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PubMed2003

Experimental and quantum-mechanical investigation of the vinylsilane-iminium ion cyclization.

A vinylsilane-ketiminium ion cyclization involving iminium species derived from amines 6 and 7 was investigated experimentally as a possible approach to some biologically interesting 1-azaspirocycles. However, even under conditions of microwave irradiation at high temperatures no such cyclization was observed whereas (in line with previous results) the corresponding vinylsilane-aldiminium ion cyclizations were more successful. Aldiminium species substituted alpha to nitrogen displayed no diastereoselectivity in the cyclization of precursors derived from 6 while high trans diastereoselectivity could be obtained for iminium species derived from 7. Quantum-mechanical investigations of the general reaction mechanism underlined the lack of reactivity of ketiminium species and also convincingly explained the observed diastereoselectivities of aldiminium species. The calculations further revealed that (Z)-vinylsilanes cyclize via a silicon-stabilized beta-carbocation, and that any formal aza-Cope rearrangement of the starting material to an allylsilane-iminium species does not take place in a concerted fashion. However, the calculations show that the aza-Cope rearrangement precedes cyclization for the corresponding (E)-vinylsilanes, the overall reaction being energetically slightly less favoured than cyclization of the (Z)-isomers.

Journal Article↗

PubMed1992

Novel cyclization chemistry especially suited for biologically derived, unprotected peptides.

A novel method is described for the cyclization of peptides--or segments of polypeptides--which requires a free N-terminal alpha-amino group and a distal amino acid residue containing a nucleophilic side chain. The reaction is conducted in two steps, both in the aqueous phase. The first step involves acylation of the N-terminal alpha-amino group with iodoacetic anhydride at pH 6. This acylation reaction has greater than 90% specificity for peptide alpha-amino groups and gives no alkylation of Arg, His, Lys or Met by the iodoacetate side product (R. Wetzel et al., Bioconjugate Chem., 1, 114-122, 1990). In the second step, the acylation reaction mixture or the isolated iodoacetyl-peptide is incubated at room temperature to give the cyclic peptide formed by reaction of the nucleophilic side chain with the iodoacetyl moiety. The pH dependence of the cyclization reaction by Met, Lys, Arg or His is consistent with the pKa of the nucleophilic side chain. Thus, peptides containing Met plus other nucleophilic amino acids should preferentially cyclize via Met at low pH. In this paper, preparation of cyclic peptides containing 3-6 amino acids is described; the full range of ring sizes and sequences which can undergo this cyclization has not been further explored. Preliminary results suggest that this method is also fairly general with respect to the amino acid sequence being cyclized. The reaction appears to be particularly suited for cyclization via Lys and Met side chains. All of the cyclized products are sufficiently stable for many biological applications.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetic Anhydrides↗

PubMed2001

Essential role of cyclization sequences in flavivirus RNA replication.

A possible role in RNA replication for interactions between conserved complementary (cyclization) sequences in the 5'- and 3'-terminal regions of Flavivirus RNA was previously suggested but never tested in vivo. Using the M-fold program for RNA secondary-structure predictions, we examined for the first time the base-pairing interactions between the covalently linked 5' genomic region (first ~160 nucleotides) and the 3' untranslated region (last ~115 nucleotides) for a range of mosquito-borne Flavivirus species. Base-pairing occurred as predicted for the previously proposed conserved cyclization sequences. In order to obtain experimental evidence of the predicted interactions, the putative cyclization sequences (5' or 3') in the replicon RNA of the mosquito-borne Kunjin virus were mutated either separately, to destroy base-pairing, or simultaneously, to restore the complementarity. None of the RNAs with separate mutations in only the 5' or only the 3' cyclization sequences was able to replicate after transfection into BHK cells, while replicon RNA with simultaneous compensatory mutations in both cyclization sequences was replication competent. This was detected by immunofluorescence for expression of the major nonstructural protein NS3 and by Northern blot analysis for amplification and accumulation of replicon RNA. We then used the M-fold program to analyze RNA secondary structure of the covalently linked 5'- and 3'-terminal regions of three tick-borne virus species and identified a previously undescribed additional pair of conserved complementary sequences in locations similar to those of the mosquito-borne species. They base-paired with DeltaG values of approximately -20 kcal, equivalent or greater in stability than those calculated for the originally proposed cyclization sequences. The results show that the base-pairing between 5' and 3' complementary sequences, rather than the nucleotide sequence per se, is essential for the replication of mosquito-borne Kunjin virus RNA and that more than one pair of cyclization sequences might be involved in the replication of the tick-borne Flavivirus species.

3' Untranslated Regions↗

PubMed1983

Energetics of DNA twisting. I. Relation between twist and cyclization probability.

The twisting potential of DNA has been determined directly by a method that measures the cyclization probability or j-factor of EcoRI restriction fragments as a function of DNA twist. The cyclization probability is proportional to Kc, the equilibrium constant for cyclization of the restriction fragment via its cohesive ends (Shore et al., 1981). Here we vary the twist of the DNA by making small internal additions to or deletions from a 242 bp EcoRI restriction fragment. A series of 12 DNA molecules has been studied, which range in length from 237 to 254 bp. The cyclization probability is measured from the rates of covalent closure by phage T4 DNA ligase of two systems: (1) a linear restriction fragment in equilibrium with its cyclized form and (2) half molecules (cut by a blunt-end endonuclease) in equilibrium with joined half molecules. The striking result is that, in this DNA size range, the j-factor depends strongly on the fractional twist: the difference between the total helical twist and the nearest integer. Thus j depends in an oscillatory manner on DNA length between 237 and 254 bp with a period of about 10 bp. These data give the free energy of DNA twisting as a function of twist. The curve of j versus DNA length can be fitted to a harmonic twisting potential with a torsional constant of C = 2.4 X 10(-19) erg cm. This value is in reasonable agreement with different estimates of C made by Barkley & Zimm (1979: C = 1.8 X 10(-19) to 4.1 X 10(-19) erg cm) and is somewhat larger than the value obtained resulting from the kinetics of DNA twisting measured by fluorescence depolarization of ethidium intercalated into DNA (C = 1.4 X 10(-19) erg cm; Millar et al., 1982; Thomas et al., 1980) or from spin label studies (Hurley et al., 1982). Our experiments provide a direct measurement of the torsional free energy and they show that the DNA twisting potential is symmetric. Our experiments also indicate that the DNA helix is continuous, or nearly so, in a nicked circle; presumably this happens because the DNA stacking interaction maintains the double helix in register across a single-strand nick. As a consequence, the twist of a singly nicked DNA circle is integral for small (approximately equal to 250 bp) planar DNA circles and there is a change in twist upon cyclization.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiography↗

PubMed2001

Computational analysis of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. A comparison with green fluorescent protein.

Density functional calculations using hybrid functionals (B3LYP) have been performed to study the mechanism of the autocatalytic posttranslational cyclization observed in histidine ammonia-lyase. Two mechanisms were analyzed, the commonly accepted mechanism in which cyclization precedes dehydrogenation (reduced mechanism) and a mechanism in which dehydrogenation precedes cyclization (oxidized mechanism). The reduced pathway is not supported by the calculations, while the alternative oxidized mechanism where a dehydration occurs prior to the formation of the ring yields reasonable energetics for the system. Database searches showed that the oxidative mechanism in which the formation of the dehydro amino acids in residue i + 1 precedes the cyclization is also structurally advantageous as it results in shorter distances between the carbonyl carbon of residue i and the amide nitrogen of residue i + 2 and, therefore, preorganizes the protein for cyclization. Conformational searches showed that these distances were also unusually short and exhibited very little variation in the Delta-Ala143 HAL tetramer, indicating that like GFP the tetrameric form of HAL is rigidly preorganized for cyclization. The monomeric form of HAL is less preorganized than the tetrameric form of HAL. Dehydro amino acids aid in the preorganization, but the main driving force in the rigid tight turn formation is the influence of the surrounding protein.

Amino Acids↗

PubMed2004

Electrophilic-induced cyclization reaction of hexahydroindolinone derivatives and its application toward the synthesis of (+/-)-erysotramidine.

A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups. The formation of a single lactam diastereomer is the result of the stereoelectronic preference for axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered side. Additional experiments showed that a variety of hexahydroindolinones containing tethered pi-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the exclusive product. With this system, initial protonation takes place on the more nucleophilic enol ether pi-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido pi-bond to give the observed product. The electrophilic promoted cyclizations were extended to include the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps.

Cyclization↗

PubMed2002

Synthesis of cyclopentapeptides and cycloheptapeptides by DEPBT and the influence of some factors on cyclization.

Three cyclic peptides - cyclo(GlyAlaTyrLeuAla), cyclo(GlyProTyrLeuAla) and cyclo(GlyTyrGlyGlyProPhePro) - isolated and identified from medicinal herbs were chosen as model cyclic peptides to study the influence of the linear precursors and coupling reagents on cyclization. The 17 linear precursors of these three cyclic peptides were synthesized and cyclized using 3-(diethoxyphosphoryloxy)-(1-3)-benzotriazin-4 (3H)-one (DEPBT) as the major coupling reagent. The present work shows that: (i) the effects of linear peptide precursors on the cyclization are complex but some guidelines for choosing suitable precursor for cyclization could be considered; and (ii) DEPBT results in a higher cyclization yield compared with other coupling reagents. In addition, it was confirmed that peptides containing alternating D and L residues favor cyclization.

Amino Acid Sequence↗

PubMed2005

Cyclization of short DNA fragments and bending fluctuations of the double helix.

Cloutier and Widom [Cloutier, T. E. & Widom, J. (2004) Mol. Cell 14, 355-362] recently reported that the cyclization efficiency of short DNA fragments, about 100 bp in length, exceeds theoretical expectations by three orders of magnitude. In an effort to resolve this discrepancy, we tried modifying the theory. We investigated how the distribution of the angles between adjacent base pairs of the double helix affects the cyclization efficiency. We found that only the incorporation of sharp kinks in the angle distribution provides the desired increase of the cyclization efficiency. We did not find a model, however, that fits all cyclization data for DNA fragments of different lengths. Therefore, we carefully reinvestigated the cyclization of 100-bp DNA fragments experimentally and found their cyclization efficiency to be in remarkable agreement with the traditional model of DNA bending. We also found an explanation for the discrepancy between our results and those of Cloutier and Widom.

Base Pairing↗

PubMed2005

Cyclization of several linear penta- and heptapeptides with different metal ions studied by CD spectroscopy.

A cyclic pentapeptide c(Tyr-Leu-Ala-Gly-Pro) (I), which was isolated and identified from Pseudostellaria heterophylla medicinal herbs, and two cyclic heptapeptides, c(Gly-Tyr-Gly-Gly-Pro-Phe-Pro) (II) and c(Gly-Ile-Pro-Tyr-Ile-Ala-Ala) (III), which were isolated and identified from Stellaria yunnanensis Franch (M), were synthesized by using 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3 H)-one (DEPBT) as a coupling reagent in solution, and mediated by different metal ions, from their linear peptide precursors H-Tyr-Leu-Ala-Gly-Pro-OH (I-1) and H-Ala-Gly-Pro-Tyr-Leu-OH (I-2), H-Gly-Tyr-Gly-Gly-Pro-Phe-Pro-OH (II-1) and H-Gly-Ile-Pro-Tyr-Ile-Ala-Ala-OH (III-1), respectively. The results show that alkali metal ions can improve the cyclization yields and/or the cyclization rates of linear peptide precursors, such as Na(+) ion is favorable for the cyclization of linear pentapeptides and Cs(+) ion is favorable for the cyclization of linear heptapeptides, while some bivalent and trivalent metal ions, such as Mg(2+), Ca(2+), Zn(2+), Fe(2+), Ni(2+) and Cr(3+) reduced/inhibited both the cyclization yields and the cyclization rates of the linear peptide precursors. The circular dichroism spectra of I-1, II-1 and III-1 with different metal ions were studied to elucidate the changes in their secondary structures. It is shown that Cs(+) can induce and stabilize the type I beta-turn conformation in the linear heptapeptide II-1 and the type II beta-turn conformation in the linear heptapeptide III-1.

Circular Dichroism↗

PubMed1980

Non-specific biosynthesis of gammacerane derivatives by a cell-free system from the protozoon Tetrahymena pyriformis. Conformations of squalene, (3S)-squalene epoxide and (3R)-squalene epoxide during the cyclization.

1. A cell-free system from the protozoon Tetrahymena pyriformis was incubated with either [12-3H]squalene or (RS)-2,3-epoxy-2,3-dihydro-[12,13-3H]squalene. Squalene was cyclized into tetrahymanol whereas racemic squalene epoxide was transformed into gammacerane-3 alpha,21 alpha-diol and gammacerane-3 beta,21 alpha-diol. After cyclization of (RS)-2,3-epoxy-2,3-dihydro-[3-3H]squalene, both epimeric gammaceranediols were labelled with a tritium atom located at C-3, showing that no isomerization via a 3-oxo compound occurred. 2. The proton NMR spectra of the cyclization products of synthetic (2E, 22E)-(1,1,1,24,24,24-2H6)squalene and (RS)-(22E)-2,3-epoxy-2,3-dihydro-(1,1,1,24,24,24-2H6)squalene show that squalene and the (3S)enantiomer of its epoxide are cyclized in an all pre-chair conformation, whereas the (3R) enantiomer of squalene epoxide is cyclized in a pre-boat conformation as concerns the cycle A. 3. The squalene cyclase of T. pyriformis presents the same lack of substrate specificity as the cyclase of Acetobacter pasteurianum: in addition to squalene, its normal substrate, it also cyclizes both enantiomers of its epoxide. This conformational versatility is characteristic of squalene cyclases but no longer exists in the squalene epoxide cyclases from eukaryotes.

Animals↗

PubMed1986

Enzymatic cyclization of all-trans pentaprenyl and hexaprenyl methyl ethers by a cell-free system from the protozoon Tetrahymena pyriformis. The biosynthesis of scalarane and polycyclohexaprenyl derivatives.

A cell-free system from the protozoon Tetrahymena pyriformis capable of cyclizing squalene into tetrahymanol cyclizes all-trans pentaprenyl methyl ether to a scalarane-type sesterterpene and all-trans hexaprenyl methyl ether to bicyclo-, tricyclo-, tetracyclo- and pentacyclohexaprenyl methyl ethers, each corresponding to a possible cationic intermediate. The structures of the cyclization products have been determined by spectroscopic methods and are compatible with a biogenetic scheme involving polyprenyl ether cyclization. This is the first direct proof of an enzymatic cyclization of higher isoprenic alcohol derivatives, and we assume it was performed by the squalene-to-hopane cyclase of the protozoon. The formation of a scalarane-type sesterterpene from C25 polyprenyl methyl ether suggests that these terpenoids, whose presence is restricted to a few sponges, might be in fact microbial metabolites. Tricyclopolyprenyl derivatives have been identified in the organic matter from numerous sediments and they were interpreted as being chemical fossils of still unidentified microorganisms. The cyclization of hexaprenyl methyl ether is the first attempt of identification of these tricyclopolyprenol derivatives in living organisms.

Animals↗

PubMed1990

Kinetics and mechanism of the facile cyclization of histidyl-prolineamide to cyclo (His-Pro) in aqueous solution and the competitive influence of human plasma.

A crucial point in the biosynthesis of cyclo (His-Pro), an endogenous and biologically active cyclic dipeptide, is the spontaneous cyclization of its precursor L-histidyl-L-prolineamide (His-ProNH2). In this study the kinetics and mechanism of the cyclization process has been investigated. His-ProNH2 was found to be converted quantitatively to cyclo(His-Pro) in aqueous solution at pH 2-10 and 37 degrees C, the rate of cyclization being maximal at pH 6-7. Buffer substances such as phosphate (pH 6-7.4) were found to catalyse the cyclization. The bell-shaped pH-rate profile observed was accounted for by assuming spontaneous and specific acid- and base-catalysed reactions of the His-ProNH2 species in which the imidazole group is protonated and the primary amino group unprotonated. The much more rapid rate of cyclization of His-ProNH2 (t1/2 of 140 min at pH 6-7 and 37 degrees C) relative to other proline-containing di- and tripeptides studied was suggested to be due to an intramolecular general acid catalytic effect by the protonated imidazole group. In the presence of human plasma enzymatic hydrolysis of His-ProNH2 competed with the cyclization and predominated greatly at 80% plasma concentration.

Buffers↗

PubMed1986

Inhibition of monoterpene cyclases by sulfonium analogs of presumptive carbocationic intermediates of the cyclization reaction.

The enzymatic cyclization of geranyl pyrophosphate to monoterpenes is thought to proceed through a series of carbocation-pyrophosphate anion paired intermediates. Sulfonium analogs of two putative carbocationic intermediates of the cyclization sequence were shown to be inhibitors of the conversion of the acyclic precursor to the bicyclic monoterpenes (+)-alpha-pinene and (+)-bornyl pyrophosphate by partially purified cyclase preparations from sage (Salvia officinalis). The sulfonium analog of the tertiary allylic, linalyl, intermediate (i.e. methyl-(4-methylpent-3-en-1-yl)vinyl-sulfonium perchlorate) provided respective Ki values of 2.5 microM and 3.0 microM against the cyclization to alpha-pinene and bornyl pyrophosphate at a substrate concentration of 5 microM, whereas the sulfonium analog of the monocyclic, alpha-terpinyl, intermediate (i.e. dimethyl-(4-methylcyclohex-3-en-1-yl) sulfonium iodide) exhibited respective Ki values of 3.4 microM and 3.9 microM against the same two cyclizations. The potency of inhibition in all cases increased with increasing substrate concentration, indicating that the affinity of the enzymes for the sulfonium analogs was increased by the presence of the pyrophosphate ester. Inorganic pyrophosphate at a concentration of 50 microM, which alone had little influence on the cyclizations, increased the effectiveness of inhibition of the sulfonium analogs severalfold, and the apparent Ki for inorganic pyrophosphate was reduced manyfold by the presence of either analog at 5 microM. That the combination of sulfonium analog and pyrophosphate provided synergistic inhibition of the electrophilic cyclizations indicated that the cyclases bind the paired species more tightly than either partner alone. Specificity studies suggested that inhibition by the above sulfonium ion:pyrophosphate pairs was due to both electronic and structural resemblance to intermediates of the reaction.

Alkanesulfonates↗

PubMed2001

The cyclization of parent and cyclic hexa-1,3-dien-5-ynes--a combined theoretical and experimental study.

The thermal cycloisomerization of both parent and benzannelated hexa-1,3-dien-5-yne, as well as of carbocyclic 1,3-dien-5-ynes (ring size 7-14), was investigated by using pure density functional theory (DFT) of Becke, Lee, Yang, and Parr (BLYP) in connection with the 6-31G* basis set and the Brueckner doubles coupled-cluster approach [BCCD(T)] with the cc-pVDZ basis set for the parent system. The initial cyclization product is the allenic cyclohexa-1,2,4-triene (isobenzene), while the respective biradical is the transition structure for the enantiomerization of the two allenes. Two consecutive [1,2]-H shifts further transform isobenzene to benzene. For the benzannelated system, the energetics are quite similar and the reaction path is the same with one exception: the intermediate biradical is not a transition state but a minimum which is energetically below isonaphthalene. The cyclization of the carbocyclic 1,3-dien-5-ynes, which follows the same reaction path as the parent system, clearly depends on the ring size. Like the cyclic enediynes, the dienynes were found to cyclize to products with reduced ring strain. This is not possible for the 7- and 8-membered dienynes, as their cyclization products are also highly strained. For 9- to 11-membered carbocycles, all intermediates, transition states, and products lie energetically below the parent system; this indicates a reduced cyclization temperature. All other rings (12- to 14-membered) have higher barriers. Exploratory kinetic experiments on the recently prepared 10- to 14-membered 1,3-dien-5-ynes rings show this tendency, and 10- and 11-membered rings indeed cyclize at lower temperatures.

Journal Article↗

PubMed2006

Computational studies on the cyclization of polycyclic aromatic hydrocarbons in the synthesis of curved aromatic derivatives.

Computational studies on the cyclization reactions of some polycyclic aromatic hydrocarbons (PAHs) were performed at the DFT level. Compounds C26H14 and C24H14, which show the connectivity of C60 fullerene fragments, were chosen as suitable models to study the formation of curved derivatives by six- or five-membered ring formation, upon oxidation to their radical cations. Four possible pathways for the cyclization process were considered: a) initial C-C bond formation to afford a curved derivative, followed by dehydrogenation; b) homolytic C-H cleavage prior to cyclization; c) initial concerted H2 elimination and subsequent cyclization; and d) deprotonation of the radical cations prior to cyclization. Computed reaction and activation energies for these reactions show that direct cyclization from radical cations (pathway a) is the lowest-energy mechanism. The formation of five-membered rings is somewhat more favourable than benzannulation. After new cycle formation, homolytic C-H dissociation to afford the corresponding cations is the most favourable process. These cations react with H* without barrier to give H2* Intermediate deprotonations are strongly disfavoured. The relatively low activation energies compared with carbon cage rearrangements suggest that ionization of PAHs can be used for the tailored preparation of nonplanar derivatives from suitable precursors.

Journal Article↗

PubMed2001

Generality of peptide cyclization catalyzed by isolated thioesterase domains of nonribosomal peptide synthetases.

The C-terminal thioesterase (TE) domains from nonribosomal peptide synthetases (NRPSs) catalyze the final step in the biosynthesis of diverse biologically active molecules. In many systems, the thioesterase domain is involved in macrocyclization of a linear precursor presented as an acyl-S-enzyme intermediate. The excised thioesterase domain from the tyrocidine NRPS has been shown to catalyze the cyclization of a peptide thioester substrate which mimics its natural acyl-S-enzyme substrate. In this work we explore the generality of cyclization catalyzed by isolated TE domains. Using synthetic peptide thioester substrates from 6 to 14 residues in length, we show that the excised TE domain from the tyrocidine NRPS can be used to generate an array of sizes of cyclic peptides with comparable kinetic efficiency. We also studied the excised TE domains from the NRPSs which biosynthesize the symmetric cyclic decapeptide gramicidin S and the cyclic lipoheptapeptide surfactin A. Both TE domains exhibit expected cyclization activity: the TE domain from the gramicidin S NRPS catalyzes head-to-tail cyclization of a decapeptide thioester to form gramicidin S, and the TE domain from the surfactin NRPS catalyzes stereospecific cyclization to form a macrolactone analogue of surfactin. With an eye toward generating libraries of cyclic molecules by TE catalysis, we report the solid-phase synthesis and TE-mediated cyclization of a small pool of linear peptide thioesters. These studies provide evidence for the general utility of TE catalysis as a means to synthesize a wide range of macrocyclic compounds.

Amino Acid Isomerases↗

PubMed2005

Stereochemistry of hexenyl radical cyclizations with tert-butyl and related large groups: substituent and temperature effects.

The long held notion that hexenyl radicals bearing large substituents on the radical carbon cyclize to give 1,2-trans-substituted cyclopentanes is experimentally disproved by study of the radical cyclization of an assortment of simple and complex substrates coupled with careful product analysis and rigorous assignment of configurations. X-ray studies and syntheses of authentic samples establish that the published assignments for cis- and trans-1-tert-butyl-2-methylcyclopentane must be reversed. The original assignment based on catalytic hydrogenation of 1-tert-butyl-2-methylenecyclopentane was compromised by migration of the double bond prior to hydrogenation. The cyclization of 1-tert-butylhexenyl radical is moderately cis selective, and the selectivity is increased by geminal substitution on carbon 3. This selectivity trend is general and extends to relatively complex substrates. It has allowed Ihara to reduce the complexity of an important class of round trip radical cyclizations to make linear triquinanes to the point where two tricyclic products-cis-syn-cis and cis-anti-cis-account for about 80% of the products. However, the further increase in selectivity that was proposed by lowering the temperature is shown to be an artifact of the analysis methods and is not correct. This work solidifies "1,2-cis selectivity" in cyclizations of 1-subsituted hexenyl radicals as one of the most general stereochemical trends in radical cyclizations.

Journal Article↗

PubMed2000

Regiochemistry in aryl radical cyclization onto methylenecycloalkanes

Bu(3)SnH-mediated aryl radical cyclization onto methylenecycloalkanes having a phenylthio, an ester, or a nitrile group at the terminus of the alkenic bond provides exclusively exo cyclization products. The results are in sharp contrast to those reported for nonsubstituted methylenecycloalkanes, which give exclusively endo cyclization products. Formation of endo cyclization products has been suggested to be a result of a consecutive 5-exo cyclization of an aryl radical and neophyl rearrangement. The exo-selective aryl radical cyclization offers a new method for synthesizing fused aromatic compounds containing a benzylic quaternary carbon atom.

Journal Article↗