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PubMed2001

Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.

Animals↗
PubMed1991

Fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease.

A new class of potent, selective, nonsteroidal inhibitors of aromatase have been discovered. The most potent member of this series is fadrozole hydrochloride, CGS 16949 A, 4-(5,6,7,8-tetrahydroimidazo[1,5-alpha]pyridin-5-yl)benzonitrile monohydrochloride, 26a. In addition, the 6,7-dihydropyrrolo[1,2-c]imidazole (21a) and the 6,7,8,9-tetrahydroimidazo[1,5-alpha]azepine (21b) analogues were synthesized and evaluated. CGS 16949 A's ability to selectively inhibit aromatase (IC50 = 4.5 nM) over other cytochrome P-450 enzymes and suppress estrogen production when administered orally make it a suitable candidate to test the potential of an aromatase inhibitor in estrogen-dependent diseases including breast cancer.

Animals↗
PubMed1989

Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol.

The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.

Animals↗
PubMed1985

Synthesis and antiinflammatory and analgesic activity of 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and related compounds.

5-Acyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and the homologous pyridine and azepine derivatives were synthesized and assayed for antiinflammatory and analgesic activity. 5-Benzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylic acid and the corresponding p-methoxy compound 74 were selected for evaluation as analgesic agents in humans on the basis of their high potency in the mouse phenylquinone writhing assay as well as on their minimal liability to elicit gastrointestinal erosion in rats on chronic administration. Extensive quantitative structure-activity relationship (QSAR) studies of the benzoylpyrrolopyrrolecarboxylic acids have demonstrated that the analgesic (mouse writhing) and antiinflammatory (rat carrageenan paw) potencies of these compounds are satisfactorily correlated with the steric and hydrogen-bonding properties of the benzoyl substituent(s). The 4-vinylbenzoyl compound 95, which was correctly predicted to be highly active in both assays on this basis, is undergoing advanced pharmacological evaluation in animals as a potential antiinflammatory agent.

Analgesics↗
PubMed1990

1,9-Alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines with affinity for the alpha 2-adrenoceptor and the 5-HT1A receptor.

A number of 1,9-alkano-bridged 2,3,4,5-tetrahydro-1H-3-benzazepines were prepared and evaluated for 5-HT1A receptor and alpha 2-adrenoceptor affinity by using radioligand receptor binding techniques. Several compounds displayed 5-HT1A receptor affinity comparable to, or greater than, the known 5-HT1A ligand buspirone. The highest affinity 5-HT1A receptor ligands were N-alkyl-, N-allyl-5-chloro-, and 5-methoxy-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azapines (4c, 4m, 4n), which had pKi values of 7.9-8.1. The S enantiomer of 4c had a higher affinity for the 5-HT1A receptor than the corresponding R isomer (pKi of 8.2 for (S)-4c vs 7.7 for (R)-4c). These compounds had a relatively low affinity for the alpha 2-adrenoceptor (pKi of 7 or less). On the other hand, the closely related 5-chloro-2-methyl-2,3,4,8,9,9a-hexahydro-1H-indeno[1,7-cd]azepine (3b) had high affinity for both the alpha 2-adrenoceptor (pKi = 8.1) and 5-HT1A receptor (pKi = 7.6). These results indicate that the two receptors may share common recognition sites.

Animals↗
PubMed1977

5,6,7,8-Tetrahydroquinolines. 5. Antiulcer and antisecretory activity of 5,6,7,8-tetrahydroquinolinethioureas and related heterocycles.

A series of thioureas derived from 5,6,7,8-tetrahydroquinoline, 1,5-, 1,6-, and 1,8-naphthyridiness, pyrido[2,3-b]azepine, and 7-azaindoline has been prepared and tested for antisecretory activity in the pylorus-ligated rat and protective activity against gastric erosions caused by cold-restraint stress. The thioureas exhibit different structure-activity relationships from the corresponding 5,6,7,8-tetrahydroquinoline-8-thiocarboxamides and these relationships are discussed. The activity of the thioureas is less affected by structural differences than the corresponding thioamides although they probably have the same mode of action.

Animals↗
PubMed1976

Synthesis of aziridinylallylaminophosphine oxides and sulfides as potential adjuvant cancer chemotherapeutic agents.

Bis (1-aziridinyl)(hexahydro-1H-azepin-1-yl)phosphine sulfide, an active anticancer agent with low hematopoietic toxicity in animals and man, was recommended several years ago for breast cancer adjuvant chemotherapy as an alternate drug to thiotepa. This hope had led to the syntheses of aziridinylallylaminophosphine oxides or sulfides (compounds I-XVII) in our laboratories. The resurgent interest in this area of cancer chemotherapy encouraged us to report our synthetic work as well as their evaluation as both anticancer agents and insect chemosterilants. Based on observed antitumor activity in animals, low chemosterilant activity in female species (insects and rats), and histochemical observation of tissue toxicity in rat testes but not in ovaries, these new agents are of potential interest to the breast cancer adjuvant chemotherapy program.

Animals↗
PubMed1985

1-Azacycloalkyl-1,4-benzodiazepin-2-ones with antianxiety-antidepressant actions.

A series of 1-azacycloalkyl-1,4-benzodiazepin-2-ones were synthesized from 1-azacycloalkyl-2-benzoylanilines and corresponding imines and then evaluated for their central nervous system activities. Pharmacological data showed that some of these compounds have potent antidepressant properties, as assessed by their antagonism of tetrabenzine (TBZ) induced ptosis and their inhibition of [3H]norepinephrine uptake into rat brain synaptosomes, as well as their moderate antianxiety properties of preventing of pentylenetetrazol (PTZ) convulsion, suppressing conflict behavior, and displacing potential for [3H]diazepam binding. Introduction of a halogen substituent at position 7 of the 1,4-benzodiazepine ring lengthened the anti-PTZ effects, although the peak effect was slightly reduced and clearly enhanced the anti-PTZ and anticonflict properties. Introduction of Cl to the ortho position of the phenyl ring at position 5 greatly reduced the antidepressant properties. The secondary amine function of the azacyclic ring at position 1 was essential for the production of the antidepressant properties. Of these new series, 7-fluoro-5-(2-fluorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-1,4-benzodi azepin-2 -one has the potential to become a useful antidepressant drug with a moderate antianxiety property.

Animals↗
PubMed1987

Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines.

To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to a suitably oriented aromatic ring (i.e., in an axial orientation approximately orthogonal to the catechol nucleus) in agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) that are selective for this subtype, cis- and trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared. These compounds are 5,6-ethano-bridged derivatives of the D-1 selective dopamine receptor agonist 1. Introduction of the bridge reduces the conformational mobility of the parent molecule. Comprehensive conformational analyses by molecular mechanical methods indicated that both the cis and trans isomers could attain a conformation that places the phenyl substituent in an axial orientation. X-ray analysis of the trans isomer showed an axial disposition of the phenyl ring; however, NMR studies suggest that this conformation is fixed in the trans isomer, but not in the cis. The dopamine receptor binding affinity and intrinsic activity of the cis isomer were considerably greater than those of its trans counterpart; the cis isomer also demonstrated a high degree of selectivity for the D-1 subtypes. One possible explanation of these results, suggested by the molecular modeling studies, is that both the axial orientation of the phenyl postulated to be required for binding to the receptor and a putatively requisite location of the nitrogen in approximately the plane of the catechol ring can be attained only by the cis isomer in which the tetrahydroazepine ring is in a twist conformation. Conversely, these results might simply suggest a preference of the D-1 receptors for benzazepine agonists having the phenyl group in an equatorial orientation. Still another possibility is that the D-1 receptor binding site is in a sterically hindered area accessible only to compounds that are relatively planar. However, it requires an axial 1-phenylbenzazepine for strong binding. Thus, a conformationally flexible cis isomer could more readily achieve the different conformations required to both gain access to and bind with the D-1 site.

Animals↗
PubMed2005

Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain.

As part of a search for dihydrofolate reductase (DHFR) inhibitors combining the high potency of piritrexim (PTX) with the high antiparasitic vs mammalian selectivity of trimethoprim (TMP), the heretofore undescribed 2,4-diamino-6-(2',5'-disubstituted benzyl)pyrido[2,3-d]pyrimidines 6-14 with O-(omega-carboxyalkyl) or omega-carboxy-1-alkynyl groups on the benzyl moiety were synthesized and tested against Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium DHFR vs rat DHFR. Three N-(2,4-diaminopteridin-6-yl)methyl)-2'-(omega-carboxy-1-alkynyl)dibenz[b,f]azepines (19-21) were also synthesized and tested. The pyridopyrimidine with the best combination of potency and selectivity was 2,4-diamino-5-methyl-6-[2'-(5-carboxy-1-butynyl)-5'-methoxy]benzyl]pyrimidine (13), with an IC(50) value of 0.65 nM against P. carinii DHFR, 0.57 nM against M. avium DHFR, and 55 nM against rat DHFR. The potency of 13 against P. carinii DHFR was 20-fold greater than that of PTX (IC(50) = 13 nM), and its selectivity index (SI) relative to rat DHFR was 85, whereas PTX was nonselective. The activity of 13 against P. carinii DHFR was 20 000 times greater than that of TMP, with an SI of 96, whereas that of TMP was only 14. However 13 was no more potent than PTX against M. avium DHFR, and its SI was no better than that of TMP. Molecular modeling dynamics studies using compounds 10 and 13 indicated a slight binding preference for the latter, in qualitative agreement with the IC(50) data. Among the pteridines, the most potent against P. carinii DHFR and M. avium DHFR was the 2'-(5-carboxy-1-butynyl)dibenz[b,f]azepinyl derivative 20 (IC(50) = 2.9 nM), whereas the most selective was the 2'-(5-carboxy-1-pentynyl) analogue 21, with SI values of >100 against both P. carinii and M. avium DHFR relative to rat DHFR. The final compound, 2,4-diamino-5-[3'-(4-carboxy-1-butynyl)-4'-bromo-5'-methoxybenzyl]pyrimidine (22), was both potent and selective against M. avium DHFR (IC(50) = 0.47 nM, SI = 1300) but was not potent or selective against either P. carinii or T. gondii DHFR.

Animals↗
PubMed2006

A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum.

A class of hybrid molecules which we term 'reversed chloroquines' (RCQs) was designed, and a prototype molecule, N'-(7-chloroquinolin-4-yl)-N-[3-(10,11-dihydrodibenzo[b,f]azepin-5-yl)propyl]-N-methylpropane-1,3-diamine (1), was synthesized and tested against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. An in vitro assay against the two strains indicated that 1 was effective at low-nM concentrations against both strains. A preliminary study in mice demonstrated oral efficacy against P. chabaudi and the absence of obvious toxicity. The RCQ approach therefore appears to be feasible.

Animals↗
PubMed1996

Analogs of 3-hydroxy-1H-1-benzazepine-2,5-dione: structure-activity relationship at N-methyl-D-aspartate receptor glycine sites.

A series of aromatic and azepine ring-modified analogs of 3-hydroxy-1H-1-benzazepine-2,5-dione (HBAD) were synthesized and evaluated as antagonists at NMDA receptor glycine sites. Aromatic ring-modified HBADs were generally prepared via a Schmidt reaction with substituted 2-methoxynaphthalene-1,4-diones followed by demethylation. Electrophilic aromatic substitution of benzazepine 3-methyl ethers gave 7-substituted analogs. The preparation of multiply substituted 2-methoxynaphthalene-1,4-diones was effected via Diels-Alder methodology utilizing substituted butadienes with 2-methoxybenzoquinones followed by aromatization. Structural modifications, such as elimination of the aromatic ring, removal of the 3-hydroxyl group, and transfer of the hydroxyl group from C-3 to C-4, were also studied. An initial evaluation of NMDA antagonism was performed using a [3H]MK801 binding assay. HBADs demonstrating NMDA antagonist activity as indicated by inhibition of [3H]MK801 binding were further evaluated employing a [3H]-5,7-dichlorokynurenic acid (DCKA) glycine site binding assay. Selected HBADs were characterized for functional antagonism of NMDA and AMPA receptors using electrophysiological assays in Xenopus oocytes and cultured rat cortical neurons. Antagonist potency of HBADs showed good correlation between the different assay systems. HBADs substituted at the 8-position possessed the highest potency with the 8-methyl (5), 8-chloro (6), and 8-bromo (7) analogs being the most active. For HBAD 6, the IC50 in [3H]-DCKA binding assays was 0.013 microM and the Kb values for antagonism of NMDA receptors in oocytes (NR1a/2C) and cortical neurons were 0.026 and 0.048 microM, respectively. HBADs also antagonized AMPA-preferring non-NMDA receptors expressed in oocytes but at a lower potency than corresponding inhibition of NMDA receptors. HBADs demonstrating a high potency for NMDA glycine sites showed the highest steady-state selectivity index relative to AMPA receptors. Substitution at the 6-, 7-, and 9-positions generally reduced or eliminated glycine site affinity. Moving the hydroxyl group from C-3 to C-4 reduced receptor affinity, and potency was eliminated by the removal of the aromatic ring or the hydroxyl group. These data indicate that the HBAD series has specific structural requirements for high receptor affinity. With the exception of substitution at C-8, modified HBADs generally have a lower affinity at NMDA receptor glycine sites than the parent compound 3. Mouse maximum electroshock-induced seizure studies show that the three HBADs selected for testing have in vivo potency with the 6,8-dimethyl analog (52) being the most potent (ED50 = 3.9 mg/kg, iv).

Animals↗
PubMed1998

d-Fused [1]benzazepines with selective in vitro antitumor activity: synthesis and structure-activity relationships.

The synthesis of novel quinolino[3,2-d][1]benzazepines and pyrido[3,2-d][1]benzazepines is described. The in vitro antitumor activity of the compounds has been tested in the antitumor screening of the National Cancer Institute (NCI). Several 2,4-diarylpyrido[3, 2-d][1]benzazepin-6-ones and -thiones turned out to exhibit considerable cytotoxicity for tumor cells. For studies of SAR within these series, substituents were introduced into the aromatic rings of the parent systems. Compounds from the thiolactam series tended to show higher potency than the corresponding lactams. Prominent compounds with noteworthy activity and remarkable selectivity for renal cancer cell lines are the lactams 10c, 10g, and 10h and the corresponding thiolactams 11c, 11g, and 11h. Methylation of the azepine nitrogen leads to complete loss of activity, whereas annelation of a triazolo ring at the lactam site or transformation of the thiolactam function to a thiolactim ether results in decreased antitumor activity and selectivity. Consequently, the secondary lactam or thiolactam structure of the seven-membered ring has to be regarded as essential for selective antitumor activity.

Antineoplastic Agents↗
PubMed2000

3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: synthesis and pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and its derivatives.

To develop a novel antidepressant drug with central nervous system-stimulating activity, we prepared a series of 1-[omega-(4-substituted phenyl-1-piperazinyl)alkyl]-3, 4-dihydro-2(1H)-quinolinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o-tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5-methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor agonists reduced the sleeping time and the time for recovery from coma whereas two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative sigma receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the sigma receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10, 11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.

Animals↗
PubMed1999

Synthesis and characterization of fluorescent ligands for the norepinephrine transporter: potential neuroblastoma imaging agents.

Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive drug used in the diagnosis and treatment of pheochromocytomas and neuroblastomas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells. Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three of 10 synthesized fluorescent compounds, 1-(1-naphthylmethyl)guanidinium sulfate (1), 1-[2-(dibenz[b, f]azepin-5-yl)ethyl]guanidinium sulfate (2), and (2R, 3S)-2beta-ethoxycarbonyl-3beta-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate (6), exhibited high affinity (IC(50) about 50 nM) for the NET. The nisoxetine derivatives 8 (rac-N-[(3-methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthale nesulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1, 3-benzoxadiazole) and especially the guanidine derivative 4 (1-[4-(4-phenyl-1,3-butadienyl)benzyl]guanidinium sulfate) which are characterized by intermediate affinity for the NET (IC(50) 370-850 nM) caused significant and nisoxetine-sensitive cell fluorescence. At least the guanidine derivative 4 might represent a potentially useful agent for imaging of neuroblastoma cells.

Carrier Proteins↗
PubMed2000

Synthesis of benzo-fused 1-azabicyclo[m.n.0]alkanes via the Schmidt reaction: a formal synthesis of gephyrotoxin.

The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.

Alkaloids↗
PubMed2002

Synthesis of azapolycyclic systems via the intramolecular [4 + 2] cycloaddition chemistry of 2-(alkylthio)-5-amidofurans.

A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with beta-alkoxy-gamma-dithiane amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.

Amides↗
PubMed2002

Novel chiral biferrocene ligands for palladium-catalyzed allylic substitution reactions.

Eleven novel aminophosphine ligands have been synthesized, all of which contain a chiral 2,2' '-bridged biferroceno unit as part of a biferrocenoazepine substructure. The efficiency of these compounds as chiral auxiliaries in palladium-mediated allylic substitution reactions has been investigated. Depending on the degree of (steric) fit between proper ligands and cyclic or noncyclic substrates, reactions with 46-87% ee were achieved. The molecular structure of a palladium dichloride complex of one of the ligands was determined by X-ray diffraction and compared to its binaphthyl analogue. In the solid state, the azepine substructure of these two complexes adopts totally different conformations with either local C(2) (binaphthyl) or local C(1) (biferrocene derivative) symmetry. These structural changes are well-reproduced by empirical force field calculations and are also reflected in significantly different behavior in asymmetric catalysis.

Journal Article↗