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At least 415 records · Page 23Linked to original sources
PubMed2006

Total synthesis of (+)-cis-sylvaticin: double oxidative cyclization reactions catalyzed by osmium.

The double oxidative cyclization of dienes is a viable procedure for making complex natural products containing cis-THF units. A double deprotection/double oxidative cyclization strategy using catalytic osmium tetroxide was used to construct the bisheterocyclic core of cis-sylvaticin and ultimately confirm its structure. The natural product was then prepared by a short sequence of reactions that is exceptionally concise: the final route being just 13 linear steps and 19 chemical operations in total.

Catalysis↗
PubMed2006

Rhodium-catalyzed arylative and alkenylative cyclization of 1,5-enynes induced by geminal carbometalation of alkynes.

A rhodium(I)-catalyzed addition-cyclization of 1,5-enynes with aryl- and alkenylboronic acids has been developed. The reaction allows for efficient C-C coupling of multiple reactive components while accomplishing a net R,H-addition in a single step under mild conditions. In the presence of [Rh(OH)(COD)]2 catalyst and triethylamine base in methanol solvent, a range of 1,5-enynes undergo an intermolecular addition with a wide variety of aryl- and alkenylboronic acids and concomitant endo-selective cyclization to yield 1-aryl and alkenyl-substituted cyclopentene derivatives as the products. Deuterium labeling studies suggest that the reaction involves formation of a rhodium vinylidene complex with the terminal alkyne of the enyne substrate. The subsequent migration of the aryl or alkenyl group from the rhodium center to the alpha-carbon of the vinylidene ligand gives a vinyl rhodium complex, a formal 1,1-carbometalation process of the alkyne. This vinyl rhodium then adds to the pendent alkene, and the protodemetalation of the resulting rhodium enolate affords the product.

Alkadienes↗
PubMed1990

Cyclization-activated prodrugs. Basic carbamates of 4-hydroxyanisole.

A series of basic carbamates of 4-hydroxyanisole was prepared and evaluated as progenitors of this melanocytotoxic phenol. All of the carbamates were relatively stable at low pH but released 4-hydroxyanisole cleanly at pH 7.4 at rates that were structure dependent. A detailed study of the N-methyl-N-[2-(methylamino)ethyl]carbamate showed that generation of the parent phenol followed first-order kinetics with t1/2 = 36.3 min at pH 7.4, 37 degrees C, and was accompanied by formation of N,N'-dimethylimidazolidinone. These basic carbamates are examples of cyclization-activated prodrugs in which generation of the active drug is not linked to enzymatic cleavage but rather depends solely upon a predictable, intramolecular cyclization-elimination reaction.

Animals↗
PubMed1990

Cyclization-activated prodrugs. Basic esters of 5-bromo-2'-deoxyuridine.

Some 3'- and 5'-[[(alkylamino)ethyl]glycyl] esters of 5-bromo-2'-deoxyuridine were prepared and evaluated in vitro as progenitors of the parent alcohol. The esters proved to be relatively stable at low pH but released 5-bromo-2'-deoxyuridine cleanly at rates which were pH and structure dependent. These basic esters are examples of cyclization-activated prodrugs in which generation of active drug is not linked to enzymatic cleavage but rather results from an intramolecular cyclization-elimination reaction.

Bromodeoxyuridine↗
PubMed2006

Structural determinants for N1/N7 cyclization of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) derivatives by ADP-ribosyl cyclase from aplysia californica: Ca2+-mobilizing activity of 8-substituted cyclic inosine 5'-diphosphoribose analogues in T-lymphocytes.

A series of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) analogues modified at C-8 (2-5) and 7-deaza-NHD+ were synthesized, and cyclization in the presence of Aplysia ADP-ribosyl cyclase was studied. All 8-substituted NHD+ analogues were converted into their N1-cyclic forms by the enzyme, while in contrast, 7-deaza-NHD+ 17 was hydrolyzed into 7-deazainosine 5'-diphosphoribose (7-deaza-IDPR) 25. Correlations are made showing that the conformation of the NHD+ substrate is the key to successful cyclization. The pharmacological activities of these novel cIDPR derivatives were evaluated in both permeabilized and intact Jurkat T-lymphocytes. The results show that in permeabilized cells both 8-iodo 1g and 8-N3-N1-cIDPR 1d have an activity comparable to that of cADPR, while 8-iodo 1g and 8-phenyl-N1-cIDPR 1c have a small but significant effect in intact cells and can therefore be regarded as membrane-permeant; thus, cIDPR derivatives are emerging as important novel biological tools to study cADPR-mediated Ca2+ release in T-cells.

ADP-ribosyl Cyclase↗
PubMed2000

Synthesis of pyrimidine 2'-deoxy ribonucleosides branched at the 2'-position via radical atom-transfer cyclization reaction with a vinylsilyl group as a radical-acceptor tether.

Recently, we developed a regio- and stereoselective method for introducing a vinyl group at the position beta to a hydroxyl group in halohydrins or alpha-phenylselenoalkanols via a radical atom-transfer cyclization reaction with a vinylsilyl group as a temporary connecting radical-acceptor tether. The synthesis of 2'-deoxy-2'-C-vinyl- and 2'-deoxy-2'-C-hydroxymethyluridines (7 and 8, respectively) and the corresponding 2'-deoxycytidine congeners (10 and 11, respectively), which were designed as potential antitumor and/or antiviral agents, was achieved using this radical atom-transfer cyclization as the key step. When the 2'-deoxy-2'-iodo-5'-O-monomethoxytrityl (MMTr) uridine derivative 19a, bearing a vinylsilyl group at the 3'-hydroxyl group, was heated with (Me(3)Sn)(2) and AIBN in benzene, the corresponding radical atom-transfer product was generated, which in turn was successively treated with tetrabutylammonium fluoride and TBSCl/imidazole to give the desired 2'-deoxy-5'-O-MMTr-3'-O-TBS-2'-C-vinyluridine (25). Compound 25 was successfully converted into the target 2'-deoxy-2'-branched pyrimidine ribonucleosides 7, 8, 10, and 11.

Antineoplastic Agents↗
PubMed2001

Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones.

1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a-e, 12 and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones 9a-f, 14 are readily available from reactions of benzotriazole (4), 2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran (5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-benzothiazepines 7a-e and 10a-f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines 13 and 15, respectively.

Antibiotics, Antineoplastic↗
PubMed2003

Mn(III)/Cu(II)-mediated oxidative radical cyclization of alpha-(Methylthio)acetamides leading to erythrinanes.

Treatment of N-[2-(3,4-dimethoxyphenyl)ethyl]-alpha-(methylthio)acetamide 3 with Mn(OAc)3 in the presence of Cu(OAc)2 gave tetrahydroindol-2-one 4, which then cyclized with Mn(OAc)3 to give 4-acetoxyerythrinane 5. A similar reaction of the 3,4-methylenedioxyphenyl congener 8 also gave tetrahydroindol-2-one 9, which, however, gave only a trace amount of the Mn(OAc)3-mediated cyclization product 11 and afforded the oxidation product 10. On the basis of these results, formation of 5 from 4 was thought to proceed via nucleophilic attack of the pyrrole ring on the cation-radical lX, generated by a single electron-transfer reaction of the acetoxy-substituted intermediate V. Treatment of compound 16 with Mn(OAc)3/Cu(OAc)2 gave no erythrinane derivative with recovery of the starting material, indicating that the presence of a methylthio group of 4 is essential for effecting the formation of erythrinane 5. On the other hand, treatment of 3 with Mn(OAc)3 using Cu(OTf)2 as an additive in place of Cu(OAc)2 gave another erythrinane 17. This method was applied to a formal synthesis of 3-demethoxyerythratidinone (20), a naturally occurring Erythrina alkaloid.

Acetamides↗
PubMed2003

A tandem metal carbene cyclization-cycloaddition approach to the pseudolaric acids.

An approach toward the synthesis of the antifungal and cytotoxic pseudolaric acids based on the tandem metal carbene cyclization-cycloaddition reaction is described. Using this strategy, the advanced intermediate 3a bearing three of the four stereocenters of the target molecules has been synthesized. The substrate-controlled diastereoselectivity of the tandem carbene cyclization-cycloaddition was preferential for the undesired diastereomer, but reagent control through the use of Hashimoto's chiral rhodium catalyst Rh(2)(S-BPTV)(4) reversed the selectivity in favor of 3a. Ring opening of the oxabicyclic nucleus to give a hydroxycycloheptene has been demonstrated in a model study.

Antifungal Agents↗
PubMed2003

Quantitating the effect of an ortho substituent on cyclization and intramolecular hydrogen-transfer reactions of aryl radicals.

Reduction of allyl 2-iodobenzyl malonates with triphenyltin hydrides generates aryl radicals that partition between 6-exo cyclization, 7-endo cyclization, and 1,5-hydrogen atom transfer. Rate constants for all of these processes are high (>10(8) M(-)(1) s(-)(1)), and the rates are only marginally reduced (<33%) by the introduction of methyl group ortho to the reacting radical.

Alkylation↗
PubMed2003

Triflic anhydride mediated cyclization of 5-hydroxy-substituted pyrrolidinones for the preparation of alpha-trifluoromethylsulfonamido furans.

The reaction of alpha-angelica lactone with alkylamines under aqueous conditions afforded 5-hydroxy-5-methylpyrrolidinones in high yield. When the reaction was carried out under anhydrous conditions, the only products obtained were the corresponding 4-oxopentanoic acid amides. Treatment of either class of compound with triflic anhydride (Tf(2)O) in pyridine resulted in the formation of various substituted sulfonamidofurans. The suggested mechanism involves initial formation of an iminium ion which is subsequently transformed into a transient imino triflate. Cyclization of the highly electrophilic imine onto the oxygen atom of the adjacent carbonyl group generates an imino dihydrofuran intermediate. This species reacts further with another equivalent of Tf(2)O to give the observed product. The nature of the Lewis acid used was found to affect the outcome of the cyclization reaction. In certain cases, the sulfonamide furan was utilized as a cycloaddition substrate for the synthesis of indolines and related heterocyclic systems.

Amides↗
PubMed2003

Stereocontrol in the EtAlCl(2)-induced cyclization of chiral gamma,delta-unsaturated methyl ketones to form cyclopentanones.

EtAlCl(2)-induced cyclization of chiral gamma,delta-unsaturated ketones 11c and 17b takes place mainly from the expected face. The selectivity is modest for 11c (60:40) in which the large substituent is a primary alkyl group and the medium substituent is a methyl group and excellent for 17b (93:7) in which the large substituent is a cyclohexyl group and the medium substituent is a methyl group. The cyclization of 17a is anomalous, suggesting that the phenyl group has more than a simple steric effect.

Cyclization↗
PubMed2005

A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach.

A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters.

Aza Compounds↗
PubMed2004

Synthesis of novel KDR kinase inhibitors through catalytic reductive cyclization of o-nitrobenzylcarbonyl compounds.

An efficient synthesis of o-nitrobenzylcarbonyl compounds is demonstrated through the Swern-type oxidation of readily accessible phenethanol analogues. Reductive cyclization of o-nitrobenzylcarbonyl 3 using catalytic Raney nickel gives 1H-indol-2-yl-1H-quinoline 2 in 95% yield. Hydrolysis of 2 affords the KDR kinase inhibitor 1 in quantitative yield. The examination of the reductive cyclization reaction and optimization of conditions is described.

Catalysis↗
PubMed2004

Effect of ligand structure on the asymmetric cyclization of achiral olefinic organolithiums.

The ability of a large and chemically diverse set of 30 chiral ligands to effect asymmetric cyclization of 2-(N,N-diallylamino)phenyllithium (1), derived from N,N-diallyl-2-bromoaniline (2) by low-temperature lithium-bromine exchange, has been investigated in an attempt to elucidate the structural motifs required to provide high enantiofacial selectivity in the ring closure. Although none of the ligands examined in this study afforded 1-allyl-3-methylindoline in significantly higher ee than previously observed for the cyclization of 1 in the presence of the benchmark ligand (-)-sparteine, several ligands, structurally unrelated to sparteine and available in either enantiomeric form, were found to match the utility of (-)-sparteine in this chemistry.

Alkenes↗
PubMed2004

Radical and palladium-catalyzed cyclizations to cyclobutenes: an entry to the BCD ring system of penitrem D.

A novel approach toward the synthesis of the BCD ring system of penitrem D is described. The strategy capitalizes on the fast cyclization rates of aryl radicals into cyclobutenes and allows access to a variety of fused tricyclic structures. Radical/polar crossover reactions of precursors 24-29 promoted by samarium diiodide in the presence of HMPA and acetone allow access to the fully functionalized BCD ring system of penitrem D. The stereochemical implications of these processes are evaluated, and a Pd-mediated cyclization approach toward the penitrems is also introduced.

Catalysis↗
PubMed2005

Extending Pummerer reaction chemistry. development of a strategy for the regio- and stereoselective oxidative cyclization of 3-(omega-nucleophile)-tethered indoles.

The brominative cyclization of diastereomeric beta-silyloxy tryptophan derivatives proceeded with divergent regiochemistry (C(2) or C(3) addition), depending on the relative stereochemistry of the silyloxy substituent. This lack of C(2) vs C(3) regiochemical predictability led to the development of a new approach, which featured Pummerer-type chemistry on an indole C(2) sulfoxide or sulfide substrate, for steering nucleophilic addition to C(3) of the indole. Extension of this transformation from carboxylate nucleophiles to carbon analogues such as allylsilane, silyl enol ether, and silyl ketene iminal bearing substrates led to the formation of spirocyclic oxindole derivatives in good yields with complete regioselectivity for C(3) cyclization and with good diastereoselectivity where relevant.

Cyclization↗