Synthetic efforts towards the protoilludenes. A formal synthesis of Δ-protoilludene

An improved route to 5,8,8-trimethylbicyclo[4.3.0]-4-nonen-3-one, a key intermediate for the synthesis of the protoilludane skeleton and in particular Δ⁷-protoilludene, is reported. Attempts on an alternative synthesis of Δ⁶-protoilludene based on a phenylsulfonyl allene cycloaddition reaction is also presented.     

HPLC and 1H-NMR Studies of Alkaline Hydrolysis of Some 7-(Oxyiminoacyl)cephalosporins

Alkaline hydrolysis (pH 10.5) of the three 7-(oxyiminoacyl)cephalosporins 1a–c (cefuroxime, ceftazidime, and ceftriaxone) was studied at 37° using HPLC and ¹H-NMR techniques. The 7-epicephalosporin 2 , the 3-methylidene compound 3 , and the 6-epimer 4 of the 3-methylidene compound 3 were identified for each cephalosporin as the major degradation products under the conditions used; ceftazidime ( 1b ) yielded also the Δ²-isomer 5b (Scheme 1). A kinetic scheme was developed to account for the production of these compounds, and the different kinetic constants involved in the process were calculated. The experimental results show that the presence of a pyridinio group at position C–C(3) favours the appearance of the Δ²-isomer, which was detected mainly in cephalosporins bearing an ester function at C(4). The presence of an oxyimino group at C? CONH? C(7) facilitates epimerization at C(7) (→ 2 ), whereas that of an electron-withdrawing group at C? C(3) results in a increased formation constant for the 3-methylidene compound 3 . The 3-methylidene compounds 3a–c produced by the three cephalosporins on cleavage of the β-lactam ring all underwent epimerization at C(6) to yield the corresponding 6-epimer 4 .     

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems

An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH₂) and Pd^II complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ⁶-protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH₂ catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N−H of the enamine motif and the C=O of the directing group MQ, and the counterion of the Pd^II complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.     

Sels de Pyrylium. XVIII. Etude par RMN du Carbone-13 de Sels d'Aminopyrylium et des Barrières de Rotation dans quelques Cations N,N-Diméthylaminopyrylium

The C-2—N bond of 2-N,N-dimethylaminopyrylium cations has a partial π character due to the conjugation of the nitrogen lone-pair with the ring. The values of ΔG^≠, ΔH^≠, ΔS^≠ parameters related to the corresponding hindered rotation have been determined by ¹³C NMR total bandshape analysis. This conjugation decreases the electrophilic character of carbon C-4 so that the displacement of the alkoxy group is no longer possible. Such a hindered rotation also exists in 4-N,N-dimethylaminopyrylium cations and the corresponding ΔG^≠ parameters have been evaluated. Comparison of these two cationic species shows that hindered rotation around the C—N bond is larger in position 4 than in position 2. Furthermore, the barrier to internal rotation around the C-2? N bond decreases with increasing electron donating power of the substituent at position 4. ΔG^≠ values decreases from 19.1 kcal mol^?1 (79.9 kJ mol^?1) to 12.6 kcal mol^?1 (52.7 kJ mol^?1) according to the following sequence for the R-4 substituents: -C₆H₅, -CH₃, -OCH₃, -N(CH₃)₂.     

Structure and Catalytic Mechanism of 3-Ketosteroid Dehydrogenases

3-Ketosteroid dehydrogenases (KSTDs) are FAD-dependent enzymes that introduce a double bond in the A ring of 3-ketosteroid substrates to initiate degradation of the steroid nucleus. Δ¹-KSTD desaturates the C1-C2 bond of the steroid, while Δ⁴-KSTD targets the C4-C5 bond. Crystal structures with bound products showed that Δ¹- and Δ⁴-KSTD use different amino acid residues to catalyze an otherwise mechanistically very similar reaction (Δ¹-KSTD: Tyr318, Tyr119, and Tyr487; Δ⁴-KSTD: Ser468, Tyr319, and Tyr466). However, the substrates are rotated by ∼40° about an axis perpendicular to their plane to bring the target bond (C1-C2 or C4-C5) in the right position.     

Sterically crowded cyclohexanes - 71). synthesis,crystal structure,conformation and dynamics of hexaspiro[2.0.3.0.2.0.3.0.3.0.3.0]docosane and hexaspiro[2.0.3.0.3.0.3.0.3.0.3.0]tricosane

The synthesis, crystal structure, conformation and dynamics of hexaspiro[2.0.3.0.2.0.3.0.3.0.3.0]docosane 6 and hexaspiro[2.0.3.0.3.0.3.0.3.0.3.0]tricosane 7 are described. Both compounds adopt a chair conformation in the solid state and in solution. Their barriers of inversion were inaccessible by DNMR but could be determined from equilibration studies with stereoselectively labeled [l-¹3C]-6 and [l, l-D₂]-7. The results were as follows: [l-¹³C]_a,e -6 ΔG³₃₃₉ = 112.1 kJ/mol and [l,l-D₂]_a,e -7: ΔG³₄₂₃ = 136.0 kJ/mol. The stereoisomers of [l-¹³C]-6 and [l,l-D₂]-7 thus represent two further examples of conformational isomerism within the cyclohexane family.     

Position of the equilibrium during the migration of double bonds in the pyrazoline ring

Data characterizing the position of the equilibrium between Δ²- and Δ¹-pyrazolines with alkyl substituents in different positions, which is established under the influence of potassium tertbutoxide in tert-butyl alcohol at 90°C, were obtained. 3-Alkyl-Δ²-pyrazolines are thermodynamically more stable than their isomers with different positions of the double bond, so that the fraction of the latter in equilibrium mixtures does not exceed 1–2%, and they are practically completely isomerized to the 3-Alkyl-Δ²-substituted derivatives. If the position of the side chains excludes the possibility of the formation of 3-alkyl-Δ²-pyrazolines by migration of the double bond (4-alkyl- and 5,5-dialkyl-substituted compounds), the fraction of Δ¹-pyrazolines in the equilibrium rises appreciably and reaches 12% for 3,3-diethyl-Δ¹-pyrazoline.     

Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics

Thiomarinol and mupirocin are assembled on similar polyketide/fatty acid backbones and exhibit potent antibiotic activity against methicillin‐resistant Staphylococcus aureus (MRSA). They both contain a tetrasubstituted tetrahydropyran (THP) ring that is essential for biological activity. Mupirocin is a mixture of pseudomonic acids (PAs). Isolation of the novel compound mupirocin P, which contains a 7‐hydroxy‐6‐keto‐substituted THP, from a ΔmupP strain and chemical complementation experiments confirm that the first step in the conversion of PA‐B into the major product PA‐A is oxidation at the C6 position. In addition, nine novel thiomarinol (TM) derivatives with different oxidation patterns decorating the central THP core were isolated after gene deletion (tmlF ). These metabolites are in accord with the THP ring formation and elaboration in thiomarinol following a similar order to that found in mupirocin biosynthesis, despite the lack of some of the equivalent genes. Novel mupirocin–thiomarinol hybrids were also synthesized by mutasynthesis.     

CrO3/NHPI Adsorbed on Activated Clay: A New Supported Reagent for Allylic Selective Oxidation of Δ5-Sterols

Chromium trioxide and N-hydroxyphthalimide (NHPI) supported on activated clay could serve as an efficient and mild oxidant for allylic selective oxidation of Δ⁵-sterols. Thus, a ketone group could be easily introduced into the allylic position of Δ⁵-sterols with the existence of a sensitive 3β-hydroxyl group. The oxidant residue can be removed easily from the reaction mixture by filtration and reused after reactivation at 120 °C for 4–6 h.     

New insight into the substituent effects on the hydrolytic deamination of saturated and unsaturated cytosine

Ab initio calculations were carried out to understand the effect of electron donating groups (EDG) and electron withdrawing groups (EWG) at the C5 position of cytosine (Cyt) and saturated cytosine (H₂Cyt) of the deamination reaction. Geometries of the reactants, transition states, intermediates, and products were fully optimized at the B3LYP/6-31G(d,p) level in the gas phase as this level of theory has been found to agree very well with G3 theories. Activation energies, enthalpies, and Gibbs energies of activation along with the thermodynamic properties (ΔE, ΔH, and ΔG) of each reaction were calculated. A plot of the Gibbs energies of activation (ΔG^‡) for C5 substituted Cyt and H₂Cyt against the Hammett σ-constants reveal a good linear relationship. In general, both EDG and EWG substituents at the C5 position in Cyt results in higher ΔG^‡ and lower σ values compared to those of H₂Cyt deamination reactions. C5 alkyl substituents ( H,  CH₃,  CH₂CH₃,  CH₂CH₂CH₃) increase ΔG^‡ values for Cyt, while the same substituents decrease ΔG^‡ values for H₂Cyt which is likely due to steric effects. However, the Hammett σ-constants were found to decrease at the C5 position of cytosine (Cyt) and saturated cytosine (H2Cyt) on the deamination reaction. Both ΔG^‡ and σ values decrease for the substituents Cl and Br in the Cyt reaction, while ΔG^‡ values increase and σ decrease in the H₂Cyt reaction. This may be due to high polarizability of bromine which results in a greater stabilization of the transition state in the case of bromine compared to chlorine. Regardless of the substituent at C5, the positive charge on C4 is greater in the TS compared to the reactant complex for both the Cyt and H₂Cyt. Moreover, as the charges on C4 in the TS increase compared to reactant, ΔG^‡ also increase for the C5 alkyl substituents ( H,  CH₃,  CH₂CH₃,  CH₂CH₂CH₃) in Cyt, while ΔG^‡ decrease in H₂Cyt. In addition, analysis of the frontier MO energies for the transition state structures shows that there is a correlation between the energy of the HOMO–LUMO gap and activation energies.     

First observation of equilibrium polymerization of cyclic sulfite

Cationic polymerization of a seven-membered cyclic sulfite ( 7CS ) was carried out with methyl trifluoromethanesulfonate as a catalyst in chlorobenzene. The final conversions of 7CS were 22, 41, 52, and 60% in the polymerizations at 25°C with the initial monomer concentrations of 3, 4, 5, and 6M, respectively. The calculated monomer concentration at equilibrium was evaluated as 2.4M in any case. The conversion of 7CS decreased as the polymerization temperature rose. These results support the fact that this polymerization is an equilibrium one. ΔH⁰ and ΔS⁰ in the polymerization were evaliuated as −0.765 kcal/mol and −4.18 cal/mol by Dainton's equation, respectively. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 3235–3240, 1997     

Effect of solvation on the thermodynamics of formation for 18-crown-6 ether complexes with glycine and triglycine in water-ethanol solutions at 298 K

Using data from calorimetric titration, standard thermodynamic parameters logK ^○, Δ_r G ^○, Δ_r H ^○, and TΔ_r S ^○ of the formation of 18-crown-6 ether (18C6) molecular complex with triglycine (3Gly), [3Gly18C6] in H₂O-EtOH solvents with contents of ethanol x ranging between 0.0 and 0.5 mole fractions are calculated. Increasing the concentration of EtOH in the solvent is found to raise the reaction’s exothermicity from ?5.9 to ?21.0 kJ mol^?1 and logK ^○ [3Gly18C6] from 1.10 to 2.53. A comparative analysis of the effect the composition of H₂O-EtOH solvent has on the reactions of [3Gly18C6] and [Gly18C6] formation is performed. As in case of [Gly18C6] formation, the changes in the complex’s enthalpy of solvation Δ_tr H ^○([3Gly18C6]) are close to the Δ_tr H ^○(18C6) parameter and differ considerably from the Δ_tr H ^○(3Gly) value, testifying to the crucial role 18C6 plays in changing the [3Gly18C6] state of solvation. The ratio between solvation contributions from reagents to Δ_tr G ^○ of [3Gly18C6] formation is found to differ from that the one between the corresponding contributions to Δ_tr H _r ^o : in transferring from water to H₂O-EtOH mixtures, the increase in the positive Δ_tr G ^○(18C6) values is slight and therefore negligible when compared to Δ_tr G ^○(3Gly).     

Author index

Electromotive-force measurements on cells without liquid junction have been used to determine the pK_a values of 7 mono-, 6 di-, and 2 tricarboxylic acids in formamide at 9 temperatures from 5 to 45°C. From the pK_a values, the thermodynamic quantities ΔG⁰, ΔH⁰, and ΔS⁰ for the acids have been calculated in formamide at 25°C.     

Stereospecific enzymic cyclization of a synthetic 2,3-oxidosqualene analogue bearing an 18Z carbon-carbon double bond

This report discloses the first successful cyclization of a squalene analogue bearing a Δ¹⁸ Z instead of E CC bond which leads to a lanosterol analogue possessing the unnatural 20S stereochemistry. The hypotheses of sterol biosynthesis are discussed in the light of these findings.     

The Course of the Catalytic Hydrogenation/Isomerization Reaction of Steroidal Ring B Olefins in the 13β- and 13α-Series

The course of the catalytic hydrogenation and isomerization (H₂/Raney-Ni/dioxane or H₂/Pd/C/EtOH) of Δ^5.7-, Δ⁷-, Δ⁸-, and Δ⁸⁽¹⁴⁾-steroid olefins was shown to depend strongly on the configuration at C(13). The known hydrogenation/isomerization of reactions of Δ^5.7-dienes in the 13β-series to Δ⁷-(H₂/Raney-Ni/dioxane) and Δ⁸⁽¹⁴⁾-olefins (H₂/Pd/C/EtOH) were also confirmed in the 3β, 19-epoxy-13β- and 3-Oxo-19-acetoxy-13β-steroid series (e.g. 32 → 35 → 37 , Scheme 3). On the other hand, in the corresponding 13α-steroid series the same reactions afforded the Δ⁷-. and the Δ⁸-olefins (mixture of products with H₂/Raney-Ni/dioxane; quantitatively the Δ⁸-compounds with H₂/Pd/C/EtOH; s. e.g. Scheme 3). A similar dependence on the C(13) configuration was observed in the allylic oxidation of these olefins with SeO₂ (Fieser's test, see Table), and in the acid catalyzed opening of the 7α, 8α-epoxides (e.g. 60 → 62 + 63 in the 13β-series, and 56 → 64 + 65 in the 13α-series, Scheme 8).     

Kinetik der Diazotierung der Chloraniline in methanolischer Chlorwasserstofflösung

The kinetics of the diazotization of o-, m-, p-chloroaniline in 0.005n- to 0.4n-methanolic HCl-solution at 25, 15, 0, ?10 ?20, and ?30°C was invertigated. It was found that the nitrosation reaction (the same as in¹) $$C_6 H_4 ClNH_2 + NOCl \mathop \rightleftharpoons \limits^k C_6 H_4 ClNH_2 NO^ + + Cl^ - $$ is a proceeding advance-back-reaction. The decomposition of C₆H₄ClNH₂NO⁺ by splitting off a proton is the rate determining step. The free activation enthalpies ΔG ^* for the nitrosation reaction, the activation entropies ΔS ^*, the activation enthalpies ΔH ^* and the activation energiesE _a at the given temperatures are calculated. The experimentally found and the calculated velocities are given in Tables 1–6. The equilibrium constants of the o-, m-, p-chloroanilinium ions, and nitrosyl-chloride in methanol are indicated in Table 7, diagram 1. TheK _M values (the ionic products of methanol, extrapolated at infinite dilution) together with theK _A values of Table 7 give theK _B values (p. 2) using the table¹⁰. The ΔG _B values can be calculated using equation ΔG _B = ?RTlnK _B Fig 2 shows the linear dependance of the logarithmus of the ΔG ^* values from the logarithmus of theK _B values.     

Einbauversuche mit (3H und 14C)-doppelmarkiertem Farnesol in Cantharidin. 5. Mitteilung zur Biosynthese des Cantharidins

Incorporation experiments with (³H and ¹⁴C) doubly labelled farnesols into cantharidin After injection of 11′, 12-[³H]-7-[¹⁴C]-farnesol or 11′, 12-[³H]-5,6-[¹⁴C]-farnesol, the ³H-label is located specifically in the C(9)-methyl-group of cantharidin, whereas the ¹⁴C-labelling pattern follows an incorporation via acetic acid (Scheme 4). C-Atoms 5, 6 and 7 from the middle part of the farnesol molecule are utilized for cantharidin biosynthesis to an extent that is about 2.1–11% of the incorporation rate of the methyl groups C(11′) and C(12), depending on the position of the ¹⁴C-label in farnesol. These results confirm our earlier hypothesis [1] that the C₁₀-molecule cantharidin is biosynthesized from the C₁₅-precursor farnesol which is cleaved between C(1)–C(2), C(4)–C(5), and C(7)–C(8). The synthesis of 7-[¹⁴C]-farnesol and of 5,6-[¹⁴C]-farnesol is described.     

The biogenesis of rifamycin S

Propionic acids labelled either with ¹⁴C in positions 1, 2, or 3, or with ¹⁴C in position 1 and ³H in position 3 have been used as precursors in biosynthesis of rifamycins by Streptomyces mediterranei. The resulting distribution of radioactivity in rifamycins S – as determined by systematic degradation – shows that 23 of the 37 carbon atoms in rifamycin S originate from propionic acid. This result and the distribution pattern of radioactivity are in agreement with those obtained recently by ¹³C-NMR. spectroscopy [7]. The S-methyl groups of methionin, labelled with ¹⁴C, are incorporated in rifamycins by Streptomyces mediterranei only in the methoxy group. The consequences of these findings for the biogenesis of other ansamycins, e.g. streptovaricins, are discussed. The similarities in the constitution and configuration of ansamycins and macrolides (cf. [9]) indicate that all these microbial metabolites are formed according to the same biogenetic pattern.     

Polymerization of Acrylonitrile Initiated by 1,4-Dimethyl-1,4-bis(p-nitrophenyl)-2-tetrazene

The polymerization of acrylonitrile (AN) initiated by 1,4-dimethyl-1,4-bis(p-nitrophenyl)-2-tetrazene (Ie) was studied in dimethylformamide (DMF) at high temperature. The polymerization proceeds by a radical mechanism. The rate of polymerization is proportional to [Ie]^0.64 and [AN]^1.36. The overall activation energy for the polymerization is 21.5 kcal/mole within the temperature range of 115-130°C. The chain transfer of Ie was also undertaken over the temperature range of 120-135°C. The activation parameters for the decomposition of Ie at 120°C are k_d = 2.78 × 10^?6 sec^?1, ΔH^? = 40.8 kcal/mole, and ΔS^? = 19.5 cal/mole-deg, respectively.     

Ambident PCN Heterocycles: N‐ and P‐Phosphanylation of Lithium 1,3‐Benzazaphospholides

Synthetic and structural aspects of the phosphanylation of 1,3‐benzazaphospholides 1_Li , ambident benzofused azaphosphacyclopentadienides, are presented. The unusual properties of phospholyl‐1,3,2‐diazaphospholes inspired us to study the coupling of 1_Li with chlorodiazaphospholene 2 , which led to the N‐substituted product 3 . Reaction of 1_Li with chlorodiphenyl‐ and chlorodicyclohexylphosphane likewise gave N‐phosphanylbenzazaphospholes 4 and 5 , whereas with the more bulky di‐tert‐butyl‐ and di‐1‐adamantylchlorophosphanes, the diphosphanes 6 and 7 are obtained; in the case of 7 they are isolated as a dimeric LiCl(THF) adduct. Structural information was provided by single‐crystal X‐ray diffraction and solution NMR spectroscopy experiments. 2D exchange spectroscopy confirmed the existence of two rotamers of the aminophosphane 5 at room temperature; variable‐temperature NMR spectroscopy studies of 6 revealed two dynamic processes, low‐temperature inversion at ring phosphorus (ΔH^≠=22 kJ mol^?1, ΔS^≠=2 J K^?1 mol^?1) and very low‐temperature rotation of the tBu₂P group. Quantum chemical studies give evidence that 2‐unsubstituted benzazaphospholides prefer N‐phosphanylation, even with bulky chlorophosphanes, and that substituents at the 2‐position of the heterocycle are crucial for the occurrence of P–N rotamers and for switching to alternative P‐substitution, beyond a threshold steric bulk, by both P‐ and 2‐position substituents.