Synthesis and pharmacological evaluation of 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles

A fast access to novel 5-carboxamide-substituted tetrahydrochromeno[7,8-d]imidazoles 4 was developed using the readily available preclinical candidate BYK 405879 (1) as starting material. The 5-amino function was installed by the Curtius rearrangement of carboxylic acid 2 or by the Hofmann rearrangement of carboxamide 8 furnishing benzimidazole 3 as key intermediate. In the Ghosh Schild rat, some of the target compounds 10-14 showed noteworthy activity as potassium-competitive acid blockers.     

Claisen rearrangements based on vinyl fluorides

2-Fluoroalk-1-en-3-ols (4), available from terminal alkenes (1) by bromofluorination, subsequent dehydrobromination of the 1-bromo-2-fluoroalkanes (2) to form 2-fluoroalkenes (3) and selenium dioxide mediated allylic oxidation with tert-butylhydroperoxide, undergo Johnson-Claisen rearrangement on treatment with trimethyl orthoacetate to give methyl 4-fluoroalk-4-enoates (7) in high yields. In contrast Ireland-Claisen rearrangement of 3-acetoxy-2-fluorodec-1-ene (9b) with triethylamine and TMSOTf in ether failed. Instead of the expected formation of a carboxylic acid, selective C-silylation of the α-position to the carboxyl group to form 14 occurred. However, Ireland-Claisen rearrangement was successful with corresponding chloroacetates 10 and propionates 11 of four 2-fluoroalk-1-en-3-ols (4) to give 2-chloro-4-fluoroalk-4-enecarboxylic acids (15) or its 2-methyl derivatives 16, respectively, in moderate yields. These [3,3]-sigmatropic rearrangements are diastereoselective giving trans-configured double bonds, exclusively. Corresponding esters derived from (Z)-2-fluorocyclododec-2-enol (22), did rearrange to yield mixtures of diastereomers much less selectively. Also 2-fluorodec-2-enol (6), which was prepared by rearrangement of 2-fluoro-2-octyloxirane (5) with TMSOTf and triethylamine, was successfully applied as a starting material for [3,3]-sigmatropic rearrangements. The corresponding 3-(1-fluoroethenyl)alkanoic acid derivatives 17 and 18 were formed in moderate yield.     

Total synthesis of (+)-ambruticin S

A convergent total synthesis of the novel antifungal agent ambruticin S (1) has been completed from the assembly of intermediates 18, 33 and 52 that served as the respective A-, B-, and C-ring precursors. The first generation approach to a potential A-ring intermediate eventuated in the synthesis of 9a via a route that featured oxidation of the dihydroxy furan 2 and elaboration of the dihydropyranone 3 derived therefrom. Although 9a served as a precursor of 31E to complete a formal synthesis of 1, there were several inefficiencies associated with the preparation of 9a. A more expedient and efficient route to an A-ring subunit was devised that commenced with the carbohydrate-derived bisacetonide aldehyde 10 and produced 18 in five steps and 46% overall yield. The synthesis of the cyclopropyl sulfone 33 was initiated with the enantioselective cyclopropanation of 19 catalyzed by Rh₂[5(S)-MEPY]₄. Ring opening of the resultant lactone 20 followed by a series of refunctionalizations gave 33 in a total of seven steps and 46% yield from 19. Coupling of the A- and B-ring precursors 18 and 33 was then achieved via a modified Julia coupling followed by deprotection and oxidation to furnish the key intermediate 35. The dihydropyran core of the C-ring subunit precursor 49 was formed from the ring closing metathesis of the diene 48, which was prepared in three steps from the known epoxide 45, followed by oxidation. A chelation-controlled addition to the methyl ketone 49 set the stage for a stereoselective [2,3]-Wittig rearrangement that delivered the alcohol 51 that was then transformed in two steps to the sulfone 52. A traditional Julia coupling of 52 and 35 proceeded with excellent stereoselectivity, and subsequent removal of the various protecting groups gave ambruticin S (1). The longest linear sequence was 13 steps and proceeded in 4.3% overall yield.     

Synthesis of 5-alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones by denitrocyclisation of N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides. Evidence of a Smiles rearrangement

An efficient method for the synthesis of hitherto unknown alkyl(or aryl)pyrrolo[1,2-a]quinoxalin-4(5H)-ones 8a-g, 16 and 17 has been established. The method is based on the synthesis of the corresponding N-alkyl(or aryl)-1-(2-nitrophenyl)-1H-pyrrole-2-carboxamides 3a-c and 7a-c,e which undergo denitrocyclisation with NaH in DMF in 4.5 or 2 h. When 3a was treated with NaH in DMF for 30 min the product of a Smiles rearrangement, 9, was isolated. Under similar conditions but for 4.5 h 9 was converted into 8a. This confirms the involvement of a Smiles rearrangement during the denitrocyclisation process. Conversion of 3b into isomeric pyrroloquinoxalinones 12 and 13 confirms a process involving two pathways, direct denitrocylisation of 3b and Smiles rearrangement of 3b followed by denitrocylisation, respectively. Furthermore, denitrocylisation of 7d into pyrroloquinoxalinones 16 and 17 suggests that similar cyclisation pathways are followed by N-arylcarboxamides.     

Synthesis of vinylcyclopropanes by allylation/ring-closing metathesis/Claisen rearrangement

A facile double allylation/ring-closing metathesis/Claisen rearrangement route for preparing vinylcyclopropanes 6 is developed. The efficient synthesis includes O-allylation of α-allyl-α-sulfonylketones 8 with allylic bromides, ring-closing metathesis of diallyl compounds 9 and sequential Claisen rearrangement of the resulting oxepines.     

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

A series of N-protected glycine and alanine esters 4-7 of different fluorinated allylic alcohols 1 was prepared using the dicyclohexylcarbodiimide/dimethylaminopyridine method. All fluorinated esters of this type failed to react in an esterenolate Claisen rearrangement under the general conditions of the Kazmaier variant of this rearrangement. Change of the solvent from tetrahydrofuran to the less coordinating diethyl ether enabled the rearrangement of N-Boc-protected glycine esters 4a-c of 2-fluoroalken-3-ols 1a-c to form N-Boc-2-amino-4-fluoroalk-4-enecarboxylic acids 8a-c, while the rearrangement failed with N-Boc-alanine esters and all amino acid esters of 2-fluoroallylic alcohol (1e). This might be due to competing deprotonation of the position β to fluorine. Similarly to the esters 4a-c, the TFA-protected glycine esters 5a-c of 2-fluoroalken-3-ols 1a-c were rearranged. Deprotection of the Boc or the TFA group under salt-free conditions yielded the free amino acids 11a-c, which might be seen as mimics for N-alkylasparagines a group of lipoproteins.     

Wagner-Meerwein rearrangement in the course of the ozonolysis of a bornene derivative

The ozonolysis of the bicyclo[2.2.1]heptene derivative 1 or 2 gave the octaline derivative 6 (the structure was confirmed by X-ray crystallographic analysis) or 7. The exo-addition of ozone to the double bond of 1 or 2 was followed by the fragmentation in carbonyl oxide and aldehyde. Then, the strong electrophilic character of the carbonyl oxide induces an unexpected Wagner-Meerwein rearrangement to give zwitterion 4. Finally, a fragmentation reaction with elimination of dioxygen gave the tetrasubstituted C-C double bonds of 6 or 7.     

Aromatics to bis-triquinane: a tandem oxidative dearomatization of bis-phenol,cycloaddition, photorearrangement and a rapid entry into carbocyclic framework of Xeromphalinone E

A novel approach for the synthesis of a bird-shaped bis-triquinane 3, a fascinating carbocyclic framework closely related to the skeleton of Xeromphalinone E 1 from readily available 2,6-dimethyl phenol 8 has been reported. The synthesis of bis-cyclohexadienones 6, 22a–e by oxidative acetylation of tetramethyl bisphenols 7, 20a–e has been investigated using two different reagents under varying reaction conditions. The cycloaddition of bis-cyclohexadienone 6 gives two carbocycles, bis-adduct 4b and mono-adduct 5d in a stereocontrolled manner. The photochemical sigmatropic 1,2-acyl shift in 4b furnished 3 and monotriquinane 9 linked with a 9-acetoxy-9-methyl-endo-tricyclo[5,2,2,0^2,6]undeca-4,10-diene-8-one system. Two different pentasubstituted phenols 13 and 14 were also isolated during an attempted oxa-di-π-methane (ODPM) rearrangement of mono-adduct 5d via aromatisation of the cyclohexadienone ring. The photochemical behaviour of bis-cyclohexadienones 6, 22a–e has also been investigated under UV irradiation and two different aromatized products were isolated for each bis-cyclohexadienone by migration and elimination of acetate groups.     

Novel formation of a bridged bicyclic furan by rearrangement of a tetrahydroxydecalinone

In the course of a synthetic approach to the arisugacins, we prepared the tetrahydroxydecalinone 8a (which exists as the hydroxytetrahydrofuran 8b) by a straightforward route from hydroxy-β-ionone. On treatment with mesyl chloride and base, the desired mesylate 9 was not formed but rather 8ab underwent a novel rearrangement to produce the bridged bicyclic furan 10 in excellent yield. A reasonable mechanism for the rearrangement is presented involving a retro-aldol reaction, a base-catalyzed β-elimination, and final furan formation from a β-hydroxymethyl enone.     

Hemisphere-shaped calixarenes and their analogs: synthesis, structure, and chiral recognition ability

The hemisphere-shaped calixarene 1a and its split-hemisphere-shaped isomer 1b were synthesized from [2.1.2.1]metacyclophane (MCP) 3 by pinacol rearrangement and subsequent intramolecular acetalization. Their structures were revealed by X-ray crystallography and ¹H NMR spectroscopy. The temperature-dependence of the intramolecular acetalization to provide 1a and 1b was examined. The results indicated that 1a is the dominant product at high temperatures, and the values of ΔH° and ΔS° were estimated to be −18.3±0.37 kJ mol⁻¹, −59.1±1.12 kJ mol⁻¹ K⁻¹, respectively. The dinitro derivative 7 and tetranitro derivatives8 were obtained by ipso-nitration at the upper rims of 1a. The optical resolution and chiral recognition ability of racemic mixture 7 were investigated by HPLC systems.     

Total synthesis of Amaryllidaceae alkaloids, (+)-vittatine and (+)-haemanthamine, starting from d-glucose

The stereoselective total synthesis of (+)-vittatine 1 and (+)-haemanthamine 2 starting from d-glucose is described. The cyclohexene ring in 1 was prepared in an optically active form from d-glucose using Ferrier's carbocyclization reaction, and the critical quaternary carbon was stereoselectively generated via chirality transfer by the Claisen rearrangement of cyclohexenol 6. The hexahydroindole skeleton was effectively constructed by the intramolecular aminomercuration-demercuration of 14, followed by Chugaev reaction to provide 16. Finally, Pictet-Spengler reaction completed the first chiral synthesis of (+)-vittatine 1. On the other hand, the α-hydroxylation of the ester 5 stereoselectively proceeded to give α-hydroxy ester 19, to which was introduced an amino function to provide 4. A similar transformation of 4, as employed in the synthesis of vittatine, furnished (+)-haemanthamine 2.     

Fries rearrangement: scalable synthesis of key fluoro building blocks 3-fluoro-4-methoxybenzoyl chloride and 1,2-diethoxy-3-fluorobenzene

Lewis acid catalyzed Fries rearrangement of 2-fluorophenyl acetate (3) was performed on kg scale. The ortho5 and para4 isomers obtained were separated in an industrially feasible way. Compound 4 was then converted into fluorinated building block 3-fluoro-4-methoxybenzoyl chloride (1) while compound 5 was converted into 1,2-diethoxy-3-fluorobenzene (2) in high yields.     

Stereochemistry of 1-hydroxyphosphonate-phosphate rearrangement. Retention of configuration at the phosphorus atom

1-Hydroxyphosphonate 1 in the presence of triethylamine in acetonitrile solution undergoes irreversible rearrangement to phosphate 2 and reversible retro-phospho-aldol (retro-Abramov) reaction. The X-ray structures for 1 and 2 revealed that the phosphonate-phosphate rearrangement occurs with retention of configuration at the phosphorus atom.     

Synthesis and thermal behavior of cis- and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene

The cothermolysis of benzoyl(tert-butyl)bis(trimethylsilyl)silane with 2,3-dimethylbutadiene in a sealed tube at 140 °C for 24 h afforded cis- and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-2-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene (2 and 3) in a ratio of approximately 1:1 in 66% combined yield. When cis-silacyclohex-4-ene 2 was heated in a sealed tube at 250 °C for 24 h, dyotropic ring contraction took place to give 1-[(tert-butyl)(trimethylsiloxy)(trimethylsilyl)silyl]-3,4-dimethyl-1-phenylcyclopent-3-ene (4), but not trans-2-tert-butyl-4,5-dimethyl-2-phenyl-1-(trimethylsiloxy)-1-(trimethylsilyl)-1-silacyclohex-4-ene (6). The thermolysis of trans-silacyclohex-4-ene 3 under the same conditions, however, afforded two products, 1-silyl-1-phenylcyclopent-3-ene 4 and trans-1-tert-butyl-4,5-dimethyl-2-phenyl-1-(trimethylsiloxy)-2-(trimethylsilyl)-1-silacyclohex-4-ene (5). The theoretical calculations were carried out to characterize the transition states and other local minima, and to evaluate the activation energies for the dyotropic rearrangement of 2 to 4 and 6, and 3 to 4 and 5. The energy barriers between 2 and 4, between 3 and 4, and between 3 and 5 were evaluated to be 188, 191, 192 kJ mol⁻¹, respectively. The energy barrier between 2 and 6, however, was calculated to be 201 kJ mol⁻¹ or higher. These results are consistent with the experimental finding that the thermal isomerization of 2 affords only 4, but 3 produces both 4 and 5.     

Trifluoro analog of Hagemann’s ester: access to angularly CF3-substituted heterobicyclic compounds

The selective reduction of the trifluoro analog of the Hagemann’s ester 1 provided corresponding cyclohexenols, which underwent a Johnson-Claisen rearrangement leading to diesters 3. These latter are precursors of tetrahydroisochromanes 5 and octahydroisoquinoline 7a bearing an angular trifluoromethyl substituent.     

Synthesis of 2-azaspiro[4.4]nonan-1-ones via phosphine-catalysed [3+2]-cycloadditions

The phosphine-catalyzed [3+2]-cycloaddition of the 2-methylene γ-lactams 4 and 5 and the acrylate 6 with the ylides derived from the ethyl ester, the amide or the chiral camphor sultam derivative of 2-butynoic acid (7a-c) give directly, or indirectly after reductive cyclization, spiro-heterocyclic products. The acid 32 underwent Curtius rearrangement and then acid hydrolysis to give two novel spiro-cyclic ketones, 41 and 42.     

Total synthesis of (−)-amathaspiramide F

The stereoselective total synthesis of the marine alkaloid, (−)-amathaspiramide F (1), was achieved from the α-hydroxy-α-ethynylsilane 2. The key steps involved in the synthesis were (1) the enolate Claisen rearrangement of the α-acyloxy-α-alkenylsilane for the stereoselective construction of the consecutive C5 and C9 chiral centers of 1 (erythro configuration), (2) the construction of aza-spirohemiaminal 28, and (3) dibromination during the final stage of the total synthesis. The reaction of the (Z)-α-acyloxy-α-alkenylsilane 22 possessing the Boc-homoallylglycine ester as the acyloxy group underwent stereoselective enolate Claisen rearrangement to give the desired erythro product 23. On the other hand, the reaction of the α-acyloxy-α-alkenylsilane (Z)-5 having Boc-proline gave the unexpected threo product 6. Oxidative cleavage of the vinylsilane group of 23 followed by treatment with heptamethyldisilazane as the methylamine equivalent gave aza-spirohemiaminal 28. The problematic regioselective dibromination to 28 was achieved using n-Bu₄NBrCl₂.     

Total synthesis of mycestericin A and its 14-epimer

The total synthesis of mycestericin A (1) and its 14-epimer 34 is described herein. The Overman rearrangement of an allylic trichloroacetimidate derived from l-tartrate generated a tetra-substituted carbon with nitrogen and subsequent stereoselective transformations afforded the highly functionalized left-half segment, vinyl iodide. Cross-coupling of the vinyl iodide with a chiral organometallic species synthesized from d-tartrate under the Negishi or Suzuki-Miyaura coupling conditions, followed by deprotection, completed the total synthesis of 1. The 14-epimer of mycestericin A was also synthesized, and a comparison of [α]_D values of peracetyl γ-lactone derivatives of mycestericin A and its 14-epimer as well as degradation studies of 1 and 34 fully confirmed the proposed absolute structure of mycestericin A.     

On the reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine with several amines in different experimental conditions: monosubstitution,disubstitution, and a new unexpected rearrangement

The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 with nucleophiles has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain, by using different experimental conditions, the mono- and the di-amino-substituted derivatives of 5,6,7,8-tetrahydro-2,7-naphthyridines 2 and 3, respectively. Thus, by carrying out the reaction in a low-boiling solvent and in the presence of a quasi-stoichiometric amount of amine, the mono-substituted derivatives 2 were obtained, which under harsher conditions was transformed into the diamino derivatives 3 when using an excess of amine. During the synthesis of some diamino derivatives 3 a new rearrangement was observed with formation of 1-oxo derivatives of 3,4-dihydro-2,7-naphthyridines 4. The structure of the unexpected compounds 4 was confirmed by X-ray crystallography. A mechanism for the rearrangement is tentatively suggested.     

Cyclisation of benzo[b]thiophen-3(2H)-one 1,1-dioxide and 1,3-indanedione into novel methylene bridged polycyclic diazocines and their rearrangement into spirocyclic compounds

Methylene bridged polycyclic diazocines 2a and 2b were obtained in reactions of 1,3-indanedione, or benzo[b]thiophen-3(2H)one-1,1-dioxide, or 2,2′-methylene derivatives 3a,b with paraformaldehyde and ammonia or hexamethylenetetramine in acidic medium. A structural revision of methylene bridged benzothieno-diazocine 2b based on results of X-ray diffraction analysis is presented. Internal rearrangement of methylene bridged polycyclic diazocines into spiroheterocycles 4a,b is also described.