Tricyclic Intermediates Research Articles

Attempting to Create a Pathway to 15-Deacetylcalonectrin with Limited Accumulation in Cultures of Fusarium Tri3 Mutants: Insight into Trichothecene Biosynthesis Machinery.

The compound 15-deacetylcalonectrin (15-deCAL) is a common pathway intermediate in the biosynthesis of Fusarium trichothecenes. This tricyclic intermediate is metabolized to calonectrin (CAL) by trichothecene 15-O-acetyltransferase encoded by Tri3. Unlike other trichothecene pathway Tri gene mutants, the Δtri3 mutant produces lower amounts of the knocked-out enzyme's substrate 15-deCAL, and instead, accumulates higher quantities of earlier bicyclic intermediate and shunt metabolites. Furthermore, evolutionary studies suggest that Tri3 may play a role in shaping the chemotypes of trichothecene-producing Fusarium strains. To better understand the functional role of Tri3p in biosynthesis and evolution, we aimed to develop a method to produce 15-deCAL by using transgenic Fusarium graminearum strains derived from a trichothecene overproducer. Unfortunately, introducing mutant Tri3, encoding a catalytically impaired but structurally intact acetylase, did not improve the low 15-deCAL production level of the ΔFgtri3 deletion strain, and the bicyclic products continued to accumulate as the major metabolites of the active-site mutant. These findings are discussed in light of the enzyme responsible for 15-deCAL production in trichothecene biosynthesis machinery. To efficiently produce 15-deCAL, we tested an alternative strategy of using a CAL-overproducing transformant. By feeding a crude CAL extract to a Fusarium commune strain that was isolated in this study and capable of specifically deacetylating C-15 acetyl, 15-deCAL was efficiently recovered. The substrate produced in this manner can be used for kinetic investigations of this enzyme and its possible role in chemotype diversification.

Convergent Assembly of the Tricyclic Labdane Core Enables Synthesis of Diverse Forskolin‐like Molecules

AbstractWe report a new synthetic strategy for the flexible preparation of forskolin‐like molecules. The approach is different from the previously published works and employs a convergent assembly of the tricyclic labdane‐type core from pre‐functionalized cyclic building blocks. Stereoselective Michael addition enabled the fragment coupling with excellent control over three newly created contiguous stereocenters, all‐carbon quaternary centers included. Silyl enol ether‐promoted ring‐opening metathesis paired with ring closure were the other key steps enabling concise assembly of the tricyclic core. Late‐stage functionalization sequences transformed the tricyclic intermediates into a set of different forskolin‐like molecules. The modular nature of the synthetic scheme described herein has the potential to become a general platform for the preparation of analogs of forskolin and other complex tricyclic labdanes.

Convergent Assembly of the Tricyclic Labdane Core Enables Synthesis of Diverse Forskolin-like Molecules.

We report a new synthetic strategy for the flexible preparation of forskolin-like molecules. The approach is different from the previously published works and employs a convergent assembly of the tricyclic labdane-type core from pre-functionalized cyclic building blocks. Stereoselective Michael addition enabled the fragment coupling with excellent control over three newly created contiguous stereocenters, all-carbon quaternary centers included. Silyl enol ether-promoted ring-opening metathesis paired with ring closure were the other key steps enabling concise assembly of the tricyclic core. Late-stage functionalization sequences transformed the tricyclic intermediates into a set of different forskolin-like molecules. The modular nature of the synthetic scheme described herein has the potential to become a general platform for the preparation of analogs of forskolin and other complex tricyclic labdanes.

6'-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations.

Here we report on the synthesis, biophysical properties and molecular modeling of oligonucleotides containing unsaturated 6’-fluoro[4.3.0]bicyclo nucleotides (6’F-bc4,3-DNA). Two 6’F-bc4,3 phosphoramidite building blocks (T and C) were synthesized starting from a previously described [3.3.0]bicyclic sugar. The conversion of this sugar to a gem-difluorinated tricyclic intermediate via difluorocarbene addition followed either by a NIS-mediated or Vorbrüggen nucleosidation yielded in both cases the β-tricyclic nucleoside as major anomer. Subsequent desilylation and cyclopropane ring opening of these tricyclic intermediates afforded the unsaturated 6’F-bc4,3 nucleosides. The successful incorporation of the corresponding phosphoramidite building blocks into oligonucleotides was achieved with tert-butyl hydroperoxide as oxidation agent. Thermal melting experiments of the modified duplexes disclosed a destabilizing effect versus DNA and RNA complements, but with a lesser degree of destabilization versus complementary DNA (ΔTm/mod = −1.5 to −3.7 °C). Molecular dynamics simulation on the nucleoside and oligonucleotide level revealed the preference of the C1’-exo/C2’-endo alignment of the furanose ring. Moreover, the simulation of duplexes with complementary RNA disclosed a DNA/RNA-type duplex structure suggesting that this modification might be a substrate for RNase H.

C-H Hydroxylation in Paralytic Shellfish Toxin Biosynthesis.

The remarkable degree of synthetic selectivity found in Nature is exemplified by the biosynthesis of paralytic shellfish toxins such as saxitoxin. The polycyclic core shared by saxitoxin and its relatives is assembled and subsequently elaborated through the installation of hydroxyl groups with exquisite precision that is not possible to replicate with traditional synthetic methods. Here, we report the identification of the enzymes that carry out a subset of C-H functionalizations involved in paralytic shellfish toxin biosynthesis. We have shown that three Rieske oxygenases mediate hydroxylation reactions with perfect site- and stereoselectivity. Specifically, the Rieske oxygenase SxtT is responsible for selective hydroxylation of a tricyclic precursor to the famous natural product saxitoxin, and a second Rieske oxygenase, GxtA, selectively hydroxylates saxitoxin to access the oxidation pattern present in gonyautoxin natural products. Unexpectedly, a third Rieske oxygenase, SxtH, does not hydroxylate tricyclic intermediates, but rather a linear substrate prior to tricycle formation, rewriting the biosynthetic route to paralytic shellfish toxins. Characterization of SxtT, SxtH, and GxtA is the first demonstration of enzymes carrying out C-H hydroxylation reactions in paralytic shellfish toxin biosynthesis. Additionally, the reactions of these oxygenases with a suite of saxitoxin-related molecules are reported, highlighting the substrate promiscuity of these catalysts and the potential for their application in the synthesis of natural and unnatural saxitoxin congeners.

Total Synthesis of Septedine and 7-Deoxyseptedine.

Septedine (2) is a hetidine type C20-diterpenoid alkaloid bearing an oxygenated heptacyclic scaffold. We have accomplished the first and asymmetric total synthesis of 2 and its 7-deoxy analogue 3. A functionalized tricyclic intermediate was prepared with excellent enantiopurity by using Carreira polyene cyclization. An unusual anionic Diels-Alder reaction was responsible for the construction of the bicyclo[2.2.2]octane. The α-methyl ketone was furnished by iridium-catalyzed allylic alcohol isomerization. Sanford Csp3-H oxidation was exploited to install the secondary hydroxy group of 2. The oxazolidinopiperidine was assembled by selective reductive amination and spontaneous N, O-ketalization at a final stage.

Synthetic studies toward tetrapetalone A: attempted palladium π-allyl cascades toward a fused tricyclic intermediate

Efforts to install the core azepine ring in tetrapetalone A via a palladium π-allyl cascade reaction failed due to competing pathways that included an unexpected and interesting TMM-like cycloaddition reaction that delivers a complex tricyclic ring system.

Carbocyclic Amino Ketones by Bredt's Rule‐Arrested Kulinkovich–de Meijere Reaction

AbstractThe TiII‐mediated formation of cyclopropylamines from alkenes and amides, the Kulinkovich–de Meijere reaction, involves two carbon–carbon bond‐forming steps. Strategic use of a tricyclic intermediate can arrest the process if the second step requires formation of a bridgehead double bond. Use of this Bredt's rule constraint results in the production of carbocyclic amino ketones, key alkaloid building blocks.

Carbocyclic Amino Ketones by Bredt's Rule-Arrested Kulinkovich-de Meijere Reaction.

The Ti(II) -mediated formation of cyclopropylamines from alkenes and amides, the Kulinkovich-de Meijere reaction, involves two carbon-carbon bond-forming steps. Strategic use of a tricyclic intermediate can arrest the process if the second step requires formation of a bridgehead double bond. Use of this Bredt's rule constraint results in the production of carbocyclic amino ketones, key alkaloid building blocks.

ChemInform Abstract: Exploratory Studies Toward a Total Synthesis of Pericine (Subincanadine E).

ChemInformVolume 46, Issue 30 Natural Products ChemInform Abstract: Exploratory Studies Toward a Total Synthesis of Pericine (Subincanadine E). M.-Lluisa Bennasar, M.-Lluisa Bennasar Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this authorDaniel Sole, Daniel Sole Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this authorTomas Roca, Tomas Roca Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this authorMagdalena Valldosera, Magdalena Valldosera Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this author M.-Lluisa Bennasar, M.-Lluisa Bennasar Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this authorDaniel Sole, Daniel Sole Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this authorTomas Roca, Tomas Roca Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this authorMagdalena Valldosera, Magdalena Valldosera Lab. Quim. Org., Fac. Farm., Univ. Barcelona, E-08028 Barcelona, SpainSearch for more papers by this author First published: 14 July 2015 https://doi.org/10.1002/chin.201530253Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume46, Issue30July, 2015 RelatedInformation

Exploratory studies toward a total synthesis of pericine (subincanadine E)

A possible synthetic approach to the bridged indole alkaloid pericine (subincanadine E), based on the combination of a ring-closing metathesis (RCM) and a Heck cyclization, is described. After having developed a convenient RCM-based route to tricyclic intermediates embodying the central nine-membered ring, the closure of the strained 1-azabicyclo[5.2.2]undecane framework of the alkaloid using a vinyl halide Heck coupling was pursued without success.

The atmospheric oxidation mechanism of 2-methylnaphthalene.

The atmospheric oxidation mechanism of 2-methylnaphthalene (2-MN) initiated by OH radicals is investigated by using quantum chemistry at BH&HLYP/6-311++G(2df,2p) and ROCBS-QB3 levels and kinetic calculations by transient state theory and unimolecular reaction theory coupled with master equation (RRKM-ME). This reaction is mainly initiated by OH additions, forming adducts Rn (2-MN-n-OH, n = 1-8). The fates of R1 and R3, representing the α- and β-adducts, are examined. The fates of R1 and R3 are found to be drastically different. In the atmosphere, R1 reacts with O2via O2 addition to the C2 position to form R1-2OO-a/s, which will undergo a bimolecular reaction with the atmospheric NO or unimolecular isomerization via intramolecular H-shifts, of which the latter is found to be dominant and accounts for the formation of dicarbonyl compounds observed in experimental studies. The role of the tricyclic radical intermediates formed from the ring-closure of R1-2OO is rather limited because their formation is endothermic and reversible, being contrary to the important role of the analogous bicyclic radical intermediates in the oxidation of benzenes. On the other hand, the fate of R3 is similar to that of the benzene-OH adduct, and the tricyclic intermediates will play an important role. An oxidation mechanism is proposed based on the theoretical predictions, and the routes for the experimentally observed products are suggested and compared.

Variation of reactivity of aziridinium ion during alkylation

Reactivity/stability of the tricyclic aziridinium ion intermediate of the mustine drug molecule varies with the ∠NCC bond angle of the tricyclic ring during alkylation of guanine. A sharp variation in reactivity of the aziridinium ion intermediate is observed along the intrinsic reaction coordinate. Further, shifting of the lowest unoccupied molecular orbital towards the carbon centre that interacts with guanine is also observed. Thermochemical analysis shows that the alkylation reaction is exothermic and presence of polar solvent effect activation energy.

The cysteine 703 to isoleucine or histidine mutation of the oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae generates an iridal-type triterpenoid

The Cys703 to Ile or His mutation within Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase ERG7 (ERG7(C703I/H)) generates an unusual truncated bicyclic rearranged intermediate, (8R,9R,10R)-polypoda-5,13E,17E,21-tetraen-3β-ol, related to iridal-skeleton triterpenoid. Numerous oxidosqualene-cyclized truncated intermediates, including tricyclic, unrearranged tetracyclic with 17α/β exocyclic hydrocarbon side chain, rearranged tetracyclic, and chair-chair-chair tricyclic intermediates (compounds 3-9), were also isolated from the ERG7(C703X) site-saturated mutations or the ERG7(F699T/C703I) double mutation, indicating the functional role of the Cys703 residue in stabilizing the bicyclic C-8 cation and the rearranged intermediate or interacting with Phe699, and opened a new avenue of engineering ERG7 for producing biological active agents.

ChemInform Abstract: Highly Regioselective Synthesis of 1,7-Diprotected 1,4,7,10- Tetraazacyclododecane Derivatives.

Reaction of dimethylformamicle diethyl acetal with monoalkylated 1,4,7,10-tetraazacyclododecane derivatives 3, followed by hydrolysis of the tricyclic intermediates 4, selectively affords 1,7-disubstituted tetraazamacrocycles 5.

Studies toward the duocarmycin prodrugs for the antibody prodrug therapy approach

A tricyclic precursor for the synthesis of the prodrugs of pro-1,2,9,9a-tetrahydrocyclopropa[ c]benz-[ e]indole-4-one tetramethoxyindolecarboxamide (CBI-TMI) was prepared using the ring-closing metathesis approach. The tricyclic intermediate was converted to an advanced precursor of a CBI-TMI prodrug equipped with a linker presumably suitable for activation using the aldolase catalytic antibody 38C2. An attempted 38C2-catalyzed two-step activation of the hydroxy- pro-CBI intermediate involving retro-aldol and the β-elimination reactions was also examined.

On the Photoisomerization of Thiophene and Thiazole Derivatives

The photochemical isomerization of thienyl and thiazolyl derivatives can be explained by assuming the formation of the Dewar isomer. The isomerization of the Dewar isomer towards the most stable one can account for the observed reaction. No biradical intermediate was found. In the case of thiophene an isomerization of the Dewar thiophene allows the formation of a tricyclic intermediate; a retroelectrocyclic reaction can afford the reaction product. This tricyclic intermediate cannot be formed in the photoisomerization of thiazole derivative.

Synthesis of 7-epineoptilocaulin, mirabilin B, and isoptilocaulin. A unified biosynthetic proposal for the ptilocaulin and batzelladine alkaloids. Synthesis and structure revision of netamines E and G.

Addition of guanidine to a 6-methylhexahydroindenone in MeOH at 85 degrees C afforded 7-epineoptilocaulin. A similar reaction with a 6-propylhexahydroindenone afforded netamine E. MnO2 oxidation of 7-epineoptilocaulin and netamine E afforded mirabilin B and netamine G, respectively. The netamines have the side chains trans, not cis as was initially proposed. A unified biosynthetic scheme for the batzelladines and ptilocaulin family is proposed. Conjugate addition of guanidine to a bis enone followed by an intramolecular Michael reaction of the enolate to the other enone, aldol reaction, dehydration, and enamine formation will lead to a tricyclic intermediate at the dehydroptilocaulin oxidation state. 1,4-Hydride addition will lead to ptilocaulin or 7-epineoptilocaulin depending on which face the hydride adds to. 1,2-Hydride addition will lead to isoptilocaulin. The key tricyclic intermediate was prepared from a tetrahydroindenone and guanidine and reduced with NaBH4 to give a mixture rich in ptilocaulin and isoptilocaulin.

Convergent Assembly of Highly Potent Analogues of Bryostatin 1 via Pyran Annulation: Bryostatin Look-Alikes That Mimic Phorbol Ester Function

Highly potent bryostatin analogues which contain the complete bryostatin core structure have been synthesized using a pyran annulation approach as a key strategic element. The A ring pyran was assembled using a pyran annulation reaction between a C1-C8 hydroxy allylsilane and an aldehyde comprising C9-C13. This pyran was transformed to a new hydroxy allylsilane and then coupled with a preformed C ring aldehyde subunit in a second pyran annulation, with concomitant formation of the B ring. This tricyclic intermediate was elaborated to bryostatin analogues which displayed nanomolar to subnanomolar affinity for PKC, but displayed properties indistinguishable from a phorbol ester in a proliferation/attachment assay.

Studies toward the total synthesis of ristocetin A aglycone using arene–ruthenium complexes as S NAr substrates: construction of an advanced tricyclic intermediate

Ruthenium-mediated S NAr reactions are used to construct the diaryl ether linkages in two key intermediates for a projected total synthesis of the aglycone of ristocetin A.