Synthesis, structure, and biological aspects of cyclopeptides related to marine phakellistatins 7-9

Phakellistatins 7, 8 and 9, three cyclic decapeptides naturally occurring in marine sponges of the genus Phakellia and characterized by the distinctive presence of Pro-Pro tracts, pose a non-trivial synthetic challenge, despite only containing coded amino acid residues. Their chemical synthesis was approached using a combination of solid and solution-phase techniques. As expected, our synthetic efforts yielded, for each cyclopeptide, a mixture of geometric isomers, owing to their cis-trans isomerism at Pro peptide linkages. A further complication arose because their synthesis yielded, together with the desired monomeric cyclopeptides, cyclodimeric species. In the case of phakellistatin 7 (originally determined as cis-Pro², cis-Pro⁸) our synthetic product was chemically and spectrally identical to the natural one, whereas none of the different isomeric products obtained for both phakellistatins 8 and 9 resulted to be fully equivalent (with respect to Pro geometries) to their natural counterparts. Finally, all synthetic cyclopeptides were submitted to biological assays and, as noted before for other members of the ‘proline rich’ family, synthetic compounds did not fully reproduce the biological properties (in terms of in vitro cytotoxicity against a panel of cancer cell lines) originally found for the natural products.     

1H-NMR.-, 13C-NMR.-, UV.- und CD.-Daten von synthetischem (3S, 3′S)-Astaxanthin,seinem 15-cis-Isomeren und einigen analogen Verbindungen

¹H-NMR., ¹³C-NMR., UV. and CD. spectral data of synthetic (3S, 3′S)-astaxanthin, its 15-cis isomer, and some related compounds ¹H-NMR., ¹³C-NMR., UV. and CD. spectra are reported for synthetic (3S, 3′S)-astaxanthin ( 1 ), its 15-cis isomer ( 2 ), its diacetate ( 3 ), and the 15, 15′-didehydro compound ( 5 ). These data prove the identity of the synthetic and the naturally occuring compound 1 . A full interpretation of the ¹H- and ¹³C-NMR. spectra is given and confirms the configuration of all the double bonds. The conformation of the cyclohexene end group of all the compounds is shown to be identical. The signs of the different CD. maxima of 15-cis-astaxanthin are found to be opposite to those of the all-trans compound.     

Determination of the geometric structure of three substituted polyacetylenes: Polymethylacetylene,polypentylacetylene, and poly(tbutylacetylene)

The geometric structure of polymethylacetylene (PMA), polypentylacetylene (PPA), and poly(t-butylacetylene) (PTA) was investigated by ¹H NMR, ¹³C NMR, and IR spectroscopies. It was shown that both NMR techniques can be used to determine the trans isomer content of PPA and PTA, whereas the ¹H NMR and IR methods can be used for PMA. A calibration curve was constructed by using the 965- and 720-cm^?1 bands of the IR spectrum of PPA, and could be used in future work for the same purpose if the samples had molecular weights similar to that of the one used in this study. The isomerization kinetics of PTA was investigated and cis^→ trans activation energies of 88 and 121 kJ/mol were calculated in solution and in the solid state, respectively. Heat treatment of the PMA and PPA samples always leads to a cis^→ trans isomerization with a 100% trans content under extreme conditions. Moreover, a cis^→ trans isomerization of PTA was induced in CCl₄, CDCl₃, toluene, and benzene, but a trans^→ cis isomerization was induced in decalin. The reversible isomerization of PTA covered a trans isomer concentration ranging form 25 to 60%.     

3D-structure of cycloreticulin C and glabrin A, cyclopeptides from the seeds of Annona reticulata

Two cyclopeptides, the cycloheptapeptide cycloreticulin C, cyclo(Pro¹-Gly²-Gln³-Pro⁴-Pro⁵-Tyr⁶-Val⁷) (1), and the cyclohexapeptide glabrin A, cyclo(Pro¹-Gly²-Leu³-Val⁴-Ile⁵-Tyr⁶) (2), have been isolated from the methanol extract of the seeds of Annona reticulata. Their structures were elucidated on the basis of the MS/MS fragmentation using a Q-TOF mass spectrometer equipped with an ESI source, chemical degradation and extensive 2D-NMR. The solution conformation of cycloreticulin C involves two β-turns, one of type II with trans-Pro¹ and Gly² at the corners, another of type VIa with trans-Pro⁴ and cis-Pro⁵ at the corners, and followed by a β-bulge at the Tyr⁶-Val⁷ level. The solid state and solution conformations of glabrin A have been analyzed by X-ray and 2D-NMR studies, respectively, and are characterized by the presence of two β-turns, the first of type VIa and the second intermediary between types I and III at the solid state and a γ-turn in solution.     

Total Synthesis of 6-Deoxydihydrokalafungin,a Key Biosynthetic Precursor of Actinorhodin,and Its Epimer

In this article, we report the total synthesis of 6-deoxydihydrokalafungin (DDHK), a key biosynthetic intermediate of a dimeric benzoisochromanequinone antibiotic, actinorhodin (ACT), and its epimer, epi-DDHK. Tricyclic hemiacetal with 3-siloxyethyl group was subjected to Et₃SiH reduction to establish the 1,3-cis stereochemistry in the benzoisochromane, and a subsequent oxidation/deprotection sequence then afforded epi-DDHK. A bicyclic acetal was subjected to AlH₃ reduction to deliver the desired 1,3-trans isomer in an approximately 3:1 ratio, which was subjected to a similar sequence to that used for the 1,3-cis isomer that successfully afforded DDHK. A semisynthetic approach from (S)-DNPA, an isolable biosynthetic precursor of ACT, was also examined to afford DDHK and its epimer, which are identical to the synthetic products.     

Methyl torsional potentials of rotational isomers of m-methylanisole studied by spectral hole-burning spectroscopy

Laser-induced fluorescence (LIF) excitation spectra of m-methylanisole in a supersonic jet were measured. Two series of progressions were observed in the spectrum, originating at 36048 and 36115 cm⁻¹, which were successfully assigned to the transitions to the methyl internal rotational vibronic levels of the two isomers, i.e. cis and trans isomers, with the aid of hole-burning spectrum measurements and quantum-chemical calculations. The progression for the trans isomer was observed up to the 6a₁ band, while only the 3a₁ band in addition to the 0a₁ and 1e bands was observed for the cis isomer. This finding can be explained by the conformational change upon the electronic excitation; the 60° rotation of the methyl torsional angle takes place for the trans isomer but not for the cis isomer.     

Heterobimetallic [Ru(II)/Fe(II)] complexes: On the formation of trans- and cis-[RuCl2(dppf)(diimines)]

The synthesis and characterization of trans/cis-[RuCl₂(dppf)(diimines)], dppf = 1,1′-bis(diphenylphosphino)ferrocene; diimines = 2,2′-bipyridine (trans/cis-(1)), the new complexes with 4,4′-dimethyl-2,2′-bipyridine (trans/cis-(2)) and 1,10-phenanthroline (cis-(3)) are presented. The complexes were synthesized using two routes and the trans/cis-isomer formation is dependent upon conditions and the precursor applied. The trans-isomer (kinetic) readily isomerizes to the cis-isomer (thermodynamic) when exposed to light (fluorescent) and this process was followed by cyclic voltammetry and UV-vis. The electrochemical studies on these complexes reveal that Fe^(III)/Fe^(II) couples are insensitive to the isomer (trans/cis) formed, but the Ru^(III)/Ru^(II) couples are dependent on the isomer. Transfer-hydrogenation reactions for reduction of acetophenone were conducted using complexes cis-(1) and cis-(2) and the results are compared with that obtained for similar complexes. X-ray structure for cis-(3) are presented and discussed.     

The vibrational spectra of cis,cis-,trans,trans- and cis,trans-1,4-dichloro-1,3-butadiene

The i.r. spectra of cis,cis,trans,_trans and cis,trans-1,4-dichloro-1,3-butadiene were recorded in cyclohexane solution in the region 600-40 cm⁻¹. Raman spectra, including polarization measurements of the neat liquids were obtained. Some previously unobserved fundamentals, particularly in the low frequency region, were assigned, and a few revisions in the earlier interpretations were made.Force fields containing 21 parameters for the cis,cis and the trans,trans compounds were constructed by transferring force constants from cis- and trans-1-chloro-1,3-butadiene. By mixing the force constants from these monochlorobutadienes a 29 parameter force field was derived for the cis,trans compound. The calculated r.m.s. amplitudes of vibration and perpendicular amplitude correction coefficients are presented.     

Synthesis and structure characterization of ladder-like polymethylsilsesquioxane (PMSQ) by isolation of stereoisomer

The stereo cyclic siloxane compounds having tetra hydroxyl and tetra methyl group were synthesized by hydrolysis of tetrahydrido tetramethyl cyclosiloxane consisting of four stereoisomers. Among the stereo cyclic isomers, cis-trans-cis tetrahydroxyl tetramethyl cyclosiloxane (2) was separated by recrystallization and was used as a monomer species for preparation of ladder-like polymethylsilsesquioxane (PMSQ). The isolated isomer was directly polymerized in THF with potassium carbonate (K₂CO₃) by systematic ring condensation. The hydrolyzed stereoisomers were characterized by ¹H and ²⁹Si NMR, and HPLC. The structure of the synthesized PMSQs were characterized by size exclusion chromatography (SEC), MALDI-TOF mass, ²⁹Si NMR, and small angle X-ray scattering (SAXS).     

The infrared,Raman and NMR spectra,conformational properties and values for the ideal gas thermodynamic functions of cis- and trans-1,2-cyclobutanedicarbonitrile

The infrared spectra above 400 cm⁻¹ and the Raman spectra above 30 cm⁻¹ have been recorded for the cis- and trans- 1,2-cyclobutanedicarbonitriles as melts. ¹H and ¹³C NMR data are also reported. The observed spectral data, and notably the Raman depolarization data, are consistent with C₂ symmetry for the trans isomer and C₁ symmetry for the cis isomer. The probable conformations of each compound have been proposed, and evidence is put forward that the cis compound exists with a relatively small degree of ring puckering. Complete vibrational assignments have been proposed for both compounds apart from the cis ring puckering frequency which was assumed to be too low to observe. Values for the thermodynamic functions of the two compounds as ideal gases have been calculated and the possible errors in these values have been described.     

Unusual Structures of the Parent Molecules Diarsene,Distibene, and Dibismuthene: Toward Their Observation

There is considerable interest, from both experimental and theoretical perspectives, in molecules incorporating multiple bonds between main group elements. Herein, we not only consider the parent molecules HE=EH (E=As, Sb, Bi), but also a number of their isomers. For each E₂H₂ molecule, a number of different structures were optimized with four different DFT methods. Final structures were determined with the coupled cluster method CCSD(T) using large basis sets, namely cc-pVQZ-PP, incorporating relativistic psuedopotentials. All feasible dissociation pathways are examined. For all three E₂H₂ molecules the trans isomer lies lowest in energy, with the cis isomer higher by 2.7 (As), 2.1 (Sb), and 1.8 (Bi) kcal mol⁻¹, respectively. However, both cis and trans structures should be observable, as large barriers (27.7, 20.5, and 17.7 kcal mol⁻¹) separate them. For both the cis and trans structures, in the infrared the strong E-H stretching frequencies should also be observable. Only the cis structures have dipole moments (0.62, 0.01, and 0.83 debye, respectively), and their observation by microwave spectroscopy would be stunning. Also considered were the higher energy vinylidene-like, pyramidal, monobridged, and linear structures. We conclude that molecules such as HSb=SbH-Fe(CO)₄, HBi=BiH-Fe(CO)₄, and related systems, should be feasible synthetic targets.     

n-Propyl cyanide and isocyantde: rotational and structural isomerization

Ab initio calculations with an STO-3G basis and geometry optimization have been performed on n-propyl cyanide and isocyanide in four rotational conformations, trans, cis, and gauche, with, in the latter case, two different dihedral angles, 90° and 120° from the trans position, being employed. The trans and gauche 120° isomers are predicted to be the most stable for both the cyanide and isocyanide, and the cyanide—isocyanide energy difference is calculated to be approximately 22 kcal mole^?1 for each rotational isomer. The results of a population analysis are employed to discuss the electronic structures of the cyanide, isocyanide, and the isomerization process.     

Cyclopentanones—VIII : Stereochemistry of the lithium-liquid ammonia reduction of 2,3-dialkyl-4-hydroxy-2-cyclopentenones

2,3-Dialkyl-1,4-cyclopentanediols are obtained by lithium-liquidammonia-alcohol reduction of 2,3-dialkyl-4-hydroxy-2-cyclopentenones. The configuration of the diastereoisomers formed was proved by ¹H-NMR spectroscopy and by chemical evidence. In the most abundant isomer the alkyl groups are trans and each is in trans position to the vicinal hydroxyl function. In another diastereoisomer formed in substantial amount the alkyl groups have a cis orientation and are trans to the vicinal hydroxyl function. The ¹H-NMR parameters found are more useful generally for configurational assignments to synthetic and modified prostaglandins.     

Molecular iodine: An efficient and environment-friendly catalyst for the synthesis of calix[4]resorcinarenes

Iodine catalyzes the cyclocondensation of various aldehydes with resorcinol to give tetrameric cyclic products, resorcinarenes. Through the reaction of resorcinol with aromatic aldehydes, the product is obtained as a mixture of two isomers, the all-cis isomer (rccc) and the cis-trans-trans isomer (rctt), whereas a single diastereomer, the all-cis, is formed with aliphatic aldehydes. Besides excellent isolated yields, the use of iodine makes this procedure simple, convenient, cost-effective and practical.     

Comparative reactivity of substituted 1,3-and 1,4-thiasilinane <Emphasis Type="Italic">S</Emphasis>-oxides in the sila-Pummerer rearrangement and inversion of the thiocarbonyl group

The thermal sila-Pummerer rearrangement of diastereomeric 2,3,3-trimethyl-1,3-thiasilinane S-oxides was studied. Introduction of the methyl group in the 2 position of 3,3-trimethyl-3-thiasilinane S-oxide slows down the rearrangement. When heated in CCl₄, the trans isomer (2-Me_eq, SO_eq) converts into the cis isomer (2-Me_eq, SO_ax) which rapidly rearranges into 2,2,7-trimethyl-1,6,2-oxathiasilepane. On the contrary, the isomeric 2,4,4-trimethyl-1,4-thiasilinane S-oxide is thermally stable up to 160°C in DMSO. The inversion at the sulfur atom in 2,3,3-trimethyl-1,3-thiasilinane S-oxides and 2,4,4-trimethyl-1,4-thiasilinane S-oxides under the action of triethyloxonium tetrafluoroborate was studied. The trans isomer of 2,3,3-trimethyl-1,3-thiasilinane S-oxide (2-Me_eq, SO_eq) forms with Et₃O⁺BF ₄ ^? a salt which decomposes in two ways. The first involves recovery of the starting sulfoxide due to Sn2 substitution at the carbon atom of the ethoxy group, and the second, convertion into the cis isomer (2-Me_eq, SO_ax) which rearranges into 2,2,7-trimethyl-1,6,2-oxathiasilepane. Under the same conditions, the cis isomer of 2,3,3-trimethyl-1,3-thiasilinane S-oxide (2-Me_eq, SO_eq) decomposes to form siloxanes. trans-2,4,4-Trimethyl-4-thiasilinane S-oxide (2-Me_eq, SO_eq) under the action of Et₃O⁺BF ₄ ^? convers into the cis isomer (2-Me_eq, SO_ax). The B3LYP/6-311G(d,p) theoretical analysis showed that the thermal inversion at the sulfur atom in the compounds studied has a high energy barrier.     

Structure of polypiperylene chain segments according to high-resolution 13C NMR spectra

The microstructure of stereoregular 1,4-trans-and 1,4-cis-polypiperylenes, as well as polymers prepared from the trans-and cis-piperylene isomers via cationic polymerization in the presence of TiCl₄, was studied by high-resolution ¹³C NMR spectroscopy. Polypiperylene synthesized through the cationic polymerization of the cis isomer had a more diversified morphology of the macromolecular chain, i.e., had higher relative amounts of 1,2-cis-units and combinations of irregular-addition 1,4-trans-units. It was shown that ¹³C NMR spectra give the most comprehensive and independent information on the details of structure of the piperylene macromolecular chain.     

Structure and reactivity of α,β-unsaturated ethers—XIV: Protonation of cis- and trans-1-ethoxybuta-1,3-dienes

The acid-catalysed hydrolysis and alcohol addition of cis- and trans-1-ethoxybuta-1,3-dienes have been investigated. It was found by product analyses with deuterium incorporation experiments that in both the reactions the cis isomer protonates at the 2-position as well as at the 4-position while the trans isomer protonates exclusively at the 4-position. The kinetic experiments showed that the trans isomer is much more reactive than the cis isomer. The possible origin of the observations is discussed.     

Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric cis- and trans-2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies

Geometrical cis- and trans- isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of corresponding cyclic P^III-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen–halogen exchange at P^IV-halogenide. Their conformation and configuration at the C₄-ring carbon and phosphorus stereocentres were studied by NMR (¹H, ³¹P) methods, X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reactions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown to depend on the nature of halogen. Cyclic cis- and trans-isomers of chlorides and bromides react with nucleophiles (HO⁻, CH₃O⁻, Me₂NH) with inversion of configuration at phosphorus. DFT calculations provided evidence that alkaline hydrolysis of cyclic thiophosphoryl chlorides proceeds according to the S_N2-P mechanism with a single transition state according to the potential energy surface (PES) observed. The alkaline hydrolysis reaction of cis- and trans-fluorides afforded the same mixture of the corresponding cyclic thiophosphoric acids with the thermodynamically more stable major product. Similar DFT calculations revealed that substitution at phosphorus in fluorides proceeds stepwise according to the A–E mechanism with formation of a pentacoordinate intermediate since a PES with two transition states was observed.     

Vibrational spectra and normal coordinate analysis of CF3 compounds: Part XLVI. Synthesis,vibrational spectra,normal coordinate analysis and electron diffraction investigation of the cis isomer of hexafluoroazomethane

The hitherto unknown cis isomer of hexafluoroazomethane has been prepared by the reaction of CICN with AgF₂ under mild conditions. It isomerizes rapidly to the trans isomer when exposed to daylight, but is stable in the dark. The compound has been characterized by NMR and UV spectra. Infrared and Raman spectra have been recorded and assigned with the assistance of a normal coordinate analysis. The molecular structure of cis-CF₃NNCF₃ has been determined by gas phase electron diffraction, and a planar CNNC skeleton, d(NN) 1.229(8) Å, d(CN) 1.494(5) Å, and ∠NNC 122.1(8)° has been established. Compared with the trans isomer, the higher sterc strain due to F?F repulsions is released by a ∮.03 Å d(CN) lengthening and a 9° widening of the NNC angle.