Biosynthesis of the 17-membered carbocyclic ring of lankacidin antibiotics

A mechanism involving contraction of an 18-membered polyketide ring was proposed for the biosynthesis of the 17-membered carbocyclic ring of lankacidin antibiotics based on the feeding experiments of deuterated glycine and ²H-NMR spectroscopy.     

Synthesis, X-ray structures, and catalytic applications of palladium(II) complexes bearing N-heterocyclic iminocarbene ligands

Two new Pd(II) N-heterocyclic iminocarbene complexes (C-N)PdCl₂ that contain 5-membered chelate rings have been prepared by carbene transfer from a silver iminocarbene precursor to (COD)PdCl₂. The new Pd imonocarbene complexes, as well as two that have been previously reported (altogether three 5-membered and one 6-membered chelate ring complexes) have been evaluated as catalysts for the Suzuki-Miyaura coupling reaction. The complexes were found to be active in the reaction, but without exceptional catalytic performances. The 5-membered chelate ring complexes appeared to be more robust and remained active for a longer time than the 6-membered ring congener. The catalytic performance of the 5-membered chelate ring complexes appeared to be rather insensitive to the steric demands of the imine-N-aryl group. The X-ray structure of one of the Ag iminocarbene complexes reveals the κ¹(C) bonding of the iminocarbene moiety in a nearly linear Ag(I) complex; two monomeric units are associated through a weak Ag-Ag interaction. The X-ray structures of two new Pd iminocarbene complexes (C-N)PdCl₂ confirm the chelating κ²(C,N) nature of the iminocarbene moiety; in both complexes, the Pd-Cl distances trans to carbene-C are slightly longer than those trans to imine-N.     

The consecutive loss of two H2O molecules from protonated 1,2- and 1,3- cyclohexanediols in the gas phase: An example for the incidence of skeletal rearrangement in chemical ionization mass spectrometry

The consecutive dehydration of protonated molecules [MH]⁺ of 1,2- and 1,3-cyclohexanediols (cis and trans isomers) by loss of two H₂O molecules has been investigated. Analysis of ²H labelled compounds showed that loss of the first H₂O molecule represents a simple heterolysis, i.e. a dissociation without exchange of hydrogens between O—H and C—H bonds. Subsequent elimination of the second H₂O molecule in the process [MH–H₂O]⁺→[MH–2H₂O]⁺ followed several competing paths. The two major ones corresponded formally (with reference to an intact 6-ring skeleton) to 1,3- and 1,4-eliminations; in comparison, the alternative 1,2-elimination is only a minor route at most. At least for the 1,3-elimination, water loss from the [MH–H₂O]⁺ ions is not direct, but is associated with skeletal rearrangement, most probably of the Wagner-Meerwein-type, effecting contraction of the 6- to a 5-membered ring.     

Synthesis and proposed conformations of l-prolyl-l-leucyl-β-alanine alkylamides

The synthesis of H-Pro-Leu-β-Ala-NH₂, H-Pro-Leu-β-Ala-NHCH₃ and H-Pro-Leu-β-Ala-N(CH₃)₂ is described. On the basis of IR and ¹H NMR spectral data, a 7-membered ring including the NH of β-alanine with the CO of proline should be assigned for the H-Pro-Leu-β-Ala-N(CH₃)₂. Consequently, the plausible conformations for H-Pro-Leu-β-Ala-NH₂ and H-Pro-Leu-β-Ala-NHCH₃ derive from the formation of an 11-membered ring, between the trans amide proton and the CO of Pro, or from the formation of an 8-membered ring, between this carboxamide proton and the CO of Leu, plus the aforementioned 7-membered ring.     

Synthesis of new crown ethers and their metal complexes: 1H and 13C NMR study

A new type of crown ethers containing a diphenyl ether unit has been prepared, the ring size ranging from 12 to 36. ¹H and ¹³C NMR spectra of both free ligands and their metal-ion complexes have been recorded. For 18- and 21-membered compounds a general downfield shift was observed for both methylene and aromatic proton resonances on metal-ion complexation. The stoichiometry of K⁺ and Na⁺ complexes was deduced from chemical shift dependence on metal-ion concentration. The K⁺ and Na⁺ complexes of 18- and 21-membered rings have a guest to host ratio of 1:1, whereas the K⁺ salt of the 15-membered ring exists as a 1:2 complex in solution. The ¹H shift observed on salt formation was attributed to electric-field and conformational effects. The ¹³C resonances for the aryl carbons, C-1, C-2 and C-3, and the α-methylene carbon in 15- and 18-membered rings were shifted upfield when an equivalent amount of KSCN was added in CDCI_3?DMSO-d₆. The shift changes were independent of the anion, and similar results were obtained for SCN^?, Br^?, and I^? salts. The upfield shift is explained by conformational factors. The spectral changes were slight for 12- and 36-membered rings. In 15- and 18-membered rings, complexation induces conformational changes which force the C-α carbon into the plane of the benzene ring. The solution conformation of these molecules is discussed.     

A mononuclear manganese(III) complex of an asymmetric macrocyclic ligand with a ring contraction [MnHL2(ClO4)](ClO4) · 2.5H2O

The template reaction of sodium 2,6-diformyl-4-chlorophenolate and N,N-bis(2-aminoethyl)–hydroxyethylamine followed by in situ transmetallation of Mn(ClO₄)₂ results in a mononuclear manganese(III) complex of one 21-membered asymmetric 2:2 Schiff base macrocycle, in which a hydroxyethyl group of the amine has been eliminated and ring contraction at one chamber of the macrocycle has occurred to form an imidazolidine ring. An X-ray study indicates that the geometry about the manganese(III) ion is distorted octahedral. The electrochemical behavior of this complex in MeCN has been studied by cyclic voltammetry.     

Polyesters containing ring units in main chains. I. Preparation and stereochemistry of monomers and polyesters

Cycloalkanone (C₅–C₈, C₁₂, and C₁₅) or cycloalkane (C₅ and C₆) ring-containing monomeric diesters and the polyesters derived from them were prepared, and their configurations were studied by ¹³C-NMR spectroscopy. Absolute configurations were determined for ring sizes 5, 6, and 7. Configurational change during reduction of a ketonic group of monomeric diesters with ring sizes 5 and 6 was discussed in terms of the steric effect of ring substituents on the ketonic group. In the polycondensation reaction epimerization of the ring units was observed in 5-, 6-, and 7-membered cycloalkanones and not in others, which is explained by steric hindrance by the ring substituents against attack of tetrabutyl titanate catalyst on the ketonic group.     

Ring contraction mechanisms in substituted cyclohexylium cations

The effect of an electron donating or withdrawing group on the ring contraction mechanism of a cyclohexylium (cyclohexane-derived) cation has been studied using density functional theory. The barrier to rearrangement of the parent cyclohexane cation (1) was previously calculated to be 7.7 kcal/mol using PBE/6-311++G(2d, 2p). We show in this work that addition of an electron withdrawing group (CF₃) lowers the average barrier to ring contraction, while an electron donating group (CH₃) increases the average barrier, relative to the parent, unsubstituted, cyclohexane cation. Calculated barrier heights for going from a 6-membered to 5-membered ring range from 4.3 to 23.3 kcal/mol for methyl-cyclohexylium (2), but only from 0.6 to 14.0 kcal/mol for trifluoromethyl-cyclohexylium (3). The lower barriers for 3 can be explained by (a) the starting structures involved, and (b) the use of dative bonding as a catalyst in stabilizing intermediates and transition states. For 1 and 3 the reaction involves starting from secondary cations and going downhill in energy through secondary intermediates to a tertiary product. However, 2 does not benefit from such favorable energetics since it more likely starts from a tertiary cation and has to first rearrange to secondary intermediates to derive the tertiary methyl-cyclopentane-type product.     

Mechanism and Selectivity of the Oxidative Ring Contraction of Cyclic α‐Formyl Ketones

The oxidative contraction of α‐formal ketone to form continuous all carbon chiral centers promoted by H₂O₂ is widely used in natural product total synthesis. Typically, using this transformation, chiral cyclic ketones are obtained as the major products and ring‐opening products as the minor products. Herein, DFT calculations have been used to investigate the detailed reaction mechanism and chemoselectivity. In addition, with the widely accepted mechanism of H₂O₂‐promoted transformation, our systematic investigation with various explicit‐solvent‐model calculations for the first time shows that H₂O and H₂O₂ are comparable at catalyzing the rate‐determining step of this reaction, which emphasis the importance of solvent effect in such transformations. It is found that both the less ring‐constrain and a later transition state in an exothermic reaction account for the origin why the reaction favors ring‐contraction pathway rather than ring‐opening one. By a comprehensive analysis for the substituted groups, it has been disclosed that the steric effects of the substituted groups on R² and R³ contribute to the selectivity with larger steric hindrance favoring the chiral cyclic products. Moreover, the electronic effects on R¹ but not R³ affect the selectivity with electron‐donating groups leading to the cyclic products. Based on our calculations, some predictions for higher selectivity have been made.     

A study of the planarity of the pyrrolone fragment in 2‐isopropyl‐2,3‐dihydro‐1H‐isoindol‐1‐one

Orthophthalaldehyde (o‐phthalaldehyde, OPA) is an aromatic dialdehyde bearing two electron‐withdrawing carbonyl groups. The reactions of OPA with primary amines are broadly applied for the synthesis of important heterocyclic compounds with biological relevance. A number of such reactions have been investigated recently and several structures of condensation products have been reported, however, the complex reaction mechanism is still not fully understood and comprises concurrent as well as consecutive reactions. The reaction products depend on the primary amine which reacts with OPA, the reaction environment (solvent) and the proportion of the reactants. The title molecule, C₁₁H₁₃NO, the product of the reaction of OPA with isopropylamine, contains a five‐membered pyrrole C₄N ring with a carbonyl substituent, which forms part of the isoindolinone unit. Though this pyrrole ring contains one C atom in the sp³‐hybridized state, it is fairly planar. The title molecule has been compared with similar structures retrieved from the Cambridge Structural Database in order to study this phenomenon. The planarity of this fragment has been explained by the presence of partially delocalized C—C, C—N and C—O bonds, and by an inner angle in the planar pentagonal ring (∼108°), which is close to the ideal tetrahedral value for the sp³‐hybridized state of the constituent C atom. Due to this propitious angle, this C atom can be present in states intermediate between sp³‐ and sp²‐hybridized in different structures, while still maintaining the planarity of the ring. There are only weak intermolecular C—H…O hydrogen bonds and C—H…π‐electron ring interactions in the structure. In particular, it is the pyrrole ring which is involved in these interactions.     

Synthese und Strukturbestimmung von (i-Pr)2NB(t-BuP)3 und (i-Pr)2NB(t-BuP)4

Synthesis and Structure Analysis of (i-Pr)₂NB(t-BuP)₃ and (i-Pr)₂NB(t-BuP)₄ The diphosphide K(t-Bu)P-(t-BuP)₂-P(t-Bu)K obtained by the cleavage reaction of the 3-membered ring system (i-Pr)₂BN(t-BuP)₂ with potassium reacts with t-BuPCl₂ at ?78°C under ring expansion to form the P₃B ring system (i-Pr)₂NB(t-BuP)₃ – 1,2,3-tri-t-butyl-tri-phospha-4-diisopropyl-aminoboretane ( 1 ). – The 5-membered P₄B ring system (i-Pr)₂NB(t-BuP)₄ – 1,2,3,4-tetra-t-butyl-tetraphospha-5-diisopropylaminoborolidine, ( 2 ) – is formed from K(t-Bu)P? (t-BuP)₂? P(t-Bu)K and (i-Pr)₂NBCl₂ analogous to the above reaction. 1 and 2 could be obtained in a pure form and characterized NMR spectroscopically and by X-ray structure analysis. 1 shows at 200 K two conformation isomers; for 2 ³¹P-^10,11B-isotopic shifts could be identified.     

Photochemical and thermal rearrangements of a benzoylnaphthobarrelene-like system

8-Benzoyl-9-deuterionaphtho[de-2.3.4]bicyclo[3.2.2]nona-2,6,8-triene (12a)rearranges in a photochemical di-π-methane-type process to the l-benzoylatho[de-[2.3.4]tricyclo[4.3.0.0^2,9]nona-3,7-dienes 14a-c.The dihydro derivate 13a and the hydroxypheoylmethyl analogs 21a and 22a undergo similarly regioselective rearrangements to 15a+c, 23a-c, and 24a, respectively. At 298 K the primary photoreaction directly occus from the S₁(n,π^*) and T₂(n,π^*) states, and it proceeds from T₁(π,π^*) and from S₂(π,π^*) either directly or via T₂. At lower temperature on direct irradiation. S₁→T intersystem crossing and triplet reaction compete with reaction from the singlet. The rearrangement 12a→14a-c proceeds along three reaction paths evolving from the two primary photochemical processes of naphthyl-vinyl and vinyl-vinyl bonding in β-position to the CO (12→25+29). Two ground-state triplet diradical intermediates such as 25 and 27 have been shown to intervene consecutively—for the first time in di-π-methane photochemistry. Each has been characterized by ESR and IR, and the second one additionally by fluorescence and fluorescence excitation, and by laser flash photolysis.The failure of products 14a-c to interconvert photochemically is ascribed to efficient energy dissipation through thermally reversible pbotocleavage of the 3-membered ring.Compounds 12 and 14 thermally interconvert in the dark which constitutes the first example of a ground-state counterpart of a di-π-methane photorearrangement. The thermal reaction includes a path with highly regioselective (and possibly concerted) product formation competing with a stepwise process causing positional scrambling. The sequence 12→14 (photochemically; Φ = 1.0 at 366 nm and 298 K) and an electrophile-catalyzed reversal 14→12 in the dark is a model of a chemical light energy storage cycle which can be conducted without loss of reactants.     

Reaction of cycloheptanone with concentrated sulfuric acid

Treatment of cycloheptanone or 2-cycloheptylidenecycloheptanone with concentrated sulfuric acid, leads to self-condensation accompanied by intramolecular rearrangement and cyclization to give substituted tetrahydrofurans, viz. 2-methyl-2, 3-cyclohexano-4, 5-cyclohepteno-(⁵)-2, 3, 4, 5-tetrahydrofuran and 2-methyl-2, 3-cyclohexano-5-hydroxy-4, 5-cycloheptano-2, 3, 4, 5-tetrahydrofuran. Self-condensation of ketones with 6-membered rings under the action of concentrated sulfuric acid, proceeding via carbonium ions, and accompanied by contraction to a 5-membered ring, is also characteristic of cycloheptanone, the 7-membered ring of which isomerizes to a 6-membered one.     

Organoaluminium assisted rearrangements of five-membered ring enol ethers with vinyl substituents

Such organoaluminium reagents as ⁱBu₃A1, PhC=CA1Et₂, and Et₂A1SPh mediate the title reactions in three different directions. (1) [3,3]sigmatropic rearrangement producing 7-membered rings. (2) isomerization to form vinylcyclopropane derivatives and (3) S_N2 type reaction with phenylthio anion via oxolane ring opening.     

Twelve-, fourteen- and sixteen-membered macrocyclic ligands and a study of the effect of ring size on ligand field strength

Complexes of Cr^III and Ni^II with a macrocyclic tetradendate 12-, 14- and 16-membered nitrogen donor ligand were prepared and characterized on the basis of elemental analysis, molar conductance, magnetic susceptibility measurements, i.r., electronic and e.p.r. spectra. The complexes are of the high-spin type. The effect of ring size on the Dq_(xy) value is also discussed and the field strength was found to have a maximum value for the 14-membered ring, when metal ion fits best into the cavity rather than when the metal ion is compressed by the macrocycle.     

Ring and nitrogen inversion in a flexible highly symmetrical molecule: The conformations of 1,3,7,9,13,15,19,21-octaazapentacyclo[19,3,1,1,3,7,19,13,115,19]

The possible conformations of the title compound and their modes of interconversion via ring and nitrogen inversion processes are delineated. At high temperatures (> +80°) the ¹H NMR spectra are consistent with time averaged D_4th symmetry and rapid ring and nitrogen inversion. At lower temperatures (ca. ?10°) the time-averaged symmetry if D_2d and inversion of the 6-membered rings is frozen out, nitrogen inversion remaining rapid. The free energy of activation for the total inversion of all four 6-membered rings is 13·5 kcal mole ^?1, higher than in similar monocyclic systems. This higher energy is a reflection of the multiple ring inversion pathway required for total inversion of all the 6-membered rings.     

Metal Complexes with Macrocyclic Ligands. Part XL. Syntheses and silver(I) complexes of mono- and disubstituted dithiadiazamacrocycles

A series of N₂S₂-macrocycles with ring sizes varying between 12 and 16, as well as two 12-membered N₂S₂-rings with a pendant carboxylic and amino group, respectively, were synthesized. Their complexation properties towards Ag⁺ were studied by pH titrations and by potentiometry with a silver electrode. The observation that 1:1 ([AgLH₂]³⁺, [AgLH]²⁺, [AgL]⁺) and 1:2 species ([AgL₂H₂]³⁺, [AgL₂H]²⁺, [AgL₂]⁺) were formed is interpreted by postulating that Ag⁺ can bind either to the S-donors only, or to both the N- and S-atoms. The most stable complex [AgL]⁺ in the series of the nonfunctionalized macrocycles was found for the 12-membered N₂S₂-ring 3 . The stability of it increased when an additional donor group was introduced into the side chain. The highest formation constant (logβ₁₁₀ = 14.43(1)) was obtained with the 12-membered ring 12 carrying the ethanamine side chain. In view of a radiochemical application, all Ag⁺ complexes were tested in blood serum for their stability, but were not stable enough against transmetallation.     

1H, 13C, 31P NMR and conformational study of 7-membered ring organophosphorus compounds. 1,3,2-dioxaphosphepanes

The ¹H, ¹³C and ³¹P NMR data of several 2-R-2-thiono-1,3-dioxa organophosphorus molecules with 7-membered rings [R = Cl, OC₆H₅, C₆H₅, CH₃, N(CH₃)₂] are reported. The conformation of the 7-membered ring is discussed by reference to the ³J(POCH) coupling constants which are compared with those observed in 6-membered 1,3,2-dioxaphosphorinanes. It is shown that caution must be exercised in using the ³J(POCH) angular dependence as a stereochemical tool. The ³¹P spin lattice relaxation times of some of these 7-membered rings have been measured and the values are discussed.     

Cuprous complexes and dioxygen. Part X. Influence of ring size on the autoxidation of Cu(I) complexes with cis-and trans-N2S2 macrocyclic ligands

The autoxidation of the Cu⁺ complexes with a series of six 12-, 14- and 16-membered macrocycles containing the N₂S₂ set of donor atoms has been studied with an oxygen electrode and with the stopped-flow technique. Inspite of the identical set of coordinating groups, the reactivity of the Cu⁼ complexes towards O₂ varies by more than 5 orders of magnitude, with rate constants between <0.1 and 2·10⁴ M^?1S^?1. Simple bimolecular rate laws are obtained from initial rates of autoxidation, but successive one-electron transfers with intermediate formation of superoxide are implied from the analysis of complete reaction curves for complexes with the 12-membered macrocycles. The kinetic parameters are compared with the redox potentials for the corresponding CuL²⁺/CuL⁺ couples. Only a rather rough correlation is found and steric factors must in addition be responsible for the observed reactivity pattern which shows a decrease of autoxidation rate with increasing size of the macrocyclic ring. No systematic effect was observed for the influence of cis- vs. trans-configuration of the donor atoms.     

Pyrolysis reaction of carpronium chloride and its structurally related compounds. 2—a mass spectrometric study of the lactonization mechanism

The mechanism of the pyrolysis reaction of carpronium chloride [(CH₃)₃N⁺? (CH₂)₃? COOCH₃CI^?] leading to γ-butyrolactone and tetramethylammonium chloride was investigated by means of thermal analysis, pyrolysis gas chromatography mass spectrometry and field desorption mass spectrometry, using deuterium labelling. The results indicated that carpronium chloride pyrolysed to yield equimolar amounts of γ-butyrolactone and tetramethylammonium chloride, methyl transfer occurred between N and O during the pyrolysis process. The mechanism is discussed on the basis of the experimental results, and with the aid of the theoretical results calculated by the CNDO/2 method. The mechanism presented is as follows. γ-Butyrolactone is formed by the intramolecular migration of the π-orbital of C?O to the carbon adjacent to [(CH₃)₃N]⁺ via a 5-membered ring transition state, accompanied by a bimolecular reaction between [(CH₃)₃N]⁺ and the CH₃ of O? CH₃, resulting in the formation of tetramethylammonium chloride in an amount equimolar with γ-butyrolactone.