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PubMed1999

Intramolecular Cyclizations of o-Acylbenzyllithiums. Formation of Benzocyclobuten-1-ol Derivatives and Their Thermal Isomerization.

The formation of benzocyclobutenol derivatives by intramolecular cyclizations of o-acylbenzyllithiums is described. Treatment of o-(trialkylsilylmethyl)phenyl ketones with lithium diisopropylamide (LDA) followed by quenching of the resulting benzylic carbanions with chlorotrialkylsilane resulted in stereoselective formation of the corresponding 1-trialkylsiloxy-2-(trialkylsilyl)benzocyclobutenes in good yields. Subsequently, o-acyl-m-methoxybenzyllithiums were found to work well in cyclization to benzocyclobuten-1-ol derivatives. The reaction of 2-benzoyl-3,4,5-trimethoxybenzyllithium, generated in situ by deprotonation of 6-methyl-2,3,4-trimethoxybenzophenone with LDA, with chlorotrimethylsilane afforded the corresponding 1-(trimethylsiloxy)benzocyclobutene. Cyclization of 2-pivaloyl-3-methoxybenzyllithiums, generated in situ from tert-butyl 2-methyl-6-methoxyphenyl ketones upon deprotonation with LDA, proceeded spontaneously even at -78 degrees C to give the corresponding benzocyclobuten-1-ols. We also describe the results of thermal isomerization of these 1-trimethylsiloxy-2-(trialkylsilyl)benzocyclobutenes.

Journal Article↗
PubMed2000

General base and general acid catalyzed intramolecular aminolysis of esters. Cyclization of esters of 2-aminomethylbenzoic acid to phthalimidine.

Plots of log k(0) vs pH for the cyclization of trifluoroethyl and phenyl 2-aminomethylbenzoate to phthalimidine at 30 degrees C in H(2)O are linear with slopes of 1.0 at pH >3. The values of the second-order rate constants k(OH) for apparent OH(-) catalysis in the cyclization reactions are 1.7 x 10(5) and 5.7 x 10(7) M(-)(1) s(-)(1), respectively. These rate constants are 10(5)- and 10(7)-fold greater than for alkaline hydrolysis of trifluoroethyl and phenyl benzoate. The k(OH) for cyclization of the methyl ester is 7.2 x 10(3) M(-)(1) s(-)(1). Bimolecular general base catalysis occurs in the intramolecular nucleophilic reactions of the neutral species. The value of the Bronsted coefficient beta for the trifluoroethyl ester is 0.7. The rate-limiting step in the general base catalyzed reaction involves proton transfer in concert with leaving group departure. The mechanism involving rate-determining proton transfer exemplified by the methyl ester in this series (beta = 1.0) can then be considered a limiting case of the concerted mechanism. General acid catalysis of the neutral species reaction or a kinetic equivalent also occurs when the leaving group is good (pK(a) </= 12.4). That the mechanism and/or rate-determining step of the intramolecular aminolysis reactions is different than in bimolecular reactions or the intramolecular reactions of other esters is attributed to the excellent steric fit of the nucleophile to the reaction center of the 2-aminomethylbenzoate esters.

Buffers↗
PubMed2000

Studies dealing with thionium ion promoted mannich cyclization reactions.

Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient intermediates. Further reaction of the alkylthio-substituted lactam with DMTSF generates an N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach toward various nitrogen-containing ring systems. The cyclization reaction was employed for a synthesis of the core skeleton of the erythrina alkaloid family.

Disulfides↗
PubMed2001

Diastereocontrol by trialkylaluminums in the synthesis of tetrahydrofurans via radical cyclization.

[reaction: see text]. The influence of various Lewis acids in the radical cyclization of beta-allyloxyalkyl phenyl selenides was investigated. Whereas the unperturbed cyclization afforded trans-2,4-disubstituted tetrahydrofurans as the major products (cis/trans approximately 1/4.5), cyclization in the presence of trialkylaluminums (3 equiv) afforded predominantly (cis/trans approximately 7/1) the corresponding cis-isomers.

Journal Article↗
PubMed2004

Nucleophilic addition to electron-rich heteroaromatics: dearomatizing anionic cyclizations of pyrrolecarboxamides.

[reaction: see text] Despite its electron-rich nature, a pyrrole ring is susceptible to intramolecular nucleophilic attack by organolithiums. The resulting dearomatizing anionic cyclization yields new 5- or 7-membered heterocyclic rings. Formation of a new 5-membered ring, by cyclization of an N-benzylpyrrolecarboxamide, is accompanied by ring opening of the original pyrrole to yield 3-aminovinylpyrrolinones. Formation of a new 7-membered ring, by cyclization of an N-allyl pyrrolecarboxamide, yields bicyclic pyrroloazepinones.

Journal Article↗
PubMed2005

Highly regioselective radical cyclizations of allenamides.

The first radical cyclizations of allenamides are described. These reactions are highly regioselective for the central carbon of the allenic moiety, leading to an efficient preparation of nitrogen heterocycles such as isoquinolines, and carbocycles such as indane and naphthalene derivatives. The exo-cyclization mode could also be achieved in some cases, leading to the synthesis of isoindoles. The feasibility of a tandem radical cyclization using allenamide is also established. [reaction: see text]

Journal Article↗
PubMed2004

Cyclization of 1-bromo-2,7- and 1-bromo-2,8-enynes mediated by indium.

[reaction: see text] The cyclization of 1-bromo-2,7- and 1-bromo-2,8-enynes mediated by indium in DMF produced five- and six-membered cyclic compounds. Although KI was a necessary additive in the cyclization of terminal 1-bromo-2,7-enynes to give the desired products at 25 degrees C, reactions of terminal 1-bromo-2,8-enynes and internal 1-bromo-2,7-enynes with indium proceeded at 100 degrees C in DMF without KI. After cyclizations, subsequent cross-coupling reaction and iodolysis increase the usefulness of this reaction.

Journal Article↗
PubMed2006

Unprecedented SnCl2-mediated cyclization of nitro arenes via N-N bond formation.

[reaction: see text] A mild, efficient, one-pot protocol for the cyclization of nitro-aryl substrates using SnCl(2) has been described. The mechanistic course of the reaction suggests the involvement of a hydroxylamine intermediate leading to an intramolecular cyclization via N-N bond formation. The versatility of the methodology has been demonstrated by using two nitro-aryl substrates derived from dihydroisoquinolines and dihydro-beta-carbolines. The intramolecular cyclization led to the formation of indazoles in high yields and purities.

Journal Article↗
PubMed2006

Regioselective unusual formation of spirocyclic 4-{2'-benzo(2',3'-dihydro)furo}- 9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indole by 4-exo-trig aryl radical cyclization and rearrangement.

4-(2'-Bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles under tri-n-butyltin hydride mediated aryl radical cyclization furnished exclusively the 4-{2'-benzo(2',3'-dihydro)furo}-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles in excellent yield (75-80%) via 4-exo-trig cyclization, opening of the oxetene ring, and 5-endo-trig cyclization.

Journal Article↗
PubMed2006

A general method for the catalytic nazarov cyclization of heteroaromatic compounds.

A general, catalytic method for efficient Nazarov cyclization of systems containing heteroaromatic components has been developed. Scandium triflate was identified as the most reactive promoter, and it was found that addition of lithium perchlorate was necessary for synthetically useful catalytic cyclizations. The method was used to synthesize a range of cyclopentanone-fused heteroaromatic systems in 36-97% yield, and the reactivity trends observed demonstrate the impact of polarization on cyclization efficiency. [reaction: see text].

Journal Article↗
PubMed2000

Aryl radical cyclizations of 1-(2'-bromobenzyl)isoquinolines with AIBN-Bu3SnH: formation of aporphines and indolo

[reaction: see text] Radical cyclization of alkoxy-substituted 1-(2'-bromobenzyl)-3,4-dihydroisoquinolines 1 with AIBN-Bu3SnH gave 6a,7-dehydroaporphines 2 preferentially. A steric repulsion between the respective alkoxy groups at the 7- and 3'-positions gave 5,6-dihydroindolo[2,1-a]isoquinolines 3 in a "disfavored" 5-endo cyclization mode. Radical cyclizations of the related substrates, such as 1-(2'-bromobenzoyl)isoquinolines or 1-(2'-bromo-alpha-hydroxybenzyl)isoquinolines, were also found to give the corresponding oxoaporphines or oxyaporphines.

Journal Article↗
PubMed2000

Acid-catalyzed cyclization of vinylsilanes bearing an amino group. Stereoselective synthesis of pyrrolidines

[reaction: see text] In the presence of an acid catalyst, vinylsilanes 1 bearing an amino group protected by an electron-withdrawing group were smoothly cyclized to 2-(silylmethyl)pyrrolidines 2. This cyclization was utilized for the stereoselective synthesis of 2,n-disubstituted pyrrolidines (n = 3-5). The cyclized products could be converted to the corresponding alcohols by oxidative cleavage of the carbon-silicon bond with TBAF and H2O2.

Journal Article↗
PubMedDate not supplied

Autocatalytic cyclization of an excised intervening sequence RNA is a cleavage-ligation reaction.

The intervening sequence (IVS) of the Tetrahymena ribosomal RNA precursor is excised as a linear RNA molecule which subsequently cyclizes itself in a protein-independent reaction. Cyclization involves cleavage of the linear IVS RNA 15 nucleotides from its 5' end and formation of a phosphodiester bond between the new 5' phosphate and the original 3'-hydroxyl terminus of the IVS. This recombination mechanism is analogous to that by which splicing of the precursor RNA is achieved. The circular molecules appear to have no direct function in RNA splicing, and we propose the cyclization serves to prevent unwanted RNA from driving the splicing reactions backwards.

Animals↗
PubMed2004

Reactions of 2,4-hexadiyne-1,6-diol with [H2Os3(CO)9(PR3)] clusters. Cyclization of the diyne and reversible exchange of the phosphine ligands between different positions of the "Os3C3" framework.

Reactions between unsaturated [H(2)Os(3)(CO)(9)(PR(3))] clusters (PR(3)= PPh(3), P(4-CF(3)-C(6)H(4))(3), PEt(3)) and 2,4-hexadiyne-1,6-diol have been studied. It was found that the diyne ligand easily reacts with all these complexes to give [HOs(3)(CO)8(PR3)-[mu3, eta1:eta3:eta1)-(CH(3)-C-C=CH-CH=C-O)]] complexes (V, VI and VII, respectively) containing the "Os3C3" pentagonal pyramid cluster framework. This structural pattern is formed through the diyne cyclization, dissociation of a CO ligand and eventual coordination of the cyclized organic moiety to the osmium triangle in the [mu3, eta1:eta3:eta1) manner. In the case of the PEt(3) substituted cluster the second hydride transfer onto the organic fragment occurs to afford the nonhydride [Os(3)(CO)(8)(PR3)[mu3), eta1:eta2:eta1)-(CH(3)-CH-C=CH-CH=C-O)]] cluster, VIII, containing distorted pentagonal pyramid framework with a broken Os-C bond. Heating V, VI of VII and in hexane solutions results in formation of the regioisomers (Va, VIa and VIIa) with the phosphine ligand located at adjacent osmium atoms across the Os-Os bond bridged by the coordinated organic fragment. The most probable mechanism of the isomerization includes reversible phosphine migration between these metal centres. Solid-state structure of V, Va, VI, VIIa and VIII have been established by single crystal X-ray diffraction. A general mechanistic scheme for the diyne ligand cyclization and cluster framework transformations is suggested and discussed.

Journal Article↗
PubMed2004

Enzymatic cyclization reactions of geraniol, farnesol and geranylgeraniol, and those of truncated squalene analogs having C20 and C25 by recombinant squalene cyclase.

The substrate specificity of squalene-hopene cyclase was investigated using the C10-C25 analogs including naturally occurring substances, e.g. geraniol (C10), farnesol (C15) and geranylgeraniol (C20). No cyclization occurred for geraniol, but a significantly high conversion ratio (64%) was observed for farnesol, yielding the cyclic sesquiterpenes consisting of 6/6-fused bicyclic ring systems. Among them, an attractive compound having C30 was produced, in the structure of which acyclic the farnesol unit is linked to the bicyclic skeleton through ether linkage. Conversion of geranylgeraniol was low (ca. 12%). The squalene analogs having C20 and C25 also were cyclized in yields of ca. 33-36%, but the analogs having the methyl group at C7 and/or at C11 underwent no cyclization; the large steric bulk size of C7-Me and/or C11-Me, which is arranged in [small alpha]-disposition for all the pre-chair conformation, would have interacted repulsively with the cyclase recognition site near to the C7 and/or C11, resulting in no construction of the all-chair conformation inside the reaction cavity. A relatively low yield of geranylgeraniol indicated that a less bulky hydrogen atom must be located at C14 for the efficient polycyclization reaction. The squalene cyclase shows remarkably broad substrate specificity to accept the truncated analogs having carbon-chain lengths of C(15)-C25 in addition to C30.

Journal Article↗
PubMed2002

Abietadiene synthase catalysis: mutational analysis of a prenyl diphosphate ionization-initiated cyclization and rearrangement.

Abietadiene synthase catalyzes the committed step in resin acid biosynthesis, forming a mixture of abietadiene double-bond isomers by two sequential, mechanistically distinct cyclizations at separate active sites. The first reaction, protonation-initiated cyclization, converts the universal diterpene precursor geranylgeranyl diphosphate to the stable bicyclic intermediate copalyl diphosphate. In the second, magnesium ion-dependent reaction, diphosphate ester ionization-initiated cyclization generates the tricyclic perhydrophenanthrene-type backbone and is coupled, by intramolecular proton transfer within a transient pimarenyl intermediate, to a 1,2-methyl migration that generates the C13 isopropyl group characteristic of the abietane structure. Alternative deprotonations of the terminal abietenyl carbocation provide a mixture of abietadiene, levopimaradiene, and neoabietadiene, and this product profile varies as a function of pH. Mutational analysis of amino acids at the active site of a modeled structure has identified residues critical for catalysis, as well as several that play roles in specifying product formation, apparently by ligation of a magnesium ion cofactor. These results strongly suggest that choice between alternatives for deprotonation of the abietenyl intermediate depends more on the positioning effects of the carbocation-diphosphate anion reaction partners than on the pKa of multiple participating bases. In one extreme case, mutant N765A is unable to mediate the intramolecular proton transfer and aborts the reaction, without catalyzing 1,2-methyl migration, to produce only sandaracopimaradiene, thereby providing supporting evidence for the corresponding stereochemistry of the cryptic pimarenyl intermediate of the reaction pathway.

Amino Acid Motifs↗
PubMed2005

Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII.

Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the alpha-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.

Animals↗