Pentacyclic laddersiloxane

A novel method which effects ring extension of the ladder oligosilsesquioxanes was developed. By applying this method, we synthesized the first functionalized tricyclic laddersiloxanes and pentacyclic laddersiloxane. The reaction of (i-PrSi(OH)O)4 with (i-PrPhClSiO)2 in pyridine gave the tetraphenyl tricyclic laddersiloxane. Following dephenylchlorination with AlCl3/HCl, and hydrolysis enabled us to isolate the tetrahydroxyl tricyclic laddersiloxane in good yield. We repeated the similar reaction from this tetrahydroxyl laddersiloxane, and the first pentacyclic laddersiloxane was obtained. The structures of the tetraphenyl and tetrahydroxyl tricyclic laddersiloxanes, and pentacyclic laddersiloxane were determined by X-ray crystallography.     

Unified Asymmetric Total Syntheses of (−)-Alotaketals A–D and (−)-Phorbaketal A

The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)-alotaketals A–D and (−)-phorbaketal A were accomplished [29–31 steps from (−)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C−H oxidation, and 3) olefin cross-metathesis to install the different side chains.     

Unified Asymmetric Total Syntheses of (−)‐Alotaketals A–D and (−)‐Phorbaketal A

The novel tricyclic spiroketal alotane‐type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)‐alotaketals A–D and (−)‐phorbaketal A were accomplished [29–31 steps from (−)‐malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ‐keto‐alcohols to forge the common tricyclic spiroketal intermediate, 2) a late‐stage allylic C−H oxidation, and 3) olefin cross‐metathesis to install the different side chains.     

Synthesis and Structure-Activity Relationships of Anticholinergics of Dibenzo[b,e] oxepin(thiepin) Hydroxycarboxylates

In order to investigate the relationships between the conformations of tricyclic hydroxycarboxylates and their anticholinergic activities, and to explore the effects of changing the linking groups between the two benzene rings in tricyclic compounds on anticholinergic activities and on the selectivity to the central nicotinic receptor, a series of new tricyclic anticholinergic compounds-dibenzo[b,e]oxepin (thiepin) hydroxycarboxylates (Fig. 1) were designed and synthesized.     

Synthesis of Pyrimidine-Annelated Heterocycles: Regioselective Heterocyclization of 5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil [1]

 5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil undergoes regioselective heterocyclization to afford fused tricyclic heterocycles upon treatment with bromine and m-CPBA. However, the same substrate furnished bridged tricyclic heterocycles when treated with N-iodosuccinimide and conc. H₂SO₄ and a mixture of bridged tricyclic heterocycles and fused tricyclic heterocycles when treated with hexamine hydrotribromide or pyridine hydrotribromide.     

Synthesis of Pyrimidine-Annelated Heterocycles: Regioselective Heterocyclization of 5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil [1]

Summary.  5-(Cyclohex-2-enyl)-1,3-dimethyl-6-hydroxyuracil undergoes regioselective heterocyclization to afford fused tricyclic heterocycles upon treatment with bromine and m-CPBA. However, the same substrate furnished bridged tricyclic heterocycles when treated with N-iodosuccinimide and conc. H₂SO₄ and a mixture of bridged tricyclic heterocycles and fused tricyclic heterocycles when treated with hexamine hydrotribromide or pyridine hydrotribromide. Corresponding author. E-mail: kcm@klyuniv.ernet.in Received September 27, 2001. Accepted (revised) December 3, 2001     

新的苯并二氮卓类三环化合物：1H，10H4，9－二氢－环戊并［1，2－b］［1，5］苯并二氮卓－10－酮及其3－甲基衍生物的合成

通过邻苯二胺与环戊酮的β－羧酸酯缩合及催化氢化，合成了由环戊基与苯并二氮并环形成的新的苯并二氮类三环化合物。     

A modular reaction pairing approach to the diversity-oriented synthesis of fused- and bridged-polycyclic sultams

A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, S(N)Ar addition and Mitsunobu alkylation) generating skeletally diverse, tricyclic and bicyclic benzofused sultams is reported. Pairing sulfonylation and S(N)Ar reactions yields bridged, tricyclic and bicyclic benzofused sultams. Application of the Mitsunobu reaction in a sulfonylation-Mitsunobu-S(N)Ar pairing allows access to benzthiazocine-1,1-dioxides, while a simple change in the order of pairing to sulfonylation-S(N)Ar-Mitsunobu affords structurally different, bridged tricyclic benzofused sultams.     

Synthesis of 2,4-diaminoquinazolines and tricyclic quinazolines by cascade reductive cyclization of methyl N-cyano-2-nitrobenzimidates

An efficient route to N(4)-substituted 2,4-diaminoquinazolines has been developed by employing tandem condensation of cyanoimidate-amine and reductive cyclization in iron-HCl system. This method is tolerant of a following intramolecular N-alkylation and produces two fused heterocycles in a one-pot procedure. This protocol is a facile two-step synthesis of tricyclic quinazolines, which is effected by potent cyanoimidation and tandem reductive cyclization from 2-nitrobenzaldehydes. Moreover, the forming process of tricyclic quinazolines has been investigated from the ring-opening/ring-closing cascade point of view. It is found that the preparation of tricyclic quinazolinones in good yields relies on the selective hydrolysis of tricyclic quinazolines in base or acid system.     

Reaction of o-oxazolinylphenyllithium with carbon monoxide. Carbonylative cyclization via an aroyllithium intermediate

The carbonylation of a phenyllithium containing an oxazoline group at the ortho position, followed by quenching with water, afforded a tricyclic compound, 3,3-dimethyl-2,3-dihydrooxazolo[2, 3-a]isoindol-5(9bH)-one, in 91% yield. This reaction proceeded via an intramolecular cyclization of the aroyllithium species, to give the tricyclic dienolate. Treatment of the tricyclic dienolate with electrophiles, such as alkyl halides, aldehydes, ketones, and epoxides gave the substituted oxazolo[2,3-a]isoindolinones in good yield.     

Metathesis cascade strategies (ROM-RCM-CM): a DOS approach to skeletally diverse sultams

The development of a ring-opening metathesis/ring-closing metathesis/cross-metathesis (ROM-RCM-CM) cascade strategy to the synthesis of a diverse collection of bi- and tricyclic sultams is reported. In this study, functionalized sultam scaffolds derived from intramolecular Diels-Alder (IMDA) reactions undergo metathesis cascades to yield a collection of tricyclic sultams. Additional appendage-based diversity was achieved by utilizing a variety of CM partners.     

Copper (II) catalysed decomposition of penicillin - derived diazoketones: formation of a novel fused β-lactam

Penicillanic acid diazoketone undergoes decomposition in the presence of copper (II) acetylacetonate in benzene solution leading to the C-6 unsubstituted tricyclic ketone (3b) and the novel tricyclic oxapenam (4b) as the minor product.     

Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.     

A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach

Hydroxyindoline-derived scaffold, 9, was synthesized with the goal of generating a library of indoline-based natural product-like tricyclic derivatives to be utilized as small-molecule chemical probes. The tricyclic ring was obtained by a Mitsunobu reaction of the N-nosyl amino acid conjugate with the primary hydroxyl group. The solid-phase synthesis was achieved by immobilizing scaffold 9 onto the solid support giving a compound, 15. This was then subjected to a series of reactions on solid phase, including the Mitsunobu reaction, leading to the desired indoline-derived tricyclic derivative. The final product has two diversity sites: (i) amino acid as the first diversity and (ii) amidation of the secondary amine for the second diversity. These two diversity sites were utilized in the library generation by IRORI split-and-mix approach.     

Enantioselective syntheses of various chiral multicyclic compounds with quaternary carbon stereocenters by catalytic intramolecular cycloaddition

The intramolecular cycloaddition of 1,n-diene-ynes (n = 4-6), where alkyne and alkene moieties are connected by a 1,1-disubstituted alkene, was examined using a chiral rhodium catalyst, and various types of cycloadducts with quaternary carbon stereocenter(s) were obtained in high to excellent enantiomeric excess. In the case of 1,4-diene-ynes, tricyclic, bicyclic, and spirocyclic compounds were obtained depending upon the substituents at the 2-position of the 1,4-diene moiety and those at their alkyne termini. On the other hand, 1,5- and 1,6-diene-ynes gave tricyclic and bicyclic compounds, which included medium-sized ring systems. The mechanistic considerations for different reaction pathways and the synthetic transformation of tricyclic products into functionalized spirocyclic compounds are also described. The reaction of enediynes, where two alkyne moieties are connected by a 1,1-disubstituted alkene, was also examined, and sterically strained tricyclic compounds with two carbon stereocenters were obtained.     

Highly diastereoselective and asymmetric Diels-Alder reactions of masked o-benzoquinones with chiral racemic and homochiral furans. Synthesis of optically active tricyclic gamma-lactones

[reaction: see text] The first examples of highly diastereoselective and asymmetric Diels-Alder cycloadditions of in situ generated masked o-benzoquinones (MOBs) with chiral racemic and homochiral furans bearing a chiral center in the alpha-position leading to highly functionalized diastereomeric/enantioselective tricyclic heterocycles and chiral tricyclic gamma-lactones are described.     

Cascade polycyclization: exploration of a convergent route to access various tricyclic and tetracyclic products related to sterols

The expedient synthesis of tricyclic and tetracyclic compounds via a cascade polycyclization methodology is described. Nazarov substrates (II) containing two Michael acceptors and a cyclohexenone ester (I) underwent cycloaddition followed by intramolecular 1,4-addition to furnish, in a highly stereoselective manner, tricyclic and tetracyclic products (III). Such compounds are interesting intermediates for the synthesis of polycyclic natural and unnatural products.     

Atmospheric pressure ionization time-of-flight mass spectrometry coupled with fast liquid chromatography for quantitation and accurate mass measurement of five pharmaceutical drugs in human plasma

The quantitative determination and accurate mass measurement of five tricyclic amine pharmaceutical drugs (doxepin, desipramine, imipramine, amitriptyline and trimipramine) fortified in human plasma within a per sample run time of 18 s was accomplished by atmospheric pressure ionization (API) time-of-flight (TOF) mass spectrometry using a turboIonspray liquid chromatography/mass spectrometry (LC/MS) interface coupled with high-performance liquid chromatography (HPLC). The relatively short HPLC separation (18 s) was achieved using a short C18 column (15 x 2.1 mm i.d.) with a high aqueous mobile phase maintained at a flow-rate of 1.4 ml min(-1). An acquisition speed of 0.2 s per spectrum accommodates these fast separation conditions. This method employs a one-step liquid-liquid extraction procedure to isolate the five tricyclic amines from biological matrix components The overall extraction recovery was 75% for desipramine and >90% for the other four tricyclic amines. The lower level of quantitation was 1-2 ng ml(-1) for each compound. The calibration curve was linear from 2 to 100 ng ml(-1) for desipramine and from 1 to 50 ng ml(-1) for the other four tricyclic amines. A deuterated internal standard, imipramine-d3, was used for all five tricyclic amines. Acceptable intra- and inter-assay precision (1.0-17.7%) and accuracy (0.2-14.5%) were obtained. The linear dynamic range was extended to 200 based on a software upgrade for correcting ion current detection saturation. The accurate masses of the five tricyclic amines were determined by on-line LC/TOFMS analyses of biological extracts using two-point internal mass calibration. This was done by infusing a reference standard, Jeffamine D230, post-column into the HPLC effluent. All results showed a mass error not greater than 9 ppm for all the target compounds. These results were obtained from both synthetic mixtures when as little as 100 pg were injected or extracts of spiked human plasma samples with analytical concentration as low as 5 ng ml(-1). The factors influencing accurate mass measurements are discussed.     

Rapid access to the tricyclic spirotetronic core of abyssomicins

[reaction: see text] Abyssomicins, a novel class of polyketide antibiotics, are characterized by an unprecedented spirotetronic tricyclic subunit in their structure. In this letter, a short synthesis of a suitably functionalized tricyclic precursor of abyssomicins is reported. Key steps of the synthesis are (i) the highly stereoselective Al(III)-tethered Diels-Alder reaction and (ii) the tandem Dieckmann cyclization/TBS trapping of the C9 hydroxyl group followed by a regioselective intramolecular epoxide opening for the assembly of the target tricyclic structure.     

Quinazolines et benzodiazépines-1,4. LX Imidazo[5,1-c]benzodiazépines-1,4

Upon treatment with oxalyl chloride followed by reaction with the appropriate nucleophile, the 3-carbamoyl-benzodiazepines 6 , 7 and 8 were converted stereospecifically to the tricyclic compounds 12, 13, 14, 16 and 19 . Epimerization of 19 in presence of p-toluenesulfonic acid led to 21 . The stereochemistry of these tricyclic compounds and of some of their N(2)-alkyl derivatives ( 22-31 ) has been established by NMR. spectroscopy. Under proper reaction conditions, attack by bases on the tricyclic esters 13 and 26 was shown to cause an inversion of the chiral center C(11a) and to yield stereospecifically rearranged products, e.g. 23 from 26 and 33 from 13 .