Semisynthetic 4-O-Methyl-ß-Rhodomycins: Synthesis and Structure-Activity Relationships

ABSTRACT

The synthesis of 7-O-α-L-daunosaminyl-4-O-methyl-β-rhodomycinone (3) and the determination of its cytotoxic potency compared to that of the natural 7-O-α-L-dau-nosaminyl-β-rhodomycinone (4) are described. Starting with natural β-rhodomycinone (7), trimethylsilyl protecting groups were attached to the hydroxy groups at position 7 and 10, and the 4-OH group was subsequently methylated (MeI/Cs₂CO₃), thus providing the 4-O-methyl-7, 10-bis-O-trimethylsilyl-β-rhodomycinone (10). The two TMS groups were then deblocked to give 4-O-methyl-β-rhodomycinone (12). In a 3-stage synthesis 12 was converted into 4-O-methyl-10-O-trifiuoroacetyl-ß-rhodomycinone (15) to which l, 4-bis-O-p-nitrobenzoyl-3-N-trifluoroacetyl-L-daunosamine 16 was selectively linked to afford the 7-O-α-glycoside 17. The acyl protective groups are removed by treatment with 1N NaOH to give 3.     

A reactive rhodium(I) carbonyl dithiolate and the formation of acyl and hydride species

The rhodium(I) complex [Rh(CO)(PEt₃)(mnt)]^? (mnt = maleonitriledithiolate) reacts with a variety of alkyl halides to form acyl complexes isolated in the presence of excess PEt₃ as five-coordinate species of formula [Rh(COR)(PEt₃)₂(mnt)]. The structure of the complex for R = n-Pr has been determined by an X-ray analysis, and is found to be a square-based pyramid with the acyl group in the apical position. Addition of HClO₄ to the rhodium(I) anion in the presence of excess PEt₃ yields rhodium(III) hydride, [RhH(CO)(PEt₃)₂(mnt)], while addition of acid to the rhodium(I) complex in CH₃CN solution with ethylene present leads slowly to formation of an acyl complex which is isolated as [Rh(COEt)(PEt₃)₂(mnt)] upon phosphine addition. A novel alkyl group migration from the acyl carbon to a donor S atom is also observed in monophosphine systems.     

Synthesis of new 5‐substitutedbenzo[b]thiophene derivatives

Previous works of our group have dealt with the synthesis of 1‐(aryl)‐3‐[4‐(aryl)piperazin‐1‐yl]propane derivatives in the search for new and efficient antidepressants with a dual mode of action: serotonin reuptake inhibition and 5‐HT_1A receptor afinity [1‐4]. From these studies we concluded that the 3‐[4‐(aryl)piperazin‐1‐yl]‐1‐(benzo[b]thiophen‐3‐yl)propane derivatives led to the best results. The continuation of this research project required the preparation of some new 3‐acyl‐5‐substituted benzo[b]thiophenes with a wide variety of substituents at the 5 position, ranging from nitro to hydroxyl derivatives. To obtain these derivatives we acylated the corresponding 5‐substituted benzo[b]thiophenes when it was possible.     

Acylation of 5-amino-3H-1,3,4-thiadiazolin-2-one

Acylation of 5-amino-3H-1,3,4-thiadiazolin-2-one (2) was undertaken selectively at either the 3-NH position or at 5-amino group depending on reaction conditions. The 3-NH is highly acidic and acylation takes place with acid anhydrides at this position in high yields in the presence of pyridine or triethylamine. The diacylation of both the 3-position and the 5-amino group was only possible via the 5-amino-3-acyl-1,3,4-thiadiazolin-2-one intermediates 4 . Under neutral conditions, acylation only occurs at the 5-amino group with acyl chlorides forming 5-acylamino-3H-1,3,4-thiadiazolin-2-ones 5 . 5-Acetylamino-3H-1,3,4-thiadiazolin-2-one can also be synthesized by the thermal transformation of 5-amino-3-acetyl-1,3,4-thiadi-azolin-2-one in acetic acid.     

Reaction of 1-amino-2-phenylethynyl-and 2-acylethynyl-1-amino-9,10-anthraquinones with HNO2. Synthesis of 1H-3-acylnaphtho[2,3-g]indazole-6,11-diones

The reactions of 1-amino-2-phenylethynyl-and 2-acylethynyl-1-amino-9,10-anthraquinones with HNO₂ in a mixture of dioxane and a mineral acid at 20 °C were studied. Under these conditions, 2-alkynyl-1-amino-9,10-anthraquinones, irrespective of the structure of the C=CR substituent, are cyclized into 3-substituted 1H-naphtho[2,3-glindazole-6,11-diones. The nature of the acetylenic group in the initial compound and the choice of the mineral acid determine the structure of the substitutent in position 3 of the product (1,1-dichloroalkyl or acyl) but have no effect on the regiospecificity of cyclization. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 110–114, January, 1997.     

Acyl‐Phosphide Anions via an Intermediate with Carbene Character: Reactions of K[PtBu2] and CO

The analogy of the reactivity of group 1 phosphides to that of FLPs is further demonstrated by reactions with CO, affording a new synthetic route to acyl‐phosphide anions. The reaction of [K(18‐crown‐6)][PtBu₂] ( 1 ) with CO affords [(18‐crown‐6)K?THF₂][Z‐tBuP=C(tBu)O] ( 2?THF₂ ) as the major product, and the minor product [K₆(18‐crown‐6)][(tBu₂PCO)₂]₃ ( 3 ). Species 2 reacts with either BPh₃ or additional CO to give [K(18‐crown‐6)][(Ph₃B)tBuPC(tBu)O] ( 4 ) and [K(18‐crown‐6)][(OCtBu)₂P] ( 5 ), respectively. The acyl‐phosphide anion 2 is thought to be formed by a photochemically induced radical process involving a transient species with triplet carbene character, prompting 1,2‐tert‐butyl group migration. A similar process is proposed for the subsequent reaction of 2 with CO to give 5 .     

A facile approach for the construction of the oxetane ring from 5α-acyloxy-Δ~(4(20)) - taxoids

An oxetane ring can be constructed from 5α-acyloxy-Δ4(20)-taxoids. Hie facile intramolecular acyl migration from 5- to 20-position under slightly basic conditions enabled the construction of the oxetane ring in a convenient short cut, whereas the acyl migration from 2- to 20-position left the 2-hydroxyl accessible to a later benzoylation. An unexpected five-mem-bered 4-O, 20- O sulfite ring was formed in the attempted construction of the oxetane ring with 5α-triflate as a leaving group. After the construction of the oxetane ring, treatment with strong base LiHMDS and acetyl chloride gave the expected 4-O-acetate while treatment with acetic anhydride and DMAP gave a 4-O-acetoacetate.     

Synthesis of 1-amino-1,2,4-triazolium 4-nitroimides and their reactions with electrophiles

A procedure was developed for the preparation of 1-amino-1,2,4-triazolium 4 nitroimides by amination of triethylammonium salts of 4-nitramino-1,2,4-triazoles with O-picrylhydroxylamine. The resulting nitroimides reacted with electrophilic reagents (acyl chlorides, aldehydes, phenyl isocyanate, NO₂BF₄, etc.) at the amino group.     

Ab initio study of 4-monosubstituted pyrimidines in ground and excited n → π* states

Ab initio SCF and SCF -CI calculations have been performed to investigate substituent effects on ground- and excited-state properties of 4-R-pyrimidines, and to compare these with substituent effects in 2- and 4-R-pyridines, with R including the π donating and σ withdrawing groups CH₃, NH₂, OH, F, and C₂H₃ and the σ and π electron-withdrawing groups CHO and CN. Substitution leads to significant changes in the internal angles of the pyrimidine ring, which are independent of the nature of the substituent. The geometry of the pyrimidine ring is more sensitive to substitution in the 4 position than the pyridine ring geometry is to substitution in either the 2 or the 4 position. The isodesmic reaction energies for substituent transfer from the 4 position of pyrimidine to the 2 or 4 position of pyridine indicate that all R groups except CN have a relative stabilizing effect in pyrimidine. The presence of a π donating group leads to an increase in the n→π* transition energy of 4-R-pyrimidines, while the π withdrawing group CN leads to a decrease in the transition energy relative to pyrimidine. Orbital energy differences and virtual excitation energies tend to correlate with n→π* transition energies of 4-R-pyrimidines with saturated R groups, but such correlations are masked by π conjugation, n orbital interaction, and configurational mixing when the unsaturated groups C₂H₃, CHO, and CN are present. The electronic effects of a π donating group are stronger when the group is bonded to pyrimidine than to pyridine, but those of a π withdrawing group are weaker when the group is bonded to pyrimidine.     

Differences in the crystal structures of two dialkyl diester triphenyl­phospho­nium ylids

Hydrogen bonding and crystal packing play major roles in determining the conformations of ethyl methyl 2‐(triphenyl­phospho­ranyl­idene)malonate, Ph₃P=C(CO₂CH₃)CO₂CH₂CH₃ or C₂₄H₂₃O₄P, (I), and dimethyl 2‐(triphenyl­phosphor­anyl­idene)malonate, Ph₃P=C(CO₂CH₃)₂ or C₂₃H₂₁O₄P, (II). In (I), the acyl O atom of the ethyl ester group is anti to the P atom, while the O atom of the methyl ester group is syn. In (II), the dimethyl diester is a 1:1 mixture of anti–anti and syn–anti conformers.     

Variantes de mycosides caracterisees par des residus glycosidiques substitues par des chaines acyles–I: Spectres de masse des mycosides G′ et A′ peracetyles

Mass spectra of peracetylated mycosides G′ and A′ are characterised by rearranged oxonium ions, corresponding to deoxysugars which have lost an acyl chain by fragmentation in the mass spectrometer. The main carboydrate constituent of mycoside G′ is a deoxysugar with one acyl chain and a methyl group. Mycoside A′ contains deoxysugars with one acyl chain and 0, 1 or 2 methyl groups. Deoxysugars with no acyl chains and one (G′, A′) or two (A′) methyl groups are also present. The mass spectra indicate that the acyl chains might be of the mycolic type: Peaks which might correspond to a fragmentation on both sides of the methyl branching are present and the CH⁺˙?C? C₂₂H₄₅ fragment, found in the spectrum of paracetylated mycoside A′ is characteristic of the branched chain. The highest peaks (m/e 1072 and 1100) in the spectrum of paracetylated mycoside A′ can be due to a mycolic chain after loss of acetic acid, methanol and H (l) on loss of acetic acif and H (m). The nature and abundance of the mycocerosic acids which esterify the aglycones can be deduced from the same spectra, as well as the structure of these aglycones which has been established previously by degradation and mass spectrometry. In order of decreasing abundance, C₂₇ and C₂₄ mycocerosic acids are present in mycoside G′, and C₂₉, C₃₂, C₃₂, C₃₀ and C₂₇ mycocerosic acids are found in mycoside A′.     

Nitropyrazoles. 11. Isomeric 1-methyl-3(5)-nitropyrazole-4-carbonitriles in nucleophilic substitution reactions. Comparative reactivity of the nitro group in positions 3 and 5 of the pyrazole ring

With reactions of isomeric 1-methyl-3-nitro- and 1-methyl-5-nitropyrazole-4-carbonitriles with anionic S-, O-, and N-nucleophiles (RSH, PhOH, and 3,5-dimethyl-4-nitropyrazole in the presence of K₂CO₃ or MeONa), it was shown that for N-substituted 3(5)-nitropyrazoles, the nitro group in position 5 is much more reactive than in position 3.     

Expected and unexpected photochemical reactions of acyl iodides

Photolysis of acyl iodides RCOI (R = Me, Me₂CH, Ph) under UV irradiation in toluene environment for 20–55 h proved to be a simple and efficient method of preparation of symmetrical α-diketones RCOCOR. In contrast, the photolysis under the same conditions of acyl iodides RCOI [R = Me(CH₂)₃, Me₃C] did not lead to the formation of the corresponding diacyls, and the reaction products were unexpected 1,1-bis(4-methylphenyl)pentane and a mixture of isomeric 3- and 4-methyl(tert-butyl)benzenes respectively. The most probable mechanism of their formation is the primary photochemical acylation of toluene in the aromatic ring followed by the photochemical reduction of the arising butyl 4-methylphenyl ketone in the case of the valeroyl iodide or the photochemical Norrish type I cleavage of isomeric 3- and 4-methylphenyl (tert-butyl) ketones in event of the pivaloyl iodide. In the photolysis of acetyl iodide (R = Me) in benzene or toluene alongside the diacetyl formation polyarylation process was observed of acylated and iodinated into the aromatic ring solvents with the formation of polymeric products with semiconductor and paramagnetic properties.     

Acid-Catalyzed Rearrangements of 5,6-exo-Epoxy-7-oxabicyclo[2.2.1]hept-2-yl Derivatives. Migratory Aptitudes of Acyl vs. Alkyl Groups in Wagner-Meerwein Transpositions

In the presence of HSO₃F/Ac₂O in CH₂CL₂, 2-exo- and 2-endo-cyano-5,6-exo-epoxy-7-oxabicyclo[2.2.1]hept-2-yl acetates ( 6a , b ) gave products derived from the epoxide-ring opening and a 1,2-shift of the unsubstituted alkyl group (σ bond C(3)–C(4)). In contrast, under similar conditions, the 5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ( 6c ) gave 5-oxo-2-oxabicyclo[2.2.1]heptane-3,7-diyl diacetates 20 and 21 arising from the 1,2-shift of the acyl group. Acid treatment of 5,6-exo-epoxy-2,2-dimethoxy-7-oxabicyclo[2.2.1]heptane ( 6d ) and of 5,6-exo-epoxy-2,2-bis(benzyloxy)-7-oxabicyclo[2.2.1]heptane ( 6e ) gave minor products arising from epoxide-ring opening and the 1,2-shift of σ bond C(3)–C(4) and major products ( 25 , 29 ) arising from the 1,3-shift of a methoxy and benzyloxy group, respectively. Under similar conditions, 5,6-exo-epoxy-2,2-ethylenedioxy-7-oxabicyclo[2.2.1]heptane ( 6f ) gave 1,1-(ethylenedioxy)-2-(2-furyl)ethyl acetate ( 32 , major) and a minor product 33 , arising from the 1,2-shift of σ bond C(3)–C(4). The following order of migratory aptitudes for 1,2-shifts toward electron-deficient centers has been established: acyl > alkyl > alkyl α-substituted with inductive electron-withdrawing groups. This order is valid for competitive Wagner-Meerwein rearrangements involving equilibria between carbocation intermediates with similar exothermicities.     

Preparation and thermal properties of polyquinazolones containing m-substituted phenyl groups on the quinazolone ring

Polyquinazolones containing m-substituted phenyl groups (Br, Cl, F, CH₃O, NO₂, and CH₃) on the quinazolone ring were synthesized in m-cresol, and their thermal properties were studied by using dynamic thermogravimetry and isothermal weight loss. Polyquinazolones with intrinsic viscosities in the range 0.2–1.6 dL/g were synthesized. The introduction of substituted groups into the pendant phenyl group resulted in a decrease in the glass transition temperature and the thermal stability. Oxidative thermal stability of the polyquinazolones was dependent on the position of substituted groups on the pendant phenyl group. The introduction of substituted groups into the meta position reduced thermal stability more than did the introduction into the para position.     

Kinetic and Molecular‐Modelling Study of the Interaction between Staphylococcus aureus PC1 Enzyme and Imipenem

The interactions between imipenem ( 3 ), a clinically significant carbapenem antibiotic, and Staphylococcus aureus PC1 enzyme, were studied in detail. Imipenem behaves as a slow substrate that reacts by a branched pathway, which suggests the formation of a second acyl‐enzyme intermediate. The individual microscopic rate constants for the process were determined. The results were analysed in the light of molecular‐modelling considerations. Based on the analysis, the Ser‐70(O^γ) group in the Michaelis‐Menten complex formed between 3 and PC1 is very distant from the carbonyl group of the β‐lactam ring of 3 , which is consistent with the decreased value of k₂ (Model 2, see Scheme 2) for imipenem relative to an appropriate substrate such as benzylpenicillin ( 2 ). The deacylation is the rate‐determining step of the turnover process. This can be ascribed to the fact that in the deacylation of the second acyl‐enzyme, the H₂O molecule lying closest to the ester group, Wat81, is in an unfavorable orientation to hydrolyse the intermediate.     

Binding of leucomycin and its derivatives to E. Coli ribosomes

Structure-activity relationships have been discussed for inhibition of [¹⁴C] erythromycin binding to Escherichia coli ribosomes by leucomycin and its acyl derivatives in the light of the Fujita-Ban de novo model. The group contributions of various substituents show that acylation at position 4″ of the mycarose moiety of leucomycin increases affinity for binding of leucomycins to ribosomes. It is also indicated that unlike at position 2' in mycaminose region a free hydroxyl at position 9 of the lactone ring is not important for binding to ribosomes.     

Studies on the Reaction of α‐Chloroformylarylhydrazine Hydrochloride with Imidazole and 1,2,4‐Triazole

α‐Imidazolformylarylhydrazine 2 and α‐[1,2,4]triazolformylarylhydrazine 3 have been synthesized through the nucleophilic substitution reaction of 1 with imidazole and 1,2,4‐triazole, respectively. 2,2′‐Diaryl‐2H,2′H‐[4,4′]bi[[1,2,4]‐triazolyl]‐3,3′‐dione 4 was obtained from the cycloaddition of α‐chloroformylarylhydrazine hydrochloride 1 with 1,2,4‐triazole at 60 °C and in absence of n‐Bu₃N. The inducing factor for cycloaddition of 1 with 1,2,4‐triazole was ascertained as hydrogen ion by the formation of 4 from the reaction of 3 with hydrochloric acid. 4 was also acquired from the reaction of 3 with 1 and this could confirm the reaction route for cycloaddition of 1 with 1,2,4‐triazole. Some acylation reagents were applied to induce the cyclization reaction of 2 and 3.1 possessing chloroformyl group could induce the cyclization of 2 to give 2‐aryl‐4‐(2‐aryl‐4‐vinyl‐semicarbazide‐4‐yl)‐2,4‐dihydro‐[1,2,4]‐triazol‐3‐one 6. 7 was obtained from the cyclization of 2 induced by some acyl chlorides. Acetic acid anhydride like acetyl chloride also could react with 2 to produce 7D . 5‐Substituted‐3‐aryl‐3H‐[1,3,4]oxadiazol‐2‐one 8 was produced from the cyclization reaction of 3 induced by some acyl chlorides or acetic acid anhydride. The 1,2,4‐triazole group of 3 played a role as a leaving group in the course of cyclization reaction. This was confirmed by the same product 8 which was acquired from the reaction of 1 , possessing a better leaving group: Cl, with some acyl chlorides or acetic acid anhydride.     

Intramolecular cyclization of O-(3,5-dinitrophenyl) and O-(3-amino-5-nitrophenyl) ketoximes, products of transformations of 1,3,5-trinitrobenzene. The synthesis of nitrobenzo[b]furans and 4-hydroxynitroindoles

O-(3,5-Dinitrophenyl) ketoximes obtained in the reactions of ketoximes with 1,3,5-trinitrobenzene undergo acid-catalyzed cyclization into 2-substituted or 2,3-disubstituted 4,6-dinitrobenzo[b]furans. In analogous cyclization, products of selective reduction of a nitro group in O-(3,5-dinitrophenyl) ketoximes unexpectedly yield, along with 6-amino-4-nitrobenzofurans, 4-hydroxy-6-nitroindoles. The 4-NO₂ group is displaced from 4,6-dinitrobenzo[b]furans in reactions with thiols in the presence of K₂CO₃. Conditions for nitration and sulfochlorination of 4,6-dinitrobenzo[b]furans in position 3 were found. Condensation of a 2-methyl derivative with dimethylformamide acetal was accomplished. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 984–991, May, 2007.     

Precursor of a β‐lactamase inhibitor: allyl (4S,8S,9R)‐10‐[(E)‐ethyl­idene]‐4‐methoxy‐11‐oxo‐1‐aza­tri­cyclo­[7.2.0.03,8]­undec‐2‐ene‐2‐carboxyl­ate

The molecular structure of the title tricyclic compound, C₁₇H₂₁NO₄, which is the immediate precursor of a potent synthetic inhibitor {Lek157: sodium (8S,9R)‐10‐[(E)‐ethyl­idene]‐4‐methoxy‐11‐oxo‐1‐aza­tri­cyclo­[7.2.0.0^3,8]­undec‐2‐ene‐2‐carboxyl­ate} with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclo­hexyl ring and the carbonyl group of the β‐lactam ring, which takes part in the formation of the initial tetrahedral acyl–enzyme complex. In this hydro­phobic mol­ecule, the overall geometry is influenced by C—H?O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) Å, with corresponding normalized H?O distances of 2.30 and 2.46 Å], whereas the mol­ecules are interconnected through intermolecular C—H?O hydrogen bonds [3.335 (4)–3.575 (5) Å].