Stereoselective synthesis of bicyclo[3.1.1]heptane derivatives via intramolecular photocycloaddition reaction

Optically active 1,3-bridged cyclobutanes 10 of the bicyclo[3.1.1]heptane ring system and 1,2-bridged cyclobutanes 11 of the bicyclo[3.2.0]heptane ring system were produced by UV irradiation of alpha,beta,gamma,delta-unsaturated esters 9a and 9c-f. The preference of endo-stereochemistry at C-6 bridged head was observed in cross-adducts 10. On the other hand, irradiation of conjugated dienol 9b led via only parallel cycloaddition to 1,2-bridged cyclobutane 11.     

Synthesis of the mitomycin and FR900482 ring systems via dimethyldioxirane oxidation

[reaction: see text] Dimethyldioxirane oxidizes a 2,3-dihydo-1H-pyrrolo[1,2-a]indole unsubstituted at the C-9 position stereoselectively to form a hydroxy ketone with all the basic elements of the mitomycin ring system. On the other hand, a 2,3-dihydo-1H-pyrrolo[1,2-a]indole derivative substituted with an alkyl group at C-9 undergoes an oxidative ring expansion in the presence of dimethyldioxirane to give an FR900482 analogue.     

Studies in the heterocyclic series. XXI. A novel tetraaza-analog of phenothiazine

As a continuation of our search for new pharmaco-active phenothiazine compounds, the synthesis of 1,4,6,8-tetraazabenzo[b]phenothiazine ring system is described. Derivatives of this new heterocycle were prepared by converting 4,5-diamino-6-hydroxypyrimidine to 4,5-diaminopyrimidine-6-(1H)thione followed by the action of 2,3-dichloroquinoxaline in refluxing DMF or DMAC. The reaction of mixed nitric and sulfuric acids with 9-amino-12-chloro-1,4,6,8-tetraazabenzo[b]phenothiazine gave 9-amino-12-chloro-13-nitro-1,4,6,8-tetraazabenzo[b]phenothiazine 5-oxide in satisfactory yields. Diazotization of 9-amino-1,4,6,8-tetraazabenzo-[b]phenothiazine led to 1,4,6,8-tetraazatriazolo[4,5,1-kl]benzo[b]phenothiazine which is a new heterocyclic compound and the parent compound of this ring system. The mechanistic pathways to these compounds are also proposed.     

Synthesis of anti-9-Bromo- and anti-9-Chlorobicyclo[4.2.1]nonatriene via Bicyclo[4.2.1]nonatriene→Bicyclo[4.2.1]nonatriene Rearrangement

The first syntheses of 9-bromo- and 9-chlorobicyclo[4.2.1]nona-2,4,6-trienes were each achieved in three stereoselective steps from the 9,9-bis(selenophenyl) derivative 9 in 79% overall yield for the bromide and 64% for the chloride. A deuterium-labeling experiment reveals the first rearrangement of a bicyclo[4.2.1]nonatriene which leaves the ring system intact.     

Efficient synthesis of the C/D rings of atisine-type C20-diterpenoid alkaloids

A bicyclo[2.2.2]octane C/D ring system,with a lactonic ring at C-8 and C-9,of the atisine-type C₂₀-diterpenoid alkaloids,was successfully synthesized,using an oxidative dearomatization/intramolecular Diels-Alder reaction.     

Synthesis of N-methyl-3-aza[10] paracyclophane: A rigid analog of phenethylamine

The synthesis of N-methyl-3-aza[10]paracyclophane is reported which represents the first example of this ring system being formed via an acyloin reaction. This 3-aza[10]paraeyclophane ring system behaves physiochemically inbetween the normal [9]- and [10]paracyclophane ring systems. Reductive desulfurization of N-methyl-3-aza[10]paracyclophane-6-ethylene thioketal in ethanol provides a small amount of the title compound and an unexpected, ring-opened product, N-ethyl-N-methyl-p-heptylphenethylamine. A possible mechanism for the ring-opening process is suggested.     

Nitrogen bridgehead compounds. Part 80 unusual reaction of ethyl 9-bromo-4-oxo-6,7,8,9-tetr ahydro-4h-pyrido[1,2-a]pyrimidine-3-carboxylates and N-Methylaniline

The acid-catalysed intramolecular nucleophilic addition of the phenyl ring to the C(9a) = N(1) double bond of ethyl 9-(N-methyl-N-phenyl)-4-oxotetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates, formed in the reactions of ethyl 9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylates and N-methylaniline, gave the first examples of a new tetracyclic pyrimido[1′,2′:1,2]pyrido[3,2-b]indole ring system ( 7 ). X-ray diffraction analysis of 7a revealed that the annelation of the pyrimidine and piperidine rings is transoid, while that of the piperidine and pyrroline rings is cis, the piperidine ring adopts an unusual ⁶T₈ twisted boat conformation, while the pyrroline ring has a ⁹T_8a conformation.     

Syntheses of Examples of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-ij]quinoline, 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk][1,4]benzodiazepine,and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-kl][1]benzazocine ring systems

Lithiation of 1-vinylbenzotriazole 9 with n-BuLi (2 equiv) generates dianion 10, which upon subsequent reaction with 1,2- and 1,4-diketones affords 14 and 13, representatives of the 5,6-dihydro-4H-[1,2,3]triazolo[4,5,1-ij]quinoline 1 and 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[4,5,1-kl][1]benzazocine 2 ring systems, respectively. Reactions of dianion 10 with isocyanates give 15a,b, which contain the 4,5,6,7-tetrahydro[1,2,3]triazolo[4,5,1-jk][1,4]benzodiazepine 3 ring system.     

Synthesis and carbon-13 NMR study of 2-benzyl, 2-methyl, 2-aryloctahydropyrrolo [3,4-c] pyrroles and the 1,2,3,5-tetrahydropyrrolo [3,4-c] pyrrole ring system

2-Benzyl, 2-phenyl, 2- (3-methoxyphenyl) and 2-(3-trifluoromethylphenyl) octahydropyrrolo[3,4-c]pyrrole ( 9a, 9b, 9c , and 9d , respectively) were prepared in five steps from 1-benzylpyrrole-3,4-dicarboxylic acid ( 2 ). 2-Methyloctahydropyrrolo [3,4-c]pyrrole ( 9′a ) was prepared analogously in six steps from 1-methylpyrrole-3,4-dicarboxylic acid ( 3 ). Diborane reduction of 1-benzyl-N-methyl-1H-pyrrole-3,4-dicarboximide ( 7′a ) and 1, N-dibenzyl-1H-pyrrole-3,4-dicarboximide ( 7a ) gave 5-benzyl-2-methyl and 2, 5-dibenzyl-1,2,3,5-tetrahydropyrrolo [3,4-c]pyrrole ( 19 ′ and 19 , respectively); the first reported members of the 1,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole ring system. A detailed study of the carbon-13 nmr shifts permitted a complete assignment for all compounds. Mono and disubstituted products produce a systematic effect on the shifts for the bicyclic ring systems which can be readily interpreted in terms of substituent chemical shifts. The effect of protonation at nitrogen is also shown to produce a series of well defined chemical shifts for the octahydropyrrolo [3,4-c] pyrrole ring system.     

Photochemistry of azole N-oxides. Facile photoisomerisation of 2H-imidazole N-oxides to 1,3-diaza-6-oxabicyclo[3.1.0]hex-3-enes and synthesis of a 1,3-diaza-4,7-dioxatricyclo[4.1.0.1,603,5]heptane

Ultraviolet irradiation of a series of 2H-imidazole N-oxides 2 has been shown to effect a clean isomerisation to derivatives of the new ring system, 1,3-diaza-6-oxabicyclo[3.1.0]hex-3-ene, 7 . Epoxidation of a representative 7 has given access to the hitherto inaccessible trans-fused 1,3-diaza-4,7-dioxatricyclo[4.1.0. ^1,60^3,5]-heptane ring system 9 .     

Synthesis of the tagetitoxin core via photo-Stevens rearrangement

The core structure of the RNA polymerase inhibitor tagetitoxin has been synthesized by one-carbon ring expansion of bridged bicyclic monothioacetals. The key steps are intramolecular ylide formation by reaction between the sulfur atom and a pendant diazoester, followed by an efficient photochemical 1,2-rearrangement to give the desired 9-oxa-3-thiabicyclo[3.3.1]nonane ring system.     

A single crystal X-Ray diffraction analysis of 1,9-dihydro[1] benzothiopyrano[4,3-c] pyrazole 5,5-dioxide

The structure of 1,4-rlihydro[1 ]benzothiopyrano[4,3-c ]pyrazole 5,5-dioxide was determined by single crystal x-ray diffraction. The molecule crystallizes in space group P2₁/c with a = 13.4378(6), b = 5.5938(3), c = 12.9837(6)Å, and β = 103.831°. The final R value is 0.083. Surprisingly, the tautomer with N(2)-H exists in the crystal with the pyrazole ring being planar. The entire system is not planar as the benzene ring is rotated about C(9a) and C(9b) with respect to the pyrazole ring. In the crystal structure the pyrazole exists as hydrogen-bonded dimers with two molecules related by a center of symmetry.     

A different route to the synthesis of 9,10-disubstituted phenanthrenes

We here report the synthesis of 10-aryl-9-hydroxy- and 10-aryl-9-aminophenanthrenes by reaction of the anions of 9-phenanthrol and 9-aminophenanthrene, respectively, with aryl halides (iodobenzene, 4-iodoanisole, 9-bromophenantrene). Good yields of 9,10-disubstituted phenanthrenes were obtained in these reactions (>75% and approximately 50% for the 9-amino and 9-hydroxyphenanthrene rings, respectively). Extension of the procedure to the reaction of both anions with o-dihalobenzenes leads to the synthesis of the ring closure products (aza- or oxa-indeno[1,2-l]phenanthrene), which bear a pentacyclic aromatic condensed ring system, although in lower overall yields (approximately 35%).     

Synthesis of C-nor-heterocyclic steroid analogues

2-Substituted-amino-10H-thiazolo[5,4-b]benz[e]indene derivatives 5 representing a novel ring system were synthesized. Their acylation led to exo-acylated derivatives 9 that could be converted to the corresponding glycine analogues 12 .     

Synthesis of the bicyclic core of tagetitoxin

A synthesis of the 9-oxa-3-thiabicyclo[3.3.1]nonane ring system, which constitutes the core of the RNA polymerase inhibitor tagetitoxin, has been achieved through cyclisation of a thiol onto an electrophilic ketone.     

Synthesis of two new heterocyclic ring systems: Benzo[3,4] cyclohepta[1,2-d]-pyrimidines and benzo[3,4]cyclohepta[2,1-d] pyrimidines

Three 2,4-diamino-l(), 11-dihydro-9H-benzo[3,4]cyclohepta[ 1,2-d]pyrimidines (6a-6c) representing the first examples of a new ring system were synthesized from 2-benzosuberones and cyanoguanidine. Similarly, 2,4-diamino-6,7-dihydro-5H-benzo[3,4]cyelohepta[2,1-d]pyrimidine ( 24 ) was prepared from 1-benzosuberone. The ultraviolet spectral properties of these compounds were examined with reference to those of the analogs in which the central ring is five- and six-mernbered.     

Antimalarial and cytotoxic activities of bicycl

Biological evaluations of bicyclo[6.4.0]dodecenone derivatives on antimalarial activity in vitro against Plasmodium falciparum and cytotoxicity against human KB cells were made. (+/-)-(1R*,4S*,7R*,8S*)-4-tert-Butyl-dimethylsiloxy-5,5-dimethyl-1-methyl-9-methylene-7-phenylsulfonylbicyclo[6.4.0]dodec-2,11-dien-10-one (15) exhibited potent antimalarial activity, whereas (+/-)-(1R*,7R*,8S*)-1-methyl-9-methylene-7-phenylsulfonylbicyclo[6.4.0]dodec-2,11-dien-10-one (14) showed significant cytotoxic activity in human KB cells. Both 14 and 15 possess, as a structural character, the exo-methylene moiety in their 6-membered ring of the 8-6 fused ring system.     

The synthesis of a new polycyclic heterocyclic ring system: Pyrimido[5,6,1-d,e]acridine

The synthesis of a new heterocylic ring system is reported. The condensation of 9,10-dihydro-9-oxo-4-acridine carboxamide (7) with diethoxymethyl acetate gave pyrimido[5,6,1-d,e]acridine-3,7-dione (8). The amide 7 reacts with ethyl chloroformate to afford 2H-pyrimido[5,6,1-d,e]acridine-1,3,7-trione (9).     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 13. Dibenzo-[f,h]phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline

The synthesis of a previously unknown polycyclic heterocyclic ring system, dibenzo[f,h]phenanthro-[9′,10′:4,5]thieno[2,3-c]quinoline ( 4 ), was accomplished via photocyclization of the appropriate amide followed by chlorination. Substitution of the chlorine atom with hydrazine followed by removal of the hydrazine moiety with 10% copper sulfate solution afforded the parent ring system 4 . The unequivocal assignment of its highly congested ¹H and ¹³C spectra was accomplished by utilizing two-dimensional nmr methods.     

Mitomycin synthetic studies: stereocontrolled and convergent synthesis of a fully elaborated aziridinomitosane

Full details of a stereocontrolled and convergent synthetic route to 9a-desmethoxymitomycin A (1) are reported. The target molecule possesses the parent tetrahydropyrrolo[1,2-a]indole ring system characteristic of the mitomycin family of antitumor agents. The synthesis was based on the diastereocontrolled addition of a fully elaborated cinnamylstannane to a pyrrolidine-based N-acyliminium ion as the key convergent step, which resulted in the installation of the C9 and C9a stereogenic centers.