding acetates 2. Lipase-catalyzed acetylation of allylic alcohols 1 in organic medium gave (S)-(−)-3-acetoxy-2-fluoroalk-1-enes of chain lengths C₁₀, C₁₆ and C₁₈ with 68-89% yield and 92-96% ee, while the remaining (R)-(+)-2-fluoroalk-1-en-3-ols were isolated with 54-96% yield and 72-86% ee. The absolute configuration was assigned by comparison of measured and calculated CD-spectra, and unambiguously by ¹H and ¹⁹F NMR spectroscopy using a modified Mosher's method. From the optically active fluorinated allylic alcohols 1 corresponding esters 2 such as propionates, 3,3,3-trifluoropropionates and Boc-glycinates were synthesized. These compounds were rearranged to 2-substituted 4-fluoroalk-4-enecarboxylic acids 3 applying modified conditions of the [3,3]-sigmatropic Ireland-Claisen rearrangement. While a complete chirality transfer from C-3 of the allylic esters to C-2 of the carboxylic acids or 2-amino acids, respectively, occurred in rearrangements of the propionates and Boc-glycinates, racemic 2-(trifluoromethyl)alk-4-enecarboxylic acids were formed from the allylic trifluoropropionates. The configurational lability of the latter products is caused by the strongly acidic proton in α-position to the trifluoromethyl and the carboxyl groups under the basic rearrangement conditions.     

Synthesis of homologously pure bacteriochlorophyll-e and f analogues from BChls-c/d via transformation of the 7-methyl to formyl group and self-aggregation of synthetic zinc methyl bacteriopheophorbides-c/d/e/f in non-polar organic solvent

Homologously pure methyl bacteriopheophorbides-e and f (BPhes-e/f_M) were prepared from modification of naturally occurring bacteriochlorophylls-c and d (BChls-c/d), respectively, by transformation of the methyl to formyl group at the 7-position. The absolute configuration of the 1-hydroxyethyl group at the 3-position of (Zn-)BPhes-e/f_M was determined from comparison with structurally known BChl-c/d epimers. Visible spectra of synthetic (Zn-)BPhe-c/d/e/f_M showed that the 7¹-oxidation and the 8²/12¹/20-methylation affected Soret, Q_x and Q_y bands of both the monomeric (in a polar organic solvent) and oligomeric species (in a non-polar solvent).     

Electrostatic Perturbations from the Protein Affect C−H Bond Strengths of the Substrate and Enable Negative Catalysis in the TmpA Biosynthesis Enzyme

The nonheme iron dioxygenase 2-(trimethylammonio)-ethylphosphonate dioxygenase (TmpA) is an enzyme involved in the regio- and chemoselective hydroxylation at the C¹-position of the substrate as part of the biosynthesis of glycine betaine in bacteria and carnitine in humans. To understand how the enzyme avoids breaking the weak C²−H bond in favor of C¹-hydroxylation, we set up a cluster model of 242 atoms representing the first and second coordination sphere of the metal center and substrate binding pocket, and investigated possible reaction mechanisms of substrate activation by an iron(IV)-oxo species by density functional theory methods. In agreement with experimental product distributions, the calculations predict a favorable C¹-hydroxylation pathway. The calculations show that the selectivity is guided through electrostatic perturbations inside the protein from charged residues, external electric fields and electric dipole moments. In particular, charged residues influence and perturb the homolytic bond strength of the C¹−H and C²−H bonds of the substrate, and strongly strengthens the C²−H bond in the substrate-bound orientation.     

Synthesis of an Isotopically Isomeric Mixture of 1,4,6,8-Tetramethyl[13C2]azulene and Its Thermal Reaction with Dimethyl Acetylenedicarboxylate

Sodium [1,3-¹³C₂]cyclopentadienide in tetrahydrofuran (THF) has been prepared from the corresponding labelled [¹³C₂]cyclopentadiene which was synthesized from ¹³CO₂ and (chloromethyl)trimethylsilane (cf. Scheme 10) according to an established procedure. It could be shown that the acetate pyrolysis of cis-cyclopentane-1,2-diyl diacetate (cis- 22 ) at 550 ± 5° under reduced pressure (60 Torr) gives five times as much cyclopentadiene as trans- 22 . The reaction of sodium [1,3-¹³C₂]cyclopentadienide with 2,4,6-trimethylpyrylium tetrafluoroborate in THF leads to the formation of the statistically expected 2:2:1 mixture of 4,6,8-trimethyl[1,3a-¹³C₂], -[2,3a-¹³C₂]-, and -[1,3-¹³C₂]azulene ( 20 ; cf. Scheme 7 and Fig. 1). Formylation and reduction of the 2:2:1 mixture [¹³C₂]- 20 results in the formation of a 1:1:1:1:1 mixture of 1,4,6,8-tetramethyl[1,3-¹³C₂]-, -[1,3a-¹³C₂]-, -[2,3a-¹³C₂]-, -[2,8a-¹³C₂]-, and -[3,8a-¹³C₂]azulene ( 5 ; cf. Scheme 8 and Fig. 2). The measured ²J(¹³C, ¹³C) values of [¹³C₂]- 20 and [¹³C₂]- 5 are listed in Tables 1 and 2. Thermal reaction of the 1:1:1:1:1 mixture [¹³C₂]- 5 with the four-fold amount of dimethyl acetylenedicarboxylate (ADM) at 200° in tetralin (cf. Scheme 2) gave 5,6,8,10-tetramethyl-[¹³C₂]heptalene-1,2-dicarboxylate ([¹³C₂]- 6a ; 22%), its double-bond-shifted (DBS) isomer [¹³C₂]- 6b (19%), and the corresponding azulene-1,2-dicarboxylate 7 (18%). The isotopically isomeric mixture of [¹³C₂]- 6a showed no ¹J(¹³C,¹³C) at C(5) (cf. Fig. 3). This finding is in agreement with the fact that the expected primary tricyclic intermediate [7,11-¹³C₂]- 8 exhibits at 200° in tetralin only cleavage of the C(1)? C(10) bond and formation of a C(7)? C(10) bond (cf. Schemes 6 and 9), but no cleavage of the C(1)? C(11) bond and formation of a C(7)? C(11) bond. The limits of detection of the applied method is ≥96% for the observed process, i.e., [1,3a-¹³C₂]- 5 + ADM→ [7,11-¹³C₂]- 8 →[1,6-¹³C₂]- 9 →[5,10a-¹³C₂]- 6a (cf. Scheme 6).     

Derivate des borabenzols: XVI. (Borinato)(cyclobutadien)cobalt-komplexe mit tetramethyl- und tetraphenylcyclobutadien-liganden. Synthese,elektrophile aromatische substitution und ringgliedsubstitution am borinato-liganden

The preparation of (borinato)(cyclobutadiene)cobalt complexes from the reactions of Co(C₅H₅BR)(1,5-C₈H₁₂) with acetylenes C₂R′₂ and of [C₄(CH₃)₄]Co(CO)₂I with Tl(C₅H₅BR) (R,R′ = CH₃, C₆H₅) is described.In electrophilic substitution reactions Co(C₅H₅BCH₃)[C₄(CH₃)₄] (IVa) is more reactive than ferrocene. CF₃CO₂D effects H/D-exchange in the α-position of the borabenzene ring within a few minutes at ambient temperature and in the γ-position within less than four hours Friedel-Crafts acetylation with CH₃COCl/AsCl₃ in CH₂Cl₂ affords the 2-acetyl and the 2,6-diacetyl derivative of IVa. With the more active catalyst AlCl₃, ring-member substitution is effected to give cations [Co(arene)C₄(CH₃)₄]⁺ (arene = C₆H₅CH₃, 2-CH₃C₆H₄COCH₃). Vilsmeier formylation gives the 2-formyl derivative of IVa. The acyl derivatives Co(2-R¹CO-6-R²C₅H₃BCH₃)[C₄(CH₃)₄] (R¹ = CH₃, R² = H, CH₃CO and R¹ = R² = H) transform to the corresponding cations [Co(ortho-R¹R²C₆H₄)C₄(CH₃)₄]⁺ in superacidic media. The mechanistic relationship between acylation and ring-member substitution is discussed in detail.     

Stapelogenin,vermutliche Struktur. Glykoside und Aglykone, 276. Mitteilung

Stapelogenin, C₂₁H₃₀O₄, shows a double bond and two hydroxyl groups which can be acetylated. On the grounds of UV.-, IR.-, and NMR-spectra as well as mass spectra, the probable structure is that of a 3β, 12β-dihydroxy-(18, 20β), (14β, 20α)-diepoxy-Δ⁵-pregnene ( 1 ). The exact position of the hydroxyl group, assumed to be 12β, is particularly unsure, as it could also be situated 11α- or 12α-position.     

Electron distribution in 3,4-dimethylanisole molecule according to quantum-chemical calculations

Calculations of two forms of 3,4-dimethylanisole molecule with full geometry optimization are performed by AM1, RHF/6-31G(d), and MP2/6-31G(d) methods. The form with cis location of H₃C-O and C¹–C⁶ bonds is somewhat more preferable energetically than that with the trans location. By the RHF/6-31G(d) method, this molecule is also calculated with fixed rotation angles of methoxy group around the C-O bond. It is shown that, in the first form, the negative charge on the C⁶ atom is considerably smaller than on C², while in the second form the charges are practically equal, which does not confirm the concerted effects of steric and electronic factors in reactions of 3,4-dimethylanisole with methyl isocyanate and isobutyraldehyde. The charge difference is due to the effect of methyl group in the 3-position of the aromatic ring and to the orientation of the methoxy group toward geminal C-C bonds of the ring.     

Molecular Sieving of Acetylene from Ethylene in a Rigid Ultra-microporous Metal Organic Framework.

Rigid molecular sieving materials are the ideal candidates for gas separation (e. g., C₂H₂/C₂H₄) due to their ultrahigh adsorption selectivity and the absence of gas co-adsorption. However, the absolute molecular sieving effect for C₂H₂/C₂H₄ separation has rarely been realized because of their similar physicochemical properties. Herein, we demonstrate the absolute molecular sieving of C₂H₂ from C₂H₄ by a rigid ultra-microporous metal-organic framework ( F−PYMO−Cu ) with 1D regular channels (pore size of ca. 3.4 Å). F−PYMO−Cu exhibited moderate acetylene uptake (35.5 cm³/cm³), but very low ethylene uptake (0.55 cm³/cm³) at 298 K and 1 bar, yielding the second highest C₂H₂/C₂H₄ uptake ratio of 63.6 up to now. One-step C₂H₄ production from a binary mixture of C₂H₂/C₂H₄ and a ternary mixture of C₂H₂/CO₂/C₂H₄ at 298 K was achieved and verified by dynamic breakthrough experiments. Coupled with excellent thermal and water stability, F−PYMO−Cu could be a promising candidate for industrial C₂ separation tasks.     

Electrophilic hydrogen-deuterium exchange of some deactivated pyrroles

The rate coefficients and partial rate factors for the hydrogen-deuterium exchange of some 1-substituted pyrroles (1-substituents = -COCH₃, - COC₆H₅, -SO₂CH₃, -SO₂CF₃, -N(CH₃)₃, -NH(CH₃)₂, -SO₂C₆H₅) in deuterated trifluoroacetic acid have been determined. In all cases the rate of exchange is faster at the 2-position. Similarly, the hydrogen-deuterium exchange of some pyrroles with electron withdrawing substituents in the 2-position indicate a relative reactivity of 4→ 5→ 3-position with the selectivity being greatest for the more electron withdrawing groups. A nitro group in the 3-position of pyrrole shows a relative reactivity of 5→2→4-position for the hydrogen-deuterium exchange in deuterated trifluoroacetic acid. A linear correlation is observed for the log of the rate coefficient of the hydrogen-deuterium exchange at the 4-position of some 2-substituted pyrroles and the difference in the calculated energy of formation of the pyrrole and the corresponding 4-deuterated cation.