Asymmetric synthesis of tricyclic tetralin derivatives via an intramolecular photoreaction

An intramolecular photoreaction for the synthesis of tricyclic tetralin derivatives through a Norrish/Yang type cyclization is described. Asymmetric studies on this reaction using ionic chiral auxiliaries gave enantiomeric excesses of up to 99% at conversions of 80%, and the reaction mechanism was mapped out by a single crystal-to-single crystal reaction.     

Synthesis of 3,4‐Fused Tricyclic Indoles Using 3‐Alkylidene Indolines as Versatile Precursors

In this personal account, our recent studies of novel synthetic methods of 3,4‐fused tricyclic indole derivatives using 3‐alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4‐fused tricyclic 3‐alkylidene indolines were developed based on a palladium‐catalyzed intramolecular Heck insertion to an allene‐allylic amination cascade and a platinum‐catalyzed intramolecular Friedel‐Crafts type C?H coupling‐allylic amination cascade. Furthermore, three types of 3,4‐fused tricyclic indoles were accessible from a single 3‐alkylidene indoline precursor via acid‐promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4‐fused tricyclic indole skeleton, (?)‐aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.     

A combined multicomponent-acid catalyzed cyclization reaction as an efficient route to novel tricyclic pyrrolo[2,1-a]isoquinoline derivatives

A simple, new two-step procedure for the synthesis of novel tricyclic pyrrolo[2,1-a]isoquinoline derivatives is described. The initially prepared polysubstituted pyrroles obtained via the four-component condensation of arylglyoxals, cyclic 1,3-dicarbonyls, aminoacetaldehyde dimethyl acetal, and β-keto esters subsequently underwent intramolecular acid-catalyzed cyclization to the desired products in moderate to good yields.     

Synthesis of higher alicyclic compounds from thiophene derivatives

A new method is proposed for the synthesis of higher alicyclic compounds in which bi- and tricyclic molecules possessing the thiophene ring are desulphurized with the aid of Raney nickel New routes to many-membered bi- and tricyclic compounds possessing the thiophene ring have been developed, based on acyloin condensation and intramolecular acylation and alkylation.     

A tactical approach for the synthesis of novel β-lactam-substituted,polycyclic-fused isoxazolidine derivatives via an intramolecular [3+2] cycloaddition reaction

The synthesis of functionalized β-lactam-substituted, tricyclic chromenoisoxazolidine and tetracyclic naphthopyranoisoxazolidine derivatives by intramolecular nitrone cycloaddition reaction is described. The O-allyl hydroxyaldehyde derivatives, obtained from Baylis–Hillman adducts (BHA) derived from β-lactam aldehyde underwent intramolecular cycloaddition reaction to give β-lactam-substituted, polycyclic isoxazolidine derivatives in good yield. All the products were confirmed by spectral analysis. The products with a β-lactam substituent may find good applications in biological chemistry.     

Synthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists

The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.     

Electron-impact-induced fragmentation of some phthalazinone derivatives

The mass spectra of 4-(ω-hydroxyalkylamino)-phthalazinone derivatives (I to IV) have been studied. The most important primary fragmentation process is the fission of the alkyl chain β to the amino group, combined with an intramolecular cyclisation reaction. This process results an ion of tricyclic structure, possessing a 4-membered ring, as was established by partial ¹⁵N labelling.     

Heterocyclic systems. VII Synthesis of 1H-pyrazolo[3,4-e]indolizine derivatives

Suitable 1-phenyl-5-(1-pyrryl)pyrazole intermediates underwent Knoevenagel or Wittig intramolecular olefination to give derivatives of 1H-pyrazolo[3,4-e]indolizine, a hitertho unknown tricyclic heteroaromatic system.     

Facile synthesis of oxa- and azacyclic dienes via cycloalkenation of alkynyltungsten compounds. Stereoselective construction of tricyclic furan and pyran derivatives via intramolecular diels-alder reaction

A convenient and short synthesis of functionalized oxacyclic and azacyclic dienes is developed on the basis of organotungsten chemistry. Alkynyltungsten compounds bearing a tethered alcohol and amine are treated with aldehydes and BF(3).Et(2)O in cold diethyl ether to give tungsten-heterocyclic carbenium salts, further leading to tungsten-heterocyclic dienes via deprotonation with Et(3)N. Hydrodemetalation of these tungsten-heterocyclic dienes is performed by the action of anhydrous Me(3)NO in CH(3)CN. This method is applicable to the synthesis of a number of oxa- and azacyclic dienes, including those tethered with an electron-deficient olefin. The oxacyclic 1,3,8-nonatrienes and 1,3,9-decatrienes undergo intramolecular Diels-Alder reactions upon heating in toluene, yielding tricyclic tetrahydropyran and -furan derivatives with excellent diastereoselectivities.     

Stereoselective diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based polycyclic derivatives

A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ring-closing metathesis as key steps in solution and on solid phase.     

Synthesis of 4,5-fused tricyclic quinolines via an acid-promoted intramolecular Friedel–Crafts allenylation of aniline derivatives

A novel method for synthesizing 4,5-fused tricyclic quinoline derivatives based on an acid-promoted intramolecular Friedel–Crafts allenylation of anilines. Using aryl group-substituted propargyl alcohol derivatives with a meta-substituted N-Boc aniline unit as substrates, a four-step reaction sequence involving an acid-promoted intramolecular Friedel–Crafts allenylation of anilines, an acid-promoted intramolecular C–N bond formation, deprotection of the Boc group, and air oxidation proceeded in a single pot, producing the corresponding 4,5-fused tricyclic quinoline derivatives in 31–84% yield.     

A traceless solid-supported synthesis of novel pyrazinediazepinedione derivatives

A simple, convenient, six-step synthesis of novel, tricyclic pyrazinebenzodiazepinedione derivatives has been described. The strategy is based on the use of the orthogonally-protected, optically pure, (S)-piperazine-2-carboxylic acid, in a Petasis reaction, followed by coupling with anthranilic acid and finally cyclizing cleavage. The investigated method was applied for the synthesis of novel bicyclic pyrazinediazepinedione derivatives. This traceless, solid-supported approach allows the preparation of a wide variety of compounds in moderate yields from commercially available or easily obtainable reagents.     

Synthesis of the optically active key intermediate of FR901483

Efficient synthesis of the tricyclic key intermediate 2 for (−)-FR901483 1 was accomplished. The precursor of the intramolecular aldol reaction 4b is constructed by the Ugi 4CC reaction and subsequent intramolecular Dieckmann condensation. This approach allows a fully stereocontrolled total synthesis of (−)-FR901483, which would provide various derivatives.     

Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin

A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl₂ and Cl₂CHOCH₃ as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery.     

[3+2] Cycloaddition of metal-containing azomethine ylides for highly efficient synthesis of mitosene skeleton

Efficient synthesis of tricyclic indole derivatives bearing a substituent at the 3-position of the indole nucleus was achieved by the [3+2] cycloaddition reaction of transition metal-containing azomethine ylides derived from N-(o-alkynylphenyl)imines with vinyl ethers. Third-row transition metal complexes, especially PtCl₂, turned out to be highly efficient for the reaction of internal alkynes and imidate substrates with wide generality. Moreover, as strong support for the reaction mechanism, the intermediate Pt-carbene complex was found to undergo intramolecular C-H bond insertion reaction to give tetracyclic indoline derivatives when benzyl vinyl ether was employed as a dipolarophile. This protocol provided a facile synthesis of highly functionalized tricyclic indole derivatives found as the basic skeleton of the mitosene family, such as mitomycin C.     

Efficient and structurally controlled synthesis of novel polyhydroxylated indolizidine derivatives with an amino group

Novel polyhydroxylated indolizidine derivatives containing an amino group have been efficiently and divergently synthesized from azasugar aldehyde. The key steps of the strategy involved an effectively microwave assisted 1,3-dipolar cycloaddition of azasugar nitrone and methacrylate for installing a potential amino group and an ester group with a extended chain, and a structurally controlled intramolecular cyclo-amidation for constructing the indolizidine ring system via a key tricyclic indolizinone-containing intermediate.     

New strategies for the synthesis of pyrimidine derivatives

Recent advances in pyrimidine synthesis are described. Modification of conventional strategies involving N-C-N fragment condensation with 1,3-dicarbonyl derivatives remains a common theme in current literature. Other methods, including N-C fragment condensation strategies, provide reactive intermediates capable of intramolecular cyclization and formation of pyrimidine derivatives. These recently developed methodologies offer a valuable addendum to azaheterocycle synthesis.     

The chemistry of 2,3-dihydroisoxazole derivatives

Methods for the synthesis and transformations of 2,3-dihydroisoxazole derivatives are reviewed. Data on reduction and oxidation reactions and intramolecular rearrangements are generalized; their mechanisms are discussed.     

Synthesis of 4‐(2‐hydroxyphenyl)‐1‐phenyl‐1,2,4‐triazolidine‐3,5‐dione derivatives through cyclic transformations of 3‐(2‐phenylcarbazoyl)‐2(3H)‐benzoxazolone derivatives

Four 3‐(3‐benzylidene‐2‐phenylcarbazoyl)‐2(3H)‐benzoxazolone derivatives 3 have been synthesized from benzoxazolone derivatives 1 and benzaldehyde N‐chloroformylphenylhydrazone 2. By acid hydrolysis, these compounds yielded 3‐(2‐phenylcarbazoyl)‐2(3H)benzoxazolone derivatives 4 which were not isolated and were transformed via an intramolecular reaction into 4‐(2‐hydroxyphenyl)‐1‐phenyl‐1,2,4‐triazolidine‐3,5‐dione derivatives 5 in a good yield. Attempts to cyclize these compounds by intramolecular elimination of water into tricyclic compounds 6 with various dehydrating agents were unsuccessful.     

Synthesis of isoquinolines through the coupling of Fischer carbene complexes with o-alkynylpyridine carbonyl derivatives

The reaction of Fischer carbene complex with o-alkynylpyridine carbonyl derivatives has been investigated. This involves the generation of furo[3,4-c]pyridine as transient intermediates through the coupling of o-alkynylpyridine carbonyl derivatives with carbene complex and subsequent Diels–Alder trapping with suitable dienophiles resulted in the formation of isoquinoline derivatives and the entire sequence can be run in one pot. When an olefinic tether was present, intramolecular Diels–Alder cycloaddition occurred followed by ring opening to yield tricyclic alcohols.