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[Structure: see text] On activation by pyridine N-acylation, enolates of N-nicotinoyl and N-isonicotinoyl glycine and alanine derivatives cyclize to yield 6,5-azabicyclic or 6,4-azaspirocyclic lactams. With an N-alpha-methyl-p-methoxybenzyl group the cyclization is diastereoselective; hydrogenation and deprotection yields azabicyclic amino acids in 94:6 er.
We systematically investigated, for the first time, the relationship between regioselectivity and acid/base effects in the cyclization reactions between carboxylic acids and carbon-carbon triple bonds. We found novel acid- and base-promoted cyclizations to selectively give isocoumarin or pyran-2(2H)-one and phthalide or furan-2(5H)-one skeletons, respectively, and established a catalytic version of regioselective heterocyclic ring synthesis. Density functional theory calculations and application to a short route to thunberginol A were also described. [reaction: see text].
Copper(I) chloride catalyzed chlorine atom transfer radical cyclization reactions of a series of olefinic alpha-chloro beta-keto esters were investigated. It was found that alpha-dichlorinated beta-keto esters were suitable substrates; the chlorine transfer mono or tandem radical cyclization reactions catalyzed by CuCl complex with bis(oxazoline) or bipyridine proceeded smoothly in dichloroethane at room temperature or 80 degrees C, providing cyclic and bicyclic compounds in moderate to high yield. [reaction: see text]
[formula: see text] beta-Siloxy unsaturated nitriles are excellent precursors to enolate and nitrile anions that cyclize to cis- and trans-decalins, respectively. The stereoelectronic requirements of endocyclic enolates and exocyclic nitrile anions are complementary, providing cis- and trans-decalins from a common intermediate. This cyclization allows the synthesis of diastereomeric cis- and trans-decalins containing a contiguous array of quaternary-tertiary-quaternary stereocenters.
An exploratory study of the rates of cyclization of the title compounds, all 3-hydroxyphenalkanolamines, with formaldehyde to 1,2,3,4-tetrahydroisoquinolines (THIQs) was performed using high-performance liquid chromatographic (HPLC) methods. Reactions occur quantitatively and practically instantaneously at room temperature and neutral pH; thus, rates were measured at acid pH. Cyclization occurs ortho or para to the 3-phenolic function, so that all but the 3,5-dihydroxyphenyl derivatives, metaproterenol and terbutaline, gave two THIQs. Terbutaline reacted significantly slower than the other compounds. Formaldehyde occurs in pharmaceutical systems and it serves as a model for other aldehydes that occur in sugars and flavors. The pharmaceutical implications of the reaction are discussed.
Lewis acid-promoted cyclizations of heteroatom-substituted enynes have been examined. The reaction of enynes and bearing silicon substituents on an alkyne afforded the halogenated five-membered gamma-lactones and gamma-lactams as the main products. The reaction of substrates and having 2-phosphonoacrylate instead of malonate also gave halogenated five-membered cyclic compounds and as the major products. The cyclized products are highly substituted and potentially useful for further synthetic transformations.
The halogen atom transfer radical cyclization (HATRC) has been evaluated on N-(indolylmethyl)trichloroacetamides under Cu(I)Cl catalysis using nitrogen containing ligands. The ring closure leads to the formation of 3,3-spiro-3H-indoles in moderate to good yields by a 5-exo-mechanism. Derivatives with an N-electron withdrawing substituent also lead to a 5-exo-trig and not to a 6-endo-trig cyclization.
Mode of radicalcyclization (5-exovs. 6-endo) was investigated by using 6-(bromomethyl)dimethylsilyl derivatives of 1',2'-unsaturated uridine with an aim to develop a new stereoselective method for the introduction of an alpha-hydroxymethyl group at the anomeric position. Although the 2'-unsubstituted derivative underwent only 6-endo-cyclization, substrates bearing 2'-CO2Me or 2'-OBz group gave exclusively 5-exo-cyclized products with a high stereoselectivity.
The study of protein-protein interactions can be hampered by the instability of one or more of the protein complex components. In this study, we showed that intein-mediated cyclization can be used to engineer an artificial intramolecular cyclic protein complex between two interacting proteins: the largely unstable LIM-only protein 4 (LMO4) and an unstructured domain of LIM domain binding protein 1 (ldb1). The X-ray structure of the cyclic complex is identical to noncyclized versions of the complex. Chemical and thermal denaturation assays using intrinsic tryptophan fluorescence and dynamic light scattering were used to compare the relative stabilities of the cyclized complex, the intermolecular (or free) complex, and two linear versions of the intramolecular complex (in which the interacting domains of LMO4 and ldb1 were fused, via a flexible linker, in either orientation). In terms of resistance to denaturation, the cyclic complex is the most stable variant and the intermolecular complex is the least stable; however, the two linear intramolecular variants show significant differences in stability. These differences appear to be related to the relative contact order (the average distance in sequence between residues that make contacts within a structure) of key binding residues at the interface of the two proteins. Thus, the restriction of the more stable component of a complex may enhance stability to a greater extent than restraining less stable components.
The various types of conformationally restricted peptides obtained by short-range cyclizations, from residue i to residue i + 1, are presented. Relevant examples of N in equilibrium C alpha, C' in equilibrium C alpha, N in equilibrium C', C alpha in equilibrium C alpha, C' in equilibrium C', and N in equilibrium N cyclizations are reported and the pertinent literature listed. In the discussion emphasis is place on the conformational consequences for peptides from the incorporation of such ring structures.
Twelve polycyclic triterpenic hydrocarbons (alpha- and gamma-polypodatetraenes, dammara-20(21),24-diene, 17-isodammara-12,24-diene, eupha-7,24-diene, hop-17(21)-ene, neohop-13(18)-ene, 17-isodammara-20(21),24-diene, neohop-12-ene, fern-8-ene, diploptene and hop-21-ene) were detected in the hydrocarbon fraction from the bacterium Zymomonas mobilis. Some of them have never been reported from bacteria. These triterpenes were present in Z. mobilis in significant amounts, comparable to those of diploptene, which is usually the major triterpenic hydrocarbon in hopanoid-producing bacteria. The occurrence of such compounds confirms the lack of specificity of bacterial squalene cyclases and the possibility of alternative cyclization routes induced by the existence in the cyclization process of intermediate carbocations of sufficient lifetime.
The cyclization of N-(5-chloropentyl)-N-methylaminoaceto-2,6-xylidide hydrochloride (RAD 150) and N-(5-bromopentyl)-N-methylamino-aceto-2,6-xylide hydrobromide (RAD 154) in red blood cells of rats and rabbits was examined under in vitro and in vivo conditions. The rate of cyclization was much slower in plasma and blood than in a buffer solution, probably due to influence of protein binding of the compounds. The tertiary amines disappeared rapidly from the blood cells in vitro and in vivo and the piperidinium derivative (RAD 179) formed from the haloalkylamines disappeared almost as rapidly as the tertiary amines from the plasma in vivo. In contrast, the efflux of RAD 179 formed in the blood cells was slow (T 1/2 for rabbit erythrocytes: 9 h in vitro; 8 h in vivo) following a 1st order reaction. RAD 179 itself was only to a small extent taken up in the blood cells.
The crystal structure of pentalenene synthase at 2.6 angstrom resolution reveals critical active site features responsible for the cyclization of farnesyl diphosphate into the tricyclic hydrocarbon pentalenene. Metal-triggered substrate ionization initiates catalysis, and the alpha-barrel active site serves as a template to channel and stabilize the conformations of reactive carbocation intermediates through a complex cyclization cascade. The core active site structure of the enzyme may be preserved among the greater family of terpenoid synthases, possibly implying divergence from a common ancestral synthase to satisfy biological requirements for increasingly diverse natural products.
Two major goals for the design of new catalysts are the facilitation of chemical transformations and control of product outcome. An antibody has been induced that efficiently catalyzes a cationic cyclization in which an acyclic olefinic sulfonate ester substrate is converted almost exclusively (98 percent) to a cyclic alcohol. The key to the catalysis of the reaction and the restriction of the product complexity is the use of antibody binding energy to rigidly enforce a concerted mechanism in accord with the design of the hapten. Thus, the ability to direct binding energy allows the experimenter to dictate a reaction mechanism which is an otherwise difficult task in chemistry. New catalysts for cationic cyclization may be of general use in the formation of carbon-carbon and carbon-heteroatom bonds leading to multi-ring molecules including steroids and heterocyclic compounds.
Cell-free cyclization of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine to isopenicillin N by lytic enzyme extracts of Cephalosporium acremonium M-0198 was stimulated by ferrous ions. The optimum concentration of FeSO4 was 80 microM. No additional stimulation was observed with ascorbate, adenosine 5'-triphosphate, or alpha-ketoglutarate, but Triton X-100 and sonication of the extracts increased activity. ZnSO4 was very inhibitory to enzyme activity; CuSO4 was somewhat less inhibitory, and the least effective of the three was MnCl2. The dimer of the tripeptide was converted to a penicillin that has the biological spectrum of isopenicillin N, and this reaction was also stimulated by FeSO4. We found that sonication can be used directly to prepare extracts with cyclization activity from mycelia, without preparing protoplast lysates. The kinetics of cyclase appearance and disappearance during fermentation were similar to those of ring-expansion activity, i.e., enzyme appeared and peaked 13 h after growth ceased and then disappeared.
The actions of cyclomaltodextrin glucanotransferases (CGTase; EC 2.4.1.19) from alkalophilic Bacillus sp. strain A2-5a (A2-5a CGTase), Bacillus macerans (Bmac CGTase), and Bacillus stearothermophilus (Bste CGTase) on amylose were investigated. All three enzymes produced large cyclic alpha-1,4-glucans (cycloamyloses) at the early stage of the reaction, but these were subsequently converted into smaller cycloamyloses. However, the rates of this conversion differed among the three enzymes. The product specificity of each CGTase in the cyclization reaction was determined by measuring the amount of each cycloamylose from CD6 to CD31 (CDn, a cycloamylose with a degree of polymerization of n). A2-5a CGTase produced 10 times more CD7, while Bmac CGTase produced 34 times more CD6 than other cycloamyloses. Bste CGTase produced 12 and 3 times more CD6 and CD7 than other cycloamyloses, respectively. The substrate specificities of the linearization reactions of CD6, CD7, CD8, and larger cycloamyloses (a mixture of CD22 to CD50) were investigated, and we found that CD7 and CD8 are extremely poor substrates for both hydrolytic and transglycosidic linearization (coupling) reactions while larger cycloamyloses are linearized at a much higher rate. By repeating these cyclization and linearization reactions, the larger cycloamyloses initially produced are converted into smaller cycloamyloses and finally into mainly CD6, CD7, and CD8. These three enzymes also differ in their hydrolytic activities, which seem to accelerate the conversion of larger cycloamyloses into smaller cycloamyloses.
Glycogen debranching enzyme (GDE) has 4-alpha-glucanotransferase and amylo-1,6-glucosidase activities in the single polypeptide chain. We analyzed the detailed action profile of GDE from Saccharomyces cerevisiae on amylose and tested whether GDE catalyzes cyclization of amylose. GDE treatment resulted in a rapid reduction of absorbance of iodine-amylose complex and the accumulation of a product that was resistant to an exo-amylase (glucoamylase [GA]) but was degraded by an endo-type alpha-amylase to glucose and maltose. These results indicated that GDE catalyzed cyclization of amylose to produce cyclic alpha-1,4 glucan (cycloamylose). The formation of cycloamylose was confirmed by high-performance anion-exchange chromatography, and the size was shown to range from a degree of polymerization of 11 to a degree of polymerization around 50. The minimum size and the size distribution of cycloamylose were different from those of cycloamylose produced by other 4-alpha-glucanotransferases. GDE also efficiently produced cycloamylose even from the branched glucan substrate, starch, demonstrating its potential for industrial production of cycloamylose.
The thionium ions 10 generated by Pummerer reaction of N-aryl-N-methyl-3-(phenylsulfinyl)propionamides 4 caused not only an electrophilic cyclization reaction producing 2-quinolones 8, but also the formation of the vinyl sulfides 5 and 6 in favor of the latter reaction. On the other hand, the treatment of the vinyl sulfides 5 and 6 with p-toluenesulfonic acid induced cyclization to afford the 2-quinolones 8 in excellent to moderate yields, depending on the electronic properties of the aromatic ring, thus providing a convenient method for the synthesis of methoxy-2-quinolones.