Free radical cyclization in molecular aggregates

The cyclization of free radicals has been investigated in micelles and multilamellar lipid bilayer vesicles. The substrate for cyclization is the amphipathic bromohydrin 7-bramo-octadec-11-ene-8-ol, 1. The radical is generated from 1 in aqueous micelles or vesicles by $\text{NaBH}{}_4\text{Bu}{}_3\text{SnCl}$. Four diastereomeric cyclopentanol products are formed in the 5-exo cyclization and the distribution of these products depends on the solvent and aggregate. Product distributions for cyclization in all media which have an aqueous/organic interface are significantly different from product distributions obtained for reactions in homogeneous media.     

Palladium-catalyzed cyclization/Heck- and cyclization/conjugate-addition-type sequences in the preparation of polysubstituted furans

Palladium-catalyzed heterocyclization-coupling sequences have been developed starting from buta-1,2,3-trienyl carbinols and electron-deficient alkenes. Polysubstituted furans are formed where the heterocyclic ring originates from the elements of the butatrienyl carbinol while the electron-deficient olefin is incorporated as a C-3 substituent. In most cases, the reaction proceeds via a Heck-type pathway leading to the efficient formation of 3-vinylfurans. However, couplings with methyl vinyl ketone display a divergent behavior to afford selectively either Heck- or hydroarylation-type products depending on reaction conditions.     

A radical cyclization route to cyclic imines

A novel route to cyclic imines based on 5-exo radical cyclization is explored. The radical precursors are imines prepared from allylamine and readily available α-phenylselenenyl ketones.     

Gold catalyzed cyclization of alkyne-tethered dihydropyrimidones

Dihydropyrimidones are an important class of biologically active heterocycles accessible from the multicomponent Biginelli condensation. Further manipulation of the dihydropyrimidone skeleton gives access to unique heterocycles. Presented herein is a Au-catalyzed cyclization of alkyne-tethered dihydropyrimidones to yield pyridopyrimidones.     

Conjugate addition-initiated Nazarov cyclization

A reaction sequence involving the 1,6-conjugate addition of a nucleophile to a dienyl diketone followed by Nazarov cyclization is described. Several nucleophiles are identified as competent initiators for the sequence. A different reaction outcome is observed when catalytic amounts of nucleophile are employed, involving elimination of the nucleophile after the electrocyclization.     

Electron impact induced cyclization of ortho-substituted diphenylmethanes

Mass spectra of 2-hydroxydiphenylmethane and its derivatives are characterized in the upper mass region by an abundant ion m/z 165. Metastable ion measurements reveal that this ion is formed from the molecular ion of the parent compound by elimination of H₂O and hydrogen. A fluorenyl cation structure is proposed for this ion on the basis of identity of collision induced mass analyzed ion kinetic energy spectra of ion m/z 165 generated from 2-hydroxydiphenylmethane and from fluorene. Four different pathways of formation of a fluorenyl cation are discussed. The contribution of each of these to the genesis of fragment m/z 165 was monitored in a reversed geometry instrument by measuring the first fragmentation in the first field free region and the second fragmentation in the second field free region.     

Intramolecular cyclization of 2-hydroxycinnamaldehydes

The effect of substituents on the intramolecular cyclization of 2-hydroxycinnamaldehydes was studied. It was established that aldehydes that contain bulky groups in the side chain and in the 3 position of the benzene ring are readily converted to intramolecular hemiacetals or bimolecular acetals either spontaneously at the moment of isolation or in solutions in DMF or DMSO, as well as on heating. An increase in the lability of the phenolic proton favors the cyclization.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 460–465, April, 1988.     

Vanadium haloperoxidase-catalyzed bromination and cyclization of terpenes

Marine red algae (Rhodophyta) are a rich source of bioactive halogenated natural products, including cyclic terpenes. The biogenesis of certain cyclic halogenated marine natural products is thought to involve marine haloperoxidase enzymes. Evidence is presented that vanadium bromoperoxidase (V-BrPO) isolated and cloned from marine red algae that produce halogenated compounds (e.g., Plocamium cartilagineum, Laurencia pacifica, Corallina officinalis) can catalyze the bromination and cyclization of terpenes and terpene analogues. The V-BrPO-catalyzed reaction with the monoterpene nerol in the presence of bromide ion and hydrogen peroxide produces a monobromo eight-membered cyclic ether similar to laurencin, a brominated C15 acetogenin, from Laurencia glandulifera, along with noncyclic bromohydrin, epoxide, and dibromoproducts; however, reaction of aqueous bromine with nerol produced only noncyclic bromohydrin, epoxide, and dibromoproducts. The V-BrPO-catalyzed reaction with geraniol in the presence of bromide ion and hydrogen peroxide produces two singly brominated six-membered cyclic products, analogous to the ring structures of alpha and beta snyderols, brominated sesquiterpenes from Laurencia, spp., along with noncyclic bromohydrin, epoxide, and dibromoproducts; again, reaction of geraniol with aqueous bromine produces only noncyclic bromohydrin, epoxide, and dibromoproducts. Thus, V-BrPO can direct the electrophilic bromination and cyclization of terpenes.     

Stereoselective cyclization reactions of IBX-generated alkoxyamidyl radicals

In this paper, a method for the generation of alkoxyamidyl radicals is presented. These N-centered radicals can efficiently be formed starting from the corresponding acylated alkoxyamines using IBX as an oxidant. Stereoselective 5-exo and 6-exo reactions with these N-heteroatom-centered radicals leading to isoxazolidines and [1,2]oxazinanes are discussed. The N-O bond in the heterocycles can readily be cleaved with SmI(2) to provide N-acylated 1,3-amino alcohols.     

A Dieckmann cyclization route to piperazine-2,5-diones

Piperazine-2,5-diones are formed by Dieckmann cyclization (NaH, THF) of substructures of the type CH(2)-N(R)C(O)CH(2)N(R')CO(2)Ph in which the terminal methylene (CH(2)) that is adjacent to nitrogen closes onto the carbonyl group of the phenyl carbamate unit at the other end of the chain. R and R' are alkyl groups, and the terminal methylene is activated by a ketone carbonyl, a nitrile, an ester, or a phosphoryl group. The starting materials are assembled by standard acylation and oxidation processes, starting from a β-(alkylamino)alcohol, an (alkylamino)acetonitrile, an (alkylamino) ester, or an (alkylamino)methyl phosphonate.     

Au-catalyzed cyclization of monoallylic diols

The Ph3PAuCl/AgOTf-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is reported. The reactions proceed rapidly at temperatures as low as -78 degrees C with catalyst loadings as low as 0.1 mol % to provide the products in 79-99% yield. A broad range of structurally diverse substrates perform well in the reaction. When 2,6-disubstituted tetrahydropyrans are produced, the reaction is highly diastereoselective for the 2,6-cis product.     

Orchestration of discoid polyketide cyclization in the resistomycin pathway

Resistomycin is a bacterial polyphenolic metabolite from Streptomyces resistomycificus with a unique pentacyclic "discoid" ring system that clearly differs from the typical linear or angular architectures of aromatic polyketides. The first comprehensive cyclase amino acid sequence-function correlation revealed that the enzymes directing the nascent polyketide chain into a peri-fused system clearly differ from canonical linear and angular cyclases. All genes that are required and sufficent for resistomycin (rem) biosynthesis were identified through systematic dissection and reconstitution of the type II polyketide synthase (PKS) complex. The minimal rem PKS and the first cyclase were successfully cross-complemented with orthologues from the linear tetracenomycin polyketide pathway, indicating that both dekaketide pathways share early biosynthetic steps. In total three cyclases that are involved in discoid cyclization (RemI, RemF, and RemL) were identified by mutational analyses and in vivo pathway reconstitution. Analyses of the metabolic profiles of mutants expressing incomplete gene sets led to the discovery of a novel tetracenomycin derivative, TcmR1. The most surprising finding is that only the concerted action of the PKS and all three cyclases leads to the discoid ring structure. These results provide strong support for a model according to which the multienzyme complex forms a cage in which the polyketide is shaped, rather than a sequential cyclization of the polyketide chain by individual enzymes.     

Density functional study of the ring effect on the Myers-Saito cyclization and a comparison with the Bergman cyclization

Myers-Saito cyclizations of a series of enyne-allenes and enyne-butatrienes have been studied by density functional methods. The pure DFT method, BPW91, in conjunction with the 6-311 basis set is demonstrated to be suitable to study these systems. Geometry optimizations and harmonic frequency calculations were applied for every reactant, transition structure, as well as product. It has been shown that the cyclic structure of reactant lowers significantly the critical distance and reaction barrier. For the Myers-Saito product of (5Z)-1,2,3,5-cyclononatetraen-7-yne (10R), the confinement of ring leads to an essential change of the biradical character from sigma-pi type to sigma-sigma type. The through-bond coupling is therefore involved in this product as in the Bergman products. With the enlargement of the ring, the geometrical distortion weakens the through-bond coupling and raises the stability of the products. As a consequence, 1,5-didehydroindene (10P) presents a particularly long critical distance and lower thermodynamic stability. Detailed comparisons of the reactivities of 10R, (Z)-1-cyclononene-3,8-diyne (13R), and (Z)-1-cyclodecene-3,9-diyne (14R) that represent the core structure of a category of natural antitumor drugs have also been made. It reveals that the reactivity of these three systems is quite similar, despite the fact that the thermochemical properties of the prototypical Myers-Saito and Bergman cyclizations are significantly different from each other.     

Radiation-induced crosslinking and cyclization in 1,2-polybutadiene

In order to get information on the radiolytic changes in 1,2-polybutadiene (1,2-PB) the sol and gel fractions, the conversion of double bonds, the structure and concentration of radicals, the formation of dienes and the formation of gaseous products were measured. In addition, the dose rate dependence and temperature dependence for the conversion of double bonds were determined. G values for double bond conversion depend on molecular weight and range from 20 to 200. G values for crosslinking are about 10. A mechanism for the double bond conversion is proposed which involves initiation by a transformation of the primary radical ion in the vinyl group into a carbonium ion and a radical. This is supported by ESR measurement. Reaction of the carbonium ion with a vinyl group in the same chain gives rise to cyclization, whereas reaction with a vinyl group in a neighboring chain results in crosslinking. A comparison of the G values for conversion of double bonds with the G values for crosslinking shows that the formation of cyclic rings exceeds the formation of crosslinks by a factor of about 10. The corresponding values in 1,4-cis- and 1,4-trans-polybutadiene are much smaller [G(cl) ? 2; G(db) ? 7]. The pendent vinyl groups in 1,2-polybutadiene therefore are more reactive than the vinylidene groups in 1,4-polybutadienes.     

Preparation of thiochromans via thermal cyclization

Formation of the thiochroman ring system is achieved by a two step synthesis that involves heating 3‐thiophenyl‐1‐propanols or 4‐thiophenyl‐2‐butanols in toluene with catalytic amounts of p‐toluenesulfonic acid. The propanols are made by the addition of sulfur stabilized carbanions to styrene oxide, ethylene oxide, propylene oxide, and isobutylene oxide. The carbanions are generated by treatment of either benzyl phenyl sulfide or thioanisole with butyllithium. The effect of substitution at the 1 and 3 positions of the propanols on the reaction yields is discussed. The mechanism of the reaction apparently involves intramolecular electrophilic aromatic substitution rather than a Claisen or thio‐Claisen rearrangement.     

Profound insights into squalene cyclization

In this issue of Chemistry & Biology, our understanding of the formation of pentacyclic hopene from the linear squalene is enhanced by an X-ray structure of a complex between squalene-hopene cyclase and the substrate analog 2-azasqualene.     

Synthesis and intramolecular cyclization of bisthiadiazinylmethane derivatives

Bisthiadiazinylmethane derivatives obtained from 1,2,6-thiadiazine 1,1-dioxides and formaldehyde, undergo unusual intramolecular cyclizations to thiadiazino [4,3-g] [2,1,3] benzothiadiazine tetraoxides. The structures of the newly synthesized compounds are discussed on the basis of ¹H and ¹³C-NMR data and X-ray analysis.     

Interrupting the Nazarov cyclization with indoles

A carbon-terminated interrupted Nazarov reaction is described. The trimethylsilyl enol ethers derived from propargyl vinyl ketones undergo selective proton transfer at the distal acetylenic carbon atom to provide allenyl vinyl ketones as transient intermediates. In the presence of indoles, a cascade of reactions is initiated that converts the initially formed pentadienyl cations to cyclopentenones bearing a quaternary alpha carbon atom.     

Regiochemistry in radical cyclization of allenes

The cyclization of allenic radicals was systematically studied for the first time by computational methods. It was found that the theoretical results at the ONIOM(QCISD(T)/6-311+G(2df,2p):UB3LYP/6-311+G(2df,2p)) level were in good agreement with all the available experimental data. For the cyclization of penta-3,4-dien-1-yl radicals the major product was penta-1,2-diene from direct reduction whereas a small amount of vinylcyclopropane may also be produced. For the cyclization of hexa-4,5-dien-1-yl radicals the major product is 1-methyl-cyclopentene. Furthermore, for the cyclization of hepta-5,6-dien-1-yl radicals both vinylcyclopentane and 1-methyl-cyclohexene are produced. Marcus theory analysis indicated that the formation of an olefinic radical product always had a lower intrinsic energy barrier than the formation of an allylic radical product. On the other hand, the formation of an olefinic radical product was always much less favorable than the formation of an allylic radical product in the thermodynamic term. For the cyclization of substituted hexa-4,5-dien-1-yl radicals, substitution at the allene moiety does not affect the regioselectivity where the allylic radical product is always favored. For the cyclization of hepta-5,6-dien-1-yl radicals, substitution at the allene moiety dramatically affects the regioselectivity, where some radical-stabilizing groups such as -CN and -COMe may even completely reserve the regioselectivity.     

The acid catalyzed cyclization of citral

Fourteen compounds have been identified as products of the acid catalyzed cyclization of citral under mild aqueous acid conditions. Three major products of the reaction, 1,8-epoxy-p-menth-2-ene (11) and trans- and cis-p-menth-2-ene-1,8-diol (16 and 18) are reported here for the first time as products from citral. Possible mechanistic pathways leading to the products are discussed.