Initial Cyclization Research Articles

Enantio- and Diastereoselective Stepwise Cyclization of Polyprenoids Induced by Chiral and Achiral LBAs. A New Entry to (−)-Ambrox, (+)-Podocarpa-8,11,13-triene Diterpenoids, and (−)-Tetracyclic Polyprenoid of Sedimentary Origin

An enantio- and diastereoselective stepwise cyclization of polyprenoids induced by Lewis acid-assisted chiral Brønsted acids (chiral LBAs) and achiral LBAs is described. In particular, the absolute stereocontrol in the initial cyclization of polyprenoids to form an A-ring induced by chiral LBAs and the importance of the nucleophilicity of the internal terminator in polyprenoids for the relative stereocontrol in subsequent cyclization are demonstrated. (-)-Ambrox was synthesized via the enantioselective cyclization of (E,E)-homofarnesyl triethylsilyl ether with tin(IV) chloride-coordinated (R)-2-(o-fluorobenzyloxy)-2'-hydroxy-1,1'-binaphthyl ((R)-BINOL-o-FBn) and subsequent diastereoselective cyclization with CF(3)CO(2)H.SnCl(4) as key steps. Protection of (E,E)-homofarnesol by a triethylsilyl group increased the enantioselectivity of chiral LBA-induced cyclization and both the chemical yield and diastereoselectivity in the subsequent cyclization. The enantioselective cyclization of homo(polyprenyl)arenes possessing an aryl group was also induced by (R)-BINOL-o-FBn.SnCl(4). Several optically active podocarpa-8,11,13-triene diterpenoids and (-)-tetracyclic polyprenoid of sedimentary origin were synthesized (75-80% ee) by the enantioselective cyclization of homo(polyprenyl)benzene derivatives induced by (R)-BINOL-o-FBn.SnCl(4) and subsequent diastereoselective cyclization induced by BF(3).Et(2)O/EtNO(2) or CF(3)CO(2)H .SnCl(4).

Backbone cleavages of [M - H](-) anions of peptides. Cyclisation of citropin 1 peptides involving reactions between the C-terminal [CONH](-) residue and backbone amide carbonyl groups. A new type of beta cleavage: a joint experimental and theoretical study.

This paper reports the study of backbone cleavages in the collision-induced negative-ion mass spectra of the [M - H](-) anions of some synthetic modifications of the bioactive amphibian peptide citropin 1 (GLFDVIKKVASVIGGL-NH(2)). The peptides chosen for study contain no amino acid residues which could effect facile side-chain cleavage, i.e. Ser (-CH(2)O, side-chain cleavage) and Asp (-H(2)O) are replaced by Ala or Lys. We expected that such peptides should exhibit standard and pronounced peaks due to alpha cleavage ions (and to a lesser extent beta cleavage ions) in their collision-induced negative-ion spectra. This expectation was realised, but the spectra also contained peaks formed by a new series of cleavage anions. These are produced following cyclisation of the C-terminal CONH(-) moiety at carbonyl functions of amide groups along the peptide backbone; effectively transferring the NH of the C-terminal CONH(-) group to other amino acid residues. We have called the product anions of these processes beta' ions, in order to distinguish them from standard beta ions. Some beta' ions also fragment directly to some other beta' ions of smaller mass. The reaction coordinates of alpha,beta and beta' backbone processes have been calculated at the HF/6-31G*//AM1 level theory for simple model systems. The initial cyclisation step of the beta' sequence is barrierless and exothermic. Subsequent steps have a maximum barrier of +40 kcal mol(-1), with the overall reaction being endothermic by some 30 kcal mol(-1) at the level of theory used. These calculations take no account of the complexity of the conformationally flexible peptide system, and it is surprising that each of the two reacting centres can 'find' each other in such a large system.

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.

Cloning and Characterization of Ginkgo biloba Levopimaradiene Synthase, Which Catalyzes the First Committed Step in Ginkgolide Biosynthesis

Levopimaradiene synthase, which catalyzes the initial cyclization step in ginkgolide biosynthesis, was cloned and functionally characterized. A Ginkgo biloba cDNA library was prepared from seedling roots and a probe was amplified using primers corresponding to conserved gymnosperm terpene synthase sequences. Colony hybridization and rapid amplification of cDNA ends yielded a full-length clone encoding a predicted protein (873 amino acids, 100,289 Da) similar to known gymnosperm diterpene synthases. The sequence includes a putative N-terminal plastid transit peptide and three aspartate-rich regions. The full-length protein expressed in Escherichia coli cyclized geranylgeranyl diphosphate to levopimaradiene, which was identical to a synthetic standard by GC/MS analysis. Removing 60 or 79 N-terminal residues increased levopimaradiene production, but a 128-residue N-terminal deletion lacked detectable activity. This is the first cloned ginkgolide biosynthetic gene and the first in vitro observation of an isolated ginkgolide biosynthetic enzyme.

Biosynthesis of the validamycins: identification of intermediates in the biosynthesis of validamycin A by Streptomyces hygroscopicus var. limoneus.

To study the biosynthesis of the pseudotrisaccharide antibiotic, validamycin A (1), a number of potential precursors of the antibiotic were synthesized in (2)H-, (3)H-, or (13)C-labeled form and fed to cultures of Streptomyces hygroscopicus var. limoneus. The resulting validamycin A from each of these feeding experiments was isolated, purified and analyzed by liquid scintillation counting, (2)H- or (13)C NMR or selective ion monitoring mass spectrometry (SIM-MS) techniques. The results demonstrate that 2-epi-5-epi-valiolone (9) is specifically incorporated into 1 and labels both cyclitol moieties. This suggests that 9 is the initial cyclization product generated from an open-chain C(7) precursor, D-sedoheptulose 7-phosphate (5), by a DHQ synthase-like cyclization mechanism. A more proximate precursor of 1 is valienone (11), which is also incorporated into both cyclitol moieties. The conversion of 9 into 11 involves first epimerization to 5-epi-valiolone (10), which is efficiently incorporated into 1, followed by dehydration, although a low level of incorporation of 2-epi-valienone (15) is also observed. Reduction of 11 affords validone (12), which is also incorporated specifically into 1, but labels only the reduced cyclitol moiety. The mode of introduction of the nitrogen atom linking the two pseudosaccharide moieties is not clear yet. 7-Tritiated valiolamine (8), valienamine (2), and validamine (3) were all not incorporated into 1, although each of these amines has been isolated from the fermentation, with 3 being most prevalent. Demonstration of in vivo formation of [7-(3)H]validamine ([7-(3)H]-3) from [7-(3)H]-12 suggests that 3 may be a pathway intermediate and that the nonincorporation of [7-(3)H]-3 into 1 is due to a lack of cellular uptake. We thus propose that 3, formed by amination of 12, and 11 condense to form a Schiff base, which is reduced to the pseudodisaccharide unit, validoxylamine A (13). Transfer of a D-glucose unit to the 4'-position of 13 then completes the biosynthesis of 1. Other possibilities for the mechanism of formation of the nitrogen bridge between the two pseudosaccharide units are also discussed.

The biosynthesis of acarbose and validamycin.

The studies reported here have established the biosynthetic origin of the mC7N units of acarbose and validamycin from sedo-heptulose 7-phosphate, and have identified 2-epi-5-epi-valiolone as the initial cyclization product. The deoxyhexose moiety of acarbose arises from glucose with deoxythymidyl-diphospho-4-keto-6-deoxy-D-glucose (dTDP-4-keto-6-deoxy-D-glucose) as a proximate intermediate. However, despite the identical origin of the aminocyclitol moieties in acarbose and validamycin A, the pathways of their formation seem to be substantially different. Validamycin A formation involves a number of discrete ketocyclitol intermediates, 5-epi-valiolone, valienone, and validone, whereas no free intermediates have been identified on the pathway from 2-epi-5-epi-valiolone to the pseudodisaccharide moiety of acarbose. The stage is now set for unraveling the mechanism or mechanisms by which the two components of the pseudodisaccharide moieties of acarbose and validamycin are uniquely coupled to each other via a nitrogen bridge.

ChemInform Abstract: An Unexpected Rearrangement During Mitsunobu Epimerization Reaction of Sugar Derivatives.

Mitsunobu reaction on the glucose derivative (3S,4R,5R,6R)-3,4,5,7-tetrabenzyloxy-6-hydroxy-1-heptene yielded an unexpected rearrangement major product. Its structure was determined as (3R,4R,5R,6S)-4,5,6,7-tetrabenzyloxy-3-hydroxy-1-heptene. The suggested rearrangement mechanism involves an initial intramolecular cyclization, followed by ring opening by the nucleophile p-nitrobenzoate. Product distribution of the Mitsunobu reaction was substrate-dependent, with the corresponding mannose derivative (the 3R epimer) giving less of the initial intramolecular reaction products and the corresponding galactose derivative (the 5S epimer) yielding almost exclusively the expected epimerization product. Varying the Mitsunobu reaction conditions (addition of base and using nonpolar solvent) led to the expected epimerization product of the glucose derivative.

Bacteriopurpurins: Synthesis from meso-Diacrylate Substituted Porphyrins

A new route to the synthesis of bacteriopurpurins from symmetrical and unsymmetrical meso-substituted diacrylate octaalkylporphyrins has been achieved using basic conditions. Reaction of 5,15-bis[β-(ethoxycarbonyl)vinyl]octaethylporphyrin or 5,15-bis[β-(ethoxycarbonyl)vinyl]etioporphyrin I, in toluene in the presence of DBU, produces the corresponding bacteriopurpurins, without formation of the corresponding iso-bacteriopurpurins. Bacteriopurpurin formation from the cyclization of the 5,10-bis[β-(ethoxycarbonyl)vinyl]porphyrins were found to be dependent on the initial cyclization process and the structure of the meso-acrylate purpurin formed. In the etioporphyrin series the cyclization process was shown to be highly specific, favoring cyclization of the acrylate groups toward a specific ethyl group on the porphyrin ring.

Enzymatic cyclization of squalene analogs

Abstract

Synthesis of macrocycles and an unusually asymmetric [2]catenane via templated acetylenic couplings

An unusually asymmetric [2]catenane has been prepared by interlocking a hybrid crown macrocycle (containing one polyether and one butadiyne linker) with a diimide-derived macrocycle itself constructed with a pair of rigid butadiyne links. This system of complementary building blocks and connectors has proved a versatile vehicle for demonstration of a number of templating effects. Synthesis of the hybrid crown monomer by intramolecular cyclisation is promoted by the presence of a benzene diimide, acting as a positive template, but a sufficiently different effect is exerted by a naphthalene diimide derivative that intermolecular dimerisation becomes significant. Templating the hybrid crown synthesis with an ‘active’ benzene diimide, itself bearing acetylene functions, allows the first tandem synthesis of a catenane comprising two different rings: the diimide first acts as a template for the formation of the hybrid crown, which itself in turn acts as a template for cyclodimerisation of the acetylenic diimide. Remarkably, the yield of catenane is essentially independent of the initial cyclisation state of the crown component. No significant production of covalently linked donor–acceptor species is observed from these reactions, supporting the presence of an intermediate complex pre-organised to catenane formation. In contrast, oxidative coupling of an alkyl solubilised diimide gave no interlocked products and yielded only small amounts of cyclic poly-imide macrocyles.

Absolute Configuration of Kelsoene and Prespatane.

The absolute configurations of the rare sesquiterpenes, kelsoene and prespatane, were determined to be (1S, 2R,5S, 6S, 7R, 8R)-2,8-dimethyl-6-(1-methylethenyl)tricyclo[5.3.0.0(2,5)] decane (IUPAC name) and (1R, 2S, 5R, 6R, 7R, 8S)-1,5-dimethyl-8-(1-methylethenyl) tricyclo-[5.3.0.0(2,6)] decane, respectively, on the basis of the observed chemical shifts and NOEs in NOESY and NOEDS experiments after conversion with the chiral reagent, 2'-methoxy-1,1'-binaphthalene-2-carbohydroximoyl chloride (MBCC). The absolute configurations of kelsoene and prespatane thus determined suggest that initial cyclization of FPP from the si-face at C-10 to form a 10R-germacradienyl cation leads to kelsoene, while that from the re-face leads to prespatane via the 10S-germacradienyl cation.

Radical Cyclization/Fragmentation Reactions of Dicyanocyclopropanes to Enaminonitriles. A Radical Alternative to the Thorpe-Ziegler Reaction

Radical cyclizations to dicyanocyclopropanes provide cyclic enaminonitriles by a series of radical reactions that features radical cyclization to a nitrile and cyclopropane cleavage. The direction of cyclopropane cleavage - and hence the ring size of the final product - depends on the nature of the ring formed in the initial cyclization to the nitrile.

Flash vacuum pyrolysis of stabilised phosphorus ylides. Part 14.1 Tandem cyclisation of intermediate aryloxy and arylthio radicals leading to tri- and tetra-cyclic aromatic heterocycles

Seven new stabilised phosphorus ylides 8–14 designed to undergo thermal tandem cyclisation have been prepared. Upon flash vacuum pyrolysis at 850 °C, loss of Ph3PO and Me˙ results in tandem cyclisation to give benzothieno[3,2-b]benzothiophene 16 in the case of 11 while for 8 an abstraction–rearrangement–extrusion sequence leads to 2-phenylbenzofuran 18. For 9 and 10 both types of process occur to give respectively benzothieno[3,2-b]benzofuran 27, prepared here for the first time, and 2-phenylbenzothiophene 29. For 12 and 13, initial cyclisation is followed by intramolecular addition and aromatisation to give the tricyclic products 31 and 32, while for 14 intramolecular homolytic substitution leads to the tetracyclic benzonaphthofuran 34 and, by rearrangement, to the isomer 37. Fully assigned 13C NMR spectra are presented for all seven ylides.

Synthesis and Application of Unprotected Cyclic Peptides as Building Blocks for Peptide Dendrimers

We describe an efficient regiospecific method for cyclization of unprotected peptide segments based on intramolecular transthioesterification of unprotected cysteinyl peptide thioesters under the control of ring−chain tautomeric equilibrium in aqueous buffered solutions at pH ranging from 5 to 7.5. The initial cyclization to form an intramolecular thioester under the ring−chain tautomeric equilibrium is reversible and could be performed in relatively high concentrations without observable oligomerization. This method overcomes the limitation of conventional cyclization methods that require high dilutions. The reaction becomes irreversible by a subsequent, spontaneous proximity-driven S- to N-acyl transfer to the adjacent Nα-amine of cysteine to form an end-to-end cyclic peptide. The cyclization is regioselective. No side reactions were observed with side-chain functionalities such as the Nε-amine of lysine, thiol of internal cysteine, or imidazole of histidine. Since a free thiol group was introduced to the product after cyclization, these cyclic peptides were exploited as building blocks for synthesizing peptides with unusual architectures such as bicyclic peptides containing end-to-end backbones and disulfide bridges as well as cascade branched peptide dendrimers.

Radical-mediated cyclisation of ω-aryl-β-dicarbonyl compounds to tetrahydrobenzocyclohepten-6-ones, hexahydrobenzocycloocten-6-ones and naphthalen-2(1H )-ones

Manganese(III) acetate in acetic acid promotes efficient radical-mediated oxidative cyclisation of Iµ-aryl-β-dicarbonyl and Z-γ,δ-unsaturated δ-aryl-β-dicarbonyl compounds carrying electron-releasing groups in the aromatic ring, forming 6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ones and naphthalen-2(1H)-ones, respectively. The process is accompanied by secondary acetoxylation at the activated benzylic position of the initial cyclisation products, and is exemplified by the conversions of the Iµ- and δ-aryl-β-dicarbonyl compounds 6 and 11 into the benzocycloheptenone 18 and the naphthalenone 21, respectively. Application of the oxidation to the formation of 8-membered hexahydro- and tetrahydro-benzocycloocten-6-ones 19 and 22 from ζ-aryl-β-dicarbonyl and Z-γ,δ-unsaturated ζ-aryl-β-dicarbonyl compounds is limited by low reactivity, and in the latter case, by radical rearrangement followed by cyclisation to a tetralin.

Kinetics of n-Butylbenzene Dehydrocyclization over Chromia−Alumina

The kinetics of dehydrogenation, cyclization, and isomerization steps in n-butylbenzene dehydrocyclization over precoked chromia-alumina has been investigated at 683--783 K. Apparent kinetic parameters of a pseudohomogeneous model were calculated from the initial-rate and integral-rate data measured with n-butylbenzene and 4-phenyl-1-butene in an isothermal fixed-bed reactor. Dehydrocyclization was shown to proceed by dehydrogenation of n-butylbenzene to n-butenylbenzenes, by their cyclization, and by dehydrogenation of the cyclic products to methylindenes and naphthalene. Direct cyclization of n-butylbenzene was of little importance over the precoked catalyst. According to the initial-rate data, dehydrogenation to n-butenylbenzenes followed an apparent order of 0.5 and the kinetic parameters seemed to be applicable also at higher conversions. The primary dehydrogenation products were 1-phenyl-1-butenes, and a surface model based on hydrogen abstraction from the {alpha}-carbon has been discussed. The initial cyclization rates measured with 4-phenyl-1-butene were appreciably lower than those observed in integral-rate experiments. The discrepancy was tentatively explained by the higher reactivity of 1-phenyl-1-butenes, which are the main constituents of the n-butenylbenzene fraction at longer contact times. High conversion runs with n-butylbenzene also showed that methylindenes and -indans were partly dealkylated and probably polymerized. The apparent orders ranged from 1 to 1.5 for 1,6-cyclization and from 0.5 to 0.8more » for 1,5-cyclization. Skeletal isomerization of n-butylbenzene to sec-butyl- and sec-butenylbenzenes was rapidly subsided during coking, and on the coked catalyst at 783 K the reaction followed an apparent order of {minus}0.5.« less

Mechanism of taxadiene synthase, a diterpene cyclase that catalyzes the first step of taxol biosynthesis in Pacific yew.

The first committed step in the formation of taxol has been shown to involve the cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene. The formation of this endocyclic diterpene olefin isomer as the precursor of taxol was unexpected, since the exocyclic isomer, taxa-4(20),11(12)-diene, had been predicted as the initial product of the taxol pathway on the basis of metabolite co-occurrence. [1-2H2,20-2H3] and [20-2H3]geranylgeranyl diphosphates were employed as substrates with the partially purified taxadiene synthase from Pacific yew (Taxus brevifolia) stems to examine the possibility of a preliminary cyclization to taxa-4(20),11(12)-diene followed by isomerization to the more stable endocyclic double bond isomer. GLC-MS analysis of the derived taxa-4(5),11(12)-diene, via selected ion monitoring of the parent ion and the P-15 and C-ring fragment ions, compared to those of unlabeled standard, showed the olefin product to possess a deuterium enrichment essentially identical to that of the acyclic precursor, thus ruling out the putative isomerization step. With [4-2H2]geranylgeranyl diphosphate as substrate, similar product analysis established the enzymatically derived taxa-4(5),11(12)-diene to contain only one deuterium atom, consistent with direct formation from a taxenyl cation by deprotonation at C5. (+/-)-Casbene, (+/-)-verticillene, and (+/-)-taxa-4(20),11(12)-diene were tested as possible olefinic intermediates in taxa-4(5),11(12)-diene formation by a series of inhibition, trapping, and direct conversion experiments; no evidence was obtained that these exogenous olefins could serve as intermediates of the cyclization reaction. However, GLC-MS analysis of the taxadiene product derived by enzymatic cyclization of [1-3H]geranylgeranyl diphosphate in 2H2O indicated little incorporation of deuterium from the medium and suggested a rapid internal proton transfer in a tightly bound olefinic intermediate. Analysis of the enzymatic product generated from [10-2H1]geranylgeranyl diphosphate confirmed the intramolecular hydrogen transfer from C11 of a verticillyl intermediate to the C-ring of taxa-4(5),11(12)-diene. From these results, a stereochemical mechanism is proposed for the taxadiene synthase reaction involving the initial cyclization of geranylgeranyl diphosphate to a transient verticillyl cation intermediate, with transfer of the C11 alpha-proton to C7 to initiate transannular B/C-ring closure to the taxenyl cation, followed by deprotonation at C5 to yield the taxa-4(5),11(12)-diene product directly.

Studies on the Synthesis of Acanthodoral and Nanaimoal: Evaluation of Cationic Cyclization Routes

Intramolecular Lewis acid-promoted reactions of α,β-unsaturated ketone 6 and aldehydes 7 and 8 were examined as potential routes to acanthodoral (1), a structurally interesting natural product. Ketone 6 afforded ene product 22 exclusively, and both 7 and 8 gave mixtures of bicyclic aldehydes 3 and 26 and tricyclic aldehyde 25. The latter most likely results from 7 by intramolecular cyclization of the alkene onto the Lewis acid-activated carbonyl moiety affording carbocation 31 followed by a 1,2-hydride shift and ring closure. Starting from 8, tricyclic aldehyde 25 apparently forms by cyclization to cation 35 and ring closure to cyclobutane 36, followed by ring opening to 31, the same cation as formed in reactions of 7. Nanaimoal (3) results from loss of H+ from 31, and bicyclic aldehyde 26 may be formed in a similar manner or by a concerted ene reaction. The configuration of 25 establishes that the stereochemistry of the initial cyclization to 31 precludes the possible use of this strategy for the synthes...

Mitomycin Betaines: Synthesis, Structure, and Solvolytic Reactivity

7-N-[2-(Methylamino)ethyl]mitomycin C (2b) and 7-N-[2-(ethylamino)ethyl]mitomycin C (2c) underwent rapid C(8) cyclization and oxidation to generate the novel quinoxaline mitomycin betaines 5a,b, respectively. Correspondingly, treatment of mitomycin A with N-methyl-1,2-phenylenediamine gave phenazine mitomycin betaine 17. Similar spectral properties were observed for the three heteroaromatic zwitterionic compounds 5a,b, and 17. We have learned that the formation of 5a,b proceeds by initial cyclization of the terminal amine group to the mitomycin C(8) quinone carbon to generate the corresponding hemiaminal intermediate. Dissolution of 5a,b in buffered methanolic solutions (“pH” 5.5, 7.4) at 25 °C did not lead to aziridine ring opening. The reactivity of 5a,b is briefly discussed in terms of their electronic structures.

The aquated form of cisplatin selectively attacks at the G[3] site in d(GTG)

While d(GpTpG) reacts with cis-[Pt(NH3)2(OH2)(OH)]+ eventually to form a G[1]N(7), G[3](7) chelate, the initial attack is exclusively at G[3], (rate constants for the initial step and cyclisation being 21.6 dm3 mol–1 s–1 and 4.4 × 10–4 s–, respectively at 37.0 °C).